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Malignant gastric outlet obstruction (MGOO) is a clinical condition characterized by the mechanical obstruction of the pylorus or the duodenum due to tumor compression/infiltration, with consequent reduction or impossibility of an adequate oral intake. MGOO is mainly secondary to advanced pancreatic or gastric cancers, and significantly impacts on patients' survival and quality of life. Patients suffering from this condition often present with intractable vomiting and severe malnutrition, which further compromise therapeutic chances. Currently, palliative strategies are based primarily on surgical gastrojejunostomy and endoscopic enteral stenting with self-expanding metal stents. Several studies have shown that surgical approach has the advantage of a more durable relief of symptoms and the need of fewer re-interventions, at the cost of higher procedure-related risks and longer hospital stay. On the other hand, enteral stenting provides rapid clinical improvement, but have the limit of higher stent dysfunction rate due to tumor ingrowth and a subsequent need of frequent re-interventions. Recently, a third way has come from interventional endoscopic ultrasound, through the development of endoscopic ultrasound-guided gastroenterostomy technique with lumen-apposing metal stent. This new technique may ideally encompass the minimal invasiveness of an endoscopic procedure and the long-lasting effect of the surgical gastrojejunostomy, and brought encouraging results so far, even if prospective comparative trial are still lacking. In this Review, we described technical aspects and clinical outcomes of the above-cited therapeutic approaches, and discussed the open questions about the current management of MGOO., Competing Interests: Conflict-of-interest statement: Dr. Anderloni reports personal fees from Boston Scientific, during the conduct of the study; personal fees from Boston Scientific, outside the submitted work; Dr. Repici reports personal fees from Boston Scientific, personal fees from Fujifilm, during the conduct of the study; personal fees from Boston Scientific, personal fees from Fujifilm, outside the submitted work; Dr. Teoh reports personal fees from Microtech Medical Corporations, personal fees from Boston Scientific, personal fees from Cook, personal fees from Taewoong, during the conduct of the study; personal fees from Microtech Medical Corporations, personal fees from Boston Scientific, personal fees from Cook, personal fees from Taewoong, outside the submitted work; The other Authors declare no conflict of interests., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

In the last years, endoscopic ultrasonography (EUS) has evolved from a purely diagnostic technique to a more and more complex interventional procedure, with the possibility to perform several type of therapeutic interventions. Among these, EUS-guided biliary drainage (BD) is gaining popularity as a therapeutic approach after failed endoscopic retrograde cholangiopancreatography in distal malignant biliary obstruction (MBO), due to the avoidance of external drainage, a lower rate of adverse events and re-interventions, and lower costs compared to percutaneous trans-hepatic BD. Initially, devices created for luminal procedures ( e.g ., luminal biliary stents) have been adapted to the new trans-luminal EUS-guided interventions, with predictable shortcomings in technical success, outcome and adverse events. More recently, new metal stents specifically designed for transluminal drainage, namely lumen-apposing metal stents (LAMS), have been made available for EUS-guided procedures. An electrocautery enhanced delivery system (EC-LAMS), which allows direct access of the delivery system to the target lumen, has subsequently simplified the classic multi-step procedure of EUS-guided drainages. EUS-BD using LAMS and EC-LAMS has been demonstrated effective and safe, and currently seems one of the most performing techniques for EUS-BD. In this Review, we summarize the evolution of the EUS-BD in distal MBO, focusing on the novelty of LAMS and analyzing the unresolved questions about the possible role of EUS as the first therapeutic option to achieve BD in this setting of patients., Competing Interests: Conflict-of-interest statement: Dr. Anderloni reports personal fees from Boston Scientific, during the conduct of the study; personal fees from Boston Scientific, outside the submitted work; Dr. Repici reports personal fees from Boston Scientific, personal fees from Fujifilm, during the conduct of the study; personal fees from Boston Scientific, personal fees from Fujifilm, outside the submitted work; Dr. Troncone, Dr. Fugazza, Dr. Del Vecchio Blanco, Dr. Cappello, Dr. Monteleone have nothing to disclose.

Gastric cancer (GC) is the fourth most common cancer in the world and the second cause of cancer-related death. Gastric carcinogenesis is a multifactorial process, in which environmental and genetic factors interact to activate multiple intracellular signals thus leading to uncontrolled growth and survival of GC cells. One such a pathway is regulated by proteinase activated-receptors (PARs), seven transmembrane-spanning domain G protein-coupled receptors, which comprise four receptors (i.e., PAR-1, PAR-2, PAR-3, and PAR-4) activated by various proteases. Both PAR-1 and PAR-2 are over-expressed on GC cells and their activation triggers and/or amplifies intracellular pathways, which sustain gastric carcinogenesis. There is also evidence that expression of either PAR-1 or PAR-2 correlates with depth of wall invasion and metastatic dissemination and inversely with the overall survival of patients. Consistently, data emerging from experimental models of GC suggest that both these receptors can be important targets for therapeutic interventions in GC patients. In contrast, PAR-4 levels are down-regulated in GC and correlate inversely with the aggressiveness of GC, thus suggesting a negative role of this receptor in the control of GC. In this article we review the available data on the expression and role of PARs in GC and discuss whether manipulation of PAR-driven signals may be useful for interfering with GC cell behavior.

