Colorectal Cancer In Inflammatory Bowel Disease Research Articles

Diagnosis and management of inflammatory bowel disease-associated neoplasia: considerations in the modern era.

Patients with inflammatory bowel disease (IBD) are at an increased risk of developing intestinal neoplasia—particularly colorectal neoplasia, including dysplasia and colorectal cancer (CRC)—as a primary consequence of chronic inflammation. While the current incidence of CRC in IBD is lower compared with prior decades, due, in large part, to more effective therapies and improved colonoscopic technologies, CRC still accounts for a significant proportion of IBD-related deaths. The focus of this review is on the pathogenesis; epidemiology, including disease- and patient-related risk factors; diagnosis; surveillance; and management of IBD-associated neoplasia.

2092 A Rare Case of Primary Colonic Lymphoma Mimicking Metastatic Adenocarcinoma in a Patient With Ulcerative Colitis

INTRODUCTION: Primary colorectal lymphoma (PCL) is uncommon and accounts for only 0.2-1% of all large intestine cancers. There is an increasing incidence in populations with Inflammatory bowel disease (IBD), Celiac disease, H. pylori and other autoimmune conditions. Here, we present a rare case of Ulcerative Colitis with primary Diffuse Large B Cell lymphoma (DLBCL) and liver metastasis. CASE DESCRIPTION/METHODS: Our patient is a 50 y/o male with left-sided ulcerative colitis presenting with a two- month history of severe left lower quadrant abdominal pain and constipation, without overt GI bleeding, diarrhea or weight loss. Examination was remarkable for left lower quadrant tenderness, without palpable mass. CT scan revealed multiple ill-defined liver masses concerning for metastasis with circumferential thickening in sigmoid colon with fat infiltration. Of note, patient had surveillance colonoscopy, few months prior to presentation which revealed marked erythema in the sigmoid colon, biopsies revealed acute on chronic inflammation without evidence of malignancy. Labs with normal CEA, AFP, CA 19- 9 levels. Repeat colonoscopy showed an ulcerated stricture with friable nodular mucosa in the sigmoid colon that was again biopsied in conjunction with biopsy of the liver lesions. Immunohistochemical staining of colon and liver lesions was positive for CD20 and negative for CK20, CK7 and CDX2, consistent with DLBCL. Patient was started on R-CHOP chemotherapy and is currently being monitored for response by Oncology. DISCUSSION: The risk of colorectal cancer significantly increases in IBD and surveillance is usually warranted. Although the suspicion of adenocarcinoma remains high in a UC patient with colonic mass and liver metastasis, PCL should also remain in the differential as correct pre-operative identification is crucial for the design of treatment. PCL is rare, with a male predominance in age 50-70 years and typically present with abdominal pain, lower GI bleeding, weight loss, palpable mass and rarely bowel obstruction. Diagnosis is aided by tissue biopsy and imaging. Multimodality approach involving both surgery and chemotherapy is the principal mode of treatment with radiotherapy in selected cases. Considering our patient’s clinical scenario, further speculations in routine CT scans to evaluate symptoms, alongside endoscopic surveillance for colorectal cancer in IBD, needs to be addressed.

Interrelations of Apoptotic and Cellular Senescence Genes Methylation in Inflammatory Bowel Disease Subtypes and Colorectal Carcinoma in Egyptians Patients.

Ras-related domain family member 1 transcript variant A (RASSF1A) controls apoptosis and cell proliferation while p14/ARF gene has a regulatory role in cellular senescence. Failure of apoptosis and cellular senescence occurs during inflammatory bowel disease (IBD) and colorectal cancer (CRC). To reveal the role of peripheral leukocyte promoter methylation of RASSF1A and p14/ARF in the pathogenesis of IBD subtypes and CRC we investigated the methylation state of the two genes by methylation-specific polymerase chain reaction (MSP-PCR) in 60 CRC patients, 60 patients with IBD; 27 with ulcerative colitis and 33 had Crohn's disease and also in 30 healthy subjects. Methylated RASSF1A and p14/ARF genes were detected in 55% and 60% of CRC, while the frequency of the methylated RASSF1A and p14/ARF genes was 23.3% and 43.3% in IBD patients and 3.3% and 13.3% in the control group (P = 0.000 each). Also, the frequency of methylated RASSF1A gene was significantly higher in ulcerative colitis than in Crohn's disease, while a non-significant frequency of methylated p14/ARF was detected between ulcerative colitis and Crohn's disease. Furthermore, methylated RASSF1A and p14/ARF were associated with the grade of CRC but not associated with the age of patients, family history, or tumor location. Results suggest that methylated RASSF1A and p14/ARF are related to CRC and IBD pathogenesis and may be used as molecular biomarkers for early detection of CRC and IBD.

