Endoscopic resection of high-risk T1 colorectal carcinoma prior to surgical resection has no adverse effect on long-term outcomes.

OBJECTIVE: It is difficult to predict the presence of histological risk factors for lymph node metastasis (LNM) before endoscopic treatment of T1 colorectal cancer (CRC). Therefore, endoscopic therapy is propagated to obtain adequate histological staging. We examined whether secondary surgery following endoscopic resection of high-risk T1 CRC does not have a negative effect on patients' outcomes compared with primary surgery. DESIGN: Patients with T1 CRC with one or more histological risk factors for LNM (high risk) and treated with primary or secondary surgery between 2000 and 2014 in 13 hospitals were identified in the Netherlands Cancer Registry. Additional data were collected from hospital records, endoscopy, radiology and pathology reports. A propensity score analysis was performed using inverse probability weighting (IPW) to correct for confounding by indication. RESULTS: 602 patients were eligible for analysis (263 primary; 339 secondary surgery). Overall, 34 recurrences were observed (5.6%). After adjusting with IPW, no differences were observed between primary and secondary surgery for the presence of LNM (OR 0.97; 95% CI 0.49 to 1.93; p=0.940) and recurrence during follow-up (HR 0.97; 95% CI 0.41 to 2.34; p=0.954). Further adjusting for lymphovascular invasion, depth of invasion and number of retrieved lymph nodes did not alter this outcome. CONCLUSIONS: Our data do not support an increased risk of LNM or recurrence after secondary surgery compared with primary surgery. Therefore, an attempt for an en-bloc resection of a possible T1 CRC without evident signs of deep invasion seems justified in order to prevent surgery of low-risk T1 CRC in a significant proportion of patients.

Risk for Incomplete Resection after Macroscopic Radical Endoscopic Resection of T1 Colorectal Cancer: A Multicenter Cohort Study.

OBJECTIVES: The decision to perform secondary surgery after endoscopic resection of T1 colorectal cancer (CRC) depends on the risk of lymph node metastasis and the risk of incomplete resection. We aimed to examine the incidence and risk factors for incomplete endoscopic resection of T1 CRC after a macroscopic radical endoscopic resection. METHODS: Data from patients treated between 2000 and 2014 with macroscopic complete endoscopic resection of T1 CRC were collected from 13 hospitals. Incomplete resection was defined as local recurrence at the polypectomy site during follow-up or malignant tissue in the surgically resected specimen in case secondary surgery was performed. Multivariate regression analysis was performed to analyze factors associated with incomplete resection. RESULTS: In total, 877 patients with a median follow-up time of 36.5 months (interquartile range 16.0-68.3) were included, in whom secondary surgery was performed in 358 patients (40.8%). Incomplete resection was observed in 30 patients (3.4%; 95% confidence interval (CI) 2.3-4.6%). Incomplete resection rate was 0.7% (95% CI 0-2.1%) in low-risk T1 CRC vs. 4.4% (95% CI 2.7-6.5%) in high-risk T1 CRC (P=0.04). Overall adverse outcome rate (incomplete resection or metastasis) was 2.1% (95% CI 0-5.0%) in low-risk T1 CRC vs. 11.7% (95% CI 8.8-14.6%) in high-risk T1 CRC (P=0.001). Piecemeal resection (adjusted odds ratio 2.60; 95% CI 1.20-5.61, P=0.02) and non-pedunculated morphology (adjusted odds ratio 2.18; 95% CI 1.01-4.70, P=0.05) were independent risk factors for incomplete resection. Among patients in whom no additional surgery was performed, who developed recurrent cancer, 41.7% (95% CI 20.8-62.5%) died as a result of recurrent cancer. CONCLUSIONS: In the absence of histological high-risk factors, a 'wait-and-see' policy with limited follow-up is justified. Piecemeal resection and non-pedunculated morphology are independent risk factors for incomplete endoscopic resection of T1 CRC.

Endoscopic mucosal resection (EMR) versus endoscopic submucosal dissection (ESD) for resection of large distal non-pedunculated colorectal adenomas (MATILDA-trial): rationale and design of a multicenter randomized clinical trial.

