Francesco Munizzi

Long-term endoscopic surveillance of patients with Barrett's esophagus. Incidence of dysplasia and adenocarcinoma: a prospective study.

OBJECTIVE:Barretts esophagus (BE) is a premalignant condition for which regular endoscopic follow-up is usually advised. We evaluated the incidence of esophageal adenocarcinoma (AC) in patients with BE and the impact of endoscopic surveillance on mortality from AC.METHODS:A cohort of newly diagnosed BE patients was studied prospectively. Endoscopic and histological surveillance was recommended every 2 yr. Follow-up status was determined from hospital and registry office records and telephone calls to the patients.RESULTS:From 1987 to 1997, BE was diagnosed in 177 patients. We excluded three with high-grade dysplasia (HGD) at the time of enrollment. Follow-up was complete in 166 patients (135 male, 31 female). The mean length of endoscopic follow-up was 5.5 yr (range 0.5–13.3). Low-grade dysplasia (LGD) was present initially in 16 patients (9.6%) and found during follow-up in another 24 patients. However, in 75% of cases, LGD was not confirmed on later biopsies. HGD was found during surveillance in three patients (1.8%), one with simultaneous AC; two with HGD developed AC later. AC was detected in five male patients during surveillance. The incidence of AC was 1/220 (5/1100) patient-years of total follow-up, or 1/183.6 (5/918) patient-years in subjects undergoing endoscopy. Four AC patients died, and one was alive with advanced-stage tumor. The mean number of endoscopies performed for surveillance, rather than for symptoms, was 2.4 (range 1–10) per patient. During the follow-up years the cohort had a total of 528 examinations and more than 4000 biopsies.CONCLUSION:The incidence of AC in BE is low, confirming recent data from the literature reporting an overestimation of cancer risk in these patients. In our patient cohort, surveillance involved a large expenditure of effort but did not prevent any cancer deaths. The benefit of surveillance remains uncertain.

Esophageal dilation in malignant dysphagia

Esophageal dilation by means of guided Neoplex (Medoc) tubes in 38 patients with malignant obstruction of the esophagus was analyzed. Peroral dilation proved to be a simple, well‐tolerated primary procedure in the management of malignant strictures. Most patients have a temporary improvement of dysphagic symptoms, but the benefit appears to decrease progressively in successive dilatatory sessions. Dilations were more difficult, with a 10% perforation rate, in previously radiated patients. Esophageal dilations may play a complementary role in addition to other palliative techniques in the management of malignant dysphagia.

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.

Value of multiple forceps biopsies in assessing the malignant potential of colonic polyps.

Fifty-nine colo-rectal polyps were detected at endoscopy and repeatedly biopsied before removal by endoscopic snare polypectomy. The aim of the present paper was to evaluate the reliability of multiple forceps biopsies in assessing both the malignant potential and the presence or absence of invasive cancers (IC) in colo-rectal adenomas (CRA). In order to achieve the first objective, the histologic types and the degree of dysplasia have been defined. The data obtained by means of multiple biopsies examination, compared with those of polyp in toto study, show that fractional biopsies were of value in the histologic classification of only the smallest 41 polyps (agreement 88.09 %), whilst no reliability of biopsies was demonstrated in the 18 largest polyps (agreement 27.68 %). In the field of dysplasia grading, the agreement was 55 % and 61 % for the smallest and the largest CRA respectively. These last figures are hardly acceptable. Biopsies examination gave also under- and overestimation of the histologic severity and of dysplasia as well as a significant incidence of false negative results in IC detection. It is concluded that polypectomy is the only method which provides adequate material for precise diagnosis, no matter how large a polyp. Therefore it should be performed whenever possible. Finally the authors discuss the management of small sessile adenomas.

Endocytoscopic imaging of a carcinoid tumor

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Localisation gastrique de sarcome de Kaposi au cours de Sida

RésuméLes auteurs présentent un cas de localisation gastrique de sarcome de Kaposi survenu chez un patient atteint de SIDA. Les aspects caractéristiques des lésions sont décrits en soulignant les éléments du diagnostic différentiel avec les lésions muqueuses et sousmuqueuses de ľestomac.SummaryThe authors present a clinical case of gastric localization of Kaposi’s sarcoma in a patient affected by AIDS. The typical characteristics of the lesion is reported. The differential diagnosis among other lesions involving the mucosal and submucosal structures of the stomach is stressed.

Left-sided stenosing lesions in colonoscopy.

