Impact of Bowel Preparation Quality on Colonoscopy Findings and Colorectal Cancer Deaths in a Nation-Wide Colorectal Cancer Screening Program.

INTRODUCTION: Adequate bowel preparation is paramount for a high-quality screening colonoscopy. Despite the importance of adequate bowel preparation, there is a lack of large studies that associated the degree of bowel preparation with long-term colorectal cancer outcomes in screening patients. METHODS: In a large population-based screening program database in Austria, quality of bowel preparation was estimated according to the Aronchick Scale by the endoscopist (excellent, good, fair, poor, and inadequate bowel preparation). We used logistic regression to assess the influence of bowel preparation on the detection of different polyp types and the interphysician variation in bowel preparation scoring. Time-to-event analyses were performed to investigate the association of bowel preparation with postcolonoscopy colorectal cancer (PCCRC) death. RESULTS: A total of 335,466 colonoscopies between January 2012 and follow-up until December 2022 were eligible for the analyses. As compared with excellent bowel preparation, adenoma detection was not significantly lower for good bowel preparation (odds ratio 1.01, 95% confidence interval [CI] 0.9971-1.0329, P = 0.1023); however, adenoma detection was significantly lower in fair bowel preparation (odds ratio 0.97, 95% CI 0.9408-0.9939, P = 0.0166). Individuals who had fair or lower bowel preparation at screening colonoscopy had significantly higher hazards for PCCRC death (hazard ratio for fair bowel preparation 2.56, 95% CI 1.67-3.94, P < 0.001). DISCUSSION: Fair bowel preparation on the Aronchick Scale was not only associated with a lower adenoma detection probability but also with increased risk of PCCRC death. Efforts should be made to increase bowel cleansing above fair scores.

Long-term outcomes of cyclosporin induction and ustekinumab maintenance combination therapy in patients with steroid-refractory acute severe ulcerative colitis.

Background: Effective management of patients with acute severe ulcerative colitis (ASUC) is a major challenge and there remains a paucity of available maintenance treatment options after efficacious cyclosporin induction therapy. Objectives: We investigated the long-term effectiveness and safety of cyclosporin and ustekinumab combination therapy in patients with steroid refractory ASUC. Design: Monocentric, prospective study. Methods: We included patients with steroid refractory ASUC with multiple failed prior advanced therapies, who were treated with cyclosporin and ustekinumab combination therapy. Results: Among the 11 included patients, 10 had prior failure to infliximab and 8 failed at least three previous biological therapies. The mean baseline Mayo and Lichtiger scores were 10.9 (9-12) and 13.3 (11-14), respectively. Ustekinumab was initiated 3.2 weeks (1-8) after initiation of cyclosporin treatment and combination therapy was continued for a mean of 11.5 (4-20) weeks. Clinical response was achieved in six patients at week 16 and clinical steroid-free clinical remission in five patients at week 48. Endoscopic remission was achieved in five patients at week 16 and together with histological remission in five patients at week 52. Intestinal ultrasound demonstrated mean bowel wall thickening in the sigmoid colon of 5.5 mm at baseline and 3.5 mm at week 52, respectively. Two patients had to undergo colectomy (mean 4.5 months, range 3-6) and three stopped ustekinumab therapy due to ineffectiveness. Overall, combination therapy was well tolerated. Conclusion: Combination of cyclosporin and ustekinumab therapy allowed nearly half of ASUC patients to reach clinical and endoscopic remission after 52 weeks, warranting further studies. Trial registration: Not applicable.

Effects of cyclosporin and ustekinumab combination therapy in acute severe ulcerative colitis In this study, we looked at how to treat patients with a severe form of ulcerative colitis, a type of inflammatory bowel disease, when the usual treatments don't work. We tested a combination of two drugs, cyclosporine and ustekinumab, to see if it could help these patients in the long term. We included eleven patients who had already tried many other treatments and didn't get better. Most of them had also tried a drug called infliximab and had failed at least three other biological therapies. At the start, these patients were very sick, with high scores on disease activity measures. We gave them ustekinumab in addtion after a therapy with cyclosporin had been started before. The combination therapy continued for an average of almost 12 weeks. After 16 weeks, six patients showed improvement in their symptoms, and five were able to stop taking steroids. Five patients also had their colon lining looking healthy again when we looked inside with a scope after 16 weeks. And after 52 weeks, five patients had normal colon lining and healthy tissue under the microscope. Ultrasound showed that the thickness of their colon wall had decreased. Unfortunately, two patients had to have surgery to remove their colon, and three had to stop taking ustekinumab because it didn't help them. Overall, the combination therapy was safe and well-tolerated. In conclusion, combining cyclosporin and ustekinumab helped about half of the patients with severe ulcerative colitis get better and have healthy colon lining after 52 weeks. This suggests that more research is needed to understand the benefits of this treatment in these patients.

