Endoscopic Gallbladder Drainage: A Comprehensive Review on Indications, Techniques, and Future Perspectives.

In recent years, therapeutic endoscopy has become a fundamental tool in the management of gallbladder diseases in light of its minimal invasiveness, high clinical efficacy, and good safety profile. Both endoscopic transpapillary gallbladder drainage (TGBD) and endoscopic ultrasound (EUS)-guided gallbladder drainage (EUS-GBD) provide effective internal drainage in patients with acute cholecystitis unfit for cholecystectomy, avoiding the drawbacks of external percutaneous gallbladder drainage (PGBD). The availability of dedicated lumen-apposing metal stents (LAMS) for EUS-guided transluminal interventions contributed to the expansion of endoscopic therapies for acute cholecystitis, making endoscopic gallbladder drainage easier, faster, and hence more widely available. Moreover, EUS-GBD with LAMS opened the possibility of several cholecystoscopy-guided interventions, such as gallstone lithotripsy and clearance. Finally, EUS-GBD has also been proposed as a rescue drainage modality in malignant biliary obstruction after failure of standard techniques, with encouraging results. In this review, we will describe the TBGD and EUS-GBD techniques, and we will discuss the available data on clinical efficacy in different settings in comparison with PGBD. Finally, we will comment on the future perspectives of EUS-GBD, discussing the areas of uncertainty in which new data are more strongly awaited.

International Delphi Consensus Study on disposable single-use endoscopy: A path to clinical adoption.

BACKGROUND/OBJECTIVE: Increasing infectious rate estimates and low microbiological surveillance affect safety of gastrointestinal endoscopy globally. Single use endoscopes and accessories have been claimed to improve safety, but there is lack of data on their indication and sustainability. We aimed to identify a series of best practice recommendations for the use of single use endoscopes and accessories using a modified Delphi. METHODS/DESIGN: Consensus statements for the use of single use endoscopy and accessories were developed using a modified Delphi process, utilizing an international endoscopist expert panel of 62 experts from 33 nations. The main steps in the process were selecting the consensus group, conducting systematic literature reviews, developing statements, and anonymous voting on the statements until consensus was reached. High-risk patients were defined as those with multi-drug-resistant infections, immunosuppressive medication or chemotherapy, post-transplantation, or with severe neutropenia. RESULTS: Of the 26 statements that were voted upon through two rounds, 17 statements reached consensus. Category 1: single use accessories (8 statements), related to defining recommendations for the use of single use accessories in all patient populations or high-risk patients. Category 2: clinical indication for single use endoscopes (9 statements), including indications to high-risk patients, protecting the endoscope apparatus and contamination measures in endoscopy units. Category 3: technical factors (4 statements), related to superior performance and technical specifications with the new innovation. Category 4: environmental issues (2 statements), concerning mechanisms that reduce the detrimental burden to the environment. Category 5: financial implications (3 statements), related to healthcare policies, cost neutrality and other financial associations of single use endoscopy. CONCLUSIONS: This is the first international initiative in determining clinical indications for single use endoscopy and accessories. The study's findings should serve as a framework for future physicians to guide future research and aid the proper evidence-based indications for the implementation of single use endoscopes in clinical practice.

Frequency and Predictors of Dysplasia in Pseudopolyp-like Colorectal Lesions in Patients with Long-Standing Inflammatory Bowel Disease.

