Colonic Neoplasia Research Articles

Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis Frequently Have Subclinical Inflammation in the Proximal Colon

Patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) have a high risk of colonic neoplasia. Neoplasia frequently develops in the proximal colon in patients with PSC. Histologic inflammation is an independent risk factor for the development of neoplasia; we investigated whether patients with UC and PSC have more subclinical disease activity than patients with UC alone. We performed a retrospective analysis of data from 143 patients (205 examinations) with ulcerative pancolitis who were in clinical remission and treated at a tertiary medical center from May 2011 through May 2016. Endoscopic and histologic activity were compared between patients with PSC (from 36 examinations) and without PSC (from 169 examinations). Disease activity was scored per colonic segment using a modified Mayo endoscopic subscore and histologic assessment. In each colonic segment, differences in disease activity and the degree of discordance between endoscopic and histologic inflammation among UC patients with and without PSC were compared. Patients with UC-PSC had significantly more subclinical endoscopic (odds ratio [OR], 4.21; 95% CI, 1.67-10.63) and histologic activity (OR, 5.13; 95% CI, 2.25-11.68) in the right colon, as well as greater degree of histologic than endoscopic inflammation in the proximal colon (OR, 3.14, 95% CI, 1.24-7.97), compared with patients without PSC. Patients with UC-PSC had significantly less histologic activity in the rectum on multivariate analysis (OR, 0.24; 95% CI, 0.08-0.72). Patients with UC and PSC who are in clinical remission are significantly more likely to have endoscopic and histologic inflammation in the right colon than patients with UC without PSC. Our findings provide insight into cause of colorectal cancer in UC patients with PSC.

Use of confocal laser endomicroscopy with a fluorescently labeled fatty acid to diagnose colorectal neoplasms.

Endoscopic treatment for early colorectal cancer closely correlates with patient prognosis. However, endoscopic differentiation between carcinomas and non-neoplastic lesions remains difficult. Here, we topically stained colorectal neoplasms with a fatty acid analogue (BODIPY-FA) and quantified the fluorescent signals using confocal laser endomicroscopy (CLE) and fluorescence microscopy. We also analyzed protein expression in colorectal cancer tissues. We found that expression of fatty acid synthase was elevated, while the expression of fatty acid transporters was reduced in colorectal cancer. In colorectal cancer mouse models and patients, the BODIPY-FA signals were higher in normal epithelia than in carcinomas or colonic intraepithelial neoplasias. BODIPY-FA staining revealed both the arrangement of intestinal glands and the intracellular structures under CLE screening. In a double-blind trial, CLE images stained with BODIPY-FA exhibited greater consistency (κ = 0.68) and overall validity (74.65%) than those stained using intravenous fluorescein sodium (κ = 0.43, 55.88%) when the results were compared with histological diagnoses. These findings suggest that topical use of BODIPY-FA with CLE is a promising imaging approach for early colorectal neoplasm screening.

Subtotal colectomy versus left hemicolectomy for the elective treatment of splenic flexure colonic neoplasia

BackgroundOptimal elective surgical treatment for splenic flexure neoplasm (SFN) is unclear. Subtotal colectomy (STC) and left hemicolectomy (LHC) are the two more common strategies used. MethodsObservational multicentric study comparing postoperative morbidity, mortality and long-term survival on patients with SFN electively operated by STC versus LHC between 2003 and 2014. ResultsAfter revision of the databases, 144 patients were included (STC group, n = 68; LHC group, n = 76). No differences were found on epidemiological and surgical data. A higher global morbidity (58%vs37%, p = 0.014), surgical morbidity (50%vs33%, p = 0.037), postoperative ileus (37%vs20%, p = 0.023) and harvested lymph nodes (26vs18, p = 0.0001) were found on the STC group. No significant differences in complications according to severity, reoperation rate, hospital stay, mortality, recurrence or long-term survival were found between groups. ConclusionsA higher surgical morbidity was found on the STC group, mainly due to mild postoperative ileus. No differences on long-term oncological results were found.

Screening key genes and miRNAs in early-stage colon adenocarcinoma by RNA-sequencing.