Case report of severe constrictive perimyocarditis and ischemic hepatitis in a Crohn's disease patient upon infliximab-induced lupus-like syndrome.

Anti-tumor necrosis factor (TNF) antibodies have become an indispensable part in the therapeutic landscape of treating inflammatory bowel disease (IBD) patients. Nevertheless, they can be associated with the occurrence of severe systemic side effects. Here, we report the case of a 23-year-old patient with ileocolonic Crohn's disease in endoscopic remission under ongoing anti-TNF infliximab therapy with occurrence of novel generalized arthralgia, pleuritic chest pain, and dyspnea. Clinical, laboratory, and imaging diagnostic workup in an extended clinical routine setting at the University Hospital of Erlangen, Germany, was used by a multidisciplinary team consisting of gastroenterologists, radiologists, cardiologists, and rheumatologists to investigate the underlying cause of the clinical symptoms in the patient. The results received using the aforementioned diagnostic setup led to the diagnosis of severe constrictive perimyocarditis due to infliximab-induced lupus-like syndrome with distinct ANA reactivity and elevated anti-dsDNA levels. Furthermore, pronounced ischemic hepatitis was diagnosed. Infliximab treatment was immediately stopped, and initiated corticosteroid pulse therapy only led to partial response as it had to be reduced due to pronounced psychiatric side effects. Persistent signs of pericarditis required additional ibuprofen therapy, which led to subsequent resolution of cardial symptoms. Formerly elevated liver enzymes returned to normal, and there were no clinical signs of recurrence of Crohn's disease activity over 18 months of follow-up. The patient was subsequently switched to ustekinumab therapy for further treatment of underlying Crohn's disease. This case report describes for the first time severe infliximab-induced lupus-like syndrome in an IBD patient, concurrently mimicking ST-elevation myocardial infarction with MRI visualization of pericarditis, occurrence of ischemic hepatitis, and pronounced signs of systemic inflammation.

Vesicle traffic in the outer hair cell.

The plasma-membrane marker FM1-43 was employed to reveal the relative significance of different types of endocytic and transcytic mechanisms in outer hair cells (OHCs) of the guinea-pig cochlea. A double-barrel local perfusion system was used to label independently the apical or synaptic pole of the isolated OHC to study mechanisms of vesicle uptake at the poles and of vesicle trafficking along and across the cell. Treatment with an inhibitor of macropino- and phagocytosis, phenylarsine oxide, or of clathrin-mediated endocytic activity, concanavalin A, significantly reduced the dye uptake at both the apical and the synaptic poles, indicating the presence of both clathrin-independent and clathrin-mediated processes at both poles. However, measurement of uptake speed in the presence of the inhibitors suggested that clathrin-independent processes contribute more extensively to endocytosis at the basal pole than the apical pole. Treatment with an inhibitor of myosin VI, 2,4,6-triiodophenol, significantly delayed both the apicobasal and the basoapical fluorescence signals. However, treatment with an inhibitor of kinesin, monastrol, or of dynein, ciliobrevin D, significantly delayed the signals only in the basoapical direction. The myosinVI inhibitor, but neither the kinesin nor dynein inhibitors, significantly delayed the signals to the subsurface cisternae. That is, myosin VI carries vesicles in both longitudinal directions as well as radially to the subsurface cisternae, whereas kinesin and dynein participate primarily in basoapical trafficking. This fundamental information is essential for elucidating recycling mechanisms of specific proteins involved in establishing, controlling and maintaining the electromechanical action of OHCs and, therefore, is vital for understanding auditory perception.

Long-term effectiveness, safety and immunogenicity of the biosimilar SB2 in inflammatory bowel disease patients after switching from originator infliximab.

