Factors associated with reclassification of hyperplastic polyps after pathological reassessment from screening and surveillance colonoscopies.

INTRODUCTION: A substantial interobserver variation in the differential diagnosis of hyperplastic polyps (HPs) and sessile or traditional serrated adenomas (SSAs/TSAs) has been described. METHODS: The aim of this study is to determine the magnitude of reclassification of HPs and associated factors after pathological reassessment of specimens from screening and surveillance colonoscopies, and to estimate its consequences for follow-up recommendations. RESULTS: Among 1694 screening and surveillance colonoscopies, a total of 536 polyps were initially diagnosed as HPs and remained unchanged in 88.5% (n = 474), whereas 7.6 (n = 41) and 1.1% (n = 6) were reclassified as SSA and TSA, respectively. Compared to definite HPs, SSAs were found more frequently in men than in women (82.9 vs. 61.2%, p < 0.05), and in individuals ≥65.0 years (51.2 vs. 31.6%, p = 0.05). Also, more SSAs were >5 mm in size (36.6 vs. 6.3%, p < 0.05) and were localized in the proximal colon (31.7 vs. 11.8%, p < 0.05). In a mixed model analysis, age ≥65.0 years (OR 4.13, 95% CI 1.22-14.2), snare polypectomy (OR 23.6, 95% CI 4.86-115), and coincident advanced adenomas (OR 7.56, 95% CI 1.31-43.5) were significantly (p < 0.05) associated with reclassification to SSAs. Only 0.53% of patients had received false recommendations for follow-up visits based on the incorrect HP diagnosis. A c.1799T>A, p.V600E BRAF mutation was detected in 21.9 % (n = 9) of reclassified SSAs. CONCLUSION: Considering these factors may be helpful in serrated lesions that are difficult to allocate. Incorrect recommendations regarding control colonoscopy intervals due to misdiagnosed HPs can explain only a small fraction of interval colorectal cancers.

Patient- and procedure-related factors affecting proximal and distal detection rates for polyps and adenomas: results from 1603 screening colonoscopies.

BACKGROUND: Screening colonoscopy is less effective in reducing the incidence of proximal compared to distal colorectal cancer, presumably because of missed adenomas and advanced lesions during endoscopy. Thus, effectiveness and success of colorectal cancer (CRC) screening programs depend decisively on the quality of the endoscopic procedures. METHODS: A retrospective analysis of 1603 average risk screening colonoscopies to calculate and to identify determinants of separate detection rates for proximally and distally located polyps, adenomas, and advanced adenomas was performed. RESULTS: 56.1 % of 1603 individuals included were men, and the mean age was 60.2 ± 10.2 years. Distal detection rates were markedly higher compared to proximal detection rates for polyps (40.9 vs. 23.8 %), adenomas (21.3 vs. 16.2 %), and advanced adenomas (4.0 vs. 2.0 %). A gradual increase in detection rates with increasing age was found for proximal and distal localization. Gender difference was also seen for polyps and adenomas, but not for advanced adenomas. In multivariate analysis, age <65.0 years and female gender were independently associated with a lower separate polyp detection rate (PDR) and adenoma detection rate (ADR). The use of propofol was the only procedure-related variable significantly associated with higher polyp detection rate. CONCLUSION: Since age and gender affect detection rates of proximally and distally located polyps and adenomas, the requirement of a specific gender-related limit in total detection rates may be insufficient as a quality indicator for screening colonoscopies.

Outcome of transarterial radioembolization in patients with hepatocellular carcinoma as a first-line interventional therapy and after a previous transarterial chemoembolization.