Risk of Early Colorectal Cancers Needs to Be Considered in Inflammatory Bowel Disease Care.

Current guidelines recommend starting colorectal cancer (CRC) surveillance 8-10years after inflammatory bowel disease (IBD) onset. Recent studies report that the incidence of CRC within 8-10years of IBD onset (i.e., early CRC) ranges from 12 to 42%. To describe the current prevalence of early CRC in a tertiary care center IBD cohort with CRC and to identify associated risk factors. We performed a single-center observational study of IBD patients diagnosed with CRC from 2005 to 2015. We compared characteristics of patients with early CRC (diagnosis of CRC within 8years of initial IBD onset) to those with CRC diagnosed later in their IBD course. Ninety-three patients met inclusion criteria. Eleven (11.8%) patients developed CRC within 8years of initial IBD onset. On multivariable logistic regression, age greater than 28 at IBD onset (adjusted OR 12.0; 95% CI 2.30, 62.75) and tobacco use (adjusted OR 8.52; 95% CI 1.38, 52.82) were significant predictors of early CRC. A validation cohort confirmed calibration and discrimination of the model. One out of every eight IBD patients with CRC developed their malignancy prior to the currently recommended timeframe for the initiation of surveillance colonoscopy. IBD onset at 28years or older and tobacco use were identified as predictors of early CRC. Early CRC should be considered in discussions of cancer surveillance in this population. Prospective cohort studies are necessary to further analyze the impact of early CRC in IBD.

New Methylation Biomarker Panel for Early Diagnosis of Dysplasia or Cancer in High-Risk Inflammatory Bowel Disease Patients.

The risk of developing colorectal cancer (CRC) is increased in patients with inflammatory bowel disease (IBD) of the colon. The aim of the study was to evaluate the effectiveness of selected methylation gene panel for the early detection of CRC in high-risk IBD patients. In a discovery phase, 73 biopsies of 48 IBD patients (associated or not to CRC) were analyzed from genome-wide DNA methylation analysis using the Illumina Human Methylation 450K BeadChip. The panel of 5 genes selected (EYA4, SLIT2, FLI1, USP44, and SND1) was validated prospectively using methylation-specific melting curve analysis in biopsies of diseased and adjacent healthy tissue of 203 patients: 38 with IBD and associated neoplasia, 81 patients with IBD (25 of them with high risk), 48 with sporadic CRC, and 36 healthy controls. The prevalence of methylation was higher in patients with IBD and associated neoplasia (both in diseased and adjacent healthy tissue, 71% and 52%, respectively) than in healthy controls (2/36, 6%; P = 6.72E-05). Methylation in IBD patients at high risk of dysplasia or cancer was more frequently detected than in patients at low risk (92% vs 57%; odds ratio, 8.63; P = 0.001). EYA4 and SLIT2 were the markers most frequently methylated. Differences in methylation levels were more evident in healthy mucosa (82% vs 15% high vs low risk, respectively; P = 1.25E-05). Analysis of this panel of methylation markers may help in the early identification of colorectal dysplasia or cancer in high-risk IBD patients.

Colorectal Cancer in Inflammatory Bowel Disease.

Patients with inflammatory bowel disease (IBD) are at significantly increased risk of colorectal cancer (CRC), principally resulting from the pro-neoplastic effects of chronic intestinal inflammation. Epidemiologic studies continue to highlight the increased risk of CRC in IBD. However, the incidence has declined over the past 30 years, attributed to both successful CRC-surveillance programs and improved control of mucosal inflammation. Risk factors that further increase the risk of IBD-related CRC include disease duration, extent and severity, the presence of inflammatory pseudopolyps, coexistent primary sclerosing cholangitis, and a family history of CRC. All major professional societies agree that IBD-CRC surveillance should occur more frequently than in the general population. Yet, guidelines and consensus statements differ on the surveillance schedule and preferred method of surveillance. Improved sensitivity to previously "invisible" flat dysplastic lesions using high definition and chromoendoscopy methods has resulted in many guidelines abandoning requirements for random untargeted biopsies of the colon. While colonic dysplasia remains a worrisome finding, and several clinical scenarios remain best addressed by total proctocolectomy due to concerns of synchronous undetected lesions and the unpredictable tempo of progression to malignancy, better detection techniques have also increased opportunities for endoscopic resection of dysplastic lesions that can be clearly delineated. Finally, the expanding armamentarium of medical options in IBD, including anti-tumor necrosis factor and anti-adhesion biologic therapies, have substantially improved our ability to control severe inflammation and likely reduce the risk of CRC over time.

