Metformin, an insulin-lowering agent, has been associated with decreased cancer risk in epidemiologic studies in diabetic patients. We performed a comprehensive literature search and meta-analysis of ...epidemiologic studies to assess the effect of metformin on cancer incidence and mortality in diabetic patients, using Pubmed, ISI Web of Science, Embase, and the Cochrane library until May 2009, with no language or time restrictions. Independent reports with sufficient information to allow risk estimation of cancer risk/mortality and a measure of uncertainty were reviewed and cross-checked independently by three investigators. Eleven studies were selected for relevance in terms of intervention, population studied, independence, and reporting of cancer incidence or mortality data, reporting 4,042 cancer events and 529 cancer deaths. A 31% reduction in overall summary relative risk (0.69; 95% confidence interval, 0.61-0.79) was found in subjects taking metformin compared with other antidiabetic drugs. The inverse association was significant for pancreatic and hepatocellular cancer, and nonsignificant for colon, breast, and prostate cancer. A trend to a dose-response relationship was noted. Metformin is associated with a decreased risk of cancer incidence compared with other treatments among diabetic patients. Given the retrospective nature of most studies and the possibility that the control treatments increase risk, phase II trials are needed before large cancer prevention trials are launched.
In recent years, many studies have highlighted the possible close correlation between human diseases and definite patterns of microbial organisms colonizing various organs. Even at sites ...traditionally considered sterile, such as the upper female reproductive tract (FRT), it is now well-recognized as hosting a low biomass of different bacterial phyla. Additionally, the data from recent studies highlight a possible link between lower and upper FRT dysbiosis with a potential predisposition to cervical and ovarian cancer. Acinetobacter, chlamydia, increased mycoplasma, and lactobacillary scarcity in the upper FRT have all been linked to a predisposition to ovarian cancer. Additionally, a high-diversity vaginal community state type (CST) is linked to the presence and persistence of high-risk human papillomavirus (HPV), resulting in decreased cellular p53 activity and a reduction in the immune activity of T lymphocytes, resulting in cervical and ovarian cancer predisposition. While these findings are still far from being clarified in all aspects, in patients with multiple risk factors for ovarian cancer, a
treatment with a product with a proven ability to restore a favorable CST should be considered as an add-on therapy.
Metabolic disorders, mainly characterized as the marked alteration of the lipid and carbohydrate profile, in addition to the clinical presence of the direct consequences of these alterations, are ...pathological conditions that have considerably increased in prevalence in recent years. They are directly linked to the onset of various pathologies, including cancer, particularly breast cancer, and are hormone-responsive. Alongside the known conditions responsible for this scenario, such as nutrition and lifestyle in general, the importance of both the colonic microbiota and the various organs and systems is becoming increasingly evident. In fact, it is now evident that microbial dysbiosis plays a fundamental role in the onset of these metabolic disorders, and therefore how these conditions are indirectly responsible for the onset and progression of neoplasms. Indirect mechanisms such as an altered Firmicutes/Bacteroidetes ratio; the formation of metabolites such as short-chain fatty acids (SCFAs), in particular, butyrate, which is capable of acting as a tumor suppressor; and the glucuronidase activity of estroboloma (bacteria responsible for estrogen metabolism) are just some of the most important mechanisms that contribute to the history of breast cancer. It is therefore understandable that in clinical terms, it is essential to associate the modulation of metabolic disorders and the microbial conditions that contribute to generating them with common therapies, preferably using compounds and solutions that are effective and acceptable for the patient without side effects. Nutraceuticals such as berberine (active both in metabolic scenarios and in the microbiota) and interventions modulating the microbial structure such as the use of probiotics and prebiotics seem to be ideal solutions for these preventive and no-longer-ignorable strategies in the light of numerous data now present in the literature.
