Polypoid Adenomas Research Articles

The frequency of dysplastic branching crypts in colorectal polypoid tubular adenomas.

Dysplastic crypt branching (DCB) was recently found in ulcerative colitis-associated dysplasia. The aim was to assess the frequency and the branching phenotype of DCB in polypoid colorectal tubular adenomas (TA). A total of 3956 DCB were found in the 139 TA: 98% were in asymmetric branching (DCAB) and the remaining 2% in symmetric branching (DCSB). A linear correlation was found between DCB frequency and the increasing digital size in TA (p < .05). Using a digital ruler, adenomas were divided into small TA (<5 mm) and larger TA (≥5 mm). The difference between the frequency of DCB in small TA (n=75) vs. larger TA (n=64), was significant (p < .05). DCB frequency was not influenced by age, gender or TA localization. In the normal colorectal mucosa (≈2 m2 ), only occasional CSB is found and no CAB. And yet, multiple DCB (mean 16.7 DCB), mostly DCAB, was found in small TA, occupying <5 mm of the mucosal area. In larger TA, as many as 42.1 DCB (mean), mostly DCAB, occurred in merely 7.8 mm (mean) of the colon mucosa. Thus it is suggestedthat DCB is a standard histologic element of TA. The natural expansion of the adenomatous tissue in larger TA appears to be follow on from newly produced, mostly DCAB, by DCSB and by the accumulation of their dysplastic offspring's progenies. The findings strongly suggest that DCB is a central microstructure in the histological events unfolding in polypoid colorectal TA.

Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer

Colorectal cancer (CRC) worldwide affects over a quarter of a million people each year. Most sporadic CRCs develop through formation of polypoid adenomas and are preceded by intramucosal carcinoma (Stage 0), which can progress into malignant forms. Detection of early cancers and their endoscopic removal are priorities for cancer control. Human gut microbiome has been associated to CRC development, and its comprehensive characterization is of a great importance to assess its potential as a diagnostic marker. We performed whole shotgun metagenomic sequencing and CE-TOFMS-based metabolomic studies on fecal samples collected from 616 participants undergoing colonoscopy to assess taxonomic and functional characteristics of gut microbiota and metabolites. As a result, microbiome and metabolite shifts were apparent in cases of multiple polypoid adenomas (MP) and Stage 0, in addition to more advanced lesions (Stage I/II and Stage III/IV). Two distinct patterns of microbiome elevations were found (P&lt;0.005). First, CRC-associated species including Fusobacterium nucleatum were elevated continuously from Stage 0 to more advanced stages. Second, Atopobium parvulum and Actinomyces odontolyticus, which co-occurred in Stage 0, were elevated only in MP and/or in Stage 0. Metabolome analyses showed elevation of branched-chain amino acids and phenylalanine in Stage 0 and bile acids including deoxycholate in MP and/or Stage 0. Metagenomic functional analyses showed amino acid metabolism and sulfide producing pathways were associated with CRCs. Our study indicates possible etiological and diagnostic significance of fecal microbiota and metabolite in the very early stages of CRC (Yachida et al., Nature Medicine 2019).

Two intertwined compartments coexisting in sporadic conventional colon adenomas.

Sporadic conventional colon adenomas are microscopically built of 2 intertwined compartments: one on top, harboring the dysplastic tissue that defines their histo-biomolecular attributes, and the other below, composed of non-dysplastic crypts with corrupted shapes (CCS). The CCS of 306 colon adenomas revealed asymmetric, haphazardly-distributed proliferating cell-domains (PC). In contrast, the PC-domains in normal controls were symmetric, being limited to the lower thirds of the crypts. In 28% out of 501 sporadic conventional adenomas, foci of p53-upregulated dysplastic tissue were found. The CCS in 30% of 108 sporadic adenomas showed p53-upregulated single cells, suggesting mounting somatic mutations. No p53-upregulated cells were found in the crypts of controls. In polypoid adenomas, the mucosa of the stalk without dysplastic tissue on top disclosed CCS with asymmetrical PC-domains and single p53-upregulated cells. The latter observations suggested that CCS had developed prior to and not after the growth of the dysplastic tissue on top. CCS were also found below colon adenomas in carcinogen-treated rats. It is concluded that the 2 intertwined histo-biological compartments of sporadic conventional colon adenomas are probably interdependent components. These findings may open new directions aimed to uncover the link between the normal colonic mucosa and the histogenesis of, conventional adenomas.

