Tadateru Maehata

Evaluation of magnifying colonoscopy in the diagnosis of serrated polyps

AIM To elucidate the colonoscopic features of serrated lesions of the colorectum using magnifying colonoscopy. METHODS Broad division of serrated lesions of the colorectum into hyperplastic polyps (HPs), traditional serrated adenomas (TSAs), and sessile serrated adenomas/polyps (SSA/Ps) has been proposed on the basis of recent molecular biological studies. However, few reports have examined the colonoscopic features of these divisions, including magnified colonoscopic findings. This study examined 118 lesions excised in our hospital as suspected serrated lesions after magnified observation between January 2008 and September 2011. Patient characteristics (sex, age), conventional colonoscopic findings (location, size, morphology, color, mucin) and magnified colonoscopic findings (pit pattern diagnosis) were interpreted by five colonoscopists with experience in over 1000 colonoscopies, and were compared with histopathological diagnoses. The pit patterns were categorized according to Kudos classification, but a more detailed investigation was also performed using the subclassification [type II-Open (type II-O), type II-Long (type II-L), or type IV-Serrated (type IV-S)] proposed by Kimura T and Yamano H. RESULTS Lesions comprised 23 HPs (23/118: 19.5%), 39 TSAs (39/118: 33.1%: with cancer in one case), 50 SSA/Ps (50/118: 42.4%: complicated with cancer in three cases), and six others (6/118: 5.1%). We excluded six others, including three regular adenomas, one hamartoma, one inflammatory polyp, and one juvenile polyp for further analysis. Conventional colonoscopy showed that SSA/Ps were characterized as larger in diameter than TSAs and HPs (SSA/P vs HP, 13.62 ± 8.62 mm vs 7.74 ± 3.24 mm, P < 0.001; SSA/Ps vs TSA, 13.62 ± 8.62 mm vs 9.89 ± 5.73 mm, P < 0.01); common in the right side of the colon [HPs, 30.4% (7/23): TSAs, 20.5% (8/39): SSA/P, 84.0% (42/50), P < 0.001]; flat-elevated lesion [HPs, 30.4% (7/23): TSAs, 5.1% (2/39): SSA/Ps, 90.0% (45/50), P < 0.001]; normal-colored or pale imucosa [HPs, 34.8% (8/23): TSAs, 10.3% (4/39): SSA/Ps, 80% (40/50), P < 0.001]; and with large amounts of mucin [HPs, 21.7% (5/23): TSAs, 17.9% (7/39): SSA/Ps, 72.0% (36/50), P < 0.001]. In magnified colonoscopic findings, 17 lesions showed either type II pit pattern alone or partial type II pit pattern as the basic architecture, with 14 HPs (14/17, 70.0%) and 3 SSA/Ps. Magnified colonoscopy showed the type II-O pit pattern as characteristic of SSA/Ps [sensitivity 83.7% (41/49), specificity 85.7% (54/63)]. Cancer was also present in three lesions, in all of which a type VI pit pattern was also present within the same lesion. There were four HPs and four TSAs each. The type IV-S pit pattern was characteristic of TSAs [sensitivity 96.7% (30/31), specificity 89.9% (72/81)]. Cancer was present in one lesion, in which a type VI pit pattern was also present within the same lesion. In our study, serrated lesions of the colorectum also possessed the features described in previous reports of conventional colonoscopic findings. The pit pattern diagnosis using magnifying colonoscopy, particularly magnified colonoscopic findings using subclassifications of surface architecture, reflected the pathological characteristics of SSA/Ps and TSAs, and will be useful for colonoscopic diagnosis. CONCLUSION We suggest that this system could be a good diagnostic tool for SSA/Ps using magnifying colonoscopy.

