Metachronous Adenomas Research Articles

290 Relevance of DNA Repair Polymorphisms As Genetic Markers of Gastric Cancer Susceptibility and Prognosis in Caucasians

Colorectal cancer (CRC) screening has been shown to reduce CRC incidence and mortality through the endoscopic detection and removal of colorectal adenomas. Still, these patients are at increased risk for developing metachronous adenomas or even cancer, with the recurrence rate reaching the 50%. The pleiotropic effects of higher levels of PGE2 contribute to key steps of cancer development, including cell proliferation, angiogenesis, invasiveness and migration, inhibition of apoptosis and immunosurveillance as a refletion of deregulation of ATP-binding cassete sub-family c member 4 (ABCC4) and solute carrier organic anion transporter family, member 2A1 (SLCO2A1) genes responsable for carrying PGE2 accross the membrane. To evaluate the influence of genetic polymorphisms in ABCC4 and SLCO2A1 on the risk and time for colorectal adenoma recurrence a retrospective case-cohort study was designed gathering 195 patients diagnosed with colorectal adenomas. Adenoma reccurence was defined has the diagnosis of an adenoma after a total normal colonoscopy at least one year after the initial diagnosis. Thirty-three tagSNPs were characterized using the MassARRAY iPLEX Gold technology based on multiplex amplification followed by mass-spectrometric product separation. Three tagSNPs were identified as susceptibility biomarkers for colorectal adenoma recurrence after a bootstrap analysis. The rs1131598GG homozygous genotype of SLCO2A1 gene was associated with an enhanced risk of 6.3 (95%CI:1.31-30.0, P=0.021). In contrast and under a dominant model of inheritance, the rs1751031 and rs9524821 polymorphisms in ABCC4 gene displayed a protective behaviour (OR=0.29, 95%CI:0.12-0.72, P=0.007 and OR=0.42, 95%CI:0.19-0.93, P=0.033, respectively). Furthermore, when stratifying patients considering the endoscopic findings at baseline colonoscopy, low-risk individuals carriers of rs2274403AA genotype in ABCC4 gene had a lower interval until recurrence (85 (29140) vs 122 (109-135), P=0.011) with 44% of metachronous tumors developing by 36 months (vs 23% for AG/GG). This study demonstrates for the first time the involvement of genetic variants in PGE2 transporters in colorectal adenoma recurrence. The incorporation of genetically-based approaches might allow an optimization of current risk models for the development of metachronous colorectal adenomas or even more advanced lesions possible laeding to a decrease in CRC burden and mortality.

Prevalence and management of colorectal neoplasia in surgically treated esophageal cancer patients

AimsThe existence of other primary tumors during the treatment of esophageal cancer patients has been an important issue. Our aim is to investigate the prevalence and management of colorectal neoplasia (CRN) in surgically treated esophageal cancer patients. MethodsBetween 2002 and 2008, 93 patients with esophageal cancer were surgically treated. Seventy-three patients underwent subtotal esophagectomy and 20 underwent lower esophagectomy for esophageal cancer. Colonoscopy was available for detecting CRN before and after surgery. ResultsEighty-nine (95.7%) of the 93 patients were screened by colonoscopy preoperatively or within a year from the operation. Thirty-nine patients (43.8%) with CRN were synchronously identified: adenoma in 34 (38.2%) and adenocarcinoma in 5 patients (5.6%). Eleven adenomas with high grade-dysplasia and 8 adenomas with low grade-dysplasia were removed endoscopically. Three superficial adenocarcinomas were endoscopically removed before surgery, and 2 adenocarcinomas were surgically removed. Seventy-four patients (83.1%) were followed using colonoscopy, and 11 subsequent CRN, including 2 superficial adenocarcinomas, were endoscopically detected in 8 patients (10.8%). The size of esophageal cancer was larger in the patients with than without CRN (p = 0.036). The body mass index in esophageal cancer patients with CRN tended to be higher than in those without CRN (p = 0.065). ConclusionsWe noted that esophageal cancer is frequently associated with synchronous and/or metachronous colorectal cancer and adenomas. Colonoscopy is useful to detect and manage CRN before and after esophagectomy, although a few limitations exist.

The association of age and race and the risk of large bowel polyps.