Incidence of Colorectal Cancer and Extracolonic Cancers in Veteran Patients With Inflammatory Bowel Disease.

The risk for colorectal cancer (CRC) and certain extracolonic cancers is thought to be increased in inflammatory bowel disease (IBD), but few recent US studies have evaluated this issue. We aimed to estimate the incidence of CRC and extracolonic cancers in IBD patients. In this case-control study, cases were all IBD patients treated in our Department of Veterans Affairs (VA) hospital who developed CRC or extracolonic cancers between 1996 and 2015. Controls were patients in the general VA population who developed these cancers during the same time. We compared cancer incidence rates (IRs) in cases and controls. There was no significant difference between cases and controls in the 20-year IR for CRC (148/100 000 in IBD patients, 97/100 000 in controls; relative risk [RR], 1.53; 95% confidence interval [CI], 0.86-2.69). In contrast, IBD cases had a significantly higher 20-year IR for all extracolonic cancers than controls (2839/100 000 in IBD patients, 1960/100 000 in controls; RR, 1.45; 95% CI, 1.27-1.65). Site-specific analyses revealed that IBD patients had significantly elevated risks for nonmelanoma skin cancers (RR, 2.38; 95% CI, 1.99-2.85), melanoma skin cancers (RR, 2.85; 95% CI, 1.63-4.88), renal tumors (RR, 2.90; 95% CI, 1.46-5.84), prostate cancer (RR, 1.70; 95% CI, 1.28-2.27), and pancreatic cancer (RR, 4.23; 95% CI, 1.35-13.29). The incidence of CRC was not significantly higher in our veteran patients with IBD than in control patients in the general VA population. In contrast, our IBD patients had a significantly higher risk for extracolonic cancers than controls, including cancers of the skin, kidneys, prostate, and pancreas. 10.1093/ibd/izx046_video1Video 1.izx046_Mosher_Video5734484616001.

Multi-target stool DNA test in the surveillance of inflammatory bowel disease: a cross-sectional cohort study

Background and aim: Colonoscopic surveillance is recommended in patients with longstanding inflammatory bowel disease (IBD) as they are at increased risk of colorectal cancer (CRC). Non-invasive surveillance may improve compliance and access. Multi-target stool DNA (MT-sDNA) has been validated for screening of sporadic CRC but has not been assessed in IBD. Our aim was to assess the performance of a MT-sDNA test in a real-life surveillance setting of patients with longstanding IBD.Material and methods: A total of 192 IBD patients enrolled from two prospective cohorts submitted an EDTA buffered stool sample and underwent chromo- or white light colonoscopy. Stools were assayed for methylated BMP3 & NDRG4, mutant KRAS and β-actin by a laboratory blinded to clinical data.Results: The multitarget-sDNA panel was positive in 2/2 CRC and 5/15 low-grade dysplasia (LGD) < 1 cm in diameter. Sensitivities were 100% (95% CI 16–100%) for CRC and 33% (95% CI 13–61%) for LGD lesions <1 cm, with specificities of 87% (95% CI 81–91%) and 93% (95% CI 88–96%), respectively. The estimated number of patients needed to screen to detect a single CRC was 96 (95% CI 93–99%) and was 28 (95% CI 22–34%) to detect any colorectal neoplasia (CRN).Conclusion: The MT-sDNA panel detected CRC in IBD. Sensitivity for sub-centimeter colorectal neoplasms in IBD patients appears similar to that observed in the general population. The test may be a valuable tool for detection of malignancy during structured surveillance of long-term IBD in a first line hospital setting.

