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Several models of genetic counseling have been proposed to tackle the increasing volume of individuals requiring access to BRCA testing. Few data are available on patient experience and retention of information with nurse-driven genetic counseling. We evaluated the experience and retention of information in women with an uninformative BRCA test result and who were not considered at high risk due to their personal/family history of cancer who underwent geneticist-supervised nurse-driven genetic counseling and who received their test result by phone. Women who received an uninformative BRCA test result between May 2017 and September 2019 were administered a questionnaire exploring experience with genetic counseling and retention of information provided. Of 366 eligible women, 299 (273 breast cancer patients and 26 women without breast cancer) completed the interview. Overall, 280 women (93.6%) positively valued their experience with genetic counseling and 287 (96.0%) considered it helpful with 57.5% of them feeling reassured for themselves and their family. Information on the clinical implications of the test result was correctly retained and women acted accordingly. Overall, 252 women (87.8%) accurately reported their test result as normal/negative. Only 67 (22.4%) recognized that despite a normal BRCA test result, a low probability of a hereditary syndrome remains. Most women showed a poor ability to estimate cancer risk in BRCA mutation carriers and in the general population. Geneticist-supervised nurse-driven genetic counseling process for women with uninformative BRCA test result is associated with a positive patient experience and an adequate retention of information concerning the management of their personal and familial cancer risk. The design and implementation of nurse-driven genetic counseling models may contribute to efficient and timely access to BRCA genetic testing.

Background Recent reports showed that the protective effect of flexible sigmoidoscopy (FS) screening was maintained up to17 years, although differences were reported by sex. Objective To assess long-term reduction of colorectal cancer (CRC) incidence and mortality after a single FS screening. Design Parallel randomized controlled trial. (ISRCTN registry number: 27814061). Setting 6 centers in Italy. Participants Persons aged 55 to 64 years expressing interest in having FS screening if invited, recruited from 1995 to 1999 and followed until 2012 (incidence) and 2014 to 2016 (mortality). Intervention Eligible persons were randomly assigned (1:1 ratio) to either the once-only FS screening group or control (usual care) group. Measurements Incidence and mortality rate ratios (RRs) and rate differences. Results A total of 34 272 persons (17 136 in each group) were included in the analysis; 9911 participants had screening in the intervention group. Median follow-up was 15.4 years for incidence and 18.8 years for mortality. Incidence of CRC was reduced by 19% (RR, 0.81 [95% CI, 0.71 to 0.93]) in the intention-to-treat (ITT) analysis, comparing the intervention with the control group, and by 33% (RR, 0.67 [CI, 0.56 to 0.81]) in the per protocol (PP) analysis, comparing participants screened in the intervention group with the control persons. Colorectal cancer mortality was reduced by 22% (RR, 0.78 [CI, 0.61 to 0.98]) in the ITT analysis and by 39% (RR, 0.61 [CI, 0.44 to 0.84]) in the PP analysis. Incidence of CRC was statistically significantly reduced among both men and women. Colorectal cancer mortality was statistically significantly reduced among men (ITT RR, 0.73 [CI, 0.54 to 0.97]) but not among women (ITT RR, 0.90 [CI, 0.59 to 1.37]). Limitation Self-selection of volunteers from the general population sample targeted for recruitment may limit generalizability. Conclusion The strong protective effect of a single FS screening for CRC incidence and mortality was maintained up to 15 and 19 years, respectively. Primary funding source Italian Association for Cancer Research, Italian National Research Council, Istituto Oncologico Romagnolo, Fondo "E. Tempia," University of Milan, and Local Health Unit ASL-Torino.

The micronucleus test in peripheral blood lymphocytes is the most widely validated technique to evaluate the DNA damage and chromosomal instability in human populations. The test is largely applied in monitoring environmental and occupational exposure to genotoxic agents. It was also proposed as a biomarker of risk/susceptibility for cancer and other degenerative diseases. The availability of “normal values” in healthy populations is a main requisite for the assay application in human biomonitoring. Age and gender-related ranges of micronucleated binucleated cells (MNBN) baseline values were established in a group of 103 healthy platelet donors (50 males and 53 females) not recently exposed to genotoxic agents and characterized for demographic, lifestyle and dietary factors. Repeatability of the test by the same scorer was evaluated. Reproducibility was estimated through analysis of repeated blood samples. High correlation between the results of the three blood samplings in two separate scoring sessions of MNBN/1000BN (R2 values were 0.83, 0.74 and 0.68; P

BackgroundIn women at high/intermediate lifetime risk of breast cancer (BC-LTR), contrast-enhanced magnetic resonance imaging (MRI) added to mammography ±ultrasound (Mx±US) increases sensitivity but decreases specificity. An alternative strategy, MRI alone, potentially more cost-effective, has never been explored. This study aims to assess the characteristics of women who participated in a randomized trial offering MRI alone.MethodsIn this feasibility multicentre randomized controlled trial we compared MRI alone versus Mx+US in women at intermediate BC-risk (allocation ratio 1:1). Eligible women were aged 40 –59, with a 15–30% LTR and/or extremely dense breasts. Two screening rounds per woman were planned in ten centres experienced in MRI screening. Primary endpoint: rate of cancers detected in the two arms after 5 years of follow-up. Secondary endpoints: distribution of the risk profiles among the women enrolled in the trial; distribution of pathological stages and histology of cancers detected; interval cancer rate in the two arms.ResultsFrom 07/2013 to 11/2015, 1,254 women (mean age 47 years) were enrolled: 624 were assigned to Mx+US, 630 to MRI. Most of them were aged below 50 (72%) and premenopausal (45%), 52% used oral contraceptives. Among postmenopausal women, 15% had used hormone replacement therapy. Breast and/or ovarian cancer in mother and/or sisters were reported by 37% of enrolled women, extreme breast density was recorded for 79%, 41% had a 15–30% BC-LTR.ConclusionsThe distribution of BC-risk profile major determinants (breast density and family of breast and ovarian cancer) of enrolled women varied across centres.Trial registrationNCT02210546Key pointsMammography plus ultrasound are commonly used to screen women with dense breastsSupplemental ultrasound increases BC detection rate but also false-positives and potential overdiagnosisWhether increased BC detection by US translates into reduced mortality is unknownMRI alone could be more risk- and cost-effective than mammography plus ultrasound

Women attending mammography screening may benefit from family history (FH) assessment for the identification of Hereditary Breast Ovarian Cancer (HBOC). Few studies explored the efficacy of tailored educational interventions in driving the attention on FH-associated risk among these women. To compare the efficacy of two educational tools in increasing attention towards FH, 6.802 women with a negative mammography were randomized to receive a note on FH of breast/ovarian cancer (letter A, n = 3.402) or a note with details on possible implication of FH patterns (letter B, n = 3.200). Upon women's request, a brief questionnaire was administered on phone at the Screening Unit (S.U.) to select those eligible for an in-depth FH evaluation at the Genetic Unit (G.U.). Each affected relative was scored 1-3 according to type of cancer, age at diagnosis, gender, position in the family tree. In all, 401 women contacted the S.U.: 244 (6.6%) in group A and 177 (5.2%) in group B (adjOR 1.27; 95%CI 1.03-1.56). FH scored ≥ 3 for 164 women: 177 (47.5%) in group B and 224 (35.7%) in group A, (adjOR 1.59, 95%CI 1.06-2.38). The G.U. traced and interviewed 148 women, 65 (43.9%) were offered an in-person consultation: 38 attended and 30 were eligible for testing. A test was performed for 24 women: no BRCA pathogenic variant was found. Among mammographic screening attendees, educational material with a simple description of FH may improve self-referral of women deserving an in-depth evaluation for HBOC identification. Additional educational efforts are needed to enhance the efficiency of the intervention.