Blacks have a higher incidence of colorectal cancer and a younger age at diagnosis compared with whites. Few studies have investigated racial differences in risk of metachronous adenomas and serrated polyps and whether this risk differs by polyp characteristics or age of patient. We analyzed data pooled from three placebo-controlled adenoma chemoprevention trials to explore racial differences in the risk of large bowel polyps in patients ≤50 and >50 years of age. Using generalized linear regression, we estimated risk ratios (RR) and 95% confidence intervals (CI) as measures of the association between race and risk of one or more adenomas or serrated polyps after randomization. Among the 2,605 subjects who completed at least one follow-up exam, blacks ≤50 years of age had a higher risk of any conventional adenoma (RR, 1.70; 95% CI, 0.99-2.92) and advanced neoplasms (RR, 4.05; 95% CI, 1.43-11.46) and a nonsignificantly lower risk of serrated polyps (RR, 0.75; 95% CI, 0.34-1.62) compared with whites. Among patients >50 years, there was no racial difference in risk of adenomas (RR, 1.08; 95% CI, 0.92-1.27) or advanced neoplasms (RR, 1.05; 95% CI, 0.71- 1.56). However, blacks had a significantly lower risk of serrated polyps (RR, 0.65; 95% CI, 0.49-0.87) than whites. Our results demonstrate a higher risk of metachronous adenomas in blacks compared with whites at younger ages. Our results suggest that the racial disparity in colorectal cancer incidence may be due to an excess of neoplasia in younger blacks.

The MIRACLE trial: A randomized, controlled trial comparing green tea extract versus placebo for the prevention of metachronous colon adenomas in a screening population.

TPS786 Background: Prevention of colorectal cancer is a major health care issue. After polypectomy there is an increased risk of polyp recurrence and various means of chemoprevention have been tried to prevent this. NSAIDs have been shown to be effective but confer side effects such as gastrointestinal bleeding. Nutraceuticals such as polyphenols from tea plants have demonstrated remarkable therapeutic and preventive effects in molecular, epidemiological and some clinical trials. However, their value in preventing colorectal polyps has not been demonstrated in a large, randomized trial. The beneficial safety profile of decaffeinated green tea extract and accumulating evidence of its cancer preventive potential justify and require, in our view, a validation of this compound for the nutriprevention of colorectal adenoma. Good accessibility and low costs might render this neutraceutical a top candidate for wider use as nutritional supplement in colon cancer prevention. Methods: Randomized, double blinded, placebo-controlled, multicenter trial. After a one month run-in period with verum, 918 patients (age: 50-80 years) who have undergone polypectomy within the last 6 months will be randomized to receive either decaffeinated green tea extract (containing 150 mg epigallocatechin gallate (EGCG) two times daily) or placebo over a period of three years. Primary outcome: Incidence of metachronous colorectal adenomas (tubulovillous, tubular, villous, serrated lesions) at the 3 year follow-up colonoscopy. Secondary outcomes: Occurrences, number, localization, size and histological subtypes of adenomas, frequency of colorectal carcinoma. In addition, genetic and biochemical biomarkers in blood samples and genetic alterations (Ras, B-raf, microRNAs) in tissue samples of adenomas will be analyzed (biobanking subprojects). Additionally, nutrikinetics and nutrigenetics of EGCG and other catechins will be assessed in healthy volunteers. Patient recruitment has started in November 2011. At September 2014, 785 patients were recruited and 651 patients were randomized. We expect the last patient out in Spring 2018. (Trial identifier NCT01360320) Clinical trial information: NCT01360320.

Metachronous cancer after endoscopic submucosal dissection of gastric neoplasia.

559 Background: Metachronous recurrence after endoscopic resection (ER) of gastric cancer is known to be high. However, recurrence rate of metachrous lesions after ER of gastric adenoma has not been studied well. The aim of the study was to compare the metachronous recurrence between gastric carcinoma and adenoma patients. Methods: Four hundred eight carcinoma and 539 adenoma patients were enrolled in this study, and median follow-up period was 27 months (IQR: 16-45 months). Clinicopathological characteristics were assessed. At the follow-up endoscopy, the whole gastric mucosa was examined thoroughly to detect any gastric neoplasia. All suspicious lesions were evaluated histologically on endoscopic biopsies. Surveillance endoscopic schedule was as follows: every 3–6 months within 1 year, then once every year. Results: Forty three metachronous recurrence was diagnosed in in carcinoma patients and 45 in adenoma patients. There was no significant difference in the incidence of recurrent metachronous neoplasm between carcinoma and adenoma patients (p=0.728, log-rank test). After excluding metachronous adenoma, cancer recurrence was not different either between two groups (p=0.943). After adjusting for age, sex, multiplicity, and Helicobacter pylori status, the risk of the metachronous development of gastric cancer in adenoma patients was similar with that in carcinoma patients (HR, 0.96; 95% CI, 0.63-1.45). Conclusions: Metachronous gastric cancer after ER of gastric adenoma was as high as that of gastric carcinoma. Similar endoscopic surveillance program should be applied for both gastric carcinoma and adenoma patients after ER.

