Local triamcinolone injection and selective add-on oral steroids to prevent esophageal post-endoscopic submucosal dissection stricture: a retrospective analysis in a Western center.

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.

Clinical, histological and molecular profiling of different stages of alcohol-related liver disease.

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.

Myeloid tumor necrosis factor and heme oxygenase-1 regulate the progression of colorectal liver metastases during hepatic ischemia-reperfusion.

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 TNFflox/flox LysMcre/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-ß, interleukin (IL)-10, inducible nitric oxyde synthase (iNOS), IL-33 and HO-1. Conversely, a monocyte/macrophage-specific deficiency in HO-1 (HO-1flox/flox LysMcre/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.

Efficacy and safety of bismuth-based quadruple therapy for Helicobacter pylori eradication in children.

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.

Long-term outcomes in patients with decompensated alcohol-related liver disease, steatohepatitis and Maddrey's discriminant function <32.

BACKGROUND & AIMS: Patients with alcoholic hepatitis and a modified Maddrey's discriminant function (mDF) <32 have a low risk of short-term mortality. However, few data exist concerning long-term outcomes. The aims of this study were to evaluate 5-year survival rates and to identify predictive factors for long-term prognosis in this patient population. METHODS: We studied patients from 2 centers who were admitted for hepatic decompensation (ascites, hepatic encephalopathy, or jaundice) and who had histological findings of steatohepatitis and an mDF <32. Clinical and biological parameters were recorded at the time of liver biopsy and alcohol consumption was recorded during follow-up. We performed Cox proportional hazard survival analysis to identify factors associated with 5-year survival. RESULTS: One hundred and twenty-one patients were included (male: 64%, mean age: 51.5 ± 10.3 years, presence of cirrhosis: 84%). The median model for end-stage liver disease and mDF scores were 14 (IQR 11.7-16.1) and 19 (IQR 11.1-24), respectively. During follow-up, 30% of the patients remained abstinent. Survival rates at 1, 6, 12, 24, and 60 months were 96.7 ± 1.6%, 90.1 ± 2.7%, 80.8 ± 3.6%, 69.9 ± 4.3%, and 50.7 ± 4.9%, respectively. The majority of deaths (80%) were liver related. In multivariable analysis, encephalopathy at baseline and alcohol abstinence were predictive of 5-year survival. The 5-year survival rates of patients without and with encephalopathy at baseline were 60.5 ± 5.8% and 29.7 ± 8.0%, respectively, and the 5-year survival rates of abstinent and non-abstinent patients were 74.0 ± 8.0% and 40.9 ± 5.8%, respectively. CONCLUSIONS: The mortality rate of patients with alcoholic hepatitis and an mDF <32 is around 50% at 5 years. Hepatic encephalopathy at baseline and lack of alcohol abstinence impair long-term prognosis. New treatment strategies, including measures to ensure abstinence, are required. LAY SUMMARY: Patients with alcoholic hepatitis that is of intermediate severity have a low risk of short-term mortality but not much is known regarding long-term outcomes for these patients. This study clearly indicates that patients with intermediate disease characteristics have poor long-term outcomes. The presence of hepatic encephalopathy at the time of diagnosis and the absence of alcohol abstinence during follow-up are factors that predict poor long-term mortality.

[Comparison of the mismatch repair deficiency of colorectal cancers between African and European cohorts]. / Comparaison du « deficit mismatch repair ¼ des cancers colorectaux entre des cohortes africaines et européennes.

INTRODUCTION: According to European and American series, up to 20% of colorectal cancers are characterised by instability at microsatellites sites. MMR deficient colorectal cancers are predominantly found in the right colon. Although an increasing rate of colorectal cancer has been observed in many low-income countries including in West-Africa, data on epidemiology and biology of colorectal cancer in native Africans from this region are scarce. MATERIALS AND METHODS: We aimed to study the incidence of MMR deficiency in Côte d'Ivoire and to compare the data with those from a tertiary center in Belgium. Immunohistochemistry for MLH1, MSH2, MSH6 and PMS2 was performed on paraffin-embedded tissue samples from 83 colorectal cancers (46% males) operated in Abidjan and from 343 colorectal cancers (53% males) from Brussels. RESULTS: Colorectal cancer was occuring at a younger age in Côte d'Ivoire compared to Belgium (median age: 53 versus 66). MMR deficiency was detected in 11,7% of Belgian cases and in 13,3% of Ivorian cases. Whereas MMR deficient cancers in Brussels were mainly found in women (24/40 i.e. 60%), in Abidjan only 3/11 (27%) were female. Moreover, the predominant location of MMR deficient tumours was different between both series: in Brussels, mainly located in the right colon (24/40 i.e. 60%) whereas in Abidjan predominantly (10/11 i.e. 91%) in the left colon. In Brussels we observed in the majority of cases (67,5%) loss of expression of MLH1 and PMS2, in Abidjan loss of expression of MSH2 and MSH6 (54,5%). CONCLUSIONS: Our pilot study reveals differences in presentation of MMR deficient colorectal cancer between the two geographic regions suggesting differences in epidemiology and biology of colorectal cancer in native Africans.

Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features.

BACKGROUND & AIMS: Genomic studies have revealed subtypes of pancreatic ductal adenocarcinoma (PDA) based on their molecular features, but different studies have reported different classification systems. It is a challenge to obtain high-quality, freshly frozen tissue for clinical analysis and determination of PDA subtypes. We aimed to redefine subtypes of PDA using a large number of formalin-fixed and paraffin-embedded PDA samples, which are more amenable to routine clinical evaluation. METHODS: We collected PDA samples from 309 consecutive patients who underwent surgery from September 1996 through December 2010 at 4 academic hospitals in Europe; nontumor tissue samples were not included. Samples were formalin fixed and paraffin embedded. DNA and RNA were isolated; gene expression, targeted DNA sequencing, and immunohistochemical analyses were performed. We used independent component analysis to deconvolute normal, tumor, and microenvironment transcriptome patterns in samples. We devised classification systems from an unsupervised analysis using a consensus clustering approach of our data set after removing normal contamination components. We associated subtypes with overall survival and disease-free survival of patients using Cox proportional hazards regression with estimation of hazard ratios and 95% confidence interval. We used The Cancer Genome Consortium and International Cancer Genome Consortium PDA data sets as validation cohorts. RESULTS: We validated the previously reported basal-like and classical tumor-specific subtypes of PDAs. We identified features of the PDA, including microenvironment gene expression patterns, that allowed tumors to be categorized into 5 subtypes, called pure basal like, stroma activated, desmoplastic, pure classical, and immune classical. These PDA subtypes have features of cancer cells and immune cells that could be targeted by pharmacologic agents. Tumor subtypes were associated with patient outcomes, based on analysis of our data set and the International Cancer Genome Consortium and The Cancer Genome Consortium PDA data sets. We also observed an exocrine signal associated with acinar cell contamination (from pancreatic tissue). CONCLUSIONS: We identified a classification system based on gene expression analysis of formalin-fixed PDA samples. We identified 5 PDA subtypes, based on features of cancer cells and the tumor microenvironment. This system might be used to select therapies and predict patient outcomes. We found evidence that the previously reported exocrine-like (called ADEX) tumor subtype resulted from contamination with pancreatic acinar cells. ArrayExpress accession number: E-MTAB-6134.

Impact of the Microenvironment on Tumour Budding in Colorectal Cancer.

Tumour Budding (TB) is recognized as an adverse prognostic factor in colorectal cancer (CRC). TB is the detachment of isolated cancer cells or small clusters of such cells mainly at the invasion front. One question that arises is of the role of the tumour stroma regarding the permissiveness of the formation and progression of TB. In this review, we will examine potential factors affecting TB, in particular we will analyse the potential effect of inflammation, hypoxia, extracellular matrix and Cancer-Associated Fibroblasts (CAFs).

ADAM-17/FHL2 colocalisation suggests interaction and role of these proteins in colorectal cancer.

FHL2 is a multifunctional scaffolding protein; its expression is associated with poor prognosis in colorectal cancer. ADAM-17 is a metalloprotease implicated in ectodomain shedding. FHL2 regulates ADAM-17 plasma membrane localisation, and FHL2 deficiency leads to decreased activity of ADAM-17 in mouse macrophages. Presence and relationship of the ADAM-17/FHL2 complex with colorectal cancer progression is unknown. We studied FHL2 and ADAM-17 expression in several colon cancer cell lines by immunocytochemistry and western blot. To highlight the interaction between both molecules, we used the Duolink® kit for proximity ligation assay on SW480 cells. We also performed proximity ligation assay on biopsies and surgical specimens of colorectal adenocarcinoma and on matched normal mucosa. Furthermore, biopsies of colorectal adenoma with matched normal mucosa were selected. For quantification, pictures of the malignant, adenomatous and normal tissues were taken. Proximity ligation assay signals were quantified. Mean numbers of proximity ligation assay signals and of proximity ligation assay signals/nucleus were calculated. All cell lines showed FHL2 immunoreactivity; strongest positivity was observed in SW480 cells. ADAM-17 was expressed in all cell lines. Proximity ligation assay signals were present in SW480 cells. Quantitative analysis revealed that the interaction between FHL2 and ADAM-17 is more frequent in malignant than in normal tissue (p = 0.005). The mean number of ADAM-17/FHL2 proximity ligation assay signals was higher in colorectal adenocarcinoma than in adenoma with low-grade dysplasia (p = 0.0004). FHL2 interacts with ADAM-17 in normal, dysplastic and malignant colon epithelial cells. Colocalisation of these proteins is more frequent in malignant than in normal and dysplastic cells, suggesting a role for ADAM-17/FHL2 complex in the development of colorectal cancer.