Of 2625 consecutive colonoscopic examinations, 122 stenotic lesions interfered with endoscopy. The sigmoid was the most frequent site of stenosis (64%). Of the two types of endoscopic patterns, type A, in which there is an intraluminal protruding mass, is the most frequent, and type B, in which a segment of colon gradually narrows, has intact mucosa. Adenocarcinoma was the most frequent cause of type A (83%), and complications related to diverticular disease (32%) and adenocarcinoma (27%) were most often associated with type B. Colonoscopy, guided multiple biopsies, and brushing cytology gave high diagnostic accuracy for type A lesions. In type B cases, brushings were usually negative.

Abstract A80: Antioxidant supplement and long‐term reduction of metachronous adenomas of the large bowel: Results of a double‐blind randomized trial

This is a double randomized trial aimed at evaluating the efficacy of antioxidants in reducing the incidence of metachronous adenomas (MA) of the large bowel after endoscopic polypectomy. A 50% reduction in the incidence of MA was expected in patients (pts) allocated to an active compound (intervention) arm as compared to those assigned to a placebo. Eligible for the study were pts aged 25–75 years with a clean colon after adenomas removal. Pts with FAP, invasive carcinoma in adenoma, previous polypectomy, IBD, bowel resection, cancer at any site, life‐threatening diseases, current use of vitamins or calcium were excluded. Pts were randomly allocated to receive daily, for 5 years, either an antioxidant compound (selenomethionine 200 g, zinc 30 mg, vitamin A 6000 IU, vitamin C 180 mg and vitamin E 30 mg) or a placebo, both were provided by Pharma Nord. Total Colonoscopy (TC) was planned on year one, three and five after randomization and then according to current guidelines. The primary endpoint of the study was the occurrence of MA detected during TC examinations. The study was approved by the Ethical Committee of the Natl. Institute for Cancer Research of Genoa. Three GI endoscopy units in northern Italy participated in the study. The study started on March 1988 and was stopped on June 1996 when 411 patients had been enrolled. Of them, 200 were assigned to the intervention arm and 211 to the placebo arm. On June 2009, information on survival was available for 396 pts (96.4%); follow up information (at least one TC performed after randomization) was available for 311 pts (80.5%): 165 in the intervention and 166 in the placebo arm. Predictors of MA (gender, age, number of adenomas and rate of advanced adenomas) were similar in pts who had follow up TC and in those who were lost. Of the 311 patients, 144 (43.5%) assumed more than 2/3 of the total amount of the assigned treatment: the rates were similar in the two arms. An intention to treat analysis was performed. The 311 pts provided 1.743 py of follow‐up and 98 pts developed MA (2 with invasive carcinoma). The observed incidence of MA was 4.2% (37 cases/886 py) in the intervention arm and 7.2% (62 cases/857 py) in the placebo arm (crude RR=0.56, 95% CI 0.36–0.87; P=0.007). The 15‐year actuarial MA‐free survival was 48.3% in pts assigned to the intervention arm and 30.5% in those assigned to the placebo arm (P=0.006). A Cox proportional hazard model was fitted to the data and GI endoscopy unit, gender, age, number of adenomas, presence of advanced adenoma were included in the model as covariates: a 41% reduction in the risk of MA was observed in the intervention as compared to the placebo arm (HR=0.59, 95% CI 0.39–0.90; P=0.013). Among pts who had advanced adenomas at randomization, those assigned to the intervention arm had a 10‐fold lower risk of advanced MA as compared to those assigned to the placebo (RR=0.11, 95%CI 0.02–0.49; P=0.004). To our knowledge, this is the first time that a specifically designed trial shows the persistence of a statistically significant reduction of colorectal MA in pts treated with a selenium‐based antioxidant compound long time after the treatment cessation. In particular, the effect observed in pts with advanced index adenoma is intriguing. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A80.

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.

Association d'une maladie de Crohn, d'une fistule anale persistante et d'un adénocarcinome mucineux de la jonction anorectale : à propos d'un cas

RésuméLes auteurs rapportent un cas associant une maladie de Crohn, une fistule péri-anale persistante et un adénocarcinome mucineux de la jonction ano-rectale.SummaryWe report a case of association between Crohn’s disease with a long-standing perianal fistula and mucinous adenocarcinoma of the anorectal junction spreading to the perianal region.ResumenLos autores informan un caso con Enfermedad de Crohn, una fístula peri-anal persistente y un adenocarcinoma mucinoso de la unión ano-rectal, asociados.ZusammenfassungEs wird berichtet über einen Fall von M. Crohn mit persistierender peri-analen Fistel und gleichzeitigem Auftreten eines muzinösen Adeno-Carcinoms an ano-rektalen Übergang.RiassuntoGli autori riportano il caso di un paziente affetto da morbo di Crohn, fistola perianale cronica e adenocarcinoma mucinoso della giunzione ano-rettale.