Colon adenocarcinoma is the third leading cause of cancer-related deaths across the world, developing novel and non-invasive diagnostic and prognostic biomarkers for the early-stage colon adenocarcinoma at molecular level is essential. In our study, RNA-sequencing was performed to identify the differentially expressed genes and miRNAs (DEmiRNAs) in early-stage colon adenocarcinoma compared to tissues of precancerous lesions, colonic intraepithelial neoplasia. The DEmiRNA-target interaction network was constructed and functional annotation of targets of DEmiRNAs was performed. The Cancer Genome Atlas was used to verify the expression of selected differentially expressed genes. The receiver operating characteristic analyses of selected differentially expressed genes was performed. In total, 865 differentially expressed genes, 26 DEmiRNAs, and 329 DEmiRNA-target pairs were obtained. Based on the early-stage colon adenocarcinoma network, miR-548c-5p, miR-548i, and miR-548am-5p were the top three DEmiRNAs that covered most differentially expressed genes. NTRK2, DTNA, and BTG2 were the top three differentially expressed genes regulated by most DEmiRNAs. Cancer and colorectal cancer pathways were two significantly enriched pathways in early-stage colon adenocarcinoma. The common differentially expressed genes in both the pathways were AXIN2, Smad2, Smad4, PIK3R1, and BCL2. The expression levels of eight differentially expressed genes (NTRK2, DTNA, BTG2, COL11A1, Smad2, Smad4, PIK3R1, and BCL2) in The Cancer Genome Atlas database were compatible with our RNA-sequencing. All these eight differentially expressed genes and AXIN2 had the potential diagnosis value for Colon adenocarcinoma. In conclusion, a total of ten differentially expressed genes (NTRK2, DTNA, BTG2, COLCA1, COL11A1, AXIN2, Smad2, Smad4, PIK3R1, and BCL2) and four DEmiRNAs (miR-548c-5p, miR-548i, mir-424-5p, and miR-548am-5p) may be involved in the pathogenesis of early-stage colon adenocarcinoma which may make a contribution for developing new diagnostic and therapeutic strategies for early-stage colon adenocarcinoma.

Abstract SY14-01: Colon cancer screening and genetics

Abstract Colorectal cancer (CRC) is the third most prevalent and second deadliest cancer in the U.S. with 134,490 cases and 49,190 deaths in 2016. Its pathogenesis stems from genetic susceptibility coupled with environmental interactions in the colon that synergize ideal conditions for neoplastic growth, initially from benign adenomatous polyps that might progress to carcinoma over several years. Adenoma initiation and progression to carcinoma may take one of a few identified genetic pathways that determine the tempo of progression as well as morbidity and mortality of the patient. Each patient’s CRC is genetically unique with variable numbers of passenger mutations and propelled by 2-8 driver mutations. CRCs can be classified as hypermutated, possessing hundreds to thousands of somatic mutations and including CRCs driven by defects in DNA mismatch repair and POLE mutations; and non-hypermutated, with tens of somatic mutations containing multiple copy number alterations and aneuploidy with oncogenic activation of KRAS and PIK3CA coupled with mutations and loss of heterozygosity of tumor suppressors APC and TP53. Epigenetic events as well as inflammatory-driven cellular alterations in DNA mismatch repair further contribute to CRC pathogenesis and metastasis. Because CRC is deadly, prevention through screening (and/or surveillance in high-risk patients) is an ideal and effective approach. Screening provides the opportunity to identify and remove the adenoma precursors before they can become CRC; it also can utilize the somatic genetic knowledge to effectively screen patients noninvasively. There are seven CRC screening tests suggested by the USPSTF and a Multi-society Task Force for effective screening, with varying abilities to detect significant colonic neoplasia and various specificities; even the most noninvasive and least sensitive test has shown a durable reduction in CRC mortality and is cost effective. Thus, any of the seven CRC screening tests is better than no test. Noninvasive strategies include guaiac-based fecal occult blood testing, fecal immunochemical testing, fecal DNA testing, and CT colonography. Luminal-invasive tests include flexible sigmoidoscopy and colonoscopy and their combinations with a noninvasive test. If any of the noninvasive tests shows a positive result, a colonoscopy should be performed to identify the cause of the positive test. For high-risk patients or the surveillance of patients, colonoscopy is the modality that should be used. Knowledge of the patient’s age and family history and personal adenoma or CRC history can influence when to commence screening; additionally, multiple lines of evidence suggest that race should be included in the algorithm influencing the timing and tempo of screening and/or surveillance. Citation Format: John M. Carethers. Colon cancer screening and genetics [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 SY14-01. doi:10.1158/1538-7445.AM2017-SY14-01

Abstract 3901: Therapeutic targeting of C-terminal binding protein: a key dependency for polyposis and cancer stem cell activity in APC mutant neoplasia