BACKGROUND: Long-term data on inflammatory bowel disease (IBD) patients switched from originator to biosimilar infliximab SB2 are lacking. The aim of the conducted study was to investigate the effectiveness, immunogenicity and safety of a large prospectively followed-up IBD patient cohort that was entirely switched from originator infliximab to biosimilar SB2 treatment. METHODS: This was a prospective, single-center, longitudinal, observational study describing clinical outcomes in IBD patients, over an 80-week period following switch from originator infliximab to SB2. Primary outcome measures were change of disease activity [Harvey-Bradshaw Index for Crohn's disease (CD), partial Mayo Score for ulcerative colitis (UC)], C-reactive protein (CRP), infliximab trough levels (TLs), anti-drug antibodies (ADAs) and adverse events. RESULTS: One hundred and forty-four IBD patients (94 CD, 50 UC), with median duration of 30.5 months' (range 2-110) treatment with originator infliximab were evaluated. Mean change of disease activity compared with baseline was -0.9 (SD 2.6), -0.4 (2.2) and -0.4 (2.0) in CD; 0.1 (1.1), 0.1 (1.1) and 0.1 (1.3) in UC patients at weeks 24, 48 and 72. Median infliximab TLs were 6.2 µg/ml (interquartile range 2.3-12.2), 5.0 µg/ml (2.7-10.0), 6.6 µg/ml (3.5-12.4) and 5.1 µg/ml (2.7-10.9) at baseline and weeks 24, 48 and 72. Median CRP levels were within normal ranges throughout the study. After the switch, 9.8% of the patients developed new ADAs. Persistence on SB2 was 90% (95% confidence interval 0.85-0.95), 79% (0.72-0.86), 72% (0.64-0.80) at weeks 26, 52 and 78. Serious adverse events occurred in 11 patients. CONCLUSION: Over the individual patient follow-up of 80 weeks, switch to biosimilar SB2 from originator infliximab does not result in increased disease activity or changed immunogenicity patterns. The switch to SB2 was well tolerated.

Patients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion.

Immune-mediated inflammatory diseases (IMIDs) of the joints, gut and skin are treated with inhibitors of inflammatory cytokines. These cytokines are involved in the pathogenesis of coronavirus disease 2019 (COVID-19). Investigating anti-SARS-CoV-2 antibody responses in IMIDs we observe a reduced incidence of SARS-CoV-2 seroconversion in IMID patients treated with cytokine inhibitors compared to patients receiving no such inhibitors and two healthy control populations, despite similar social exposure. Hence, cytokine inhibitors seem to at least partially protect from SARS-CoV-2 infection.

Baseline levels of dynamic CD4+ T cell adhesion to MAdCAM-1 correlate with clinical response to vedolizumab treatment in ulcerative colitis: a cohort study.

BACKGROUND: While the number of therapeutic options for treating inflammatory bowel diseases (IBD) is increasing, evidence for rational treatment decisions is scarce in many cases. In particular, appropriate biomarkers to predict the response to the anti-α4ß7 integrin antibody vedolizumab are currently lacking. METHODS: We performed a cohort study with 21 patients suffering from ulcerative colitis (UC), in which first-time treatment with vedolizumab was initiated. CD4+ T cells were isolated from the peripheral blood and dynamic adhesion to recombinant mucosal vascular addressin cell adhesion molecule (MAdCAM-)1 in vitro as well as the effect of vedolizumab on such adhesion in vitro was determined. The expression of α4ß1 integrin on peripheral blood CD4+ T cells was quantified by flow cytometry. Electronic patient records were reviewed to determine clinical response to vedolizumab. RESULTS: Dynamic adhesion of peripheral blood CD4+ T cells to MAdCAM-1 and the reduction of adhesion following vedolizumab treatment in vitro were higher and the change in α4ß1 expression on CD4+ T cells was different in vedolizumab responders and non-responders. Responders could be identified with high specificity and positive-predictive value. CONCLUSIONS: Determining dynamic adhesion of CD4+ T cells to MAdCAM-1 and the in vitro response to vedolizumab before treatment initiation or dynamic integrin regulation in the early course of treatment seem to be promising tools to predict the clinical response to vedolizumab therapy. Larger prospective studies are warranted.

Magnification endoscopy with optical chromoendoscopy shows strong correlation with histologic inflammation in patients with inflammatory bowel disease.

