The safety profile of probiotic VSL#3®. A meta-analysis of safety data from double-blind, randomized, placebo-controlled clinical trials.

The article "The safety profile of probiotic VSL#3®. A meta-analysis of safety data from double-blind, randomized, placebo-controlled clinical trials", by V. Panetta, A. Bacchieri, S. Papetti, E. De Stefani, P. Navarra, published in Eur Rev Med Pharmacol Sci 2020; 24 (2): 963-973-DOI: 10.26355/eurrev_202001_20082-PMID: 32017005, has been retracted based on commentary received from a new set of reviewers.  The authors will be able to resubmit a new article addressing the reviewers' comments for the Journal's consideration. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/20082.

The safety profile of probiotic VSL#3®. A meta-analysis of safety data from double-blind, randomized, placebo-controlled clinical trials.

OBJECTIVE: A high-concentration of a multi-strain probiotic mixture, VSL#3® is widely used 'whenever it is useful to promote the balance of intestinal flora'. As a food supplement, VSL#3® has been so far scarcely investigated on the aspect of safety. To fill this gap, in this paper, we analyzed the adverse events (AEs) recorded during the conduct of three (3) double-blind, randomized, placebo-controlled trials carried out to explore the efficacy of VSL#3® in various clinical settings. Data from a large open-label observational trial were also considered. MATERIALS AND METHODS: All trials included in the analysis were carried out according to good clinical practice (GCP) rules. AEs were classified by System Organ Class (SOC), Preferred Term (PT) and frequency. Differences vs. placebo control were considered as statistically significant if the p-value was < 0.05. RESULTS: A total of 120 patients were analyzed, 70 patients being included in the randomized controlled trials. In this population, 45 patients had at least one AE, 20 (64.5%) in the placebo group and 25 (64.1%) in the VSL#3® group. 29 patients had at least one related AE, 14 (45.2%) and 15 (38.5%) in the two treatment groups, respectively. Only one AE was assessed as serious, i.e., Foetal malformation, which occurred in the placebo group and was considered unrelated. No significant difference was found between VSL#3® and placebo for any of the SOC considered, with the exception of Injury, poisoning and procedural complications, which was in favor of VSL#3®. CONCLUSIONS: Based on GCP-quality data from clinical trials, we conclude that VSL#3® is a safe and well-tolerated agent.

Hot infusions and risk of colorectal cancer in Uruguay: a case-control study.

BACKGROUND/OBJECTIVES: The evidence of possible roles for the most common hot infusions intake (tea and coffee) in the risk of colorectal cancer (CRC) needs additional data. Regarding 'mate' intake (infusion of Ilex paraguariensis herb), a previous multi-site study reported lack of association for its highest intake on CRC risk. The present study was conducted to better understand the associations between the intake of this and other infusions and CRC risk. SUBJECTS/METHODS: Patients (611 CRC incident cases and 2394 controls, all belonging to public hospitals) were interviewed through a questionnaire, including socio-demographic, reproductive and lifestyle variables, and a food-frequency questionnaire of 64 items, analyzing tea, 'mate' and coffee intake (consumer status, daily intake, age at start and at quit). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated through unconditional logistic regression, adjusting for relevant potential confounders. RESULTS: Tea and coffee intake displayed significant and inverse associations with CRC risk, mainly among men (OR=0.54, 95% CI 0.38-0.76 for tea and OR=0.59, 95% CI 0.41-0.85 for coffee). Mate intake showed a significant inverse association among women (OR=0.50, 95% CI 0.33-0.77), with a marginal heterogeneity between sexes (P=0.07). Concerning age strata, tea intake displayed inverse associations in all ages, whereas 'mate' and coffee intake showed stronger inverse associations for age ⩾70, suggesting a gradient along time. CONCLUSIONS: We found evidence of different significant inverse associations for tea, 'mate' and coffee intake and CRC risk. To our knowledge, this is the first epidemiologic study reporting inverse results on 'mate' intake and CRC, which are explained by a stronger association among women.European Journal of Clinical Nutrition advance online publication, 23 August 2017; doi:10.1038/ejcn.2017.130.