Abstract The C terminal binding proteins (CtBP) 1 and 2 are a family of transcriptional co-repressors overexpressed in a variety of cancers, and are frequently associated with poor prognosis and chemoresistance. CtBP has also been characterized in cell culture models as drivers of migration/invasion and epithelial-mesenchymal transition. CtBP mediates its transcriptional corepressor activity via its dehydrogenase domain, and inhibition of this domain interferes with CtBP oncogenic functions. The role of CtBP in APC mutant neoplasia remains obscure even though APC is responsible for degradation of both β-catenin and CtBP in suppressing colorectal tumorigenesis. Our prior work demonstrates that CtBP proteins can be effectively therapeutically targeted with substrate analogues of their intrinsic dehydrogenase domains. We now observe that pharmacologic inhibition of CtBP using either the 1st generation inhibitor 2-keto-4-methylthiobutyrate (MTOB) or the 2nd generation inhibitor hydroxyimino-3-phenylpropanoic acid (HIPP) significantly reduces the burden of intestinal polyps in the Apcmin mouse model of the human cancer predisposition syndrome Familial Adenomatous Polyposis. The number of intestinal polyps in mice with CtBP2 inhibitors were significantly lower (21 polyps/mouse for MTOB, 15 polyps/mouse for HIPP) as compared with vehicle treated mice (45 polyps/mouse) with a P value <0.0001. Pointing to the anti-neoplastic mechanism of MTOB and HIPP, polyps that did grow in MTOB or HIPP treated mice demonstrated robust downregulation of β catenin and Ctbp2 proteins. This observation points to the role of Ctbp2 as a putative driver oncogene that can be therapeutically targeted in vivo. In addition, CtBP2 has been reported to play an important role in human colon cancer stem cells via its interaction with the transcription factor TCF4 on chromatin. We now show that inhibiting CtBP with HIPP or HIPP analogues attenuates CtBP2 protein levels in colon cancer stem cells with resultant decreased expression of CtBP transcriptional target genes, such as the motility/invasion regulator TIAM1, and c-MYC, a known driver of the cancer stem cell phenotype. Moreover, colonospheres treated with CtBP inhibitor showed downregulation of cancer stem cell markers CD133 and c-MYC, as compared with vehicle treatment. Flow cytometry analysis of intestinal epithelium from Apcmin mice treated with CtBP inhibitor vs. vehicle indicated a significant reduction in CD133+/CXCR4+ cells that are associated with a tumor initiating cell phenotype. Our data demonstrate that CtBP inhibition may reduce colon neoplasia via downregulation of c-MYC and the cancer stem cell/tumor initiating cell compartment, and that CtBP is a promising and novel target for therapy in colon cancer. Citation Format: Ayesha T. Chawla, Agnes Cororaton, Rashmi Seth, Barbara Szomju, Evan T. Sumner, Steven R. Grossman. Therapeutic targeting of C-terminal binding protein: a key dependency for polyposis and cancer stem cell activity in APC mutant neoplasia [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 3901. doi:10.1158/1538-7445.AM2017-3901

Post Hoc Analysis of Polyps in 9 Short Bowel Syndrome Patients Treated with Teduglutide

Introduction: Preclinical data raise the possibility that teduglutide may be associated with a risk of small intestinal and/or colonic neoplasia. This report aims to evaluate data from 2 clinical trials in patients with short bowel syndrome (SBS) who reported polyps at baseline or during long-term teduglutide treatment. Methods: Post hoc analysis of data was reported in patient e-case forms (eCRFs) regarding gastrointestinal polyps at baseline and over the course of 2 therapeutic trials of teduglutide (STEPS: NCT00798967, EudraCT2008-006193-15; STEPS-2: NCT00930644, EudraCT2009-011679-65). A baseline colonoscopy was required unless a normal colonoscopy had been performed <6 months before screening. Patients with benign polyps removed pre-randomization were eligible for enrollment. Results: Of the patients enrolled (STEPS, n=86; STEPS-2, n=88), 54 who had not undergone prior colectomy received a baseline colonoscopy and 50 received a study completion colonoscopy (remaining patients refused or no colon was present). Baseline colonic polyps were reported in 9 patients (ages 39–75 years; women 67%); per inclusion criteria they were removed before treatment initiation. By the end of STEPS-2, 9 patients (ages 35–63 years; women, 67%) had reported polyps. In 6 of these 9 patients, polyps were recorded as a treatment-emergent adverse event (TEAE). Patients had been on teduglutide for 3 months (1 patient, TEAE), 8 months (1 patient, TEAE), 10 months (1 patient, TEAE), 24 months (5 patients, 3 TEAEs) and 30 months (1 patient, 0 TEAE) at polyp detection. Polyp locations were colon (7 patients), duodenum (1 patient), and unknown (1 patient). Recorded polyp sizes were 2–7 mm (4 patients). 7 patient eCRFs noted that biopsies were performed; 2 recorded low-grade dysplasia (rectal/colorectal polyps), but none recorded overt malignancy. Conclusion: Polyps were reported in 9 of 50 patients receiving long-term teduglutide who had a colonoscopy at study completion (106.3 patient-years exposure). There were no reports of malignancy related to the presence of these polyps. Additional information regarding polyp incidence will be acquired from an ongoing SBS registry. Shire International GmbH, Zug, Switzerland.