An updated review of gastric cancer in the next-generation sequencing era: Insights from bench to bedside and vice versa

Gastric cancer (GC) is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. There is an increasing understanding of the roles that genetic and epigenetic alterations play in GCs. Recent studies using next-generation sequencing (NGS) have revealed a number of potential cancer-driving genes in GC. Whole-exome sequencing of GC has identified recurrent somatic mutations in the chromatin remodeling gene ARID1A and alterations in the cell adhesion gene FAT4, a member of the cadherin gene family. Mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) have been found in 47% of GCs. Whole-genome sequencing and whole-transcriptome sequencing analyses have also discovered novel alterations in GC. Recent studies of cancer epigenetics have revealed widespread alterations in genes involved in the epigenetic machinery, such as DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs and microRNAs. Recent advances in molecular research on GC have resulted in the introduction of new diagnostic and therapeutic strategies into clinical settings. The anti-human epidermal growth receptor 2 (HER2) antibody trastuzumab has led to an era of personalized therapy in GC. In addition, ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor (VEGFR)-2, is the first biological treatment that showed survival benefits as a single-agent therapy in patients with advanced GC who progressed after first-line chemotherapy. Using NGS to systematically identify gene alterations in GC is a promising approach with remarkable potential for investigating the pathogenesis of GC and identifying novel therapeutic targets, as well as useful biomarkers. In this review, we will summarize the recent advances in the understanding of the molecular pathogenesis of GC, focusing on the potential use of these genetic and epigenetic alterations as diagnostic biomarkers and novel therapeutic targets.

Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas.

Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal (GI) cancers. In this study, we sought to evaluate the effect of a new tyrosine kinase inhibitor of IGF-IR, NVP-AEW541, on the signal transduction and the progression of GI carcinomas. We assessed the effect of NVP-AEW541 on signal transduction, proliferation, survival, and migration in four GI cancer cells: colorectal adenocarcinoma HT29, pancreatic adenocarcinoma BxPC3, esophageal squamous cell carcinoma TE1, and hepatoma PLC/PRF/5. The effects of NVP-AEW541 alone and with chemotherapy were studied in vitro and in nude mouse xenografts. We also analyzed the effects of NVP-AEW541 on insulin signals and hybrid receptor formation between IGF-IR and insulin receptor. NVP-AEW541 blocked autophosphorylation of IGF-IR and both Akt and extracellular signal-regulated kinase activation by IGF but not by insulin. NVP-AEW541 suppressed proliferation and tumorigenicity in vitro in a dose-dependent manner in all cell lines. The drug inhibited tumor as a single agent and, when combined with stressors, up-regulated apoptosis in a dose-dependent fashion and inhibited mobility. NVP-AEW541 augmented the effects of chemotherapy on in vitro growth and induction of apoptosis. Moreover, the combination of NVP-AEW541 and chemotherapy was highly effective against tumors in mice. This compound did not influence hybrid receptor formation. Thus, NVP-AEW541 may have significant therapeutic utility in human GI carcinomas both alone and in combination with chemotherapy. [Mol Cancer Ther 2008;7(6):1483–93]

Hypermethylation of Sox17 gene is useful as a molecular diagnostic application in early gastric cancer

Although minimal invasive treatment is widely accepted in the early stages of gastric cancer (GCa), we still do not have any appropriate risk markers to detect residual neoplasia and the potential for recurrence. We previously reported that aberrant DNA methylation is an early and frequent process in gastric carcinogenesis and could be useful for the detection of gastric neoplasia. Our goal is to find and identify some candidate genes, using genome-wide DNA methylation analysis, as a treatment marker for early gastric cancer (EGC). We performed methylated CpG island amplification microarray analysis using 12 gastric washes (six each of pre- and post-endoscopic treatment in each of the same patients). We finally focused on Sox17 gene. We examined the DNA methylation status of Sox17 in a validation set consisting of 128 wash samples (pre, 64; post, 64) at EGC. We next carried out functional studies to identify Sox17. Sox17 showed significant differential methylation between pre- and post-treatments in EGC patients (Sox17, p < 0.0001). Moreover, treating GCa cells that lacked Sox17 expression with a methyltransferase inhibitor, 5-aza-2′-deoxycytidine, restored the gene’s expression. Additionally, the introduction of exogenous Sox17 into silenced cells suppressed colony formation. Gastric wash-based DNA methylation analysis could be useful for early detection of recurrence following endoscopic resection in EGC patients. Our data suggest that the silencing of Sox17 occurs frequently in EGC and may play a key role in the development and progression of the disease.

Safer endoscopic gastric mucosal resection: preoperative proton pump inhibitor administration.

