Nat Rev Gastroenterol Hepatol Research Articles

The 2023 Impact of Inflammatory Bowel Disease in Canada: Access to and Models of Care.

Rising compounding prevalence of inflammatory bowel disease (IBD) (Kaplan GG, Windsor JW. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021;18:56-66.) and pandemic-exacerbated health system resource limitations have resulted in significant variability in access to high-quality, evidence-based, person-centered specialty care for Canadians living with IBD. Individuals with IBD have identified long wait times, gaps in biopsychosocial care, treatment and travel expenses, and geographic and provider variation in IBD specialty care and knowledge as some of the key barriers to access. Care delivered within integrated models of care (IMC) has shown promise related to impact on disease-related outcomes and quality of life. However, access to these models is limited within the Canadian healthcare systems and much remains to be learned about the most appropriate IMC team composition and roles. Although eHealth technologies have been leveraged to overcome some access challenges since COVID-19, more research is needed to understand how best to integrate eHealth modalities (i.e., video or telephone visits) into routine IBD care. Many individuals with IBD are satisfied with these eHealth modalities. However, not all disease assessment and monitoring can be achieved through virtual modalities. The need for access to person-centered, objective disease monitoring strategies, inclusive of point of care intestinal ultrasound, is more pressing than ever given pandemic-exacerbated restrictions in access to endoscopy and cross-sectional imaging. Supporting learning healthcare systems for IBD and research relating to the strategic use of innovative and integrative implementation strategies for evidence-based IBD care interventions are greatly needed. Data derived from this research will be essential to appropriately allocating scarce resources aimed at improving person-centred access to cost-effective IBD care.

Exploring novel therapies for coeliac disease: are safe drugs tolerable?

Coeliac disease is the only autoimmune condition where the main environmental trigger, gluten, is known. 1 Catassi C Verdu EF Bai JC Lionetti E Coeliac disease. Lancet. 2022; 399: 2413-2426 Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar Adherence to a strict gluten-free diet for life is essential for intestinal mucosal recovery, alleviation of symptoms, and to reduce the risk of complications such as anaemia, osteoporotic fractures, and small bowel cancer. 2 Kivelä L Caminero A Leffler DA et al. Current and emerging therapies for coeliac disease. Nat Rev Gastroenterol Hepatol. 2020; 18: 1-15 Google Scholar However, strict long-term compliance with a gluten-free diet can be socially inconvenient and expensive. 3 Pinto-Sanchez MI Verdu EF Gordillo MC et al. Tax-deductible provisions for gluten-free diet in Canada compared with systems for gluten-free diet coverage available in various countries. Can J Gastroenterol Hepatol. 2015; 29: 104-110 Crossref PubMed Scopus (21) Google Scholar Moreover, up to 30% of people with coeliac disease continue to have symptoms despite attempting the strict diet 4 Penny HA Baggus EMR Rej A et al. Non-responsive coeliac disease: a comprehensive review from the NHS England National Centre for Refractory Coeliac Disease. Nutrients. 2020; 12: 216 Crossref PubMed Scopus (43) Google Scholar , and almost 80% indicated a desire for therapy to liberalise their diet. 5 De Leon Morilla D Ventoso M Lebovits J et al. Patients' risk tolerance for non-dietary therapies in celiac disease. Clin Gastroenterol Hepatol. 2022; 20: 2647-2649 Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar Therefore, emerging therapies to support the gluten-free diet, including those targeting induction of tolerogenic mechanisms, are currently being investigated in clinical trials. 6 Pinto-Sanchez MI Silvester JA Lebwohl B et al. Society for the Study of Celiac Disease position statement on gaps and opportunities in coeliac disease. Nat Rev Gastroenterol Hepatol. 2021; 18: 875-884 Crossref PubMed Scopus (13) Google Scholar Safety and tolerability of KAN-101, a liver-targeted immune tolerance therapy, in patients with coeliac disease (ACeD): a phase 1 trialKAN-101 has an acceptable safety profile in patients with coeliac disease with no dose-limiting toxicities and no maximum tolerated dose was observed. Rapid systemic clearance of KAN-101 was observed and no accumulation on repeated dosing. A future study will evaluate the safety and efficacy, including biomarker responses with a gluten challenge, of KAN-101 at doses 0·6 mg/kg and greater in patients with coeliac disease. Full-Text PDF

Long-term disease course, cost and prognosis of inflammatory bowel disease: epidemiological studies of a European and a Danish inception cohort.