Macrophage inhibitory cytokine-1/growth differentiation factor-15 as a predictor of colonic neoplasia.

Serum macrophage inhibitory cytokine-1 (MIC-1/GDF15) concentration has been associated with colonic adenomas and carcinoma. To determine whether circulating MIC-1/GDF15 serum concentrations are higher in the presence of adenomas and whether the level decreases after excision. Patients were recruited prospectively from a single centre and stratified into five groups: no polyps (NP); hyperplastic polyps (HP); sessile serrated ademona (SSA); adenomas (AP); and colorectal carcinoma (CRC). Blood samples were collected immediately before and 4 weeks after colonoscopy. MIC-1/GDF15 serum levels were quantified using ELISA. Participants (n=301) were stratified as: NP; n=116 (52%), HP; n=37 (12%), SSA; n=19 (7%), AP; n=68 (23%); and CRC; n=3 (1%). Patients were excluded from the study due to nondiagnostic pathology (n=9, 3%) and exclusion criteria (n=20, 6%). In the 272 remaining subjects (M=149; F=123), age (P=.005), history of colonic polyps (P=.003) and family history of colonic polyps (P=.002) were associated with presence of adenomas. Baseline median MIC-1/GDF15 serum levels increased significantly from NP 609 (460-797) pg/mL, HP 582 (466-852) pg/mL, SSA 561 (446-837) pg/mL to AP 723 (602-1122) pg/mL and CRC 1107 (897-1107) pg/mL; (P<.001). In the pre- and postpolypectomy paired adenoma samples median MIC-1/GDF15 reduced significantly from 722 (603-1164) pg/mL to 685 (561-944) pg/mL (P=.002). A ROC analysis for serum MIC-1/GDF15 to identify adenomatous polyps indicated an area under the curve of 0.71. Our data suggest that serum MIC-1/GDF15 has the diagnostic characteristics to increase the detection of colonic neoplasia and improve screening.

Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia.

Colorectal cancer (CRC) is characterized by genome-wide alterations to DNA methylation that influence gene expression and genomic stability. Less is known about the extent to which methylation is disrupted in the earliest stages of CRC development. In this study we have combined laser-capture microdissection (LCM) with reduced representation bisulfite sequencing (RRBS) to identify cancer-associated DNA methylation changes in human aberrant crypt foci (ACF), the earliest putative precursor to CRC. Using this approach, methylation profiles have been generated for 10 KRAS-mutant ACF and 10 CRCs harboring a KRAS mutation, as well as matched samples of normal mucosa. Of 811 differentially methylated regions (DMRs) identified in ACF, 537 (66%) were hypermethylated and 274 (34%) were hypomethylated. DMRs located within intergenic regions were heavily enriched for AP-1 transcription factor binding sites and were frequently hypomethylated. Furthermore, gene ontology (GO) analysis demonstrated that DMRs associated with promoters were enriched for genes involved in intestinal development, including homeobox genes and targets of the Polycomb repressive complex 2 (PRC2). Consistent with their role in the earliest stages of colonic neoplasia, 75% of the loci harboring methylation changes in ACF were also altered in CRC samples, though the magnitude of change at these sites was lesser in ACF. While aberrant promoter methylation was associated with altered gene expression in CRC, this was not the case in ACF, suggesting the insufficiency of methylation changes to modulate gene expression in early colonic neoplasia. Together, these data demonstrate that DNA methylation changes, including significant hypermethylation, occur more frequently in early colonic neoplasia than previously believed, and identify epigenomic features of ACF that may provide new targets for cancer chemoprevention or lead to the development of new biomarkers for CRC risk.