Processed meat consumption and risk of cancer: a multisite case-control study in Uruguay.

BACKGROUND: The role of processed meat in the aetiology of several cancers was explored in detail. METHODS: In the time period 1996-2004, a multisite case-control study was conducted in Montevideo, Uruguay. The study included 6 060 participants (3 528 cases and 2 532 controls) corresponding to cancers of the oral cavity, pharynx, oesophagus, stomach, colon, rectum, larynx, lung, female breast, prostate, urinary bladder, and kidney (renal cell carcinoma only). RESULTS: The highest odds ratios (ORs) were positively associated with cancers of the colon, rectum, stomach, oesophagus, and lung. With the exception of renal cell carcinoma, the remaining cancer sites were significantly associated with elevated risks for processed meat consumption. Furthermore, mortadella, salami, hot dog, ham, and salted meat were strongly associated with risk of several cancer sites. CONCLUSION: It could be concluded that processed meat intake could be a powerful multiorgan carcinogen.

Dietary folate intake and the risk of 11 types of cancer: a case-control study in Uruguay.

BACKGROUND: There is limited, but inconclusive, epidemiological evidence that high folate intake decreases the risk of colorectal and esophageal cancers. For other cancer sites, the evidence is even less consistent or extensive. MATERIALS AND METHODS: We conducted a case-control study of dietary folate intake and risk of 11 cancer sites in Uruguay between 1996 and 2004, including 3539 cancer cases and 2032 hospital controls. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of cancer associated with folate intake. RESULTS: In the multivariable model, there was a significant decrease in the risk of cancers of the oral cavity and pharynx (OR = 0.49, 95% CI 0.24-0.98), esophagus (OR = 0.29, 95% CI 0.14-0.60), upper aerodigestive tract (OR = 0.41, 95% CI 0.26-0.65), colorectum (OR = 0.42, 95% CI 0.23-0.76) and kidney (OR = 0.35, 95% CI 0.13-0.93) for the highest versus the lowest quartile of dietary folate intake. CONCLUSIONS: Our results not only confirm earlier findings of decreased risk of colorectal and esophageal cancers with a high dietary folate intake but also suggest decreased risk of several other cancers. However, we cannot exclude the possibility that residual confounding, multiple comparisons or other forms of bias could explain these results.

Food groups and risk of squamous cell carcinoma of the oesophagus: a case-control study in Uruguay.

In the time period January 1998-December 2000, a case-control study on squamous cell cancer of the oesophagus was conducted in Montevideo, Uruguay. The main objective of the study was to estimate the odds ratios (ORs) associated with main food groups. For this purpose, 166 patients afflicted with squamous cell oesophageal cancer and 664 hospitalised controls were frequency matched on age and sex. Both series of patients were administered with a structured questionnaire. Aside from queries related with tobacco smoking, alcohol drinking and maté drinking, patients were interviewed with a food-frequency questionnaire (FFQ) on 64 items, representative of the usual Uruguayan diet. Red meat, salted meat and boiled meat displayed strong direct associations (OR for red meat 2.4, 95% CI 1.4-4.2). On the other hand, fish and total white meat showed moderate protective effect (OR for total white meat 0.5, 95% CI 0.3-0.9). Total fruit intake displayed a strong inverse association (OR 0.2, 95% CI 0.1-0.4), whereas total vegetable consumption presented a weak inverse association (OR for total vegetable intake 0.7, 95% CI 0.4-1.2). These results suggest that vegetables, mainly cooked vegetables, are rich in thermolabile protective substances. On the other hand, boiled (stewed) meat, which is ingested at high temperature could be, like maté, a risk factor for squamous cell cancer of the oesophagus.

Dairy foods and risk of breast cancer: a case-control study in Montevideo, Uruguay.

