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1.  Quality indicators for colonoscopy: Current insights and caveats 
Colonoscopy is the diagnostic modality of choice for investigation of symptoms suspected to be related to the colon and for the detection of polyps and colorectal cancer (CRC). Colonoscopy with removal of detected polyps has been shown to reduce the incidence and mortality of subsequent CRC. In many countries, population screening programs for CRC have been initiated, either by selection of patients for colonoscopy with fecal occult blood testing or by offering colonoscopy directly to average-risk individuals. Several endoscopy societies have formulated quality indicators for colonoscopy. These quality indicators are almost always incorporated as process indicators, rather than outcome measures. This review focuses on the quality indicators bowel preparation, cecal intubation rate, withdrawal time, adenoma detection rate, patient comfort, sedation and complication rate, and discusses the scientific evidence supporting them, as well as their potential shortcomings and issues that need to be addressed. For instance, there is still no clear and generally accepted definition of adequate bowel preparation, no robust scientific evidence is available supporting a cecal intubation rate ≥ 90% and the association between withdrawal time and occurrence of interval cancers has not been clarified. Adenoma detection rate is currently the only quality indicator that has been shown to be associated with interval colorectal cancer, but as an indicator it does not differentiate between subjects with one or more adenoma detected.
PMCID: PMC4265954  PMID: 25512766
Colonoscopy; Quality indicators; Bowel preparation; Cecal intubation; Withdrawal time; Adenoma detection rate; Screening; Complication; Interval colorectal cancer; Post-colonoscopy colorectal cancer
2.  Endoscopic innovations to increase the adenoma detection rate during colonoscopy 
Up to a quarter of polyps and adenomas are missed during colonoscopy due to poor visualization behind folds and the inner curves of flexures, and the presence of flat lesions that are difficult to detect. These numbers may however be conservative because they mainly come from back-to-back studies performed with standard colonoscopes, which are unable to visualize the entire mucosal surface. In the past several years, new endoscopic techniques have been introduced to improve the detection of polyps and adenomas. The introduction of high definition colonoscopes and visual image enhancement technologies have been suggested to lead to better recognition of flat and small lesions, but the absolute increase in diagnostic yield seems limited. Cap assisted colonoscopy and water-exchange colonoscopy are methods to facilitate cecal intubation and increase patients comfort, but show only a marginal or no benefit on polyp and adenoma detection. Retroflexion is routinely used in the rectum for the inspection of the dentate line, but withdrawal in retroflexion in the colon is in general not recommended due to the risk of perforation. In contrast, colonoscopy with the Third-Eye Retroscope® may result in considerable lower miss rates compared to standard colonoscopy, but this technique is not practical in case of polypectomy and is more time consuming. The recently introduced Full Spectrum Endoscopy™ colonoscopes maintains the technical capabilities of standard colonoscopes and provides a much wider view of 330 degrees compared to the 170 degrees with standard colonoscopes. Remarkable lower adenoma miss rates with this new technique were recently demonstrated in the first randomized study. Nonetheless, more studies are required to determine the exact additional diagnostic yield in clinical practice. Optimizing the efficacy of colorectal cancer screening and surveillance requires high definition colonoscopes with improved virtual chromoendoscopy technology that visualize the whole colon mucosa while maintaining optimal washing, suction and therapeutic capabilities, and keeping the procedural time as low and patient discomfort as optimal as possible.
PMCID: PMC3942825  PMID: 24605019
Colonoscopy; Endoscopic innovations; Adenoma detection; Polyp detection; Gastrointestinal endoscopy
3.  Technical advances in endoscopic ultrasound-guided fiducial placement for the treatment of pancreatic cancer 
Endoscopy International Open  2015;3(4):E373-E377.
Radiation therapy has an important role in the treatment of locally advanced or metastatic pancreatic cancer and can be used alone or in conjunction with surgery and/or systemic chemotherapy. Because of the challenge of delivering an accurate and optimal radiation dose, image-guided radiation therapy can be used to improve targeting. Fiducial markers can be placed in the tumor and used for localization in patients undergoing image-guided radiation therapy. The safety and feasibility of endoscopic ultrasound (EUS)-guided placement of fiducials has been assessed and reported for the management of pancreatic cancer. We herein review the technique, efficacy, and safety profile of EUS-guided fiducial placement. In addition, we highlight recent advances and technological upgrades in EUS-guided fiducial delivery systems for pancreatic cancer most relevant to practicing gastroenterologists and interventional endoscopists.
PMCID: PMC4554510  PMID: 26355267
4.  Retrograde-viewing device improves adenoma detection rate in colonoscopies for surveillance and diagnostic workup 
AIM: To determine which patients might benefit most from retrograde viewing during colonoscopy through subset analysis of randomized, controlled trial data.
METHODS: The Third Eye® Retroscope® Randomized Clinical Evaluation (TERRACE) was a randomized, controlled, multicenter trial designed to evaluate the efficacy of a retrograde-viewing auxiliary imaging device that is used during colonoscopy to provide a second video image which allows viewing of areas on the proximal aspect of haustral folds and flexures that are difficult to see with the colonoscope’s forward view. We performed a post-hoc analysis of the TERRACE data to determine whether certain subsets of the patient population would gain more benefit than others from use of the device. Subjects were patients scheduled for colonoscopy for screening, surveillance or diagnostic workup, and each underwent same-day tandem examinations with standard colonoscopy (SC) and Third Eye colonoscopy (TEC), randomized to SC followed by TEC or vice versa.
