No abstract

Large intergenic noncoding RNAs (lincRNA) have been less studied than miRNAs in cancer, although both offer considerable theranostic potential. In this study, we identified frequent upregulation of miR-196a and lincRNA HOTAIR in high-risk gastrointestinal stromal tumors (GIST). Overexpression of miR-196a was associated with high-risk grade, metastasis and poor survival among GIST specimens. miR-196a genes are located within the HOX gene clusters and microarray expression analysis revealed that the HOXC and HOTAIR gene were also coordinately upregulated in GISTs which overexpress miR-196a. In like manner, overexpression of HOTAIR was also strongly associated with high-risk grade and metastasis among GIST specimens. RNA interference-mediated knockdown of HOTAIR altered the expression of reported HOTAIR target genes and suppressed GIST cell invasiveness. These findings reveal concurrent overexpression of HOX genes with noncoding RNAs in human cancer in this setting, revealing miR-196a and HOTAIR as potentially useful biomarkers and therapeutic targets in malignant GISTs.

Altered expression of microRNA (miRNA) is strongly implicated in cancer, and recent studies have shown that the silencing of some miRNAs is associated with CpG island hypermethylation. To identify epigenetically silenced miRNAs in gastric cancer (GC), we screened for miRNAs induced by treatment with 5-aza-2'-deoxycytidine and 4-phenylbutyrate. We found that miR-34b and miR-34c are epigenetically silenced in GC and that their downregulation is associated with hypermethylation of the neighboring CpG island. Methylation of the miR-34b/c CpG island was frequently observed in GC cell lines (13/13, 100%) but not in normal gastric mucosa from Helicobacter pylori-negative healthy individuals. Transfection of a precursor of miR-34b and miR-34c into GC cells induced growth suppression and dramatically changed the gene expression profile. Methylation of miR-34b/c was found in a majority of primary GC specimens (83/118, 70%). Notably, analysis of non-cancerous gastric mucosae from GC patients (n = 109) and healthy individuals (n = 85) revealed that methylation levels are higher in gastric mucosae from patients with multiple GC than in mucosae from patients with single GC (27.3 versus 20.8%; P < 0.001) or mucosae from H. pylori-positive healthy individuals (27.3 versus 20.7%; P < 0.001). These results suggest that miR-34b and miR-34c are novel tumor suppressors frequently silenced by DNA methylation in GC, that methylation of miR-34b/c is involved in an epigenetic field defect and that the methylation might be a predictive marker of GC risk.

Gaps in colonoscopy skills among endoscopists, primarily due to experience, have been identified, and solutions are critically needed. Hence, the development of a real-time robust detection system for colorectal neoplasms is considered to significantly reduce the risk of missed lesions during colonoscopy. Here, we develop an artificial intelligence (AI) system that automatically detects early signs of colorectal cancer during colonoscopy; the AI system shows the sensitivity and specificity are 97.3% (95% confidence interval [CI] = 95.9%–98.4%) and 99.0% (95% CI = 98.6%–99.2%), respectively, and the area under the curve is 0.975 (95% CI = 0.964–0.986) in the validation set. Moreover, the sensitivities are 98.0% (95% CI = 96.6%–98.8%) in the polypoid subgroup and 93.7% (95% CI = 87.6%–96.9%) in the non-polypoid subgroup; To accelerate the detection, tensor metrics in the trained model was decomposed, and the system can predict cancerous regions 21.9 ms/image on average. These findings suggest that the system is sufficient to support endoscopists in the high detection against non-polypoid lesions, which are frequently missed by optical colonoscopy. This AI system can alert endoscopists in real-time to avoid missing abnormalities such as non-polypoid polyps during colonoscopy, improving the early detection of this disease.

Endoscopic submucosal dissection (ESD) is known as a curative treatment for colorectal superficial neoplasms. There is however a need for more long-term clinical data to establish the full advantages of colorectal ESD regarding very low recurrence rates. The aim of this retrospective study was to determine long-term clinical outcomes of colorectal ESD. A total of 423 lesions treated by ESD for colorectal adenoma/dysplasia or adenocarcinoma between 1998 and 2008 at a single high volume referral center were included. We conducted a retrospective survey on patients with follow-up and obtained complete 1-, 3-, and 5-year outcome data for 358 (85 %), 292 (69 %), and 209 (49 %) lesions, respectively. Curative resection was defined when the pathological specimen had carcinoma-free resection margins, irrespective of piecemeal or en bloc resection, without submucosal deep invasion (≥ 1000 µm), lymphovascular involvement, or a poorly differentiated adenocarcinoma component.After a median 4.9 years of follow-up, the 3-year overall cumulative endoscopic recurrence rate and cancerous recurrence rate were 2.9 % (95 % confidence interval [95 %CI] 1.2 - 4.7) and 1.1 % (0 - 2.1), respectively. The 5-year overall cumulative endoscopic recurrence and cancerous recurrence rates were 3.8 % (1.7 - 5.9) and 1.6 % (0.1 - 3.0), respectively. In 361 lesions eligible for endoscopic follow-up, the 3-year endoscopic recurrence and cancerous recurrence rates were 2.4 % (0.8 - 4.1) and 0.4 % (0 - 1.4), respectively. Multivariate analysis revealed that piecemeal resection and submucosal deep tumor invasion were associated with recurrence. The current study demonstrated favorable long-term clinical outcomes of colorectal ESD when en bloc curative resection is achieved.