Recurrent Primary Hyperparathyroidism: A Diagnostic Challenge in a Supernumerary Intrathyroidal Dormant Adenoma

ABSTRACTIntroductionRecurrent primary hyperparathyroidism is a rare entity and presents a significant surgical challenge.Presentation of caseWe present the case of a 53-year-old female with recurrent primary hyperparathyroidism, which was caused by the very rare occurrence of a metachronous parathyroid adenoma in a supernumerary intrathyroidal parathyroid.DiscussionThis unique case highlights the challenges that arise in the evaluation of recurrent hyperparathyroidism in which even a thorough preoperative evaluation including radiographic, nuclear medicine studies and fine needle aspiration cytology did not facilitate a definitive preoperative diagnosis.ConclusionThe management approach for these patients requires meticulous planning, experience and appropriate use of intraoperative adjuncts to guide surgical strategy.How to cite this articleLowery A, Vanbrugghe C, Golffier C, Sebag F, Henry JF. Recurrent Primary Hyperparathyroidism: A Diagnostic Challenge in a Supernumerary Intrathyroidal Dormant Adenoma. World J Endoc Surg 2015;7(2):39-43.

Surveillance Colonoscopy After a Resection of Colorectal Cancer.

Postoperative surveillance colonoscopy is regarded as an effective tool for the detection and the diagnoses of metachronous cancer and adenomas. Detection and removal of adenomatous polyps though postoperative colonoscopy may reduce the risk of recurrence of colon cancer and advanced adenomas [1]. National Comprehensive Cancer Network guidelines recommend postoperative surveillance colonoscopy within the first year after a resection of colorectal cancer [2]. Postpolypectomy surveillance guidelines published by the US Multi-society Task Force on Colorectal Cancer and based on the number of polyps, the polyp size, and the pathology were presented in 2006. In 2012, those guidelines added surveillance recommendations for serrated lesions to the previous guidelines. Guidelines are to delineate predictors of advanced pathology, both cancer and advanced adenomas. According to the guidelines, patients can be more definitely stratified at their baseline colonoscopies into those at lower risk and those at increased risk for advanced neoplasia [3]. Guidelines for postoperative surveillance colonoscopy recommend that the presence of adenomas and sessile serrated polyps be considered to determine the follow-up interval [3]. Also recommended is that the surveillance interval be based on the risk of polyps found at index colonoscopy [3]. Ratuapli et al. [4] said that knowledge of the pathology of the actual polyp does not change the postpolypectomy surveillance recommendations. Interval cancers within one year after surgery may also represent lesions that were missed on the index colonoscopy. The experienced endoscopist will miss about 15% of neoplastic polyps smaller than 10 mm in size, but will rarely miss larger polyps [5]. Another study showed an overall miss rate for adenomas of 24%; only 6% of adenomas with sizes larger than 1 cm were overlooked during the first examination [6]. Brenner et al. [7] demonstrated that the protective effect of colonoscopy against colorectal cancer was not uniform throughout the colon and that the right colon had a lower rate of protection. Factors that may contribute to lower adenoma detection, particularly in the right colon, include the prevalence of flat and depressed lesions, as well as serrated adenomas, in the more proximal segments, which are more difficult to visualize [7]. A higher proportion of polyps were adenomatous in the right and the proximal colon compared with the distal colon [8]. The adenoma detection rates for the proximal colon (22.9%) and the right colon (17.1%) were significantly higher than the adenoma detection rate for the left colon (13.5%) (both P < 0.001) [8]. A considerable variation in adenoma detection exists among endoscopists. Colonoscopies performed by endoscopists with higher adenoma detection rates are associated with lower rates of interval cancer [8]. In this study, the authors said that in the 116 enrolled patients, the incidence of total polyps during postoperative surveillance colonoscopy was 53.4% and that the incidence of neoplastic polyps was 25.9%. They also said that the miss rate of total polyps was 37.4% and the miss rate of neoplastic polyps was 24.2% during postoperative colonoscopy. The missed neoplastic polyps were located in the right colon and the proximal part from the primary tumor at a higher percentage. When more neoplastic polyps were detected during preoperative colonoscopy, more neoplastic polyps were missed during postoperative colonoscopy [9]. Repeat surveillance colonoscopy earlier than recommended may increase healthcare expenditures, and delayed surveillance colonoscopy may increase the number of patients with an interval cancer [4]. Baseline postoperative surveillance colonoscopy with excellent patient preparation and adequate withdrawal time could reduce the miss rate for colorectal cancer and adenomas. Postoperative surveillance colonoscopy is very important because it can have a great effect on reducing the incidence of colorectal cancer in patients with adenomatous polyps. Especially, the right side of Correspondence to: Byung Chun Kim, M.D. Department of Surgery, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, 1 Singil-ro, Yeongdeungpo-gu, Seoul 07441, Korea Tel: +82-2-829-5130, Fax: +82-2-849-4469 E-mail: bckimgs@hallym.or.kr

C-reactive protein and risk of colorectal adenomas or serrated polyps: a prospective study.