RESULTS: Indication for colonoscopy was screening in 176/345 subjects (51.0%), surveillance after previous polypectomy in 87 (25.2%) and diagnostic workup in 82 (23.8%). In 4 subjects no indication was specified. Previously reported overall results had shown a net additional adenoma detection rate (ADR) with TEC of 23.2% compared to SC. Relative risk (RR) of missing adenomas with SC vs TEC as the initial procedure was 1.92 (P = 0.029). Post-hoc subset analysis shows additional ADRs for TEC compared to SC were 4.4% for screening, 35.7% for surveillance, 55.4% for diagnostic and 40.7% for surveillance and diagnostic combined. The RR of missing adenomas with SC vs TEC was 1.11 (P = 0.815) for screening, 3.15 (P = 0.014) for surveillance, 8.64 (P = 0.039) for diagnostic and 3.34 (P = 0.003) for surveillance and diagnostic combined. Although a multivariate Poisson regression suggested gender as a possibly significant factor, subset analysis showed that the difference between genders was not statistically significant. Age, bowel prep quality and withdrawal time did not significantly affect the RR of missing adenomas with SC vs TEC. Mean sizes of adenomas detected with TEC and SC were similar at 0.59 cm and 0.56 cm, respectively (P = NS).
CONCLUSION: TEC allows detection of significantly more adenomas compared to SC in patients undergoing surveillance or diagnostic workup, but not in screening patients ( Identifier: NCT01044732).
PMCID: PMC3396192  PMID: 22807609
Colonoscopy; Colorectal cancer; Adenomas; Miss rates; Retrograde-viewing
5.  Pre-diagnostic concordance with the WCRF/AICR guidelines and survival in European colorectal cancer patients: a cohort study 
BMC Medicine  2015;13:107.
Cancer survivors are advised to follow lifestyle recommendations on diet, physical activity, and body fatness proposed by the World Cancer Research Fund/American Institute of Cancer Research (WCRF/AICR) for cancer prevention. Previous studies have demonstrated that higher concordance with these recommendations measured using an index score (the WCRF/AICR score) was associated with lower cancer incidence and mortality. The aim of this study was to evaluate the association between pre-diagnostic concordance with WCRF/AICR recommendations and mortality in colorectal cancer (CRC) patients.
The association between the WCRF/AICR score (score range 0–6 in men and 0–7 in women; higher scores indicate greater concordance) assessed on average 6.4 years before diagnosis and CRC-specific (n = 872) and overall mortality (n = 1,113) was prospectively examined among 3,292 participants diagnosed with CRC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (mean follow-up time after diagnosis 4.2 years). Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality.
The HRs (95% CIs) for CRC-specific mortality among participants in the second (score range in men/women: 2.25–2.75/3.25–3.75), third (3–3.75/4–4.75), and fourth (4–6/5–7) categories of the score were 0.87 (0.72–1.06), 0.74 (0.61–0.90), and 0.70 (0.56–0.89), respectively (P for trend <0.0001), compared to participants with the lowest concordance with the recommendations (category 1 of the score: 0–2/0–3). Similar HRs for overall mortality were observed (P for trend 0.004). Meeting the recommendations on body fatness and plant food consumption were associated with improved survival among CRC cases in mutually adjusted models.
Greater concordance with the WCRF/AICR recommendations on diet, physical activity, and body fatness prior to CRC diagnosis is associated with improved survival among CRC patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0332-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4423114  PMID: 25948112
Colorectal cancer; Diet; Healthy lifestyle; Physical activity; Survival; Weight
6.  Surveillance for hepatocellular carcinoma in chronic liver disease: Evidence and controversies 
Primary liver cancer is the sixth most common cancer in the world and the third cause of cancer-related death. Hepatocellular carcinoma (HCC) represents more than 90% of primary liver cancers and generally occurs in patients with underlying chronic liver disease such as viral hepatitis, hemochromatosis, primary biliary cirrhosis and non-alcoholic steatohepatitis. Especially cirrhotic patients are at risk of HCC and regular surveillance could enable early detection and therapy, with potentially improved outcome. We here summarize existing evidence for surveillance including ultrasound, other radiological modalities and various serum biomarkers, and current international guideline recommendations for surveillance. Ultrasound and α-fetoprotein (alone or in combination) are most frequently used for surveillance, but their sensitivities and specificities are still far from perfect, and evidence for surveillance remains weak and controversial. Various other potential surveillance tools have been tested, including serum markers as des-carboxyprothrombin, lectin-bound α-fetoprotein, and (most recently) circulating TIE2-expressing monocytes, and radiological investigations such as computed tomography-scan or magnetic resonance imaging-scan. Although early results appear promising, these tools have generally been tested in diagnostic rather than surveillance setting, and in most cases, no detailed information is available on their cost-effectiveness. For the near future, it remains important to define those patients with highest risk of HCC and most benefit from surveillance, and to restrict surveillance to these categories.
PMCID: PMC3812474  PMID: 24187450
Hepatocellular carcinoma; Surveillance; Chronic liver disease
7.  Cryospray ablation using pressurized CO2 for ablation of Barrett’s esophagus with early neoplasia: early termination of a prospective series 
Endoscopy International Open  2015;3(2):E107-E112.
Background: Cryotherapy is a relatively novel ablation modality for the endoscopic ablation of Barrett’s esophagus (BE). Data on the use of pressurized carbon dioxide (CO2) gas for cryoablation are scarce.
Study aim: To determine the efficacy and safety of cryospray ablation using pressurized CO2 gas in the treatment of BE with early neoplasia.