Interleukin-33 (IL-33) was recently shown to be involved in the inflammatory tumour microenvironment and the progression of colorectal cancer (CRC). We report here that the expression level of sST2, a soluble form of the IL-33 receptor (ST2L), is inversely associated with the malignant growth of CRC. sST2 is downregulated in high-metastatic cells compared with low-metastatic human and mouse CRC cells. Knockdown of sST2 in low-metastatic cells enhances tumour growth, metastasis and tumour angiogenesis, whereas its overexpression in high-metastatic cells suppresses these processes. Circulating and intratumourally administered sST2-Fc fusion protein reduce tumour growth, metastatic spread and tumour angiogenesis in mice bearing high-metastatic CRC. Mechanistically, sST2 suppresses IL-33-induced angiogenesis, Th1- and Th2-responses, macrophage infiltration and macrophage M2a polarization. In conclusion, we show that sST2 negatively regulates tumour growth and the metastatic spread of CRC through modification of the tumour microenvironment. Thus, the IL-33/ST2L axis may be a potential therapeutic target in CRC.

This systematic review aimed to assess the efficacy of the current approach to tissue traction during the endoscopic submucosal dissection (ESD) of superficial esophageal cancer, early gastric cancer, and colorectal neoplasms. We performed a systematic electronic literature search of articles published in PubMed and selected comparative studies to investigate the treatment outcomes of tractionassisted versus conventional ESD. Using the keywords, we retrieved 381 articles, including five eligible articles on the esophagus, 13 on the stomach, and 12 on the colorectum. A total of seven randomized controlled trials and 23 retrospective studies were identified. Clip line traction and submucosal tunneling were effective in reducing the procedural time during esophageal ESD. The efficacy of traction methods in gastric ESD varied in terms of the devices and strategies used depending on the lesion location and degree of submucosal fibrosis. Several prospective and retrospective studies utilized traction devices without the need to reinsert the colonoscope. When pocket creation is included, the traction devices and methods effectively shorten the procedural time during colorectal ESD. Conclusions: Although the efficacy is dependent on the organ and tumor locations, several traction techniques have been demonstrated to be efficacious in facilitating ESD by maintaining satisfactory traction during dissection. (Gut Liver,

Background Magnifying Narrow Band Imaging (NBI) during colonoscopy is a reliable method for differential and depth diagnoses of colorectal lesions. This study examined the diagnostic yield of magnifying NBI based on the Japan NBI Expert Team (JNET) classification in a clinical setting using a large-scale clinical practice database. Types 1, 2A, 2B and 3 correspond to the histopathological classifications of hyperplastic polyp/sessile-serrated polyp, low-grade intramucosal neoplasia, high-grade intramucosal neoplasia/shallow submucosal invasive cancer, and deep submucosal invasive cancer, respectively. Methods The prospective records of colonoscopy reports and pathological data of 1558 consecutive superficial colorectal lesions removed by colonoscopy were retrospectively analysed. After excluding 156 lesions, the documented JNET classifications of the remaining 1402 colorectal lesions were analysed. Diagnostic yield was analysed and also compared between expert endoscopists and nonexpert endoscopists. Results The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were respectively 75%, 96%, 74%, 96% and 93% for type 1; 91%, 70%, 92%, 67% and 87% for type 2A; 42%, 95%, 26%, 98% and 93% for type 2B; and 35%, 100%, 93%, 98% and 98% for type 3. Nonexpert and expert endoscopists alike had specificity, NPV and accuracy >90% for types 1, 2B and 3, and a sensitivity and PPV >90% for type 2A. Type 2B had a low sensitivity of 42% because it included various histological features. Conclusions The JNET classification proved useful in a clinical setting both for expert and nonexpert endoscopists, as was expected from the original JNET definition, but type 2B requires further investigation using pit pattern diagnosis.