In order to investigate possible associations of milk and dairy products and the risk of breast cancer (BC) in Montevideo, the authors performed a case-control study in the period 1999-2001. A total of 333 women were interviewed with a specific questionnaire; 111 of them had been diagnosed with BC and 222 were frequency-matched healthy women, with a recent normal mammography (BIRADS 1). The questionnaire included a detailed 120-item food-frequency section, as well as questions related to socio-demographic, reproductive, familial, medical and lifestyle variables. There was particular emphasis on types of milk and dairy products. After controlling for age, years of urban status, education, body mass index, age at menarche, menopausal status, family history of BC, number of childbirths, total energy and total fruits, a multivariate analysis found that high intakes of whole milk, chocolate milk and Gruyère cheese were associated with significant increased risk of BC, whereas ricotta cheese and skim yoghurt were associated with significant decreased risks. Low-fat and fermented products combined appear to be the most protective dairy foods. The results suggest that separate analyses for types of milk and cheese, as well as for dairy products in general should be performed in the future.

Plant foods and differences between colon and rectal cancers.

A case-control study on plant food intake and its role in the risk of colon and rectal cancers was carried out in Montevideo, Uruguay. Four hundred and eighty-four (484) cases of colorectal cancer and 1452 controls were frequency matched on age, sex, residence and urban/rural status. Among cases, 260 patients had colon cancer whereas 224 had rectal tumours. Controls had non-neoplastic conditions. Both cases and controls were interviewed in the four major hospitals in Montevideo shortly after admittance for diagnosis or treatment. The questionnaire included a section on frequency of foods, which included 64 items, in particular, queries on 18 vegetables, 10 fruits and 6 cereal dishes were included. Thus, the amount of plant foods consumed was complete and included the main plant foods in the Uruguayan diet. The analysis showed that rectal cancer displayed inverse associations with total plant foods, total vegetables, cooked vegetables, potatoes and legumes. When data were stratified by tumour site and sex, only men showed a protective effect of plant foods (odds ratio (OR) of rectal cancer for men 0.4, 95% confidence interval (CI) 0.2-0.7). In contrast, women with rectal carcinoma were not associated with plant food intake. It can be concluded that plant foods are protective factors for men afflicted with colorectal cancer but that plant food intake is not associated with risk in women. This is, at least in part, due to the high risk associated with bread intake in this gender.

Foods and risk of bladder cancer: a case-control study in Uruguay.

A case-control study on 144 cases of transitional cell bladder carcinoma and 576 hospitalized controls was conducted in Montevideo, Uruguay. Barbecued meat, salted meat and fried eggs were associated with significant increased risks of bladder cancer (odds ratio (OR) for high intake of salted meat 4.04, 95% confidence interval (CI) 2.24-7.27). On the other hand, all fruits, cooked vegetables, potatoes and cheese were associated with inverse associations (OR for high consumption of potatoes 0.38, 95% CI 0.23-0.64). The associations with salted and barbecued meat suggest that the way of preserving or cooking meat play a role in bladder carcinogenesis. More precisely, N-nitroso compounds and heterocyclic amines could be involved in this process.

Plant foods and risk of gastric cancer: a case-control study in Uruguay.

The association between plant foods intake and gastric cancer risk was investigated in a Uruguayan study on environmental factors and cancer. The study included 160 newly diagnosed and histologically verified cases of gastric carcinoma and 320 hospitalized controls. These controls were frequency-matched to the cases on age, sex, residence and urban/rural status. Total vegetable intake was associated with a reduction in risk (odds ratio (OR) 0.64, 95% confidence interval (CI) 0.38-1.08), which was markedly attenuated after adjustment for total fruit intake. The only group of vegetables that persisted as significantly protective after controlling for total energy and total fruit consumption were allium vegetables (OR 0.56, 95% CI 0.34-0.92). On the other hand, total fruit consumption displayed a strong inverse association after controlling for total vegetable intake (OR 0.35, 95% CI 0.21-0.59). Neither tubers nor pulses were associated with gastric cancer risk. Finally, total plant foods were strongly associated with a reduced risk of stomach cancer (OR 0.31, 95% CI 0.18-0.54). It is suggested that vitamins (vitamin C and carotenoids) and bioactive substances (diallyl sulfide) could be involved in the mechanisms of action of plant foods.