Background and study aims Apart from mucosal healing as an established treatment goal in inflammatory bowel diseases (IBD), recent evidence suggests that histologic healing may become another key prognostic parameter in IBD patients. We aimed to evaluate whether magnification endoscopy with optical chromoendoscopy can accurately assess histologic inflammation in IBD patients. Patients and methods In this prospective study, 82 patients with IBD (30 UC, 52 CD) were included. In all patients, magnification endoscopy in conjunction with optical chromoendoscopy was performed and rated on a novel magnification endoscopy score by three independent endoscopists. Targeted biopsies of the imaged areas were obtained and results were compared against two histological scores in UC (Robarts Histopathology Index, RHI; Nancy Histology Index, NHI) and one score in CD (modified Riley index, mRI). Moreover, interobserver agreement was calculated. Results Magnification endoscopy showed strong correlation with histopathologic scoring in both UC (RHI: r = 0.83, NHI: r = 0.78, P  < 0.05) and CD (mRI: r = 0.74, P  < 0.05) with high accuracy, sensitivity, and specificity. Further, 25 % of patients with mucosal healing on standard endoscopy showed signs of microinflammation on magnification endoscopy with optical chromoendoscopy, while none of the patients with mucosal and vascular healing under magnification endoscopy with optical chromoendoscopy exhibited microscopic inflammation. Interobserver agreement for grading intestinal inflammation by magnification endoscopy with optical chromoendoscopy was substantial (κ > 0.7). Conclusion Magnification endoscopy in combination with optical chromoendoscopy shows strong correlation with histologic inflammation in patients with IBD. This approach has potential to reduce physical biopsies for monitoring of inflammatory activity in patients with IBD during colonoscopy.

Targeting mucosal healing in Crohn's disease: what the clinician needs to know.

In recent years, mucosal healing has emerged as a key therapeutic goal in the clinical management of patients with Crohn's disease, as it has been associated with improved long-term clinical outcomes. With the vast improvements in endoscopic imaging techniques and the increase in available treatment options, which reportedly are able to induce mucosal healing, the practising physician is left to wonder: how is endoscopic mucosal healing exactly defined in Crohn's disease, and how can it effectively be achieved and monitored in daily clinical practice? Within this review, we will give an overview of the ongoing debate about the definition of mucosal healing and the modalities to monitor inflammation, and finally present available therapies with the capacity to induce mucosal healing.

Cellular Mechanisms of Etrolizumab Treatment in Inflammatory Bowel Disease.

Background: Anti-integrin therapy is a new frontline strategy in the treatment of inflammatory bowel diseases (IBD). The anti-ß7 integrin antibody etrolizumab is currently being investigated for safety and efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in several phase III trials. Mechanistically, etrolizumab is known to block ß7 integrin ligand binding and reduces intestinal trafficking of ß7-expressing cells. Etrolizumab blocks ß7 integrin ligand binding and reduces ß7-positive lymphocyte migration and retention in the inflamed gut mucosa, but the exact mechanisms by which this inhibition occurs are not fully understood. Methods: Cellular effects of etrolizumab or etrolizumab surrogate antibody (etrolizumab-s) were investigated in cell culture models and analyzed by flow cytometry, fluorescence microscopy, ImageStream®, stimulated emission depletion (STED) microscopy and functional dynamic in vitro adhesion assays. Moreover, effects on α4ß7 integrin were compared with the pharmacodynamically similar antibody vedolizumab. Results: As demonstrated by several different approaches, etrolizumab and etrolizumab-s treatment led to internalization of ß7 integrin. This resulted in impaired dynamic adhesion to MAdCAM-1. Internalized ß7 integrin localized in endosomes and re-expression of ß7 was dependent on de novo protein synthesis. In vitro etrolizumab treatment did not lead to cellular activation or cytokine secretion and did not induce cytotoxicity. Internalization of α4ß7 integrin was increased with etrolizumab compared with vedolizumab. Discussion: Our data suggest that etrolizumab does not elicit secondary effector functions on the single cell level. Integrin internalization may be an important mechanism of action of etrolizumab, which might explain some but not all immunological effects observed with etrolizumab.

Drug Levels in the Maternal Serum, Cord Blood and Breast Milk of a Ustekinumab-Treated Patient with Crohn's Disease.

Ustekinumab [UST] therapy during pregnancy has not yet been extensively evaluated in patients with Crohn's disease. Here, we present the case of a 24-year-old woman with therapy-refractory Crohn's disease, who was treated with UST until Week 30 of pregnancy and successfully delivered a healthy baby boy, who had normal development in the follow-up period of one year. The cord blood UST level was markedly higher than the measured maternal serum drug level. The trough level in the breast milk after re-initiating postpartum UST therapy was initially in the same range as the corresponding serum trough level, and then decreased during maintenance therapy. This is one of the first reports describing the drug levels in the breast milk after re-initiating UST treatment in a Crohn's disease patient.