Current endoscopic surveillance programs do not consider inflammatory bowel disease (IBD)-associated post-inflammatory polyps (pseudopolyps) per se clinically relevant, even though their presence seems to increase the risk of colorectal cancer (CRC). However, it remains unclear whether the link between pseudopolyps and CRC is indirect or whether some subsets of pseudopolyp-like lesions might eventually undergo neoplastic transformation. This study aimed to assess the frequency and predictors of dysplasia in pseudopolyp-like lesions in a population with long-standing colonic IBD. This was a retrospective, single-center study including patients with a colonic IBD (median disease duration of 192 months) and at least a pseudopolyp-like lesion biopsied or resected in the period from April 2021 to November 2022. One hundred and five pseudopolyps were identified in 105 patients (80 with ulcerative colitis and 25 with Crohn's disease). Twenty-three out of 105 pseudopolyp samples (22%) had dysplastic foci, and half of the dysplastic lesions were hyperplastic. Multivariate analysis showed that the age of the patients (odds ratio (OR) 1.1; p = 0.0012), size (OR 1.39; p = 0.0005), and right colonic location (OR 5.32; p = 0.04) were independent predictors of dysplasia, while previous exposure to immunosuppressors/biologics and left colonic location of the lesions were inversely correlated to dysplasia (OR 0.11; p = 0.005, and OR 0.09; p = 0.0008, respectively). No differences were seen between ulcerative colitis and Crohn's disease patients. Lesions with a size greater than 5 mm had a sensitivity of 87% and a specificity of 63% to be dysplastic. These data show that one-fourth of pseudopolyp-like lesions evident during surveillance colonoscopy in patients with longstanding IBD bear dysplastic foci and suggest treating such lesions properly.

Liver-Specific Contrast-Enhanced Magnetic Resonance Cholangio-Pancreatography (Ce-MRCP) in Non-Invasive Diagnosis of Iatrogenic Biliary Leakage.

Current non-invasive diagnostic modalities of iatrogenic bile leak (BL) are not particularly sensitive and often fail to localise the BL origin. Percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP) are considered the gold standard, yet are invasive studies with potential complications. Ce-MRCP has been not comprehensively studied in this setting but may prove particularly helpful given its non-invasive nature and the anatomical dynamic detail. This paper reports a monocentric retrospective study of BL patients referred between January 2018 and November 2022 submitted to Ce-MRCP followed by PTC. The primary outcome was the accuracy of Ce-MRCP in detecting and localising BL compared to PTC and ERCP. Blood tests, coexisting cholangitis features and time for leak resolution were also investigated. Thirty-nine patients were included. Liver-specific contrast-enhanced MRCP detected BL in 69% of cases. The BL localisation was 100% accurate. Total bilirubin above 4 mg/dL was significantly associated with false negative results of Ce-MRCP. Ce-MRCP is highly accurate in detecting and localising BL, but sensitivity is significantly reduced by a high bilirubin level. Ce-MRCP may be very useful in early BL diagnosis and in accurate pre-treatment planning, but can only be reliably used in selected patients with TB < 4 mg/dL. Non-surgical techniques, both radiological and endoscopic, are proven to be effective in terms of leak resolution.

Hemostatic Powders in Non-Variceal Upper Gastrointestinal Bleeding: The Open Questions.

Hemostatic powder (HP) is a relatively recent addition to the arsenal of hemostatic endoscopic procedures (HEPs) for gastrointestinal bleeding (GIB) due to benign and malignant lesions. Five types of HP are currently available: TC-325 (Hemospray™), EndoClot™, Ankaferd Blood Stopper®, and, more recently, UI-EWD (NexpowderTM) and CEGP-003 (CGBio™). HP acts as a mechanical barrier and/or promotes platelet activation and coagulation cascade. HP may be used in combination with or as rescue therapy in case of failure of conventional HEPs (CHEPs) and also as monotherapy in large, poorly accessible lesions with multiple bleeding sources. Although the literature on HP is abundant, randomized controlled trials are scant, and some questions remain open. While HP is highly effective in inducing immediate hemostasis in GIB, the rates of rebleeding reported in different studies are very variable, and conditions affecting the stability of hemostasis have not yet been fully elucidated. It is not established whether HP as monotherapy is appropriate in severe GIB, such as spurting peptic ulcers, or should be used only as rescue or adjunctive therapy. Finally, as it can be sprayed on large areas, HP could become the gold standard in malignancy-related GIB, which is often nonresponsive or not amenable to treatment with CHEPs as a result of multiple bleeding points and friable surfaces. This is a narrative review that provides an overview of currently available data and the open questions regarding the use of HP in the management of non-variceal upper GIB due to benign and malignant diseases.