Meat, fat and risk of laryngeal cancer: a case-control study in Uruguay.

The effect of meat and fat in laryngeal carcinogenesis was examined in a case-control study carried out in Uruguay in the time period 1998-1999. One-hundred and forty patients with squamous cell laryngeal carcinoma and 420 hospitalized patients, afflicted with conditions not related with tobacco smoking, alcohol drinking or recent dietary changes comprised the cases and controls in this study. All patients were interviewed face-to-face in the hospitals with a detailed questionnaire which included queries on 64 food items. Red and total meat intakes were associated with strong increases in risk of laryngeal cancer (odds ratio [OR] for high total meat intake 3.32, 95% confidence interval [C.I.] 1.23-8.95). This effect disappeared after controlling for total fat intake. On the other hand, total fat intake displayed a strong association with risk of laryngeal cancer when red meat was included in the same model (OR for high fat intake 7.05, 95% C.I. 2.51-19.8). Total fat intake combines its effect multiplicatively with tobacco smoking.

Meat consumption and risk of stomach cancer in Uruguay: a case-control study.

We previously reported an association between meat intake and stomach cancer in Uruguay: in that analysis, we did not control for total energy intake. To better study the relationship between intake of meat and meat constituents and gastric cancer, we conducted a further case-control study including 123 cases and 282 controls who were enrolled between September 1997 and August 1999. Total meat intake (highest tertile) was associated with an odds ratio (OR) of 4.6 [95% confidence interval (CI) = 2.3-9.0]. After adjustment for total energy intake and intake of proteins and total fat by the residuals method, the OR was 1.7 (95% CI = 0.7-4.0). The energy-adjusted OR for high intake of processed meat was 1.9 (95% CI = 1.1-3.5). Intake of fried, barbecued, and salted meat and 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine was not associated with risk of gastric cancer. The energy-adjusted OR of high intake of nitrosodimethylamine was 1.5 (95% CI = 0.9-2.8). These results suggest that, in a country with elevated meat consumption, total energy intake and intake of proteins and fat are powerful confounders in the relationship between meat intake and gastric cancer risk. However, a modest independent effect of meat, in particular of processed meat, is suggested.

Smoking and drinking cessation and risk of esophageal cancer (Spain).

OBJECTIVES: To explore the effectiveness of alcohol drinking and tobacco smoking cessation in reducing esophageal cancer risk, taking into account the key characteristics of each habit and the simultaneous exposure to both habits. METHODS: Data from a series of five hospital-based case-control studies of incident squamous-cell carcinoma of the esophagus conducted by the International Agency for Research on Cancer (IARC, Lyon, France) in high-risk areas in South America were combined and analyzed by multivariate logistic regression procedures. A total of 2063 men (655 case patients and 1408 control subjects) were included in the pooled analysis. RESULTS: For either habit, the risk of esophageal cancer decreased rapidly, strongly and significantly with longer periods of abstention. The risk reduction was statistically significant regardless of the intensity and duration of each habit and the type of tobacco or alcoholic drink consumed. For subjects exposed to both risk factors, the protective effect of quitting both habits appeared to be synergistic, reaching, after only five to nine years of simultaneous cessation of both exposures, a 70% risk reduction, a reduction that clearly overlapped with the risk intervals of both never-smokers and never-drinkers. The risk benefit of merely quitting alcohol drinking was delayed (>10 years of cessation) unless it was also accompanied by a few years of smoking cessation. CONCLUSIONS: Our findings solidly demonstrate for the first time the effectiveness of smoking and drinking cessation in reducing esophageal cancer risk. For the large proportion of subjects in the general population exposed to both risk factors, our results further emphasize the importance of smoking cessation to effectively reduce cancer risk.

Dietary carotenoids and risk of gastric cancer: a case-control study in Uruguay.