Molecular imaging in gastroenterology: A route for personalized endoscopy.

With the rapid expansion and diversification of the repertoire of biological agents utilized in inflammatory bowel diseases and cancer and the increase in oncological patients in gastroenterology, visualization of single receptor or molecular target expression and the subsequent initiation of expression tailored therapy are gaining increasing attention. Through the combination of utilizing fluorescently labeled probes with high specificity towards defined molecular targets and their subsequent detection and visualization with endoscopic devices, molecular imaging is a new emerging field focusing on the receptor expression within the mucosa on a cellular level rather than on macroscopic changes. In the past years various new technological and molecular probes have been successfully utilized for molecular imaging. Within this review, we summarize different technologies as well as molecular probes applied in molecular imaging and review current and past approaches for functional imaging with molecular endoscopy within the GI Tract and resulting clinical applications. It can be expected that molecular imaging allows for individualized diagnostic approaches and patient tailored medicine in the future.

I-scan optical enhancement for the in vivo prediction of diminutive colorectal polyp histology: Results from a prospective three-phased multicentre trial.

BACKGROUND AND AIMS: Dye-less chromoendoscopy is an emerging technology for colorectal polyp characterization. Herein, we investigated whether the newly introduced I-scan optical enhancement (OE) can accurately predict polyp histology in vivo in real-time. METHODS: In this prospective three-phased study, 84 patients with 230 diminutive colorectal polyps were included. During the first two study phases, five endoscopists assessed whether analysis of polyp colour, surface and vascular pattern under i-scan OE can differentiate in vivo between adenomatous and hyperplastic polyps. Finally, junior and experienced endoscopists (JE, EE, each n = 4) not involved in the prior study phases made a post hoc diagnosis of polyp histology using a static i-scan OE image database. Histopathology was used as a gold-standard in all study phases. RESULTS: The overall accuracy of i-scan OE for histology prediction was 90% with a sensitivity, specificity, positive (PPV) and negative prediction value (NPV) of 91%, 90%, 86% and 94%, respectively. In high confidence predictions, the diagnostic accuracy increased to 93% with sensitivity, specificity, PPV and NPV of 94%, 91%, 89% and 96%. Colonoscopy surveillance intervals were predicted correctly in ≥ 90% of patients. In the post hoc analysis EE predicted polyp histology under i-scan OE with an overall accuracy of 91%. After a single training session, JE achieved a comparable diagnostic performance for predicting polyp histology with i-scan OE. CONCLUSION: The histology of diminutive colorectal polyps can be accurately predicted with i-scan OE in vivo in real-time. Furthermore, polyp differentiation with i-scan OE appears to require only a short learning curve.

Double fluorescent labelling of a bipolar epithelial cell in vitro: The outer hair cell.

BACKGROUND: Fluorescence membrane markers are efficient tools for visualizing the dynamics of membrane recycling processes in living cells. The outer hair cell (OHC) - a bipolar epithelial cell in the cochlea - possesses endocytic activity at both its apical and basal poles. The best visual overview of transcytosis in the OHC is achieved when the cell is isolated, so that both the apical and the basal poles are in the same focal plane to allow confocal imaging. Until now, fluorescent markers were applied to the extracellular environment of isolated OHCs without distinguishing the apical and basal poles. The drawback of that configuration is that apicobasal and basoapical vesicle traffic labelled at the opposite poles cannot be visualized independently because the same fluorescent marker has access to both poles. NEW METHOD: A double-barrel, capillary perfusion system was developed to independently stain either one pole or both the apical and the basal poles of isolated OHCs using different types of fluorescence membrane markers. RESULTS: Producing laminar fluid flow, the double-barrel perfusor allows investigation of the dynamics of apicobasal and basoapical vesicle traffic independently and/or simultaneously in the same OHC. COMPARISON WITH EXISTING METHOD: This method offers a unique option for investigating bidirectional vesicle traffic in bipolar epithelial cells, which is superior to other already established labelling techniques. CONCLUSIONS: The double-barrel perfusion system, suitable for selectively staining a longitudinal section of the plasma membrane of an isolated bipolar epithelial cell, opens new possibilities for investigating cell labelling and intracellular vesicle traffic.