Several studies have identified an increased risk of cancer in type 2 diabetic patients and this is in accordance with the hypothesis that increased insulin levels might promote cancer. Thus, there ...is a great interest in exploring the possibility that antidiabetic therapies lowering insulin levels could decrease cancer incidence or cancer-related mortality. Recent observational studies have shown that metformin, an oral safe and well-tolerated insulin-sensitizer antidiabetic drug, has been associated with reduced cancer risk. Recently, several preclinical studies have evaluated the effect of metformin in vivo on nude mice and showed a significant reduction of both breast epithelial cell proliferation and protein synthesis. Further investigations in the clinical setting are well-supported by the promising results obtained thus far. At the European Institute of Oncology, the Division of Cancer Prevention and Genetics is planning to conduct a clinical trial to evaluate the activity of metformin on tumor cell proliferation in breast cancer patients undergoing surgery. It will be a presurgical randomized, double blind, placebo-controlled phase II biomarker trial: 100 histologically confirmed breast cancer patients will be randomly assigned to metformin (850 mg twice/daily) or placebo for 28+7 days till surgery to assess drug activity on tumor proliferation, as measured by Ki-67. The confirmation of the efficacy of metformin on cancer cell proliferation may lead the way to larger chemoprevention clinical trials.
Metformin is associated with reduced breast cancer risk in observational studies in patients with diabetes, but clinical evidence for antitumor activity is unclear. The change in Ki-67 between ...pretreatment biopsy and post-treatment surgical specimen has prognostic value and may predict antitumor activity in breast cancer.
After tumor biopsy, we randomly allocated 200 nondiabetic women with operable breast cancer to either metformin 850 mg/twice per day (n = 100) or placebo (n = 100). The primary outcome measure was the difference between arms in Ki-67 after 4 weeks adjusted for baseline values.
Overall, the metformin effect on Ki-67 change relative to placebo was not statistically significant, with a mean proportional increase of 4.0% (95% CI, -5.6% to 14.4%) 4 weeks apart. However, there was a different drug effect depending on insulin resistance (homeostasis model assessment HOMA index > 2.8, fasting glucose mmol/L × insulin mU/L/22.5; P(interaction) = .045), with a nonsignificant mean proportional decrease in Ki-67 of 10.5% (95% CI, -26.1% to 8.4%) in women with HOMA more than 2.8 and a nonsignificant increase of 11.1% (95% CI, -0.6% to 24.2%) with HOMA less than or equal to 2.8. A different effect of metformin according to HOMA index was noted also in luminal B tumors (P(interaction) = .05). Similar trends to drug effect modifications were observed according to body mass index (P = .143), waist/hip girth-ratio (P = .058), moderate alcohol consumption (P = .005), and C-reactive protein (P = .080).
Metformin before surgery did not significantly affect Ki-67 overall, but showed significantly different effects according to insulin resistance, particularly in luminal B tumors. Our findings warrant further studies of metformin in breast cancer with careful consideration to the metabolic characteristics of the study population.
Many clinical studies have now highlighted how the composition of the intestinal microbiota can regulate the effects of many oncological therapies. In particular, the modulation of microbial ...composition has been shown to enhance their efficacy and reduce potential side effects. Numerous adverse events induced by chemotherapy and radiotherapy appear to be strongly associated with an alteration in the intestinal microbiota caused by these treatments. This supports the hypothesis that the modulation or correction of the microbiota may decrease the toxic impact of therapies, improving patient compliance and quality of life. Among the most debilitating disorders related to oncological treatments is certainly mucositis, and recent clinical data highlight how the deficiency of short-chain fatty acids, especially butyrate, and specifically the lack of certain bacterial groups responsible for its production (butyrate producers), is strongly associated with this disorder. It is hypothesized that restoring these elements may influence the onset and severity of adverse events. Therefore, the intake of probiotics, especially butyrate producers, and specifically
(CBM588), currently the only cultivable and usable strain with a history of data proving its safety, could be a valuable ally in oncological therapies, reducing the associated discomfort and improving compliance, efficacy, and quality of life for patients.
Recent studies have highlighted a possible correlation between microbiota composition and the pathogenesis of various oncological diseases. Also, many bacterial groups are now directly or indirectly ...associated with the capability of stimulating or inhibiting carcinogenic pathways. However, little is known about the importance and impact of microbiota patterns related to the efficacy and toxicity of cancer treatments. We have recently begun to understand how oncological therapies and the microbiota are closely interconnected and could influence each other. Chemotherapy effectiveness, for example, appears to be strongly influenced by the presence of some microorganisms capable of modulating the pharmacokinetics and pharmacodynamics of the compounds used, thus varying the real response and therefore the efficacy of the oncological treatment. Similarly, chemotherapeutic agents can modulate the microbiota with variations that could facilitate or avoid the onset of important side effects. This finding has or could have considerable relevance as it is possible that our ability to modulate and modify the microbial structure before, during, and after treatment could influence all the clinical parameters related to pharmacological treatments and, eventually, the prognosis of the disease.
The altered patterns of a microbial population colonizing an organ are increasingly recognized as a relevant item in human disease pathogenesis. The female urogenital tract is no exception, as some ...vaginal microbiota patterns, named community state types (CSTs), and urinary tract microbiota patterns, named urotypes (UTs), have been linked to viral, inflammatory, and gestational diseases. Treating these conditions is an issue, as antibiotic therapies alone are not always effective. Lactobacillus crispatus M247 is a strain with good intestinal and vaginal adhesion capability, combined with local antibacterial and anti-inflammatory properties; this strain also has proven nontransferable resistance to antibiotics commonly used in female genital tract infections, such as metronidazole. Lactobacillus crispatus M247 could, therefore, be considered as a potential add-on therapy to antibiotics in vaginal tract infections, with the aim to restore a favorable microbiota pattern.
The ketogenic diet has proven to be effective in many recent studies not only as a weight-losing strategy but also as a valuable add-on therapy in medical conditions such as diabetes and epilepsy. ...Additionally, frequent conditions such as autism spectrum disorders and Alzheimer disease could have a benefit derived from ketogenic diet metabolic changes. Many of these benefits could be driven by an intestinal microbiota change. While the effects of a ketogenic diet on microbiota should still be thoroughly clarified, as most studies observe an increase in bacterial strains considered neuroprotective such as Akkermansia muciniphila, with a concomitant reduction in some pathogenic strains such as Salmonella spp. it is important to highlight how many studies show a reduction in butyrate-producing strains, leading to a colonic proinflammatory state with increased intestinal permeability and an increase in pathogenic bacterial strains. The Clostridium butyricum strain MIYAIRI 588 (CBM588) is a butyrate-producing strain that was recently approved for human use in Europe due to its safety and effectiveness. The beneficial effect of CBM588 on the human colon could derive from a mucosal layer thickness increase and mucosal immune cell regulation, leading to a reduction in diarrhea and mucosal damage. Additionally, CBM588 could improve systemic insulin sensitivity and reduce the splanchnic organ inflammatory state. Therefore, CBM588 is a bacterial strain that should be considered an add-on when following a ketogenic diet, leading to a reduction in some of the potential gastrointestinal side effects and improving weight management through increased insulin sensitivity and the optimization of the lipid metabolism.
Cesarean section is considered a possible trigger of atopy and gut dysbiosis in newborns. Bifidobacteria, and specifically B. bifidum, are thought to play a central role in reducing the risk of atopy ...and in favoring gut eubiosis in children. Nonetheless, no trial has ever prospectively investigated the role played by this single bacterial species in preventing atopic manifestations in children born by cesarean section, and all the results published so far refer to mixtures of probiotics. We have therefore evaluated the impact of 6 months of supplementation with B. bifidum PRL2010 on the incidence, in the first year of life, of atopy, respiratory tract infections, and dyspeptic syndromes in 164 children born by cesarean (versus 249 untreated controls). The results of our multicenter, randomized, and controlled trial have shown that the probiotic supplementation significantly reduced the incidence of atopic dermatitis, upper and lower respiratory tract infections, and signs and symptoms of dyspeptic syndromes. Concerning the gut microbiota, B. bifidum supplementation significantly increased α-biodiversity and the relative values of the phyla Bacteroidota and Actinomycetota, of the genus Bacteroides, Bifidobacterium and of the species B. bifidum and reduced the relative content of Escherichia/Shigella and Haemophilus. A 6-month supplementation with B. bifidum in children born by cesarean section reduces the risk of gut dysbiosis and has a positive clinical impact that remains observable in the following 6 months of follow-up.
PDF