Methods: In this prospective single center case series, we aimed to include 30 patients with BE and early neoplasia. Nodular neoplastic lesions were treated with endoscopic mucosal resection (EMR). Residual BE mucosa was treated with cryospray ablation every 4 weeks until the complete BE segment was eliminated or up to seven treatment sessions. If no reduction of the BE segment was observed after two subsequent treatment sessions, cryoablation was terminated. Patients were contacted at days 1 and 4 post-treatment to evaluate the level of discomfort. Endoscopic and histologic follow-up evaluations were performed up to 24 months post-treatment.
Results: After the inclusion of 10 patients, insufficient effect of cryoablation was observed, resulting in early termination of the study. In total, seven patients with intramucosal carcinoma (IMC) and three with high grade dysplasia (HGD) were included. Prior EMR was performed in nine patients. A median of 2.5 (IQR 2.0 – 4.0) cryoablation sessions were performed. At 6 months of follow-up, complete eradication of intestinal metaplasia was observed in 11 % (1 /9; one patient died, not treatment or disease related) of the patients and complete eradication of dysplasia in 44 % (4 /9). In three patients, HGD or IMC was detected during follow-up, and was endoscopically treated. Apart from a gastric perforation as a result of gastric distension caused by CO2 gas during the first treatment, cryospray treatments were well tolerated.
Conclusion: After a short learning curve, cryoablation using CO2 gas was found to be a safe and well tolerated treatment modality. However, in our experience, the efficacy of CO2 cryoablation combined with EMR for nodular lesions is disappointing for the treatment of BE associated neoplasia.
PMCID: PMC4477021  PMID: 26135648
8.  Refractory Esophageal Strictures: What To Do When Dilation Fails 
Opinion statement
Benign esophageal strictures arise from a diversity of causes, for example esophagogastric reflux, esophageal resection, radiation therapy, ablative therapy, or the ingestion of a corrosive substance. Most strictures can be treated successfully with endoscopic dilation using bougies or balloons, with only a few complications. Nonetheless, approximately one third of patients develop recurrent symptoms after dilation within the first year. The majority of these patients are managed with repeat dilations, depending on their complexity. Dilation combined with intra lesional steroid injections can be considered for peptic strictures, while incisional therapy has been demonstrated to be effective for Schatzki rings and anastomotic strictures. When these therapeutic options do not resolve the stenosis, stent placement should be considered. Self bougienage can be proposed to a selected group of patients with a proximal stenosis. As a final step surgery is an option, but even then the risk of stricture formation at the anastomotic site remains. This chapter reviews refractory benign esophageal strictures and the treatment options that are currently available.
PMCID: PMC4328110  PMID: 25647687
Refractory benign esophageal stricture; Dysphagia; Dilation; Incisional therapy; Intralesional steroid injection; Stent placement; Self-expandable plastic stent; Self-expandable metal stent; Biodegradable stent placement; Esophagectomy; Self-bougienage
9.  Lifestyle, dietary factors and antibody levels to oral bacteria in cancer-free participants of a European cohort study 
Cancer causes & control : CCC  2013;24(11):10.1007/s10552-013-0265-2.
Increasing evidence suggests that oral microbiota play a pivotal role in chronic diseases, in addition to the well-established role in periodontal disease. Moreover, recent studies suggest that oral bacteria may also be involved in carcinogenesis; periodontal disease has been linked several cancers. In this study, we examined whether lifestyle factors have an impact on antibody levels to oral bacteria.
Data on demographic characteristics, lifestyle factors, and medical conditions were obtained at the time of blood sample collection. For the current analysis, we measured antibody levels to 25 oral bacteria in 395 cancer-free individuals using an immunoblot array. Combined total immunglobin G (IgG) levels were obtained by summing concentrations for all oral bacteria measured.
IgG antibody levels were substantially lower among current and former smokers (1697 and 1677 ng/mL, respectively) than never smokers (1960 ng/mL; p-trend = 0.01), but did not vary by other factors, including BMI, diabetes, physical activity, or by dietary factors, after adjusting for age, sex, education, country and smoking status. The highest levels of total IgG were found among individuals with low education (2419 ng/mL).
Our findings on smoking are consistent with previous studies and support the notion that smokers have a compromised humoral immune response. Moreover, other major factors known to be associated with inflammatory markers, including obesity, were not associated with antibody levels to a large number of oral bacteria.
PMCID: PMC3823529  PMID: 23901020
10.  Combined impact of healthy lifestyle factors on colorectal cancer: a large European cohort study 
BMC Medicine  2014;12:168.
Excess body weight, physical activity, smoking, alcohol consumption and certain dietary factors are individually related to colorectal cancer (CRC) risk; however, little is known about their joint effects. The aim of this study was to develop a healthy lifestyle index (HLI) composed of five potentially modifiable lifestyle factors – healthy weight, physical activity, non-smoking, limited alcohol consumption and a healthy diet, and to explore the association of this index with CRC incidence using data collected within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
In the EPIC cohort, a total of 347,237 men and women, 25- to 70-years old, provided dietary and lifestyle information at study baseline (1992 to 2000). Over a median follow-up time of 12 years, 3,759 incident CRC cases were identified. The association between a HLI and CRC risk was evaluated using Cox proportional hazards regression models and population attributable risks (PARs) have been calculated.
