A sexually dimorphic hepatic cycle of periportal VLDL generation and subsequent pericentral VLDLR-mediated re-uptake.

Recent single-cell transcriptomes revealed spatiotemporal programmes of liver function on the sublobular scale. However, how sexual dimorphism affected this space-time logic remained poorly understood. We addressed this by performing scRNA-seq in the mouse liver, which revealed that sex, space and time together markedly influence xenobiotic detoxification and lipoprotein metabolism. The very low density lipoprotein receptor (VLDLR) exhibits a pericentral expression pattern, with significantly higher mRNA and protein levels in female mice. Conversely, VLDL assembly is periportally biased, suggesting a sexually dimorphic hepatic cycle of periportal formation and pericentral uptake of VLDL. In humans, VLDLR expression is also pericentral, with higher mRNA and protein levels in premenopausal women compared to similarly aged men. Individuals with low hepatic VLDLR expression show a high prevalence of atherosis in the coronary artery already at an early age and an increased incidence of heart attack.

Histological Outcomes and JAK-STAT Signalling in Ulcerative Colitis Patients Treated with Tofacitinib.

BACKGROUND AND AIMS: Histological outcomes and JAK-STAT signalling were assessed in a prospective ulcerative colitis [UC] patient cohort after 8 weeks treatment with tofacitinib, an oral Janus kinase [JAK] inhibitor. METHODS: Forty UC patients received tofacitinib 10 mg twice daily for 8 weeks. Treatment response was defined as histo-endoscopic mucosal improvement [HEMI]. Histological remission was defined as a Robarts Histopathology Index [RHI] ≤3 points and histological response as 50% decrease in RHI. Mucosal expression of JAK1-3, tyrosine kinase 2 [TYK2], and total signal transducer and activator of transcription [STAT] 1-6 were assessed using immunohistochemistry [IHC]. RESULTS: At baseline, the median RHI was 14 (interquartile range [IQR] 10-19). Of 40 [65%] patients, 26 had severe endoscopic disease [endoscopic Mayo score 3] and 31/40 [78%] failed prior anti-tumour necrosis factor [anti-TNF] treatment. At Week 8, 15 patients [38%] had HEMI, 23 patients [58%] histological remission, and 34 [85%] histological response. RHI decreased by a median of 14 points [IQR 9-21] in responders [p <0.001] and by 6 points [IQR 0-13] in non-responders [p = 0.002]. STAT1, STAT3, and STAT5 expression levels decreased significantly in the whole cohort. Responders had lower Week 8 STAT1 expression levels compared with non-responders [0.2%, IQR 0.1-2.8 vs 4.3%, IQR 1.2-11.9, p = 0.001], suggesting more profound STAT1 blockade. A trend of higher baseline JAK2 expression was observed in tofacitinib non-responders [2.7%, IQR 0.1-7.7] compared with responders [0.4%, IQR 0.1-2.1]. CONCLUSIONS: Tofacitinib treatment resulted in histological improvement in the majority of UC patients and in a substantial decrease of STAT1, STAT3, and STAT5 expression. HEMI was associated with more profound suppression of STAT1.

Definitions of Histological Abnormalities in Inflammatory Bowel Disease: an ECCO Position Paper.

Histological assessment of endoscopic biopsies in inflammatory bowel disease [IBD] plays an important role in clinical management, investigative studies, and clinical trials. Scoring schemes consisting of multiple histological items and offering considerable precision are widely available. However, definitions of histological abnormalities are often inconsistent. Furthermore, interobserver variability for their recognition and assessment may be high. The European Crohn's and Colitis Organisation [ECCO] formed an expert panel to explore definitions of histological abnormalities in IBD, with the aim of improving the quality of diagnosis and facilitating development of scoring schemes. The process confirmed that the current definitions often have no evidence base and vary between sources. Using available evidence and expert knowledge, the panel produced a series of ECCO consensus position statements on histological features in IBD.