Sa1466 - A National Study of Cancer Diagnoses in Irish Liver Transplant Recipients with Primary Sclerosing Cholangitis

Background Primary sclerosing cholangitis (PSC) is associated with an increased risk of cholangiocarcinoma, colorectal and gallbladder cancers. Orthotopic liver transplantation (OLT) patients are at risk of developing de novo malignancies, however limited/conflicting data exists regarding cancer risk post OLT for PSC. Aim To examine all recorded malignancies over 2 decades in OLT-PSC patients; to compare these to non-transplanted PSC cohort; to analyse for any associated factors. Method We studied PSC patients attending SVUH (1/1/1994–30/9/2016). We integrated this database with National Cancer Registry Ireland, to enable accurate determination of number of malignancies. Results 173 PSC pts (75.7% male) have attended SVUH since 1994. 107 (61.8%) have undergone 124 OLT. 27/107 were transplanted for cholangiocarcinoma. 12 de novo cancers (excluding non-melananomatous skin) were found during 737.8 person years of follow-up. Median time to cancer diagnosis post OLT was 5 years. As expected, cholangiocarcinoma as OLT indication (p=0.005) and older age at transplant (p=0.05) were associated with higher mortality. Post-transplant lymphoproliferative disease (PTLD) remains a major complication. 5 pts developed lymphoma post OLT (4.7% of cohort). Two patients developed CRC post OLT; 4 developed colonic dysplasia. 3/4 underwent colectomy. All who developed colonic dysplasia/CRC post OLT had IBD. All 5 colectomies for dysplasia/CRC showed significant co-existing inflammation. Conclusions This represents national cancer figures for PSC-OLT. The rates of PTLD are slightly higher than previously reported. We could not find any association between the development of PTLD and immunosuppressive regimes for IBD post OLT. This study highlights that IBD/PSC patients remain at significant risk of colonic neoplasia after OLT and require intensive surveillance.

Tu1996 - Macrophage Inhibitory Cytokine 1 (MIC1/GDF15) as a Novel Serum Biomarker of Colonic Neoplasia

Tu1996 - Macrophage Inhibitory Cytokine 1 (MIC1/GDF15) as a Novel Serum Biomarker of Colonic Neoplasia

Su2059 - Location and Kudo Pit Pattern Reflect Neoplastic Histology of Lesions Detected at Surveillance Colonoscopy in Inflammatory Bowel Disease

Introduction Effective colonoscopic surveillance of IBD benefit from having reliable predictors of neoplasia, since targeted biopsies and endoscopic resection are increasingly used as standard of practice. It is not clear whether Kudo pit patterns may be applicable in characterising IBD associated lesions. We aimed to identify the specific clinical and endoscopic features of colonic lesions which predict dysplasia in IBD. Method All lesions identified in a randomised study to determine the detection rates of neoplastic lesion (NL) in patients with long standing colitis in IBD ( NCT02098798) were included. NL were classified by the Paris classification, Kudo pit pattern, and by the Vienna classification. Univariate analysis was performed, and age, duration of disease, extra-intestinal manifestations,family or personal history of polyps/cancer, smoking, size of lesion, Paris classification, Kudo pit pattern, localization/extension were considered .Subsequently a multivariate logistic regression model analyses was created and analysed with candidate variables which had p values≤0.05 on univariate analysis. Results A total of 270 patients (55% men; median age 49y) were assessed by High Definition (n=90), virtual chromoendoscopy (n=90) or dye chromoendoscopy (n=90). Among 270 patients, ninety- one (33.7%) colonic dysplastic lesions and 1 adenocarcinoma were found. Sixty–two (68.8%) were polypoid and twenty-nine (31.8%) were non polypoid. Most of these lesions (92.3%) had Kudo pit pattern III-V. By univariate analysis, age- Odds Ratio (OR) 1.05 (95% CI:1.02–1.08), localization of the lesions in the right colon- OR 6.15 ( 95% CI: 3.12–12.12), Kudo pit pattern IIO, III-IV and V- OR 20.91 (95% CI:9.34–46.7) and Paris Is/Ip classification OR- 3.29 (95% CI 1.69–6.38) were associated with NL. Subsequently proportional multivariate logistic regression model for the prediction of colonic neoplasia confirmed that the endoscopic Kudo pit pattern- OR 21.50 (95% CI:86.5–60.1) and localization of the lesions in the right colon- OR 6.52 (95% CI:1.98–22.5) were predictors of colonic neoplasia at surveillance colonoscopy in IBD (Table). The overall accuracy of independent variables which predict neoplastic histological changes was 78% (95% CI 68%–88%), sensitivity 82% (95% CI 68%–97%), specificity 68% (95% CI 47%–89%), PPV 85% (95% CI 76%–95%) and NPV 64% (95% CI 42%–86%) which were significant in the multivariate analysis. Conclusion We demonstrated that the endoscopic Kudo pit pattern and localization of the lesions in the right colon were predictors of neoplasia in IBD. This may guide management strategy of NL detected at IBD surveillance. Disclosure of Interest M. Iacucci Conflict with: Pentax, O Akinola: None Declared, R Panaccione: None Declared, G Kaplan: None Declared, Y Leung: None Declared, K Novak: None Declared, C Seow: None Declared, X Gui: None Declared, S Urbanski: None Declared, P Minoo: None Declared, B Lethebe: None Declared, M Lowerison: None Declared, S Ghosh: None Declared