Long-term disease course, cost and prognosis of inflammatory bowel disease: epidemiological studies of a European and a Danish inception cohort.

N19 Fear of not being accepted: a synthesis of qualitative experiences of children and adolescents living with IBD

Abstract Background There is an increasing number of paediatric and adolescent patients being diagnosed with Inflammatory Bowel Disease (IBD) 1. Being diagnosed at an early age can have a detrimental effect on a child’s development, so the need for support is vital. Adult experiences of living with IBD are known 2 , but very little is known about paediatric experiences. This literature review aimed to identify the paediatric and adolescent experiences of living with IBD and explore how IBD impacts their life. Methods A search was performed on following databases: Medline, CINAHL, and British Nursing Index. The inclusion criteria were: IBD, age under 18 years old, English language, primary qualitative research, and a publication date between 2016-2021. Out of the 43 papers identified, only three were selected as they met the inclusion/exclusion criteria. A qualitative synthesis of evidence was conducted, and the data was reinterpreted 3. Results Among the three papers, there was a dominant theme about the ‘Fear of not being accepted'. This overarching theme revolved around peer acceptance, and included two main themes: ‘Fear of disclosure' and 'How do I fit in?', as patients did not want to disclose their condition and expressed their desire to be viewed as normal. Throughout their experiences, children and adolescents expressed embarrassment as the primary feeling since living with IBD. Having IBD as a child or adolescent could adversely affect their psycho-social development, especially during their sexual development, affecting their romantic relationships and interactions with other people. The fear of not being accepted led participants to feel unattractive and apprehensive when forming new relationships. Conclusion It is imperative for children and adolescents to feel accepted, to feel comfortable disclosing their illness, and to feel equal to their peers. Children and adolescents face a variety of psycho- socio- emotional challenges living with IBD. Due to the limited number of studies that have explored the challenges that paediatrics and adolescents encounter, the need for more evidence is crucial. More evidence on children experiences of living with IBD would help healthcare professionals understand the impact of illness, and develop strategies to support children and adolescents living with IBD to minimise the fear of social stigma and rejection. 1. Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. 2015;12(12). 2. Fourie S, Jackson D, Aveyard H. Living with Inflammatory Bowel Disease: A review of qualitative research studies. Int J Nurs Stud. 2018;87:149-156. 3. Thomas J ;Harden A. Methods for the Thematic Synthesis of Qualitativeresearch in Sistematic Reviews.; 2007.

CEND-1: a game changer for pancreatic cancer chemotherapy?

The clinical development of systemic therapies for patients with metastatic pancreatic ductal adenocarcinoma has been a series of disappointments. Immunotherapy has been largely ineffective, targeted therapy only works in a few patients, and chemotherapy is less effective than in other cancer types. 1 Springfeld C Jäger D Büchler MW et al. Chemotherapy for pancreatic cancer. Presse Med. 2019; 48: e159-e174 Crossref PubMed Scopus (83) Google Scholar There are more than 530 000 deaths worldwide each year, ranking pancreatic ductal adenocarcinoma as the fifth most common cause of cancer death. In the USA there has been a small improvement in 5-year survival for all stages, increasing from approximately 5% to 11% in the past three decades, but this increase is insignificant when compared with other tumour types. Pancreatic ductal adenocarcinoma is characterised by a dense desmoplastic stroma that might contribute to chemotherapy resistance. 2 Hosein AN Brekken RA Maitra A Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat Rev Gastroenterol Hepatol. 2020; 17: 487-505 Crossref PubMed Scopus (228) Google Scholar Cancer-associated fibroblasts secrete TGF-β which promotes the stromal matrix and αvβ5 integrin expression involved in cancer cell adhesion, migration, and proliferation. In The Lancet Gastroenterology & Hepatology, Andrew Dean and colleagues 3 Dean A Gill S McGregor M Broadbridge V Järveläinen HA Price T Dual αV-integrin and neuropilin-1 targeting peptide CEND-1 plus nab-paclitaxel and gemcitabine for the treatment of metastatic pancreatic ductal adenocarcinoma: a first-in-human, open-label, multicentre, phase 1 study. Lancet Gastroenterol Hepatol. 2022; (published online July 5.)https://doi.org/10.1016/S2468-1253(22)00167-4 Summary Full Text Full Text PDF PubMed Google Scholar report the results from a phase 1 study in patients with untreated metastatic pancreatic ductal adenocarcinoma that might be a game changer at enhancing tumour delivery of standard chemotherapy by coadministration with the CEND-1 cyclic peptide. Dual αV-integrin and neuropilin-1 targeting peptide CEND-1 plus nab-paclitaxel and gemcitabine for the treatment of metastatic pancreatic ductal adenocarcinoma: a first-in-human, open-label, multicentre, phase 1 studyCEND-1 with nab-paclitaxel and gemcitabine has an acceptable safety profile, with no dose-limiting toxicities and encouraging activity. Adverse events were generally consistent with those seen with nab-paclitaxel and gemcitabine. Further randomised trials to determine the efficacy of CEND-1 are warranted. Full-Text PDF

