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Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolising enzyme that induces immune tolerance by modulating T-cell responses. Carcinomas may create an immunosuppressive state via IDO1 expression. Here we examined a possible contribution of IDO1 on this phenomenon and investigated whether IDO1 has prognostic value in colorectal cancer (CRC).Methods: IDO1 expression was investigated by quantitative PCR and western blotting in three colon cancer cell lines, in basal state and after interferon (IFN)-γ stimulation. Semi-quantitative immunohistochemistry was used to evaluate IDO1 expression in 265 pT1-4N0-2Mx-staged CRCs. Results were related to clinical variables and correlated with amounts of CD3(+) and CD8(+) T lymphocytes, which were quantitatively evaluated using image analysis.Results: In vitro expression of IDO1 depended on IFN-γ stimulation. Higher IDO1 expression at the tumour invasion front was an independent adverse prognostic factor in pT1-4N1Mx-staged CRC. It was associated with overall survival (P=0.001) and with metachronous metastases (P=0.018). IDO1 expression was not associated with the presence of CD3(+) or CD8(+) T lymphocytes.Conclusion: Higher IDO1 expression at the tumour invasion front is involved in CRC progression and correlates with impaired clinical outcome, suggesting that IDO1 is an independent prognostic indicator for CRC. [ABSTRACT FROM AUTHOR]

Background: Extensive esophageal endoscopic submucosal dissections (ESDs) without preventive measures carry a high risk of stricture. Oral steroids and local injection of triamcinolone acetonide have proven to be effective in Asia for the prevention of esophageal stricture. This study aimed to assess the efficacy of a systematic steroid administration protocol for stricture prevention in a Western center., Methods: A retrospective review was conducted of all esophageal ESDs performed at H.U.B. Erasme Hospital, Brussels between 2016 and 2022. Injection of triamcinolone was performed for mucosal defects between 50% and 89% of the circumference. We added oral corticosteroids for patients with resections of ≥90% of the circumference. The primary outcome was the incidence of symptomatic stenosis at 3 months. Secondary outcomes included the cumulative stricture rate assessed by endoscopy within 6 months of ESD. Potential risk factors of stricture were evaluated with univariate and multivariate analysis., Results: 111 patients underwent 130 esophageal ESDs, with 59 patients receiving triamcinolone acetonide local injection and eight receiving local and oral corticosteroids. The primary outcome demonstrated a stricture incidence of 8.4%. The cumulative stricture rate assessed by endoscopy within 6 months of ESD was 10.4%. A mucosal defect of ≥60 mm in length was associated with a 15-fold increased risk of stricture, with circumferential extent also identified as being an independent prognostic factor for stricture., Conclusions: Our protocol led to a low stricture rate, even after extensive resection. As a single session treatment without systemic side effects, triamcinolone injection could provide benefits as a preventive method after large esophageal resections., Competing Interests: A. Lemmers: speaker's fees to Institution from Erbe, consultancy fees to Institution for Boston Scientific, research grant to Institution from Medtronic., (Thieme. All rights reserved.)

Background: Multidisciplinary team (MDT) meetings aim to optimize patient management. We evaluated the impact of MDT discussions on the management and diagnosis of focal pancreatic lesions in a single tertiary center., Methods: All patients with an initial diagnosis of solid or cystic pancreatic lesion discussed in our institution's MDT meeting on pancreatic diseases between January 1, 2020, and December 31, 2021, were included. The impact of MDT discussion on patient management, defined as a modification of the initially proposed therapeutic plan after MDT discussion, as well as the criteria leading to this modification, were the primary outcomes. Impact on diagnosis was the secondary outcome., Results: A total of 522 patients were included. Of these, 185 (35.4%) and 337 (64.6%) had an initial diagnosis of cystic or solid lesion, respectively. The most common referral query was regarding the management plan (349/522; 66.9%). Endoscopy was the procedure most often proposed before MDT discussion (109/522; 20.9%). Overall, the MDT discussion led to modification of the management plan in 377/522 patients (72.2%), with a statistically significant difference between cystic and solid lesions (63.2% vs. 77.2%; P<0.001). Management modifications were mainly driven by revision of cross-sectional radiological images. MDT discussion led to modification of the diagnosis in 92/522 patients (17.6%), with a significant difference regarding cystic lesions (35.7% vs. 7.7%; P<0.001)., Conclusion: MDT discussion impacts the management of patients with cystic and solid pancreatic lesions, leading to a modification of the initially proposed management in two-thirds of them, mainly through revision of cross-sectional imaging., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Radiotherapy is part of the standard of care treatment for a great majority of cancer patients. As a result of radiation, both tumor cells and the environment around them are affected directly by radiation, which mainly primes but also might limit the immune response. Multiple immune factors play a role in cancer progression and response to radiotherapy, including the immune tumor microenvironment and systemic immunity referred to as the immune landscape. A heterogeneous tumor microenvironment and the varying patient characteristics complicate the dynamic relationship between radiotherapy and this immune landscape. In this review, we will present the current overview of the immunological landscape in relation to radiotherapy in order to provide insight and encourage research to further improve cancer treatment. An investigation into the impact of radiation therapy on the immune landscape showed in several cancers a common pattern of immunological responses after radiation. Radiation leads to an upsurge in infiltrating T lymphocytes and the expression of programmed death ligand 1 (PD-L1) which can hint at a benefit for the patient when combined with immunotherapy. In spite of this, lymphopenia in the tumor microenvironment of 'cold' tumors or caused by radiation is considered to be an important obstacle to the patient's survival. In several cancers, a rise in the immunosuppressive populations is seen after radiation, mainly pro-tumoral M2 macrophages and myeloid-derived suppressor cells (MDSCs). As a final point, we will highlight how the radiation parameters themselves can influence the immune system and, therefore, be exploited to the advantage of the patient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Iliadi, Verset, Bouchart, Martinive, Van Gestel and Krayem.)

