Efficacy and safety of a new low-volume PEG with citrate and simethicone bowel preparation for pediatric elective colonoscopy: Phase 3 RCT.

Background and study aims Currently available polyethylene glycol (PEG)-based preparations continue to represent a challenge in children. The aim of this study was to compare the efficacy and safety of a new low-volume PEG preparation with a conventional PEG-electrolyte solution (PEG-ES) in children and adolescents. Patients and methods This was a multicenter, randomized, observer-blind, parallel-group, phase 3 clinical trial, where patients were randomized between PMF104 (Clensia) and a conventional PEG-ES (Klean-Prep), and stratified by age stratum (2 to <6; 6 to < 12;12 to <18 years). The primary endpoint was to test the non-inferiority of PMF104 versus PEG-ES, in terms of colon cleansing. Safety, tolerability, acceptability, palatability, and compliance were also assessed. Efficacy endpoints were analyzed in the per protocol set (PPS) and full analysis set (FAS) and safety and tolerability endpoints in the safety set (SAF). Results Of the 356 patients enrolled, 258 were included in the PPS, 346 in the FAS, and 351 in the SAF. Non-inferiority of PMF104 was confirmed for children aged > 6 years and for all age groups in PPS and FAS, respectively. Optimal compliance was reported more frequently in the PMF104 than in the PEG-ES group, in both PPS (86.1% vs. 68.4%) and FAS (82.9% vs. 65.3%). Both preparations were equally safe and tolerable. Palatability and acceptability were considered better in the PMF104 group than in the PEG-ES group (27.1% vs. 15.3% and 15.3% vs. 3.5%, respectively). Conclusions In children aged 6 to 17 years, the new low-volume product PMF104 is non-inferior to the reference PEG-ES in terms of bowel cleansing, safety, and tolerability, with slightly better results in compliance, palatability, and acceptability.

Synergism between sinusoidal-50 Hz magnetic field and formaldehyde in triggering carcinogenic effects in male Sprague-Dawley rats.

BACKGROUND: Experimental rodent bioassays performed up to now have failed to provide conclusive confirmation of the carcinogenicity of extremely low frequency magnetic fields (ELFMF). OBJECTIVES: To evaluate the potential synergistic carcinogenic effects of concurrent exposure to ELFMF and formaldehyde in four groups of male and female Sprague-Dawley rats. METHODS: One group was exposed from prenatal life until natural death to S-50 Hz MF and to formaldehyde in drinking water from 6 weeks of age for 104 weeks, two groups were treated only with formaldehyde or only with MF and one group served as untreated control. RESULTS: Compared to untreated controls, exposure to MF and formaldehyde causes in males a statistically significant increased incidence of malignant tumors (P ≤ 0.01), thyroid C-cell carcinomas (P ≤ 0.01), and hemolymphoreticular neoplasias (P ≤ 0.05). No statistically significant differences were observed among female groups. CONCLUSIONS: Life-span exposure to MF and formaldehyde induces statistically significant carcinogenic effects in male rats. Am. J. Ind. Med. 59:509-521, 2016. © 2016 Wiley Periodicals, Inc.

Life-span exposure to sinusoidal-50 Hz magnetic field and acute low-dose γ radiation induce carcinogenic effects in Sprague-Dawley rats.

Background In 2002 the International Agency for Research on Cancer classified extremely low frequency magnetic fields (ELFMF) as a possible carcinogen on the basis of epidemiological evidence. Experimental bioassays on rats and mice performed up to now on ELFMF alone or in association with known carcinogens have failed to provide conclusive confirmation. Objectives To study the carcinogenic effects of combined exposure to sinusoidal-50 Hz (S-50 Hz) magnetic fields and acute γ radiation in Sprague-Dawley rats. Methods We studied groups of male and female Sprague-Dawley rats exposed from prenatal life until natural death to 20 or 1000 µT S-50 Hz MF and also to 0.1 Gy γ radiation delivered as a single acute exposure at 6 weeks of age. Results The results of the study showed significant carcinogenic effects for the mammary gland in males and females and a significant increased incidence of malignant schwannomas of the heart as well as increased incidence of lymphomas/leukemias in males. Conclusions These results call for a re-evaluation of the safety of non-ionizing radiation.

Gene expression profiling of mammary glands at an early stage of DMBA-induced carcinogenesis in the female Sprague-Dawley rat.