BACKGROUND: Endoscopic mucosal resection (EMR) is currently the most used technique for resection of large distal colorectal polyps. However, in large lesions EMR can often only be performed in a piecemeal fashion resulting in relatively low radical (R0)-resection rates and high recurrence rates. Endoscopic submucosal dissection (ESD) is a newer procedure that is more difficult resulting in a longer procedural time, but is promising due to the high en-bloc resection rates and the very low recurrence rates. We aim to evaluate the (cost-)effectiveness of ESD against EMR on both short (i.e. 6 months) and long-term (i.e. 36 months). We hypothesize that in the short-run ESD is more time consuming resulting in higher healthcare costs, but is (cost-) effective on the long-term due to lower patients burden, a higher number of R0-resections and lower recurrence rates with less need for repeated procedures. METHODS: This is a multicenter randomized clinical trial in patients with a non-pedunculated polyp larger than 20 mm in the rectum, sigmoid, or descending colon suspected to be an adenoma by means of endoscopic assessment. Primary endpoint is recurrence rate at follow-up colonoscopy at 6 months. Secondary endpoints are R0-resection rate, perceived burden and quality of life, healthcare resources utilization and costs, surgical referral rate, complication rate and recurrence rate at 36 months. Quality-adjusted-life-year (QALY) will be estimated taking an area under the curve approach and using EQ-5D-indexes. Healthcare costs will be calculated by multiplying used healthcare services with unit prices. The cost-effectiveness of ESD against EMR will be expressed as incremental cost-effectiveness ratios (ICER) showing additional costs per recurrence free patient and as ICER showing additional costs per QALY. DISCUSSION: If this trial confirms ESD to be favorable on the long-term, the burden of extra colonoscopies and repeated procedures can be prevented for future patients. TRIAL REGISTRATION: NCT02657044 (Clinicaltrials.gov), registered January 8, 2016.

Transdermal nicotine inhibits interleukin 2 synthesis by mononuclear cells derived from healthy volunteers.

BACKGROUND: Smoking has either a beneficial or harmful effect on the course and recurrence of ulcerative colitis (UC) and Crohn's disease respectively. Transdermal application of nicotine had similar effects in UC and therefore was considered to be an effective basic drug that could be further developed in the search for new compounds in the treatment of acute exacerbations of corticosteroid-resistant UC. To clarify the hypothesis that nicotine exerts its anti-inflammatory effect in UC through selective inhibition of T-cell-derived cytokine synthesis, we studied in vivo effects of nicotine on cytokine production by human non-adherent mononuclear cells isolated from peripheral blood in a randomized, double-blind, placebo-controlled trial. METHODS: Healthy non-smoking volunteers applied for 2 weeks of nicotine patches (n = 12) with incremental doses of nicotine during the first week to achieve a maintenance dose of 15 mg per day, or placebo (n = 12). Blood was obtained before treatment and 1, 2, 3 and 6 weeks after the start of treatment. Cells were cultured in the absence or presence of phytohaemagglutinin for 48 h, and total amounts of interleukin 2 (IL-2), IL-4, IL-10, IL-13, interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha) were measured. RESULTS: Transdermal nicotine caused a significant inhibition of IL-2 after 2 weeks' treatment compared with the placebo group. In addition, a diminished production of IL-10 and TNF-alpha in comparison with day 0 was observed. CONCLUSION: The beneficial effect of transdermal nicotine in ulcerative colitis may be mediated by a selective inhibition of the IL-2 production by mucosal mononuclear cells, which could result in diminished cell proliferation and consequently a reduction in the inflammatory process.

Diminished nitroprusside-induced relaxation of inflamed colonic smooth muscle in mice.

The dextran sodium sulphate (DSS) induced colitis in mice was used as a experimental model to study the contractility of murine longitudinal colonic smooth muscle during inflammation. Smooth muscle segments of proximal, middle and distal colon were mounted in organ baths. Smooth muscle contraction was induced by carbachol showing an aboral increase in activity, whereas in the inflamed middle colonic segment a marked decrease in activity was observed. The dilatative effect of sodium-nitroprusside (SNP) as a nitric oxide donor was investigated after precontraction by carbachol. Both in normal and DSS segments administration of SNP to isolated mouse colonic smooth muscle preparations caused regional differences in relaxation, the highest relaxation seen in normal proximal colonic tissue. However, this relaxation was markedly reduced in inflamed proximal preparations, associated with a diminished cGMP contents.