Vitamin D Reduces Colitis- and Inflammation-Associated Colorectal Cancer in Mice Independent of NOD2

ABSTRACTInflammatory bowel disease (IBD) patients are at increased risk of developing colorectal cancer (CRC). Vitamin D (vD) induces NOD2 gene expression, enhancing immunity, while deficiency impairs intestinal epithelial integrity, increasing inflammation. This study investigated the effect of vD on CRC in colitis, and if preventive benefits are mediated via NOD2. Inflammation-associated CRC was induced by treating C57BL/6J and Nod2−/− mice with azoxymethane (AOM) and dextran sodium sulfate (DSS) cycles (×3). vD-deficient mice displayed more severe colitis compared to vD-supplemented mice, with greater weight loss, higher colitis activity index, increased colonic weight/length ratios, and lower survival rates. Increased histological inflammation score and increased IL-6 were observed in the mucosa of vD-deficient mice. Overall incidence of colonic tumors was not significantly different between vD-deficient and vD-supplemented mice. Higher tumor multiplicity was observed in vD-deficient vs vD-supplemented groups (both mouse strains). After AOM/DSS treatment, decreased plasma 25(OH)D3 levels and downregulation of vD target genes Cyp24 and Vdr were observed in both mice strains (vD-deficient or vD-supplemented diet), compared to saline-treated controls on the vD-deficient diet. In conclusion, vD supplementation reduced colitis severity and decreased the number of inflammation-associated colorectal tumors in both C57BL/6J and Nod2−/− mice, independent of NOD2.

The Role of Proinflammatory Pathways in the Pathogenesis of Colitis-Associated Colorectal Cancer.

Patients with inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC). The risk factors of CRC in IBD patients include long disease duration, extensive colitis, severe histological inflammation, and coexistence with primary sclerosing cholangitis (PSC). Several molecular pathways that contribute to sporadic CRC are also involved in the pathogenesis of colitis-associated CRC. It is well established that long-standing chronic inflammation is a key predisposing factor of CRC in IBD. Proinflammatory pathways, including nuclear factor kappa B (NF-κB), IL-6/STAT3, cyclooxygenase-2 (COX-2)/PGE2, and IL-23/Th17, promote tumorigenesis by inducing the production of inflammatory mediators, upregulating the expression of antiapoptotic genes, and stimulating cell proliferation as well as angiogenesis. Better understanding of the underlying mechanisms may provide some promising targets for prevention and therapy. This review aims to elucidate the role of these signaling pathways in the pathogenesis of colitis-associated CRC using evidence-based approaches.

5-ASA and Chemoprevention in Inflammatory Bowel Disease: A Population-Based Analysis

Introduction: Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, relapsing and remitting inflammatory disease of the gastrointestinal tract. Colorectal cancer (CRC) is a well-documented complication of IBD and is associated with IBD severity, extent and duration. Treatment with 5-aminosalicylic acid (5-ASA) reduces the risk of CRC in IBD. Our objective was to test the association of cumulative exposure to 5-ASA on CRC risk. Methods: A retrospective cohort study was performed using a population-based IBD cohort derived from administrative health data in Saskatchewan, Canada. Data were from 1979 to 2011. Exposure to 5-ASA and CRC diagnosis during the study period were examined. CRC rates were compared between 5-ASA exposed and non-exposed groups using chi-square tests. Exposure to 5-ASA was evaluated using survival analysis. To account for differences in 5-ASA exposure, propensity scores (PS) based on IBD duration, immunomodulator (IM) and anti-TNF exposure, number of endoscopies, and decade of IBD diagnosis were used to match non-exposed to exposed patients. The Kaplan-Meier estimator was used to describe the time-to-event data and Cox proportional hazards regression models were used to test the association of exposure with CRC diagnosis. Analyses were stratified by type of IBD (UC, CD). Results: A total of 8821 IBD patients were included in the study, of which 289 (3.3%) developed CRC. In the CRC-free group, 73.9% (n = 6307) of patients had exposure to 5-ASA, whereas 61.9% (n = 179) had exposure in the CRC group. Figure 1 contains a Kaplan Meier curve for time-to-diagnosis of CRC for the exposure groups. In the PS-matched cohort, the hazard ratio (HR) was 2.56 (95% CI: [1.9, 3.5]) while controlling for gender, location (urban/sub-urban/rural), diagnosis and previous corticosteroid use. The risk of CRC diagnosis was higher in the UC sub-group (HR=3.54, 95% CI: [2.3, 5.5]) when compared to the CD sub-group (1.73, 95% CI: [1.1, 2.6]), controlling for gender, location and decade of diagnosis. A dose response survival model was developed to attempt to control for the duration of 5-ASA exposure on CRC rates, and the HRs were similar.Figure 1Conclusion: This population-based cohort study suggests a chemoprotective effect of 5-ASA exposure for CRC diagnosis amongst patients with IBD. A larger protective effect was observed amongst UC patients than CD patients.