Background and Aim:  Control of bleeding is crucial in improving the safety of endoscopic mucosal resection (EMR), and intragastric acidity has a great impact on hemostasis and blood coagulation. Proton pump inhibitors (PPI) are potent suppressors of gastric acid; however, PPI need to be continuously administered orally for several days, and thus initial effects may be insufficient if PPI is only administered immediately after EMR. The aim of this study was to determine whether preoperative administration of PPI prior to EMR can elevate intragastric acidity, facilitate better control of intraoperative bleeding (complete coagulation and hemostasis), prevent postoperative bleeding, and facilitate healing of artificial ulcers.

Gastric Wash-Based Molecular Testing for Antibiotic Resistance in Helicobacter pylori

Background: A number of noninvasive tests have been developed to establish the presence of Helicobacter pylori infection. However, thus far these tests have only been capable of detecting its presence. An increasing number of antibiotic-resistant H. pylori infections have been reported and they are known to be correlated with 23S rRNA single nucleotide polymorphisms (SNPs). We hypothesized that genomic analysis of H. pylori recovered from gastric washes could not only be less invasive, but also useful as a screening test and for assessing the outcome of eradication therapy. Methods: Biopsy specimens and gastric washes were collected from 100 patients during endoscopic examination. Then we analyzed 23S rRNA, ureA, and cagA genes using PCR and high-throughput pyrosequencing analysis. Results: Forty-five percent (44/97) of patients tested positive for ureA and 42.3% (41/97) tested positive by a rapid urease test. One hundred percent (35/35) of patients who tested positive by both methods were observed to have the cagA gene. Among these 35 patients, 23S rRNA SNPs were present in 34.3% (12/35). Conclusions: Gastric wash-based PCR and a pyrosequencing assay were used to rapidly detect and estimate the number of 23S rRNA SNPs in clinical isolates of H. pylori. Not only is this a less invasive technique, but it can also diagnose drug resistance.

Correlation of laterally spreading type and JC virus with methylator phenotype status in colorectal adenoma

Accurate frequencies of CpG island methylator phenotype (CIMP) have not been determined for laterally spreading tumors (LSTs) and other flat-type colorectal adenomas, and the role of JC virus T-antigen (T-Ag) in these tumors is unclear. We used MethyLight assay to analyze the relationship between CIMP status and clinicopathologic characteristics in tissue from 72 LST of granular-type (LST-G), 35 LST of nongranular-type (LST-NG), 54 protruded-type adenomas, and 89 colorectal cancers. We also investigated the relationship between CIMP status and T-Ag by immunohistochemistry. With the use of 5 markers for CIMP status, tumors were classified as CIMP-high (> or = 4/5 methylated promoters), CIMP-low (1/5 to 3/5 methylated promoters), or CIMP-0 (no methylated promoters). The proportion classified as CIMP-0 status was 5.6% for protruded-type adenoma, 17.1% for LST-NG, and 29.2% for LST-G (LST-G versus protruded-type adenoma, P = .001). CIMP-low status was established for 62.5% of LST-G, 74.3% of LST-NG, and 81.5% of protruded-type adenomas. CIMP-high status was established for 8.3% of LST-G, 8.6% of LST-NG, and 12.9% of protruded-type adenomas. The proportions of CIMP-low and CIMP-high status were not significantly different between the 3 groups. Multiple logistic analysis showed that LST-G appearance was the only significant factor for identifying CIMP-0 status. BRAF mutation was the only significant factor for identifying CIMP-high status. T-Ag expression increased with CIMP status and was not associated with macroscopic appearance. In conclusion, among colorectal adenomas, CIMP-high status was determined by BRAF mutation and not by macroscopic type, unlike CIMP-0. JC virus T-Ag may be important in determining methylator phenotype.