The impact of COVID-19 on elective and urgent digestive endoscopic procedures: a report on a year of pandemic in a gastroenterology centre in Italy.

Introduction: The COVID-19 pandemic (COVID-19) affected digestive endoscopic activity worldwide. Resumption and maintenance of elective endoscopic activity are crucial to containing the impact of COVID-19 on mortality and prognosis of gastrointestinal disorders, primarily cancers. Aim: To assess the impact of COVID-19 during and after the lockdown period on endoscopic activity. Material and methods: The endoscopic activity undertaken during the COVID-19-related lockdown (March 2020-May 2020) and in the post-lockdown period (June 2020-March 2021) was compared with that in the corresponding periods of the year before COVID-19 in a gastroenterology centre in Italy. Results: During the lockdown period, there was a reduction in esophagogastroduodenoscopy (EGD), colonoscopy (CSPY), endoscopic ultrasound (EUS), and endoscopic-retrograde cholangiopancreatography (ERCP) of 75.8%, 74.8%, 60%, and 42%, respectively, compared with the corresponding period of the year before COVID-19. During the post-lockdown period to date, EGD, CSPY, EUS, and ERCP increased as compared to the lockdown period (30.6%, 50.6%, 33.6%, and 65.4%, respectively), but only ERCP showed a full recovery when compared with the corresponding period of the year before COVID-19. Conclusions: Endoscopic activity decreased significantly during the COVID-19 lockdown, and only ERCP had a full recovery in the post-lockdown period. The pandemic-related limitations and the backlog of endoscopic procedures represent important reasons for the increased risk or delayed diagnosis of GI cancers.

Endoscopic Predictors of Neoplastic Lesions in Inflammatory Bowel Diseases Patients Undergoing Chromoendoscopy.

Dye-based chromoendoscopy (DCE) with targeted biopsies is recommended for surveillance of patients with long-standing inflammatory bowel diseases (IBD), but endoscopic features that predict dysplasia are not fully clarified. We here aimed at identifying predictive factors of dysplastic/neoplastic lesions in IBD patients undergoing DCE. Two-hundred-and-nineteen patients were consecutively and prospectively enrolled from October 2019 to March 2022. One-hundred-and-forty-five out of 219 patients underwent DCE, and 148 lesions were detected in 79/145 (54%) patients. Thirty-nine lesions (26%) were dysplastic and one of them contained a CRC. Among these lesions, 7 (17.9%) had Kudo pit pattern I-II and 32 (82.1%) had a neoplastic pit pattern (Kudo III-IV). Multivariate analysis showed that neoplastic lesions Kudo III-IV (OR: 5.8, 95% CI: 2.3−14.6; p = 0.0002), lesion's size (OR 1.16, 95% CI: 1.06−1.26; p = 0.0009), and polypoid lesions according to Paris Classification (OR 7.4, 95% CI: 2.7−20.2; p = 0.0001) were independent predictors of dysplasia. A cut-off of lesion's size > 7 mm was identified as the best predictor of dysplasia. Among such features, Kudo pit pattern III-IV had the highest sensitivity and specificity to predict dysplasia (79% and 80%, respectively). Lesions with all three endoscopic features had a sensitivity of 90% and specificity of 100% to predict dysplasia. In contrast, non-polypoid lesions were inversely associated with dysplasia (OR 0.13, 95% CI: 0.05−0.36; p = 0.0001). These findings indicate that, in IBD patients, DCE-evidenced polypoid lesions with Kudo pit pattern III-IV and size > 7 mm are frequently dysplastic.

Role of endoscopic ultrasound in vascular interventions: Where are we now?