Cancer in Elderly Onset Inflammatory Bowel Disease: A Population-Based Study.

Cancer may be a complication of inflammatory bowel disease (IBD) or its treatment. In elderly onset IBD patients the risk of malignancy is of particular concern. We studied this risk in a population-based cohort of elderly onset IBD patients. In a French population-based cohort, we identified 844 patients aged >60 years at IBD diagnosis from 1988 to 2006, including 370 Crohn's disease (CD) and 474 ulcerative colitis (UC). We compared incidence of cancer among IBD patients with that observed in the French Network of population-based Cancer Registries (FRANCIM). Confidence interval (CI) was estimated assuming a Poisson-specific law for rare events. Results were expressed using the standardized incidence ratios (SIRs) and their CI 95%. Median age at IBD diagnosis was 70 (65-76) years in CD and 69 (64-74) in UC. Median follow-up was 6 (2-11) years for both diseases with a number of person-years of 5,598. Among the 844 elderly onset IBD cases, 98 (11.6%; 42 CD and 56 UC) developed a cancer after IBD diagnosis (67 men and 31 women) corresponding to an overall SIR of 0.97 (0.80-1.18). These cancers occurred at a median age of 77 years (71-80) and 75 years (71-81) in patients with CD and UC, respectively. Median time between IBD diagnosis and cancers was 78 months (40-121). There was no significant increased risk of colorectal cancer in IBD (SIR=1.03 (0.62-1.70), CD (SIR=1.20 (0.57-2.52) nor in UC (SIR=0.91 (0.45-1.82) without significant protective role of 5-aminosalicylic acid (hazard ratio (HR)=0.7 (0.2-2.6)). No significant risk for other intestinal cancers was found, especially for small bowel carcinoma. An increased risk of malignant lymphoproliferative disorders was found in all IBD and in CD: SIR=2.49 (1.25-4.99) and SIR=3.09 (1.16-8.23), respectively. An increased risk of myeloproliferative disorders was found in all IBD (SIR=2.18 (1.09-4.35)). Thiopurines exposure, using a time-dependant Cox model, was not found as associated with an increased risk to develop cancer, HR=0.90 (0.48-1.68). There is no increased risk for developing intestinal cancer among patients with elderly onset IBD in this population-based cohort. There are increased risks of developing lymphoproliferative and myeloproliferative disorders in all IBD. Thiopurines exposure was not found as associated with an increased risk to lymphoproliferative disorders. These data reinforce the difference between elderly onset IBD as compared with patients with younger age at IBD onset.

Worldwide Incidence of Colorectal Cancer, Leukemia, and Lymphoma in Inflammatory Bowel Disease: An Updated Systematic Review and Meta-Analysis

Background/Aims. Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC). In addition, there may be an association between leukemia and lymphoma and IBD. We conducted a systematic review and meta-analysis of the IBD literature to estimate the incidence of CRC, leukemia, and lymphoma in adult IBD patients. Methods. Studies were identified by a literature search of PubMed, Cochrane Library, Medline, Web of Science, Scopus, EMBASE, and ProQuest Dissertations and Theses. Pooled incidence rates (per 100,000 person-years [py]) were calculated through use of a random effects model, unless substantial heterogeneity prevented pooling of estimates. Several stratified analyses and metaregression were performed to explore potential study heterogeneity and bias. Results. Thirty-six articles fulfilled the inclusion criteria. For CRC, the pooled incidence rate in CD was 53.3/100,000 py (95% CI 46.3–60.3/100,000). The incidence of leukemia was 1.5/100,000 py (95% CI −0.06–3.0/100,000) in IBD, 0.3/100,000 py (95% CI −1.0–1.6/100,000) in CD, and 13.0/100,000 py (95% CI 5.8–20.3/100,000) in UC. For lymphoma, the pooled incidence rate in CD was 0.8/100,000 py (95% CI −0.4–2.1/100,000). Substantial heterogeneity prevented the pooling of other incidence estimates. Conclusion. The incidence of CRC, leukemia, and lymphoma in IBD is low.

