Giuseppe De Roberto

Same-day 2-L PEG-citrate-simethicone plus bisacodyl vs split 4-L PEG: Bowel cleansing for late-morning colonoscopy

AIM To evaluate the efficacy, tolerability, acceptability and feasibility of bisacodyl plus low volume polyethyleneglycol-citrate-simeticone (2-L PEG-CS) taken the same day as compared with conventional split-dose 4-L PEG for late morning colonoscopy. METHODS Randomised, observer-blind, parallel group, comparative trial carried out in 2 centres. Out patients of both sexes, aged between 18 and 85 years, undergoing colonoscopy for diagnostic investigation, colorectal cancer screening or follow-up were eligible. The PEG-CS group received 3 bisacodyl tablets (4 tablets for patients with constipation) at bedtime and 2-L PEG-CS in the morning starting 5 h before colonoscopy. The control group received a conventional 4-L PEG formulation given as split regimen; the morning dose was taken with the same schedule of the low volume preparation. The Ottawa Bowel Preparation Scale (OBPS) score was used as the main outcome measure. RESULTS A total of 164 subjects were enrolled and 154 completed the study; 78 in the PEG-CS group and 76 in the split 4-L PEG group. The two groups were comparable at baseline. The OBPS score in the PEG-CS group (3.09 ± 2.40) and in the PEG group (2.39 ± 2.55) were equivalent (difference +0.70; 95%CI: -0.09-1.48). This was confirmed by the rate of successful bowel cleansing in the PEG-CS group (89.7%) and in the PEG group (92.1%) (difference -2.4%; 95%CI: -11.40- 6.70). PEG-CS was superior in terms of mucosa visibility compared to PEG (85.7% vs 72.4%, P = 0.042). There were no significant differences in caecum intubation rate, time to reach the caecum and withdrawal time between the two groups. The adenoma detection rate was similar (PEG-CS 43.6% vs PEG 44.7%). No serious adverse events occurred. No difference was found in tolerability of the bowel preparations. Compliance was equal in both groups: more than 90% of subjects drunk the whole solution. Willingness to repeat the same bowel preparations was about 90% for both regimes. CONCLUSION Same-day PEG-CS is feasible, effective as split-dose 4-L PEG for late morning colonoscopy and does not interfere with work and daily activities the day before colonoscopy.

Positron emission tomography for the detection of colorectal adenomas

BACKGROUND (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) has been reported to detect colorectal adenomas. AIMS This study aimed at evaluating the sensitivity of (18)F-FDG PET with computed tomography image fusion (PET/CT) for detecting colorectal adenomas. METHODS We retrospectively compared the results of 92 (18)F-FDG PET/CT studies followed by colonoscopy. Colonoscopy and histology were considered as the gold standard. RESULTS One hundred fifty-seven lesions were observed. All the 12 malignancies were identified by (18)F-FDG PET/CT but only 27 out of 119 resected adenomas (sensitivity 22.7%) and none of the hyperplastic polyps were detected. At the univariate and multivariate analyses there was a significant statistical association between adenomas sized more than 10mm, presence of villous component and high-grade dysplasia and the ability of (18)F-FDG PET/CT to detect adenomas. (18)F-FDG PET/CT showed an overall sensitivity of 29.8%, a specificity of 81.1%, a positive predictive value (PPV) of 84.8% and a negative predictive value (NPV) of 24.6% for the neoplastic colorectal lesions globally considered. CONCLUSION (18)F-FDG PET/CT has a low sensitivity for detecting adenomas. However, because of the specificity and PPV of the technique for neoplastic colorectal lesions, the presence of a focal colorectal FDG uptake justifies the patient undergoing colonoscopy.