From a mere diagnostic tool to an imperative treatment modality, endoscopic ultrasound (EUS) has evolved and revolutionized safer efficient options for vascular interventions. Currently it is an alternative treatment option in the management of gastrointestinal bleeding, primarily variceal type bleeding. Conventional treatment option prior to EUS incorporation had limited efficiency and high adverse events. The characterization and detail provided by EUS gives a cutting edge towards a holistically successful management choice. Data indicates that EUS-guided combination therapy of coil embolization and glue injection has the higher efficacy for the treatment of varices. Conversely, similar treatment options that exist for esophageal and other ectopic variceal bleeding was also outlined. In conclusion, many studies refer that a combination therapy of coil and glue injection under EUS guidance provides higher technical success with fewer recurrence and adverse events, making its adaptation in the guideline extremely favorable. Endo-hepatology is a novel disciple with a promising future outlook, we reviewed topics regarding portal vein access, pressure gradient measurement, and thrombus biopsy that are crucial interventions as alternative of radiological procedures. The purpose of this review is to provide an update on the latest available evidence in the literature regarding the role of EUS in vascular interventions. We reviewed the role of EUS in variceal bleeding in recent studies, especially gastric varices and novel approaches aimed at the portal vein.

Targeting IL-34/MCSF-1R Axis in Colon Cancer.

Colorectal carcinoma (CRC) is one of the most common neoplasias in the Western world and it is still one of the most deadly cancers worldwide mainly due to the fact that metastatic CRC is not responsive to current pharmacologic treatment. Identification of pathways that sustain CRC cell behaviour could help develop effective therapeutic compounds. A large body of evidence indicates that colon carcinogenesis is a dynamic process in which multiple cell types present in the tumor microenvironment either stimulate or suppress CRC cell growth, survival, and diffusion mainly via the production of cytokines. Interleukin-34 (IL-34), a cytokine initially known for its ability to regulate monocyte/macrophage survival and function, is highly produced in human CRC by both cancer cells and non-tumoral cells. IL-34 function is mainly mediated by interaction with the macrophage colony-stimulating factor-1 receptor (MCSF-1R), which is also over-expressed by CRC cells as well as by tumour-associated macrophages (TAMs) and cancer-associated fibroblasts. IL-34-driven MCSF-1R activation triggers several pro-tumoral functions in the colon. In this article, we review the current understanding of the involvement of IL-34 and its receptor in CRC, with particular attention to the available evidence about the IL-34/MCSF-1R axis-mediated regulation of TAMs and the role of IL-34 and MCSF-1R in promoting cancer resistance to chemotherapy and immunotherapy. Manuscript Contribution to the Field: In this review, we highlight the multiple effects of IL-34 and its receptor, macrophage colony-stimulating factor-1 receptor, on the activity of colorectal cancer (CRC) cells and non-tumoral cells, with particular attention to the available data supporting the role of IL-34/MCSF-1R axis in the control of tumor-associated macrophages. The findings summarized in this manuscript could help understand whether targeting IL-34/MCSF-1R can be exploited for therapeutic intervention in CRC.

Digital single-operator cholangioscopy in diagnostic and therapeutic bilio-pancreatic diseases: A prospective, multicenter study.

BACKGROUND AND AIM: Digital single-operator cholangioscopy (D-SOC) is an endoscopic procedure that is increasingly used for the management of bilio-pancreatic diseases. We aimed to investigate the efficacy and safety of D-SOC for diagnostic and therapeutic indications. METHODS: This is a multicenter, prospective study(January 2016-June 2019) across eighteen tertiary centers. The primary outcome was procedural success of D-SOC. Secondary outcomes were: D-SOC visual assessment and diagnostic yield of SpyBite biopsy in cases of biliary strictures, stone clearance rate in cases of difficult biliary stones, rate of adverse events(AEs) for all indications. RESULTS: D-SOC was performed in 369 patients (201(54,5%) diagnostic and 168(45,5%)therapeutic). Overall, procedural success rate was achieved in 360(97,6%) patients. The sensitivity, specificity, PPV, NPV and accuracy in biliary strictures were: 88,5%, 77,3%, 83,3%, 84,1% and 83,6% for D-SOC visual impression; 80,2%, 92,6%, 95,1%, 72,5% and 84,7% for the SpyBite biopsy, respectively. For difficult biliary stones, complete duct clearance was obtained in 92,1% patients (82,1% in a single session). Overall, AEs occurred in 37(10%) cases.The grade of AEs was mild or moderate for all cases, except one which was fatal. CONCLUSION: D-SOC is effective for diagnostic and therapeutic indications.Most of the AEs were minor and managed conservatively, even though a fatal event has happened that is not negligible and should be considered before using D-SOC.

