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.

Current methods to diagnose the unresponsive and complicated forms of coeliac disease.

Coeliac disease is a common disorder. Due to the protean manifestations of the disease and the often mild but indolent course, the diagnosis is often missed. The method to diagnose this in principle reversible disease after the introduction of a gluten-free diet has attracted the attention of several scientific disciplines to find the simplest and most patient-friendly test. This has resulted in a noticeable impact on the clinical practice next to a general increased awareness of its existence, its pathogenesis, its course and recent evidence of increased mortality. Amendments made in the diagnostic criteria of coeliac disease over the last half century have simplified the diagnosis. However, the aspect most relevant to the specialist in internal medicine is related to its grave consequences when the disease fails to respond to a gluten-free diet. These refractory cases may culminate in severe complications with sombre endings and malignancy. Fortunately, current technology can offer the specialist in internal medicine more facilities to diagnose the cause of the complicated cases in order to attempt to intervene in the course of disease and hopefully save these patients. We review the available tools that now exist and their indications that can be practiced in a modern clinical setting for the diagnosis of the complicated forms of this disease.

Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience.

BACKGROUND: Coeliac disease may be regarded as refractory disease (RCD) when symptoms persist or recur despite strict adherence to a gluten-free diet. RCD may be subdivided into types I and II with a phenotypically normal and aberrant intraepithelial T-cell population, respectively. RCD I seems to respond well to azathioprine/prednisone therapy. RCD II is usually resistant to any known therapy and transition into enteropathy-associated T-cell lymphoma (EATL) is common. AIM: To provide further insight into RCD and the development of EATL, by reporting on long-term survival and risk of transition of RCD into EATL in a large cohort of patients with complicated coeliac disease. DESIGN AND METHODS: Retrospective comparison of responses to therapy in four groups of patients with complicated coeliac disease: 43, RCD I; 50, RCD II (total), of whom 26 with RCD II developed EATL after a period of refractoriness to a gluten-free diet (secondary EATL) and 13 were EATL patients without preceding history of complicated coeliac disease (de novo EATL). RESULTS: No coeliac-disease-related mortality was recognised in the RCD I group. The overall 5-year survival in the RCD I group it was 96%; in the RCD II (total) group was 58%; and in the RCD II group after developing EATL it was only 8%. The 2-year survival in the de novo EATL group was 20% versus 15% in secondary EATL group (p = 0.63). Twenty-eight (56%) of the 50 patients with RCD II died, 23 (46%) due to EATL, 4 due to a progressive refractory state with emaciation and 1 from neurocoeliac disease. CONCLUSION: Remarkably, no patient with RCD I developed RCD II or EATL within the mean follow-up period of 5 years (range 2-15 years). A total of 52% of the RCD II patients developed EATL within 4-6 years after the diagnosis of RCD II. More aggressive and targeted therapies seem necessary in RCD II and EATL.

Association between heterophil/lymphocyte ratio, a marker of 'resistance' to stress, and some production and fitness traits in chickens.

1. A stock of cross-bred CD hens was divided into 'resistant' (R) and 'sensitive' (S) to stress on the basis of the heterophil/lymphocyte (H/L) ratio using the lower 99% confidence limit method for selection. A first generation was produced from these R and S females mated with similarly selected R and S local Barred males. The association between 'resistance' and some production traits was investigated. 2. The proportions of R:S among CD females and Barred males was 51.2:48.8 and 52:48, respectively. Mean H/L ratios for Barred males and females, respectively, were 0.87 +/- 0.03 and 0.83 +/- 0.03 (P > 0.05). 3. Compared with the S group in CD females, the R group had greater egg production (59% vs 51%), egg weight (65.5 g vs 62.6 g) and body weight at 39 weeks (115 g heavier). 4. The superiority of R in terms of proportion of fertile eggs, hatchability and the proportion hatched from those set amounted to 4.8, 6.1 and 5.4%, respectively. 5. The proportion of dead embryos in the R group (5.4%) was lower than in the S group (9.3%). 6. With the F1 generation the R chicks were heavier at hatching. 7. Percentage mortality of male F1 chicks, from hatching to 4 weeks and from 4 to 8 weeks, was lower in the R group. A similar, but non-significant, trend was noted for R females. 8. The progeny of the R group was heavier than the S progeny at 4 and 8 weeks and also the percentage dressed weight of males was greater at 8 weeks. The R group was heavier than the S group at 4, 8 and 12 weeks. 9. These results suggest that selection for general 'resistance', on the basis of the H/L ratio using the 99% lower confidence limit method of selection, is positively correlated with several important production and reproduction traits. Establishing resistant lines with high production rates seems feasible.