Background: Breast cancer is the most common cause of cancer death among women worldwide and the second leading cause of tumor-related death for women in westernized countries. Most research efforts to find a breast cancer biomarker have focused on the stage after the cancer is diagnosed. To investigate more deeply into mammary cancer prevention, a study of precancerous lesion development seems a priority. Experimentally-induced mammary tumors in rats constitute a powerful tool for studying the pathogenesis of this cancer and the molecular mechanisms involved in neoplastic progression. Furthermore, in vivo experimental animal models provide information not otherwise available in human populations. 7,12-dimethylbenz[a] anthracene (DMBA) induced rat mammary carcinomas have several similarities with human breast cancers including: histopathology, origination in the ductal epithelial cells, and hormone dependence. To better understand the molecular events associated with mammary carcinogenesis, we used a time-course high throughput gene expression approach on a DMBA-induced mammary cancer model to identify the early precancerous events as well as new potential diagnostic biomarkers. Materials and Methods: Twelve 7 wk-old virgin female Sprague-Dawley rats were randomized into 2 experimental groups: 1) DMBA-treated (40 mg/kg b.w. by intragastric administration (i.g.) in corn oil as the vehicle and 2) treated with corn oil (vehicle) by ig. At 2 and 4 weeks after DMBA administration, 3 animals randomly chosen from each experimental group were sacrificed and necropsied. Total RNA was extracted and the global gene expression patterns from the mammary gland and liver samples collected were used to identify the molecular profile of the precancerous stage genome. Significantly altered genes as evinced by multivariate data analysis were further confirmed by quantitative real time PCR and siRNA knockdown assays. Results and Discussion: Genes involved in cancer progression, migration, proliferation and oxidative stress were identified in this study. MARK, Wnt and Jak-STAT pathway signaling, known to play a major role at the precancerous stage, were also identified. Two novel less known cancer progression/proliferation related genes, Pcbd1 and Ppil1, upregulated in both liver and mammary glands, were also identified.

Life-span carcinogenicity studies on Sprague-Dawley rats exposed to γ-radiation: design of the project and report on the tumor occurrence after post-natal radiation exposure (6 weeks of age) delivered in a single acute exposure.

BACKGROUND: Experimental long-term carcinogenicity bioassays conducted on rats and mice proved that ionizing radiation can induce a variety of tumor types. However few studies have been conducted on rats. METHODS: This report deals with the effects of γ-radiation in groups of 416-1,051 6-weeks old Sprague-Dawley rats exposed to 0, 0.1, 1, or 3 Gy of γ-radiation delivered in a single acute exposure. The experiment lasted for the animals' lifespan and all were necropsied and underwent full histopathological evaluation. RESULTS: The results confirm the dose-related carcinogenic effects of γ-radiation for several organs and tissues. Moreover they indicate that exposure to 0.1 Gy induces a statistically significant increased incidence in Zymbal gland carcinomas and pancreas islet cell carcinomas in females. CONCLUSIONS: Our data show that exposure to γ-radiation induces carcinogenic effects at all tested doses.

The carcinogenic effects of aspartame: The urgent need for regulatory re-evaluation.

Aspartame (APM) is an artificial sweetener used since the 1980s, now present in >6,000 products, including over 500 pharmaceuticals. Since its discovery in 1965, and its first approval by the US Food and Drugs Administration (FDA) in 1981, the safety of APM, and in particular its carcinogenicity potential, has been controversial. The present commentary reviews the adequacy of the design and conduct of carcinogenicity bioassays on rodents submitted by G.D. Searle, in the 1970s, to the FDA for market approval. We also review how experimental and epidemiological data on the carcinogenic risks of APM, that became available in 2005 motivated the European Commission (EC) to call the European Food and Safety Authority (EFSA) for urgent re-examination of the available scientific documentation (including the Searle studies). The EC has further requested that, if the results of the evaluation should suggest carcinogenicity, major changes must be made to the current APM specific regulations. Taken together, the studies performed by G.D. Searle in the 1970s and other chronic bioassays do not provide adequate scientific support for APM safety. In contrast, recent results of life-span carcinogenicity bioassays on rats and mice published in peer-reviewed journals, and a prospective epidemiological study, provide consistent evidence of APM's carcinogenic potential. On the basis of the evidence of the potential carcinogenic effects of APM herein reported, a re-evaluation of the current position of international regulatory agencies must be considered an urgent matter of public health.

Distinct effects of calorie restriction and exercise on mammary gland gene expression in C57BL/6 mice.