Transesophageal endoscopic ultrasound in the diagnosis of the lung masses: a multicenter experience with fine-needle aspiration and fine-needle biopsy needles.

BACKGROUND AND AIM: Intraparenchymal lung masses inaccessible through bronchoscopy or endobronchial ultrasound guidance pose a diagnostic challenge. Furthermore, some fragile or hypoxic patients may be poor candidates for transbronchial approaches. Endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) offers a potential diagnostic approach to lung cancers adjacent to the esophagus. We aimed to evaluate the feasibility, accuracy, and safety of trans-esophageal EUS-FNA/FNB for tissue sampling of pulmonary nodules. METHODS: We retrospectively analyzed data from patients with pulmonary lesions who underwent EUS-FNA/FNB between March 2015 and August 2021 at eight Italian endoscopic referral centers. RESULTS: A total of 47 patients (36 male; mean age 64.47 ± 9.05 years) were included (22 EUS-FNAs and 25 EUS-FNBs). Overall diagnostic accuracy rate was 88.9% (76.3-96.2%). The sensitivity and diagnostic accuracy were superior for EUS FNB sampling versus EUS-FNA (100% vs. 78.73%); P = 0.05, and (100% vs. 78.57%); P = 0.05, respectively. Additionally, sample adequacy was superior for EUS-FNB sampling versus EUS-FNA (100% vs. 78.5%); P = 0.05. Multivariate logistic regression analysis for diagnostic accuracy showed nodule size at the cutoff of 15 mm (OR 2.29, 1.04-5.5, P = 0.05) and use of FNB needle (OR 4.33, 1.05-6.31, P = 0.05) as significant predictors of higher diagnostic accuracy. There were no procedure-related adverse events. CONCLUSION: This study highlights the efficacy and safety of EUS-FNA/FNB as a minimally invasive procedure for diagnosing and staging peri-esophageal parenchymal lung lesions. The diagnostic yield of EUS-FNB was superior to EUS-FNA.

Endoscopic Ultrasound Plus Endoscopic Retrograde Cholangiopancreatography Based Tissue Sampling for Diagnosis of Proximal and Distal Biliary Stenosis Due to Cholangiocarcinoma: Results from a Retrospective Single-Center Study.

Differentiating between benign and malignant biliary stenosis (BS) is challenging, where tissue diagnosis plays a crucial role. Endoscopic retrograde cholangiopancreatography (ERCP)-based tissue sampling and endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) or biopsy (FNB) are used to obtain tissue specimens from BS. The aim of this retrospective study was to evaluate the diagnostic yield of EUS-FNA/B plus ERCP with brushing or forceps biopsy in BS. All endoscopic procedures performed in patients with BS at our gastroenterology unit were reviewed. The gold standard for diagnosis was histopathology of surgical specimens or the progression of the malignancy at radiological or clinical follow-up. A total of 70 endoscopic procedures were performed in 51 patients with BS. Final endoscopic diagnosis was reached in 96% of the patients and was malignant in 61.7% and benign in 38.3% of cases. Sensitivity, specificity, and diagnostic accuracy were 73.9%, 100%, and 80%, respectively, for EUS-FNA/B; 66.7%, 100%, and 82.5% for ERCP; and 83.3%, 100%, and 87.5% for both procedures carried out in the same session. The combination of EUS and ERCP tissue sampling seems to increase diagnostic accuracy in defining the etiology of BS. Performing both procedures in a single session reduces the time required for diagnostic work-up and optimizes resources.

GATA6 Deficiency Leads to Epithelial Barrier Dysfunction and Enhances Susceptibility to Gut Inflammation.

