Pasquale Spinelli

Multiple Approach to the Exploration of Genotype-Phenotype Correlations in Familial Adenomatous Polyposis

PURPOSE Familial adenomatous polyposis (FAP), caused by a mutation in the APC gene, is a colorectal cancer predisposition syndrome associated with several other clinical conditions. The severity of the FAP is related to the position of the inherited mutation in the APC gene. We analyzed a large series of FAP patients to identify associations among major clinical manifestations and to correlate the mutation site with specific disease manifestations. MATERIALS AND METHODS APC mutations were identified in 953 FAP patients from 187 families. We used unconditional logistic regression models and a method involving generalized estimating equations to investigate the association between genotype and phenotype. We used multiple correspondence analysis to represent the interrelationships of a multiway contingency table of the considered variables. RESULTS APC germline mutations were located between codons 156 and 2011 of the APC gene. Mutations spanning the region between codons 543 and 1309 were variable, but strongly associated with congenital hypertrophy of retinal pigment epithelium. Mutations between codons 1310 and 2011 were associated with a six-fold risk of desmoid tumors relative to the low-risk reference region (159 to 495). Mutations at codon 1309 were associated with early development of colorectal cancer. Mutations between codons 976 and 1067 were associated with a three- to four-fold increased risk of duodenal adenomas. The cumulative frequency of extracolonic manifestations was highest for mutations between codons 976 and 1067, followed by mutations between 1310 and 2011. CONCLUSION Analysis of the relation between APC mutation site and phenotype identifies subgroups of FAP patients at high risk for major extracolonic disease, which is useful for surveillance and prevention.

Predictors of metachronous colorectal neoplasms in sporadic adenoma patients.

Our objective was to assess the overall risk of subsequent colorectal neoplasms (cancer or adenoma) in relation with the various characteristics of the index lesion in a cohort of patients who underwent endoscopic polypectomies of colorectal adenomas. A total of 1,086 patients with adenomas of the large bowel were reported between 1979 and 1999 at the National Cancer Institute of Milan during a screening program for colorectal carcinoma. Data on patients who had colonoscopic examinations and treatments were collected prospectively. The relation between colorectal cancer (CRC) and adenoma features was assessed by computing the hazard ratio (HR) values and corresponding confidence intervals (95% CI) according to Cox proportional hazard models. Of the 1,086 eligible patients (487 females, 579 males), 736 had single adenomas (67.7%) and 350 had multiple adenomas (32.3%). Histologic examination revealed 772 cases of tubular adenoma (73%), 205 cases of tubulovillous adenoma and 80 cases of villous adenoma (7.5%). Severe dysplasia was found in 3.3% of the cases. During the 11,393 person‐years of follow‐up, with an average time of surveillance of 10.5 years, colorectal carcinomas developed in 10 patients (0.8%) and a new adenoma in 323 patients (29%). Multivariate analysis showed that male gender (HR 1.6; 95% CI 1.3–2.0), multiple polyps (HR 1.6; 95% CI 1.3–2.0), polyps larger than 2 cm (HR 1.5; 95% CI 1.1–2.1), tubulovillous and villous histology (HR 1.3; 95% CI 1.0–1.6 and HR 1.8; 95% CI 1.2–2.6, respectively) at index polypectomy were statistically significant risk factors for developing metachronous adenomatous polyps. The standardized incidence rates (SIR) for CRC was 0.52 (95% CI 0.25–0.95). The SIR was increased in subjects with severe dysplasia (2.8; 95% CI 0.34–1.02). Some features of large bowel adenomas are strongly correlated with an increased risk of metachronous adenomas and colorectal cancer. However, the endoscopic polypectomy is able to reduce by 50% the incidence of CRC in patients with large bowel adenomas.