Immunotherapy in colorectal cancer: an unmet need deserving of change.

The efficacy of immunotherapy in colorectal cancer is currently restricted to patients with metastatic colorectal cancer presenting deficient mismatch repair (dMMR) or microsatellite instability (MSI). So far, neither immunotherapy agents as monotherapy nor immunotherapy-based combinations have shown benefit for metastatic colorectal cancer with proficient mismatch repair (pMMR) or microsatellite stability (MSS), which are mostly immunologically cold. 1 Ganesh K Stadler ZK Cercek A et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol. 2019; 16: 361-375 Crossref PubMed Scopus (480) Google Scholar However, the immune landscape of colorectal cancer is complex and heterogenous, and the development of these treatment strategies must consider, not only the histological context, but also its potential distinctive features. 2 Guinney J Dienstmann R Wang X et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015; 21: 1350-1356 Crossref PubMed Scopus (2403) Google Scholar In The Lancet Oncology, Carlotta Antoniotti and colleagues 3 Antoniotti C Rossini D Pietrantonio F et al. Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 2022; (published online May 27.)https://doi.org/10.1016/S1470-2045(22)00274-1 Summary Full Text Full Text PDF PubMed Google Scholar report the results of the addition of atezolizumab to front-line FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab (the atezolizumab group) compared with FOLFOXIRI plus bevacizumab (the control group) in patients with metastatic colorectal cancer from the phase 2 AtezoTRIBE trial, irrespective of tumour microsatellite status. The superiority of FOLFOXIRI plus bevacizumab over FOLFIRI (leucovorin, fluorouracil, and irinotecan) plus bevacizumab as front-line treatment of metastatic colorectal cancer was previously demonstrated in the phase 3 TRIBE trial. Drawing from this rationale, in this multicentre, academic study, the investigators raised the question of whether the restoration of the anticancer immunity through inhibition of the PD-1–PD-L1 axis enhances efficacy of an upfront intensified chemotherapy regimen. The underlying hypothesis was that chemotherapy can induce tumour cells to release more neoantigens, leading to immunogenic cell death and activation of CD8 T lymphocytes, while bevacizumab-mediated vasculature normalisation upon VEGF or VEGFR blockade promotes increased tumour-infiltrating lymphocytes and activation of effector immune cells. 4 Kanterman J Sade-Feldman M Biton M et al. Adverse immunoregulatory effects of 5FU and CPT11 chemotherapy on myeloid-derived suppressor cells and colorectal cancer outcomes. Cancer Res. 2014; 74: 6022-6035 Crossref PubMed Scopus (113) Google Scholar , 5 Terme M Pernot S Marcheteau E et al. VEGFA–VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 2013; 73: 539-549 Crossref PubMed Scopus (413) Google Scholar Given that no significant benefit has been derived from the combination of immunotherapy with non-intensified regimens, 6 Grothey A Tabernero J Arnold D et al. Fluoropyrimidine (FP) + bevacizumab (BEV) + atezolizumab vs FP/BEV in BRAFwt metastatic colorectal cancer (mCRC): findings from Cohort 2 of MODUL—a multicentre, randomized trial of biomarker-driven maintenance treatment following first-line induction therapy. Ann Oncol. 2018; 29: viii714-viii715 Google Scholar , 7 Lenz HJ Parikh AR Spigel DR et al. Nivolumab (NIVO) + 5-fluorouracil/leucovorin/oxaliplatin (mFOLFOX6)/bevacizumab (BEV) versus mFOLFOX6/BEV for first-line (1L) treatment of metastatic colorectal cancer (mCRC): phase 2 results from CheckMate 9X8. Proc Am Soc Clin Oncol. 2022; 40 (abstr).: 8 Crossref PubMed Google Scholar the use of FOLFOXIRI is a rational partner in an untreated RAS-mutated enriched metastatic colorectal cancer population. Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trialThe addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab is safe and improved progression-free survival in patients with previously untreated metastatic colorectal cancer. Full-Text PDF

