Predicting residual neoplasia after a non-curative gastric ESD: validation and modification of the eCura system in the Western setting: the W-eCura score.

OBJECTIVE: To evaluate the risk factors for lymph node metastasis (LNM) after a non-curative (NC) gastric endoscopic submucosal dissection (ESD) and to validate and eventually refine the eCura scoring system in the Western setting. Also, to assess the rate and risk factors for parietal residual disease. DESIGN: Retrospective multicentre multinational study of prospectively collected registries from 19 Western centres. Patients who had been submitted to surgery or had at least one follow-up endoscopy were included. The eCura system was applied to assess its accuracy in the Western setting, and a modified version was created according to the results (W-eCura score). The discriminative capacities of the eCura and W-eCura scores to predict LNM were assessed and compared. RESULTS: A total of 314 NC gastric ESDs were analysed (72% high-risk resection (HRR); 28% local-risk resection). Among HRR patients submitted to surgery, 25% had parietal disease and 15% had LNM in the surgical specimen. The risk of LNM was significantly different across the eCura groups (areas under the receiver operating characteristic curve (AUC-ROC) of 0.900 (95% CI 0.852 to 0.949)). The AUC-ROC of the W-eCura for LNM (0.916, 95% CI 0.870 to 0.961; p=0.012) was significantly higher compared with the original eCura. Positive vertical margin, lymphatic invasion and younger age were associated with a higher risk of parietal residual lesion in the surgical specimen. CONCLUSION: The eCura scoring system may be applied in Western countries to stratify the risk of LNM after a gastric HRR. A new score is proposed that may further decrease the number of unnecessary surgeries.

Risk of Residual Neoplasia after a Local-Risk Resection of Colorectal Lesions by Endoscopic Submucosal Dissection: A Multinational Study.

Endoscopic submucosal dissection (ESD) in colorectal lesions is demanding, and a significant rate of non-curative procedures is expected. We aimed to assess the rate of residual lesion after a piecemeal ESD resection, or after an en bloc resection but with positive horizontal margins (local-risk resection-LocRR), for colorectal benign neoplasia. A retrospective multicenter analysis of consecutive colorectal ESDs was performed. Patients with LocRR ESDs for the treatment of benign colorectal lesions with at least one follow-up endoscopy were included. A cohort of en bloc resected lesions, with negative margins, was used as the control. A total of 2255 colorectal ESDs were reviewed; 352 of the ESDs were "non-curative". Among them, 209 were LocRR: 133 high-grade dysplasia and 76 low-grade dysplasia. Ten cases were excluded due to missing data. A total of 146 consecutive curative resections were retrieved for comparison. Compared to the "curative group", LocRRs were observed in lengthier procedures, with larger lesions, and in non-granular LSTs. Recurrence was higher in the LocRR group (16/199, 8% vs. 1/146, 0.7%; p = 0.002). However, statistical significance was lost when considering only en bloc resections with positive horizontal margins (p = 0.068). In conclusion, a higher rate of residual lesion was found after a piecemeal ESD resection, but not after an en bloc resection with positive horizontal margins.

Feasibility of Continuous Monitoring of Endoscopy Performance and Adverse Events: A Single-Center Experience.

BACKGROUND: We integrated a standardized questionnaire focusing on adverse events and performance measures in gastrointestinal endoscopy as a mandatory component of the electronical medical record. METHODS: This retrospective study was conducted using prospectively collected data on quality parameters and adverse events (AEPM) for all diagnostic and therapeutic endoscopic procedures at our center between 2018 and 2020. RESULTS: A total of 7532 consecutive endoscopic procedures were performed in 5035 patients. The proportion of high-risk examinations and high-risk patients was 20% and 23%, respectively. Severe adverse events (AEs, n = 21) occurred in 0.3% of procedures and significantly more often in patients with an ASA score > II (0.6%, p < 0.01). We observed no long-term morbidity after severe AEs. Mortality was 0.03% (n = 2). Following screening colonoscopy (n = 242), four endoscopists documented AEPM in more than 98% of the examinations. The cecal intubation rate was 97%, and the mean adenoma detection rate 60%. The quality of lavage was documented in 97% (rated as good in 70% and moderate in 24%). CONCLUSIONS: The risk of adverse events is significantly increased in patients with an ASA score > II, which should be considered when choosing treatment methods and precautionary measures. Continuous recording of AEPM can be effectively integrated into the clinical reporting process, enabling analysis of the data and feedback to be provided to endoscopists.