Genotype and phenotype factors as determinants for rectal stump cancer in patients with familial adenomatous polyposis

Familial adenomatous polyposis (FAP), an autosomal dominantly inherited disorder with a penetrance of nearly 100%, is characterized by the progressive development of hundreds of adenomatous colorectal polyps, some of which inevitably progress to cancer. The clinical features of this syndrome and its variants have been known for many years. Diagnosis still relies largely on the detection of numerous colorectal polyps during the second or third decade of life, as well as extracolonic lesions. Mutations of the APC gene, identified in 1991, are responsible for the disease in most FAP families. Several reports have shown a correlation among mutations occurring within specific regions of APC, the severity of polyposis, and the presence of extracolonic manifestations. 1–6 Treatment for FAP is the prophylactic surgical resection of affected colon to prevent malignant degeneration of adenomas. Colectomy with ileorectal anastomosis (IRA) is the most common surgical procedure in many institutions. This procedure carries low rates of complications and death and produces a good functional outcome. However, the rectal remnant should be carefully observed for the possible occurrence of cancer. Beginning in the 1980s, several reports have indicated that the risk of rectal cancer gradually increases with time, amounting to 10% to 55% after 20 years of follow-up. 5,7–15 However, some have reported spontaneous regression of the remaining polyps in the retained rectum, 16,17 for a reduced proliferation of the rectal mucosa. 18–20 The aims of this study were to examine the risk of rectal cancer in patients with FAP after IRA and to identify clinical or genetic factors that can predict the development of cancer in the retained rectum.

Survival of patients with hereditary colorectal cancer: Comparison of HNPCC and colorectal cancer in FAP patients with sporadic colorectal cancer

Conflicting data exist on the prognosis of hereditary colorectal cancer. HNPCC patients, in particular, are often reported to have a better survival. We examined 2,340 colorectal‐cancer patients treated in our Institution: 144 HNPCC patients (Amsterdam Criteria), 161 FAP patients and 2,035 patients with sporadic cancer. Data on hereditary‐cancer patients treated between 1980 and 1995 was collected in a registry. The 2,035 sporadic colorectal‐cancer patients (controls) included all new cases treated in the Department of Gastrointestinal‐Tract Surgery during the same period. Observed survival was estimated using the Kaplan‐Meier method. Cumulative survival probability was estimated at 5 years within each group and stratified by various clinical and pathological variables. The age distribution at diagnosis of sporadic patients was significantly higher than that of FAP and HNPCC patients (median 60 years vs. 43 and 49 years; p < 0.0001). In the HNPCC group, 40% had a right cancer location, vs. 14% in the FAP group and 13% in the sporadic‐cancer group. In the sporadic group, 51% were early‐stage cancers (Dukes A or B) vs. 48.4% and 52.1% in the FAP and HNPCC groups respectively. In the HNPCC, FAP and sporadic‐cancer groups, the 5‐year cumulative survival rate was 56.9%, 54.4% and 50.6% respectively. Survival analysis by the Cox proportional‐hazards method revealed no substantial survival advantage for HNPCC and FAP patients compared with the sporadic group, after adjustment for age, gender, stage and tumor location. The hazard ratio for HNPCC was 1.01 (95% CI 0.72–1.39) and 1.27 (95% CI 0.95–1.7) for FAP patients compared with the sporadic‐colorectal‐cancer group. Int. J. Cancer 80:183–187, 1999.

Light-induced fluorescence spectroscopy of adenomas, adenocarcinomas and non-neoplastic mucosa in human colon I. In vitro measurements

In an attempt to evaluate whether induced fluorescence could be exploited to discriminate neoplastic from non-neoplastic tissue, fluorescence spectroscopy was performed at 450-800 nm on 83 biopsy specimens of colonic mucosa. Measurements showed that fluorescence spectra of adenoma, adenocarcinoma and non-neoplastic mucosa manifest dissimilar patterns. Nine variables, whose photophysical and/or biological bases need further investigation, were derived from the spectra. Discriminant functions between the groups of lesions were determined by using a stepwise discriminant analysis. The diagnostic test had a sensitivity of 80.6% and 88.2%, and a specificity of 90.5% and 95.2% in discriminating neoplastic from non-neoplastic mucosa and adenoma from non-neoplastic mucosa respectively. These results suggest that fluorescence spectroscopy has the potential to improve endoscopic diagnosis of premalignant and malignant lesions of colonic mucosa.

Self-expanding mesh stent for endoscopic palliation of rectal obstructing tumors: a preliminary report

SummaryThe endoscopic insertion of self-expanding mesh stents in four patients affected by obstructing rectal malignant tumors is reported. The preliminary experience shows that, in the short term, normal defecation was achieved, with no complications. Longer follow-up is necessary to evaluate the duration and the quality of the palliative effect.