BACKGROUND AND AIMS: Intestinal barrier dysfunction is a hallmark of inflammatory bowel diseases [IBD], but the mechanisms that lead to such a defect are not fully understood. This study was aimed at characterising the factors involved in the defective barrier function in IBD. METHODS: Transcriptome analysis was performed on colon samples taken from healthy controls [CTR] and IBD patients. Expression of GATA-binding factor 6 [GATA6], a transcription factor involved in intestinal epithelial cell differentiation, was evaluated in colon samples taken from CTR and IBD patients by real-time polymerase chain reaction [PCR] and immunohistochemistry. Intestinal sections of wild-type and Gata6del mice, which exhibit a conditional Gata6 deletion in intestinal epithelial cells and which are either left untreated or receive subcutaneous indomethacin or rectal trinitrobenzene sulphonic acid, were stained with haematoxylin and eosin. In parallel, some Gata6del mice received antibiotics to deplete intestinal flora. Mucosal inflammatory cell infiltration and cytokine production were evaluated by flow cytometry and real-time PCR, respectively, and tight junction proteins were examined by immunofluorescence. Intestinal barrier integrity was assessed by fluorescein isothiocyanate [FITC]-dextran assay. RESULTS: Multiple genes involved in cell commitment/proliferation and wound healing were differentially expressed in IBD compared with CTR. Among these, GATA6 was significantly decreased in the IBD epithelium compared with CTR. In mice, conditional deletion of GATA6 in the intestinal epithelium induced primarily epithelial damage, diminished zonula occludens-1 expression, and enhanced intestinal permeability, ultimately resulting in bacteria-driven local immune response and enhanced susceptibility to gut inflammation. CONCLUSIONS: Reduced expression of GATA6 promotes intestinal barrier dysfunction, thus amplifying intestinal inflammatory pathology.

Difficult biliary cannulation in patients with distal malignant biliary obstruction: An underestimated problem?

BACKGROUND: Failed biliary cannulation still poses a major challenge in patients undergoing Endoscopic Retrograde Cholangiopancreatography (ERCP). To date, there is a lack of data on rates of Difficult Biliary Cannulation (DBC) in patients with distal malignant biliary obstruction (DMBO). MATERIALS: This was a retrospective study (09/2015 to 02/2019) of consecutive patients with DMBO that underwent ERCP in four Italian centers. The primary outcome was to evaluate the rate of DBC. Secondary outcomes were: cannulation failure, rate of adverse events (AEs), the predictive factors for DBC as well as for AEs. RESULTS: A total of 622 patients with DMBO, were included in the study, with 351(56,4%) matching the definition of DBC. One-hundred and two ERCP-related AEs occurred in 97 of 622 patients (15,6%). Subjects with DBC showed a higher risk for AEs (p = 0.02). The lack of pancreatitis prophylaxis (p = 0.03), diagnosis of cholangiocarcinoma (p = 0.02), the use of papillotomy (OR=1.98; 95%CI = 1.14-3.45) and the combination of two or more techniques for cannulation (OR = 2.88; 95%CI = 1.04-7.97) were associated with the occurrence of AEs. CONCLUSIONS: According to the results of this study, patients with DMBO carries a higher rate of DBC thus requiring alternative techniques for biliary drainage. Furthermore, DBC carries a high risk for AEs. Further prospective multicentric studies are needed to confirm these data in this specific subgroup of patients.

