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.
Hepatocellular carcinoma; Surveillance; Chronic liver disease
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.
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.
Achalsia; balloon dilation; esophageal
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 (ClinicalTrials.gov Identifier: NCT01044732).
Colonoscopy; Colorectal cancer; Adenomas; Miss rates; Retrograde-viewing
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.
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.
Colorectal cancer; Crohn’s disease; Dysplasia; Guidelines; Surveillance; Ulcerative colitis
The continuous exposure of esophageal epithelium to refluxate may induce ectopic expression of bile-responsive genes and contribute to the development of Barrett's esophagus (BE) and esophageal adenocarcinoma. In normal physiology of the gut and liver, the nuclear receptor Pregnane × Receptor (PXR) is an important factor in the detoxification of xenobiotics and bile acid homeostasis. This study aimed to investigate the expression and genetic variation of PXR in reflux esophagitis (RE), Barrett's esophagus (BE) and esophageal adenocarcinoma.
PXR mRNA levels and protein expression were determined in biopsies from patients with adenocarcinoma, BE, or RE, and healthy controls. Esophageal cell lines were stimulated with lithocholic acid and rifampicin. PXR polymorphisms 25385C/T, 7635A/G, and 8055C/T were genotyped in 249 BE patients, 233 RE patients, and 201 controls matched for age and gender.
PXR mRNA levels were significantly higher in adenocarcinoma tissue and columnar Barrett's epithelium, compared to squamous epithelium of these BE patients (P < 0.001), and RE patients (P = 0.003). Immunohistochemical staining of PXR showed predominantly cytoplasmic expression in BE tissue, whereas nuclear expression was found in adenocarcinoma tissue. In cell lines, stimulation with lithocholic acid did not increase PXR mRNA levels, but did induce nuclear translocation of PXR protein. Genotyping of the PXR 7635A/G polymorphism revealed that the G allele was significantly more prevalent in BE than in RE or controls (P = 0.037).
PXR expresses in BE and adenocarcinoma tissue, and showed nuclear localization in adenocarcinoma tissue. Upon stimulation with lithocholic acid, PXR translocates to the nuclei of OE19 adenocarcinoma cells. Together with the observed association of a PXR polymorphism and BE, this data implies that PXR may have a function in prediction and treatment of esophageal disease.
Antireflux surgery (ARS) for gastroesophageal reflux disease (GERD) is one of the most frequently performed major operations in children. Many studies have described the results of ARS in children, however, with a wide difference in outcome. This study aims to systematically review the efficacy of pediatric ARS and its effects on gastroesophageal function, as measured by gastroesophageal function tests. This is the first systematic review comprising only prospective, longitudinal studies, minimizing the risk of bias.
Three electronic databases (Medline, Embase, and the Cochrane Library) were searched for prospective studies reporting on ARS in children with GERD.
In total, 17 eligible studies were identified, reporting on a total of 1,280 children. The median success rate after ARS was 86% (57–100%). The success rate in neurologically impaired children was worse in one study, but similar in another study compared to normally developed children. Different surgical techniques (total versus partial fundoplication, or laparoscopic versus open approach) showed similar reflux recurrence rates. However, less postoperative dysphagia was observed after partial fundoplication and laparoscopic ARS was associated with less pain medication and a shorter hospital stay. Complications of ARS varied from minimal postoperative complications to severe dysphagia and gas bloating. The reflux index (RI), obtained by 24-h pH monitoring (n = 8) decreased after ARS. Manometry, as done in three studies, showed no increase in lower esophageal sphincter pressure after ARS. Gastric emptying (n = 3) was reported either unchanged or accelerated after ARS. No studies reported on barium swallow x-ray, endoscopy, or multichannel intraluminal impedance monitoring before and after ARS.
ARS in children shows a good overall success rate (median 86%) in terms of complete relief of symptoms. Efficacy of ARS in neurologically impaired children may be similar to normally developed children. The outcome of ARS does not seem to be influenced by different surgical techniques, although postoperative dysphagia may occur less after partial fundoplication. However, these conclusions are bound by the lack of high-quality prospective studies on pediatric ARS. Similar studies on the effects of pediatric ARS on gastroesophageal function are also very limited. We recommend consistent use of standardized assessment tests to clarify the effects of ARS on gastroesophageal function and to identify possible risk factors for failure of ARS in children.