Serum C-reactive protein (CRP) is a sensitive marker of systemic inflammation. Because there is a well-recognized relationship between local inflammation and colorectal cancer, we aimed to evaluate whether serum CRP levels were associated with the occurrence of colorectal adenomas and serrated polyps using data from a large adenoma prevention trial. A total of 930 participants with a history of colorectal adenomas were enrolled in a randomized trial of calcium supplementation (1,200 mg/day) for the prevention of colorectal adenomas. Outcomes in this analysis are metachronous adenomas (and advanced neoplasms specifically), and serrated polyps at follow-up colonoscopy. High-sensitivity CRP levels were measured 1 year following baseline colonoscopy. Multivariate analysis was performed to estimate risk ratios (RR) using Poisson regression, controlling for potential confounders. We measured serum CRP levels in 689 participants (mean CRP, 3.62 ± 5.72 mg/L). There was no difference in CRP levels with respect to calcium versus placebo treatment assignment (P = 0.99). After adjustment for potential confounders, we found no association between CRP level and risk of recurrent adenoma or advanced lesion [quartile 4 vs. quartile 1: RR, 95% confidence interval (CI) = 0.99 (0.73-1.34) and 0.92 (0.49-1.75), respectively]. Similarly, no association was seen between CRP levels and risk of serrated polyps or proximal serrated polyps [quartile 4 vs. quartile 1: RR (95% CI) = 1.32 (0.85-2.03) and 1.19 (0.54-2.58), respectively]. In conclusion, this large prospective colorectal adenoma chemoprevention study found no significant relationship between CRP levels and occurrence of adenomas, advanced neoplasms, or serrated polyps.

Abstract CT335: A clinical trial of supplementation with vitamin D and/or calcium for the prevention of colorectal adenomas

Abstract Considerable epidemiological and preclinical evidence suggests that high vitamin D status confers a lower risk of colorectal neoplasia. High calcium intake has also been associated with reduced risks, and trials using calcium have shown a reduction in the occurrence of adenomas. To study these issues, we conducted a randomized, double blind, placebo-controlled trial of supplementation with vitamin D and/or calcium for the prevention of colorectal adenomas. We hypothesized that subjects receiving Vitamin D supplementation would have a lower risk of metachronous adenomas than those given placebo, that those randomized to calcium would have a lower risk, and that subjects given calcium and vitamin D together would have a lower risk than those given calcium alone. Secondary hypotheses involved effects of study agents on advanced lesions. Methods: In 11 US centers, we recruited subjects recently diagnosed with at least one adenoma; with no known polyps remaining in the bowel; and with no known contraindication to, or need for, the study agents. In a modified 2 x 2 factorial design, 2259 subjects were randomized to vitamin D3 (1000 IU daily), calcium (1200 mg daily), both agents, or neither. Women could elect to be randomized only to vitamin D. Follow-up colonoscopy was planned by the subjects’ clinicians at either 3 or 5 years after the baseline exam. Every 6 months, subjects were queried about endoscopic procedures, major medical events, and compliance with study procedures. Intention to treat risk ratios (RRs) and 95% confidence intervals (CIs) were computed with adjustment for age, sex, study center, number of baseline adenomas, planned follow-up interval (3 or 5 years) and participation in calcium randomization. Results: Treatment arms were well balanced with regard to personal characteristics and risk factors for metachronous neoplasia. Treatment adherence was very good; 90% of subjects reported taking at least half their study tablets during the trial. About 93% of subjects had a follow-up colonoscopy at least 1 year after randomization; nearly all were complete examinations. Baseline 25-OH vitamin D levels were 24.6 ng/ml overall; by the end of study treatment, subjects given vitamin D had levels 7.8 ng/ml higher than those given placebo. Overall, 42% of subjects had one or more adenomas during follow-up (mean size 5 mm). The study treatments had no effect on adenoma outcomes. The RR for vitamin D vs. placebo was 0.97 (95% CI 0.88-1.08); for vitamin D plus calcium vs. calcium alone, 0.99 (95% CI 0.86-1.13); and for calcium alone, 0.95 (95% CI 0.85-1.06). RRs for advanced adenomas were similar. Numbers of subjects with major medical events were low, but study agents had no material effect on risk of cardiovascular endpoints, cancer or kidney stones. Conclusion: Despite previous evidence, we found supplemental vitamin D and calcium to be ineffective in reducing risk of metachronous colorectal adenomas over 3 - 5 years. Citation Format: John A. Baron, Elizabeth L. Barry, Dennis J. Ahnen, Carol A. Burke, Roberd M. Bostick, Robert S. Bresalier, Timothy R. Church, Marcia Cruz-Correa, Michael Goodman, Robert Haile, Anastasia Ivanova, Richard I. Rothstein, Robert S. Sandler, Dale Snover, Robert W. Summers. A clinical trial of supplementation with vitamin D and/or calcium for the prevention of colorectal adenomas. [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 CT335. doi:10.1158/1538-7445.AM2014-CT335