Colorectal cancer in colitis: a relic of the past?

The incidence of dysplasia and colorectal cancer in patients with long-standing colitis seems to be decreasing and controversy surrounds our detection and management strategies. Dysplasia is rarer, flatter, and smaller than in previous decades. Current surveillance guidelines, onerous in terms of colonoscopic workload and an emphasis on random biopsies, have yet to be shown to prevent colon cancers and colon cancer death in these patients. The evidence base for adjunct techniques such as chromoendoscopy is strong but adoption has been slow. We need to better risk-stratify patients with colitis and direct diminishing medical resources accordingly. Modulating dysplasia and cancer risk will involve optimizing medical therapies and focusing our colonoscopic efforts on those who will most likely benefit.

Immunohistochemical expression of SP-NK-1R-EGFR pathway and VDR in colonic inflammation and neoplasia.

To determine the expression of neurokinin-1 receptor (NK-1R), phosphorylated epidermal growth factor receptor (pEGFR), cyclooxygenase-2 (Cox-2), and vitamin D receptor (VDR) in normal, inflammatory bowel disease (IBD), and colorectal neoplasia tissues from Puerto Ricans. Tissues from patients with IBD, colitis-associated colorectal cancer (CAC), sporadic dysplasia, and sporadic colorectal cancer (CRC), as well as normal controls, were identified at several centers in Puerto Rico. Archival formalin-fixed, paraffin-embedded tissues were de-identified and processed by immunohistochemistry for NK-1R, pEGFR, Cox-2, and VDR. Pictures of representative areas of each tissues diagnosis were taken and scored by three observers using a 4-point scale that assessed intensity of staining. Tissues with CAC were further analyzed by photographing representative areas of IBD and the different grades of dysplasia, in addition to the areas of cancer, within each tissue. Differences in the average age between the five patient groups were assessed with one-way analysis of variance and Tukey-Kramer multiple comparisons test. The mean scores for normal tissues and tissues with IBD, dysplasia, CRC, and CAC were calculated and statistically compared using one-way analysis of variance and Dunnett's multiple comparisons test. Correlations between protein expression patterns were analyzed with the Pearson's product-moment correlation coefficient. Data are presented as mean ± SE. On average, patients with IBD were younger (34.60 ± 5.81) than normal (63.20 ± 6.13, P < 0.01), sporadic dysplasia (68.80 ± 4.42, P < 0.01), sporadic cancer (74.80 ± 4.91, P < 0.001), and CAC (57.50 ± 5.11, P < 0.05) patients. NK-1R in cancer tissue (sporadic CRC, 1.73 ± 0.34; CAC, 1.57 ± 0.53) and sporadic dysplasia (2.00 ± 0.45) were higher than in normal tissues (0.73 ± 0.19). pEGFR was significantly increased in sporadic CRC (1.53 ± 0.43) and CAC (2.25 ± 0.47) when compared to normal tissue (0.07 ± 0.25, P < 0.05, P < 0.001, respectively). Cox-2 was significantly increased in sporadic colorectal cancer (2.20 ± 0.23 vs 0.80 ± 0.37 for normal tissues, P < 0.05). In comparison to normal (2.80 ± 0.13) and CAC (2.50 ± 0.33) tissues, VDR was significantly decreased in sporadic dysplasia (0.00 ± 0.00, P < 0.001 vs normal, P < 0.001 vs CAC) and sporadic CRC (0.47 ± 0.23, P < 0.001 vs normal, P < 0.001 vs CAC). VDR levels negatively correlated with NK-1R (r = -0.48) and pEGFR (r = -0.56) in normal, IBD, sporadic dysplasia and sporadic CRC tissue, but not in CAC. Immunohistochemical NK-1R and pEGFR positivity with VDR negativity can be used to identify areas of sporadic colorectal neoplasia. VDR immunoreactivity can distinguish CAC from sporadic cancer.