Results of EUS in detecting perirectal lymph node metastases of rectal cancer: the pathologist makes the difference ☆ ☆☆

BACKGROUND Accurate preoperative staging of primary rectal cancer is mandatory because the result may affect therapeutic decisions. Endoscopic ultrasonography (EUS) is considered the most accurate method for locoregional staging, but the issue of possible variations in the assessment of its accuracy related to technical aspects of pathologic staging has never been raised. The aim of this study was to assess EUS results as determined by two different methods of dissection of surgical specimens. METHODS Among all cases with primary rectal cancer staged with EUS from April 1991 to April 1997, 131 patients underwent surgery without preoperative radiotherapy; EUS results for nodal staging were compared with those obtained by pathology. Resected specimens were examined using two different techniques (conventional vs. special dissection). RESULTS There was a significant decrease in diagnostic accuracy of EUS according to pathologic technique. Overall accuracy, sensitivity, specificity, positive and negative predictive values for conventional versus special dissection were as follows: 74.6% vs. 43. 3% (p = 0.0001), 67.8% vs. 21.8% (p = 0.0002), 79.1% vs. 67.8% (p = 0.14), 67.8% vs. 43.7% ( p = 0.02), and 79.1% vs. 43.2% (p = 0.0003), respectively. EUS sensitivity according to size of metastatic lymph nodes was significantly lower for nodes smaller than 5 mm in diameter (p = 0.025) when special dissection was performed because of a larger number of lymph nodes harvested. CONCLUSIONS Our findings raise concern about the results of EUS staging of lymph node metastases in rectal cancer. Further prospective studies on a node-by-node basis could clarify the real diagnostic yield of EUS.

Preoperative radiation therapy for patients with T2–T3 carcinoma of the middle-to-lower rectum

The aim of this study was to determine the effects of preoperative radiation therapy (RT) on the objective responses of patients with rectal carcinoma to their treatment. These effects were assessed with endorectal ultrasound (EUS) evaluation, histopathologic grading of postirradiation tumor mass reduction in the surgical specimen, and analysis of local and distant recurrences.

Effect of lifestyle, smoking, and diet on development of intestinal metaplasia in H. pylori-positive subjects

Effect of lifestyle, smoking, and diet on development of intestinal metaplasia in H. pylori -positive subjects

Observation of thoracic duct morphology in portal hypertension by endoscopic ultrasound

BACKGROUND Thoracic duct dilation has been demonstrated in portal hypertension and hepatic cirrhosis by lymphangiography and laparotomy and at autopsy. It is thought to be secondary to increased hepatic lymph flow and has been described in the absence of ascites or esophageal varices. The aim of the present study was to observe thoracic duct morphology by endoscopic ultrasound in various subsets of patients with portal hypertension and hepatic cirrhosis and also to validate existing radiologic/surgical data. METHODS The thoracic duct of 33 patients with cirrhosis and portal hypertension was studied by endoscopic ultrasound. Patients were divided into four groups: 1, patients with ascites and esophageal varices; 2, esophageal varices without ascites; 3, without esophageal varices or ascites; 4, extrahepatic portal hypertension due to pancreatic malignancy. The thoracic duct diameter was also measured in 14 control subjects (group 5). RESULTS When the thoracic duct diameter for the five groups was compared with analysis of variance, significance was p < 0.0001; by pairwise comparison, group 1 differed from the other four groups (p < 0.05). Thoracic duct dilation (5.61 mm) was seen in group 1 patients, whereas no dilation was present in groups 2 through 4. Additionally, thoracic duct diameter in 33 portal hypertensive and/or cirrhotic patients was significantly different from that in the 14 control subjects (p = 0. 003). CONCLUSION The thoracic duct can be reliably identified by EUS in patients with hepatic cirrhosis and portal hypertension. Dilation of the duct is seen only in patients with hepatic cirrhosis, ascites, and esophageal varices. No thoracic duct dilation is present in extrahepatic portal hypertension. Contrary to existing radiologic/surgical data, thoracic duct dilation is not seen in all patients with hepatic cirrhosis and portal hypertension signifying advanced disease. A dilated thoracic duct by endoscopic ultrasound should be considered yet another sign of portal hypertension.