Double-balloon enteroscopy: indications, diagnostic yield, and complications in a series of 275 patients with suspected small-bowel disease.

BACKGROUND AND STUDY AIMS: Until recently, only the proximal small bowel was accessible for diagnostic and therapeutic endoscopy. This paper describes experience in the first 275 patients examined and treated with the new method of double-balloon enteroscopy (DBE), which is expected to make full-length enteroscopy possible. PATIENTS AND METHODS: Between November 2003 and May 2005, double-balloon enteroscopy was conducted in 275 consecutive patients presenting at two tertiary referral hospitals. The characteristics of the patients, indications for the procedures, procedural parameters, and diagnostic yield are described here. All conventional treatment options were available. The tolerability of the procedure was assessed in a small subset of the patients. After the procedure, the patients were monitored in a recovery room for at least 2h. They were discharged afterwards, provided there were no signs of complications or complaints. RESULTS: The main indication for DBE was suspected small-bowel bleeding (n=168), and the lesions responsible for the bleeding were found in 123 patients (73 %) and treated in 61 (55 %). In patients with refractory celiac disease (n=25), DBE revealed a high proportion (six patients, 23 %) of enteropathy-associated T-cell lymphomas that had not been suspected on other tests. Further DBE indications were surveillance and treatment of hereditary polyposis syndromes (n=20); and suspected Crohn's disease, which was diagnosed with DBE in four of 13 patients (30 %). No relevant pathology was found in 24 % of the patients. Panenteroscopy was successfully performed in 26 of 62 patients (42 %) in whom it was attempted, in either one or two sessions. The average duration of the procedures was 90 min (range 30 - 180 min, SD 42), and the average insertion length was 270 cm (range 60 - 600 cm, SD 104). Patients' tolerance of the procedure was excellent. Severe complications were recognized in three cases (1 %), all involving pancreatitis. CONCLUSIONS: This large pilot series shows that DBE is a well-tolerated and safe new endoscopic technique with a high diagnostic yield in selected patients.

A microarray screen for novel candidate genes in coeliac disease pathogenesis.

BACKGROUND AND AIMS: The causative molecular pathways underlying the pathogenesis of coeliac disease are poorly understood. To unravel novel aspects of disease pathogenesis, we used microarrays to determine changes in gene expression of duodenal biopsies. METHODS: cDNA microarrays representing 19 200 genes were used to compare gene expression profiles of duodenal biopsies from 15 coeliac disease patients with villous atrophy (Marsh III) and seven control individuals with normal biopsies (Marsh 0). In addition, the specific effect of gluten was studied by comparing the expression profiles of Marsh III lesions of seven patients exposed to gluten with four patients on a gluten free diet. RESULTS: Comparing Marsh III with Marsh 0 lesions identified 109 genes that differed significantly (p<0.001) in expression levels between patients and controls. A large number of these genes have functions in proliferation and differentiation pathways and might be important for correct development of crypt-villous units. Alterations in these pathways may lead to the characteristic hyperplasia and villous atrophy seen in coeliac disease. The analyses also revealed 120 differentially expressed genes (p<0.005) when comparing patients on a gluten free diet with those exposed to gluten. These genes further strengthen our observation of increased cell proliferation in the presence of gluten. CONCLUSIONS: Our study provides new candidate genes in the pathogenesis of coeliac disease. Based on our results, we hypothesise that villous atrophy in coeliac disease patients is due to failure in cell differentiation. These genes are involved in pathways not previously implicated in coeliac disease pathogenesis and they may provide new targets for therapy.

Exercise-induced spontaneous hemothorax insinuates trauma; yet unmasks a lament disorder.

The investigation for a plausible explanation of the development of massive spontaneous hemothorax during exercise in two patients led to the disclosure of two different malignancies. The first patient (pleural fibrosarcoma) passed away shortly after diagnosis. The second patient is alive without signs of disease (peripheral neuro-ectodermal tumor, PNET) since the diagnosis was made 3 years before. Spontaneous hemothorax (SH) arising during exercise does not exclusively designate trauma and full search for anatomical abnormality is warranted.

A bone biopsy is mandatory in the optimal management of bone lesions in patients with a long-term history of malignancy of the breast.

Bone lesions, present in two women with primary breast cancer treated more than 5 years ago, were investigated thoroughly by biochemical markers and imaging techniques. The definite diagnosis was established by bone biopsy, which revealed two totally unrelated disorders that altered the management and prognosis for these two patients. One patient had Paget's disease, and the other had metastatic hepatocellular carcinoma.