In the period 1997-1999, 120 incident and histologically verified cases of stomach cancer were frequency matched on age, sex, residence and urban/rural status with 360 controls in order to study the role of diet in gastric cancer in Uruguay. Our attention was focused on the role of carotenoids in gastric carcinogenesis, after controlling for major confounders. According to the results, vitamin A, alpha-carotene and lycopene were associated with strong inverse relationships with stomach cancer (OR of stomach cancer for high alpha-carotene intake 0.34, 95% CI 0.17-0.65). Joint exposure to high intakes of alpha-carotene and vitamin C intakes were associated with a strong reduction in risk (OR 0.11, 95% CI 0.03-0.36). It was also suggested that high lycopene intake explained most of the reduction in risk of gastric cancer associated with vegetable intake, whereas no such effect was observed for fruit intake.

Influence of mate drinking, hot beverages and diet on esophageal cancer risk in South America.

To estimate the effects of consuming hot beverages, including mate (an infusion of the herb Ilex paraguayensis), tea, coffee and coffee with milk, and other food items on esophageal cancer risk, we analyzed data from 830 cases and 1,779 controls participating in a series of 5 hospital-based case-control studies of squamous-cell carcinoma of the esophagus conducted in high-risk areas of South America. After adjusting for the strong effects of tobacco and alcohol consumption, both heavy mate drinking (>1 l/day) and self-reported very hot mate drinking were significantly associated with esophageal cancer risk in men and women. The magnitude and strength of the association for mate amount and, to a lesser extent, mate temperature were higher for women than men. The joint effects of mate amount and mate temperature were more than multiplicative, following a statistically significant synergistic interaction (p = 0.02) which was particularly evident among heavy drinkers (>1.50 l/day) of very hot mate (odds ratio = 4.14, 95% confidence interval: 2.24-7.67) compared to light drinkers (<0.50 l/day) of cold/warm/hot mate. Consumption of other very hot beverages, such as tea and coffee with milk but not coffee alone, was also significantly associated with an increased risk, in the 2- to 4-fold range. Statistically significant protective associations were identified for high consumption of vegetables, fruits, cereals and tea. In contrast, frequent consumption of meat, animal fats and salt was associated with a moderately increased risk. This pooled analysis adds evidence for a carcinogenic effect of chronic thermal injury in the esophagus induced by the consumption of very hot drinks, including mate. Our study further confirms the protective effect of a dietary pattern characterized by daily consumption of fruits and vegetables and low consumption of meat and animal fats.

Tomatoes, tomato-rich foods, lycopene and cancer of the upper aerodigestive tract: a case-control in Uruguay.

In order to study the relationship between tomatoes, tomato products, lycopene and cancers of the upper aerodigestive tract (UADC; oral cavity, pharynx, larynx, esophagus) a case-control study was carried out in Uruguay, in the time period 1996-98. Two-hundred and thirty eight cases and 491 hospitalized controls were frequency matched on age, sex, residence and urban/rural status. Both series were submitted to a detailed questionnaire, including tobacco smoking, alcohol drinking and queries on 64 food items. These data were analyzed by unconditional logistic regression, after adjusting by total energy intake. Tomato intake was associated with a reduction in risk of 0.30 (95% confidence interval [CI], 0.18-0.51), whereas tomato sauce-rich foods displayed a protective effect of 0.57 (95% CI, 0.33-0.96 for the highest quartile of intake). The food group composed of raw tomato and tomato-rich foods showed a strong inverse association with UADC (odds ratio [OR], 0.23; 95% CI, 0.13-0.39 for the highest quartile of intake). Lycopene was also strongly associated with a reduced risk of 0.22 (95% CI, 0.13-0.37). Adjustment of tomato intake for several phytochemicals explained almost completely its protective effect, which disappears in this model. Finally, the joint effect of lycopene and total phytosterols was associated with a significant reduction in risk (OR, 0.11; 95% CI, 0.05-0.23).

Plant foods and risk of laryngeal cancer: A case-control study in Uruguay.