Colorectal Adenocarcinoma and Inflammatory Bowel Disease: An Update and Review

Inflammatory bowel disease and its two prototypic illnesses: Crohn’s disease and ulcerative colitis have long been thought to confer an increased risk of colorectal cancer, although the magnitude of this effect has been difficult to elucidate. The driving factors behind this relationship include genetics, microbial disturbances, alongside molecular and inflammatory misregulation. The epidemiologic understanding of the inflammatory bowel disease-colorectal cancer relationship has evolved over the last decade. This review will focus on the epidemiology of colorectal cancer in inflammatory bowel disease, and detail the elements driving disease development. Patient risk factors, many that increase the intensity or duration of inflammation, will be detailed. Finally, a practical approach to the tools that clinicians have at their disposal in preventing this disease, including the effect of different medications and timing of colonoscopy will be presented.

Abstract 4926: Molecular imaging of colorectal cancer in the setting of colitis

Abstract Introduction: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is defined by chronic inflammation of the gastrointestinal tract. In the colon, persistent colitis is a major risk factor in IBD-associated colorectal cancer (CRC). While primary and metastatic CRC can often be visualized using radiotracers such as 18F-FDG for PET imaging, the sensitivity for detection of primary CRC is decreased in the setting of IBD due to increased glucose metabolism at sites of inflammation. EGFR overexpression is reported in up to 97% of CRCs. The lower expression in inflammatory cells makes it a valuable imaging target to identify CRC in the setting of colitis. Objective: The goal of this effort is to develop and test in murine models an EGFR targeted PET imaging probe for the detection of CRC, with the ability to differentiate neoplasia from colonic inflammation. Methods: The F(ab')2 fragment of cetuximab was generated by enzymatic digestion. After the integrity and purity of the F(ab')2 was evaluated with SDS-PAGE and FPLC, the F(ab')2 fragment was conjugated with the p-SCN-Bn-DOTA chelate, and then radiolabeled with 64Cu. The receptor binding affinity and specificity of the 64Cu-DOTA-F(ab')2 was evaluated using EGFR expressing CT26 murine colon cancer cells. Tumor to bowel ratio of the EGFR PET imaging probe was compared with 18F-FDG using DSS-treated CT26 tumor-bearing BALB/c mice at 24 h. The in vivo behavior of the probe was demonstrated with PET-CT in two different mouse models of CRC (ApcCKOp53flox/flox and ApcLoxP/ LoxPMsh2null/LoxP). Histochemical examination were also performed. Results: F(ab')2 fragments of cetuximab can be generated efficiently and with high purity. The radioligand binding assay revealed that 64Cu labeled EGFR-DOTA-F(ab')2 conjugate bound specifically to EGFR on CT26 xenografts, with KD and Bmax values in vitro of 6.6 0.7 nM and 3.3 0.1 x 106 receptors/cell respectively. DSS-induced colitis was confirmed with relative change in body weight, 18F-FDG PET imaging, and histological examination. 64Cu-DOTA-F(ab')2 showed a significantly higher (p &amp;lt; 0.001) tumor to bowel ratio (TBR = 3.8 0.10) in comparison with 18F-FDG (TBR =1.5 0.05) during inflammation in the colon. Colon tumors in GEMM were successfully visualized and showed high correlation with ex-vivo PET imaging results and IHC examination. Conclusions: The developed EGFR targeted PET imaging probe demonstrated high target specificity for colonic tumors in the setting of colitis as compared to 18F-FDG. Future clinical translation of this paradigm is promising for the detection of CRC in IBD. Citation Format: N. Selcan Turker, Umar Mahmood, Melani H. Kucherlapati, Raju Kucherlapati. Molecular imaging of colorectal cancer in the setting of colitis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4926. doi:10.1158/1538-7445.AM2014-4926

Primary sclerosing cholangitis as an independent risk factor for colorectal cancer in the context of inflammatory bowel disease: a review of the literature.

To examine and evaluate recent evidence regarding the epidemiology, pathogenesis and management of colorectal cancer (CRC) development in inflammatory bowel disease (IBD)-primary sclerosing cholangitis (PSC) patients. Using the PubMed database, a literature search was conducted for relevant articles in English from the past 10 years. Relevant studies investigating PSC as a risk factor for CRC in IBD in the context of incidence and prevalence, pathogenesis, prevention and prognosis were included in this review. Recent evidence increasingly points to PSC as a significant risk factor in the development of CRC in patients with concomitant IBD. PSC may be an important risk factor for CRC in different populations worldwide. The mechanism for this increase in risk is still unclear. The efficacy of UDCA as a chemopreventive agent remains controversial. Liver transplantation does not halt the development of CRC, although there is not enough evidence to suggest that it is associated with increased incidence of CRC. While routine colonoscopic surveillance should be performed in patients with concurrent PSC and IBD, more high-level evidence is required to support the benefits of the procedure. While many new developments have taken place in the last decade, the pathogenesis and optimal management of CRC development in IBD-PSC patients remain unclear.