Energy balance, including diet, weight, adiposity, and physical activity, is associated with carcinogenesis. Epidemiologic studies indicate that obesity and sedentary and/or active behavior are risk factors for breast cancer in postmenopausal women and survival in both premenopausal and postmenopausal breast cancer patients. Thus, understanding the influence of energy balance modulation on changes in gene expression patterns in the normal mammary gland is important for understanding mechanisms linking energy balance and breast cancer. In a 6-week-long study, female C57BL/6 mice (9-week-old) were randomized into four groups: (a) food consumed ad libitum (AL), (b) AL with access to running wheels (AL+EX), (c) 30% calorie restricted (CR), and (d) 30% CR with access to running wheels (CR+EX). CR mice received 70% of calories but 100% of all other nutrients compared with AL mice. Diet and exercise treatments, individually and combined, had significant effects on body composition and physical activity. Affymetrix oligomicroarrays were used to explore changes in gene expression patterns in total RNA samples from excised whole mammary glands. Contrasting AL versus CR resulted in 425 statistically significant expression changes, whereas AL versus AL+EX resulted in 45 changes, with only 3 changes included among the same genes, indicating that CR and EX differentially influence expression patterns in noncancerous mammary tissue. Differential expression was observed in genes related to breast cancer stem cells, the epithelial-mesenchymal transition, and the growth and survival of breast cancer cells. Thus, CR and EX seem to exert their effects on mammary carcinogenesis through distinct pathways.

Results of long-term carcinogenicity bioassay on Sprague-Dawley rats exposed to aspartame administered in feed.

Aspartame (APM) is one of the most widely used artificial sweeteners in the world. Its ever-growing use in more than 6000 products, such as soft drinks, chewing gum, candy, desserts, etc., has been accompanied by rising consumer concerns regarding its safety, in particular its potential long-term carcinogenic effects. In light of the inadequacy of the carcinogenicity bioassays performed in the 1970s and 1980s, a long-term mega-experiment on APM was undertaken at the Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation on groups of male and female Sprague-Dawley rats (100-150/sex/group), 8 weeks old at the start of the experiment. APM was administered in feed at concentrations of 100,000, 50,000, 10,000, 2,000, 400, 80, or 0 ppm. Treatment lasted until spontaneous death of the animals. The results of the study demonstrate that APM causes: (a) an increased incidence of malignant tumor-bearing animals, with a positive significant trend in both sexes, and in particular in females treated at 50,000 ppm (P < or = 0.01) when compared to controls; (b) an increase in lymphomas-leukemias, with a positive significant trend in both sexes, and in particular in females treated at doses of 100,000 (P < or = 0.01), 50,000 (P < or = 0.01), 10,000 (P < or = 0.05), 2000 (P < or = 0.05), and 400 ppm (P < or = 0.01); (c) a statistically significant increased incidence, with a positive significant trend, of transitional cell carcinomas of the renal pelvis and ureter in females and particularly in those treated at 100,000 ppm (P < or = 0.05); and (d) an increased incidence of malignant schwannomas of the peripheral nerves, with a positive trend in males (P < or = 0.05). The results of this mega-experiment indicate that APM, in the tested experimental conditions, is a multipotential carcinogenic agent.

Results of long-term experimental studies on the carcinogenicity of methyl alcohol and ethyl alcohol in rats.

Methyl alcohol was administered in drinking water supplied ad libitum at doses of 20,000, 5,000, 500, or 0 ppm to groups of male and female Sprague-Dawley rats 8 weeks old at the start of the experiment. Animals were kept under observation until spontaneous death. Ethyl alcohol was administered by ingestion in drinking water at a concentration of 10% or 0% supplied ad libitum to groups of male and female Sprague-Dawley rats; breeders and offspring were included in the experiment. Treatment started at 39 weeks of age (breeders), 7 days before mating, or from embryo life (offspring) and lasted until their spontaneous death. Under tested experimental conditions, methyl alcohol and ethyl alcohol were demonstrated to be carcinogenic for various organs and tissues. They must also be considered multipotential carcinogenic agents. In addition to causing other tumors, ethyl alcohol induced malignant tumors of the oral cavity, tongue, and lips. These sites have been shown to be target organs in man by epidemiologic studies.

Results of long-term experimental studies on the carcinogenicity of formaldehyde and acetaldehyde in rats.

Formaldehyde was administered for 104 weeks in drinking water supplied ad libitum at concentrations of 1500, 1000, 500, 100, 50, 10, or 0 mg/L to groups of 50 male and 50 female Sprague-Dawley rats beginning at seven weeks of age. Control animals (100 males and 100 females) received tap water only. Acetaldehyde was administered to 50 male and 50 female Sprague-Dawley rats beginning at six weeks of age at concentrations of 2,500, 1,500, 500, 250, 50, or 0 mg/L. Animals were kept under observation until spontaneous death. Formaldehyde and acetaldehyde were found to produce an increase in total malignant tumors in the treated groups and showed specific carcinogenic effects on various organs and tissues.