The clinical relevance of an inflamed appendix in Crohn's disease.

BACKGROUND AND AIMS: An appendectomy for appendiceal inflammation has been suggested to ameliorate the clinical course of patients with ulcerative colitis (UC). In contrast, for Crohn's disease (CD) an inverse association has been suggested with a higher incidence of CD and worse prognosis after appendectomy. The aim of this study was to analyse the clinical relevance of an inflamed appendix in CD patients undergoing ileocoecal resection (ICR). METHODS: All consecutive patients undergoing primary ICR between 2007 and 2018 were considered for inclusion. Microscopic data of available appendiceal resection specimens (n=99) were revised by a dedicated IBD-pathologist and scored as inflamed or not inflamed. Eighteen patients had a previous appendectomy. Pathological findings were correlated with disease characteristics and recurrence rates (clinical, endoscopic and intervention-related). RESULTS: In total, 117 patients were included: 77 (65.8%) females with a median age of 30 years [IQR 24 - 43] with a median follow up of 102 months [IQR 76-114]. Of patients without previous appendectomy (n=99), 39% had an inflamed appendix. No significant differences in disease characteristics (e.g. disease location, behaviour, time to surgery) or prognosis could be demonstrated between the two groups. In contrast, previous appendectomy (n=18) was associated with penetrating disease and numerically shorter disease duration at the time of resection. Furthermore, a trend was seen towards a stronger association with postoperative recurrence. CONCLUSION: The current study could not confirm a different prognosis for CD patients with and without an inflamed appendix. In contrast, in patients with a previous appendectomy a trend was seen towards increased postoperative recurrence, which might be related to the higher incidence of penetrating disease.

Early versus Late Use of Vedolizumab in Ulcerative Colitis: Clinical, Endoscopic, and Histological Outcomes.

BACKGROUND AND AIMS: We explored the potential for differential efficacy of vedolizumab between "early" and "late" ulcerative colitis (UC) with evaluation of clinical, endoscopic, and histological endpoints. METHODS: This was a multicentre, multinational open-label study in patients with moderately-to-severely active UC, defining "early" UC by a disease duration <4 years and bio-naïve and "late" UC by a disease duration >4 years and additional exposure to tumour necrosis factor antagonists. Patients received standard treatment with intravenous vedolizumab for 52 weeks (300 mg weeks 0-2-6, every 8 weeks thereafter without escalation). The primary endpoint was corticosteroid-free clinical remission with endoscopic improvement (total Mayo score ≤2 with no subscore >1) at both week 26 and 52. RESULTS: A total of 121 patients were included: in the "early" group 25/59 (42.4%) achieved the primary endpoint versus 19/62 (30.6%) in the "late" group (P = 0.18). There were no significant differences between the two groups in endoscopic improvement (week 26: "early" 32/59 [54.2%] vs. "late" 29/62 [46.8%]; P = 0.412; week 52: 27/59 [45.8%] vs. 25/62 [40.3%]; P = 0.546) or histological remission (Robarts Histopathology Index <3 without neutrophils in the epithelium and lamina propria) (week 26: 24/59 [40.7%] vs. 21/62 [33.9%]; P = 0.439; week 52: 22/59 [37.3%] vs. 22/62 [35.5%]; P = 0.837). CONCLUSIONS: No significant differences in clinical, endoscopic, and histological outcomes were observed between "early" and "late" disease.

Pathologist Computer-Aided Diagnostic Scoring of Tumor Cell Fraction: A Swiss National Study.