Female BRCA1/BRCA2 mutation carriers are at substantially increased risk for developing breast and/or ovarian cancer, and are offered enhanced surveillance including screening from a young age and risk-reducing surgery (RRS)-mastectomy (RRM) and/or salpingo-oophorectomy (RRSO). While there are established guidelines for early detection of breast cancer in high-risk women who have not undergone RRM, there are less developed guidelines after RRM. We evaluated the schemes offered before and after RRS in internationally diverse high-risk clinics. An e-mailed survey was distributed to high-risk clinics affiliated with CIMBA. Overall, 22 centers from 16 countries responded. Pre RRS surveillance schemes overwhelmingly included breast imaging (primarily MRI) from 18 to 30 years and clinical breast exam (CBE) at 6-12 month intervals. For ovarian cancer, all but 6 centers offered semiannual/annual gynecological exam, transvaginal ultrasound, and CA 125 measurements. Post RRM, most centers offered only annual CBE while 4 centers offered annual MRI, primarily for substantial residual breast tissue. After RRSO only 4 centers offered specific gynecological surveillance. Existing guidelines for breast/ovarian cancer detection in BRCA carriers are being applied pre RRS but are not globally harmonized, and most centers offer no specific surveillance post RRS. From this comprehensive multinational study it is clear that evidence-based, long-term prospective data on the most effective scheme for BRCA carriers post RRS is needed.

Colorectal cancer screening programmes in Italy invite 50-69-year-old residents for a faecal immunochemical test every two years, regardless of their citizenship.The 2013 National Survey on Italian colorectal cancer screening programmes compared immigrants born in low- or middle-income countries with subjects who were born in Italy, by collecting aggregated data on compliance, faecal immunochemical test results, compliance with colonoscopy, detected lesions and stage at diagnosis separately for Italians and immigrants.Overall, 85 screening programmes invited 3,292,451 subjects, of whom 192,629 had been born abroad (5.9%). Compliance with invitation was lower in immigrants (34.3% vs. 51.3% in Italians), with p0.001. Compliance was higher in females, regardless of the country of birth, in the youngest age group of immigrants but in the oldest of Italians. Immigrants showed a borderline excess of standardised faecal immunochemical test positivity rate at first screening (5.4% vs. 5.1% in Italians, p=0.05) and a significant excess at repeat screenings (4.8% vs. 4.4%, p=0.002). The detection rates for carcinoma and advanced adenomas were lower in immigrants than in Italians at first screening (respectively 1.34‰ vs. 1.62‰ and 8.41‰ vs. 9.25‰) - although the differences were not statistically significant - but not at repeat screening (respectively 1.06‰ vs. 0.98‰ and 6.90‰ vs. 6.79‰).Migrants showed a lower compliance with screening than Italians. The prevalence of neoplasia was lower at first screening and similar to the Italians' at repeat screenings.

To determine prevalence, spectrum and genotype-phenotype correlations of MUTYH variants in Italian patients with suspected MAP (MUTYH-associated polyposis), a retrospective analysis was conducted to identify patients who had undergone MUTYH genetic testing from September 2002 to February 2014. Results of genetic testing and patient clinical characteristics were collected (gender, number of polyps, age at polyp diagnosis, presence of colorectal cancer (CRC) and/or other cancers, family data). The presence of large rearrangements of the MUTYH gene was evaluated by Multiplex Ligation-dependent Probe Amplification analysis. In all, 299 patients with colorectal neoplasia were evaluated: 61.2% were males, the median age at polyps or cancer diagnosis was 50 years (16-80 years), 65.2% had

Purpose To evaluate in current practice the performance of BOADICEA and BRCAPRO risk models and empirical criteria based on cancer family history for the selection of individuals for BRCA genetic testing. Patients and methods The probability of BRCA mutation according to the three tools was retrospectively estimated in 918 index cases consecutively undergone BRCA testing at 15 Italian cancer genetics clinics between 2006 and 2008. Results 179 of 918 cases (19.5%) carried BRCA mutations. With the strict use of the criteria based on cancer family history 173 BRCA (21.9%) mutations would have been detected in 789 individuals. At the commonly used 10% threshold of BRCA mutation carrier probability, the genetic models showed a similar performance [PPV (38% and 37%), sensitivity (76% and 77%) and specificity (70% and 69%)]. Their strict use would have avoided around 60% of the tests but would have missed approximately 1 every 4 carriers. Conclusion Our data highlight the complexity of BRCA testing referral in routine practice and question the strict use of genetic models for BRCA risk assessment.

to describe the performance and the impact on the population coverage of a population-based organised screening programme with primary HPV-DNA test.population-based cohort study.organised screening programme for women aged 30-64 years.coverage of the target population with Pap test and HPV-DNA test, compliance to invitation, positivity at HPV-DNA testing, proportion of positive Pap test (squamous cells of undetermined significance or more severe, ASC-US+), referral for colposcopy, positive predictive value (PPV) of the cytology triage for grade-2 or more severe intraepithelial neoplasia (CIN2+), detection rate of CIN2+. Regarding coverage, seasonally adjusted trends of the PASSI surveillance from 2008 to 2014 were analysed. To evaluate performance, data of the information screening system were used.from December 2011 to December 2014, 48,852 women were invited for screening and 22,991 participated (48.4%); in addition, 968 women spontaneously participated in the programme, achieving a total of 23,959 screened women. The HPV test resulted positive for 2,000 women (8.4%). After triage 1,049 women were referred for colposcopy because of ASC-US+ (No. 968) or inadequate result (No. 81). The compliance at 12 months retesting among women with positive HPV test and negative triage was 79.3%, and the HPV positive rate was 60.4%. In the whole, 1,322 women were referred for colposcopy (5.5%) and 1,221 were actually tested. The overall detection rate for CIN2+ was 6.2/1,000. From 2011 to 2014, spontaneous Pap tests passed from 7,461/year to 2,491/year; the test coverage achieved a positive trend and it settles in recent years to 83%, including 43% of HPV-DNA.compliance to screening of invited women was satisfactory compared to previous experiences in Liguria Region (Northern Italy). Performance indicators confirm what was observed in other Italian experiences.

Lynch syndrome is an inherited cancer syndrome caused by germline mutations in mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. LS predisposes to high risk of early-onset colorectal, endometrial and other tumors. Patients with Lynch syndrome have also been shown to have an elevated risk for pancreatic cancer (PC). In this study, we aimed to estimate the frequency of suspected Lynch syndrome among a series of 135 PC patients. Further, we wanted to determine the frequency of MMR gene mutations in the suspected Lynch syndrome cases. We also aimed to verify the pathogenicity of any novel non-truncating variants we might detect with a functional assay. Based on personal and/or familial cancer history, 19 patients were classified as suspected Lynch syndrome cases. DNA material for mutation analysis was available for eleven of them. Four patients were found to carry a total of five MLH1 or MSH2 variants. Of these, MSH2-Q402X, MSH2-G322D, and MLH1-K618A had been previously reported, while the MSH2-E205Q and MSH2-V367I variants were novel. MSH2-Q402X is a known stop mutation and reported here for the first time here in association with PC. MLH1-K618A was found in the unaffected branch of a kindred, suggesting that it may be a polymorphism or a low penetrance variant. MSH2-G322D likely does not cause a MMR defect, although this variant has also been associated with breast cancer as indeed seen in our patient. The novel variants MSH2-E205Q and MSH2-V367I were found in the same patient. Both novel variants were however functional in the applied MMR assay. Our findings suggest that only a small subset of pancreatic cancer patients carry pathogenic MMR mutations.