Video 1Difficult choice between anterograde versus retrograde motorized spiral enteroscopy based on video-capsule endoscopy findings to target a lesion illustrated in a clinical case., (© 2022 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc.)

Objective: Alcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH). A multidimensional study of the clinical, histological and molecular features of these subtypes is lacking., Design: Two large cohorts of patients were recruited in an international, observational multicentre study: a retrospective cohort of patients with ndALD (n=110) and a prospective cohort of patients with AH (n=225). Clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis of both disease phenotypes were performed., Results: Age and mean alcohol intake were similar in both groups. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma-glutamyl transferase levels than in ndALD patients. Patients with AH demonstrated profound liver failure and increased mortality. One-year mortality was 10% in ndALD and 50% in AH. Histologically, steatosis grade, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and ductular reaction were more frequent among AH patients. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. While ndALD was characterised by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism., Conclusions: Despite comparable alcohol intake, AH patients presented with worse liver function compared with ndALD patients. Bilirubinostasis, severe fibrosis and ductular reaction were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared with ndALD patients., Competing Interests: Competing interests: JAl has received support to attend conferences from Gilead. BS has been consulting for Ferring Research Institute, Intercept Pharmaceuticals, HOST Therabiomics and Patara Pharmaceuticals. BS’s institution UC San Diego has received grant support from BiomX, NGM Biopharmaceuticals, CymaBay Therapeutics and Synlogic Operating Company., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: The authors declare that they have no conflict of interest.

A woman, followed for chronic myeloid leukaemia, presented for a routine examination. Her medical history was marked by recurrent Helicobacter pylori gastritis and polymyalgica rheumatica. She was under dasatinib and hormone replacement therapy. At clinical examination, she complained about digestive disorders with altered bowel habits. Biology, including leucocyte count, remained normal. A colonoscopy was performed. Endoscopic examination revealed a colonic mucosa covered by multiple tiny nodular lesions (<5mm) from the hepatic angle to the sigmoid and with an abnormal pattern of vascularisation (Fig. 1). Staged biopsies were taken. Microscopic examination revealed discrete achi-tectural distortions. The stroma contained a mixed inflammatory infiltrate composed of neutrophils, eosinophils and lymphocytes. Immunohistochemistry for CD3, CD5, CD20 and CD79 did not bring arguments for a lymphoma. There were no malignant or dysplastic cells. (Fig. 2). What is your diagnosis?, Competing Interests: The authors declare that they have no conflict of interest, (© Acta Gastro-Enterologica Belgica.)