Methylglyoxal-Mediated Stress Correlates with High Metabolic Activity and Promotes Tumor Growth in Colorectal Cancer.

Cancer cells generally rely on aerobic glycolysis as a major source of energy. Methylglyoxal (MG), a dicarbonyl compound that is produced as a side product during glycolysis, is highly reactive and induces the formation of advanced glycation end-products that are implicated in several pathologies including cancer. All mammalian cells have an enzymatic defense against MG composed by glyoxalases GLO1 and GLO2 that converts MG to d-lactate. Colorectal cancer (CRC) is one of the most frequently occurring cancers with high morbidity and mortality. In this study, we used immunohistochemistry to examine the level of MG protein adducts, in a series of 102 CRC human tumors divided into four clinical stages. We consistently detected a high level of MG adducts and low GLO1 activity in high stage tumors compared to low stage ones suggesting a pro-tumor role for dicarbonyl stress. Accordingly, GLO1 depletion in CRC cells promoted tumor growth in vivo that was efficiently reversed using carnosine, a potent MG scavenger. Our study represents the first demonstration that MG adducts accumulation is a consistent feature of high stage CRC tumors. Our data point to MG production and detoxification levels as an important molecular link between exacerbated glycolytic activity and CRC progression.

Marked 25-hydroxyvitamin D deficiency is associated with poor prognosis in patients with alcoholic liver disease.

BACKGROUND & AIMS: Vitamin D deficiency has been frequently reported in advanced liver disease. However, its influence on alcoholic liver disease (ALD) has been poorly elucidated. We investigated the association of vitamin D with clinical, biological, and histological parameters and survival in ALD patients. Furthermore, we explored the effect of vitamin D treatment on ALD patient peripheral blood mononuclear cells (PBMCs), and in a murine experimental model of ALD. METHODS: Serum levels of 25-hydroxyvitamin D [25(OH)D] were determined in 324 Caucasian ALD patients and 201 healthy controls. In vitro experiments on vitamin D pre-treated PBMCs evaluated TNFα production by ELISA in culture supernatants. Mice were submitted to an ethanol-fed diet and some of them were orally supplemented three times per week with 1,25(OH)2D. RESULTS: Severe deficiency in 25(OH)D (<10 ng/ml) was significantly associated with higher aspartate aminotransferase levels (p=1.00 × 10(-3)), increased hepatic venous pressure gradient (p=5.80 × 10(-6)), MELD (p=2.50 × 10(-4)), and Child-Pugh scores (p=8.50 × 10(-7)). Furthermore, in multivariable analysis, a low 25(OH)D concentration was associated with cirrhosis (OR=2.13, 95% CI=1.18-3.84, p=0.013) and mortality (HR=4.33, 95% CI=1.47-12.78, p=7.94 × 10(-3)) at one year. In addition, in vitro, 1,25(OH)2D pretreatment decreased TNFα production by stimulated PBMCs of ALD patients (p=3.00 × 10(-3)), while in vivo, it decreased hepatic TNFα expression in ethanol-fed mice (p=0.04). CONCLUSIONS: Low 25(OH)D levels are associated with increased liver damage and mortality in ALD. Our results suggest that vitamin D might be both a biomarker of severity and a potential therapeutic target in ALD.

The current understanding of the immune landscape relative to radiotherapy across tumor types.

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.

The impact of a multidisciplinary team approach on the management of focal pancreatic lesions: a single tertiary center experience.

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.

Ovarian Clear Cell Carcinoma with Functioning Stroma and Associated Endometrial Intraepithelial Neoplasia.

We report the case of a 79-year-old woman with a large pelvic mass and postmenopausal bleeding, associated with hyperestrogenism. A pelvic MRI shows the presence of a large mass of 12.6 cm originating from the right ovary without signs of metastasis. A total abdominal hysterectomy with unilateral salpingooophorectomy was performed, knowing the patient underwent a left salpingooophorectomy decades ago. The pathological findings showed an ovarian clear cell carcinoma (pT1A) with associated endometrial intraepithelial neoplasia. There is convincing evidence that the production of estrogen is located in the activated ovarian stroma. This supports the view that functioning stroma of ovarian cancer can lead to hyperestrogenism and eventually endometrial cancer.