We evaluated the contribution of germline CDKN2A mutations and MC1R variants to the development of melanoma in a hospital-based study of single (SPM, n = 398) and multiple primary melanoma (MPM, n = 95). The overall frequency of CDKN2A mutations was 15.2%, and four-fold higher in MPM than in SPM cases (OR = 4.27; 95% CI 2.43-7.53). The likelihood of identifying a CDKN2A mutation increased with family history of melanoma and younger age at diagnosis in MPM cases. Compared to SPM patients, the risk of harboring a CDKN2A mutation rose as the number of primary melanomas increased and was not influenced by family history. The G101W and E27X founder mutations were the most common. Several other mutations (W15X, Q50X, R58X, A68L, A127P and H142R) were detected for the first time in Italian patients. One novel mutation, T77A, was identified. Several non-coding variants with unknown functional significance were also found (5'UTR -25C > T, -21C > T, -67G > C, IVS1 +37G > C); the novel 5'UTR -21C > T variant was not detected in controls. The CDKN2A A148T polymorphism was more frequent in MPM patients than in the control population (15.7% versus 6.6%). Compared to the SPM patients, MPM cases had a 2-fold increased probability of being MC1R variant carriers and a higher probability of carrying two or more variants. No specific association was observed between the type of variant and the number of melanomas, suggesting that the number rather than the type of MC1R variant increases the risk of MPM. We observed no interaction between CDKN2A status and the presence of MC1R variants. The high frequency of CDKN2A mutations in our MPM cases, independent of their family history, is of relevance to genetic counseling and testing in our population.

Background: Few reports have investigated the association of two p53 polymorphisms (Arg72Pro and PIN3-A2) with colorectal cancer (CRC) risk, and no previous study has analyzed their role as susceptibility alleles for colorectal adenoma. Aim: To explore the impact of the p53 PIN3-Arg72Pro haplotype on colorectal adenoma formation and progression to cancer. Methods: One hundred and eighty-four colorectal tumor patients (124 with adenomas and 60 with adenocarcinoma) and 188 controls (42 subjects with a clean colon, 54 hospital controls and 92 blood donors) from the Italian population were tested for PIN3-Arg72Pro haplotype status. Results: A significantly increased risk of colorectal adenomas was observed in patients carrying the PIN3 A2-Pro72 haplotype (OR = 2.02, 95% CI: 1.17–3.48; p = 0.01), while those carrying the PIN3 A1-Pro72 haplotype had a significantly increased risk of developing CRC (OR = 3.33; 95% CI: 1.40–7.89; p = 0.006). Comparisons of cases with the clean colon control group provided stronger evidence of the associations. A family history of CRC did not affect the risk estimates. No association was observed between the pathologic features of adenomas, the Arg72Pro and PIN3 polymorphisms, and the PIN3-Arg72Pro haplotype. Conclusions: Our finding that two different p53 haplotypes are associated with colorectal adenoma and cancer, respectively, suggests that each of these haplotypes may independently impact on p53 function(s) within different genetic pathways of colorectal carcinogenesis.

This study was designed to assess the predictive value for advanced proximal neoplasms (cancer, adenomaor = 10 mm, or villous component20 percent, or severe dysplasia) of the characteristics of distal polyps.The study was conducted among patients, aged 55 to 64 years, referred for colonoscopy in the Italian trial of sigmoidoscopy screening for colorectal cancer. Patients reporting a history of colorectal cancer, adenomas, inflammatory bowel disease, recent colorectal endoscopy, or two first-degree relatives with colorectal cancer were excluded. We compared the prevalence of advanced proximal neoplasia in patients with "low-risk" (1-2 tubular adenomas,10 mm, with low-grade dysplasia, or hyperplastic polyp) and in those with "high-risk" (size,or = 10 mm, oror = 3 adenomas, or villous component20 percent, or severe dysplasia) polyps in the distal colon.Of 426 patients with polyps5 mm, 29 (6.9 percent) were detected with an advanced proximal neoplasm (including 4 colorectal cancers). The prevalence of proximal advanced neoplasia was 9.4 percent among patients with high-risk distal polyps and 2.5 percent among those with low-risk lesions (adjusted odds ratio, 3.19; 95 percent confidence interval, 1.06-9.59). Approximately 40 people with low-risk distal polyps 6 to 9 mm should undergo colonoscopy to detect one proximal advanced neoplasm; the corresponding number for patients with high-risk distal polyps is 10.The 2.5 percent prevalence of proximal advanced neoplasms among people with low-risk 6-mm to 9-mm distal polyps is similar to the prevalence observed among people without distal polyps. Restricting colonoscopy referral to patients with high-risk distal polyps might represent a cost-effective strategy in a screening context.

A single sigmoidoscopy examination at around age 60 years has been proposed as a cost-effective strategy to prevent colorectal cancer. A multicenter randomized controlled trial, the SCORE trial, is in progress in Italy to estimate the impact of this strategy on colorectal cancer incidence and mortality and the duration of the protective effect. We present the baseline screening outcomes.A questionnaire was mailed to a random sample of 236 568 people aged 55-64 years to assess their eligibility for and interest in screening. Those reporting a history of colorectal cancer, adenomas, inflammatory bowel disease, recent colorectal endoscopy, or two first-degree relatives with colorectal cancer were excluded. Eligible, interested respondents were assigned randomly to the control group (no further contact) or the intervention group (invitation to undergo sigmoidoscopy). Screenees with colorectal cancer, polyps larger than 5 mm, three or more adenomas, adenomas 5 mm or smaller with a villous component of more than 20%, or severe dysplasia were referred for colonoscopy.Of the 56 532 respondents (23.9% of those invited), 34 292 were enrolled and 17 148 were assigned to the screening group. Of those, 9999 attended and 9911 were actually examined by sigmoidoscopy. Distal adenomas were detected in 1070 subjects (10.8%). Proximal adenomas were detected in 116 of 747 (15.5%) subjects without cancer at sigmoidoscopy who then underwent colonoscopy. A total of 54 subjects was found to have colorectal cancer, a rate of 5.4 per 1000 (54% of which were Dukes' A). The procedures were relatively safe, with two perforations (one in 9911 sigmoidoscopy exams and one in 775 colonoscopies) and one hemorrhage requiring hospitalization after polypectomy during colonoscopy. The pain associated with sigmoidoscopy was described as mild or less than expected by 83.3% of the screenees.Sigmoidoscopy screening is generally acceptable to recipients and safe. The high yield of advanced adenomas is consistent with the projected impact of sigmoidoscopy screening on colorectal cancer incidence.

BACKGROUND Several reports indicated that volunteers enrolled in preventive trials tend to show a different profile, with respect to sociodemographic characteristics, health-related behaviors, or medical history, compared with the source population. We conducted an incidence and mortality follow-up within a cohort of subjects who had been mailed a recruitment questionnaire in the SCORE trial of sigmoidoscopy (FS) screening for colorectal cancer (CRC) to assess the impact of self-selection in the study of volunteers willing to be screened on the outcomes estimates and on the generalizability of the results. METHODS We compared baseline demographics, CRC risk, and overall mortality at 11-year follow-up of responders declaring their interest in screening, with those of nonresponders and of responders not interested in screening using logistic regression and Cox proportional hazards multivariable models. RESULTS Both subjects who volunteered in the trial and those who refused were better educated than nonresponders. Men and people younger than age 60 years were more likely to volunteer among responders. At 11-year follow-up, interested responders showed a similar CRC risk as nonresponders, while CRC mortality was substantially reduced (hazard ratio [HR] = 0.70, 95% confidence interval [CI] = 0.54 to 0.91). All-cause mortality was reduced both among interested (HR = 0.61, 95% CI = 0.57 to 0.65) and uninterested responders (HR = 0.81, 95% CI = 0.76 to 0.86). CONCLUSION The implementation of an FS population-based screening program would result in a similar reduction in CRC incidence, as observed in the SCORE trial, and likely in a larger impact on CRC mortality.