Intestinal permeability and contractility in murine colitis.

We developed an in vitro organ bath method to measure permeability and contractility simultaneously in murine intestinal segments. To investigate whether permeability and contractility are correlated and influenced by mucosal damage owing to inflammation, BALB/c mice were exposed to a 10% dextran sulphate sodium (DSS) solution for 8 days to induce colitis. The effect of pharmacologically induced smooth muscle relaxation and contraction on permeability was tested in vitro. Regional permeability differences were observed in both control and 10% DSS-treated mice. Distal colon segments were less permeable to 3H-mannitol and 14C-PEG 400 molecules compared with proximal colon and ileum. Intestinal permeability in control vs. 10% DSS mice was not altered, although histologic inflammation score and IFN-gamma pro-inflammatory cytokine levels were significantly increased in proximal and distal colon. IL-1beta levels were enhanced in these proximal and distal segments, but not significantly different from controls. Any effect of pharmacologically induced contractility on intestinal permeability could not be observed. In conclusion, intestinal permeability and contractility are not correlated in this model of experimentally induced colitis in mice. Although simultaneous measurement in a physiological set-up is possible, this method has to be further validated.

Somatostatin does not attenuate intestinal injury in dextran sodium sulphate-induced subacute colitis.

FRom several in vitro and in vivo studies involvement of somatostatin (SMS) in intestinal inflammation emerge. Acute colitis induced in rats is attenuated by the long-acting SMS analogue octreotide. We studied the potential beneficial effect of SMS on non-acute experimental colitis. BALB/c mice received either saline, SMS-14 (36 or 120 microg daily) or octreotide (3 microg daily) subcutaneously delivered by implant osmotic pumps. A non-acute colitis was induced by administration of dextran sodium sulphate (DSS) 10% in drinking water during 7 days. DSS evoked a mild, superficial pancolitis, most characterized by mucosal ulceration and submucosal influx of neutrophils. Neither SMS-14 nor octreotide reduced mucosal inflammatory score or macroscopical disease activity, although reduction of intestinal levels of interleukin-1beta (IL-1beta), IL-6 and IL-10 during DSS was augmented both by SMS and octreotide. A slight increase of neutrophil influx was seen during SMS administration in animals not exposed to DSS. In conclusion, SMS or its long-acting analogue did not reduce intestinal inflammation in non-acute DSS-induced colitis. According to the cytokine profile observed, SMS-14 and octreotide further diminished the reduction of intestinal macrophage and Th2 lymphocyte activity.

Somatostatin in inflammatory bowel disease.

Intestinal inflammation is controlled by various immunomodulating cells, interacting by molecular mediators. Neuropeptides, released by enteric nerve cells and neuroendocrine mucosa cells, are able to affect several aspects of the general and intestinal immune system, with both pro- as well as anti-inflammatory activities. In inflammatory bowel disease (IBD) there is both morphological as well as experimental evidence for involvement of neuropeptides in the pathogenesis. Somatostatin is the main inhibitory peptide in inflammatory processes, and its possible role in IBD is discussed.

Percutaneous endoscopic gastrostomy (PEG): comparison of push and pull methods and evaluation of antibiotic prophylaxis.

