Barrett Esophagus: Improving Surveillance Strategies

The aim of surveillance in patients with a Barrett esophagus (BE) is to detect progression of dysplasia at an early and therefore likely curable stage. The interval of endoscopic surveillance in patients with BE is currently based on the histopathological stage (i.e. grade of dysplasia). This approach is however known to have several pitfalls. First, only patients with intestinal metaplasia (IM) in the columnar-lined segment of the esophagus (CLE) have so far been regarded to have a premalignant condition and are enrolled in an endoscopic surveillance program, in contrast to patients with only cardiac-type mucosa (CM) in their biopsies. However, as IM and CM can be both present in the CLE and are endoscopically indiscernible, sampling error can occur, and exclusion of patients with only CM from endoscopic follow-up might therefore be incorrect. In addition, it has been suggested that IM in CLE may develop over time, and a follow-up endoscopy in the course of time may than detect IM. Secondly, in line with the risk of neoplastic progression, the presence or absence of dysplasia in IM determines the frequency of endoscopic surveillance, but the interpretation of dysplasia is subject to considerable interobserver variability, leading to both superfl uous follow-up endoscopies in some patients and insuffi cient control of others. Therefore, it is relevant to perform risk stratifi cation to defi ne which subgroup of patients with CLE with or without IM should undergo endoscopic follow-up, and at which frequency. The aim of the work described in this thesis was to assess the currently used criteria for performing endoscopic surveillance in patients with CLE, and to evaluate which clinical characteristics and biomarkers could contribute to risk stratifi cation in patients with CLE, in order to refi ne surveillance strategies in these patients

Does CDX2 expression predict Barrett's metaplasia in oesophageal columnar epithelium without goblet cells?

Background: Intestinal metaplasia (Barrett's oesophagus), but not cardiac-type mucosa in columnar-lined oesophagus, is regarded as premalignant. As intestinal metaplasia and cardiac-type mucosa are endoscopically indiscernible, it is difficult to take targeted samples from columnar-lined oesophagus with consequently a risk of having undetected intestinal metaplasia. Aim: To investigate whether the intestinal markers CDX2, MUC2 and villin can predict the presence of undetected intestinal metaplasia in columnar-lined oesophagus. Methods: Presence of intestinal metaplasia or cardiac-type mucosa was identified in 122 biopsy sets of columnar-lined oesophagus from 61 patients, collected at two subsequent follow-up upper endoscopies. CDX2, MUC2 and villin expression were determined by immunohistochemistry. Results: All intestinal metaplasia samples (55) were positive for CDX2 and MUC2 and 32 of 55 for vil

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

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Purpose: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome

Diagnosis of T1 colorectal cancer in pedunculated polyps in daily clinical practice : a multicenter study

T1 colorectal cancer can be mimicked by pseudo-invasion in pedunculated polyps. British guidelines are currently one of the few which recommend diagnostic confirmation of T1 colorectal cancer by a second pathologist. The aim of this study was to provide insights into the accuracy of histological diagnosis of pedunculated T1 colorectal cancer in daily clinical practice. A sample of 128 cases diagnosed as pedunculated T1 colorectal cancer between 2000 and 2014 from 10 Dutch hospitals was selected for histological review. Firstly, two Dutch expert gastrointestinal pathologists reviewed all hematoxylin-eosin stained slides. In 20 cases the diagnosis T1 colorectal cancer was not confirmed (20/128; 16%). The discordant cases were subsequently discussed with a third Dutch gastrointestinal pathologist and a consensus diagnosis was agreed. The revised diagnoses were pseudo-invasion in 10 cases (10/128; 8%), high-grade dysplasia in 4 cases (4/128; 3%), and equivocal in 6 cases (6/128; 5%). To further validate the consensus diagnosis, the discordant cases were reviewed by an independent expert pathologist from the United Kingdom. A total of 39 cases were reviewed blindly including the 20 cases with a revised diagnosis and 19 control cases where the Dutch expert panel agreed with the original reporting pathologists diagnosis. In 19 of the 20 cases with a revised diagnosis the British pathologist agreed that T1 colorectal cancer could not be confirmed. Additionally, amongst the 19 control cases the British pathologist was unable to confirm T1 colorectal cancer in a further 4 cases and was equivocal in 3 cases. In conclusion, both generalist and expert pathologists experience diagnostic difficulty distinguishing pseudo-invasion and high-grade dysplasia from T1 colorectal cancer. In order to prevent overtreatment, review of the histology of pedunculated T1 colorectal cancers by a second pathologist should be considered with discussion of these cases at a multidisciplinary meeting.Modern Pathology advance online publication, 7 October 2016; doi:10.1038/modpathol.2016.165

The prognostic value of lymph node yield in the earliest stage of colorectal cancer : a multicenter cohort study