Background and Objectives Recent studies have demonstrated that the sentinel lymph node (sN) can be considered a reliable predictor of axillary lymph node status in breast cancer patients. However, some important issues, such as optimization of the technique for the intraoperative identification of the sN, and the clinical implications of sN metastasis as regards the surgical management of the axilla still require further elucidation. The objectives of this study was to assess (1) the feasibility of sN identification with a combined approach (vital blue dye lymphatic mapping and radioguided surgery, RGS) and the specific contribution of either techniques to the detection of the sN, and (2) the correlation between the size of sN metastasis (micrometastasis ≤ 2 mm; macrometastasis > 2), primary tumour size, and the status of nonsentinel nodes (nsN) in the axilla. Methods Between October of 1997 and December of 1999, 212 patients with breast cancer (average age: 61 years; range, 40–79 years) underwent sN biopsy before performing standard axillary dissection. In a subset of 153 patients, both vital blue dye (Patent Blue-V) lymphatic mapping and RGS were used to identify the sN, and the relative contribution of each of the two techniques was assessed. Results Overall, the sN was identified in 206 of 212 patients (97.1%); at histologic examination of all dissected nodes, 77 of 206 patients had positive nodes (37.3%). The false-negative rate was 6.5% (5/77), the negative predictive value was 96.3% (129/134), and accuracy was 97.6% (201/206). Among 72 patients with positive sN, micrometastases were detected in 21 cases and macrometastases in 51. When micrometastases only were observed, the sN was the exclusive site of nodal metastasis in 17 of 21 cases (80.9%); in the remaining 4 cases (19.1%), nsN metastases were detected in 3 of 14 pT1c patients (21.5%), and 1 of 5 pT2 patients (20%). Macrometastases were detected in patients with tumors classified as pT1b or larger: the sN was the exclusive site of metastasis in 3 of 4 pT1b patients (75%), in 14 of 29 pT1c patients (48.2%), and in 3 of 18 pT2 patients (16.6%). The specific contribution of the two different techniques used in the identification of the sN was evaluated; the detection rate was 73.8% (113 of 153) with Patent Blue-V alone, 94.1% (144 of 153) with RGS alone, and 98.7% (151 of 153) with Patent Blue-V combined with RGS (P

Our purpose was to evaluate the relationshipbetween the clinical and histological features in acohort of patients who had gastroesophagealreflux-related lesions diagnosed after upper digestiveendoscopy. In all, 589 patients scheduled for electiveendoscopy in a multicentric prospective study wereevaluated. Multiple biopsies from the distal esophagusshowing aspects of esophagitis or metaplastic epithelium were taken. Esophagitis was histologicallydetected in 25.6%, gastric-type Barrett's esophagus in36.2%, and specialized columnar epithelium in 33.1%. Thefrequency of esophagitis was constant across age decades. Patients with specialized columnarepithelium were significantly older (P = 0.01) and hada greater extent of metaplastic epithelium (P

BACKGROUND Barrett's oesophagus is a premalignant condition leading to adenocarcinoma. The incidence of adenocarcinoma of the oesophagus and the gastrooesophageal junction is rapidly increasing in the USA, northern and central Europe. Data from southern Europe are still unavailable. OBJECTIVE To evaluate the incidence of oesophageal adenocarcinoma in a large cohort of Italian patients with Barrett's oesophagus. METHODS A total of 344 patients (253 males and 91 females, age range 19-75 years) with histologically proven Barrett's oesophagus (length of metaplasia > or = 3 cm) were enrolled from November 1987 to June 1995. Endoscopic and histological examinations were scheduled at yearly intervals. RESULTS One hundred and eighty-seven patients complied with the follow-up. The mean duration of the follow-up period was 36 months (total follow-up 562 patient-years; range 12-90 months). Low grade dysplasia was found in five patients at the initial examination. During the surveillance period, dysplasia increased in frequency as well as in severity and was found exclusively in the intestinal type of Barrett's oesophagus. In all, dysplastic changes were found in seven patients (five low grade and two high grade) and adenocarcinoma developed in three patients during the follow-up. In a single case, both adenocarcinoma and specialized columnar epithelium developed without any evidence of dysplasia or intestinal metaplasia at the previous follow-up examination. This prospective study shows an incidence of adenocarcinoma in Barrett's oesophagus of 1/187 patient-years. When only patients with specialized columnar epithelium were considered, the risk of adenocarcinoma was 1/88 patient-years. CONCLUSION The present report shows that the incidence of adenocarcinoma in Italian Barrett's oesophagus patients is in the range of that reported from other Western countries.

Patients who undergo polypectomy are at increased risk of adenoma recurrence. The preventive potential of vitamins (A, C and E) and selenium supplementation represent an interesting opportunity for colorectal cancer prevention.To assess the efficacy of a combination of these micronutrients in reducing the incidence of recurrent adenomas in subjects on post-polypectomy endoscopic follow-up, a double-blind placebo-controlled randomized trial was started in Italy in 1988. A total of 411 patients were randomized to receive either an active compound (200 μg selenium, 30 mg zinc, 2 mg vitamin A, 180 mg vitamin C, 30 mg vitamin E) or a placebo daily for 5 years. Of them, 330 had follow-up colonoscopy (164 in the intervention and 166 in the placebo group).After a median follow-up of 4 years (range 1-15 years), 100 patients had recurrence: 38 in the intervention and 62 in the placebo arm. The 15-year cumulative incidence of recurrence was 48.3% in the intervention and 64.5% in the placebo arm (HR = 0.59; log-rank P = 0.009). A 39% reduction of the risk of recurrence was observed in the intervention compared to the placebo group (adjusted HR = 0.61; 95% CI 0.41-0.92): the risk reduction was similar for small tubular (adjusted HR = 0.61; 95% CI 0.37-0.99) and advanced adenomas (adjusted HR = 0.50; 95% CI 0.24-1.01).Our study showed a statistically significant effect of antioxidant supplementation on adenoma recurrence. Further clinical trials are needed to address the role of antioxidants in subgroups of subjects at increased risk for colorectal cancer.

Background The natural history of acute diverticulitis (AD) is still unclear. This study investigated the recurrence rate, and the risks of emergency surgery, associated stoma and death following initial medical or surgical treatment of AD. Methods The Italian Study Group on Complicated Diverticulosis conducted a 4-year multicentre retrospective and prospective database analysis of patients admitted to hospital for medical or surgical treatment of AD and then followed for a minimum of 9 years. The persistence of symptoms, recurrent episodes of AD, new hospital admissions, medical or surgical treatment, and their outcome were recorded during follow-up. Results Of 1046 patients enrolled at 17 centres, 743 were eligible for the study (407 recruited retrospectively and 336 prospectively); 242 patients (32·6 per cent) underwent emergency surgery at accrual. After a mean follow-up of 10·7 years, rates of recurrence (17·2 versus 5·8 per cent; P < 0·001) and emergency surgery (6·9 versus 1·3 per cent; P = 0·021) were higher for medically treated patients than for those treated surgically. Among patients who had initial medical treatment, age less than 40 years and a history of at least three episodes of AD were associated with an increased risk of AD recurrence. There was no association between any of the investigated parameters and subsequent emergency surgery. The risk of stoma formation was below 1 per cent and disease-related mortality was zero in this group. The disease-related mortality rate was 0·6 per cent among patients who had surgical treatment. Conclusion Long-term risks of recurrent AD or emergency surgery were limited and colectomy did not fully protect against recurrence.