Gastroesophageal reflux; Antireflux surgery; Fundoplication; Children
Regular colonoscopic surveillance for detection of dysplasia is recommended in longstanding inflammatory bowel disease (IBD), however, its sensitivity is disputed. Screening accuracy may increase by using a biomarker-based surveillance strategy.
A case-control study was performed to determine the prognostic value of DNA ploidy and p53 in IBD-related neoplasia. Cases with IBD-related colorectal cancer (CRC), detected in our surveillance program between 1985-2008, were selected and matched with two controls, for age, gender, disease characteristics, interval of follow-up, PSC, and previous surgery. Biopsies were assessed for DNA ploidy, p53, grade of inflammation and neoplasia. Progression to neoplasia was analyzed with Cox regression analysis, adjusting for potentially confounding variables.
Adjusting for age, we found statistically significant Hazard ratios (HR) between development of CRC, and low grade dysplasia (HR5.5; 95%CI 2.6-11.5), abnormal DNA ploidy (DNA index (DI) 1.06-1.34, HR4.7; 95%CI 2.9-7.8 and DI>1.34, HR6.6; 95%CI 3.7-11.7) and p53 immunopositivity (HR3.0; 95%CI 1.9-4.7) over time. When adjusting for all confounders, abnormal DNA ploidy (DI 1.06-1.34, HR4.7; 95%CI 2.7-7.9 and DI>1.34, HR5.0; 95%CI 2.5-10.0) and p53 immunopositivity (HR1.7; 95%CI 1.0-3.1) remained statistically significant predictive of neoplasia.
In longstanding IBD, abnormal DNA ploidy and p53 immunopositivity are important risk factors of developing CRC. The yield of surveillance may potentially increase by adding these biomarkers to the routine assessment of biopsies.
Inflammatory bowel disease; Colorectal cancer; Surveillance; Abnormal DNA ploidy; p53 immunopositivity
Ampicillin-resistant Enterococcus faecium (ARE) and vancomycin-resistant E. faecium (VRE) are important nosocomial pathogens. We quantified effects of probiotics and antibiotics on intestinal acquisition of ARE colonization in patients hospitalized in two non-intensive care unit (non-ICU) wards with high ARE prevalence. In a prospective cohort study with crossover design, all patients with a length of stay of >48 h were offered a multispecies probiotic product twice daily until discharge (4.5 months, intervention period) or not (4.5 months, control period). Perianal ARE carriage was determined <48 h after admission, twice weekly, and <48 h before discharge. The first isolates were genotyped by multiple-locus variable-number tandem repeat analysis (MLVA). Risk factors for acquisition were determined by Cox proportional hazards modeling, with special emphasis on ecological postantibiotic effects and delays between actual acquisition and culture positivity. Of 530 patients included, 94 (18%) were ARE colonized on admission. Of the remaining 436 noncolonized patients, 92 acquired ARE colonization: 28 (25%) of 110 probiotic users and 64 (20%) of 326 control patients (χ2 test, P = 0.325). In all, 661 ARE strains were isolated from 186 patients, of which 186 were genotyped. In both wards, two MLVA types (MTs; MT1 and MT159) were responsible for >80% of acquisitions. Both MTs were genetically different from the probiotic E. faecium strain. Antibiotics to which ARE is resistant (hazard ratio [HR], 7.73 [95% confidence interval (CI), 4.52 to 13.22]), an ecological postantibiotic effect (HR, 7.11 [95% CI, 3.10 to 16.30]), and age (HR, 1.01 [95% CI, 0.99 to 1.02]) were associated with ARE acquisition. The HR of probiotics was 1.43 (95% CI, 0.88 to 2.34). In a setting with high selective antibiotic pressure, probiotics failed to prevent acquisition of multiresistant enterococci.
Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of mediastinal lymphadenopathy has been shown to be a valuable diagnostic tool in high-volume EUS centers (≥50 mediastinal EUS-FNA/endoscopist/year). Our goal was to assess the diagnostic accuracy of EUS-FNA and its impact on clinical management and costs in low-volume EUS centers (<50 mediastinal EUS-FNA/endoscopist/year).
Consecutive patients referred to two Dutch endoscopy centers in the period 2002–2008 for EUS-FNA of mediastinal lymphadenopathy were reviewed. The gold standard for a cytological diagnosis was histological confirmation or clinical follow-up of more than 6 months with repeat imaging. The impact of EUS-FNA on clinical management was subdivided into a positive impact by providing (1) adequate cytology that influenced the decision to perform surgery or (2) a diagnosis of a benign inflammatory disorder, and a negative impact which was subdivided into (1) false-negative or inconclusive cytology or (2) an adequate cytological diagnosis that did not influence patient management. Costs of an alternative diagnostic work-up without EUS-FNA, as established by an expert panel, were compared to costs of the actual work-up.
In total, 213 patients (71% male, median age = 61 years, range = 23–88 years) underwent EUS-FNA. Sensitivity, specificity, and negative and positive predictive values were 89%, 100%, 80%, and 100%, respectively. EUS-FNA had a positive impact on clinical management in 84% of cases by either influencing the decision to perform surgery (49%) or excluding malignant lymphadenopathy (35%), and a negative impact in 7% of cases because of inadequate (3%) or false-negative (4%) cytology. In 9% of cases, EUS-FNA was performed without an established indication. Two nonfatal perforations occurred (0.9%). Total cost reduction was €100,593, with a mean cost reduction of €472 (SD = €607) per patient.
Mediastinal EUS-FNA can be performed in low-volume EUS centers without compromising diagnostic accuracy. Moreover, EUS-FNA plays an important role in the management of patients with mediastinal lymphadenopathy and reduces total diagnostic costs.
EUS-FNA; Costs; Accuracy; Mediastinal lymphadenopathy
Benign biliary strictures may be a consequence of surgical procedures, chronic pancreatitis or iatrogenic injuries to the ampulla. Stents are increasingly being used for this indication, however it is not completely clear which stent type should be preferred.
A systematic review on stent placement for benign extrahepatic biliary strictures was performed after searching PubMed and EMBASE databases. Data were pooled and evaluated for technical success, clinical success and complications.
In total, 47 studies (1116 patients) on outcome of stent placement were identified. No randomized controlled trials (RCTs), one non-randomized comparative studies and 46 case series were found. Technical success was 98,9% for uncovered self-expandable metal stents (uSEMS), 94,8% for single plastic stents and 94,0% for multiple plastic stents. Overall clinical success rate was highest for placement of multiple plastic stents (94,3%) followed by uSEMS (79,5%) and single plastic stents (59.6%). Complications occurred more frequently with uSEMS (39.5%) compared with single plastic stents (36.0%) and multiple plastic stents (20,3%).
Based on clinical success and risk of complications, placement of multiple plastic stents is currently the best choice. The evolving role of cSEMS placement as a more patient friendly and cost effective treatment for benign biliary strictures needs further elucidation. There is a need for RCTs comparing different stent types for this indication.
Discrete choice experiments (DCEs) allow systematic assessment of preferences by asking respondents to choose between scenarios. We conducted a labelled discrete choice experiment with realistic choices to investigate patients' trade-offs between the expected health gains and the burden of testing in surveillance of Barrett esophagus (BE).
Fifteen choice scenarios were selected based on 2 attributes: 1) type of test (endoscopy and two less burdensome fictitious tests), 2) frequency of surveillance. Each test-frequency combination was associated with its own realistic decrease in risk of dying from esophageal adenocarcinoma. A conditional logit model was fitted.
Of 297 eligible patients (155 BE and 142 with non-specific upper GI symptoms), 247 completed the questionnaire (84%). Patients preferred surveillance to no surveillance. Current surveillance schemes of once every 1–2 years were amongst the most preferred alternatives. Higher health gains were preferred over those with lower health gains, except when test frequencies exceeded once a year. For similar health gains, patients preferred video-capsule over saliva swab and least preferred endoscopy.