Tumor cell fraction (TCF) estimation is a common clinical task with well-established large interobserver variability. It thus provides an ideal test bed to evaluate potential impacts of employing a tumor cell fraction computer-aided diagnostic (TCFCAD) tool to support pathologists' evaluation. During a National Slide Seminar event, pathologists (n = 69) were asked to visually estimate TCF in 10 regions of interest (ROIs) from hematoxylin and eosin colorectal cancer images intentionally curated for diverse tissue compositions, cellularity, and stain intensities. Next, they re-evaluated the same ROIs while being provided a TCFCAD-created overlay highlighting predicted tumor vs nontumor cells, together with the corresponding TCF percentage. Participants also reported confidence levels in their assessments using a 5-tier scale, indicating no confidence to high confidence, respectively. The TCF ground truth (GT) was defined by manual cell-counting by experts. When assisted, interobserver variability significantly decreased, showing estimates converging to the GT. This improvement remained even when TCFCAD predictions deviated slightly from the GT. The standard deviation (SD) of the estimated TCF to the GT across ROIs was 9.9% vs 5.8% with TCFCAD (P < .0001). The intraclass correlation coefficient increased from 0.8 to 0.93 (95% CI, 0.65-0.93 vs 0.86-0.98), and pathologists stated feeling more confident when aided (3.67 ± 0.81 vs 4.17 ± 0.82 with the computer-aided diagnostic [CAD] tool). TCFCAD estimation support demonstrated improved scoring accuracy, interpathologist agreement, and scoring confidence. Interestingly, pathologists also expressed more willingness to use such a CAD tool at the end of the survey, highlighting the importance of training/education to increase adoption of CAD systems.

Temperature-triggered in situ forming lipid mesophase gel for local treatment of ulcerative colitis.

Ulcerative colitis is a chronic inflammatory bowel disease that strongly affects patient quality of life. Side effects of current therapies necessitate new treatment strategies that maximise the drug concentration at the site of inflammation, while minimizing systemic exposure. Capitalizing on the biocompatible and biodegradable structure of lipid mesophases, we present a temperature-triggered in situ forming lipid gel for topical treatment of colitis. We show that the gel is versatile and can host and release drugs of different polarities, including tofacitinib and tacrolimus, in a sustained manner. Further, we demonstrate its adherence to the colonic wall for at least 6 h, thus preventing leakage and improving drug bioavailability. Importantly, we find that loading known colitis treatment drugs into the temperature-triggered gel improves animal health in two mouse models of acute colitis. Overall, our temperature-triggered gel may prove beneficial in ameliorating colitis and decreasing adverse effects associated with systemic application of immunosuppressive treatments.

Prognostic Value of T-Cell Density in the Tumor Center and Outer Margins in Gastric Cancer.

Tumor-infiltrating lymphocytes are associated with the survival of gastric cancer patients. T-cell densities in the tumor and its periphery were previously identified as prognostic T-cell markers for resectable gastric cancer. Immunohistochemistry for 5 T-cell markers, CD3, CD45RO, CD8, FOXP3, and granzyme B was performed on serial sections of N = 251 surgical resection specimens of patients treated with surgery only in the D1/D2 trial. Positive T cells were digitally quantified into tiles of 0.25 mm2 across 3 regions: the tumor center (TC), the inner invasive margin, and the outer invasive margin (OIM). A classification and regression tree model was employed to identify the optimal combination of median T-cell densities per region with cancer-specific survival (CSS) as the outcome. All statistical tests were 2-sided. CD8OIM was identified as the most dominant prognostic factor, followed by FOXP3TC, resulting in a decision tree containing 3 prognostically distinct subgroups with high (Hi) or low (Lo) density of the markers: CD8OIMHi, CD8OIMLo/FOXP3TCHi, and CD8OIMLo/FOXP3TCLo. In a multivariable Cox regression analysis, which included pathological T and N stages, Lauren histologic types, EBV status, microsatellite instability, and type of surgery, the immune subgroups were independent predictors for CSS. CSS was lower for CD8OIMLo/FOXP3TCHi (HR: 5.02; 95% CI: 2.03-12.42) and for CD8OIMLo/FOXP3TCLo (HR: 7.99; 95% CI: 3.22-19.86), compared with CD8OIMHi (P < .0001). The location and density of both CD8+ and FOXP3+ T cells in resectable gastric cancer are independently associated with survival. The combination of CD8OIM and FOXP3TC T-cell densities is a promising stratification factor that should be validated in independent studies.