Host, environmental and genetic factors differently modulate cutaneous melanoma (CM) risk across populations. Currently, the main genetic risk determinants are germline mutations in the major known high-risk susceptibility genes, CDKN2A and CDK4, and variants of the low-risk gene MC1R, which is key in the pigmentation process. This case-control study aimed at investigating the influence of the main host and environmental risk factors and of MC1R variation on CM risk in 390 CDKN2A-negative and 49 CDKN2A-positive Italian individuals. Multivariate analysis showed that MC1R variation, number of nevi and childhood sunburns doubled CM risk in CDKN2A-negative individuals. In CDKN2A-positive individuals, family history of CM and presence of atypical nevi, rather than MC1R status, modified risk (20.75- and 2.83-fold, respectively). Occupational sun exposure increased CM risk (three to sixfold) in both CDKN2A-negative and CDKN2A-positive individuals, reflecting the occupational habits of the Ligurian population and the geographical position of Liguria.

Background A single flexible sigmoidoscopy at around the age of 60 years has been proposed as an effective strategy for colorectal cancer (CRC) screening. Methods We conducted a randomized controlled trial to evaluate the effect of flexible sigmoidoscopy screening on CRC incidence and mortality. A questionnaire to assess the eligibility and interest in screening was mailed to 236,568 men and women, aged 55-64 years, who were randomly selected from six trial centers in Italy. Of the 56,532 respondents, interested and eligible subjects were randomly assigned to the intervention group (invitation for flexible sigmoidoscopy; n = 17,148) or the control group (no further contact; n = 17,144), between June 14, 1995, and May 10, 1999. Flexible sigmoidoscopy was performed on 9911 subjects. Intention-to-treat and per-protocol analyses were performed to compare the CRC incidence and mortality rates in the intervention and control groups. Per-protocol analysis was adjusted for noncompliance. Results A total of 34,272 subjects (17,136 in each group) were included in the follow-up analysis. The median follow-up period was 10.5 years for incidence and 11.4 years for mortality; 251 subjects were diagnosed with CRC in the intervention group and 306 in the control group. Overall incidence rates in the intervention and control groups were 144.11 and 176.43, respectively, per 100,000 person-years. CRC-related death was noted in 65 subjects in the intervention group and 83 subjects in the control group. Mortality rates in the intervention and control groups were 34.66 and 44.45, respectively, per 100,000 person-years. In the intention-to-treat analysis, the rate of CRC incidence was statistically significantly reduced in the intervention group by 18% (rate ratio [RR] = 0.82, 95% confidence interval [CI] = 0.69 to 0.96), and the mortality rate was non-statistically significantly reduced by 22% (RR = 0.78; 95% CI = 0.56 to 1.08) compared with the control group. In the per-protocol analysis, both CRC incidence and mortality rates were statistically significantly reduced among the screened subjects; CRC incidence was reduced by 31% (RR = 0.69; 95% CI = 0.56 to 0.86) and mortality was reduced by 38% (RR = 0.62; 95% CI = 0.40 to 0.96) compared with the control group. Conclusion A single flexible sigmoidoscopy screening between ages 55 and 64 years was associated with a substantial reduction of CRC incidence and mortality.

The purpose of this study was to investigate the correlation of flow cytometric (FCM) DNA content and cell cycle characteristics of Barrett's Esophagus (BE) with age and sex of the patients, length, histologic type and dysplasia of BE. Forty-one patients affected by histologically confirmed BE had multiple biopsies taken from the metaplastic epithelium and one biopsy taken from the gastric fundus, as control. The samples were either stored at -80 degrees C or immediately measured. Nuclei suspensions were obtained, stained with DAPI, measured with a high resolution flow cytometer (ICP22A, Ortho Instruments) and analyzed for the evaluation of the relative DNA content and the S- and G2 + M phases of the cell cycle. DNA histograms having two distinct G0/G1 peaks were classified as DNA aneuploid. The degree of DNA aneuploidy (DNA Index, DI), defined as the ratio of abnormal to normal DNA content, was obtained from the mixture of each BE sample with its control sample and trout erythrocytes. We found six patients with DNA aneuploid populations (14.6%), whose DNA Index values were 1.05 (in two), 1.8 (in one), and 2.0 (in three cases). DNA ploidy did not correlate with age and sex of the patients, length, histologic type, and dysplasia of BE. Among the 13 patients with dysplasia (6 indefinite, 4 low grade and 2 high grade with intramucous adenocarcinoma) only two (one indefinite and one low grade) showed DNA aneuploidy (15.4%). In addition, we found that the S-phase and the G2 + M-phase fractions in BE samples were both significantly higher than those of the controls (respectively, p = 0.01 and p = 0.0008).(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to investigate the clinical significance of DNA ploidy, as assessed by flow cytometry, for pancreatic and peripancreatic cancers. Between 1988 and 1990, we examined fresh/frozen samples from 49 patients who had histologically confirmed adenocarcinomas of the bilio-pancreatic carrefour: They had 23 cancers of the pancreas, 21 of the Vater's papilla, and 5 of the common bile duct. All patients were selected among a cohort of subjects who underwent Endoscopic Retrograde Cholangio Pancreatography (ERCP) and/or surgery. No prognostic impact of age, sex, stage, and surgical treatment on survival was observed by univariate analysis. When the affected organ was considered, a statistically significant difference in survival was observed: At 88 wk, survival was 0% for pancreatic and common bile duct cancer patients, and 18.2% at 175 wk for Vater's papilla cancer patients (p=0.04). In addition, we found, irrespective of affected organ, that the patients with DNA diploid tumors had a statistically significant survival advantage as compared to those with DNA aneuploidy (p=0.02). Furthermore, the statistically significant prognostic power of DNA ploidy was confirmed when patients with tumors of the pancreas and those with tumors of the Vater's papilla were separately analyzed. Finally, multivariate analysis showed that DNA content and affected organ were the only independent prognostic factors: Relative risks of dying were 3.9 (95% confidence interval CI=1.6–9.7) for patients with pancreatic cancer and 2.5 (CI=0.7–8.8) for those with common bile duct tumor when compared to those with ampullary cancer; the relative risk for DNA aneuploid tumors, as compared to DNA diploid ones, was 2.4 (CI=1.2–5.0). In conclusion, our results indicate that abnormal nuclear DNA content in pancreatic and peripancreatic cancers is an independent and powerful, indicator of poor prognosis.

CONTEXT: Computed tomographic (CT) colonography has been recognized as an alternative for colorectal cancer (CRC) screening in average-risk individuals, but less information is available on its performance in individuals at increased risk of CRC. OBJECTIVE: To assess the accuracy of CT colonography in detecting advanced colorectal neoplasia in asymptomatic individuals at increased risk of CRC using unblinded colonoscopy as the reference standard. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, cross-sectional study. Individuals at increased risk of CRC due to either family history of advanced neoplasia in first-degree relatives, personal history of colorectal adenomas, or positive results from fecal occult blood tests (FOBTs) were recruited in 11 Italian centers and 1 Belgian center between December 2004 and May 2007. Each participant underwent CT colonography followed by colonoscopy on the same day. MAIN OUTCOME MEASURES: Sensitivity and specificity of CT colonography in detecting individuals with advanced neoplasia (ie, advanced adenoma or CRC) 6 mm or larger. RESULTS: Of 1103 participants, 937 were included in the final analysis: 373 cases in the family-history group, 343 in the group with personal history of adenomas, and 221 in the FOBT-positive group. Overall, CT colonography identified 151 of 177 participants with advanced neoplasia 6 mm or larger (sensitivity, 85.3%; 95% confidence interval [CI], 79.0%-90.0%) and correctly classified results as negative for 667 of 760 participants without such lesions (specificity, 87.8%; 95% CI, 85.2%-90.0%). The positive and negative predictive values were 61.9% (95% CI, 55.4%-68.0%) and 96.3% (95% CI, 94.6%-97.5%), respectively; after group stratification, a significantly lower negative predictive value was found for the FOBT-positive group (84.9%; 95% CI, 76.2%-91.3%; P < .001). CONCLUSIONS: In a group of persons at increased risk for CRC, CT colonography compared with colonoscopy resulted in a negative predictive value of 96.3% overall. When limited to FOBT-positive persons, the negative predictive value was 84.9%.