This first example of a labelled DCE using realistic scenarios in a healthcare context shows that such experiments are feasible. A comparison of labelled and unlabelled designs taking into account setting and research question is recommended.
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.
Meat intake; Heme iron; Upper aero-digestive tract cancer; Smoking; cohort study
Few studies have evaluated patients’ perceived burden of cancer surveillance tests. Cancer screening and surveillance, however, require a large number of patients to undergo potentially burdensome tests with only some experiencing health gains from it. We investigated the determinants of patients’ reported burden of upper gastrointestinal (GI) endoscopy by comparing data from three patient groups.
Patients and methods
A total of 476 patients were included: 180 patients under regular surveillance for Barrett esophagus (BE), a premalignant disorder; 214 patients with non-specific upper GI symptoms (NS), and 82 patients recently diagnosed with upper GI cancer (CA). We assessed pain, discomfort and overall burden experienced during endoscopy, symptoms in the week afterwards and psychological distress over time (Hospital Anxiety and Depression scale and Impact of Event Scale).
Two-thirds (66%) of patients reported discomfort and overall burden of upper GI endoscopy. Only 23% reported any pain. BE patients reported significantly less discomfort, pain and overall burden than the other patients: those with NS reported more discomfort, CA patients more pain, and both more overall burden. These differences could be statistically explained by the number of previous endoscopies and whether sedation was provided or not, but not by patient characteristics.
The perception of upper GI endoscopy varies by patient group, due to potential adaptation after multiple endoscopies and aspects of the procedure.
Upper gastrointestinal endoscopy; Endoscopic surveillance; Barrett esophagus; Perceived patient burden; Discomfort; Anxiety; Distress
Acute left-sided colonic obstruction is most often caused by malignancy and the surgical treatment is associated with a high mortality and morbidity rate. Moreover, these operated patients end up with a temporary or permanent stoma. Initial insertion of an enteral stent to decompress the obstructed colon, allowing for surgery to be performed electively, is gaining popularity. In uncontrolled studies stent placement before elective surgery has been suggested to decrease mortality, morbidity and number of colostomies. However stent perforation can lead to peritoneal tumor spill, changing a potentially curable disease in an incurable one. Therefore it is of paramount importance to compare the outcomes of colonic stenting followed by elective surgery with emergency surgery for the management of acute left-sided malignant colonic obstruction in a randomized multicenter fashion.
Patients with acute left-sided malignant colonic obstruction eligible for this study will be randomized to either emergency surgery (current standard treatment) or colonic stenting as bridge to elective surgery. Outcome measurements are effectiveness and costs of both strategies. Effectiveness will be evaluated in terms of quality of life, morbidity and mortality. Quality of life will be measured with standardized questionnaires (EORTC QLQ-C30, EORTC QLQ-CR38, EQ-5D and EQ-VAS). Morbidity is defined as every event leading to hospital admission or prolonging hospital stay. Mortality will be analyzed as total mortality as well as procedure-related mortality. The total costs of treatment will be evaluated by counting volumes and calculating unit prices. Including 120 patients on a 1:1 basis will have 80% power to detect an effect size of 0.5 on the EORTC QLQ-C30 global health scale, using a two group t-test with a 0.05 two-sided significance level. Differences in quality of life and morbidity will be analyzed using mixed-models repeated measures analysis of variance. Mortality will be compared using Kaplan-Meier curves and log-rank statistics.
The Stent-in 2 study is a randomized controlled multicenter trial that will provide evidence whether or not colonic stenting as bridge to surgery is to be performed in patients with acute left-sided colonic obstruction.
Current Controlled Trials ISRCTN46462267.
Gastrojejunostomy (GJJ) is the most commonly used palliative treatment modality for malignant gastric outlet obstruction. Recently, stent placement has been introduced as an alternative treatment. We reviewed the available literature on stent placement and GJJ for gastric outlet obstruction, with regard to medical effects and costs.
