Vincenzo Bagnardi

Mortality in patients with coeliac disease and their relatives: a cohort study

BACKGROUND Although previous studies have shown increased mortality in patients with coeliac disease and their relatives, no data are available in relation to different patterns of clinical presentation. We assessed mortality in patients with coeliac disease and their first-degree relatives. METHODS We enrolled, in a prospective cohort study, 1072 adult patients with coeliac disease consecutively diagnosed in 11 gastroenterology units between 1962 and 1994, and their 3384 first-degree relatives. We compared the number of deaths up to 1998 with expected deaths and expressed the comparison as standardised mortality ratio (SMR) and relative survival ratio. FINDINGS 53 coeliac patients died compared with 25.9 expected deaths (SMR 2.0 [95% CI 1.5-2.7]). A significant excess of mortality was evident during the first 3 years after diagnosis of coeliac disease and in patients who presented with malabsorption symptoms (2.5 [1.8-3.4]), but not in those diagnosed because of minor symptoms (1.1 [0.5-2.2]) or because of antibody screening (1.2 [0.1-7.0]). SMR increased with increasing delay in diagnosis and for patients with poor compliance with gluten-free diet. Non-Hodgkin lymphoma was the main cause of death. No excess of deaths was recorded in relatives with coeliac disease. INTERPRETATION Prompt and strict dietary treatment decreases mortality in coeliac patients. Prospective studies are needed to clarify the progression of mild or symptomless coeliac disease and its relation to intestinal lymphoma.

A meta-analysis of alcohol drinking and cancer risk

To evaluate the strength of the evidence provided by the epidemiological literature on the association between alcohol consumption and the risk of 18 neoplasms, we performed a search of the epidemiological literature from 1966 to 2000 using several bibliographic databases. Meta-regression models were fitted considering linear and non-linear effects of alcohol intake. The effects of characteristics of the studies, of selected covariates (tobacco) and of the gender of individuals included in the studies, were also investigated as putative sources of heterogeneity of the estimates. A total of 235 studies including over 117 000 cases were considered. Strong trends in risk were observed for cancers of the oral cavity and pharynx, oesophagus and larynx. Less strong direct relations were observed for cancers of the stomach, colon and rectum, liver, breast and ovary. For all these diseases, significant increased risks were found also for ethanol intake of 25g per day. No significant nor consistent relation was observed for cancers of the pancreas, lung, prostate or bladder. Allowance for tobacco appreciably modified the relations with laryngeal, lung and bladder cancers, but not those with oral, oesophageal or colorectal cancers. This meta-analysis showed no evidence of a threshold effect for most alcohol-related neoplasms. The inference is limited by absence of distinction between lifelong abstainers and former drinkers in several studies, and the possible selective inclusion of relevant sites only in cohort studies.

Smoking and colorectal cancer: a meta-analysis.

CONTEXT Colorectal cancer is the third most common form of cancer and the fourth most frequent cause of cancer deaths worldwide. The association between cigarette smoking and colorectal cancer has been inconsistent among studies. OBJECTIVE To clarify the association of cigarette smoking and colorectal cancer, we performed a comprehensive literature search and a meta-analysis of observational studies considering both incidence and mortality. DATA SOURCES We performed a literature search using PubMed, ISI Web of Science (Science Citation Index Expanded), and EMBASE to May 2008, with no restrictions. We also reviewed references from all retrieved articles. STUDY SELECTION All articles that were independent and contained the minimum information necessary to estimate the colorectal cancer risk associated with cigarette smoking and a corresponding measure of uncertainty. DATA EXTRACTION Articles were reviewed and data were extracted and cross-checked independently by 3 investigators, and any disagreement was resolved by consensus among all 3. RESULTS One hundred six observational studies were included in the analysis of incidence. Twenty-six studies provided adjusted risk estimates for ever smokers vs never smokers, leading to a pooled relative risk of 1.18 (95% confidence interval [CI], 1.11-1.25). Smoking was associated with an absolute risk increase of 10.8 cases per 100,000 person-years (95% CI, 7.9-13.6). We found a statistically significant dose-relationship with an increasing number of pack-years and cigarettes per day. However, the association was statistically significant only after 30 years of smoking. Seventeen cohort studies were included in the analysis of mortality. The pooled risk estimate for ever vs never smokers was 1.25 (95% CI, 1.14-1.37). Smoking was associated with an absolute risk increase of 6.0 deaths per 100,000 person-years (95% CI, 4.2-7.6). For both incidence and mortality, the association was stronger for cancer of the rectum than of the colon. CONCLUSION Cigarette smoking is significantly associated with colorectal cancer incidence and mortality.