BACKGROUND AND STUDY AIMS: Infection of the gastrostomy opening after placement of a percutaneous endoscopic gastrostomy (PEG) catheter has been reported to occur quite often, especially when the pull method is used. We therefore compared complications occurring with the pull and push methods, and evaluated the role of antibiotic prophylaxis. PATIENTS AND METHODS: In a prospective study, 100 consecutive patients were randomly assigned to group A (pull plus antibiotic prophylaxis: amoxycillin-clavulanic acid 3 x 1.2 g i.v. over 24 hours; 37 patients), group B (pull without antibiotic prophylaxis; 34 patients) and group C (push without antibiotic prophylaxis; 29 patients). The indications for PEG placement were dysphagia due to oropharyngeal tumors (56%), neurological disease (32%), or other (12%). Patients were evaluated twice weekly for one month after the PEG placement. RESULTS: PEG catheters were successfully placed in 96% of the patients. The total procedure-related complication rate was significantly lower in group A than in groups B and C (28%, 58%, and 70%, respectively; p < 0.01). Major complications occurred in one patient in group A (seeding metastasis of a hypopharyngeal carcinoma in the gastrostomy tract), and in four patients in group B (three cases of peritonitis and one aspiration, resulting in two deaths), but in none of the group C patients. Group A patients experienced fewer peristomal infections than the other two groups (14%, 30%, and 41%, respectively: p = 0.05). The risk of peristomal pain was similar (11%, 15%, and 11%, respectively; p = n.s.). In three patients in group C, the PEG catheter had to be replaced by the pull method, due to repeated dislocation of the balloon catheter. CONCLUSIONS: The complication rate with PEG placement is high with both the push and pull methods. The complication rate with the pull method is significantly reduced when antibiotic prophylaxis is used.

Coeliac disease. Three cases of delayed diagnosis after a sojourn in the tropics.

Three patients are described in whom the diagnosis of coeliac disease was missed because of a recent sojourn in the tropics. The differences between coeliac disease and tropical sprue, as well as the diagnostic pathways, are discussed.

Coeliac disease. Diagnostic and therapeutic pitfalls.

Gluten-free diet (GFD) as the standard treatment for coeliac disease (CD) was discovered by Dicke. In 1989 Holmes attributed a protective role to GFD with regard to the development of malignancy in untreated CD. Gluten sensitivity is in general an asymptomatic condition. The identification of subclinical cases is becoming a major topic of current interest. Defining high-risk groups for coeliac disease is mandatory. The evaluation of small-intestine biopsies (SIB), however, is much more complicated, as was suggested in the past. Recognition of the Corazza sign and rediscovery of the endoscopic guided capsule may well be of help. Screening patients with a high-risk of CD with a minimal number of tests prior to SIB makes more and more sense. Therefore intestinal permeability tests might be helpful. GFD appears simple, but in practice it represents a challenge to patients, dietitians and physicians. Management of coeliac disease seems much more complicated, as was thought in the early 1980s.

Effects of group size and gentling on behaviour, selected organ masses and blood constituents in female Rivm: TOX rats.

The effects of group size (individually versus 3 in a cage) and gentling on behaviour and blood constituents were studied in female rats. Gentled rats showed less freezing and/or escaping when approached in an objective handling test than non-gentled rats; the type of caging had no significant influence. In a small field, gentled rats displayed significantly more turning and standing upright, whereas these parameters did not differ between rats housed either individually or three in a cage. In both tests, gentled rats produced significantly less urine than did control rats. Neither caging nor gentling significantly influenced the group mean values and variance of masses of adrenals, spleen and thymus and plasma concentrations of glucose, cholesterol, triglycerides and corticosterone. Removal of a cage from the rack and getting out a rat caused increase in plasma concentrations of corticosterone in its remaining cage mates.

Triamterene increases lithium excretion in healthy subjects: evidence for lithium transport in the cortical collecting tubule.

The possible presence of lithium transport beyond the proximal tubule was examined by measuring lithium excretion after administration of triamterene, a potassium-sparing diuretic, exclusively acting in the cortical collecting tubule. Eight young and healthy volunteers were studied on two occasions during maximal water diuresis. After obtaining baseline values triamterene (100 mg orally) or placebo was administered, and measurements continued for 4 hours. Creatinine clearance was used as a marker of glomerular filtration rate, and phosphate excretion was used as an additional marker of proximal sodium transport. Compared to placebo (P), triamterene (T) caused a significant increase in fractional excretion of sodium (P, 0.74 +/- 0.08%; T, 1.73 +/- 0.24%, mean +/- SEM; P less than 0.01), and lithium (P, 21.2 +/- 1.3%; T, 27.5 +/- 1.5%; P less than 0.01), whereas fractional excretion of phosphate remained unchanged (P, 9.8 +/- 1.3%; T, 9.4 +/- 1.5%; P = NS). These results indicate that lithium is transported in the cortical collecting tubule, and provide further evidence that the use of lithium as a marker of purely proximal tubular sodium transport is of limited value.