Risk of residual neoplasia after a noncurative colorectal endoscopic submucosal dissection for malignant lesions: a multinational study.

BACKGROUND : Endoscopic submucosal dissection (ESD) in colorectal lesions is technically demanding and a significant rate of noncurative procedures is expected. We aimed to assess the rate of residual lesions after a noncurative ESD for colorectal cancer (CRC) and to establish predictive scores to be applied in the clinical setting. METHODS : Retrospective multicenter analysis of consecutive colorectal ESDs. Patients with noncurative ESDs performed for the treatment of CRC lesions submitted to complementary surgery or with at least one follow-up endoscopy were included. RESULTS : From 2255 colorectal ESDs, 381 (17 %) were noncurative, and 135 of these were performed in CRC lesions. A residual lesion was observed in 24 patients (18 %). Surgery was performed in 96 patients and 76 (79 %) had no residual lesion in the colorectal wall or in the lymph nodes. The residual lesion rate for sm1 cancers was 0 %, and for > sm1 cancers was also 0 % if no other risk factors were present. Independent risk factors for lymph node metastasis were poor differentiation and lymphatic permeation (NC-Lymph score). Risk factors for the presence of a residual lesion in the wall were piecemeal resection, poor differentiation, and positive/indeterminate vertical margin (NC-Wall score). CONCLUSIONS : Lymphatic permeation or poor differentiation warrant surgery owing to their high risk of lymph node metastasis, mainly in > sm1 cancers. In the remaining cases, en bloc and R0 resections resulted in a low risk of residual lesions in the wall. Our scores can be a useful tool for the management of patients who undergo noncurative colorectal ESDs.

Novel technique of flexible endoscopic therapy of Zenker's diverticulum using a pulsed Holmium laser-a retrospective single-center analysis.

BACKGROUND: In recent years, flexible endoscopic therapy of Zenker's diverticulum seems to become the standard approach. The aim of this study was to assess the safety, efficacy and short-term outcome of flexible endoscopic diverticulotomy of Zenker's diverticulum with a pulsed Holmium laser (PHL). PATIENTS AND METHODS: All patients treated with endoscopic laser-diverticulotomy using a PHL between February 2013 and November 2021 at the University Hospital Salzburg were extracted from our prospectively maintained endoscopic database. Demographic data, size of Zenker's diverticulum, procedure duration, complications, short-term outcome and rate of recurrence were evaluated. RESULTS: In the study period, 45 procedures in 36 patients were performed. Mean depth of the Zenker diverticulum was 21 mm (10-60 mm), mean procedure time was 31 min (15-60 min), intraprocedural adverse events occurred in 2 out of 45 patients (5%) which were both managed endoscopically, post-procedural stenosis occurred in 1 patient (2%). In the follow-up examinations (mean follow-up after 6.4 months), 27 out of 36 patients (75%) were symptom-free, 6 patients (17%) reported an improvement of dysphagia. 3 patients (9%) suffered from persistent dysphagia. After initial symptom relief, a recurrent diverticulum occurred in 5 patients. Endoscopic re-intervention with PHL was done in these cases. CONCLUSIONS: Flexible endoscopic treatment of primary and recurrent Zenker's diverticulum using a PHL is a promising, safe and effective treatment with, in our opinion, technical advantages in comparison to the CO2 laser. Further controlled prospective trials are needed.

New method for real-time visualization and quantitative characterization of early colorectal cancer in endoscopy: a pilot study.