Abstract 5712: Dietary polyphenols as BRD7 and 9 inhibitors for cancer interception

Abstract Introduction Epigenetic mechanisms play an important role in the initiation and advancement of colorectal cancer (CRC) and other malignancies due, in part, to deregulated bromodomain (BRD) functions1,2. We examined compounds from natural sources as BRD7/9 inhibitors, seeking lead candidates outside of the widely studied bromodomain and extraterminal (BET) family3. Methods As reported4,5, docking in silico involved STRAP and AutoDock Vina, ligand-protein interactions employed PDBePISA and LPC/CSU, and BROMOscan®-Bromodomain arrays were used to screen for BRD7/9 interacting compounds. BRD7/9 inhibitors also were assessed by isothermal titration calorimetry (ITC) and by anticancer activities in human colon cancer cells. Results Docking in silico identified several dietary polyphenols as potential BRD7/9 inhibitors, with binding energies ≤ -8.0 kcal/mol. BROMOscan® and ITC experiments prioritized aspalathin, orientin, epigallocatechin-3-gallate, quercetin and equol for further investigation. Treatment with selected polyphenols mimicked BRD7/9 siRNA-mediated knockdown in reducing colon cancer cell viability and inhibiting colony formation, leading to DNA damage and apoptosis induction. Normal colonic epithelial cells were unaffected by the treatments, signifying cancer-specific targeting. These findings suggest that dietary polyphenols can recognize and target BRD7/9 proteins for potential cancer interception. Acknowledgements Research supported in part by NCI grant CA122959, the John S. Dunn Foundation, and a Chancellor's Research Initiative.1)Jung G et al., Nat Rev Gastroenterol Hepatol 2020;17:111-130. 2)Fujisawa T, Filippakopoulos P. Nat Rev Mol Cell Biol 2017;18:246-262.3)Damiani E et al., J Cancer Prev 2020;25:189-203. 4)Rajendran P et al., Cancer Res 2019;79:918-927. 5)Kapoor S et al., Cancers (Basel) 2021;13:1438. Citation Format: Sabeeta Kapoor, Roderick H. Dashwood. Dietary polyphenols as BRD7 and 9 inhibitors for cancer interception [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5712.

Endoscopic Ultrasound-guided Portal Pressure Gradient Measurement Is Technically Successful and Safe Without Deep Sedation: A Proof-of-Concept Case Series

The hepatic venous pressure gradient (HVPG), which is the difference between the wedged (WHVP) and free hepatic vein pressures (FHVP), is the gold standard to evaluate portal hypertension in patients with cirrhosis 1 Bosch J Abraldes JG Berzigotti A et al. The clinical use of HVPG measurements in chronic liver disease. Nat Rev Gastroenterol Hepatol. 2009; 6: 573-582 Crossref PubMed Scopus (436) Google Scholar . Unfortunately, there currently exists a gap in the evaluation of patients with pre-sinusoidal portal hypertension, where HVPG is known to underestimate portal pressure. Endoscopic ultrasound-guided portal pressure gradient measurement (EUS-PPG) has recently brought back the possibility of safely obtaining direct portal vein pressure (PVP) and represents a long-awaited less-invasive diagnostic tool for patients with suspected pre-sinusoidal portal hypertension.

Ultraprocessed Foods and the Risk of Inflammatory Bowel Disease: Is it Time to Modify Diet?

Intake of specific dietary macro- and micronutrients has been implicated in modulating the risk of inflammatory bowel disease (IBD)(Nat Rev Gastroenterol Hepatol 2018;15:525-535). Recent epidemiological and pre-clinical studies have additionally examined the impact of non-nutritional dietary components on IBD. Ultra-processed foods (UPF), as defined by the NOVA classification, are foods of mainly industrial origin, often containing little or no whole foods but many ingredients including food additives such as artificial colors and flavors, stabilizers, emulsifiers, and preservatives(Public Health Nutr 2019;22:936-941). The objective of the study by Narula et al (BMJ 2021;374:n1554) was to examine the association between intake of UPF and the risk of developing IBD.