After accounting for study centre, age, sex and education, compared with 0 or 1 healthy lifestyle factors, the hazard ratio (HR) for CRC was 0.87 (95% confidence interval (CI): 0.44 to 0.77) for two factors, 0.79 (95% CI: 0.70 to 0.89) for three factors, 0.66 (95% CI: 0.58 to 0.75) for four factors and 0.63 (95% CI: 0.54 to 0.74) for five factors; P-trend <0.0001. The associations were present for both colon and rectal cancers, HRs, 0.61 (95% CI: 0.50 to 0.74; P for trend <0.0001) for colon cancer and 0.68 (95% CI: 0.53 to 0.88; P-trend <0.0001) for rectal cancer, respectively (P-difference by cancer sub-site = 0.10). Overall, 16% of the new CRC cases (22% in men and 11% in women) were attributable to not adhering to a combination of all five healthy lifestyle behaviours included in the index.
Combined lifestyle factors are associated with a lower incidence of CRC in European populations characterized by western lifestyles. Prevention strategies considering complex targeting of multiple lifestyle factors may provide practical means for improved CRC prevention.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0168-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4192278  PMID: 25319089
lifestyle factors; combined impact; population attributable risks; colorectal cancer; European Prospective Investigation into Cancer and Nutrition (EPIC)
11.  Squamous Tissue Lymphocytes in the Esophagus of Controls and Patients with Reflux Esophagitis and Barrett’s Esophagus Are Characterized by a Non-Inflammatory Phenotype 
PLoS ONE  2014;9(8):e106261.
Background and Objective
Reflux esophagitis (RE) is characterized by inflammation of the squamous epithelium (SQ) of the esophagus and may progress to Barrett’s esophagus (BE) characterized by intestinal metaplasia. The role of inflammation in this transition has been postulated but lacks experimental evidence. Here, the inflammatory responses in the esophagus of these patients were investigated.
Patients and Methods
Fifty-one esophageal biopsies from with patients BE (n = 19), RE (n = 8) and controls (n = 23) were analyzed. T-cells were analyzed before and after ex vivo expansion (14 days) by multicolor flow cytometric analysis. The following markers were studied: CD3, CD4, CD8 (T-cell markers), Granzyme B (marker of cytotoxicity), CD103 (αE/epithelial integrin) and NKg2a (inhibitory receptor on T-cells and NK-cells).
Analysis of ex vivo cultures from normal looking SQ from controls, RE patients, and BE patients revealed no significant differences in the number and phenotypes of T-cells. In contrast, tissue from RE was different to normal SQ in four aspects: 1) higher percentages of CD3+CD4+-cells (72±7% vs 48±6%, p = 0.01) and 2) CD8+GranzymeB+ -cells (53±11% vs 26±4%, p<0.05), while 3) lower percentages of CD4+CD103+-cells (45±19% vs 80±3%, p = 0.02) and 4) CD8+NKg2a+- cells (31±12% vs 44±5%).
Despite the fact that both tissues are exposed to the same reflux associated inflammatory triggers, the immune response observed in RE is clearly distinct from that in SQ of BE. The differences in immune responses in BE tissue might contribute to its susceptibility for transformation into intestinal metaplasia.
PMCID: PMC4149547  PMID: 25170842
12.  Standard forward-viewing colonoscopy versus full-spectrum endoscopy: an international, multicentre, randomised, tandem colonoscopy trial 
The lancet oncology  2014;15(3):353-360.
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.
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, number NCT01549535.
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.
Full-spectrum endoscopy represents a technology advancement for colonoscopy and could improve the efficacy of colorectal cancer screening and surveillance.
PMCID: PMC4062184  PMID: 24560453
13.  Hemochromatosis (HFE) gene mutations and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study 
Carcinogenesis  2013;34(6):1244-1250.
Hereditary hemochromatosis (HH) is a strong risk factor for hepatocellular cancer, and mutations in the HFE gene associated with HH and iron overload may be related to other tumors, but no studies have been reported for gastric cancer (GC). A nested case–control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC), including 365 incident gastric adenocarcinoma and 1284 controls matched by center, sex, age and date of blood collection. Genotype analysis was performed for two functional polymorphisms (C282Y/rs1800562 and H63D/rs1799945) and seven tagSNPs of the HFE genomic region. Association with all gastric adenocarcinoma, and according to anatomical localization and histological subtype, was assessed by means of the odds ratio (OR) and 95% confidence interval (CI) estimated by unconditional logistic regression adjusted for the matching variables. We observed a significant association for H63D with OR (per rare allele) of 1.32 (CI = 1.03–1.69). In subgroup analyses, the association was stronger for non-cardia anatomical subsite (OR = 1.60, CI = 1.16–2.21) and intestinal histological subtype (OR = 1.82, CI = 1.27–2.62). Among intestinal cases, two tagSNPs (rs1572982 and rs6918586) also showed a significant association that disappeared after adjustment for H63D. No association with tumors located in the cardia or with diffuse subtype was found for any of the nine SNPs analyzed. Our results suggest that H63D variant in HFE gene seems to be associated with GC risk of the non-cardia region and intestinal type, possibly due to its association with iron overload although a role for other mechanisms cannot be entirely ruled out.
PMCID: PMC3670256  PMID: 23389292
14.  Plasma Alkylresorcinols, Biomarkers of Whole-Grain Wheat and Rye Intake, and Incidence of Colorectal Cancer 
Few studies have investigated the association between whole-grain intake and colorectal cancer. Because whole-grain intake estimation might be prone to measurement errors, more objective measures (eg, biomarkers) could assist in investigating such associations.