The Deubiquitinating Enzyme OTUD5 Sustains Inflammatory Cytokine Response in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: The inflammatory bowel disease [IBD]-associated immune response is marked by excessive production of a variety of inflammatory cytokines, which are supposed to sustain and amplify the pathological process. OTUD5 is a deubiquitinating enzyme, which regulates cytokine production by both innate and adaptive immune cells. Here, we investigated the expression and role of OTUD5 in IBD. METHODS: OTUD5 expression was evaluated in mucosal samples of patients with Crohn's disease [CD], patients with ulcerative colitis [UC], and controls, as well as in mice with trinitrobenzene-sulphonic acid [TNBS]-induced colitis by real-time polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence. Moreover, OTUD5 was assessed in lamina propria mononuclear cells [LPMC] stimulated with inflammatory cytokines. TNF-α, IL-6, and IL-10 were evaluated in LPMCs of IBD patients and in colitic mice transfected with a specific OTUD5 antisense oligonucleotide [AS]. RESULTS: OTUD5 protein, but not RNA, expression was increased in inflamed ileal and colonic mucosal samples of patients with CD and patients with UC as compared with controls. In IBD, OTUD5-expressing cells were abundant in both epithelial and lamina propria compartments, and non-CD3+, HLA-DR+ LPMC were one of the major sources of the protein. OTUD5 expression was enhanced by IFN-γ through a p38/MAPK-dependent mechanism, and the AS-induced knockdown of OTUD5 in LPMCs of IBD patients and colitic mice reduced TNF-α. CONCLUSIONS: Our data show that OTUD5 is overexpressed in both CD and UC and suggest the involvement of such a protein in the amplification of the aberrant cytokine response in IBD.

Tips and tricks for the diagnosis and management of biliary stenosis-state of the art review.

Biliary stenosis may represent a diagnostic and therapeutic challenge resulting in a delay in diagnosis and initiation of therapy due to the frequent difficulty in distinguishing a benign from a malignant stricture. In such cases, the diagnostic flowchart includes the sequential execution of imaging techniques, such as magnetic resonance, magnetic resonance cholangiopancreatography, and endoscopic ultrasound, while endoscopic retrograde cholangiopancreatography is performed to collect tissue for histopathological/cytological diagnosis or to treat the stenosis by insertion of stent. The execution of percutaneous transhepatic drainage with subsequent biopsy has been shown to increase the possibility of tissue diagnosis after failure of the above techniques. Although the diagnostic yield of histopathology and imaging has increased with improvements in endoscopic ultrasound and peroral cholangioscopy, differential diagnosis between malignant and benign stenosis may not be easy in some patients, and strictures are classified as indeterminate. In these cases, a multidisciplinary workup including biochemical marker assays and advanced technologies available may speed up a diagnosis of malignancy or avoid unnecessary surgery in the event of a benign stricture. Here, we review recent advancements in the diagnosis and management of biliary strictures and describe tips and tricks to increase diagnostic yields in clinical routine.

Interleukin-34 promotes tumorigenic signals for colon cancer cells.

Colorectal carcinoma (CRC) is one of the most common forms of malignancy in the Western world. Accumulating evidence indicates that colon carcinogenesis is tightly controlled by tumour-associated immune cells and stromal cells, which can either stimulate or suppress CRC cell growth and survival, mainly via the production of cytokines. Interleukin-34 (IL-34), a cytokine known to regulate mainly monocyte/macrophage survival and function, is highly produced within the CRC microenvironment by several cell types, including cancer cells, tumour-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), and regulates the pro-tumoural functions of such cells. In this article, we summarize the available data supporting the multiple effects of IL-34 in human CRC.

Efficacy and tolerability of very low-volume bowel preparation in patients with inflammatory bowel diseases.

OBJECTIVES: An adequate bowel preparation is essential for a quality colonoscopy. Patients with inflammatory bowel disease (IBD) show low compliance with bowel preparation due to the large volume of lavage solution to be ingested, especially if active symptoms are present, and the frequency of having a colonoscopy. We evaluated the efficacy and tolerability of a very low-volume (VLV) polyethylene glycol (PEG)-based solution in patients with IBD. METHODS: A cohort of 103 consecutive patients, 56 with Crohn's disease and 47 with ulcerative colitis, received a 1-L PEG-based bowel preparation divided into two 500-mL doses taken the evening before and the morning of the colonoscopy, each dose followed by at least another 500-mL of clear fluids. Colon cleansing was scored according to the Boston Bowel Preparation Scale (BBPS) and evaluated in relation to influencing variables. RESULTS: Bowel cleansing was adequate (BBPS ≥ 6) in 88 patients (85.4%). The time interval between the end of bowel preparation and the beginning of colonoscopy and the disease activity significantly affected colon cleansing. Most patients declared a complete intake of lavage solution (99%), the willingness to repeat the same bowel preparation in a future colonoscopy (86.4%), and a good taste assessment. CONCLUSION: The VLV PEG-based bowel preparation is effective and well accepted by IBD patients. As minimizing the volume of lavage solution required, the VLV-bowel preparation here tested could be of choice in subjects who perform periodically colonoscopy or in those who do not tolerate a larger amount of liquids.