Significance of the gut microbiome in multistep colorectal carcinogenesis.

Colorectal cancer (CRC) is highly prevalent worldwide. In 2018, there were over 1.8 million new cases. Most sporadic CRC develop from polypoid adenomas and are preceded by intramucosal carcinoma (stage 0), which can progress into more malignant forms. This developmental process is known as the adenoma‐carcinoma sequence. Early detection and endoscopic removal are crucial for CRC management. Accumulating evidence suggests that the gut microbiota is associated with CRC development in humans. Comprehensive characterization of this microbiota is of great importance to assess its potential as a diagnostic marker in the very early stages of CRC. In this review, we summarized recent studies on CRC‐associated bacteria and their carcinogenic mechanisms in animal models, human cell lines and human cohorts. High‐throughput technologies have facilitated the identification of CRC‐associated bacteria in human samples. We have presented our metagenome and metabolome studies on fecal samples collected from a large Japanese cohort that revealed stage‐specific phenotypes of the microbiota in CRC. Furthermore, we have discussed the potential carcinogenic mechanisms of the gut microbiota, from which we can infer whether changes in the gut microbiota are a cause or effect in the multi‐step process of CRC carcinogenesis.

Integrated Imaging Methodology Detects Claudin-1 Expression in Premalignant Nonpolypoid and Polypoid Colonic Epithelium in Mice.

OBJECTIVES:Conventional colonoscopy with white light illumination detects colonic adenomas based on structural changes alone and is limited by a high miss rate. We aim to demonstrate an integrated imaging strategy that combines wide-field endoscopy and confocal endomicroscopy in real time to visualize molecular expression patterns in vivo to detect premalignant colonic mucosa.METHODS:A peptide specific for claudin-1 is labeled with Cy5.5 and administrated intravenously in genetically engineered mice that develop adenomas spontaneously in the distal colon. Wide-field endoscopy is used to identify the presence of nonpolypoid and polypoid adenomas. Anatomic landmarks are used to guide placement of a confocal endomicroscope with side-view optics to visualize claudin-1 expression patterns with subcellular resolution.RESULTS:Wide-field fluorescence images show peak uptake in colon adenoma at ∼1 hour after systemic peptide administration, and lesion margins are clearly defined. Further examination of the lesion using a confocal endomicroscope shows dysplastic crypts with large size, elongated shape, distorted architecture, and variable dimension compared with normal. The mean fluorescence intensity is significantly higher for dysplasia than normal. Increased claudin-1 expression in dysplasia vs normal is confirmed ex vivo, and the binding pattern is consistent with the in vivo imaging results.DISCUSSION:Wide-field endoscopy can visualize molecular expression of claudin-1 in vivo to localize premalignant colonic mucosa, and confocal endomicroscopy can identify subcellular feature to distinguish dysplasia from normal.

Impact of linked-color imaging on colorectal adenoma detection

Linked-color imaging (LCI) is a new technology that emphasizes changes in mucosal color by providing clearer and brighter images, thus allowing red and white areas to be visualized more clearly. We investigated whether LCI increases the detection of colorectal adenomas compared with white-light imaging (WLI) and blue-laser imaging (BLI)-bright. Consecutive patients undergoing colonoscopy were randomized (1:1:1) into examination by WLI, BLI-bright, or LCI during withdrawal of the colonoscope. The adenoma detection rate (ADR), mean number of adenomas per patient, and withdrawal time were evaluated. The lesions were evaluated according to size, morphology, location, and histology. A total of 379 patients were randomized, and 412 adenomas were detected. The ADR was 43.2%, 54.0%, and 56.9% for WLI, BLI-bright, and LCI, respectively, and was significantly higher in the LCI group than in the WLI group (P= .03). No significant difference was observed between LCI and BLI-bright (P= .71) or BLI-bright and WLI (P= .09). The mean number of adenomas per patient was 0.82, 1.06, and 1.38 for WLI, BLI-bright, and LCI, respectively, with a significant difference between LCI and WLI (P= .03). Withdrawal time did not differ among the groups. A total of 102 adenomas were detected by WLI, 131 by BLI-bright, and 179 by LCI. LCI provided a higher rate of detection of adenomas≤5mm in size than WLI (P= .02), with a borderline significance for a higher detection of sessile serrated adenomas (P= .05). Nonpolypoid adenomas were more commonly located in the right colon segment and polypoid adenomas in the left colon segment, with a significant difference only between BLI-bright (P< .01) and LCI (P= .03). Our findings show that LCI increases the detection of colorectal adenomas during colonoscopy. (Clinical trial registration number: RBR-9xg6dx.).

Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer.

In most cases of sporadic colorectal cancers, tumorigenesis is a multistep process, involving genomic alterations in parallel with morphologic changes. In addition, accumulating evidence suggests that the human gut microbiome is linked to the development of colorectal cancer. Here we performed fecal metagenomic and metabolomic studies on samples from a large cohort of 616 participants who underwent colonoscopy to assess taxonomic and functional characteristics of gut microbiota and metabolites. Microbiome and metabolome shifts were apparent in cases of multiple polypoid adenomas and intramucosal carcinomas, in addition to more advanced lesions. We found two distinct patterns of microbiome elevations. First, the relative abundance of Fusobacterium nucleatum spp. was significantly (P < 0.005) elevated continuously from intramucosal carcinoma to more advanced stages. Second, Atopobium parvulum and Actinomyces odontolyticus, which co-occurred in intramucosal carcinomas, were significantly (P < 0.005) increased only in multiple polypoid adenomas and/or intramucosal carcinomas. Metabolome analyses showed that branched-chain amino acids and phenylalanine were significantly (P < 0.005) increased in intramucosal carcinomas and bile acids, including deoxycholate, were significantly (P < 0.005) elevated in multiple polypoid adenomas and/or intramucosal carcinomas. We identified metagenomic and metabolomic markers to discriminate cases of intramucosal carcinoma from the healthy controls. Our large-cohort multi-omics data indicate that shifts in the microbiome and metabolome occur from the very early stages of the development of colorectal cancer, which is of possible etiological and diagnostic importance.

Abstract 1937: Inhibition of a novel cancer target, PDE10, suppresses Wnt/β-catenin signaling and colon tumorigenesis: Benefits from combining with ornithine decarboxylase inhibitors

Abstract Sulindac has been shown in clinical trials to reduce the number and size of precancerous colon adenomas, but is not recommended for the long-term management of polyposis syndromes because of potentially fatal toxicities resulting from cyclooxygenase (COX) inhibition and the suppression of prostaglandin synthesis. Here we characterize the activity of a non-COX inhibitory sulindac derivative, MCI-030, that inhibits a novel cancer target, phosphodiesterase 10A (PDE10), recently reported to be overexpressed in colon tumors and essential for tumor cell growth (Oncogene 34:1499-509, 2015). PDE10 is an attractive cancer target because of limited expression and no known function in normal peripheral tissues. MCI-030 potently and selectively inhibits the growth of multiple colon tumor cell lines expressing PDE10 with IC50 values of 0.3 μM, but does not affect the growth of normal colonocytes (NCM460) that do not express PDE10. Sulindac inhibits colon tumor cell growth with IC50 values approximately 200 fold higher and modest tumor cell selectivity. MCI-030 is PDE10 selective, but sulindac inhibits multiple PDE isozymes (PDE2, 3, 5, and 10). MCI-030 treatment of colon tumor cells increased intracellular cGMP levels and activated protein kinase G at concentrations that inhibit recombinant PDE10 and tumor cell growth. Inhibition of PDE10 by MCI-030 or siRNA increased the phosphorylation and degradation of β-catenin and inhibited Wnt-induced nuclear translocation to suppress TCF-mediated transcription of cyclin D and survivin, leading to cell cycle arrest and apoptosis. With attractive pharmacokinetics and ability to achieve high concentrations in colon mucosa following oral administration, MCI-030 was tested in the APC+/min-FCCC mouse model of colon tumorigenesis. At 7-8 weeks of age, mice endoscopically determined to be adenoma-free were assigned to receive either control or MCI-030 supplemented diet (1500ppm) for 14 weeks. MCI-030 reduced the multiplicity of colonic adenomas by 50% (control: 3.95 ± 0.81 vs. MCI-030: 1.95 ± 0.58, P &amp;lt; 0.05) and incidence by 36.7%. MCI-030 also reduced the multiplicity of polypoid adenomas (36%), microadenomas (69%), and flat adenomas (100%, P &amp;lt; 0.05). These data indicate that MCI-030 strongly inhibits tumorigenesis in a predictive preclinical mouse model of colorectal cancer without discernable toxicity and could be effective together with colonoscopy in humans to reduce polyp formation and prevent malignant progression. In addition, in vitro colony formation and transformation assays using human colon tumor cells showed benefits of combining MCI-030 with the ornithine decarboxylase inhibitor, DFMO, supporting testing of this novel combination in the APC+/min-FCCC mouse model as a strategy to further improve efficacy. Funding from NCI R01CA131378, R01CA148817, R01CA197147, and R01CA155638. Citation Format: Gary A. Piazza, Ashleigh Neese, Kevin Lee, Adam Keeton, Yulia Maxuitenko, Veronica Ramirez Alcantara, Kristy Berry, Jacob Valiyaveettil, Antonio Ward, Luciana Madeira da Silva, Jennifer Scalici, Bing Zhu, Tyler Mattox, Xi Chen, Margie Clapper, Harry Cooper, Wen-Chi Chang. Inhibition of a novel cancer target, PDE10, suppresses Wnt/β-catenin signaling and colon tumorigenesis: Benefits from combining with ornithine decarboxylase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1937.