Purpose: Due to a lack of data, there is an ongoing debate regarding the optimal frontline interventional therapy for unresectable hepatocellular carcinoma (HCC). The aim of the study is to compare the results of transarterial radioembolization (TARE) as the first-line therapy and as a subsequent therapy following prior transarterial chemoembolization (TACE) in these patients. Methods: A total of 83 patients were evaluated, with 38 patients having undergone at least one TACE session prior to TARE [27 male; mean age 67.2 years; 68.4% stage Barcelona clinic liver cancer (BCLC) B, 31.6% BCLC C]; 45 patients underwent primary TARE (33 male; mean age 69.9 years; 40% BCLC B, 58% BCLC C). Clinical [age, gender, BCLC stage, activity in gigabecquerel (GBq), Child-Pugh status, portal vein thrombosis, tumor volume] and procedural [overall survival (OS), local tumor control (LTC), and progression-free survival (PFS)] data were compared. A regression analysis was performed to evaluate OS, LTC, and PFS. Results: No differences were found in OS (95% CI: 1.12, P = 0.289), LTC (95% CI: 0.003, P = 0.95), and PFS (95% CI: 0.4, P = 0.525). The regression analysis revealed a relationship between Child-Pugh score (P = 0.005), size of HCC lesions (>10 cm) (P = 0.022), and OS; neither prior TACE (Child-Pugh B patients; 95% CI: 0.120, P = 0.729) nor number of lesions (>10; 95% CI: 2.930, P = 0.087) correlated with OS. Conclusion: Prior TACE does not affect the outcome of TARE in unresectable HCC.

First evaluation of Neighbor of Punc E11 (NOPE) as a novel marker in human hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide and the search for clinically useful biomarkers is ongoing. Neighbor of Punc E11 (NOPE) is an established biomarker of murine HCC that remains undetectable in normal liver and at preneoplastic stages. OBJECTIVE: The aim of our study was to evaluate the presence of NOPE in human HCC. METHODS: Histologically confirmed HCC and corresponding non-tumor liver samples from 20 patients were analyzed for expression of NOPE using qRT-PCR and mRNA-in-situ technology in a conserved tissue context. RESULTS: In our cohort, 30% of HCC samples were expressing NOPE which proved particularly useful in non-cirrhotic HCC samples with up to 155-fold higher expression than in adult liver. Using mRNA-in-situ technology, NOPE was clearly identified within epithelial tumor cells of NOPE positive human HCCs. In our analyzed cohort, the combination of AFP with NOPE did not reach more than 40% sensitivity while GPC-3 and NOPE were complementary to each other reaching a combined sensitivity of 85.7%. CONCLUSIONS: This is the first characterization of NOPE as a potential biomarker for human HCC. Our results underline the value of NOPE as a complementing biomarker for human HCC.

Copy-number variation and protein expression of DOT1L in pancreatic adenocarcinoma as a potential drug target.

Adenocarcinoma of the pancreas has a poor prognosis. At present, no relevant personalized targets have been identified. Sequencing studies have implicated gene alterations of disruptor of telomeric silencing 1 like histone lysine methyltransferase (DOT1L) in pancreatic adenocarcinoma. DOT1L is part of the histone modification system and catalyzes methylation of H3K79, which is crucial in cell signaling and DNA damage repair. DOT1L is considered to be a target of therapy in mixed lineage leukemia gene-deficient leukemia cases and a potential target in breast carcinoma. The frequencies and importance of DOT1L copy-number variations and their specific correlation with protein expression in adenocarcinoma of the pancreas have yet to be investigated. In the present study, tissue microarrays of 230 resected pancreatic adenocarcinoma cases were constructed. The tumor tissue was analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry. In total, 10/225 carcinoma cases (4.4%) analyzed by immunohistochemistry demonstrated intense nuclear protein expression of DOT1L and in 9/224 tumors analyzed using FISH (4.0%), copy-number variations (CNV) were detectable. No DOT1L amplification was detected in the carcinoma cohort. To the best of our knowledge, the present study describes for the first time the frequency of CNV of DOT1L using the gold standard fluorescence in situ hybridization (FISH) and their specific correlation to the protein expression in adenocarcinomas of the pancreas. Although the positive cases by immunohistochemistry and copy-number variations by FISH were not congruent with each other, the data suggest a potential role for DOT1L in a small subset of pancreatic cancer cases. The significance of the two analysis methods concerning their druggability in pancreatic adenocarcinoma requires further studies.