The association between alkylresorcinols, biomarkers of whole-grain rye and wheat intake, and colorectal cancer incidence were investigated using prediagnostic plasma samples from colorectal cancer case patients and matched control subjects nested within the European Prospective Investigation into Cancer and Nutrition. We included 1372 incident colorectal cancer case patients and 1372 individual matched control subjects and calculated the incidence rate ratios (IRRs) for overall and anatomical subsites of colorectal cancer using conditional logistic regression adjusted for potential confounders. Regional differences (Scandinavia, the Mediterranean, Central Europe) were also explored.
High plasma total alkylresorcinol concentration was associated with lower incidence of distal colon cancer; the adjusted incidence rate ratio of distal colon cancer for the highest vs lowest quartile of plasma total alkylresorcinols was 0.48 (95% confidence interval [CI] = 0.28 to 0.83). An inverse association between plasma total alkylresorcinol concentrations and colon cancer was found for Scandinavian participants (IRR per doubling = 0.83; 95% CI = 0.70 to 0.98). However, plasma total alkylresorcinol concentrations were not associated with overall colorectal cancer, proximal colon cancer, or rectal cancer. Plasma alkylresorcinols concentrations were associated with colon and distal colon cancer only in Central Europe and Scandinavia (ie, areas where alkylresorcinol levels were higher).
High concentrations of plasma alkylresorcinols were associated with a lower incidence of distal colon cancer but not with overall colorectal cancer, proximal colon cancer, and rectal cancer.
PMCID: PMC3906988  PMID: 24317181
15.  Adherence to surveillance guidelines for dysplasia and colorectal carcinoma in ulcerative and Crohn’s colitis patients in the Netherlands 
AIM: To study adherence to the widely accepted surveillance guidelines for patients with long-standing colitis in the Netherlands.
METHODS: A questionnaire was sent to all 244 gastroenterologists in the Netherlands.
RESULTS: The response rate was 63%. Of all gastroenterologists, 95% performed endoscopic surveillance in ulcerative colitis (UC) patients and 65% in patients with Crohn’s colitis. The American Gastroenterological Association (AGA) guidelines were followed by 27%, while 27% and 46% followed their local hospital protocol or no specific protocol, respectively. The surveillance was correctly initiated in cases of pancolitis by 53%, and in cases of left-sided colitis by 44% of the gastroenterologists. Although guidelines recommend 4 biopsies every 10 cm, less than 30 biopsies per colonoscopy were taken by 73% of the responders. Only 31%, 68% and 58% of the gastroenterologists referred patients for colectomy when low-grade dysplasia, high-grade dysplasia (HGD) or Dysplasia Associated Lesion or Mass (DALM) was present, respectively.
CONCLUSION: Most Dutch gastroenterologists perform endoscopic surveillance without following international recommended guidelines. This practice potentially leads to a decreased sensitivity for dysplasia, rendering screening for colorectal cancer in this population highly ineffective.
PMCID: PMC2653310  PMID: 19132774
Colorectal cancer; Crohn’s disease; Dysplasia; Guidelines; Surveillance; Ulcerative colitis
16.  Meat and heme iron intake and risk of squamous cell carcinoma of the upper aero-digestive tract in the European Prospective Investigation into Cancer and Nutrition (EPIC) 
Evidence from prospective studies on intake of meat and fish and risk of squamous cell carcinoma (SCC) of the upper aero-digestive tract (UADT) is scarce. We prospectively investigated the association of meat and fish intake with risk of SCC of the UADT and the possible mechanism via heme iron in the large multi-center European Prospective Investigation into Cancer and Nutrition (EPIC) study.
Multivariable proportional hazards models were used to estimate relative risks of SCC of the UADT in relation to intake of total meat, as well as subtypes of meat, fish and heme iron among 348,738 individuals from 7 European countries.
During an average follow-up of 11.8 years, a total of 682 incident cases of UADT SCC were accrued. Intake of processed meat was positively associated with risk of SCC of the UADT in the total cohort (highest versus lowest quintile: RR=1.41; 95% CI=1.03-1.94), however, in stratified analyses, this association was confined to the group of current smokers (highest versus lowest quintile: RR=1.89; 95% CI=1.22-2.93). Red meat, poultry, fish and heme iron were not consistently related to UADT SCC.
Higher intake of processed meat was positively associated with SCC of the UADT among smokers. Although this finding was stable in various sensitivity analyses, we cannot rule out residual confounding by smoking. Confirmation in future studies and identification of biological mechanisms is warranted.
Smokers may further increase their risk for SCC of the UADT if they additionally consume large amounts of processed meat.
PMCID: PMC3519922  PMID: 23033453
Meat intake; Heme iron; Upper aero-digestive tract cancer; Smoking; cohort study
17.  Early surgery versus optimal current step-up practice for chronic pancreatitis (ESCAPE): design and rationale of a randomized trial 
BMC Gastroenterology  2013;13:49.
In current practice, patients with chronic pancreatitis undergo surgical intervention in a late stage of the disease, when conservative treatment and endoscopic interventions have failed. Recent evidence suggests that surgical intervention early on in the disease benefits patients in terms of better pain control and preservation of pancreatic function. Therefore, we designed a randomized controlled trial to evaluate the benefits, risks and costs of early surgical intervention compared to the current stepwise practice for chronic pancreatitis.