Colorectal Adenoma Stem-like Cell Populations: Associations with Adenoma Characteristics and Metachronous Colorectal Neoplasia

Cancer stem cells have tumor-initiation and tumor-maintenance capabilities. Stem-like cells are present in colorectal adenomas, but their relationship to adenoma pathology and patient characteristics, including metachronous development of an additional adenoma ("recurrence"), has not been studied extensively. We evaluated the expression of aldehyde dehydrogenase isoform 1A1 (ALDH1A1), a putative stem cell marker, in baseline adenomas from the placebo arm of chemoprevention trial participants with colonoscopic follow-up. An exploratory set of 20 baseline adenomas was analyzed by ALDH1A1 immunohistochemistry with morphometry, and a replication set of 89 adenomas from 76 high-risk participants was evaluated by computerized image analysis. ALDH1A1-labeling indices (ALI) were similar across patient characteristics and in advanced and nonadvanced adenomas. There was a trend toward higher ALIs in adenomas occurring in the right than left colon (P = 0.09). ALIs of synchronous adenomas were correlated (intraclass correlation coefficient 0.67). Participants in both sample sets who developed a metachronous adenoma had significantly higher ALIs in their baseline adenoma than participants who remained adenoma free. In the replication set, the adjusted odds for metachronous adenoma increased 1.46 for each 10% increase in ALIs (P = 0.03). A best-fit algorithm-based cutoff point of 22.4% had specificity of 75.0% and positive predictive value of 70.0% for metachronous adenoma development. A larger population of ALDH1A1-expressing cells in an adenoma is associated with a higher risk for metachronous adenoma, independent of adenoma size or histopathology. If confirmed, ALDH1A1 has potential as a novel biomarker in risk assessment and as a potential stem cell target for chemoprevention.

PTH-046 Analysis of Metachronous Colorectal Adenoma Sites Suggests Proximal Occurrence is More Probable

IntroductionA human sporadic colorectal adenoma may influence the formation of another adenoma even after its removal, with up to 60% of such patients developing metachronous adenomas following adenoma excision. However...

Metachronous adenoma on ileorectal anastomosis suture line and submucosal deep invasive cancer suspected of rapid growth in rectal remnant following long‐term interval after curative surgery for advanced colon cancer

There is general agreement as to the value of postoperative surveillance and the effectiveness of colonoscopy in the early detection of metachronous colorectal lesions. In the present case, a 56-year-old woman with no family history of colon cancer underwent surveillance colonoscopy in which a metachronous flat adenoma was detected following an interval of 23 years after a colectomy and 20 years subsequent to treatment for uterine cancer. A second metachronous flat lesion histopathologically determined to be a submucosal (sm) deep invasive cancer with lymphovascular involvement was detected 12 months later. This second metachronous lesion was suspected of having developed rapidly in the rectal remnant accounting for its sm deep invasion. The findings of this case suggest colonoscopy surveillance guidelines proposed for individuals at high risk should be evaluated based on cancer history and an analysis of possible mismatch repair gene mutations. In addition, the first metachronous lesion was located directly on the suture line of the anastomosis. Endoscopic submucosal dissection (ESD) was indicated despite severe fibrosis into the sm layer. This case also demonstrates the successful use of improved ESD instruments, sm injection agents and technique refinements in the treatment of a technically difficult lesion with a high risk of complications.

Role of dietary polyamines in a phase III clinical trial of difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal adenomas

Background:The polyamine-inhibitory regimen difluoromethylornithine (DFMO)+sulindac has marked efficacy in preventing metachronous colorectal adenomas. Polyamines are synthesised endogenously and obtained from dietary sources. Here we investigate dietary polyamine intake and outcomes in the DFMO+sulindac colorectal adenoma prevention trial.Methods:Dietary polyamine data were available for 188 of 267 patients completing the study. Total dietary polyamine content was derived by the sum of dietary putrescine, spermine and spermidine values and categorised into two groups: highest (>75–100%) vs the lower three quartiles (0–25, 25–50 and 50–75%). Baseline tissue polyamine concentration and ODC1 genotype were determined. Logistic regression models were used for risk estimation.Results:A significant interaction was detected between dietary polyamine group and treatment with regard to adenoma recurrence (P=0.012). Significant metachronous adenoma risk reduction was observed after DFMO+sulindac treatment in dietary polyamine quartiles 1–3 (risk ratio (RR) 0.19; 95% confidence interval (CI) 0.08–0.42; P<0.0001) but not in quartile 4 (RR 1.51; 95% CI 0.53–4.29; P=0.44). However, a lower number of events in the placebo group within dietary quartile 4 confound the aforementioned risk estimates.Conclusion:These preliminary findings reveal complex relationships between diet and therapeutic prevention, and they support further clinical trial-based investigations where the dietary intervention itself is controlled.