558 Reactivity of Lower Esophageal Sphincter (LES) Upon Pharyngeal Provocation in Infants With Hypoxic Ischemic Encephalopathy (HIE)

The ageing of the population makes elderly-onset inflammatory bowel diseases (IBD) a rising problem. Risk of cancer is unknown in this population. We studied this risk in a populationbased cohort of patients with IBD. Patients and methods: In a French population-based cohort, we identified 841 IBD patients >60 years of age at diagnosis from 1988 to 2006, including 367 Crohn's disease (CD) and 472 ulcerative colitis (UC)1. We compared incidence of cancer among patients with IBD with that observed in the French Network of populationbased Cancer Registries (FRANCIM). Only cancers occurring after IBD diagnosis were taken into account. Confidence interval (CI) was estimated assuming a Poisson specific law for rare events. Results were expressed using the standardized ratios of incidence (SIR) and their CI 95%. Results: After a median follow-up of 6 years [2-11], 103 (12.3%) patients with IBD including 42 CD and 61 UC developed a cancer corresponding to a SIR of 1.00 [0.83-1.21]. Eleven patients (1.3%) developed at least 2 cancers.There was no increased risk of colorectal cancer in IBD (SIR=1.06 [0.65-1.72], CD (SIR=1.15 [0.54-2.40] and UC (SIR=0.99 [0.52-1.91] without significant protective role of 5-ASA (HR=0.7 [0.2-2.6]). An increased risk of malignant lymphoproliferative disorders was found in IBD (SIR=2.71 [1.415.20] and in UC (SIR=3.05 [1.37-6.79]) but not in CD (SIR=2.21 [0.71-6.86]). An increased risk of extraintestinal tumors was observed only for the liver in CD (SIR=3.25 [1.04-4.07]). Immunomodulator exposure (n=26) was not associated with an increased risk of cancer (SIR=0.75 [0.43-1.29]) nor with any specific risk including malignant lymphoproliferative disorders (SIR=1.89 [0.26-13.44]). Only 2 patients of this cohort received biotherapy. Conclusions: There is no increased risk for developing intestinal cancer among patients with elderly-onset IBD in this population-based cohort. There is an increased risk of developing malignant lymphoproliferative disorders in UC and an increased risk for developing liver cancer in CD. These data reinforce the peculiarity of elderly-onset IBD as compared with younger age at onset IBD1. 1 Charpentier C et al. Gut 2013

Colorectal cancer in inflammatory bowel disease: The risk, pathogenesis, prevention and diagnosis

Patients with inflammatory bowel disease (IBD) are at increased risk for developing colorectal cancer (CRC), although the overall incidence of IBD-associated CRC has been diminishing in recent decades in western countries. As demonstrated in previous studies, the risk of CRC in IBD increases with longer duration, extent of colitis, a familial history of CRC, coexistent primary sclerosing cholangitis, and the degree of inflammation. The pathogenesis of CRC in IBD is poorly understood. Similar to sporadic CRC, IBD-associated CRC is a consequence of sequential episodes of genomic alteration. Multiple inter-related pathways, including immune response by mucosal inflammatory mediators, oxidative stress, and intestinal microbiota, are also involved the pathogenesis of IBD-associated CRC. Continuing colonic inflammation appears to be a factor in the development of CRC; therefore, anti-inflammatory agents such as 5-aminosalicylate compounds and immune modulators have been considered as potential chemopreventive agents. Colonoscopic surveillance is widely accepted as being effective in reducing the risk of IBD-associated CRC, although no clear evidence has confirmed that surveillance colonoscopy prolongs survival in patients with extensive colitis. The traditional recommendation has been quadrantic random biopsies throughout the entire colon; however, several guidelines now have endorsed chromoendoscopy with a target biopsy because of increasing diagnostic yields and reduced workloads for endoscopists and pathologists. New technologies such as narrow band imaging, confocal endomicroscopy, and autofluorescence imaging have not yet been confirmed as surveillance strategies in IBD.