Infigratinib in pretreated cholangiocarcinoma with FGFR2 fusions or rearrangements

Although they are the second leading cause of primary liver cancer after hepatocellular carcinoma, biliary tract cancers are rare tumours (excluding endemic areas in Asia), with less than six new cases per 100 000 people each year. 1 Banales JM Cardinale V Carpino G et al. Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016; 13: 261-280 Crossref PubMed Scopus (561) Google Scholar Biliary tract cancers are classified into three subtypes on the basis of their anatomical origin: intrahepatic cholangiocarcinoma (the incidence of which is increasing in the USA and Europe), extra-hepatic cholangiocarcinoma, and gallbladder carcinoma. Prognosis for patients with biliary tract cancers is poor (5-year overall survival <20%), mainly due to late diagnosis, frequently at an advanced stage (in around 65% of patients). 1 Banales JM Cardinale V Carpino G et al. Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016; 13: 261-280 Crossref PubMed Scopus (561) Google Scholar Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 studyInfigratinib has promising clinical activity and a manageable adverse event profile in previously treated patients with locally advanced or metastatic cholangiocarcinoma harbouring FGFR2 gene fusions or rearrangements, and so represents a potential new therapeutic option in this setting. Full-Text PDF

Liver Field during Immunotherapy of Hepatocellular Carcinoma: Some Like It Hot

Liver Field during Immunotherapy of Hepatocellular Carcinoma: Some Like It Hot

Recent Advances in Hepatocellular Carcinoma Treatment

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related morbidity and mortality worldwide, largely as a result of 3 main factors: (1) competing risk of cirrhosis, which accompanies 80% to 90% of HCC diagnoses; (2) ineffective early detection programs; and (3) a historical lack of effective therapies, specifically for patients with intermediate- or advanced-stage disease. 1 Yang J.D. Hainaut P. Gores G.J. et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019; 16: 589-604 Crossref PubMed Scopus (718) Google Scholar Although the burden of HCC is projected to increase, several recent advances in HCC therapeutics allow for optimism as new treatment algorithms are developed to improve patient quantity and quality of life.

Outcomes of Fecal Microbiota Transplantation in Patients With Inflammatory Bowel Diseases and Recurrent Clostridioides difficile Infection

Outcomes of Fecal Microbiota Transplantation in Patients With Inflammatory Bowel Diseases and Recurrent Clostridioides difficile Infection

Inflammatory Bowel Diseases and COVID-19: The Invisible Enemy

Inflammatory Bowel Diseases and COVID-19: The Invisible Enemy

Subsets of mononuclear phagocytes are enriched in the inflamed colons of patients with IBD

BackgroundMyeloid cells, especially mononuclear phagocytes, which include monocytes, macrophages and dendritic cells (DC), play vital roles in innate immunity, and in the initiation and maintenance of adaptive immunity. While T cell-associated activation pathways and cytokines have been identified and evaluated in inflammatory bowel disease (IBD) patients (Neurath, Nat Rev Gastroenterol Hepatol 14:269–78, 1989), the role of mononuclear phagocytes are less understood. Recent reports support the crucial role of DC subsets in the development of acute colitis models (Arimura et al., Mucosal Immunol 10:957–70, 2017), and suggest they may contribute to the pathogenesis of ulcerative colitis (UC) by inducing Th1/Th2/Th17 responses (Matsuno et al., Inflamm Bowel Dis 23:1524–34, 2017).ResultsWe performed in silico analysis and evaluated the enrichment of immune cells, with a focus on mononuclear phagocytes in IBD patient colonic biopsies. Samples were from different gut locations, with different levels of disease severity, and with treatment response to current therapies. We observe enrichment of monocytes, M1 macrophages, activated DCs (aDCs) and plasmacytoid dendritic cells (pDCs) in inflamed tissues from various gut locations. This enrichment correlates with disease severity. Additionally, the same mononuclear phagocytes subsets are among the top enriched cell types in both infliximab and vedolizumab treatment non-responder samples. We further investigated the enrichment of selected DC and monocyte subsets based on gene signatures derived from a DC- and monocyte-focused single cell RNA-seq (scRNA-seq) study (Villani et al., Science 356:eaah4573, 2017), and verified enrichment in both inflamed tissues and those with treatment resistance. Moreover, we validated an increased mononuclear phagocyte subset abundance in a Dextran Sulphate Sodium (DSS) induced colitis model in C57Bl/6 mice representative of chronic inflammation.ConclusionsWe conducted an extensive analysis of immune cell populations in IBD patient colonic samples and identified enriched subsets of monocytes, macrophages and dendritic cells in inflamed tissues. Understanding how they interact with other immune cells and other cells in the colonic microenvironment such as epithelial and stromal cells will help us to delineate disease pathogenesis.