E‐Poster Presentations ‐ C) Endoscopy

E‐Poster Presentations ‐ C) Endoscopy

Improvement to ultrasonographical differential diagnosis of gastric lesions: The value of contrast enhanced sonography with gastric distention.

ObjectiveThe purpose of this retrospective study is to evaluate the diagnostic value of contrast enhanced sonography plus gastric distention sonography, the Double Contrast-enhanced Ultrasound (DCUS) in gastric lesions.Methods107 cases with pathology confirmed gastric lesions were retrospectively reviewed, DCUS and oral contrast agent ultrasound (US) were performed in all cases prior to operation. Perfusion parameters including arrival time (AT), peak intensity (PI), time to peak (TTP), and area under the curve (AUC) of the lesion and surrounding normal tissue were analyzed. A reader blinded to pathology results were asked to rate and compare each case with surgical or resection biopsy pathology results.ResultsFrom the 107 gastric lesions, 75 were malignant gastric lesions (33 gastric cancers,42 gastrointestinal stromal tumors (GISTs)) and 32 were benign gastric lesions (11 inflammatory masses and 21 polypoid adenomas). Compared with US, DCUS achieved higher value in sensitivity (90.6% vs. 70.6%), specificity (75% vs. 62.5%), positive predictive value (89.5% vs. 81.5%), negative predictive value (77.4% vs. 47.6%), and overall accuracy (85.9% vs. 68.2%). When US was tested against DCUS, the increase in correct diagnoses value was significant (P = .01). Furthermore, gastric cancer had faster AT, higher PI and AUC than normal tissue (P<0.05); GIST and Inflammatory mass had higher PI than normal tissue (P<0.05); gastric cancer and GIST had faster AT than polypoid adenoma (P<0.05), Inflammatory mass showed higher PI than other 3 lesions and gastric cancer had higher PI than polypoid adenoma and GIST (P<0.05); gastric cancer and inflammatory mass had larger AUC than polypoid adenoma and GIST (P<0.05). Conclusion DCUS improved diagnostic performance compared with US. The combination of different CEUS enhancement characteristics with quantitative perfusion parameters may provide a promising tool to help differentiate gastric cancer and GIST from benign lesions.

Abstract 5243: Novel non-COX inhibitory sulindac derivative with β-catenin suppressing activity reduces the formation of colorectal adenomas and adenocarcinomas in the APC +/min-FCCC mouse model