The relationship between socio-economic characteristics, previous tonsillectomy, family history of cancer and risk of Hodgkin's disease (HD) was investigated in a case-control study. One hundred and sixty patients, aged 15-78, with histologically confirmed HD, and 185 hospital controls were interviewed. A statistically significant decrease in risk of HD was observed among subjects with large sibship size (RR = 0.63, C.I. 0.46-0.86) and among those who underwent tonsillectomy prior to the age of 10 (RR = 0.46, C.I. 0.22-0.94). High educational level was associated with an increased risk of HD (RR = 6.68, C.I. I.94-23.08). Analysis by age-group (15-39 yrs and 40 yrs or more) confirmed the role of high educational level as a risk factor in both young and old subjects, while the protective effect of tonsillectomy at an early age seems to be confined to young subjects. Analysis by histological subtype showed a statistically significant decrease in risk of HD in large sibship size for both nodular sclerosis (NS) and mixed-cell subtypes; the role of education and tonsillectomy was observed only for NS. These data confirm the role of social factors in HD risk and suggest a protective effect of tonsillectomy performed early in life that needs to be confirmed in larger population-based studies.

Few reports have investigated the association of two p53 polymorphisms (Arg72Pro and PIN3-A2) with colorectal cancer (CRC) risk, and no previous study has analyzed their role as susceptibility alleles for colorectal adenoma.To explore the impact of the p53 PIN3-Arg72Pro haplotype on colorectal adenoma formation and progression to cancer.One hundred and eighty-four colorectal tumor patients (124 with adenomas and 60 with adenocarcinoma) and 188 controls (42 subjects with a clean colon, 54 hospital controls and 92 blood donors) from the Italian population were tested for PIN3-Arg72Pro haplotype status.A significantly increased risk of colorectal adenomas was observed in patients carrying the PIN3 A2-Pro72 haplotype (OR = 2.02, 95% CI: 1.17-3.48; p = 0.01), while those carrying the PIN3 A1-Pro72 haplotype had a significantly increased risk of developing CRC (OR = 3.33; 95% CI: 1.40-7.89; p = 0.006). Comparisons of cases with the clean colon control group provided stronger evidence of the associations. A family history of CRC did not affect the risk estimates. No association was observed between the pathologic features of adenomas, the Arg72Pro and PIN3 polymorphisms, and the PIN3-Arg72Pro haplotype.Our finding that two different p53 haplotypes are associated with colorectal adenoma and cancer, respectively, suggests that each of these haplotypes may independently impact on p53 function(s) within different genetic pathways of colorectal carcinogenesis.

Screening sigmoidoscopy can reduce incidence of colorectal cancer and mortality. The optimal re-screening interval has not yet been defined. This study is aimed at estimating the risk of distal advanced adenomas (diameter/=10 mm, villous component20%, high-grade dysplasia) and cancer at screening flexible sigmoidoscopy in subjects aged 55-64 years who reported pre-screening negative colorectal endoscopy.Eight thousands two hundred two subjects aged 55-64 years who underwent screening flexible sigmoidoscopy within the SCORE trial in Italy and who were able to report their previous history of colorectal endoscopy.Eight hundred eighty three of 8,202 subjects (10.8%) reported at least one prescreening negative endoscopy: among them, after 3-5 years, 6-10 years and10 years intervals between last reported examination and screening endoscopy, the Absolute Risk of advanced adenomas was 1.5%, 0.9% and 0.9%; one cancer was detected (0.1%). Among the 7,319 subjects who did not report prescreening endoscopy the risks of advanced adenoma and cancer were 3.2% and 0.4%, respectively. Subjects with a previous colorectal examination had a 65% decreased risk of advanced adenomas (OR=0.35, 95%CI 0.18-0.66) and a 71% decreased risk of cancer (OR=0.29, 95%CI 0.04-1.12) as compared to those who did not. For subjects without family history of colorectal cancer the statistically significant decrease of the risk persisted up to ten years. The observed benefit seems not to apply to subjects with family history of colorectal cancer.Our results are consistent with the hypothesis that the interval between screening sigmoidoscopies could be safely expanded beyond 5 years for subjects without specific risk factors for colorectal cancer.

Colorectal cancer (CRC) is a major health problem in western countries. It is the most frequently diagnosed cancer in EU countries with about 220,000 new cases per year; the number of CRC deaths approaches 112,000. Most cancer arises from adenomatous polyps through the adenoma-carcinoma sequence; the natural history of the disease is long: the risk of invasive cancer in adenoma is about 2% per year. Given the natural history of CRC, early diagnosis represents the most appropriate tool to reduce the disease-related mortality. Several tests are available to screen healthy subjects at average risk for CRC: faecal occult blood tests, flexible sigmoidoscopy, combined faecal occult blood tests and flexible sigmoidoscopy, total colonoscopy and double contrast barium enema. Issues related to the introduction on a large scale of population-based screening programmes for CRC are discussed.

Patients with squamous cell carcinoma of the head and neck (HNSCC) after being treated radically remain at high risk for both recurrent and second primary tumours. 13-cis retinoic acid (13-cRA) was demonstrated to reverse pre-malignant lesions of the oral cavity and to reduce the incidence of second primary tumours in patients treated radically for HNSCC. Synergism between retinoids and interferon in tumoural cell lines have been demonstrated. Based on these data, the Italian Head and Neck Chemoprevention Study Group started a randomized chemoprevention study in patients radically treated for stage III and IV HNSCC. From February 1992 to January 1996, 267 patients were randomized: 126 were allocated to the control group, 126 were randomized to receive 13-cRA at a dose of 0.5 mg/kg per day per os and 15 patients have been assigned to the group of 13-cRA plus interferon alpha2a (IFN-alpha2a) at a dose of 3,000,000 UI 3 times a week (randomization in this arm interrupted due to administrative financial problems). The mean follow-up was 39 months. The 5-year actuarial survival was 58.9% for patients of the 13-cRA group and 57.2% for those of the control group (P=0.94). Among evaluable patients, disease progression was observed in 45 of 123 patients (36.6%) of the 13-cRA group and in 42 of 124 (33.9%) of the control group. The 5-year actuarial relapse-free survival was 48.9% for the 13-cRA group and 55.6% for the control group (P=0.62). Adverse effects, mostly of grade I were reported in 69.4% of treated patients (haematologic disorders, mucositis, conjunctivitis, cutaneous toxicity, hypertriglyceridemia and hypercholesterolemia). Only 5 patients (4.1%) reported grade III-IV toxicity. Low-dose of 13-cRA given for 1 year is ineffective as chemoprevention in patients with radically treated HNSCC.

The aim of this study was to determine the diagnostic value of rectal bleeding for distal colorectal cancer (CRC), or large (> or =10 mm) adenomas among an average-risk population. A cross-sectional survey was conducted among individuals aged 55-64 years, who attended sigmoidoscopy (FS) screening in the context of a multicentre randomised trial of FS screening for CRC. Sensitivity, specificity and positive predictive value (PPV) of rectal bleeding for large distal adenomas or CRC were calculated. Rectal bleeding was reported by 8.8% of 8507 patients examined (15% of those with large adenomas and 29% of those with CRC). The risk of CRC was increased when bleeding was associated with an altered bowel habit: odds ratio (OR)=10.42; 95% Confidence Interval (CI): 4.08-26.59; the corresponding OR for isolated bleeding was 5.29 (95% CI: 2.28-12.30). Rectal bleeding carries an increased risk of distal neoplastic lesions. However, most lesions are detected among asymptomatic subjects. This finding suggests that screening represents the optimal strategy to detect CRC or large adenomas in the distal colon in the targeted age range.