In order to examine the relationships between plant foods, defined as the grouping of vegetables, fruits, tubers and legumes, with the risk of developing laryngeal cancer, a case-control study was conducted in Uruguay between 1998-1999. The study included 148 cases with histologically verified squamous cell carcinoma of the larynx, which were frequency matched on age, residence and urban/rural status with 444 hospitalized controls, afflicted by non-neoplastic conditions. Both series of patients were face-to-face interviewed in the hospitals shortly after admittance using a detailed questionnaire. This questionnaire included 62 queries on food items, representative of the usual diet of the Uruguayan population. Food items and food groups were adjusted for tobacco smoking, alcohol drinking and total energy intake. High consumption of plant foods was associated with an OR of 0.42 (95% CI 0.21-0.84). Among subgroups of plant foods, fruits and raw vegetables were associated with a strong reduction in risk (OR for the highest quartile of raw vegetables 0.29, 95% CI 0.15-0.56). Also, legumes were associated with a protective effect (OR 0.62, 95% CI 0.33-1.19). Among individual food items, tomatoes and oranges were associated with the stronger protective effects (OR for tomato intake 0.32, 95% CI 0. 17-0.58). The joint effect of heavy smoking and the low intake of vegetables and fruits displayed an increased risk of 19.2 (95% CI 5. 7-64.9).

Alpha-linolenic acid and risk of prostate cancer: a case-control study in Uruguay.

In the time period of 1994-1998, a case-control study on diet and prostate cancer was carried out in Uruguay to examine the risk associated with fat intake. Two hundred and seventeen (217) incident cases afflicted with advanced prostate cancer were frequency-matched with 431 controls on age, residence, and urban/rural status. The analysis was carried out using unconditional multiple logistic regression. Alpha-linolenic acid was associated with a strong positive association (fourth quartile of intake odds ratio, 3.91; 95% confidence interval, 1.50-10.1) after controlling for total calorie intake and for the other types of fat. The effect was similar when alpha-linolenic acid was analyzed by its sources of origin (odds ratio for vegetable linolenic acid, 2.03; 95% confidence interval, 1.01-4.07). Including this report, five of six studies that have examined the relationship between alpha-linolenic acid and prostate cancer yielded a positive association, which was significant in four studies. Thus, there appears to be evidence of a role of alpha-linolenic acid in prostate carcinogenesis.

Plant sterols and risk of stomach cancer: a case-control study in Uruguay.

In 1997-1999, 120 incident and histologically verified cases of stomach cancer were frequency matched on age, gender, residence, and urban/rural status with 360 controls to study the role of diet in gastric cancer in Uruguay. We focused on the role of plant sterols (beta-sitosterol, campesterol, stigmasterol, and total plant sterols) after controlling for major confounders. Total phytosterols were associated with a strong inverse relationship with stomach cancer (odds ratio of stomach cancer for total phytosterol intake in the highest tertile = 0.33, 95% confidence interval = 0.17-0.65). Joint exposure to high intake of total phytosterol and alpha-carotene was also inversely associated with gastric cancer risk (odds ratio = 0.09, 95% confidence interval = 0.02-0.32). High intake of total plant sterols explained most of the attenuation in risk of gastric cancer associated with vegetable and fruit intakes.

Vegetables, fruits, related dietary antioxidants, and risk of squamous cell carcinoma of the esophagus: a case-control study in Uruguay.

In 1998-1999, a case-control study on esophageal cancer was conducted in Uruguay. For this purpose, 111 cases with squamous cell carcinoma of the esophagus and 444 controls with conditions unrelated to tobacco smoking, alcohol drinking, or recent changes in the diet were frequency matched on age, gender, residence, and urban/rural status. Vegetables and, more markedly, fruits were associated with strong reductions in risk. On the other hand, 12 of 15 dietary antioxidants displayed significant inverse associations with esophageal cancer risk. The strongest effect was observed for high intake of beta-cryptoxanthin (odds ratio = 0.16, 95% confidence interval = 0.08-0.36). Also, alpha-carotene, lycopene, and beta-sitosterol were associated with significant reductions in risk. Most antioxidants lost their effect when they were further adjusted for a term for all vegetables and fruits. beta-Carotene showed an increased risk with high intakes. On the other hand, vegetables and fruits remained as significant variables after adjustment for each antioxidant, suggesting that other substances or other mechanisms could explain this effect.