Abstract Sulindac can reduce the number and size of precancerous colonic adenomas in patients with familial adenomatous polyposis (FAP), but is not recommended for long-term use as a cancer chemopreventive drug because of potentially fatal toxicities associated with cyclooxygenase (COX) inhibition. Here we characterize the antineoplastic properties of a novel sulindac derivative, ADT-061, that lacks COX-1 and COX-2 inhibitory activity. ADT-061 potently and selectively inhibited colon tumor cell growth in vitro with IC50 values of 0.3-0.5 μM by inducing apoptosis without affecting the growth of normal colonocytes at concentrations 100x higher. By comparison, sulindac sulfide (SS) inhibited colon tumor cell growth with IC50 values of 40-60 μM, and had only modest tumor cell selectivity. While SS non-selectively inhibits multiple cyclic GMP phosphodiesteraes (PDE) isozymes, previous studies have suggested an important role for PDE10 in colon cancer (Li et al, Oncogene, 2014; Lee et al, Oncotarget, 2015). At concentrations comparable to its IC50 values, ADT-061 selectively inhibits PDE10 to induce an increase in intracellular cGMP levels and activate protein kinase G (PKG). ADT-061 also suppressed nuclear levels of β-catenin and induced cell cycle arrest and apoptosis, within the same concentration range that inhibits tumor cell growth. With attractive drug-like properties, the chemopreventive activity ADT-061was assessed using the APC+/min-FCCC mouse model of spontaneous colorectal tumorigenesis. Prior to treatment, colonoscopy exams were performed on all APC+/min-FCCC mice (males, 6-7 weeks of age) to ensure the absence of colorectal adenomas. At 7-8 weeks of age, mice were assigned (19 per group) to receive either unsupplemented chow (control) or chow supplemented with ADT-061 (1500ppm) for 14 weeks. No discernible toxicity was observed during the experimental period. Double-blinded pathological analysis of fixed colon tissues revealed that ADT-061 not only reduced the multiplicity of colonic adenomas by 50% (Mean ± SEM, control vs. ADT-061, 3.95 ± 0.81 vs. 1.95 ± 0.58, P &amp;lt; 0.05), but also decreased the incidence of colonic adenomas by 36.7% (control vs. ADT-061, 94.7% vs. 57.9%, respectively). ADT-061 treatment reduced the multiplicity of polypoid adenomas (36%), flat adenomas (100%, P &amp;lt; 0.05), and microadenomas (69%). The formation of colonic adenocarcinomas found in 15.8% of untreated mice was completely inhibited in mice treated with ADT-061. These data indicate that ADT-061 inhibits colon tumorigenesis when given to APC+/min-FCCC mice prior to the detection of gross colonic tumors. These observations support further evaluation of ADT-061 and analogs for colorectal cancer chemoprevention. Citation Format: Kevin J. Lee, Xi Chen, Jacob Valiyaveettil, Ashley S. Lindsey, Joel Andrews, Veronica Ramirez-Alcantara, Adam B. Keeton, Gary A. Piazza, Harry Cooper, Margie Clapper, Wen-Chi L. Chang. Novel non-COX inhibitory sulindac derivative with β-catenin suppressing activity reduces the formation of colorectal adenomas and adenocarcinomas in the APC+/min-FCCC mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5243. doi:10.1158/1538-7445.AM2017-5243

The Immune Landscapes of Polypoid and Nonpolypoid Precancerous Colorectal Lesions.

Little is known about the immunoediting process in precancerous lesions. We explored this aspect of benign colorectal adenomas with a descriptive analysis of the immune pathways and immune cells whose regulation is linked to the morphology and size of these lesions. Two series of polypoid and nonpolypoid colorectal adenomas were used in this study: 1) 84 samples (42 lesions, each with matched samples of normal mucosa) whose gene expression data were used to quantify the tumor morphology- and size-related dysregulation of immune pathways collected in the Molecular Signature Database, using Gene Set Enrichment Analysis; 2) 40 other lesions examined with immunohistochemistry to quantify the presence of immune cells in the stromal compartment. In the analysis of transcriptomic data, 429 immune pathways displayed significant differential regulation in neoplasms of different morphology and size. Most pathways were significantly upregulated or downregulated in polypoid lesions versus nonpolypoid lesions (regardless of size). Differential pathway regulation associated with lesion size was observed only in polypoid neoplasms. These findings were mirrored by tissue immunostaining with CD4, CD8, FOXP3, MHC-I, CD68, and CD163 antibodies: stromal immune cell counts (mainly T lymphocytes and macrophages) were significantly higher in polypoid lesions. Certain markers displayed significant size-related differences regardless of lesion morphology. Multivariate analysis of variance showed that the marker panel clearly discriminated between precancerous lesions of different morphologies and sizes. Statistical analysis of immunostained cell counts fully support the results of the transcriptomic data analysis: the density of infiltration of most immune cells in the stroma of polypoid precancerous lesions was significantly higher than that observed in nonpolypoid lesions. Large neoplasms also have more immune cells in their stroma than small lesions. Immunoediting in precancerous colorectal tumors may vary with lesion morphology and stage of development, and this variability could influence a given lesion’s trajectory to cancer.

Patients with Endoscopically Visible Polypoid Adenomatous Lesions Within the Extent of Ulcerative Colitis Have an Increased Risk of Colorectal Cancer Despite Endoscopic Resection.