Alcohol drinking and colorectal cancer risk: an overall and dose–response meta-analysis of published studies

BACKGROUND The International Agency for Research on Cancer (IARC) concluded that alcohol consumption is related to colorectal cancer (CRC). However, several issues remain unresolved, including quantification of the association for light (≤1 drink/day) and moderate (2-3 drinks/day) alcohol drinking, investigation of the dose-response relationship, and potential heterogeneity of effects by sex, colorectal site, and geographical region. METHODS Twenty-seven cohort and 34 case-control studies presenting results for at least three categories of alcohol intake were identified from a PubMed search of articles published before May 2010. The summary relative risks (RRs) were estimated by the random effects model. Second-order fractional polynomials and random effects meta-regression models were used for modeling the dose-risk relation. RESULTS The RRs were 1.21 [95% confidence interval (CI) 1.13-1.28] for moderate and 1.52 (95% CI 1.27-1.81) for heavy (≥4 drinks/day) alcohol drinking. The RR for moderate drinkers, compared with non-/occasional drinkers, was stronger for men (RR = 1.24, 95% CI 1.13-1.37) than for women (RR = 1.08, 95% CI 1.03-1.13; P(heterogeneity) = 0.02). For heavy drinkers, the association was stronger in Asian studies (RR = 1.81, 95% CI 1.33-2.46; P(heterogeneity) = 0.04). The dose-risk analysis estimated RRs of 1.07 (95% CI 1.04-1.10), 1.38 (95% CI 1.28-1.50), and 1.82 (95% CI 1.41-2.35) for 10, 50, and 100 g/day of alcohol, respectively. CONCLUSIONS This meta-analysis provides strong evidence for an association between alcohol drinking of >1 drink/day and colorectal cancer risk.

Serum and plasma BDNF levels in major depression: A replication study and meta-analyses

Abstract Objectives. Alterations of BDNF signalling in major depression (MD) are supported by studies demonstrating decreased levels of the neurotrophin serum and plasma content in MD patients. We conducted a replication study and we performed two meta-analyses on studies analysing serum and plasma BDNF levels in MD patients. Methods. The samples were composed by 489 patients/483 controls for the meta-analysis on serum and by 161 patients/211 controls for that on plasma levels. We performed also subgroup analyses to examine whether the decrease in BDNF levels in MD was influenced by gender. Results. In the replication study we found decreased serum BDNF levels in MD patients (P<0.01) and we demonstrated that is down-regulated the mature form of the neurotrophin (mBDNF). No significant difference was evidenced for plasma BDNF levels. The meta-analyses showed a reduction of both BDNF serum (P<0.0001) and plasma levels (P=0.02) in MD. No difference in the effect size on serum BDNF was observed between males and females (P=0.18). Conclusions. In conclusion, our results provide evidence of peripheral BDNF alteration in MD and support the rationale for further investigation aiming to the identification of biomarkers for differential diagnosis and personalization of therapies in this disorder.

Alcohol consumption and site-specific cancer risk: a comprehensive dose-response meta-analysis

Background:Alcohol is a risk factor for cancer of the oral cavity, pharynx, oesophagus, colorectum, liver, larynx and female breast, whereas its impact on other cancers remains controversial.Methods:We investigated the effect of alcohol on 23 cancer types through a meta-analytic approach. We used dose–response meta-regression models and investigated potential sources of heterogeneity.Results:A total of 572 studies, including 486 538 cancer cases, were identified. Relative risks (RRs) for heavy drinkers compared with nondrinkers and occasional drinkers were 5.13 for oral and pharyngeal cancer, 4.95 for oesophageal squamous cell carcinoma, 1.44 for colorectal, 2.65 for laryngeal and 1.61 for breast cancer; for those neoplasms there was a clear dose–risk relationship. Heavy drinkers also had a significantly higher risk of cancer of the stomach (RR 1.21), liver (2.07), gallbladder (2.64), pancreas (1.19) and lung (1.15). There was indication of a positive association between alcohol consumption and risk of melanoma and prostate cancer. Alcohol consumption and risk of Hodgkin’s and Non-Hodgkin’s lymphomas were inversely associated.Conclusions:Alcohol increases risk of cancer of oral cavity and pharynx, oesophagus, colorectum, liver, larynx and female breast. There is accumulating evidence that alcohol drinking is associated with some other cancers such as pancreas and prostate cancer and melanoma.