Immunobiology of cholangiocarcinoma.

SummaryCholangiocarcinoma (CCA) represents a heterogeneous group of epithelial tumours that are classified according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Although surgical resection and liver transplantation following neoadjuvant therapy are potentially curative options for a subset of patients with early-stage disease, the currently available medical therapies for CCA have limited efficacy. Immunotherapeutic strategies such as immune checkpoint blockade (ICB) harness the host immune system to unleash an effective and durable antitumour response in a subset of patients with a variety of malignancies. However, response to ICB monotherapy has been relatively disappointing in CCA. CCAs are desmoplastic tumours with an abundant tumour immune microenvironment (TIME) that contains immunosuppressive innate immune cells such as tumour-associated macrophages and myeloid-derived suppressor cells. A subset of CCAs may be classified as immune ‘hot’ tumours with a high density of CD8+ T cells and enhanced expression of immune checkpoint molecules. Immune ‘hot’ tumour types are associated with higher response rates to ICB. However, the suboptimal response rates to ICB monotherapy in human clinical trials of CCA imply that the preponderance of CCAs are immune ‘cold’ tumours with a non-T cell infiltrated TIME. An enhanced comprehension of the immunobiology of CCA, particularly the innate immune response to CCA, is essential in the effort to develop effective combination immunotherapeutic strategies that can target a larger subset of CCAs.

Outcomes based on age in the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC).

4090Background: The incidence of HCC generally increases with age, although the age of onset varies depending on disease etiology and geographic region (Yang, Nat Rev Gastroenterol Hepatol 2010). I...

PTH-006 Computer-Aided Lesion Measurement in Capsule Endoscopy Images

Introduction A novel image segmentation algorithm is applied & assessed for lesion size measurements in capsule endoscopy (CE). It is based solely on colour features of CE lesions. Methods The lesion images are available online from KID database (Dataset 1). 1 Size reference standards were made by manual annotation. The proposed algorithm uses the CIE-Lab colour representation instead of the standard RGB used in CE. 1 The components of this space represent lightness (L), the quantity of red (a > 0) or the quantity of green (-a >0), the quantity of yellow (b > 0) or the quantity of blue (-b >0) of a pixel. Initially, the user specifies a point on the lesion of interest (with a single click). Simple Linear Iterative Clustering (SLIC) is applied to group the pixels of similar colour into contiguous regions, called superpixels. 2 Subsequently the superpixels are clustered using the k-means approach into three clusters using information from component a. Thereafter, each superpixel neighbouring to the superpixel that contains the user-specified point is represented by a colour vector (a, b). The proposed algorithm estimates a) its Euclidean distance d1 from the respective vector of the selected superpixel, b) its Euclidean distance d2 from the mean of the respective vectors obtained from all superpixels that do not belong to the cluster of the selected superpixel. Then, the neigerpixel is considered to belong to the abnormal region of interest if d1 Results Seven types of GI lesions were used for evaluation. The measurement accuracy was assessed by comparing the area of the lesion (as identified by the method) with the reference standard area of each lesion. Average accuracies obtained for the measurement of angioectasias, aphthae, chylous cysts, lymphangiectasias, polypoid lesions, stenoses, and ulcers are 98.6%, 92.8%, 94.3%, 99.1%, 80.0%, 82.9%, and 94.8%, respectively. Comparatively, using the well-known colour space proposed by Ohta (I1I2I3) for image segmentation instead of CIE-Lab 2 the results are lower; 97.1%, 92.1%, 92.6%, 97.8%, 75.2%, 78.8%, and 91%, respectively. Conclusion A novel algorithm was proposed & evaluated for accurate computer-aided size measurement of lesions in CE. The overall accuracy on a public dataset was ~92%. This algorithm can be incorporated as a novel measurement tool in contemporary CE reading software. References 1 Iakovidis DK, Koulaouzidis A. Software for enhanced video capsule endoscopy: challenges for essential progress. Nat Rev Gastroenterol Hepatol . 2015; 12 :172–8. 2 Achanta R, et al . Slic superpixels compared to state-of-the-art superpixel methods. IEEE Transactions on Pattern Analysis and Machine Intelligence . 2012; 34 :2274–8. Disclosure of Interest None Declared