Accuracy of biopsy for the preoperative diagnosis of superficial nonampullary duodenal adenocarcinoma

BACKGROUND AND AIMS Endoscopic biopsy sampling for the diagnosis of duodenal adenocarcinoma is not perfect. We investigated the accuracy of biopsy specimen diagnoses of superficial nonampullary duodenal epithelial tumors (NADETs). METHODS Clinicopathologic data were retrospectively reviewed for 95 superficial NADETs from 95 patients who underwent endoscopic resection. Preoperative diagnoses based on biopsy specimens were compared with histologic diagnoses of resected specimens. RESULTS Among the 21 lesions with biopsy specimen diagnoses of carcinoma, 12 (57.1%) were histologically diagnosed as adenomas after resection. Among the 74 lesions with biopsy specimen diagnoses of adenoma, 15 (20.3%) were histologically diagnosed as carcinomas after resection. The duodenal biopsy specimen predicted final histologic diagnoses of carcinoma with a sensitivity of 37.5% (95% CI, 18.8-59.4), specificity of 83.1% (95% CI, 72.3-91.0), accuracy of 71.6% (95% CI, 61.4-80.4), positive predictive value of 42.9% (95% CI, 21.8-66.0), and negative predictive value of 79.7% (95% CI, 68.8-88.2). Among 61 cases considered suitable for EMR, treatment modality was converted from EMR to endoscopic submucosal dissection because of the nonlifting sign in 15 cases (24.6%). CONCLUSIONS The accuracy of duodenal biopsy sampling was relatively low. Duodenal biopsy sampling may induce unexpected fibrosis. New endoscopic modalities that can improve preoperative diagnosis yield of NADETs are eagerly awaited.

Urgent computed tomography for determining the optimal timing of colonoscopy in patients with acute lower gastrointestinal bleeding.

OBJECTIVE We evaluated the diagnostic performance of computed tomography (CT) as an initial radiologic test for assessing the optimal timing of colonoscopy in patients with acute lower gastrointestinal bleeding (LGIB) and investigated the effectiveness of contrast-enhanced (CE) CT for detecting colonic diverticular bleeding. METHODS This was a retrospective study of 1,604 consecutive patients who visited or were referred to St. Marianna University Hospital due to acute LGIB and underwent colonoscopy within three months after presentation between September 2004 and December 2012. The clinicopathological data of the subjects were obtained from their medical records. RESULTS Among the 1,604 patients presenting with LGIB, 879 (55%) underwent a CT scan. Elective colonoscopy was considered in cases in which typical colonic wall thickening was observed on CT, suggesting colonic inflammation or malignancy (239 patients; 27%). The diagnoses in the elective cases included ischemic colitis (38%), infectious colitis (8%), inflammatory bowel disease (8%) and malignancy (5%). Urgent colonoscopy was performed after the CT examination in 640 cases (73%). The most common presumptive CT diagnosis was diverticulum (402/640; 63%). Of the 638 patients who underwent CE-CT, diverticula were observed in 346 cases, including 104 cases of extravasation indicating ongoing diverticular bleeding. Among these 104 patients, the site of bleeding was identified in 71 subjects (68%) during colonoscopy. The rate of detection of the bleeding source on colonoscopy was significantly higher in the patients with extravasation on CE-CT than in those without extravasation on CE-CT (68% vs. 20%, respectively; p<0.001). CONCLUSION Urgent CT is useful for determining the optimal timing of colonoscopy in cases of acute LGIB. CE-CT may be used to depict the presence and location of active hemorrhage and provides useful information for subsequent colonoscopy, especially in patients with diverticular bleeding.

Gastrointestinal stromal tumor presenting with prominent calcification

We present a rare case of a gastrointestinal stromal tumor (GIST) in the stomach with prominent calcification at presentation. A 61-year-old woman visited our hospital because of epigastric discomfort. A spherical calcified lesion with a diameter of about 30 mm was incidentally shown in the left upper quadrant on an abdominal X-ray. Computed tomography demonstrated that the tumor was growing from the upper gastric body, with calcification in the peripheral ring area. A laparoscopic partial gastrectomy was performed, and the resected specimen revealed a well-circumscribed tumor with exophytic growth from the gastric muscularis propria. Microscopic examination revealed spindle-shaped tumor cells with calcification and hemorrhage. Additionally, positive immunoreactivity of the tumor to KIT and CD34 and a low mitotic index resulted in the diagnosis of very low risk GIST. There are a few case reports of heavily calcified GIST, although solitary or punctate calcification of primary GIST has been reported in several case series. Dystrophic calcification of necrotic or degenerative tissue is the supposed cause of primary calcified GISTs. In contrast, appearance of calcification after administration of imatinib mesylate, which may be one indicator of disease response, is possibly caused by a different mechanism.