Background and study aims Endoscopic optical diagnosis is crucial to the therapeutic strategy for early gastrointestinal cancer. It accurately (> 85 %) predicts pT category based on microsurface (SP) and vascular patterns (VP). However, interobserver variability is a major problem. We have visualized and digitalized the graded irregularities based on bioinformatically enhanced quantitative endoscopic image analysis (BEE) of high-definition white-light images. Methods In a pilot study of 26 large colorectal lesions (LCLs, mean diameter 39 mm), we retrospectively compared BEE variables with corresponding histopathology of the resected LCLs. Results We included 10 adenomas with low-grade intraepithelial neoplasia (LGIN), nine with high-grade intraepithelial neoplasia (HGIN) and early adenocarcinoma (EAC), and seven deeply submucosal invasive carcinomas. Quantified density (d) and nonuniformity (C U ) of vascular and surface structures correlated with histology (r s d VP: -0.77, r s C U VP: 0.13, r s d SP: -0.76, and r s C U SP: 0.45, respectively). A computed BEE score showed a sensitivity and specificity of 90 % and 100 % in the group with LGINs, 89 % and 41 % in the group with HGINs and EACs, and 100 % and 95 % in the group with deeply invasive carcinoma, respectively. Conclusions In this pilot study, BEE showed promise as a tool for endoscopic characterization of LCLs during routine endoscopy. Prospective clinical studies are needed.

Systematic Review on Optical Diagnosis of Early Gastrointestinal Neoplasia.

BACKGROUND: Meticulous endoscopic characterization of gastrointestinal neoplasias (GN) is crucial to the clinical outcome. Hereby the indication and type of resection (endoscopically, en-bloc or piece-meal, or surgical resection) are determined. By means of established image-enhanced (IEE) and magnification endoscopy (ME) GN can be characterized in terms of malignancy and invasion depth. In this context, the statistical evidence and accuracy of these diagnostic procedures should be elucidated. Here, we present a systematic review of the literature. RESULTS: 21 Studies could be found which met the inclusion criteria. In clinical prospective trials and meta-analyses, the diagnostic accuracy of >90% for characterization of malignant neoplasms could be documented, if ME with IEE was used in squamous cell esophageal cancer, stomach, or colonic GN. CONCLUSIONS: Currently, by means of optical diagnosis, today's gastrointestinal endoscopy is capable of determining the histological subtype, exact lateral spread, and depth of invasion of a lesion. The prerequisites for this are an exact knowledge of the anatomical structures, the endoscopic classifications based on them, and a systematic learning process, which can be supported by training courses. More prospective clinical studies are required, especially in the field of Barrett's esophagus and duodenal neoplasia.

Expression of the microRNA-200 Family, microRNA-205, and Markers of Epithelial-Mesenchymal Transition as Predictors for Endoscopic Submucosal Dissection over Esophagectomy in Esophageal Adenocarcinoma: A Single-Center Experience.

Endoscopic submucosal dissection (ESD) is an effective treatment of early esophageal adenocarcinomas (EACs). The decision of ESD over esophagectomy is based on clinical evaluation of tumor depth and invasion. On a molecular level, tumor invasion is strongly associated with epithelial-to-mesenchymal transition (EMT). Here, we investigated whether localized ESD-resected and surgically resected EAC samples displayed different expression profiles of EMT protein and microRNA markers and whether these different expression profiles were able to retrospectively discriminate localized and surgically resected samples. By doing this, we aimed to evaluate whether preoperative measurement of EMT marker expression might support the decision regarding ESD over surgery. The results showed that ESD-resected samples displayed an epithelial expression profile, i.e., high expression of epithelial protein markers, whereas surgically resected samples displayed high expression of mesenchymal markers. In addition, the anti-EMT microRNA-205 was significantly more expressed in ESD-resected samples, whereas we found no significant differences in the expression levels of microRNA-200 family members. Furthermore, in our retrospective approach, we have demonstrated that measurement of selected EMT markers and microRNA-205 has significant discrimination power to distinguish ESD-resected and surgically resected samples. We suggest that the assessment of EMT status of EAC samples on a molecular level may support clinical evaluation regarding the applicability of ESD.

Pharmacological Inhibition of Class IIA HDACs by LMK-235 in Pancreatic Neuroendocrine Tumor Cells.