Confocal laser endomicroscopy for in vivo diagnosis of Barrett's oesophagus and associated neoplasia: A pilot study conducted in a single Italian centre

BACKGROUND Diagnosis and management of Barretts oesophagus are controversial. Technical improvements in real-time recognition of intestinal metaplasia and neoplastic foci provide the chance for more effective target biopsies. Confocal laser endomicroscopy allows to analyze living cells during endoscopy. AIMS To assess the diagnostic accuracy, inter- and intra-observer variability of endomicroscopy for detecting in vivo neoplasia (dysplasia and/or early neoplasia) in Barretts oesophagus. METHODS Prospective pilot study. Patients referred for known Barretts oesophagus were screened. Endomicroscopy was carried out in a circular fashion, every 1-2 cm, on the whole columnar-lined distal oesophagus. Visible lesions, when present, were analyzed first. Targeted biopsies were taken. Confocal images were classified according to confocal Barrett classification. Endomicroscopic and histological findings were compared. RESULTS Forty-eight out of 50 screened patients underwent endomicroscopy. Visible lesions were observed in 3 patients. In a per-biopsy analysis, Barretts-oesophagus-associated neoplasia could be predicted with an accuracy of 98.1%. The agreement between endomicroscopic and histological results was substantial (κ=0.76). CONCLUSIONS This study suggests that endomicroscopy can provide in vivo diagnosis of Barretts oesophagus-associated neoplasia. Because it allows for the study of larger surface areas of the mucosa, endomicroscopy may lead to significant improvements in the in vivo screening and surveillance of Barretts oesophagus.

A Randomized, Placebo-Controlled, Preoperative Trial of Allopurinol in Subjects with Colorectal Adenoma

Inflammation and oxidative stress play a crucial role in the development of colorectal cancer (CRC) and interference with these mechanisms represents a strategy in CRC chemoprevention. Allopurinol, a safe molecular scavenger largely used as antigout agent, has been shown to increase survival of patients with advanced CRC and to reduce CRC incidence in long-term gout users in epidemiologic studies. We conducted a randomized, double-blind, placebo-controlled preoperative trial in subjects with colorectal adenomatous polyps to assess the activity of allopurinol on biomarkers of colorectal carcinogenesis. After complete colonoscopy and biopsy of the index polyp, 73 subjects with colorectal adenomas were assigned to either placebo or one of two doses of allopurinol (100 mg or 300 mg) and treated for four weeks before polyp removal. Change of Ki-67 labeling index in adenomatous tissue was the primary endpoint. Secondary endpoints were the immunohistochemical (IHC) expression of NF-κB, β-catenin, topoisomerase-II-α, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) in adenomatous polyps and normal adjacent colonic tissue. Compared with placebo, Ki-67 levels were not significantly modulated by allopurinol, whereas β-catenin and NF-κB expression levels decreased significantly in adenomatous tissue, with a mean change from baseline of −10.6%, 95% confidence interval (CI), −20.5 to −0.7, and −8.1%, 95% CI, −22.7 to 6.5, respectively. NF-κB also decreased significantly in normal adjacent tissue (−16.4%; 95% CI, −29.0 to −3.8). No dose–response relationship was noted, except for NF-κB expression in normal tissue. Allopurinol can inhibit biomarkers of oxidative activation in colon adenomatous polyps and normal adjacent tissue. Further studies should define its potential chemopreventive activity. Cancer Prev Res; 6(2); 74–81. ©2012 AACR.

Linear array ultrasonography to stage rectal neoplasias suitable for local treatment

BACKGROUND Because of the many therapeutic options available, a reliable staging is crucial for rectal neoplasia management. Adenomas and cancers limited to the submucosa without lymph node involvement may be treated locally. AIMS The aim of this study is to evaluate the diagnostic accuracy of endorectal ultrasonography in the staging of neoplasias suitable for local treatment. METHODS We considered all patients who underwent endorectal ultrasonography between 2001 and 2010. The study population consisted of 92 patients with 92 neoplasias (68 adenocarcinomas and 24 adenomas). A 5 and 7.5MHz linear array echoendoscope was used. The postoperative histopathologic result was compared with the preoperative staging defined by endorectal ultrasonography. Adenomas and cancers limited to the submucosa were considered together (pT0-1). RESULTS The sensitivity, specificity, overall accuracy rate, positive predictive value, and negative predictive value of endorectal ultrasonography for pT0-1 were 86%, 95.6%, 91.3%, 94.9% and 88.7%. Those for nodal involvement were 45.4%, 95.5%, 83%, 76.9% and 84%, with 3 false positive results and 12 false negative. For combined pT0-1 and pN0, endorectal ultrasonography showed an 87.5% sensitivity, 95.9% specificity, 92% overall accuracy rate, 94.9% positive predictive value and 90.2% negative predictive value. CONCLUSION Endorectal linear array ultrasonography is a reliable tool to detect rectal neoplasias suitable for local treatment.

