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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 birth. Methods In this multicentre 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 18 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, one in a stillbirth at 22 weeks of gestational age and one in an induced abortion due to trisomy 21. In total, 109 neonates were born from 101 singleton pregnancies and four twin pregnancies. One child was born with a congenital abnormality [cleft palate]. In the singleton pregnancies, 10 children were born prematurely and 10 were born small for gestational age. Screening for myelosuppresion was performed in 16 neonates [14.7%]; two had anaemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from three 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.

Background & Aims: Most patients with pedunculated T1 colorectal tumors referred for surgery are not found to have lymph node metastases, and were therefore unnecessarily placed at risk for surgery-associated complications. We aimed to identify histologic factors associated with need for surgery in patients with pedunculated T1 colorectal tumors. Methods: We performed a cohort-nested matched case–control study of 708 patients diagnosed with pedunculated T1 colorectal tumors at 13 hospitals in The Netherlands, from January 1, 2000 through December 31, 2014, followed for a median of 44 months (interquartile range, 20–80 months). We identified 37 patients (5.2%) who required surgery (due to lymph node, intramural, or distant metastases). These patients were matched with patients with pedunculated T1 colorectal tumors without a need for surgery (no metastases, controls, n = 111). Blinded pathologists analyzed specimens from each tumor, stained with H&E. We evaluated associations between histologic factors and patient need for surgery using univariable conditional logistic regression analysis. We used multivariable least absolute shrinkage and selection operator (LASSO; an online version of the LASSO model is available at: http://t1crc.com/calculator/) regression to develop models for identification of patients with tumors requiring surgery, and tested the accuracy of our model by projecting our case–control data toward the entire cohort (708 patients). We compared our model with previously developed strategies to identify high-risk tumors: conventional model 1 (based on poor differentiation, lymphovascular invasion, or Haggitt level 4) and conventional model 2 (based on poor differentiation, lymphovascular invasion, Haggitt level 4, or tumor budding). Results: We identified 5 histologic factors that differentiated cases from controls: lymphovascular invasion, Haggitt level 4 invasion, muscularis mucosae type B (incompletely or completely disrupted), poorly differentiated clusters and tumor budding, which identified patients who required surgery with an area under the curve (AUC) value of 0.83 (95% confidence interval, 0.76–0.90). When we used a clinically plausible predicted probability threshold of ≥4.0%, 67.5% (478 of 708) of patients were predicted to not need surgery. This threshold identified patients who required surgery with 83.8% sensitivity (95% confidence interval, 68.0%–93.8%) and 70.3% specificity (95% confidence interval, 60.9%–78.6%). Conventional models 1 and 2 identified patients who required surgery with lower AUC values (AUC, 0.67; 95% CI, 0.60–0.74; P =.002 and AUC, 0.64; 95% CI, 0.58–0.70; P

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.

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

OBJECTIVES: Surveillance of patients with Barrett's esophagus (BE) aims at early detection and treatment of neoplastic changes, particularly esophageal adenocarcinoma (EAC). The histological evaluation of biopsy samples has its limitations, and biomarkers may improve early identification of BE patients at risk for progression to EAC. The aim of this study was to determine the predictive value of p53, Ki67, and aneuploidy as markers of neoplastic progression in BE. METHODS: A total of 27 BE patients with histologically proven progression to high-grade dysplasia (HGD) or EAC (cases) and 27 BE patients without progression (controls) were selected and matched for age, gender, and duration of follow-up. Dysplasia grade was determined in 212 biopsy samples obtained during surveillance endoscopies from cases and in 231 biopsy samples collected from controls. DNA ploidy status was determined by flow cytometry, whereas Ki67 and p53 expression was determined by immunohistochemistry. Hazard ratios (HRs) were calculated by Cox regression adjusted for potentially confounding variables. RESULTS: A univariate analysis showed that low-grade dysplasia (LGD) increased the risk of developing HGD/EAC compared with no dysplasia (HR 3.6; 95 % confidence interval (CI): 1.6-8.1). Aneuploidy (HR 3.5; 95 % CI: 1.3-9.4), strong Ki67 overexpression (HR 5.2; 95 % CI: 1.5-17.6), and moderate p53 overexpression (HR 6.5; 95 % CI: 2.5-17.1) were also associated with an increased risk of developing HGD/EAC, independent of the histological result. A multivariable analysis showed that in the presence of LGD, p53 overexpression, and to a lesser extent, Ki67 overexpression remained important risk factors for neoplastic progression, whereas aneuploidy was no longer predictive. CONCLUSIONS: p53 overexpression and, to a lesser extent, Ki67 overexpression could predict neoplastic progression in BE irrespective of the histological result. These markers may be useful for identifying patients at an increased risk of developing EAC, either alone or used as a panel.