Background Roughly 40% of germinal mutations in melanoma families (MF) affect p16INK4a and p14ARF. We investigated the association between INK4/ARF alterations and the occurrence of pancreatic cancer in MF and in sporadic pancreatic cancer (SPC) patients. Patients and methods Forty-nine MF, 66 SPC cases and 54 controls were enrolled. The INK4/ARF locus was screened. Results As compared with the general population, the risk of pancreatic cancer (PC) was increased 9.4-fold [95% confidence interval (CI) 2.7–33.4] and 2.2-fold (95% CI 0.8–5.7) in G101W-positive and -negative MF, respectively, while mean ages at onset were 61 and 77 years, respectively. A 1.7 (95% CI 1.06–2.79) increased risk of cancer at any site was observed among first-degree relatives of SPC cases as compared with controls. The G101W founder mutation was detected in 4% of SPC cases but the rate increased to 13% when tumor clustering in either branch of families was taken into account. One G101W-positive PC patient with a melanoma in a first-degree relative harbored a germline deletion of the second allele, including exon 1B. Conclusions The presence of a deletion including exon 1B in two PC patients points to the involvement of p14ARF in the development of PC and may suggest that the increased risk of PC in MF is caused by impairment of both loci.

This study was aimed at evaluating the efficacy of beta-carotene in improving survival (S) and in disease-free survival (DFS) and reducing the incidence of second primary tumors (SPT) in patients with a radically treated stage I-II squamous head and neck tumors. Eligible patients were randomly allocated to receive beta-carotene (n=104) or no treatment (n=110). beta-carotene was administered at the dose of 75 mg/day for 3-month cycles within one month intercycle intervals for a 3-year period. The 3-year compliance to the beta-carotene was 68.7%. Only eight patients reported drug-related toxicity (7.8%). The median follow-up of all patients was 59 months. The median follow-up was 61 months (range 1-116 months) in the beta-carotene and 58 months (1-123 months) in the control group. The 10-year DFS was 75.7% for the patients in the beta-carotene and 74.3% for those in the control group (P=0.56). The 10-year S was 85.9% in the beta-carotene group and 80.9% in the control group (P=0.20). beta-carotene supplementation had no significant effect on the incidence of second primary tumors (RR=0.99; 95% C.I. 0.28-3.44). A statistically non-significant 40% reduction in the risk of death among subjects assigned to the beta-carotene compared to the controls was observed (RR=0.60; 95% C.I. 0.26-1.38). No increase in the death from cardiovascular diseases was observed among patients treated with beta-carotene. Our results might support the hypothesis that an adequate beta-carotene treatment could be potentially associated with a decreased risk of death in these patients.

The role of cigarette smoking and diabetes mellitus as risk factors for exocrine pancreatic cancer (PC) was investigated in a hospital based case-control study. Current smokers were at increased risk for PC (OR = 2.36, 95% CI 1.53-3.63): the magnitude of the risk was related to the lifetime amount of smoking (chi2(trend) = 17.00; P < 0.0001). Among former smokers, after 15 years from ceasing smoking, the risk for PC dropped to the level of a lifetime non-smoker, whichever the lifetime smoking amount. Diabetes was associated with a 2.89-fold increased risk for PC (95% CI 1.71-4.86): the risk was 4.76 (95% CI 1.99-11.53) for diabetes diagnosed up to 2 years before the diagnosis of PC and dropped to 2.07 (95% CI 1.02-4.20) for diabetes diagnosed more than 5 years before PC. The risk for PC was estimated according to the treatment used to control diabetes: it was 6.49 (95% CI 2.28-18.48) for insulin treated diabetes and 2.12 (95% CI 1.16-3.87) for diabetes treated with oral hypoglycemic drugs. The risk of PC for diabetes treated for more than 5 years before the diagnosis of PC was 6.21 (95% CI 1.61-23.96) for patients treated with insulin and 1.21 (95% CI 0.50-2.92) for those treated with oral hypoglycemic drugs: the type of treatment needed to control the disease may discriminate between the diabetes that represents a consequence of cancer from the diabetes that could represent an etiological co-factor. More studies are needed to clarify whether long-lasting insulin-treated diabetes is an etiological co-factor in PC.

Current clinical practice guidelines for patients with colorectal polyps are mainly based on the histologic characteristics of their lesions. However, interobserver variability in the assessment of specific polyp characteristics was evaluated in very few studies. The purpose of this study was to evaluate the interobserver agreement of four pathologists in the diagnosis of histologic type of colorectal polyps and in the degree of dysplasia and of infiltrating carcinoma in adenomas. A stratified random sample of 100 polyps was obtained from the 4,889 polyps resected within the Multicentre Adenoma Colorectal Study (SMAC), and the slides were blindly reviewed by the four pathologists. Agreement was analyzed using kappa statistics. A median kappa of 0.89 (range 0.79-1.0) was estimated for the interobserver agreement for the diagnosis of hyperplastic polyp vs. adenoma. The agreement in the diagnosis of tubular, tubulovillous, and villous type, was given by median kappa values of 0.50, 0.15, and 0.36, respectively. The median kappa for the diagnosis of infiltrating carcinoma was 0.78 (range 0.73-0.84). Agreement on diagnosis of adenoma histologic subtypes, degrees of dysplasia, or infiltrating carcinoma in adenoma was moderate. A simpler classifications might help to better identify patients at different risk of colorectal cancer.

Loss of APC is an initial, rate-limiting event in inherited and sporadic colorectal tumorigenesis. Rare germline APC mutations have been identified in patients with multiple colorectal adenomas. Recently, the E1317Q APC variant has been associated with a predisposition to the development of multiple colorectal adenomas. In this study, the prevalence of the E1317Q variant was examined in 182 patients with single or multiple colorectal adenomas, and in 235 controls. In all, E1317Q was identified in two of 182 patients with adenomatous polyps (1.1%) and in two of 235 controls (0.8%) (p = 0.59). The risk of harboring adenoma(s) among subjects bearing the E1317Q variant was 1.29 (95% CI 0.09-18.0). No difference in the prevalence of E1317Q between cases with single (2.0%) or multiple colorectal adenomas (0.7%) and controls (0.8%) was found. None of the subjects with a family history of colorectal cancer carried the E1317Q variant. In conclusion, our results confirm that only a very small fraction of colorectal adenomas may be associated with the presence of E1317Q.

Background. Volunteers enrolled in preventive trials tend to show a different risk profile, compared to the source population. In the SCORE trial of sigmoidoscopy (FS) screening for colorectal cancer (CRC) we enrolled subjects who responded to an interest in screening questionnaire declaring their interest in having FS. Aim. To assess the impact of self-selection in the study of volunteers willing to be screened on the estimates of CRC incidence and mortality and on the generalisability of the results. Methods. We conducted an incidence and mortality follow-up within the cohort of subjects who had been mailed the recruitment questionnaire in 2 centres (Turin and Genova), where information concerning socio-demographic characteristics of all individuals targeted for recruitment was available from the local population registries. We considered in the analysis 3 response groups: 1) non-responders; 2) uninterested responders, including both eligible and non-eligible refusers; 3) interested responders, including subjects allocated to the control group and a sample of non-eligible interested responders. Subjects allocated to the intervention group were excluded, since their CRC risk was reduced as a result of screening. We compared baseline demographics, CRC risk, all-cause and CRC mortality at 11-year follow-up of enrolled volunteers, nonresponders and refusers, using logistic regression and Cox proportional hazards multivariable models Results. Both subjects who volunteered in the trial and those who refused were better educated than non-responders. Men and people younger than 60 were more likely to volunteer among responders. The median follow-up time was 11.2 years both for incidence and for mortality. CRC incidence was 1.83 x 1000 person-years (PY 95%CI:1.76-1.90; 2,677 CRC cases/1,466,838.6 PY); overall mortality was 11.42 x 1000 PY (95% CI: 11.2511.59; 16,794 deaths/ 1,470,840.0 PY); CRC mortality was 0.60 x 1000 PYs (95% CI: 0.560.64; 881 CRC-related deaths/ 1,470,840.0 PY). Interested responders showed a similar CRC risk as non-responders to the recruitment questionnaire, but their CRC mortality was substantially lower: HR:0.70; 95%CI:0.54-0.91. Similarly, CRCmortality was observed when comparing controls enrolled in the SORE trial to non responders to the recruitment questionnaire (HR:0.72; 95%CI:0.53-0.97). All-cause mortality was reduced both among interested responders (HR:0.61; 95%CI:0.57-0.65) and among thosewho refused recruitment (HR:0.81; 95%CI:0.76-0.86). Conclusion. The implementation of a population based FS screening program would result in a similar reduction in CRC incidence, as observed in the SCORE trial, and in a larger impact on CRC mortality. Individual's awareness of CRC risk, as indicated by the positive response to an interest in screening questionnaire, emerged as a determinant of the SES gradient in CRC mortality.

The association between distal hyperplastic polyps and proximal adenomas is still a matter of debate. We investigated this association while taking into account patient characteristics.After exclusion of patients with inflammatory bowel diseases, familial adenomatous polyposis, or any cancer, 3088 eligible consecutive subjects aged 18 to 69 years underwent total colonoscopy in four gastroenterology units. The odds ratios (OR) of having proximal adenomas according to patient characteristics (age, sex, medical center, year of endoscopy, reasons for referral, and distal findings) were estimated in univariate and multivariate analyses.Patients with distal polyps of any type showed an adjusted OR of 2.5 (95% CI [1.9, 3.1] p.001) of having proximal adenomas as compared with those without distal polyps. When distal adenomas and distal hyperplastic polyps were included in the multivariate model as independent factors, the presence of adenomas significantly increased the risk of proximal adenomas (OR = 2.8: 95% CI [2.2, 3.6] p.001), whereas the presence of hyperplastic polyps did not (OR = 1.1: 95% CI [0.8, 1.5] p = .64). No association with number, size, or location of distal hyperplastic polyps was seen.Our data show that the presence of hyperplastic polyps should not be the sole indication for total colonoscopy because they are not associated with proximal adenomas when adjusting for patient characteristics and presence of distal adenomas.

Summary Purpose: The goal of the present analyses is to assess the association between different therapeutic approaches and both the probability of achieving a complete response and the risk of death in patients with stage III—IV, inoperable, squamous cell carcinoma of the head and neck (SCC-HN). Patients and methods: Between August 1983 and December 1990, 273 patients with stage III—IV, previously untreated, unresectable SCC of the oral cavity, pharynx and larynx, were included into two consecutive randomized multi-institutional trials (HN-7 and HN-8 protocols) coordinated by the National Institute for Cancer Research (NICR) of Genoa. The HN-7 protocol compared neo-adjuvant chemotherapy (four cycles of vinblastine, 6 mg/m2 i.v. followed by bleomycin, 30 IU i.m. six hours later, day 1; methotrexate, 200 mg i.v., day 2; leucovorin, 45 mg orally, day 3) (VBM) followed by standard radiotherapy (70-75 Gy in 7-8 weeks) (55 patients) to alternating chemoradiotherapy based on four cycles of the same chemotherapy alternated with three splits of radiation, 20 Gy each (61 patients). In the HN-8 protocol standard radiotherapy (77 patients) was compared to the same alternating program as the one used in the previous protocol but employing cisplatin, 20 mg/m2/day and fluorouracil, 200 mg/m2/day, bolus, both given for five consecutive days (CF) instead of VBM (80 patients). A single database was created with the patients on the two protocols. Age at diagnosis, gender, site of the primary tumor, size of the primary, nodal involvement, performance status and treatment approach were analyzed by the multiple logistic regression model and the Cox regression method. The analyses were repeated including the treating institutions as a covariate (coordinating center versus others). Results: The multiple logistic regression analysis indicates that treatment (alternating more so than others, regardless of the chemotherapy regimen used) (P = 0.0001) is more likely to be associated with complete response. In addition, size of the primary tumor (P = 0.004), nodal involvement (P = 0.02) and performance status (P = 0.009) are prognostic variables affecting the probability of achieving a complete response. The Cox regression analysis indicates that treatment, performance status, size of the primary tumor, nodal involvement and, marginally, site of the primary tumor, are independent prognostic variables affecting the risk of death. When the radiationalone therapy is adopted as the reference treatment, the relative risk of death is 0.58 (95% confidence interval (CI) 0.400.84) for alternating CFand radiation, 0.79 (95% CI 0.53-1.16) for alternating VBM and radiation and 1.30 (95% CI 0.89-1.92) for sequential VBM and radiation. When the treating institution is included in the model, a 34% increased risk of death (P - 0.04) is observed for patients treated outside the coordinating center. Conclusion: In our series of patients with advanced, unresectable SCC-HN, treatment with cisplatin and fluorouracil alternating with radiation was associated with a more favourable prognosis. The role of the treating institution in the modulation of the treatment outcomes was also relevant.

Background : In 1992, we reported the first analysis of a randomized trial comparing alternating radiotherapy and chemotherapy with radiotherapy alone in the treatment of squamous cell carcinoma of the head and neck. The results of that 3-year analysis indicated that the combined treatment had superior efficacy. Purpose : After an additional 2 years of follow-up, we again compared the efficacy of the two treatment regimens, with attention paid to differences in overall survival, progression-free survival, and locoregional relapse-free survival. Methods : One hundred fifty-seven patients with untreated, unresectable squamous cell carcinoma of the head and neck were randomly assigned to receive either chemotherapy (four courses of cisplatin [20 mg/m 2 ] and fluorouracil [200 mg/m 2 ], given daily for 5 consecutive days during weeks 1, 4, 7, and 10) plus radiotherapy (three courses of 20 Gy each, given in fractions of 2 Gy per day during weeks 2-3, 5-6, and 8-9) or radiotherapy alone (70 Gy total dose, given in fractions of 2 Gy per day, 5 days per week). Eighty patients received the combined therapy, and 77 were treated with radiotherapy alone. Responses, failures, and toxic effects associated with the two treatment regimens were compared. Overall survival, progression-free survival, and locoregional relapse-free survival were calculated according to the Kaplan-Meier method ; the logrank test was used to compare survival parameters between the two patient groups. Reported P values are two-sided. Results : As reported previously, toxic effects associated with the combined therapy included both chemotherapy- and radiotherapy-related effects ; however, the incidence and severity of mucositis were nearly identical among patients in the two treatment arms. The combined treatment was associated with a statistically significant increase in the frequency of complete response (i.e., the disappearance of clinically detectable disease for at least 4 weeks) (43% for the combined-treatment group compared with 22% for the radiotherapy-only group ; P =.037, chi-squared test). Five-year estimates of overall survival in the combined-treatment group compared with the radiotherapy-only group were 24% (95% confidence interval [CI] = 14%-40%) and 10% (95% CI = 4%-24%), respectively (P = .01, logrank test). The estimates of progression-free survival at 5 years in the combined-treatment group compared with the radiotherapy-only group were 21% (95% CI = 11%-37%) and 9% (95% CI = 3%-22%), respectively (P =.008, logrank test). Finally, the 5-year estimates of locoregional relapse-free survival were 64% (95% CI = 36%-84%) in the combined-treatment group and 32% (95% CI = 10%-65%) in the radiotherapy-only group (P =.038, logrank test). Conclusions and Implications : The superiority of alternating chemotherapy and radiotherapy over radiotherapy alone in treating unresectable squamous cell carcinoma of the head and neck seen at 3 years was confirmed at 5 years. However, additional trials must be conducted before considering the combined approach as standard therapy.