Clinical Relevance of HER2 Overexpression/Amplification in Patients With Small Tumor Size and Node-Negative Breast Cancer

PURPOSE To assess the prognostic role of HER2 overexpression/amplification in patients with node-negative, pT1a-b breast cancers. PATIENTS AND METHODS All patients with HER2-positive breast cancer were identified among a population of 2,130 patients whose diseases were staged as pT1a-b, pN0 and who underwent surgery at the European Institute of Oncology from 1999 to 2006. A matched cohort was selected by using variables of hormone receptor status, age, and year of surgery. We estimated rates of local and distant recurrence, disease-free survival (DFS), and overall survival (OS) in the two groups. RESULTS We identified 150 consecutive patients with pT1a-b, pN0, HER2-positive tumors. No patient received adjuvant trastuzumab. The median follow-up was 4.6 years (range, 1.0 to 9.0 years). In the hormone receptor-positive group, 5-year DFS rates were 99% (95% CI, 96% to 100%) for HER2-negative disease and 92% (95% CI, 86% to 99%) for HER2-positive disease. In the hormone receptor-negative group, 5-year DFS rates were 92% (95% CI, 84% to 100%) for HER2-negative disease and 91% (95% CI, 84% to 99%) for HER2-positive disease. Overall, the hazard ratio (HR) associated with HER2 overexpression was 2.4 (95% CI, 0.9 to 6.5; P = .09). After analysis was adjusted for pT1 stage, hormone receptor-positive disease with HER2-positive status was associated with a worse prognosis (HR, 5.1; 95% CI, 1.0 to 25.7). OS in HER2-positive, pT1a-b, pN0 breast cancer was similar irrespective of the hormone receptor status (P = .93). CONCLUSION Patients with node-negative, HER2 positive, pT1a-b breast cancer have a low risk of recurrence at 5 years of follow-up. In patients with hormone receptor-positive disease and pT1a-b, N0 tumors, HER2 overexpression was associated with a worse DFS.

Coffee drinking and hepatocellular carcinoma risk: A meta‐analysis

Several studies suggest an inverse relation between coffee drinking and risk of hepatocellular carcinoma (HCC). We conducted a meta‐analysis of published studies on HCC that included quantitative information on coffee consumption. Ten studies were retrieved (2,260 HCC cases), including 6 case–control studies from southern Europe and Japan (1551 cases) and 4 cohort studies from Japan (709 cases). The summary relative risk (RR) for coffee drinkers versus non‐drinkers was 0.54 (95% confidence interval [CI] 0.38‐0.76) for case–control studies and 0.64 (95% CI 0.56‐0.74) for cohort studies. The overall RR was 0.59 (95% CI 0.49‐0.72), with significant heterogeneity between studies. The overall summary RR for low or moderate coffee drinkers was 0.70 (95% CI 0.57‐0.85), and that for high drinkers was 0.45 (95% CI 0.38‐0.53). The summary RR for an increase of 1 cup of coffee per day was 0.77 (95% CI 0.72‐0.83) from case–control studies, 0.75 (95% CI 0.65‐0.85) from cohort studies, and 0.77 (95% CI 0.72‐0.82) overall. The consistency of an inverse relation between coffee drinking and HCC across study design and geographic areas weighs against a major role of bias or confounding. Coffee drinking has also been related to reduced risk of other liver diseases, thus suggesting a continuum of the favorable effect of coffee on liver function. However, subjects with liver conditions may selectively reduce their coffee consumption. Conclusion: The present analysis provides evidence that the inverse relation between coffee and HCC is real, though inference on causality remains open to discussion. (HEPATOLOGY 2007.)

A meta-analysis on alcohol drinking and gastric cancer risk

BACKGROUND Whether an association between alcohol drinking and gastric cancer risk exists is an open question. In order to provide a definite quantification of the association between alcohol drinking and gastric cancer risk, we conducted a meta-analysis of available data. PATIENTS AND METHODS We carried out a PubMed search of articles published up to June 2010 and identified 44 case-control and 15 cohort studies, including a total of 34 557 gastric cancer cases. We derived meta-analytic estimates using random-effects models, taking into account correlation between estimates. We carried out a dose-risk analysis using nonlinear random-effects meta-regression models. RESULTS Compared with nondrinkers, the pooled relative risk (RR) was 1.07 [95% confidence interval (CI) 1.01-1.13] for alcohol drinkers and 1.20 (95% CI 1.01-1.44) for heavy alcohol drinkers (≥4 drinks per day). The pooled estimates were apparently higher for gastric noncardia (RR for heavy drinkers = 1.17, 95% CI 0.78-1.75) than for gastric cardia (RR = 0.99, 95% CI 0.67-1.47) adenocarcinoma. The dose-risk model estimated a RR of 0.95 (95% CI 0.91-0.99) for 10 g/day and 1.14 (95% CI 1.08-1.21) for 50 g/day. CONCLUSIONS This meta-analysis provides definite evidence of a lack of association between moderate alcohol drinking and gastric cancer risk. There was, however, a positive association with heavy alcohol drinking.BACKGROUND Whether an association between alcohol drinking and gastric cancer risk exists is an open question. In order to provide a definite quantification of the association between alcohol drinking and gastric cancer risk, we conducted a meta-analysis of available data. PATIENTS AND METHODS We carried out a PubMed search of articles published up to June 2010 and identified 44 case-control and 15 cohort studies, including a total of 34 557 gastric cancer cases. We derived meta-analytic estimates using random-effects models, taking into account correlation between estimates. We carried out a dose-risk analysis using nonlinear random-effects meta-regression models. RESULTS Compared with nondrinkers, the pooled relative risk (RR) was 1.07 [95% confidence interval (CI) 1.01-1.13] for alcohol drinkers and 1.20 (95% CI 1.01-1.44) for heavy alcohol drinkers (≥4 drinks per day). The pooled estimates were apparently higher for gastric noncardia (RR for heavy drinkers=1.17, 95% CI 0.78-1.75) than for gastric cardia (RR=0.99, 95% CI 0.67-1.47) adenocarcinoma. The dose-risk model estimated a RR of 0.95 (95% CI 0.91-0.99) for 10 g/day and 1.14 (95% CI 1.08-1.21) for 50 g/day. CONCLUSIONS This meta-analysis provides definite evidence of a lack of association between moderate alcohol drinking and gastric cancer risk. There was, however, a positive association with heavy alcohol drinking.

Epidemiology and Pathophysiology of Alcohol and Breast Cancer: Update 2012

AIMS To update epidemiological data on alcohol and breast cancer, with special emphasis on light alcohol consumption, and to review mechanisms of alcohol mediated mammary carcinogenesis. METHODS For epidemiological data, in November 2011 we performed a literature search in various bibliographic databases, and we conducted a meta-analysis of data on light alcohol drinking. Relevant mechanistic studies were also reviewed to November 2011. RESULTS A significant increase of the order of 4% in the risk of breast cancer is already present at intakes of up to one alcoholic drink/day. Heavy alcohol consumption, defined as three or more drinks/day, is associated with an increased risk by 40-50%. This translates into up to 5% of breast cancers attributable to alcohol in northern Europe and North America for a total of approximately 50,000 alcohol-attributable cases of breast cancer worldwide. Up to 1-2% of breast cancers in Europe and North America are attributable to light drinking alone, given its larger prevalence in most female populations when compared with heavy drinking. Alcohol increases estrogen levels, and estrogens may exert its carcinogenic effect on breast tissue either via the ER or directly. Other mechanisms may include acetaldehyde, oxidative stress, epigenetic changes due to a disturbed methyl transfer and decreased retinoic acid concentrations associated with an altered cell cycle. CONCLUSIONS Women should not exceed one drink/day, and women at elevated risk for breast cancer should avoid alcohol or consume alcohol occasionally only.