Effects of Dietary Resistant Starch on the Wnt Signaling Pathway and Preneoplastic Cells in the Colons of Azoxymethane-Treated Rats

ABSTRACTDietary resistant starch (RS) has been suggested to reduce colonic neoplasia. To determine the effects of digestion-resistant cornstarch on colonic carcinogenesis and Wnt signaling in azoxymethane (AOM)-treated F344 rats, diets containing naturally occurring RS from corn lines derived partially from Guat209 (GUAT), AR16035 (AR), or a hybrid (ARxGUAT), containing 34.5 ± 2.0, 0.2 ± 0.1, and 1.9 ± 0.1% RS, respectively, were fed at 55% of the diet. GUAT-fed rats had increased cecal content and tissue weight and decreased cecal pH compared with AR- or ARxGUAT-fed rats. Numbers of aberrant crypt foci (ACF) were not different among diet groups. Increased numbers of crypts/focus were observed in AOM-injected rats fed GUAT compared with rats fed other diets. β-catenin mRNA expression of the crypts was significantly increased in GUAT-fed rats injected with AOM relative to those injected with saline. These findings suggest that selected dietary RSs may at some level further enhance colonocyte proliferation and differentiation in an AOM-treated colon.

State of Art Update: Detection and Classification of Early Colonic Neoplasia

Colonoscopy has been shown to be effective in the detection and removal of precancerous lesions and early cancers, and as a result, colorectal screening programs are in preparation, or in place throughout the world. Screening efforts are reducing the incidence of colorectal cancer (CRC) and allow diagnosis CRCs at an earlier stage.

Risk of Rectal Neoplasia after Colectomy and Ileorectal Anastomosis for Ulcerative Colitis

Colectomy can be required in the management of ulcerative colitis [UC]. While ileal-pouch anal anastomosis [IPAA] is the recommended reconstruction technique, ileorectal anastomosis [IRA] is still performed and might present some advantages. However, the risk of rectal neoplasia might limit its indication. The aims of our study were to determine the incidence of rectal neoplasias following IRA for UC and to identify risk factors associated with rectal carcinomas. We performed a multicenter retrospective study including patients who underwent IRA for UC from 1960 to 2014 in 13 centers. Cox-proportional hazard models were used to determine carcinoma-associated risk factors. A total of 343 patients were included, with a median follow-up of 10.4 years after IRA. At the end of follow-up, 38 rectal neoplasias (including 19 carcinomas) were diagnosed, and 7 patients [2%] had either died from rectal carcinoma or had a metastatic disease. Incidences of rectal carcinoma after IRA for UC were estimated at 3.2% at 10 years and at 7.3% at 20 years, whereas incidences of neoplasia were estimated at 7.1% and 14% at 10 and 20 years, respectively. In multivariate analysis, age at IRA, IBD duration, primary sclerosing cholangitis [PSC] and history of prior colonic carcinoma were independently associated with the risk of rectal carcinoma following IRA. The risk of rectal carcinoma in patients with IRA for UC remains, and this justifies long-term endoscopic surveillance. Either IPAA or end ileostomy should be considered in 'high-risk' patients i.e. those with PSC and/or with prior colonic neoplasia.

Differential expression of M3 muscarinic receptors in progressive colon neoplasia and metastasis.