Competing Interests: None

Background and study aims  Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease worldwide with limited treatment options. Duodenal mucosal resurfacing (DMR) has been associated with improvement in glycaemic parameters and liver function tests (LFTs) in type 2 diabetes. This study aimed to assess the effect of DMR in patients with NASH. Patients and methods  This was a single-center, open-label pilot study. Patients with definite, biopsy-proven NASH (nonalcoholic fatty liver disease activity score [NAS] ≥ 4) underwent a single DMR procedure followed by a 2-week postprocedural diet, without lifestyle intervention. The primary outcome was either resolution of NASH with no worsening of fibrosis or improvement in fibrosis (≥ 1 stage) with no worsening of NASH at 12 months. Secondary outcomes were changes in key histological parameters of NASH, surrogate markers of fibrosis, LFTs, and metabolic factors at 12 months. Results  From 2017 to 2019, 14 patients underwent successful DMR, of whom 11 were included in the analysis. After 12 months, no resolution of NASH was observed, while three patients (27 %) had marginal improvement in fibrosis with no worsening of NASH. Serious adverse events related to the procedure were reported in two patients out of 14 (14 %). Neither weight loss nor improvement in NAS score, or in the other secondary outcomes, were observed at 12 months. Conclusions  In this small and heterogenous study population, we found that DMR, in the absence of lifestyle intervention, did not induce NASH resolution and marginally improved liver fibrosis at 12 months., Competing Interests: Competing interests This investigator-initiated study was supported in part through a grant from Fractyl Inc., Lexington, Massachusetts, United States. Dr. Devière receives institutional research support for IRB-approved studies from Fractyl Inc, Lexington, Massachusetts, United States. Dr. Hadefi is supported by a research grant from the “Fonds Erasme pour la recherche médicale” (doctoral research fellow grant). Dr. Trépo is a Research Associate of the Fund for Scientific Research-FNRS. , (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Objectives: To evaluate the efficacy and safety of a 10-day quadruple therapy containing colloidal bismuth sub-citrate (CBS), esomeprazole (ESO), amoxicillin (AMO), and metronidazole (MET) for Helicobacter pylori (H. pylori) eradication in children., Methods: Monocentric, open-label, prospective, single-arm clinical trial in children aged 6-17 years with H. pylori infection. The study was carried out on consecutive patients with upper gastrointestinal symptoms and H. pylori infection confirmed by histology and culture of gastric biopsies. The outcome was evaluated using a 13 C-urea breath test 8-10 weeks post-therapy. Adverse events and compliance were evaluated by daily journal and pill counting., Results: A total of 36 children fulfilling the inclusion criteria were enrolled. Eight (22.2%) of them had a prior H. pylori eradication treatment. Thirteen (36.1%) patients were infected by a strain resistant to MET and 8 (22.2%) by a strain resistant to both MET and Clarithromycin (CLA). In the intention-to-treat population (ITT), eradication was achieved in 35/36 patients (95%CI: 85%-99%). Twenty-three children reported at least one adverse event (63.8%), mostly mild (nausea, vomiting, abdominal pain, diarrhea, dark stool, metallic taste, headache, and rash). The compliance rate was high, with 30 (83.3%) patients taking >90% of the treatment., Conclusion: 10-day quadruple therapy containing CBS, ESO, AMO, and MET for H. pylori eradication in children is a safe and very effective solution, especially for previously treated patients and those infected with double resistant strains., (© 2021 John Wiley & Sons Ltd.)

Background and Aims: Endoscopic ultrasound fine-needle aspiration/biopsy (EUS-FNA/FNB) is highly accurate, but discrepancies between cytological and surgical diagnoses are still observed. We aimed to determine its accuracy and monitor quality indicators in our facilities., Patients and Methods: We performed a retrospective review of all cases of pancreatic solid lesions evaluated by EUS-FNA/FNB, between July 2015 and June 2018, in two centers. Cytological and surgical findings were categorized into five groups: benign, malignant, suspect of malignancy, undetermined and insufficient for diagnosis. Final diagnosis was based on surgical diagnosis and, in patients who did not undergo surgery, on clinical outcome after 6 months follow-up., Results: Altogether, 142 patients were included. FNA was the preferred tissue acquisition method (88%), with a predilection for the FNA 22G needle (57%). Cytology was insufficient for diagnosis in 2 cases, therefore a full diagnostic sample was available in 98.6% of the patients (>90%, ESGE target). Fifty-five (38.7%) patients underwent surgery. In term of cancer diagnosis, comparison with final surgical pathology (n=55) revealed 89% true positives, 5.5% true negatives, 3.6% false positives and 1.8% false negatives. When combining surgical diagnosis and clinical outcomes together, EUS-guided sampling sensitivity was 97.4% (92.5-99.5), specificity was 92.3% (74.9-99.1), positive predictive value was 98.2% (93.6- 99.5), negative predictive value was 88.9% (72.3-96.1) and accuracy was 96.4% (91.9-98.8). Post-procedural acute pancreatitis was reported in 2 patients (1.4%)., Conclusions: These results reveal a performance for diagnostic tissue sampling well above the ESGE proposed target standard. Also, the uncommon high specificity illustrates the determining role of the pathologist's final interpretation and diagnosis., Competing Interests: The authors declare that they have no conflict of interest, (© Acta Gastro-Enterologica Belgica.)