Ghrelin, the ligand of growth hormone secretagogue receptor 1a, takes part in several functions of the digestive system, including regulation of appetite, energy homeostasis, gastric acid secretion and motility. Ghrelin has also immunoregulatory properties and is supposed to inhibit some inflammatory pathways that can mediate gastric damage. Interestingly, ghrelin synthesis is reduced in the gastric mucosa of patients with Helicobacter pylori (H. pylori) infection, a worldwide condition inducing a T helper (Th)1/Th17 cell response-driven gastritis, which may evolve towards gastric atrophy and cancer. In this article, we review the available data on the expression of ghrelin in H. pylori infection and discuss how the defective ghrelin synthesis may contribute to sustain the ongoing inflammatory response in this disease.

Crohn's disease and ulcerative colitis, the major forms of inflammatory bowel diseases (IBD) in man, are complex diseases in which genetic and environmental factors interact to promote an excessive mucosal immune response directed against normal components of the bacterial microflora. There is also evidence that the pathologic process is due to defects in counter-regulatory mechanisms, such as those involving the immunosuppressive cytokine transforming growth factor (TGF)-β1. Indeed, studies in human IBD tissues and murine models of colitis have documented a disruption of TGF-β1 signalling marked by a block in the phosphorylation of Smad3, a signalling molecule associated with the activated TGF-β receptor, due to up-regulation of Smad7, an intracellular inhibitor of Smad3 phosphorylation. Knock-down of Smad7 with a specific antisense oligonucleotide restores TGF-β1/Smad3 signalling, thus resulting in a marked suppression of inflammatory cytokine production and attenuation of murine colitis. These findings together with the demonstration that Smad7 antisense oligonucleotide is not toxic when administered in mice have paved the way for the development of a Smad7 antisense oligonucleotide-based pharmaceutical compound that is now ready to enter the clinics. In this article we review the available data supporting the pathogenic role of Smad7 in IBD and discuss whether and how Smad7 antisense therapy could help dampen the ongoing inflammation in IBD.

Acute pancreatitis is the most common serious complication of endoscopic retrograde cholangio-pancreatography (ERCP) and its incidence may exceed 25% in some high-risk patient subsets. In some patients, pancreatitis may follow a severe course with pancreatic necrosis, multiorgan failure, permanent disability and even death. Hence, approaches which minimize both the incidence and severity of post-ERCP pancreatitis are worth pursuing. Pancreatic stents have been used with some success in the prevention of post-ERCP, while so far pharmacological trials have yielded disappointing results. A recent multicenter, randomized, placebo-controlled, double-blind trial has shown that rectally administered indomethacin is effective in reducing the incidence of post-ERCP pancreatitis, the occurrence of episodes of moderate-to-severe pancreatitis and the length of hospital stay in high-risk patients. These results together with the demonstration that rectal administration of indomethacin is not associated with enhanced risk of bleeding strongly support the use of this drug in the prophylaxis of post-ERCP pancreatitis.

Chronic inflammation is thought to be the leading cause of many human cancers including colorectal cancer (CRC). Accordingly, epidemiologic and clinical studies indicate that patients affected by ulcerative colitis and Crohn's disease, the two major forms of inflammatory bowel disease, have an increased risk of developing CRC. In recent years, the role of immune cells and their products have been shown to be pivotal in initiation and progression of colitis-associated CRC. On the other hand, activation of the immune system has been shown to cause dysplastic cell elimination and cancer suppression in other settings. Clinical and experimental data herein reviewed, while confirming chronic inflammation as a risk factor for colon carcinogenesis, do not completely rule out the possibility that under certain conditions the chronic activation of the mucosal immune system might protect from colonic dysplasia.

In the gut of patients with Crohn's disease and patients with ulcerative colitis, the major forms of inflammatory bowel diseases (IBD) in humans, the tissue-damaging immune response is mediated by an active cross-talk between immune and non-immune cells. Accumulating evidence indicates also that cytokines produced by these cells play a major role in initiating and shaping this pathologic process. One such cytokine seems to be interleukin (IL)-21, a member of the common gamma-chain-receptor family. IL-21 is produced in excess in the inflamed intestine of patients with IBD mostly by activated CD4+ T helper cells co-expressing interferon-gamma and follicular T helper cells. Moreover, both in vitro and in vivo studies indicate that excessive IL-21 production leads to the activation of multiple signaling pathways that expand and sustain the ongoing mucosal inflammation. In this article, we review the available data supporting the pathogenic role of IL-21 in IBD.

Spondyloarthropathies (SpA) are commonly observed extra-intestinal manifestations of both Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel diseases (IBD). However, the immunological link between these two clinical entities is still poorly understood. Several lines of evidence indicate that SpA may originate from the relocation to the joints of the immune process primarily induced in the gut. The transfer of the intestinal inflammatory process into the joints implicates that immune cells activated in the gut-draining lymph nodes can localize, at a certain point of the intestinal disease, either into the gut or into the joints. This is indicated by the overlapping expression of adhesion molecules observed on the surface of intestinal and synovial endothelial cells during inflammation. Moreover bacterial antigens and HLA-B27 expression may be implicated in the reactivation of T cells at the articular level. Finally, accumulating evidence indicates that a T helper 17 cell-mediated immune response may contribute to IBD and IBD-related SpA with a crucial role played by tumor necrosis factor-alpha in CD and to a lesser extent in UC.