Evaluation of Clensia®, a new low-volume PEG bowel preparation in colonoscopy: Multicentre randomized controlled trial versus 4L PEG

BACKGROUND Success of colonoscopy is linked to the adequacy of bowel cleansing. Polyethylene glycol 4L (PEG 4L) solutions are widely used for colonic cleansing but with limitations concerning tolerability and acceptability. AIM To demonstrate the equivalence of a new low-volume PEG containing citrates and simeticone (Clensia) versus a standard PEG 4L. METHODS In this, multicentre, randomised, observer-blind trial, patients received either Clensia 2L or PEG 4L solution. Primary endpoint was the proportion of patients with colon cleansing evaluated as excellent or good. RESULTS 422 patients received Clensia (n=213) or PEG 4L (n=209). Rate of excellent/good bowel cleansing was 73.6% and 72.3% in Clensia and PEG 4L group respectively. Clensia was demonstrated to be equivalent to PEG 4L. No SAEs were observed. Clensia showed better gastrointestinal tolerability (37.0% vs 25.4%). The acceptability was significantly better with Clensia in terms of proportion of subjects who felt no distress (Clensia 72.8% vs PEG 4L 63%, P=0.0314) and willingness-to-repeat (93.9% vs 82.2%, P=0.0002). The rate of optimal compliance was similar with both formulations (91.1% for Clensia vs 90.9% for PEG 4L, P=0.9388). CONCLUSIONS The low-volume Clensia is equally effective and safe in bowel cleansing compared to the standard PEG 4L, with better gastrointestinal tolerability and acceptability.

Predictors of advanced colorectal neoplasia at initial and surveillance colonoscopy after positive screening immunochemical faecal occult blood test

BACKGROUND Characteristics such as gender and lifestyle are not taken in account in colorectal cancer screening and surveillance recommendations. AIMS To identify factors associated with advanced neoplasia at initial and surveillance colonoscopy. METHODS In this observational study, 750 individuals with positive faecal occult blood test, aged 50-74 years, underwent a first screening colonoscopy in 2007-2009. We collected anthropometric data as well as data on physical activity, smoking and drinking habits, fruit and vegetable consumption and low-dose aspirin use through a questionnaire. RESULTS At initial colonoscopy advanced neoplasia (n=399, 53.2%) was positively associated with age, male gender, smoking and alcohol drinking, and inversely associated with physical activity, fruit and vegetables consumption and long-term use of aspirin. These 7 factors were used to calculate a risk score, ranging from 0 (no unfavourable characteristics) to 7 (all unfavourable characteristics present), which was significantly associated with advanced neoplasia (odds ratio 1.55 for one point increase, P<0.01). Among the 372 adenoma patients who returned for follow-up surveillance colonoscopy, the score remained associated with advanced neoplasia (odds ratio 1.28 for one point increase, P=0.01). CONCLUSION Besides age and gender, modifiable factors such as lifestyle and aspirin use were associated with the risk of advanced neoplasia at initial and surveillance colonoscopy.