Histone deacetylases (HDACs) play a key role in epigenetic mechanisms in health and disease and their dysfunction is implied in several cancer entities. Analysis of expression patterns in pancreatic neuroendocrine tumors (pNETs) indicated HDAC5 to be a potential target for future therapies. As a first step towards a possible treatment, the aim of this study was to evaluate the in vitro cellular and molecular effects of HDAC5 inhibition in pNET cells. Two pNET cell lines, BON-1 and QGP-1, were incubated with different concentrations of the selective class IIA HDAC inhibitor, LMK-235. Effects on cell viability were determined using the resazurin-assay, the caspase-assay, and Annexin-V staining. Western Blot and immunofluorescence microscopy were performed to assess the effects on HDAC5 functionality. LMK-235 lowered overall cell viability by inducing apoptosis in a dose- and time-dependent manner. Furthermore, acetylation of histone-H3 increased with higher LMK-235 concentrations, indicating functional inhibition of HDAC4/5. Immunocytochemical analysis showed that proliferative activity (phosphohistone H3 and Ki-67) decreased at highest concentrations of LMK-235 while chromogranin and somatostatin receptor 2 (SSTR2) expression increased in a dose-dependent manner. HDAC5 expression was found to be largely unaffected by LMK-235. These findings indicate LMK-235 to be a potential therapeutic approach for the development of an effective and selective pNET treatment.

Endoscopic submucosal dissection (ESD) for anal high-grade intraepithelial neoplasia: a case report.

Anal intraepithelial neoplasia (AIN) is a precursor of anal carcinoma. Conventional therapy is based on topical and local ablative approaches. However, the recurrence rates are very high, leading to repetitive treatment sessions and need for long-term surveillance. Endoscopic submucosal dissection (ESD) is an established treatment for malignant early neoplasias of the gastrointestinal tract, especially in the esophagus, stomach, and colorectum. Japanese centers have reported few cases of ESD for early anal carcinoma. We report a case of high-grade AIN diagnosed with magnifying narrow-band imaging and chromoendoscopy that was resected R0 with ESD en bloc.

Single-center implementation of endoscopic submucosal dissection (ESD) in the colorectum: Low recurrence rate after intention-to-treat ESD.

BACKGROUND AND AIM: Colorectal endoscopic submucosal dissection (ESD) shows higher R0 resection and lower local recurrence rates than endoscopic mucosal resection (EMR) in Japan. In Europe, independent learning of ESD in the colorectum is feasible, but yet to be analyzed for curative resection and recurrence rates. METHODS: After experimental training under supervision by Japanese experts (T.O., N.Y.), three endoscopists independently carried out 83 ESD procedures intention-to-treat for lesions in the entire colorectum of 67 patients in a prospective registry (November 2009 to June 2016). RESULTS: ESD was feasible in 80 (96%) colorectal neoplasias (mean diameter 33.6 [± 1.8] mm), and three more required conversion to piecemeal EMR. The lesions were adenomas in 66% with low-grade intraepithelial neoplasia (LGIN), 29% with high-grade intraepithelial neoplasia, and 5% with carcinomas (G2, pT1). ESD had to be facilitated by the final use of snaring (hybrid-ESD, n = 45), especially in the initial learning period. En-bloc resection rate was 85%. Complications were microperforations (7%, conducive to one hemicolectomy), and delayed bleeding (1%) without mortality or long-term morbidity. Residual adenomas with LGIN (5%) after hybrid-ESD did not recur after endoscopic ablation. All malignant neoplasias (34%) were curatively resected without recurrence after a mean follow up of 19.5 (± 3.2) months. CONCLUSIONS: During independent ESD learning in the colorectum, ESD intention-to-treat showed a low recurrence rate after appropriate training, and hybrid-ESD showed acceptable complication and recurrence rates, justifying hybrid-ESD as a strategy for self-completion and rescue.

The histone methyltransferase G9a: a new therapeutic target in biliary tract cancer.

