High uptake of colonoscopy in first-degree relatives of patients with colorectal cancer in a healthcare region: a population-based, prospective study.

BACKGROUND AND STUDY AIMS: A screening program in first-degree relatives (FDRs) of colorectal cancer (CRC) patients (index patients) was started in Trentino, Italy, to analyze factors that influence uptake of CRC screening among invited FDRs (first objective) and to describe colorectal findings among those undergoing colonoscopy (secondary objective). PATIENTS AND METHODS: FDRs aged between 45 and 75 years were invited; exclusion criteria were: colonoscopy or barium enema in the preceding 5 years, a history of familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, inflammatory bowel diseases, and severe comorbidities. FDRs who were eligible but were not invited for screening because consent was not obtained from the index patients were considered as the control group. FDRs were invited by the education campaign targeted at the population at risk (both study and control groups); in the study group, interventions targeting individuals at risk (letters, phone calls, face-to-face counseling) were implemented. RESULTS: Starting from 626 new index cases of diagnosed CRC, 725 FDRs were invited to counseling; 77.6 % of these attended for colonoscopy in the study group vs. 8 % in the control group ( P < 0.0001). Predictors of colonoscopy uptake were FDR age above 60 years [odds ratio (OR) 2.50, 95 %CI 1.72 - 3.62], complex family history (simple family history: one CRC at age above 60 years; complex family history: one CRC at age below 60 or two or more CRC; OR 1.54; 95 %CI 1.04 - 2.33) and living in a rural area (OR 1.64, 95 %CI 1.12 - 2.44). Of the 560 FDRs in the study group, 186 (33.8 %) had adenomas, and 48 (8.8 %) had advanced adenomas or cancer. CONCLUSIONS: Interventions that target FDRs of patients with CRC, especially those younger than 60 years, with a complex family history of CRC and who live in a rural area, may improve uptake of CRC screening via colonoscopy.

Prevalence of gastrointestinal symptoms in coronavirus disease 2019: a meta-analysis.

BACKGROUND AND STUDY AIMS: The coronavirus disease 2019 (COVID-19) is a pandemic infection spreading worldwide at an unprecedented rate. Our aim was to assess the frequency of gastrointestinal (GI) involvement in COVID-19. PATIENTS AND METHODS: We performed a systematic review and meta-analysis of all studies reporting clinical data about COVID-19 patients, published until 25th March 2020. The primary endpoint was the pooled prevalence of COVID-19 patients complaining of GI symptoms. Secondary endpoints were the pooled prevalence of cases with COVID-19 positive stool samples, and of asymptomatic COVID-19 patients. We used random-effects model for meta-analysis. RESULTS: Thirty-three studies were included in the meta-analysis. Out of 4434 COVID-19 patients, the pooled prevalence of GI manifestations was 11.51% (95% CI : 8.16 to 15.35). The most frequent GI symptom was diarrhea (7.78% of cases ; 95% CI : 5.05 to 11.04), followed by nausea/vomiting (3.57% ; 95% CI : 1.87 to 5.80), poor appetite (2.39% ; 95%CI : 0.55 ; 5.46) and abdominal pain (0.78% ; 95% CI : 0.26 to 1.57). Positivity for COVID-19 in stool samples was observed in 41.50% (95% CI : 17.70 to 67.65) of cases. 11.85% (95% CI : 3.53 to 24.17) of COVID-19 patients remained asymptomatic. CONCLUSIONS: The present meta-analysis shows that a significant proportion of COVID-19 patients suffer from GI manifestations, as well as COVID-19 positivity in stool samples. Asymptomatic patients need to be considered a further potential route of viral transmission.

n-3 PUFA and alpha-tocopherol control of tumor cell proliferation.

Subjects at high risk for colon cancer received different doses of fish oil on a 30-day randomized double-blind trial to evaluate the chemopreventive effect of n-3 fatty acids against colorectal cancer. Using rectal mucosal proliferation, assessed with 3H-thymidine autoradiography, fish oil induced in the treated groups but not in the placebo group a change in the proliferative pattern, which resulted similar to that observed in low risk population; in the same groups rectal mucosal n-3 fatty acid content increased, where arachidonic acid level decreased. Moreover, n-3 PUFA treatment induced modifications of Vitamin E status. The results suggest that n-3 PUFA could protect high-risk subjects from colon cancer by a mechanism involving a modulation of Vitamin E.

n-3 fatty acids induce oxidative modifications in human erythrocytes depending on dose and duration of dietary supplementation.

The present work was performed to study an optimal dose and duration of dietary n-3 polyunsaturated fatty acid (PUFA) supplementation that would not result in harmful modifications of oxidative cell metabolism. Forty healthy subjects were divided into four groups that received 2.5 g/d eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), 5.1 g EPA + DHA/d, 7.7 g EPA + DHA/d, or placebo. Fatty acid composition, tocopherol status, and susceptibility to lipid peroxidation induced in vitro by 2,2'-azobis-(2-amidinopropane) (AAPH) were evaluated in human red blood cell (RBC) membranes on days 30 and 180. n-3 PUFA treatment increased EPA and DHA concentrations in RBC membranes in a time-dependent manner in all of the n-3 PUFA groups. These modifications occurred with concomitant dose- and time-dependent increases in the membrane unsaturation index. After 30 d of treatment with n-3 PUFAs, alpha-to-copherol significantly increased in RBC membranes of the intermediate- and high-dose groups. Because of the higher concentration of this antioxidant in these groups, the susceptibility of RBC membranes to peroxidation was decreased. However, after 180 d of treatment, alpha-tocopherol decreased to baseline values and AAPH-induced lipid peroxidation increased in a dose-dependent manner. These results show that high doses of dietary n-3 PUFAs, as well as long-time treatments, affect human RBC susceptibility to lipid peroxidation by changes in fatty acid composition and tocopherol content.

Cowden's disease with extensive gastrointestinal polyposis.

Cowden's disease, or multiple hamartoma syndrome, is a rare condition classified recently as a hereditary preneoplastic syndrome. Multiple orocutaneous hamartomas are associated with involvement of other organ systems, including fibrocystic breast disease and breast carcinoma, goiter, thyroid cancer, gastrointestinal polyps, and endometrial carcinoma. We describe a patient with Cowden's disease who underwent extensive gastroenterological work-up and review other cases in the literature.

Reliability of rectal epithelial kinetic patterns as an intermediate biomarker of colon cancer.

The use of biomarkers to assess cancer risk is based on the model of cancer as a multistep process; such markers are assumed to reflect an early stage in this process. A valid biomarker of risk must therefore show differential expression in normal and high-risk subjects, as well as quantitative correlation with the stage of carcinogenesis. It should also be easy to detect in small tissue specimens and responsive to modulation by chemopreventive agents. Cell proliferation is one of the most widely investigated markers of cancer risk. Case-control studies have shown that epithelial cell proliferation parameters, assessed in rectal mucosal biopsies by means of in vitro autoradiographic or immunohistochemical techniques, can discriminate between populations with normal and high risks for colon cancer. However, we recently reviewed rectal biopsies from 152 subjects (43 controls, 84 with adenomas, 25 resected for colon cancer) processed for in vitro 3H-thymidine autoradiography, and attempted to correlate various proliferative parameters with clinical and pathological variables by means of multiple regression analysis. Elevations of total crypt labeling indices (LIs), particularly upper crypt LIs, were significantly associated with the presence of adenomatous polyps, although subsequent linear discriminant analysis revealed that the accuracy of LIs in discriminating between polyp patients and controls was actually quite low. However, we have also found that upper crypt LIs are reliable predictors of adenomatous polyp recurrence. Repeated evaluations of rectal proliferative indices over a 2-year post-polypectomy follow-up of 40 patients with colonic adenomas revealed substantial stability.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of omega-3 fatty acids on rectal mucosal cell proliferation in subjects at risk for colon cancer.

The effects of 12 weeks of omega-3 fatty acid supplementation on rectal mucosal proliferation were assessed with [3H]thymidine autoradiography in a double-blind, placebo-controlled study of 20 patients with sporadic adenomatous colorectal polyps. In the group of 10 that received fish oil containing eicosapentaenoic acid (4.1 g/day) and docosahexaenoic acid (3.6 g/day), the mean percentage of replicative "S"-phase cells in the upper part of colonic crypts (considered a reliable marker of colon cancer risk) significantly dropped from the baseline level after only 2 weeks of treatment and remained lower throughout the study period; no change in upper-crypt labeling was observed in the 10 placebo patients. Rectal mucosal eicosapentaenoic acid content increased in fish oil patients, whereas arachidonic acid levels decreased. The fish oil-induced kinetic changes represent contraction of the proliferative compartment to the levels of a low-risk population and may be related to omega-3 fatty acid effects on the arachidonic prostaglandin pathway. In this short-term trial, fish oil appeared to exert a rapid effect that may protect high-risk subjects from colon cancer.

The effect of family size on estimates of the frequency of hereditary non-polyposis colorectal cancer.

Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is currently based on phenotypical analysis of an expanded pedigree. Diagnostic guidelines ('Amsterdam criteria') proposed by the International Collaborative Group on HNPCC are often too stringent for use with small families. There is also the possibility of false-positive diagnosis in large pedigrees that may contain chance clusters of tumours. This study was conducted to determine the effect of family size on the probability of diagnosing HNPCC according to the Amsterdam criteria. A total of 1052 patients with colorectal cancer were classified as HNPCC or non-HNPCC according to the Amsterdam criteria. Associations between this diagnosis and the size of the first-degree pedigree were evaluated in logistic regression and linear discriminant analyses. Logistic regression showed a significant association for family size with the Amsterdam-criteria-based HNPCC diagnosis. Linear discriminant analysis showed that HNPCC diagnosis was most likely to occur when first-degree pedigrees contained more than seven relatives. Failure to consider family size in phenotypic diagnosis of HNPCC can lead to both under- and overestimation of the frequency of this disease. Small pedigrees must be expanded to reliably exclude HNPCC. Positive diagnoses based on assessment of eight or more first-degree relatives should be supported by other clinical features.

Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas.

BACKGROUND/AIMS: Fish oil supplementation can reduce cytokinetic anomalies in the flat rectal mucosa of patients with sporadic colorectal adenoma. This study attempted to identify an optimum dose for fish oil supplementation and evaluate the persistence of its effects during long-term administration. METHODS: In a double-blind study, 60 patients with sporadic adenomas received 2.5, 5.1, or 7.7 g of fish oil per day or placebo for 30 days. [3H]thymidine autoradiographic labeling indices were calculated in flat rectal mucosal biopsy specimens collected before and after supplementation. In a subsequent study, 15 patients with polyps received 2.5 g of fish oil per day. Proliferative parameters, mucosal fatty acids, and mucosal and plasma alpha-tocopherol levels were evaluated before, during, and after 6 months of supplementation. RESULTS: Mean proliferative indices and mucosal arachidonic acid levels decreased significantly (and to similar degrees) in all treated groups, whereas mucosal eicosapentaenoic and docosahexaenoic acid levels increased. Significantly reduced proliferation was observed only in patients with abnormal baseline patterns. These effects persisted during long-term, low-dose treatment. A transient reduction in mucosal (but not plasma) alpha-tocopherol levels was observed after 1 month of treatment. Side effects were insignificant. CONCLUSIONS: Low-dose fish oil supplementation has short-term and long-term normalizing effects on the abnormal rectal proliferation patterns associated with increased colon cancer risk.

Role of clinical criteria in the diagnosis of hereditary non-polyposis colorectal cancer (HNPCC): results of a multivariate analysis.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by early-onset colorectal tumors, primarily in the right colon, that are frequently associated with other cancers. In the absence of a reliable biomarker, clinical criteria for diagnosing HNPCC have been proposed by the International Collaborative Group on HNPCC (ICG-HNPCC). However, these criteria are often too restrictive for application in small families. We analyzed 6 clinical/pathological features suggestive of genetic colon-cancer risk in 970 colorectal-cancer patients defined according to the ICG criteria as HNPCC (96) or non-HNPCC (874). Logistic regression analysis was used to determine their relative potentials for predicting the diagnosis of HNPCC. The most predictive were then used to estimate HNPCC risk levels within the non-HNPCC group. Multivariate analysis showed the following associations with HNPCC diagnosis: vertically transmitted cancer ("highly predictive"), early-onset (< 50 yrs) colorectal cancer, aggregation of tumors in the nuclear pedigree and proximal-colon tumors (the last 3 considered "predictive"). Re-evaluation of all families revealed that 76 non-HNPCC families (8.9% of the whole series) satisfied our highly predictive vertical-transmission criterion plus at least one of the other "predictive" criteria. The presence of 2 consecutive generations affected by colorectal cancer or early primaries seems to be a major risk indicator of hereditary colorectal cancer. Using this approach we identified a large group of families that require further evaluation, although they do not currently meet the ICG-HNPCC criteria for HNPCC.

Rectal epithelial cell proliferation patterns as predictors of adenomatous colorectal polyp recurrence.

To determine whether proliferative patterns in flat rectal mucosal samples can predict the recurrence of adenomatous colorectal polyps, after polypectomy, biopsy specimens from normal looking rectal mucosa were obtained at endoscopy from 55 patients diagnosed for the first time as having adenomatous colorectal polyps. Epithelial cell proliferation was assessed in biopsy specimens through 3H-thymidine autoradiography. After polypectomy, patients were followed for 24 months and underwent complete colonoscopy every 6 months to detect and remove any metachronous lesions. In 40 patients second biopsy specimens were taken during one of the follow up colonoscopies to evaluate the stability of proliferative indices over time. The ratio of labelled (S phase) to total cells (labelling index) for the entire crypt, as well as ratios for each of the five equal compartments into which the crypt had been divided longitudinally, was calculated for each patient. Mean labelling indices for upper crypt compartments 3 and 4 + 5 in the 22 patients in whom polyps recurred were significantly higher (respectively p < 0.05 and p < 0.01) than those of the 33 without recurrence suggesting that an upward shift of the crypt's replicative compartment is associated with polyp recurrence. Labelling indices remained essentially unchanged in those patients who underwent biopsy twice. Reproducible kinetic parameters such as these might be useful in planning follow up of patients with adenomatous polyps after polypectomy.

Circadian variations of epithelial cell proliferation in human rectal crypts.

BACKGROUND/AIMS: Evidence (almost exclusively from animal studies) suggests that proliferation within the colorectal mucosa undergoes circadian variations. The epithelial cells that line the human colorectal crypt occupy definite positions along the longitudinal axis according to their proliferative potential and degree of differentiation. Thus, circadian rhythmicity was investigated in humans to locate the areas along the longitudinal crypt axis in which diurnal fluctuation might occur. METHODS: Rectal mucosal biopsy specimens were obtained every 4 hours for a 24-hour span from each of 23 subjects (8 healthy volunteers and 15 with histories of sporadic adenomatous polyps). [3H]thymidine histoautoradiography was used to determine ratios of S-phase to total cells (total labeling index) in the crypt. Glands were also divided into 5 equal compartments from base (compartment 1) to mouth (compartment 5), and labeling indices were calculated for each. RESULTS: Important temporal variations were confined to compartment 2 (F = 5.15, P = 0.0003) and total labeling indices (F = 3.57, P = 0.005). Despite individual variations, proliferation was generally higher at night and lower during afternoon. Upper-crypt proliferative rates (compartments 4 and 5) remained decidedly stable (F = 0.5, P = NS). Normal subjects and patients with polyps displayed similar circadian behaviors. CONCLUSIONS: Circadian fluctuation in proliferation is confined to the area of the crypt normally associated with replication. Upper-crypt indices, including those that were higher than normal (a colon-cancer risk marker) are stable over 24 hours. These findings should be useful in planning chemoprevention trials and chemotherapeutic regimens.