Lobular Metastatic Breast Cancer Patients With Gastrointestinal Involvement: Features and Outcomes

Micro‐Abstract An infrequent metastatic site from breast cancer is the gastrointestinal (GI) tract, and the outcomes remain unclear. We identified 40 patients with GI metastases from breast cancer during a 14‐year study period; 75% of these patients had primary lobular carcinoma. Recognition of the range of possible presentations of GI involvement is important for an early and accurate diagnosis and treatment. Introduction: Metastatic breast cancer typically involves the lungs, bones, brain, and liver and only occasionally affects the gastrointestinal (GI) tract. The relevant published data have been limited to case reports and small series of patients. Patients and Methods: The present study focused on the treatment and outcomes of breast cancer patients with GI involvement diagnosed at the European Institute of Oncology. We analyzed the clinicopathologic features of the GI metastases and compared them with those of the primary tumors according to their histologic type (ductal or lobular carcinoma). Results: From the database of the Department of Pathology, 40 patients who had undergone endoscopy or GI surgery with a final diagnosis of metastatic breast cancer from 2000 to 2014 were identified. The greatest proportion of patients (75%) had had primary invasive lobular carcinoma. Of the 40 patients, 82% had hormone receptor‐positive disease in the metastatic lesion; 34 patients were candidates for systemic therapy. The median length of observation after GI metastasis was 18 months (range, 0.6‐79 months). The overall survival from the diagnosis of GI involvement was 33 months (95% confidence interval, 16.8‐38.3 months). Conclusion: Lobular breast carcinoma has a greater propensity to metastasize to the GI tract compared with other breast cancer subtypes. In the presence of GI symptoms, even if nonspecific, the GI tract should be thoroughly studied. Systemic treatment, including hormonal therapy, should be considered.

Abstract A57: Randomized double-blind trial of a rational combination of anthocyanins and curcumin for colon cancer prevention in subjects with colorectal adenomas: MIRACOL study

Rationale: Colorectal cancer (CRC) is one of the most frequent malignant neoplasms in both sexes within developed countries. Colorectal carcinogenesis is a multistage process that occurs over a period of 10–20 years. Colorectal adenomas (CA) are well recognized CRC risk markers. Evidence from epidemiological studies and clinical trials, suggests that removal of CA decreases the incidence of CRC, supporting the hypothesis that regression or elimination of CA through chemopreventive strategies would also reduce CRC9s incidence. Inflammation and oxidative stress appear to play a crucial role in the development of CRC; NF-kB activation has been associated with multiple pathways of oncogenesis, including apoptosis, cell cycle control, differentiation, angiogenesis and cell migration; interference with these mechanisms may represent a strategy in CRC chemoprevention. Anthocyanins and curcumin represent, so far, the two most reliable candidates mainly due to their integrated capacity of modulating key steps of inflammatory processes, cell proliferation and tumor progression. Anthocyanins are a group of natural occurring pigments responsible for the red-blue color of many fruits and vegetables and are provided with remarkable antiproliferative, apoptogenic, antiinflammatory and antioxidant effects and with the capacity of inhibiting tumor progression in experimental models of gastrointestinal cancerogenesis. In a recent pilot study in CRC patients, anthocyanins administered for 7 days were dose-dependently effective in reducing the proliferation index Ki-67. Curcumin is a polyphenolic compound obtained from turmeric (Curcuma longa L.) endowed with marked anti-inflammatory, antioxidant and antineoplastic effects; due to its peculiar proximal carbonyls, curcumin is also effective in interacting with the intracellular redox status contributing to modulate main steps of cellular activation and proliferation. In the present study, we propose to test a rational combination of a natural enriched source of anthocyanins from bilberry (Vaccinium myrtillus L.), MIRTOSELECT© (standardized to contain 36 % anthocyanins) with a bioavailable form of curcumin, MERIVA©. Based on previous experience in humans, the proposed daily dosages of 1g of MIRTOSELECT© and 1g of MERIVA© would assure an effective concentration of anthocyanins and curcumin in the target tissue; and at plasmatic level. Design: To assess the effects of MIRTOSELECT© and MERIVA© on cell proliferation in both adenomatous and unaffected colonic tissue, we designed a presurgical, double blind, placebo-controlled, randomized phase I/II trial in patients with colorectal adenomatous polyps. After a complete colonoscopy and biopsy of the index polyp, 100 subjects with histologically confirmed CA will be assigned (50 per arm) to either placebo or MIRTOSELECT© 1g/d + MERIVA© 1gr/die treatment for 4–6 weeks before polyp removal. Primary endpoint will be the nuclear transcriptional activation marker β-Catenin in adenoma tissue in subjects treated with the complex compared with placebo. The study is designed to have 85% power to detect an absolute difference of 10% between arms in β-Catenin expression levels in adenoma tissue after treatment, assuming 10% lost to follow-up. Secondary endpoints include treatment modulation of biomarkers of oxidative activation (NF-kB), proliferation and apoptosis (Ki67, TUNEL), phlogosis (u-CRP), circulating IGFs (IGF-1, IGFBP-3), genetic expression profile and tolerability. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A57.