The histone methyltransferase G9a (EHMT2) is a key enzyme for dimethylation of lysine 9 at histone 3 (H3K9me2), a suppressive epigenetic mark. G9a is over-expressed in tumor cells and contributes to cancer aggressiveness. Biliary tract cancer (BTC) is a rare cancer with dismal prognosis due to a lack of effective therapies. Currently, there are no data on the role of G9a in BTC carcinogenesis. We analyzed G9a expression in n=68 BTC patient specimens and correlated the data with clinicopathological and survival data. Moreover, we measured G9a expression in a panel of BTC cell lines and evaluated the cytotoxic effect of G9a inhibition in BTC cells using established small-molecule G9a inhibitors. G9a was considerably expressed in about half of BTC cases and was significantly associated with grading and tumor size. Additionally, we observed significant differences of G9a expression between growth type and tumor localization groups. G9a expression diametrically correlated with Vimentin (positive) and E-Cadherin (negative) expression. Importantly, survival analysis revealed G9a as a significant prognostic factor of poor survival in patients with BTC. In BTC cells, G9a and H3K9me2 were detectable in a cell line-dependent manner on mRNA and/or protein level, respectively. Treatment of BTC cells with established small-molecule G9a inhibitors resulted in reduction of cell viability as well as reduced G9a and H3K9me2 protein levels. The present study strongly suggests that G9a contributes to BTC carcinogenesis and may represent a potential prognostic factor as well as a therapeutic target.

Reduced complication rates of percutaneous transhepatic biliary drainage with ultrasound guidance.

BACKGROUND: We aimed to analyze the benefits of adding ultrasound (US) guidance to the standard fluoroscopically assisted percutaneous transhepatic biliary drainage (F-PTBD). We also performed a systematic literature review of success and complication rates of US-PTBD in a wide field of indications. METHODS: We evaluated a total of 81 US-PTBDs carried out in our institution, 74% of which were part of the management of malignancy. In addition, we compared our results with those of a total of 5,272 procedures (3,779 F-PTBD and 1,493 US-PTBD) reported in the literature. RESULTS: US-PTBD was technically successful in 94% of attempts with a mean of 2.2 needle passes. Procedural success was achieved in 86% of cases. There were no procedure-related deaths or severe complications. Minor complications were catheter dislodgement (15%) as well as one case each of a porto-biliary fistula, hematoma, and biloma. A systematic review of the literature also showed that US-PTBD has a similar technical success rate to F-PTBD but lower median rates of severe early complications (0% versus 8%) and procedural death (0% versus 1%). CONCLUSIONS: Given our results and our review of the literature, US-PTBD is as effective as F-PTBD and has significantly lower complication rates. US-PTBD should be preferred to F-PTBD. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound 45:400-407, 2017.

Metabolomic profiling identifies potential pathways involved in the interaction of iron homeostasis with glucose metabolism.

OBJECTIVE: Elevated serum ferritin has been linked to type 2 diabetes (T2D) and adverse health outcomes in subjects with the Metabolic Syndrome (MetS). As the mechanisms underlying the negative impact of excess iron have so far remained elusive, we aimed to identify potential links between iron homeostasis and metabolic pathways. METHODS: In a cross-sectional study, data were obtained from 163 patients, allocated to one of three groups: (1) lean, healthy controls (n = 53), (2) MetS without hyperferritinemia (n = 54) and (3) MetS with hyperferritinemia (n = 56). An additional phlebotomy study included 29 patients with biopsy-proven iron overload before and after iron removal. A detailed clinical and biochemical characterization was obtained and metabolomic profiling was performed via a targeted metabolomics approach. RESULTS: Subjects with MetS and elevated ferritin had higher fasting glucose (p < 0.001), HbA1c (p = 0.035) and 1 h glucose in oral glucose tolerance test (p = 0.002) compared to MetS subjects without iron overload, whereas other clinical and biochemical features of the MetS were not different. The metabolomic study revealed significant differences between MetS with high and low ferritin in the serum concentrations of sarcosine, citrulline and particularly long-chain phosphatidylcholines. Methionine, glutamate, and long-chain phosphatidylcholines were significantly different before and after phlebotomy (p < 0.05 for all metabolites). CONCLUSIONS: Our data suggest that high serum ferritin concentrations are linked to impaired glucose homeostasis in subjects with the MetS. Iron excess is associated to distinct changes in the serum concentrations of phosphatidylcholine subsets. A pathway involving sarcosine and citrulline also may be involved in iron-induced impairment of glucose metabolism.