A systematic review of the literature was performed by searching PubMed for the period January 1996 and January 2006. A total of 44 publications on GJJ and stents was identified and reported results on medical effects and costs were pooled and evaluated. Results from randomized and comparative studies were used for calculating odds ratios (OR) to compare differences between the two treatment modalities.
In 2 randomized trials, stent placement was compared with GJJ (with 27 and 18 patients in each trial). In 6 comparative studies, stent placement was compared with GJJ. Thirty-six series evaluated either stent placement or GJJ. A total of 1046 patients received a duodenal stent and 297 patients underwent GJJ. No differences between stent placement and gastrojejunostomy were found in technical success (96% vs. 100%), early and late major complications 7% vs. 6% and 18% vs. 17%, respectively) and persisting symptoms (8% vs. 9%). Initial clinical success was higher after stent placement (89% vs. 72%). Minor complications were less frequently seen after stent placement in the patient series (9% vs. 33%), however the pooled analysis showed no differences (OR: 0.75, p = 0.8). Recurrent obstructive symptoms were more common after stent placement (18% vs. 1%). Hospital stay was prolonged after GJJ compared to stent placement (13 days vs. 7 days). The mean survival was 105 days after stent placement and 164 days after GJJ.
These results suggest that stent placement may be associated with more favorable results in patients with a relatively short life expectancy, while GJJ is preferable in patients with a more prolonged prognosis. The paucity of evidence from large randomized trials may however have influenced the results and therefore a trial of sufficient size is needed to determine which palliative treatment modality is optimal in (sub)groups of patients with malignant gastric outlet obstruction.
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.
Chronic pancreatitis; Pain; Surgical management; Surgery; Endoscopic treatment; Endoscopy; ERCP; Opioid; Pancreaticojejunostomy; Frey procedure
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.
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.
Dutch trial register: NTR3291 ClinicalTrial.gov: NCT01544790
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.
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.
vitamin D; colorectal neoplasms; survival; VDR; CASR
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.
Benign esophageal ruptures and anastomotic leaks are life-threatening conditions that are often treated surgically. Recently, placement of partially and fully covered metal or plastic stents has emerged as a minimally invasive treatment option. We aimed to determine the clinical effectiveness of covered stent placement for the treatment of esophageal ruptures and anastomotic leaks with special emphasis on different stent designs.
Consecutive patients who underwent placement of a fully covered self-expandable metal stent (FSEMS), a partially covered SEMS (PSEMS) or a self-expanding plastic stent (SEPS) for a benign esophageal rupture or anastomotic leak after upper gastrointestinal surgery in the period 2007-2010 were included. Data on patient demographics, type of lesion, stent placement and removal, clinical success and complications were collected
A total of 52 patients received 83 esophageal stents (61 PSEMS, 15 FSEMS, 7 SEPS) for an anastomotic leak (n = 32), iatrogenic rupture (n = 13), Boerhaave's syndrome (n = 4) or other cause (n = 3). Endoscopic stent removal was successful in all but eight patients treated with a PSEMS due to tissue ingrowth. Clinical success was achieved in 34 (76%, intention-to-treat: 65%) patients (PSEMS: 73%, FSEMS: 83%, SEPS: 83%) after a median of 1 (range 1-5) stent and a median stenting time of 39 (range 7-120) days. In total, 33 complications in 24 (46%) patients occurred (tissue in- or overgrowth (n = 8), stent migration (n = 10), ruptured stent cover (all Ultraflex; n = 6), food obstruction (n = 3), severe pain (n = 2), esophageal rupture (n = 2), hemorrhage (n = 2)). One (2%) patient died of a stent-related cause.
Covered stents placed for a period of 5-6 weeks may well be an alternative to surgery for treating benign esophageal ruptures or anastomotic leaks. As efficacy between PSEMS, FSEMS and SEPS is not different, stent choice should depend on expected risks of stent migration (SEPS and FSEMS) and tissue in- or overgrowth (PSEMS).
This is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed.
This trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test.
There were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio [HR] 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the log-rank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms.
Preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC.