The intestinal mucosa provides a selective permeable barrier for nutrient absorption and protection from external factors. It consists of epithelial cells, immune cells and their secretions. The gut microbiota participates in regulating the integrity and function of the intestinal barrier in a homeostatic balance. Pathogens, xenobiotics and food can disrupt the intestinal barrier, promoting systemic inflammation and tissue damage. Genetic and immune factors predispose individuals to gut barrier dysfunction, and changes in the composition and function of the gut microbiota are central to this process. The progressive identification of these changes has led to the development of the concept of ‘leaky gut syndrome’ and ‘gut dysbiosis’, which underlie the relationship between intestinal barrier impairment, metabolic diseases and autoimmunity. Understanding the mechanisms underlying this process is an intriguing subject of research for the diagnosis and treatment of various intestinal and extraintestinal diseases.

The intestinal barrier, with its multiple layers, is the first line of defense between the outside world and the intestine. Its disruption, resulting in increased intestinal permeability, is a recognized pathogenic factor of intestinal and extra-intestinal diseases. The identification of a gut–vascular barrier (GVB), consisting of a structured endothelium below the epithelial layer, has led to new evidence on the etiology and management of diseases of the gut–liver axis and the gut–brain axis, with recent implications in oncology as well. The gut–brain axis is involved in several neuroinflammatory processes. In particular, the recent description of a choroid plexus vascular barrier regulating brain permeability under conditions of gut inflammation identifies the endothelium as a key regulator in maintaining tissue homeostasis and health.

The treatment perspectives of advanced hepatocellular carcinoma (HCC) have deeply changed after the introduction of immunotherapy. The results in responders show improved survival compared with Sorafenib, but only one-third of patients achieve a significant benefit from treatment. As the tumor microenvironment exerts a central role in shaping the response to immunotherapy, the future goal of HCC treatment should be to identify a proxy of the hepatic tissue condition that is easy to use in clinical practice. Therefore, the search for biomarkers that are accurate in predicting prognosis will be the hot topic in the therapeutic management of HCC in the near future. Understanding the mechanisms of resistance to immunotherapy may expand the patient population that will benefit from it, and help researchers to find new combination regimens to improve patients’ outcomes. In this review, we describe the current knowledge on the prognostic non-invasive biomarkers related to treatment with immune checkpoint inhibitors, focusing on serological markers and gut microbiota.

Lipopolysaccharide (LPS), also known as endotoxin, is a component of the membrane of gram-negative bacteria and a well-recognized marker of sepsis. In case of disruption of the intestinal barrier, as occurs with unhealthy diets, alcohol consumption, or during chronic diseases, the microbiota residing in the gastrointestinal tract becomes a crucial factor in amplifying the systemic inflammatory response. Indeed, the translocation of LPS into the bloodstream and its interaction with toll-like receptors (TLRs) triggers molecular pathways involved in cytokine release and immune dysregulation. This is a critical step in the exacerbation of many diseases, including metabolic disorders and cancer. Indeed, the role of LPS in cancer development is widely recognized, and examples include gastric tumor related to Helicobacter pylori infection and hepatocellular carcinoma, both of which are preceded by a prolonged inflammatory injury; in addition, the risk of recurrence and development of metastasis appears to be associated with endotoxemia. Here, we review the mechanisms that link the promotion and progression of tumorigenesis with endotoxemia, and the possible therapeutic interventions that can be deployed to counteract these events.

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Background: an increased risk of malignancies (1.5-5 times) was found in Systemic Sclerosis (SSc). Well recognized risk factors are the diffuse form, advanced age and (1), more recently, the positivity for anti-RNA Polimerase III antibodies (aRNAP3) has assumed considerable importance (2). Objectives: the aim of this study was to evaluate the frequency of neoplasms and precancerous conditions, as well as the main risk factors, in our cohort of patients with SSc. Methods: we enrolled 312 consecutive patients (288/92% females and 24/8% males, mean age 62.3 years, average disease duration 108 months) afferent at our department from 2000 to 2018, with a diagnosis of SSc confirmed according to the 2013 aCR/EULAR criteria (3). All patients underwent clinical, instrumental and laboratory evaluation. In 93 patients, negative for anti-topoisomerase I antibodies (aScl70) and anti-centromere antibodies (ACA), the presence of aRNAP3 antibodies was evaluated by an ELISA method (QUANTA LiteTM RNA Pol III).Results: we found a limited form of disease in 229 patients (73.4%) and a diffuse form in 83 (26.6%). Eighty eight (28.2%) patients were positive for aScl70, 112 (35.9%) for aCA and 17 (5.4%) for aRNAP3. In the whole group, 44 (14%) patients had a positive familiar history for neoplasm while 105 (33.65%) had a history of neoplasms and/or precancerous conditions. Among these 105 cases, 44 (41.9%) were malignant, 50 (47.6%) benign and 11 (10.5%) had precancerous conditions. The most frequent neoplasms were breast carcinomas (14 cases/14.9%), thyroid (7 cases/7.4%), lung and kidney (3 cases/3.1%), melanomas (5 cases/5.3%). The most frequent precancerous condition was Barrett’s esophagus (7 cases/63.3%). Regarding the antibody profile, 5 (4.8%) patients were positive for anti-RNAP3 and only 2 (1.9%) of these patients presented a malignant neoplasm, breast cancer in both cases. In 30 cases (28.6%) these neoplastic/precancerous conditions had arisen in the close period (± 36 months) at the SSc diagnosis and only 3 of them were anti-RNAP3 positive. Among the evaluated risk factors. Only familiarity was significantly associated with the development of neoplasia (p = 0.003), confirmed at the multivariate analysis (OR 2.9, IC95% [1,5-5,7]; p=0,002). Conclusion: our study evaluated not only malignant neoplasms, but also benign neoplasms and precancerous conditions and identified familiarity as the only significant risk factor. In our cohort we did’nt find any relationship between the presence of anti-RNAP3 antibodies and the development of neoplasms, not even stratifying for the type of neoplasm. However, to better define our data, we should analyze anti-RNAP3 also in the double negative (antiScl70 and aCA) cases, in light of the recent evidence of double antibody positivity, as well as other newly investigated rare autoantibodies, associated with neoplasm in many connective tissue diseases, including SSc.References[1] Szekanecz E, et al. (2012) autoimmun Rev11, 852;[2] Shaha aAet al(2017) J Scleroderma Relat Disord. 2, 153;[3] Van den ...