Although the overall survival rate of papillary or follicular thyroid cancers is good, anaplastic carcinomas and radio iodine refractory cancers remain a significant therapeutic challenge. Galectin-1 (Gal-1) is overexpressed in tumor cells and tumor-associated endothelial cells, and is broadly implicated in angiogenesis, cancer cell motility and invasion, and immune system escape. Our team has previously demonstrated a higher serum level of Gal-1 in patients with differentiated thyroid cancers versus healthy patients, and explored, by a knockdown strategy, the effect of Gal-1 silencing on cell proliferation and invasion in vitro, and on tumor and metastasis development in vivo. OTX008 is a calixarene derivative designed to bind the Gal-1 amphipathic β-sheet conformation and has previously demonstrated anti-proliferative and anti-invasive properties in several cancer cell lines including colon, breast, head and neck, and prostate cancer lines. In the current work, the impacts of OTX008 were evaluated in six thyroid cancer cell lines, and significant inhibitions of proliferation, migration, and invasion were observed in all lines expressing high Gal-1 levels. In addition, the signaling pathways affected by this drug were examined using RPPA (reverse phase protein array) and phosphoprotein expression assays, and opposite regulation of eNos, PYK2, and HSP27 by OTX008 was detected by comparing the two anaplastic lines 8505c and CAL 62. Finally, the sensitive 8505c line was xenografted in nude mice, and 3 weeks of OTX008 treatment (5 mg/kg/day) demonstrated a significant reduction in tumor and lung metastasize sizes without side effects. Overall, OXT008 showed significant anti-cancer effects both in vitro and in vivo in thyroid cancer lines expressing Gal-1, supporting further investigation of the molecular mechanisms of the drug and future clinical trials in patients with anaplastic thyroid cancer.

Undifferentiated carcinoma of the pancreas is an aggressive but rare tumor for which several other terms have been used to describe its histological appearance. In addition, as osteoclast-like giant cells may accompany undifferentiated carcinoma of the pancreas, the WHO Classification distinguishes undifferentiated carcinoma with osteoclast-like giant cells (UC-OGC) from plain undifferentiated carcinoma since there are a few histopathological and clinical differences. UC-OGC was initially thought to be associated with worse prognosis compared to invasive ductal pancreatic adenocarcinoma, since it is often unresectable at diagnosis and tends to recur rapidly even if completely resected. When true UC-OGGs are carefully dissected out from other anaplastic carcinomas, it becomes, however, clear that UC-OGCs do have more indolent behavior, especially the pure UC-OGCs. This mini-review summarizes the current knowledge on UC-OGC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Demetter, Maréchal, Puleo, Delhaye, Debroux, Charara, Gomez Galdon, Van Laethem and Verset.)

The liver ischemia-reperfusion (IR) injury that occurs consequently to hepatic resection performed in patients with metastases can lead to tumor relapse for not fully understood reasons. We assessed the effects of liver IR on tumor growth and the innate immune response in a mouse model of colorectal (CR) liver metastasis. Mice subjected to liver ischemia 2 days after intrasplenic injection of CR carcinoma cells displayed a higher metastatic load in the liver, correlating with Kupffer cells (KC) death through the activation of receptor-interating protein 3 kinase (RIPK3) and caspase-1 and a recruitment of monocytes. Interestingly, the immunoregulatory mediators, tumor necrosis factor-α (TNF-α) and heme oxygenase-1 (HO-1) were strongly upregulated in recruited monocytes and were also expressed in the surviving KC following IR. Using TNF flox/flox LysM cre/wt mice, we showed that TNF deficiency in macrophages and monocytes favors tumor progression after IR. The antitumor effect of myeloid cell-derived TNF involved direct tumor cell apoptosis and a reduced expression of immunosuppressive molecules such as transforming growth factor-β, interleukin (IL)-10, inducible nitric oxyde synthase (iNOS), IL-33 and HO-1. Conversely, a monocyte/macrophage-specific deficiency in HO-1 (HO-1 flox/flox LysM cre/wt ) or the blockade of HO-1 function led to the control of tumor progression post-liver IR. Importantly, host cell RIPK3 deficiency maintains the KC number upon IR, inhibits the IR-induced innate cell recruitment, increases the TNF level, decreases the HO-1 level and suppresses the tumor outgrowth. In conclusion, tumor recurrence in host undergoing liver IR is associated with the death of antitumoral KC and the recruitment of monocytes endowed with immunosuppressive properties. In both of which HO-1 inhibition would reinforce their antitumoral activity., (© 2020 UICC.)