Ulcerative colitis (UC) is associated with an increased risk of colorectal cancer (CRC). Few studies have looked at long-term outcomes of endoscopically visible adenomatous lesions removed by endoscopic resection in these patients. We aimed to assess the risk of developing CRC in UC patients with adenomatous lesions that develop within the segment of colitis compared to the remainder of an ulcerative colitis cohort. We identified patients with a confirmed histological diagnosis of UC from 1991 to 2004 and noted outcomes till June 2011. The Kaplan-Meier method was used to estimate cumulative probability of subsequent CRC. Factors associated with risk of CRC were assessed in a Cox proportional hazards model. Twenty-nine of 301 patients with UC had adenomatous lesions noted within the segment of colitis. The crude incidence rate of developing colon cancer in patients with UC was 2.45 (95% CI 1.06-4.83) per 1000 PYD and in those with UC and polypoid adenomas within the extent of inflammation was 11.07 (95% CI 3.59-25.83) per 1000 PYD. Adjusted hazards ratio of developing CRC on follow-up in UC patients with polypoid dysplastic adenomatous lesions within the extent of inflammation was 4.0 (95% CI 1.3-12.4). The risk of developing CRC is significantly higher in UC patients with polypoid adenomatous lesions, within the extent of inflammation, despite endoscopic resection. Patients and physicians should take the increased risk into consideration during follow-up of these patients.

Overexpressed Claudin-1 Can Be Visualized Endoscopically inColonic Adenomas InVivo.

Background & AimsConventional white-light colonoscopy aims to reduce the incidence and mortality of colorectal cancer (CRC). CRC has been found to arise from missed polypoid and flat precancerous lesions. We aimed to establish proof-of-concept for real-time endoscopic imaging of colonic adenomas using a near-infrared peptide that is specific for claudin-1.MethodsWe used gene expression profiles to identify claudin-1 as a promising early CRC target, and performed phage display against the extracellular loop of claudin-1 (amino acids 53–80) to identify the peptide RTSPSSR. With a Cy5.5 label, we characterized binding parameters and showed specific binding to human CRC cells. We collected in vivo near-infrared fluorescence images endoscopically in the CPC;Apc mouse, which develops colonic adenomas spontaneously. With immunofluorescence, we validated specific peptide binding to adenomas from the proximal human colon.ResultsWe found a 2.5-fold increase in gene expression for claudin-1 in human colonic adenomas compared with normal. We showed specific binding of RTSPSSR to claudin-1 in knockdown and competition studies, and measured an affinity of 42 nmol/L and a time constant of 1.2 minutes to SW620 cells. In the mouse, we found a significantly higher target-to-background ratio for both polypoid and flat adenomas compared with normal by in vivo images. On immunofluorescence, we found significantly greater intensity for human adenomas (mean ± SD, 25.5 ± 14.0) vs normal (mean ± SD, 9.1 ± 6.0) and hyperplastic polyps (mean ± SD, 3.1 ± 3.7; P = 10-5 and 8 × 10-12, respectively), and for sessile serrated adenomas (mean ± SD, 20.1 ± 13.3) vs normal and hyperplastic polyps (P = .02 and 3 × 10-7, respectively).ConclusionsClaudin-1 is overexpressed in premalignant colonic lesions, and can be detected endoscopically in vivo with a near-infrared, labeled peptide.

Prevalence of advanced histological features and synchronous neoplasia in patients with flat adenomas

The prevalence of advanced histology in flat adenomas is uncertain. There are limited data on the prevalence of synchronous adenomas in patients with flat adenomas. The aims of this study were to determine whether the flat adenomas harbor advanced histology more than the polypoid adenomas and whether the presence of flat adenomas is an independent predictor of synchronous adenomas. A retrospective analysis of data from 3 prospective clinical trials conducted at 2 tertiary care referral centers that included patients undergoing screening or surveillance colonoscopy was performed. The location, size, and morphology of each polyp resected was documented and sent for histopathological examination in a unique specimen jar. A total of 2931 polyps were removed in 1340 patients. Of the 1911 adenomas (65.2%), 293 (15.3%) were flat and 1618 (84.7%) were polypoid. The prevalence of advanced histology did not differ between flat and polypoid adenomas (1.4% vs 3.1%; P = .13). Multivariate analysis confirmed that the presence of at least 1 flat adenoma was a predictor of the presence of a large adenoma (P < .01; odds ratio [OR], 2.80; 95% CI, 1.86-4.22), advanced adenoma (P < .01; OR, 2.70; 95% CI, 1.80-4.06), and 3 or more adenomas (P < .01; OR, 2.44; 95% CI, 1.66-3.59). Although the prevalence of advanced histology in flat adenomas is similar to that of polypoid adenomas, flat adenomas are associated with increased prevalence of synchronous large and advanced adenomas. Whether these results imply shorter surveillance intervals in patients with flat adenomas needs to be explored in future studies.