A Pharmacological Batch of Mongersen that Downregulates Smad7 is Effective as Induction Therapy in Active Crohn's Disease: A Phase II, Open-Label Study.

BACKGROUND: A recent phase III trial did not confirm the previous clinical and endoscopic improvements seen in patients with Crohn's disease (CD) receiving Mongersen, an oral Smad7 antisense oligonucleotide. Factors accounting for such a discrepancy are unknown. OBJECTIVE: Our objective was to further assess whether Mongersen was effective as induction therapy in active CD and evaluate the in vitro inhibitory effect of various batches of Mongersen used in the previous and present trials on Smad7 expression. METHODS: In a phase II, open-label study, 18 patients with active CD (Crohn's Disease Activity Index [CDAI] score > 220 and evidence of endoscopic lesions) received Mongersen 160 mg/day for 12 weeks. The rates of clinical remission, defined as CDAI < 150, and clinical response, defined as a CDAI score decrease ≥ 100, were evaluated at week 4, 8, and 12. The fraction of circulating CCR9-expressing leukocytes was assessed by flow cytometry. Smad7 expression was evaluated in the human colorectal cancer cell line HCT-116 transfected with different batches of Mongersen using real-time polymerase chain reaction (PCR) and Western blotting, RESULTS: The proportions of patients experiencing clinical remission were 38.9%, 55.6%, and 50.0% at week 4, 8, and 12, respectively. At the same time points, the rates of clinical response were 72.2%, 77.8%, and 77.8%, respectively. Mongersen reduced the percentages of CCR9-expressing CD45+ cells. The batch of Mongersen used in this study, but not two batches used in the phase III study, inhibited Smad7 expression in HCT-116 cells. CONCLUSIONS: The present findings support the clinical benefit of Mongersen in active CD and show that various batches manufactured during the GED0301 program differ in their ability to inhibit in vitro Smad7. TRIAL REGISTRATION NUMBER: NCT02685683; EudraCT 2015-001693-18.

Involvement of Smad7 in Inflammatory Diseases of the Gut and Colon Cancer.

In physiological conditions, the human intestinal mucosa is massively infiltrated with various subsets of immune cells, the activity of which is tightly regulated by several counter-regulatory factors. One of these factors is transforming growth factor-ß1 (TGF-ß1), a cytokine produced by multiple cell types and targeting virtually all the intestinal mucosal cells. Binding of TGF-ß1 to its receptors triggers Smad2/3 signaling, thus culminating in the attenuation/suppression of immune-inflammatory responses. In patients with Crohn's disease and patients with ulcerative colitis, the major human inflammatory bowel diseases (IBD), and in mice with IBD-like colitis, there is defective TGF-ß1/Smad signaling due to high levels of the intracellular inhibitor Smad7. Pharmacological inhibition of Smad7 restores TGF-ß1 function, thereby reducing inflammatory pathways in patients with IBD and colitic mice. On the other hand, transgenic over-expression of Smad7 in T cells exacerbates colitis in various mouse models of IBD. Smad7 is also over-expressed in other inflammatory disorders of the gut, such as refractory celiac disease, necrotizing enterocolitis and cytomegalovirus-induced colitis, even though evidence is still scarce and mainly descriptive. Furthermore, Smad7 has been involved in colon carcinogenesis through complex and heterogeneous mechanisms, and Smad7 polymorphisms could influence cancer prognosis. In this article, we review the data about the expression and role of Smad7 in intestinal inflammation and cancer.