Outcome of a public consultation on the draft guidance of the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) on the scientific requirements for health claims related to the immune system, the gastrointestinal tract and defence against pathogenic microorganisms

Outcome of a public consultation on the draft guidance of the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) on the scientific requirements for health claims related to the immune system, the gastrointestinal tract and defence against pathogenic microorganisms

MafG, A Novel Target of FXR that Regulates Bile Acid Homeostasis

Bile acids, the major products of hepatic cholesterol catabolism, are indispensable for lipid absorption and cholesterol metabolism. Systemic bile acid metabolism is tightly regulated by various nuclear receptors, including farnesoid X receptor (FXR; Nat Rev Gastroenterol Hepatol 2014;11:55–67). In humans, approximately 500 mg of cholesterol are converted into bile acids every day via the classical pathway initiated by CYP7A1 or an alternative pathway through CYP7B1 (Nat Rev Drug Discov 2008;7:678–693). CYP8B1 is responsible for cholic acid synthesis (J Clin Invest 2002;110:1191–1200). FXR signaling regulates bile acid synthetic pathways by repressing both Cyp7a1 and Cyp8b1 expression. FXR-mediated small heterodimer partner (Shp) induction is a mechanism of the repression of Cyp7a1 expression. However, bile acid synthetic pathways are also regulated by SHP-independent mechanisms. In a recent article published in Cell Metabolism, de Aguiar Vallim et al discovered a novel FXR-regulated transcriptional repressor, MafG (V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog G) as an important regulator of negative feedback mechanism of bile acids. MafG belongs to small MAF proteins, which is a bidirectional transcriptional regulator. On 1 hand, MafG interacts with transcription factors Nrf2 and HIF1α to increase their transcriptional activity (Biochim Biophys Acta 2008; 1783:1847–1856; FEBS Lett 2008;582:2357–2364). On the other hand, MafG binds to DNA as a homodimer (or sometimes as a heterodimer), which leads to transcriptional repression owing to a lack of transactivation domain (Mol Cell Biol 2006;26:4652–4663). To find the repression mechanism of bile acid synthesis genes by FXR, de Aguiar Vallim et al focused on transcriptional repressors, such as MafG. The ChIP-seq analysis of hepatic FXR from 2 different datasets determined four putative transcriptional repressor genes expressed in the liver MafG, cysteine-rich intestinal protein 2 (Crips2), zinc finger protein 385a (Zfp385a), and Shp. In vivo overexpression of MafG, introduced by injection of adenoviral vector, repressed the expression of Cyp8b1, but not Cyp7a1, in the liver. Crip2 or Zfp385a overexpression did not change either Cyp7a1 or Cyp8b1 expression. Interestingly, MafG overexpression changed the composition of bile acid pool, but not the pool size. The analysis of the hepatic gene profile showed the significant reductions in the expression of bile acid synthesis genes including Cyp7b1 and Cyp27a1 by MafG overexpression. In contrast, the loss-of-gene studies using antisense oligonucleotides or in MafG heterozygous mice showed increased expression of bile acid synthesis genes including Cyp8b1, Cyp7b1, and Cyp27a1, but not Cyp7a1. This confirms that MafG is a repressor of cholic acid synthesis as well as a key regulator of bile acid metabolism. Then, the study investigated to identify MafG binding sites (MAREs) in bile acid synthetic genes through MafG ChIP-seq analysis. The ChIP-seq analysis identified MAREs at loci for multiple bile acid synthetic genes, including Cyp8b1, Cyp27a1, Cyp7b1, Acox2, Akr1d1, Akr1c14, Ntcp, Hsd17b4, and Scp2, but not Cyp7a1. Taken together, the present study demonstrates that FXR signaling regulates bile acid synthesis gene expression through induction of a transcriptional repressor MafG, a novel FXR target gene. MafG binds to MAREs on the promoter and/or intronic regions of multiple bile acid synthetic genes and suppresses their transcription, thereby regulating the bile acid synthesis.