Suboptimal Bowel Preparation Significantly Impairs Colonoscopic Detection of Non-polypoid Colorectal Neoplasms.

It is unclear whether the quality of bowel preparation affects colonoscopic detection of non-polypoid colorectal neoplasms (NP-CRNs). To evaluate the impact of bowel-cleansing quality on detection of NP-CRNs. We performed a retrospective analysis of asymptomatic screening colonoscopy cases after standardized bowel preparation at an academic teaching hospital between June 2011 and May 2013. Primary outcome was a comparison of the adenoma detection rate (ADR) of non-polypoid morphology according to quality of bowel preparation. Secondary outcomes included detection prevalence of non-polypoid adenomas. Of the enrolled 6097 screening examinations, the preparation quality was rated as adequate (excellent or good) in 5224 (85.7%), fair in 615 (10.1%), and poor in 258 (4.2%) patients. The prevalence of NP-CRNs was 40.5% (1962/4847) of all CRNs. The overall ADR of non-polypoid morphology was 12.3% (747/6097) of all colonoscopies, but it significantly differed among participating endoscopists (all P<0.05). The ADR of non-polypoid morphology was significantly lower with fair- or poor-quality preparation, versus adequate-quality preparation (adjusted odds ratio [aOR] 0.55, 95% confidence interval [CI] 0.41-0.75; aOR 0.49, 95% CI 0.30-0.79, respectively). Poor-quality preparation was also associated with impaired detection of polypoid, proximal colon, and sub-centimeter adenomas (all P<0.05). Suboptimal (fair or poor) bowel preparation significantly impairs colonoscopic detection of NP-CRNs. Given that the prevalence of NP-CRNs is substantial in our average-risk screening cohort, ongoing efforts to improve the preparation quality are practically valuable in increasing the detection of NP-CRNs, thereby improving the efficacy of screening colonoscopies.

CT colonography for the detection of nonpolypoid adenomas: sensitivity assessed with restricted national CT colonography trial criteria.

The purpose of this study was to determine the prevalence of nonpolypoid adenomas and the sensitivity of CT colonography (CTC) in their detection by use of the restricted criteria of height-to-width ratio<50% and height elevation≤3 mm. In the National CT Colonography Trial (American College of Radiology Imaging Network protocol 6664), a cohort of 2531 participants without symptoms underwent CTC and screening colonoscopy. The CTC examinations were interpreted with both 2D and 3D techniques. Nonpolypoid adenomatous polyps identified with CTC or colonoscopy were retrospectively reviewed to determine which polyps met the restricted criteria. The prevalence of nonpolypoid adenomas and the prospective sensitivity of CTC were determined. Descriptive statistics were used to report the prevalence, size, and histologic features. The sensitivities (with 95% CIs) for nonpolypoid and polypoid lesions were compared by two-sided Z test for independent binomial proportions. The retrospective review confirmed 21 nonpolypoid adenomas, yielding a prevalence of 0.83% (21 of 2531 participants). Eight (38.1%) were advanced adenomas, many (50% [4/8]) only because of large size (≥10 mm). The overall per polyp sensitivity of CTC (combined 2D and 3D interpretation) for detecting nonpolypoid adenomas≥5 mm (n=21) was 0.76; ≥6 mm (n=16), 0.75; and ≥10 mm (n=5), 0.80. These values were not statistically different from the sensitivity of detecting polypoid adenomas (p>0.37). In this large screening population, nonpolypoid adenomas had a very low prevalence (<1%), and advanced pathologic features were uncommon in polyps<10 mm in diameter. Most nonpolypoid adenomas are technically visible at CTC. The prospective sensitivity is similar to that for polypoid adenomas when the interpretation combines both 2D and 3D review.

Mutational profiles of different macroscopic subtypes of colorectal adenoma reveal distinct pathogenetic roles for KRAS, BRAF and PIK3CA.