Abstract A69: Randomized, presurgical study of allopurinol vs. placebo in subjects with colorectal adenomas

Rationale: Colorectal adenomas are well recognized colorectal cancer (CRC) risk markers, and regression of adenomas through chemopreventive strategies may reduce the incidence of CRC. Inflammation and oxidative stress appear to play a crucial role in the development of CRC, and interference with the mechanisms inducing oxidative stress and possibly cancer progression may represent a new strategy in CRC chemoprevention. Colonic cancerous tissue contains high levels of reactive oxygen metabolites (ROM), which may play an important role in the pathogenesis of CRC, and the effects of ROM scavengers are presently being tested for CRC chemoprevention. Allopurinol, a structural analogue of hypoxanthine inhibiting the action of xantine oxidase (XO), is a ROM scavenger largely employed as an anti-gout agent in clinical practice. Allopurinol use is highly safe, with very uncommon adverse events. Allopurinol was shown to increase survival of patients with advanced CRC, and a recent population-based case-control study showed that its use for at least 5 years was correlated with a diminished risk of developing CRC (Odds Ratio=0.33; 95% CI=0.16-0.71, Rennert G et al. AACR 3rd International Conference on Frontiers in Cancer Prevention Research 2004, Abstract #C88) after adjustment for other known risk factors. Design: To assess the effects of allopurinol on cell proliferation in both adenomatous and unaffected colonic tissue, we designed a randomized phase I/II, double blind, placebo-controlled, multicenter trial in patients with colorectal adenomatous polyps. After a complete colonoscopy and biopsy of the index polyp, subjects with histologically confirmed adenomas were assigned to either placebo or two doses of allopurinol (100mg or 300mg) and treated for 4-6 weeks before polyp removal. Samples of normal colonic tissue were also collected on both baseline and end-of-study colonoscopy. Treatment effect on cell proliferation was assessed by measuring changes of Ki-67 labeling index (primary endpoint: Ki-67 %change) on both adenomatous and normal colonic tissue. We calculated a total of 75 subjects (25 per arm), required (α = 0.05, 1-β = 0.85, one-sided test) to show a 27% to 40% reduction in Ki-67 LI depending on standard deviation of Ki-67. Secondary endpoints included treatment modulation of biomarkers of oxidative activation (NF-Kb and β-catenin), apoptosis (topoisomerase-II-α, Cox-3, Bcl-2), inflammation (u-CRP) and of circulating IGFs (IGF-1, IGFBP-3). Preliminary results: The first patient entered the study on May 13th 2006 and the last on May 31th, 2010, for a total study enrolment duration of about 4 years. Enrolment stopped on July 1, 2010, with a total of 73 subjects enrolled. An interim analysis performed on November 2008 (48 patients enrolled, mean age 62 yrs, mean BMI 25kg/m2) showed a 98% treatment compliance, with only 3 G1 adverse events (1 leg cramps, 1 erythema and 1 skin rush), confirming the high safety of allopurinol. Ki-67 analysis on the first 13 subjects enrolled showed a favourable trend: median Ki-67 expression in normal tissue doubled on placebo compared with a 5% increase in both treatments arms; in adenomas, it increased by 70% on placebo compared with 6% and 12% in the 100 mg and 300 mg allopurinol arm, respectively. Tissue and serum biomarker analyses on all subjects enrolled are underway and further results will be presented at the conference. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A69.