Mercaptopurine for the Treatment of Ulcerative Colitis: A Randomized Placebo-Controlled Trial.

BACKGROUND AND AIMS: Scepticism about the efficacy of thiopurines for ulcerative colitis [UC] is rising. This study aimed to evaluate mercaptopurine treatment for UC. METHODS: In this prospective, randomized, double-blind, placebo-controlled trial, patients with active UC, despite treatment with 5-aminosalicylates [5-ASA], were randomized for therapeutic drug monitoring [TDM]-guided mercaptopurine treatment or placebo for 52 weeks. Corticosteroids were given in the first 8 weeks and 5-ASA was continued. Proactive metabolite-based mercaptopurine and placebo dose adjustments were applied from week 6 onwards by unblinded clinicians. The primary endpoint was corticosteroid-free clinical remission and endoscopic improvement [total Mayo score ≤2 points and no item >1] at week 52 in an intention-to-treat analysis. RESULTS: Between December 2016 and April 2021, 70 patients were screened and 59 were randomized at six centres. In the mercaptopurine group, 16/29 [55.2%] patients completed the 52-week study, compared to 13/30 [43.3%] on placebo. The primary endpoint was achieved by 14/29 [48.3%] patients on mercaptopurine and 3/30 [10%] receiving placebo (Δ = 38.3%, 95% confidence interval [CI] 17.1-59.4, p = 0.002). Adverse events occurred more frequently with mercaptopurine [808.8 per 100 patient-years] compared to placebo [501.4 per 100 patient-years]. Five serious adverse events occurred, four on mercaptopurine and one on placebo. TDM-based dose adjustments were executed in 22/29 [75.9%] patients, leading to lower mercaptopurine doses at week 52 compared to baseline. CONCLUSIONS: Optimized mercaptopurine treatment was superior to placebo in achieving clinical, endoscopic and histological outcomes at 1 year following corticosteroid induction treatment in UC patients. More adverse events occurred in the mercaptopurine group.

Increased Proportion of Colorectal Cancer in Patients With Ulcerative Colitis Undergoing Surgery in the Netherlands.

INTRODUCTION: The aim of the current study was to assess whether there is an indication shift for surgery in patients with ulcerative colitis (UC) from refractory disease to malignant degeneration over the past 3 decades. METHODS: All patients with histologically confirmed UC who underwent a colorectal resection between 1991 and 2020 were extracted from the nationwide Dutch Pathology Registry. The primary outcome was the proportion of colorectal cancer (CRC) in the colon specimens. Outcomes were compared between 3 periods (P1: 1991-2000, P2: 2001-2010, and P3: 2011-2020). RESULTS: Overall, 6,094 patients with UC were included of which 4,854 underwent a (procto)colectomy and 1,240 a segmental resection. In 1,031 (16.9%) patients, CRC was demonstrated in the pathological resection specimen after a median disease duration of 11 years (IQR 3.0-19.0). The proportion of CRC increased from 11.3% in P1, to 16.1% in P2, and 22.8% in P3 ( P < 0.001). Median disease duration at the time of resection increased from 4 years in P1, to 10 years in P2, and 17 years in P3 ( P < 0.001). The proportion of patients diagnosed with advanced malignancy (pT3/T4) (P1: 61.2% vs P2: 65.2% vs P3: 62.4%, respectively, P = 0.633) and lymph node metastasis (N+) (P1: 33.0% vs P2: 41.9% vs P3: 38.2%, respectively, P = 0.113) did not change over time. DISCUSSION: This nationwide pathology study demonstrated an increased proportion of surgery for CRC over the past 3 decades. We hypothesize that the expanding therapeutic armamentarium for UC leads to exhausting medical options and hence postponed colectomy. This, however, might be at the expense of an increased risk of CRC in the long term.