BACKGROUND: In patients with stage II colorectal cancer (CRC) the number of surgically retrieved lymph nodes (LNs) is associated with prognosis, resulting in a minimum of 10-12 retrieved LNs being recommended for this stage. Current guidelines do not provide a recommendation regarding LN yield in T1 CRC. Studies evaluating LN yield in T1 CRC suggest that such high LN yields are not feasible in this early stage, and a lower LN yield might be appropriate. We aimed to validate the cut-off of 10 retrieved LNs on risk for recurrent cancer and detection of LN metastasis (LNM) in T1 CRC, and explored whether this number is feasible in clinical practice. METHODS: Patients diagnosed with T1 CRC and treated with surgical resection between 2000 and 2014 in thirteen participating hospitals were selected from the Netherlands Cancer Registry. Medical records were reviewed to collect additional information. The association between LN yield and recurrence and LNM respectively were analyzed using 10 LNs as cut-off. Propensity score analysis using inverse probability weighting (IPW) was performed to adjust for clinical and histological confounding factors (i.e., age, sex, tumor location, size and morphology, presence of LNM, lymphovascular invasion, depth of submucosal invasion, and grade of differentiation). RESULTS: In total, 1017 patients with a median follow-up time of 49.0 months (IQR 19.6-81.5) were included. Four-hundred five patients (39.8%) had a LN yield ≥ 10. Forty-one patients (4.0%) developed recurrence. LN yield ≥ 10 was independently associated with a decreased risk for recurrence (IPW-adjusted HR 0.20; 95% CI 0.06-0.67; P = 0.009). LNM were detected in 84 patients (8.3%). LN yield ≥ 10 was independently associated with increased detection of LNM (IPW-adjusted OR 2.27; 95% CI 1.39-3.69; P = 0.001). CONCLUSIONS: In this retrospective observational study, retrieving < 10 LNs was associated with an increased risk of CRC recurrence, advocating the importance to perform an appropriate oncologic resection of the draining LNs and diligent LN search when patients with T1 CRC at high-risk for LNM are referred for surgical resection. Given that both gastroenterologists, surgeons and pathologists will encounter T1 CRCs with increasing frequency due to the introduction of national screening programs, awareness on the consequences of an inadequate LN retrieval is of utmost importance

The prognostic value of lymph node yield in the earliest stage of colorectal cancer: a multicenter cohort study

Abstract Background In patients with stage II colorectal cancer (CRC) the number of surgically retrieved lymph nodes (LNs) is associated with prognosis, resulting in a minimum of 10–12 retrieved LNs being recommended for this stage. Current guidelines do not provide a recommendation regarding LN yield in T1 CRC. Studies evaluating LN yield in T1 CRC suggest that such high LN yields are not feasible in this early stage, and a lower LN yield might be appropriate. We aimed to validate the cut-off of 10 retrieved LNs on risk for recurrent cancer and detection of LN metastasis (LNM) in T1 CRC, and explored whether this number is feasible in clinical practice. Methods Patients diagnosed with T1 CRC and treated with surgical resection between 2000 and 2014 in thirteen participating hospitals were selected from the Netherlands Cancer Registry. Medical records were reviewed to collect additional information. The association between LN yield and recurrence and LNM respectively were analyzed using 10 LNs as cut-off. Propensity score analysis using inverse probability weighting (IPW) was performed to adjust for clinical and histological confounding factors (i.e., age, sex, tumor location, size and morphology, presence of LNM, lymphovascular invasion, depth of submucosal invasion, and grade of differentiation). Results In total, 1017 patients with a median follow-up time of 49.0 months (IQR 19.6–81.5) were included. Four-hundred five patients (39.8%) had a LN yield ≥ 10. Forty-one patients (4.0%) developed recurrence. LN yield ≥ 10 was independently associated with a decreased risk for recurrence (IPW-adjusted HR 0.20; 95% CI 0.06–0.67; P = 0.009). LNM were detected in 84 patients (8.3%). LN yield ≥ 10 was independently associated with increased detection of LNM (IPW-adjusted OR 2.27; 95% CI 1.39–3.69; P = 0.001). Conclusions In this retrospective observational study, retrieving < 10 LNs was associated with an increased risk of CRC recurrence, advocating the importance to perform an appropriate oncologic resection of the draining LNs and diligent LN search when patients with T1 CRC at high-risk for LNM are referred for surgical resection. Given that both gastroenterologists, surgeons and pathologists will encounter T1 CRCs with increasing frequency due to the introduction of national screening programs, awareness on the consequences of an inadequate LN retrieval is of utmost importance

Exposure to thioguanine during 117 pregnancies in women with inflammatory bowel disease

BACKGROUND: Safety of thioguanine in pregnant patients with inflammatory bowel disease (IBD) is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and in birth. METHODS: In this multicenter case series, IBD patients treated with thioguanine during pregnancy were included. Data regarding disease and medication history, pregnancy course, obstetric complications and neonatal outcomes were collected. RESULTS: Data on 117 thioguanine-exposed pregnancies in 99 women were collected. Most (78%) had Crohn's disease and the mean age at delivery was 31 years. In eighteen pregnancies (15%) IBD flared. Obstetric and infectious complications were seen in 15% (n=17) and 7% (n=8) of pregnancies, respectively. Ten pregnancies (8.5%) resulted in a first trimester miscarriage and one in a stillbirth at 22 weeks gestational age. Congenital abnormalities were observed in one induced abortion (trisomy 21) and in one of the live-born children (cleft palate) . In total 109 neonates were born from 101 singleton pregnancies and 4 twin pregnancies. In the singleton pregnancies, ten children were born prematurely and ten were born small for gestational age. Screening for myelosuppresion was performed in sixteen neonates (14.7%); two had anemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from 3 Dutch cohort studies on the use of conventional thiopurines in pregnant IBD patients. CONCLUSION: In this large case series the use of thioguanine during pregnancy is not associated in excess with adverse maternal or neonatal outcomes