Metachronous Pleomorphic Adenomas Occurring in the Parotid and a Minor Salivary Gland With Genetic Changes Detected by Comparative Genomic Hybridization

A 32-year-old female underwent an extracapsular dissection for a pleomorphic adenoma (PA) of the parotid gland. Six months later, she presented with an increasing lump on the upper lip that, following excision, was confirmed to be a second PA. Formalin-fixed paraffin embedded tissues were analyzed for chromosomal aberrations. Comparative genomic hybridization analysis showed multiple chromosomal aberrations in the parotid PA. In comparison, no chromosomal aberrations were found in the lip PA. To our knowledge, metachronous benign pleomorphic adenomas occurring in both a major and minor salivary gland is unreported, and furthermore, there are no comparative genomic hybridization reports of this rare occurrence. We discuss the clinicopathological implications.

15-Hydroxyprostaglandin Dehydrogenase in Colorectal Mucosa as a Potential Biomarker for Predicting Colorectal Neoplasms

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is downregulated during the early stages of colorectal carcinogenesis. The aim of the present study was to investigate the potential role of 15-PGDH in normal-appearing colorectal mucosa as a biomarker for predicting colorectal neoplasms. We obtained paired tumor and normal tissues from the surgical specimens of 32 sporadic colorectal cancer patients. mRNA expression of 15-PGDH was measured using a quantitative real-time PCR assay. We evaluated the association between 15-PGDH mRNA expression in normal-appearing mucosa, the presence of synchronous adenoma, and the cumulative incidence of metachronous adenoma. The relative 15-PGDH expression of normal-appearing mucosa in patients with synchronous adenoma was significantly lower than in patients without synchronous adenoma (0.71 vs 1.00, P = 0.044). The patients in the lowest tertile of 15-PGDH expression in normal-appearing mucosa were most likely to have synchronous adenoma (OR: 10.5, P = 0.024). Patients with low 15-PGDH expression in normal-appearing mucosa also demonstrated more advanced stage colorectal cancer (P = 0.045). However, there was no significant difference in the cumulative incidence of metachronous adenoma according to 15-PGDH mRNA expression in normal-appearing mucosa (P = 0.333). Hence, 15-PGDH in normal-appearing colorectal mucosa can be a useful biomarker of field effect for the prediction of sporadic synchronous neoplasms.

Abstract CN04-03: Development of NSAID eflornithine combinations for treating cancer risk factors