The ESCAPE trial is a randomized controlled, parallel, superiority multicenter trial. Patients with chronic pancreatitis, a dilated pancreatic duct (≥ 5 mm) and moderate pain and/or frequent flare-ups will be registered and followed monthly as potential candidates for the trial. When a registered patient meets the randomization criteria (i.e. need for opioid analgesics) the patient will be randomized to either early surgical intervention (group A) or optimal current step-up practice (group B). An expert panel of chronic pancreatitis specialists will oversee the assessment of eligibility and ensure that allocation to either treatment arm is possible. Patients in group A will undergo pancreaticojejunostomy or a Frey-procedure in case of an enlarged pancreatic head (≥ 4 cm). Patients in group B will undergo a step-up practice of optimal medical treatment, if needed followed by endoscopic interventions, and if needed followed by surgery, according to predefined criteria. Primary outcome is pain assessed with the Izbicki pain score during a follow-up of 18 months. Secondary outcomes include complications, mortality, total direct and indirect costs, quality of life, pancreatic insufficiency, alternative pain scales, length of hospital admission, number of interventions and pancreatitis flare-ups. For the sample size calculation we defined a minimal clinically relevant difference in the primary endpoint as a difference of at least 15 points on the Izbicki pain score during follow-up. To detect this difference a total of 88 patients will be randomized (alpha 0.05, power 90%, drop-out 10%).
The ESCAPE trial will investigate whether early surgery in chronic pancreatitis is beneficial in terms of pain relief, pancreatic function and quality of life, compared with current step-up practice.
Trial registration
PMCID: PMC3610165  PMID: 23506415
Chronic pancreatitis; Pain; Surgical management; Surgery; Endoscopic treatment; Endoscopy; ERCP; Opioid; Pancreaticojejunostomy; Frey procedure
18.  Complementary Role of HCV and HIV in T-Cell Activation and Exhaustion in HIV/HCV Coinfection 
PLoS ONE  2013;8(3):e59302.
To investigate whether T-cell activation and exhaustion is linked to HCV- and HIV disease parameters in HIV/HCV infected individuals, we studied T-cell characteristics in HIV/HCV coinfected patients and controls.
14 HIV/HCV coinfected, 19 HCV monoinfected, 10 HIV monoinfected patients and 15 healthy controls were included in this cross-sectional study. Differences in expression of activation and exhaustion markers (HLA-DR, CD38, PD-1, Tim-3 and Fas) and phenotypic markers on CD4+ and CD8+ T-cells were analysed by flow cytometry and were related to HCV disease parameters (HCV-viremia, ALT and liver fibrosis).
Frequencies of activated CD4+ and CD8+ T-cells were higher in HIV/HCV-coinfected compared to healthy controls and HCV or HIV mono-infected individuals. Coinfected patients also showed high expression of the exhaustion marker PD-1 and death receptor Fas. In contrast, the exhaustion marker Tim-3 was only elevated in HIV-monoinfected patients. T-cell activation and exhaustion were correlated with HCV-RNA, suggesting that viral antigen influences T-cell activation and exhaustion. Interestingly, increased percentages of effector CD8+ T-cells were found in patients with severe (F3–F4) liver fibrosis compared to those with no to minimal fibrosis (F0–F2).
HIV/HCV coinfected patients display a high level of T-cell activation and exhaustion in the peripheral blood. Our data suggest that T-cell activation and exhaustion are influenced by the level of HCV viremia. Furthermore, high percentages of cytotoxic/effector CD8+ T-cells are associated with liver fibrosis in both HCV monoinfected and HIV/HCV coinfected patients.
PMCID: PMC3598709  PMID: 23555014
19.  Esophageal dilation with integrated balloon imaging: initial evaluation in a porcine model 
When treating achalasia, balloon dilation is often combined with fluoroscopy to allow the lower esophageal sphincter to be visualized as it is being dilated. We sought to evaluate a new balloon dilation technology, EsoFLIP, which allows the shape of the balloon to be visualized in a nonradiographic manner by using impedance planimetry electrodes located within the dilation balloon.
Two pigs weighing 35 kg were used. The EsoFLIP balloon dilator was introduced under endoscopic visualization. Successive injections of 50, 60, 70 and 85 mL into the dilation balloon permitted dilations at increasing diameters to be achieved. Following each dilation fluid was withdrawn to leave 30 mL in the balloon and an EsoFLIP image was captured to track progressive dilation of the gastroesophageal junction (GEJ).
The EsoFLIP catheter was safely deployed in the two pigs and no complications were noted. For pig 1, during dilation, the measured balloon diameter at the waist was 24.1, 28.9, 29.2 and 30.0 mm for balloon dilation volumes of 50, 60, 70 and 85 mL respectively. For pig 2 the corresponding diameter at the waist was 22.8, 27.1, 28.5 and 29.4 mm. The GEJ diameter increased from 12.5 and 12.4 mm to 17.4 and 17.5mm for pigs 1 and 2 respectively. Distensibility of the GEJ in pig 1 increased from 2.3 mm2/mmHg before to 4.4 mm2/mmHg after dilation and in pig 2 from 4.4 to 9.6 mm2/mmHg. The GEJ substantively achieved its final diameter after the dilation using just 50 mL in the balloon.
We demonstrated technical feasibility and safety of the EsoFLIP dilator in a porcine model. Further studies in humans with achalasia remain to be conducted, which, besides demonstrating technical feasibility, should also evaluate the use of distensibility measurements taken during dilation to predict outcomes.
PMCID: PMC3589132  PMID: 23503681
Achalsia; balloon dilation; esophageal
20.  Development of a Real-Time PCR for Identification of Brachyspira Species in Human Colonic Biopsies 
PLoS ONE  2012;7(12):e52281.