BackgroundInvestigations of genetic alterations and correlations with histology or morphology could provide further insights into colorectal carcinogenesis. Nevertheless, such genetic changes were less investigated in adenoma stage and a comprehensive survey of oncogenic mutations in EGFR signaling pathway according to different morphologic subtypes has not been performed.MethodsA total of 94 neoplasms, including 34 polypoid adenoma, 16 lateral spreading tumors-granular (LST-G), 20 non-granular LST (LST-NG), and 24 depressed tumors, were subjected for mutational analysis of KRAS (exon 2), BRAF (exon 11 and 15), PIK3CA (exon 9 and 20), AKT (exon 4), EGFR (exon 18–24) and HER2 (exon18-24).ResultsKRAS mutation was noted more frequently in LST (13/36, 36.1%) than polypoid neoplasms (5/34, 14.7%, p = 0.041). When comparing with LST-NG, LST-G had a significantly higher frequency of KRAS mutation. (9/16, 56.3% vs. 4/20, 20.0%, p = 0.024). BRAF mutation (V600E) was found in 2 of 36 (5.6%)LSTs and 1 of 34 (2.9%) polypoid lesions. The two LST lesions with BRAF mutation were pathologically proven to be serrated adenoma. PIK3CA mutation (exon 9 E545K) was identified only in LST (5/36, 13.9%). Mutations in KRAS, BRAF or PIK3CA occurred in a mutually exclusive manner. All mutations were absent in the specimens obtained from depressed type neoplasms.ConclusionsThree different macroscopic subtypes of colorectal neoplasms display distinct carcinogenetic pathways in EGFR networking. Further molecular studies of CRCs should take macroscopic subtypes into consideration and highlight the importance of consensus and communication between endoscopic and pathologic diagnosis.

Factors associated with false-positive and false-negative fecal immunochemical test results for colorectal cancer screening

Certain subgroups have higher rates of false fecal immunochemical test (FIT) results, yet few studies have addressed this topic. To identify demographic factors associated with false-positive and false-negative FIT results in colorectal cancer screening. Retrospective database review of prospectively collected data. A bowel cancer screening center in Hong Kong invited participants for colorectal cancer screening (2008-2012). Study participants who underwent both FIT and colonoscopy in the first year (n= 4482) and underwent colonoscopy after negative FIT results for 3 consecutive years (n= 857). The diagnostic accuracy and predictive values of FIT according to participant characteristics. The sensitivity, specificity, positive predictive values, and negative predictive values for advanced neoplasiawere 33.1%, 91.9%, 19.0%, and 96.0%, respectively. Participants 66 to 70 years of age had higher sensitivity, whereas older age, smoking, and use of aspirin/nonsteroidal anti-inflammatory drugs were associated with lower specificity. The rates of false-positive and false-negative results were 8.1% and 66.9%, respectively. Older age (66-70 years;adjusted odds ratio [AOR] 1.95; 95% confidence interval [CI], 1.35-2.81; P< .001), smoking (AOR 1.68; 95% CI, 1.08-2.61; P= .020), and the presence of polypoid adenoma (AOR 1.71; 95% CI, 1.14-2.57; P= .009) were associated with false-positive results. Younger participants (AOR for elderly participants 0.31) and the use ofaspirin/nonsteroidal anti-inflammatory drugs (AOR 4.44) in participants with 1 FIT with negative results and the absence of high-grade dysplasia (AOR for presence 0.41) were associated with false-negative results. Self-referred participants who received one type of qualitative FIT. These findings could be used to target screening more toward those with a higher risk of false-negative results and those with a lower risk of false-positive results for earlier colonoscopy.

Vasculo-smooth muscle hamartomatous structure is linked to morphogenesis of colorectal polypoid adenoma.

To investigate the difference of surrounding stromal structure between the polypoid and flat adenomas in the colorectum, we performed microscopic study including immunohistochemistry in a total of 32 colorectal adenomas (typical 24 polypoid and eight flat adenomas), especially focusing on vessels around muscularis mucosa. All 24 polypoid adenomas accompanied vasculo-smooth muscle hamartomatous structure in association with muscularis mucosa and submucosal vessels, whereas none of eight flat adenomas had vasculo-smooth muscle hamartomatous structure; surrounding muscularis mucosa and submucosa of the flat adenomas are identical to those of normal colorectal tissue. Vasculo-smooth muscle hamartomatous structure is linked to the morphogenesis of colorectal polypoid adenomas.