Abstract Nonsteroidal anti-inflammatory drugs (NSAIDS) have been found to be potent inhibitors of carcinogenesis in both preclinical models and in randomized controlled prospective clinical trials in humans. NSAIDS exert their anti-carcinogenic effects by inhibiting cyclooxygenases (COXs) involved in arachidonic acid metabolism and by COX-independent mechanisms. Empirical data indicates eflornithine (difluoromethylornithine or DFMO), an enzyme-activated inhibitor of ornithine decarboxylase (ODC) (Meyskens and Gerner, 1999), is one of the most potent agents known acting in combination with NSAIDS to inhibit carcinogenesis in rodent models (Steele and Lubet, 2010). At least part of the rationale for combining NSAIDS with eflornithine for inhibition of carcinogenesis is that eflornithine inhibits the activity of ODC, the first enzyme in polyamine synthesis, while NSAIDS activate the spermidine/spermine acetyltransferase (SAT1), which targets polyamines for export by specific solute carrier transporters (Gerner and Meyskens, 2009). Thus, NSAIDS and eflornithine both reduce tissue levels of the growth-associated polyamines, but by complementary mechanisms. A clinical trial of the combination of eflornithine and the NSAID sulindac showed dramatic treatment-associated reductions of metachronous colorectal adenomas in patients with prior sporadic colorectal polyps (Meyskens et al., 2008). Several clinical trials in progress or soon to commence will further test the hypothesis that NSAID eflornithine combinations can successfully treat cancer risk factors in patients with specific cancers, or risk of cancer. One group of clinical trials involves patients with neuroblastoma (NB). Patients with poor prognosis NB often have tumors in which MYCN is overexpressed. Preclinical data indicates that MYCN as well as c-MYC drive expression of ODC and other genes in the polyamine pathway, and that inhibiting this pathway with eflornithine suppressed carcinogenesis in mouse models of NB (Hogarty et al., 2008). Likewise, COX-2 is expressed in NB tumors and cell lines, and COX-2 inhibitors such as celecoxib can suppress the growth of NB xenografts (Ponthan et al., 2007). The Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) and the New Approaches to Neuroblastoma Therapy (NANT) group are conducting clinical trials to evaluate the safety and efficacy of eflornithine alone or in combination with NSAIDS and other agents in patients with high risk NB. The NMTRC is conducting an especially novel prevention trial of eflornithine in patients with high risk NB in remission (NCT01586260). Eflornithine NSAID combinations are also being evaluated in other MYC-associated diseases. Familial adenomatous polyposis (FAP) is a genetic syndrome associated with increased risk of colon cancer and other neoplasia and is caused by mutation/deletions in the adenomatous polyposis coli (APC) tumor suppressor gene. MYC mediates intestinal tumorigenesis (Ignatenko et al., 2006) and combinations of eflornithine and NSAIDS are potent inhibitors of intestinal carcinogenesis (Ignatenko et al., 2008) in murine models of FAP. Notable is the change in clinical management of FAP patients over the past two decades. FAP is now managed primarily by surgery, with duodenal polyposis and desmoid disease constituting two current significant clinical problems. An international consortium will be evaluating the combination of eflornithine and sulindac in adult patients with FAP, using time to FAP-related events as the primary outcome (NCT01483144). This same combination will be evaluated in patients with prior sporadic colon cancer in a study to be conducted by a national cooperative group (S0820, Adenoma and second primary prevention trial, NCT01349881) (Rial et al., 2012). These and other trials have been designed to include assessment of a range of biological correlates, including genetic (Zell et al., 2010), tissue (Thompson et al., 2010) and urinary markers (Hiramatsu et al., 2005) of disease prognosis and prediction of treatment responses, including therapy-associated toxicities. Citation Format: Eugene W. Gerner. Development of NSAID eflornithine combinations for treating cancer risk factors. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN04-03.

The MIRACLE trial: A randomized, controlled trial comparing green tea extract versus placebo for the prevention of metachronous colon adenomas in a screening population.

TPS1612 Background: Prevention of colorectal cancer is a major health care issue. After polypectomy there is an increased risk of polyp recurrence and various means of chemoprevention have been tried to prevent this. NSAIDs have been shown to be effective but confer side effects such as gastrointestinal bleeding. Nutraceuticals such as polyphenols from tea plants have demonstrated remarkable therapeutic and preventive effects in molecular, epidemiological and some clinical trials. However, their value in preventing colorectal polyps has not been demonstrated in a large, randomized trial. The beneficial safety profile of decaffeinated green tea extract and accumulating evidence of its cancer preventive potential justify and require, in our view, a validation of this compound for the nutriprevention of colorectal adenoma. Good accessibility and low costs might render this neutraceutical a top candidate for wider use as nutritional supplement in colon cancer prevention. Methods: Randomized, double blinded, placebo-controlled, multicenter trial. After a one month run-in period with verum, 2534 patients (age: 50-80 years) who have undergone polypectomy within the last 6 months will be randomized to receive either decaffeinated green tea extract (containing 150 mg epigallocatechin gallate (EGCG) two times daily) or placebo over a period of three years. 2028 patients are expected to complete the whole study course. Primary outcome: Incidence of metachronous colorectal adenomas (tubulovillous, tubular, villous, serrated lesions) at the 3 year follow-up colonoscopy Secondary outcomes: Occurrences, number, localization, size and histological subtypes of adenomas, frequency of colorectal carcinoma. In addition, genetic and biochemical biomarkers in blood samples and genetic alterations (e.g. K-ras, B-raf, specific microRNAs) in tissue samples of adenomas will be analyzed (biobanking subprojects). Additionally, nutrikinetics and nutrigenetics of EGCG and other catechins will be assessed in healthy volunteers. Patient recruitment has started in November 2011. We expect the last patient out in fall 2017. (Trial identifier: NCT01360320)

Polyp surveillance after surgery for colorectal cancer

Although it is known that those patients who have developed colorectal cancer (CRC) are at a higher risk to develop metachronous adenoma or CRC, no study has been performed to analyze the relationship between the risk factors and the time course for the formation of postoperative adenoma using survival analysis. One hundred seventy-six patients with CRC,who had received surgical resection, were endoscopically followed-up to detect the development of metachronous adenoma or adenocarcinoama. The association between the risk factors such as age, synchronous adenomas with index CRC or other clinicopathological variables and the formation of postoperative adenoma was assessed using the logrank test and the Cox proportional hazard model. Age over 60, synchronous lesions at the time of surgery for primary CRCs and presence of diabetes mellitus(DM) as the associated disease were positively related to the formation of postoperative adenoma. Among those patients with the three risk factors, only 27.8% remained adenoma-free during 5 years after operation, whereas in the group without any risk factor, it was 90.4%. From our data, age over 60, synchronous adenomas or CRCs and DM were the potential risk factors for the postoperative formation of adenoma or CRC, and they should be taken into consideration when defining the appropriate interval of postoperative colonoscopy.

Abstract PR-01: Properties of adenomas in subjects treated with difluoromethylornithine and sulindac for reduction of colorectal adenomas

Abstract Difluoromethyl ornithine (DFMO), an ornithine decarboxylase inhibitor, and sulindac reduced the occurrence of colorectal adenomas by 70% in a phase III randomized placebo controlled clinical trial. The goal of the current study was to compare adenoma location in the colorectum and biomarker expression by immunohistochemistry of formalin fixed paraffin embedded adenomas from treatment and placebo groups in the trial. To take into account the relationship between the locations in the colorectum of multiple adenoma that were removed from individual subjects, the generalized estimation equation (GEE) method was applied for all analyses. The decrease in the reappearance of metachronous adenomas was similar throughout the colorectum in subjects treated with DFMO and sulindac (P = 0.44). For TP53, Ki67, and c-MYC there were no significant differences in the estimated mean percent of cells staining positive between treated and untreated subjects (P&amp;gt;0.5 for all). For BCL-2, LC3B, CEA, sialy1-Tn, cleaved caspase 3 and apoptosis, the proportion of adenoma with expression levels 1+ to 3+ did not differ between subjects treated with DFMO plus sulindac versus those treated with double placebos. For hMSH2, hMSH6, hMLH1 and hPMS2, there was a loss of staining of a greater number of cells on average in adenomas from the control group compared to adenomas from the subjects treated with DFMO and sulindac. For hMSH2, this difference was statistically significant (P = 0.0004). This finding raises the possibility that DFMO and sulindac protect adenomas from loss of DNA mismatch repair protein expression and provides a rationale for further study of the possible role of DFMO and sulindac on DNA mismatch repair protein regulation and chemoprevention in patients at risk for colorectal carcinoma. In conclusion, DFMO decreases the occurrences of adenomas throughout the colorectum, including the right colon, and may have an effect on DNA mismatch repair enzyme expression. These findings provide further rationale for the use of DFMO as a chemopreventative agent for colorectal carcinoma. Citation Information: Cancer Prev Res 2011;4(10 Suppl):PR-01.

Protocol for MInimizing the Risk of Metachronous Adenomas of the CoLorectum with Green Tea Extract (MIRACLE): a randomised controlled trial of green tea extract versus placebo for nutriprevention of metachronous colon adenomas in the elderly population

BackgroundPrevention of colorectal cancer is a major health care issue. People who have undergone colonoscopy screening and had colorectal polyps removed have a higher risk of being diagnosed with polyps again compared to the normal population. Therefore, it would be ideal to find appropriate means that effectively help to prevent the reoccurrence of polyps after polypectomy. So far, pharmaceutical chemoprevention with NSAIDs including aspirin has been shown to be effective but not gained general acceptance due to side effects. Nutraceuticals such as polyphenols from tea plants have demonstrated remarkable therapeutic and preventive effects in molecular, epidemiological and clinical trials. However, placebo-controlled trials demonstrating the efficacy of nutraceuticals for the (secondary) prevention of colorectal polyps as precursors for colorectal cancer are missing.Methods/DesignWe present the design of a randomized, placebo controlled, multicentre trial to investigate the effect of diet supplementation with green tea extract containing 300 mg epigallocatechin gallate (EGCG), the major polyphenol in green tea, on the recurrence of colon adenomas. Patients who have undergone polypectomy for colonic polyps will be randomized to receive either green tea extract containing 150 mg EGCG two times daily or a placebo over the course of three years. After a one month run-in period in which all patients will receive the active intervention, 2534 patients will be randomized, and 2028 patients are expected to complete the whole study course. Incidence, number and histology of adenoma at endpoint colonoscopy at three years will be compared in both groups.DiscussionThe beneficial safety profile of decaffeinated green tea extract, the quantifiable and known active content EGCG, and the accumulating evidence of its cancer preventive potential require, in our view, a validation of this compound for the nutriprevention of colorectal adenoma. Good accessibility and low costs might render this neutraceutical a top candidate for wider use as food supplement in colon cancer prevention.Trial registrationClinicalTrials.gov: NCT01360320