Brachyspira species are fastidious anaerobic microorganisms, that infect the colon of various animals. The genus contains both important pathogens of livestock as well as commensals. Two species are known to infect humans: B. aalborgi and B. pilosicoli. There is some evidence suggesting that the veterinary pathogenic B. pilosicoli is a potential zoonotic agent, however, since diagnosis in humans is based on histopathology of colon biopsies, species identification is not routinely performed in human materials.
The study population comprised 57 patients with microscopic evidence of Brachyspira infection and 26 patients with no histopathological evidence of Brachyspira infection. Concomitant faecal samples were available from three infected patients. Based on publically available 16S rDNA gene sequences of all Brachyspira species, species-specific primer sets were designed. DNA was extracted and tested by real-time PCR and 16S rDNA was sequenced.
Sensitivity and specificity for identification of Brachyspira species in colon biopsies was 100% and 87.7% respectively. Sequencing revealed B. pilosicoli in 15.4% of patients, B. aalborgi in 76.9% and a third species, tentatively named “Brachyspira hominis”, in 26.2%. Ten patients (12.3%) had a double and two (3.1%) a triple infection. The presence of Brachyspira pilosicoli was significantly associated with inflammatory changes in the colon-biopsy (p = 0.028).
This newly designed PCR allows for sub-differentiation of Brachyspira species in patient material and thus allows large-scaled surveillance studies to elucidate the pathogenicity of human Brachyspira infections. One-third of affected patients appeared to be infected with a novel species.
PMCID: PMC3527525  PMID: 23284968
21.  Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer, a randomized controlled trial (ROBOT trial) 
Trials  2012;13:230.
For esophageal cancer patients, radical esophagolymphadenectomy is the cornerstone of multimodality treatment with curative intent. Transthoracic esophagectomy is the preferred surgical approach worldwide allowing for en-bloc resection of the tumor with the surrounding lymph nodes. However, the percentage of cardiopulmonary complications associated with the transthoracic approach is high (50 to 70%).
Recent studies have shown that robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RATE) is at least equivalent to the open transthoracic approach for esophageal cancer in terms of short-term oncological outcomes. RATE was accompanied with reduced blood loss, shorter ICU stay and improved lymph node retrieval compared with open esophagectomy, and the pulmonary complication rate, hospital stay and perioperative mortality were comparable. The objective is to evaluate the efficacy, risks, quality of life and cost-effectiveness of RATE as an alternative to open transthoracic esophagectomy for treatment of esophageal cancer.
This is an investigator-initiated and investigator-driven monocenter randomized controlled parallel-group, superiority trial. All adult patients (age ≥18 and ≤80 years) with histologically proven, surgically resectable (cT1-4a, N0-3, M0) esophageal carcinoma of the intrathoracic esophagus and with European Clinical Oncology Group performance status 0, 1 or 2 will be assessed for eligibility and included after obtaining informed consent. Patients (n = 112) with resectable esophageal cancer are randomized in the outpatient department to either RATE (n = 56) or open three-stage transthoracic esophageal resection (n = 56). The primary outcome of this study is the percentage of overall complications (grade 2 and higher) as stated by the modified Clavien–Dindo classification of surgical complications.
This is the first randomized controlled trial designed to compare RATE with open transthoracic esophagectomy as surgical treatment for resectable esophageal cancer. If our hypothesis is proven correct, RATE will result in a lower percentage of postoperative complications, lower blood loss, and shorter hospital stay, but with at least similar oncologic outcomes and better postoperative quality of life compared with open transthoracic esophagectomy. The study started in January 2012. Follow-up will be 5 years. Short-term results will be analyzed and published after discharge of the last randomized patient.
Trial registration
Dutch trial register: NTR3291 NCT01544790
PMCID: PMC3564860  PMID: 23199187
22.  Pharmacological Activation of the Bile Acid Nuclear Farnesoid X Receptor Is Feasible in Patients with Quiescent Crohn's Colitis 
PLoS ONE  2012;7(11):e49706.
The bile acid-activated nuclear receptor Farnesoid X Receptor (FXR) is critical in maintaining intestinal barrier integrity and preventing bacterial overgrowth. Patients with Crohn's colitis (CC) exhibit reduced ileal FXR target gene expression. FXR agonists have been shown to ameliorate inflammation in murine colitis models. We here explore the feasibility of pharmacological FXR activation in CC.
Nine patients with quiescent CC and 12 disease controls were treated with the FXR ligand chenodeoxycholic acid (CDCA; 15 mg/kg/day) for 8 days. Ileal FXR activation was assessed in the fasting state during 6 hrs after the first CDCA dose and on day 8, by quantification of serum levels of fibroblast growth factor (FGF) 19. Since FGF19 induces gallbladder (GB) refilling in murine models, we also determined concurrent GB volumes by ultrasound. On day 8 ileal and cecal biopsies were obtained and FXR target gene expression was determined.
At baseline, FGF19 levels were not different between CC and disease controls. After the first CDCA dose, there were progressive increases of FGF19 levels and GB volumes during the next 6 hours in CC patients and disease controls (FGF19: 576 resp. 537% of basal; GB volumes: 190 resp. 178% of basal) without differences between both groups, and a further increase at day 8. In comparison with a separate untreated control group, CDCA affected FXR target gene expression in both CC and disease controls, without differences between both groups.
Pharmacological activation of FXR is feasible in patients with CC. These data provide a rationale to explore the anti-inflammatory properties of pharmacological activation of FXR in these patients.