Somatic BRCA1-associated protein 1 (BAP1) loss is an early and rare event in esophageal adenocarcinoma.

Esophageal cancer is the eighth most common malignant tumor worldwide, and the number of incidences of esophageal adenocarcinoma is increasing in the Western world. Despite improvements in perioperative treatment, the overall survival rate of patients with esophageal adenocarcinoma remains poor. Breast cancer type 1 susceptibility protein (BRCA1)-associated protein (BAP1) is located on chromosome 3p21, and it is an enzyme with ubiquitin carboxyl hydrolase activity that regulates cell growth. It interacts with BRCA1, and the nuclear localization of BAP1 is required for its tumor suppressor function. BAP1 is frequently mutated in uveal melanomas, malignant mesothelioma and several carcinomas, including a subtype of renal cell carcinoma, intrahepatic cholangiocarcinoma and squamous cell carcinoma of the esophagus. Furthermore, several germline-associated mutations of tumors have been described (BAP1 hereditary cancer syndrome). However, the importance and frequency of BAP1 alterations in adenocarcinoma of the esophagus remain to be elucidated. In the present study, tissue microarrays of 332 resected adenocarcinomas (including a few cases of concomitant Barrett dysplasia) of the esophagus were constructed. The tumor tissue was analyzed using immunohistochemistry to investigate the levels of BAP1 expression. Fibroblasts or inflammatory cells served as an internal positive control. Three adenocarcinomas revealed nuclear loss of BAP1 (0.9%). One case with concomitant Barrett dysplasia also exhibited a loss of BAP1. Of the resected adenocarcinomas, 329 of them exhibited an intact and uniform strong nuclear staining pattern. To the best of our knowledge, this is the first description of BAP1 deficiency in adenocarcinomas of the esophagus. Furthermore, it has been demonstrated that BAP1 loss is possibly an early event in esophageal adenocarcinoma. These results warrant further functional and clinical evaluation.

A Novel Easy-to-Use Prediction Scheme for Upper Gastrointestinal Bleeding: Cologne-WATCH (C-WATCH) Risk Score.

Acute upper gastrointestinal bleeding (UGIB) is the leading indication for emergency endoscopy. Scoring schemes have been developed for immediate risk stratification. However, most of these scores include endoscopic findings and are based on data from patients with nonvariceal bleeding. The aim of our study was to design a pre-endoscopic score for acute UGIB--including variceal bleeding--in order to identify high-risk patients requiring urgent clinical management. The scoring system was developed using a data set consisting of 586 patients with acute UGIB. These patients were identified from the emergency department as well as all inpatient services at the University Hospital of Cologne within a 2-year period (01/2007-12/2008). Further data from a cohort of 322 patients who presented to our endoscopy unit with acute UGIB in 2009 served for external/temporal validation.Clinical, laboratory, and endoscopic parameters, as well as further data on medical history and medication were retrospectively collected from the electronic clinical documentation system. A multivariable logistic regression was fitted to the development set to obtain a risk score using recurrent bleeding, need for intervention (angiography, surgery), or death within 30 days as a composite endpoint. Finally, the obtained risk score was evaluated on the validation set. Only C-reactive protein, white blood cells, alanine-aminotransferase, thrombocytes, creatinine, and hemoglobin were identified as significant predictors for the composite endpoint. Based on the regression coefficients of these variables, an easy-to-use point scoring scheme (C-WATCH) was derived to estimate the risk of complications from 3% to 86% with an area under the curve (AUC) of 0.723 in the development set and 0.704 in the validation set. In the validation set, no patient in the identified low-risk group (0-1 points), but 38.7% of patients in the high-risk group (≥ 2 points) reached the composite endpoint. Our easy-to-use scoring scheme is able to distinguish high-risk patients requiring urgent endoscopy, from low-risk cases who are suitable candidates for outpatient management or in whom endoscopy may be postponed. Based on our findings, a prospective validation of the C-WATCH score in different patient populations outside the university hospital setting seems warranted.