Unless detected at an early stage, esophageal adenocarcinoma (EAC) has a poor prognosis. Changes in cellular DNA content and expression levels of p53 and Ki67 in Barrett esophagus (BE) are associated with the development EAC and might serve as markers to identify EAC at an early stage. The aim of this study was to examine the presence of these three markers in various steps of neoplastic progression in BE towards EAC. Dysplasia was graded in 212 biopsy sets taken during follow-up upper endoscopy in 27 patients in whom ultimately high-grade dysplasia (HGD) or EAC was detected. Ploidy status was determined by flow cytometry, whereas Ki67 and p53 expression were determined by immunohistochemistry. Smoothing splines were used to analyze trends in time. We found an increasing fraction of Ki67 overexpression and, to a lesser extent, abnormal DNA content in biopsies closer to the time-point of detecting HGD/EAC in BE, suggesting the potential value of these biomarkers in identifying patients at increased risk of progression towards HGD/EAC. Accumulation of p53 was seen several years before development of HGD/EAC, and may therefore be an early marker in BE at a stage when dysplasia is not yet detected. A prospective follow-up study is needed to confirm these findings.

Background and study aims In patients with presumed Barrett esophagus we evaluated clinical risk factors that could predict the presence of intestinal metaplasia and dysplasia in biopsies of columnar-lined esophagus (CLE), independently of histological results. Patients and methods In 908 patients with CLE of length > or = 2 cm, data on age, sex, reflux symptoms, tobacco and alcohol use, medication use, and upper gastrointestinal endoscopy findings were prospectively collected. Multivariate logistic regression analysis was performed, and a model for predicting the histological results was developed. Results In 127/908 patients, biopsies of CLE did not contain intestinal metaplasia. Of the 781 patients with intestinal metaplasia, 663 patients (85%) had no dysplasia, and 118 (15%) had low grade dysplasia (LGD). The most important predictors for the presence of intestinal metaplasia were length of CLE, size of hiatal hernia, and male sex, while among those with intestinal metaplasia, age and male sex were most important for the presence of LGD. Multivariate combinations of these predictors yielded reliable models, which were able to discriminate intestinal metaplasia well from no intestinal metaplasia (area under receiver operating characteristic [ROC] curve 0.82), but only reasonably discriminated LGD from no dysplasia (area under ROC 0.65). Conclusions A simple model based on clinical findings can be used to predict the presence of intestinal metaplasia in biopsies from CLE. In contrast, predicting the presence of LGD versus no dysplasia in intestinal metaplasia is more difficult. Predictions from these models may aid decision making on whether a patient with CLE should have surveillance, in view of the known sampling error at endoscopy and interobserver variability at histology.

Barrett esophagus (BE) is caused by chronic gastroesophageal reflux and predisposes to the development of esophageal adenocarcinoma through different grades of dysplasia. Only a subset of BE patients will finally develop esophageal adenocarcinoma. The majority will therefore not benefit from an endoscopic surveillance program, based on the histological identification of dysplasia. Several studies have been performed to find additional biomarkers that can be used to detect the subgroup of patients with an increased risk of developing malignancy in BE. In this review, we will summarize the most promising tissue biomarkers, i.e. proliferation/cell cycle proteins, tumor suppressor genes, adhesion molecules, DNA ploidy status and inflammation associated markers, that can be used for risk stratification in BE, and discuss their respective clinical application.

Background The risk of developing esophageal adenocarcinoma (EAC) for patients with Barrett's esophagus (BE) is approximately 0.5% per year. Objective To investigate how patients with BE estimate and perceive their risk of developing EAC. Design Questionnaire study. Setting Patients with BE who were undergoing surveillance endoscopy based on histologic and flow cytometric results. Patients A total of 192 patients with BE were included. Main Outcome Measurements Individual patients were asked to estimate the numerical risk to develop EAC for patients with BE in general and for themselves. How patients perceived their own risk was measured on a scale from "very small" to "very large." Results At least 1 question was filled out by 169 patients (88% response). Sixty percent of respondents underestimated the numerical risk for patients with BE, in general, to develop EAC, while even more patients (69%) underestimated their own risk. Most respondents perceived their own risk as very small or small (63%). Limitations Risk estimations may depend on the response scale used. Conclusions Most patients with BE underestimated the numerical risk and perceived their risk of developing EAC as (very) low. Despite a low perceived risk, all patients in this group adhered to endoscopic surveillance.

OBJECTIVE: To identify risk factors for esophageal adenocarcinoma (EAC) in patients with Barrett’s esophagus (BE). METHODS: A hospital-based case-control study was performed in which 91 cases with EAC and 244 controls with histologically confirmed BE (>2 cm) with no dysplasia or low-grade dysplasia were included. Information on demographic, anthropometric, and lifestyle characteristics, physical activity levels, working posture, family history, gastroesophageal reflux disease (GERD) symptoms, and medication use was collected by questionnaire. RESULTS: Cases more often were current smokers (odds ratio 3.7, 95% confidence interval 1.4‐9.9), more often had a body mass index >25 assessed at age 20 (2.6, 1.2‐5.5), and more frequently had been working in a stooped posture at age 20 (2.0, 1.1‐3.9), compared to controls. In addition, cases less often experienced symptoms of heartburn (0.3, 0.2‐0.5) and less frequently used proton pump inhibitors (0.1, 0.05‐0.2), compared to controls, whereas use of nonsteroidal anti-inflammatory drugs/aspirin was more common among cases (1.8, 1.1‐3.2). Cases more often were men, compared to controls (91% vs 67%, p < 0.001). CONCLUSION: In patients with BE, the risk of EAC is related to risk factors for GERD, which is, however, asymptomatic. As these risk factors are common in Western countries, they are probably not helpful in individualization of surveillance intervals.