Trial Registration NTR2009
PMCID: PMC3506649  PMID: 23189156
23.  Pre-diagnostic 25-Hydroxyvitamin D, VDR and CASR Polymorphisms, and Survival in Patients with Colorectal Cancer in Western European Populations 
Individuals with higher blood 25-hydroxy-vitamin D [25(OH)D] levels have a lower risk of developing colorectal cancer (CRC), but the influence of 25(OH)D on mortality after CRC diagnosis is unknown.
The association between pre-diagnostic 25(OH)D levels and CRC-specific (N=444) and overall mortality (N=541) was prospectively examined among 1,202 participants diagnosed with CRC between 1992-2003 in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) according to 25(OH)D quintiles and genetic variation within the VDR and CASR genes. Potential dietary, lifestyle and metabolic effect modifiers were also investigated.
There were 541 deaths, 444 (82%) due to CRC. Mean follow-up was 73 months. In multivariable analysis, higher 25(OH)D levels were associated with a statistically significant reduction in CRC-specific (Ptrend=0.04) and overall mortality (Ptrend=0.01). Participants with 25(OH)D levels in the highest quintile had an adjusted HR of 0.69 (95%CI: 0.50-0.93) for CRC-specific and 0.67 (95%CI: 0.50-0.88) for overall mortality, compared to the lowest quintile. Except for a possible interaction by pre-diagnostic dietary calcium intake (Pinteraction=0.01), no other potential modifying factors related to CRC survival were noted. The VDR (FokI and BsmI) and CASR (rs1801725) genotypes were not associated with survival.
High pre-diagnostic 25(OH)D levels are associated with improved survival of patients with CRC.
Our findings may stimulate further research directed at investigating the effects of blood vitamin D levels before, at, and after CRC diagnosis on outcomes in CRC patients.
PMCID: PMC3378514  PMID: 22278364
vitamin D; colorectal neoplasms; survival; VDR; CASR
24.  Social Inequalities and Mortality in Europe – Results from a Large Multi-National Cohort 
PLoS ONE  2012;7(7):e39013.
Socio-economic inequalities in mortality are observed at the country level in both North America and Europe. The purpose of this work is to investigate the contribution of specific risk factors to social inequalities in cause-specific mortality using a large multi-country cohort of Europeans.
A total of 3,456,689 person/years follow-up of the European Prospective Investigation into Cancer and Nutrition (EPIC) was analysed. Educational level of subjects coming from 9 European countries was recorded as proxy for socio-economic status (SES). Cox proportional hazard model's with a step-wise inclusion of explanatory variables were used to explore the association between SES and mortality; a Relative Index of Inequality (RII) was calculated as measure of relative inequality.
Total mortality among men with the highest education level is reduced by 43% compared to men with the lowest (HR 0.57, 95% C.I. 0.52–0.61); among women by 29% (HR 0.71, 95% C.I. 0.64–0.78). The risk reduction was attenuated by 7% in men and 3% in women by the introduction of smoking and to a lesser extent (2% in men and 3% in women) by introducing body mass index and additional explanatory variables (alcohol consumption, leisure physical activity, fruit and vegetable intake) (3% in men and 5% in women). Social inequalities were highly statistically significant for all causes of death examined in men. In women, social inequalities were less strong, but statistically significant for all causes of death except for cancer-related mortality and injuries.
In this European study, substantial social inequalities in mortality among European men and women which cannot be fully explained away by accounting for known common risk factors for chronic diseases are reported.
PMCID: PMC3405077  PMID: 22848347
25.  The Immune Cell Composition in Barrett's Metaplastic Tissue Resembles That in Normal Duodenal Tissue 
PLoS ONE  2012;7(4):e33899.
Background and Objective
Barrett's esophagus (BE) is characterized by the transition of squamous epithelium into columnar epithelium with intestinal metaplasia. The increased number and types of immune cells in BE have been indicated to be due to a Th2-type inflammatory process. We tested the alternative hypothesis that the abundance of T-cells in BE is caused by a homing mechanism that is found in the duodenum.
Patients and Methods
Biopsies from BE and duodenal tissue from 30 BE patients and duodenal tissue from 18 controls were characterized by immmunohistochemistry for the presence of T-cells and eosinophils(eos). Ex vivo expanded T-cells were further phenotyped by multicolor analysis using flowcytometry.
The high percentage of CD4+-T cells (69±3% (mean±SEM/n = 17, by flowcytometry)), measured by flowcytometry and immunohistochemistry, and the presence of non-activated eosinophils found in BE by immunohistochemical staining, were not different from that found in duodenal tissue. Expanded lymphocytes from these tissues had a similar phenotype, characterized by a comparable but low percentage of αE(CD103) positive CD4+cells (44±5% in BE, 43±4% in duodenum of BE and 34±7% in duodenum of controls) and a similar percentage of granzyme-B+CD8+ cells(44±5% in BE, 33±6% in duodenum of BE and 36±7% in duodenum of controls). In addition, a similar percentage of α4β7+ T-lymphocytes (63±5% in BE, 58±5% in duodenum of BE and 62±8% in duodenum of controls) was found. Finally, mRNA expression of the ligand for α4β7, MAdCAM-1, was also similar in BE and duodenal tissue. No evidence for a Th2-response was found as almost no IL-4+-T-cells were seen.
The immune cell composition (lymphocytes and eosinophils) and expression of intestinal adhesion molecule MAdCAM-1 is similar in BE and duodenum. This supports the hypothesis that homing of lymphocytes to BE tissue is mainly caused by intestinal homing signals rather than to an active inflammatory response.
PMCID: PMC3317926  PMID: 22509265

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