M3 muscarinic receptor (M3R) activation promotes colon cancer cell proliferation, migration, and invasion in vitro. Although over-expression of CHRM3, the gene encoding M3R, is reported in primary colon cancers, expression of M3R itself has not been studied in colon neoplasia. We compared M3R expression in normal colon to colon adenomas, and primary and metastatic colon cancers. Compared to adjacent normal colon, CHRM3 expression was increased up to 128-fold in 10 of 18 consecutive surgical cancer specimens (56%) and associated with metastatic spread (P < 0.05). To analyze M3R protein expression we interrogated 29 consecutive paraffin-embedded colon adenocarcinomas and adjacent normal colon using a specific anti-M3R antibody and immunoperoxidase staining. This revealed weak M3R expression in normal colonocytes, primarily on basolateral surfaces. In contrast, in 25 of 29 cancer tissues (86%) we observed both cytoplasmic and plasma membrane over-expression of M3R; compared to normal epithelium, mean M3R staining intensity was increased more than two-fold in colon cancer (P < 0.001). M3R staining was also increased in 22 colon adenomas compared to adjacent normal colon (P < 0.001). In contrast, M3R staining intensity was not increased in lymph node or liver metastases. These findings suggest M3R expression plays an important role in early progression and invasion of colon neoplasia but is less important once tumors have spread.

Алгоритм діагностики та ендоскопічного лікування неоплазій товстого кишечника

Колоноскопія (КС) є "золотим" стандартом для виявлення новоутворень товстого кишечника (ТК). Однак не всі вони виявляються і видаляються при КС. Якість обстеження і постановка правильного діагнозу залежать від індивідуального підходу вибору методу підготовки в залежності від часу проведення КС, наявності супутньої патології, запорів. Хромоскопія підвищує можливості стандартного ендоскопічного дослідження ТК. Вона дозволяє частіше виявляти неоплазії малих розмірів і особливо плоскі поразки, головним чином, в правій половині ТК в порівнянні з виявленням при КС в білому світі. Також ця техніка може використовуватися в комбінації зі збільшенням, що дозволяє проводити ендоскопічний прогноз морфологічного діагнозу неоплазии. Виявлення і видалення утворень малих розмірів (до 10 мм) як під час введення, так і під час виведення колоноскопа можливо, безпечно, займає менше часу, ніж "традиційна" стратегія видалення тільки під час виведення колоноскопа. З огляду на прагматичний підхід до вибору методу лікування поверхневих неоплазій проксимальних відділів ТК, все поліпи проксимально від сигмовидної кишки і все аденоми, незалежно від їх місця розташування, повинні бути видалені. Метою нашого дослідження було розробити алгоритм діагностики та ендоскопічного лікування неоплазій товстого кишечника. З 2007 по 2015 року було обстежено 4615 пацієнтів. У першому періоді нашої роботи (з 2007 по 2011 г.) КС було проведено 2375 пацієнтам за загальноприйнятою методикою (1 група) - огляд виконувався в білому світі, і в разі виявлення ураження бралася біопсія, після морфологічної верифікації проводилося його видалення. За цей період на підставі проведених досліджень був розроблений алгоритм діагностики та ендоскопічного лікування неоплазій ТК. У другому періоді (з 2011 по 2015 г.) відповідно до алгоритму було обстежено 2240 пацієнтів (2 група). В 1 групі пацієнтів було виявлено 126 (5,3%), а у 2 групі - 463 (20,7%) неоплазии, що достовірно більше (Р &lt;0,0001, c2 = 245,79). В 1 групі все неоплазии віддалялися тільки шляхом петлевий Поліпектомія, а у 2 - при петлевий Поліпектомія 213 освіти (0-Ip - 126 і 87 - 0-Isp), резекції слизової - 227 (114 - 0-Isp, 104 - 0-IIa і 9 - 0-IIb), диссекции в підслизовому шарі - 23 (11 - LST NG, 5 - 0-IIa + 0-Is і 7 - 0-Is + 0-IIa). Впровадження розробленого алгоритму діагностики та лікування уражень товстого кишечника збільшило Виявлення поразок, поліпшило результати їх ендоскопічного лікування і зменшило кількість повторних КС на 16%.

Abstract A31: Biological effects of lutein and kale on the prevention of colonic inflammation and carcinogenesis

Abstract Ulcerative colitis is a risk factor for colon cancer. Dietary lutein, a nutrient rich in kale, is inversely associated with the risk of developing colon cancer in human observational epidemiologic studies. Besides lutein, kale also contains abundant amounts of other bioactive components with anti-inflammatory, antioxidant, and anti-cancer properties. As a whole food approach, kale may provide more favorable biologic effects on colonic inflammation and neoplasia than lutein alone. Additionally, it is unclear if lutein prevents colon neoplasia via the inhibition of colonic inflammation. Using a dextran sulfate sodium (DSS)-induced colitis and neoplasia mouse model, we evaluated the effects of dietary lutein supplementation and kale on the DSS-induced colorectal inflammation, ulceration, hyperplasia, dysplasia and cancer. Two hundred sixty four 8-week old Swiss-Webster (CFW) mice were assigned to one of ten groups (n = 26 to 27 in each group [13 males and 13 to 14 females]) for 21 weeks as follows: 1) 0.0005% of lutein plus DSS; 2) 0.001% of lutein plus DSS; 3) 0.002% of lutein plus DSS; 4) 0.005% of lutein plus DSS; 5) kale equivalent to 0.0005% of lutein plus DSS; 6) kale equivalent to 0.001% of lutein plus DSS; 7) kale equivalent to 0.002% of lutein plus DSS; 8) kale equivalent to 0.005% of lutein plus DSS; 9) DSS only; and 10) control with no treatment. During the 21-week experimental period, mouse body weights were recorded weekly. At week 7, the mice in groups 1-9 were given DSS for 4 cycles (1 cycle = 1 week 3% of DSS in drinking water followed by 2-week water) to induce colitis and colorectal neoplasia. This report described the findings on the presence of clinical signs of colitis (hemoccult and loose stools, which were evaluated at the end of each week throughout the experiments), and the findings from histopathological evaluations (inflammation, ulceration, hyperplasia, dysplasia, and neoplasia). Dietary lutein and kale, particularly two higher doses (0.002% and 0.005%), reduced the DSS-induced hemoccult and loose stools, as well as the DSS-induced inflammation, ulceration, hyperplasia, dysplasia, and neoplasia. These data suggest that dietary lutein and kale may prevent the DSS-induced colorectal inflammation and associated preneoplastic and neoplastic lesions. Grant Funding Sources: This project was supported by Agriculture and Food Research Initiative Competitive Grant no. 2014-67017-21754 from the USDA National Institute of Food and Agriculture and by USDA/ARS grant 1950-51000-074S. Citation Format: Chun Liu, Roderick T. Bronson, Xiang-Dong Wang. Biological effects of lutein and kale on the prevention of colonic inflammation and carcinogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A31.

The depletion of ATM inhibits colon cancer proliferation and migration via B56γ2-mediated Chk1/p53/CD44 cascades

Ataxia-telangiectasia mutated (ATM) protein kinase is a major guardian of genomic stability, and its well-established function in cancer is tumor suppression. Here, we report an oncogenic role of ATM. Using two isogenic sets of human colon cancer cell lines that differed only in their ATM status, we demonstrated that ATM deficiency significantly inhibits cancer cell proliferation, migration, and invasion. The tumor-suppressive function of ATM depletion is not modulated by the compensatory activation of ATR, but it is associated with B56γ2-mediated Chk1/p53/CD44 signaling pathways. Under normal growth conditions, the depletion of ATM prevents B56γ2 ubiquitination and degradation, which activates PP2A-mediated Chk1/p53/p21 signaling pathways, leading to senescence and cell cycle arrest. CD44 was validated as a novel ATM target based on its ability to rescue cell migration and invasion defects in ATM-depleted cells. The activation of p53 induced by ATM depletion suppresses CD44 transcription, thus resulting in epithelial–mesenchymal transition (EMT) and cell migration suppression. Our study suggests that ATM has tumorigenic potential in post-formed colon neoplasia, and it supports ATM as an appealing target for improving cancer therapy.

The genetics and molecular biology of colonic neoplasia: practical implications for the clinician.

Despite the large investment of resources from screening, the fact that colorectal cancer remains the second leading cause of cancer deaths among Americans underscores the need for alternative strategies. Thus, a major clinical and research imperative is personalize clinical care, while focusing on risk stratification for screening, surveillance, chemoprevention, and therapeutic intervention. A complicating factor that colorectal cancer is biologically heterogeneous for at least four consensus molecular subtypes presents clear challenges for developing robust molecular biomarkers. The purpose of the review is to discuss the genetics and molecular biology of colonic neoplasia, high and low penetrance, and racial disparities in colonic neoplasia. Finally, we put forth the emerging concept of greater genomic landscape and the idea of chromatin protection therapy as a novel adjuvant to chemotherapy.