Integrating the Patient Perspective to Validate a Measure of Disease Severity in Inflammatory Bowel Disease: Online Survey of Patients and Their Physicians.

BACKGROUND: The patient perspective is essential for assessing disease severity, but it is not always adequately considered. We describe how a comprehensive clinical disease severity index (DSI) for inflammatory bowel disease (IBD) correlates with patient global self-assessment (PGSA). METHODS: In an individually linked parallel online survey, physicians provided the DSI, and patients provided self-assessed severity using a global question and visual analog scale (0-100) (PGSA). Mean DSI values by PGSA were calculated with 95% confidence intervals. Pearson correlation (r) and the intraclass correlation coefficient were calculated for PGSA vs DSI. Positive predictive values for identifying severe disease with PGSA categories as a reference were based on a threshold >22 points. RESULTS: The primary analysis included 89 pairs (46 Crohn's disease [CD], 43 ulcerative colitis [UC]) with strict criteria and 147 pairs when less stringent. Common reasons for exclusion were missing values for albumin or colonoscopy. Mean DSI values showed no clear trend with increasing PGSA in CD but good discrimination between moderate, severe, and very severe PGSA in UC. For PGSA on the visual analog scale, r was 0.54 for CD and 0.59 for UC (difference in means: CD 27.7, UC 13.8; intraclass correlation coefficient: CD 0.48, UC 0.58). A high DSI predicted severe disease in 76.2% of CD and 65.2% of UC. CONCLUSIONS: The DSI showed good discrimination for patient-reported disease severity in UC but performed unsatisfactorily in CD. Correlations were moderate. Further refinement of the DSI is suggested to better reflect the patient perspective.

The performance of an inflammatory bowel disease severity score was compared with self-perceived severity based on an individually linked online survey of patients and their physicians. Agreement and prediction of severe disease were moderate and should be improved by integrating the patients' perspective.

Quantitative Phase Imaging Using Digital Holographic Microscopy to Assess the Degree of Intestinal Inflammation in Patients with Ulcerative Colitis.

Ulcerative colitis (UC) is characterized by chronic inflammation of the colorectum. Histological remission has emerged as a potential future treatment goal; however, the histopathological assessment of intestinal inflammation in UC remains challenging with a multitude of available scoring systems and the need for a pathologist with expertise in inflammatory bowel disease (IBD). In previous studies, quantitative phase imaging (QPI) including digital holographic microscopy (DHM) was successfully applied as an objective method for stain-free quantification of the degree of inflammation in tissue sections. Here, we evaluated the application of DHM for the quantitative assessment of histopathological inflammation in patients with UC. In our study, endoscopically obtained colonic and rectal mucosal biopsy samples from 21 patients with UC were analyzed by capturing DHM-based QPI images that were subsequently evaluated using the subepithelial refractive index (RI). The retrieved RI data were correlated with established histological scoring systems including the Nancy index (NI) as well as with endoscopic and clinical findings. As a primary endpoint, we found a significant correlation between the DHM-based retrieved RI and the NI (R2 = 0.251, p < 0.001). Furthermore, RI values correlated with the Mayo endoscopic subscore (MES; R2 = 0.176, p < 0.001). An area under the receiver operating characteristics (ROC) curve of 0.820 confirms the subepithelial RI as a reliable parameter to distinguish biopsies with histologically active UC from biopsies without evidence of active disease as determined by conventional histopathological examination. An RI higher than 1.3488 was found to be the most sensitive and specific cut-off value to identify histologically active UC (sensitivity of 84% and specificity of 72%). In conclusion, our data demonstrate DHM to be a reliable tool for the quantitative assessment of mucosal inflammation in patients with UC.

Utility of Digital Single-operator Video Cholangioscopy for the Endoscopic Management of Biliary Complications After Liver Transplantation-A Single-center Experience.

BACKGROUND: Liver transplant recipients (LTRs) frequently develop biliary complications, and endoscopy is crucial for their subsequent management. Recently, single-operator video cholangioscopy (SOVC) with digital imaging quality was introduced. This study evaluated the utility of digital SOVC for the management of biliary complications in LTRs. METHODS: This observational study retrospectively analyzed all LTRs undergoing digital SOVC between 2015 and 2019 at a tertiary referral center. Endpoints included the assessment of biliary strictures, performance of selective guidewire passage across biliary strictures, and diagnosis and treatment of biliary stone disease. RESULTS: In total, 79 digital SOVCs performed in 50 LTRs were identified. Fifty-eight percent of the procedures were performed for biliary stricture assessment, and using visual signs or guided biopsies, SOVC excluded malignancy in all cases (100%). Of all the examinations, 29.1% (23/79) were performed solely because of a previous failure of conventional endoscopic methods to pass a guidewire across a biliary stricture. Using SOVC, guidewire passage was successfully performed in 73.9% of these examinations, enabling subsequent endoscopic therapy. Furthermore, biliary stones were found in 16.5% (13/79) of the examinations. In 38.5% of these cases, standard fluoroscopy failed to detect stones, which were only visualized using digital SOVC. Biliary stone treatment was successful in 92% (12/13) of the examinations. Complications occurred in 11.4% of all SOVCs. No procedure-associated mortalities were observed. CONCLUSIONS: Digital SOVC is effective and safe for the endoscopic management of biliary complications in LTRs and offers unique diagnostic and therapeutic opportunities that strongly impact the clinical course in selected cases.

Balloon enteroscopy-assisted endoscopic retrograde cholangiography and rendezvous procedures in patients with altered gastrointestinal anatomy.

BACKGROUND: Standard endoscopic retrograde cholangiography (ERC) frequently fails to treat biliary obstruction in patients with altered gastrointestinal anatomy. Balloon enteroscopy-assisted ERC (BE-ERC) and combined percutaneous transhepatic endoscopic rendezvous procedures (PTE-RVs) may offer effective rescue approaches. OBJECTIVE: This study aimed to evaluate the efficacy and safety of BE-ERC and PTE-RV for the treatment of biliary obstruction in patients with altered gastrointestinal anatomy. METHODS: In this observational study, all patients with altered gastrointestinal anatomy underwent BE-ERC between 2003 and 2016 at a tertiary referral center. In case of procedural failure, a combined PTE-RV was performed in selected cases. Endpoints included the success and safety of the procedures. RESULTS: A total of 180 BE-ERC performed in 106 patients with altered gastrointestinal anatomy were included. Of the procedures, 76.7% were performed due to benign and 23.3% due to malignant biliary obstruction. BE-ERC was successful in 53% (96/180) of cases. In case of failure, in 23/32 cases a combined PTE-RV was successfully performed, improving the overall success rate of BE-ERC, including PTE-RV, to 66% (119/180). Benign biliary obstruction and repeated procedures were positive predictors of successful BE-ERC (odds ratio 6.8 (95% CI 2.7-17.0), p < .001 and odds ratio 4.1 (2.1-8.2), p < .001). Complications were significantly more frequent in combined PTE-RVs than in BE-ERC procedures alone (34.4% vs. 7.4%; p < .001). CONCLUSIONS: BE-ERC is effective and safe for the endoscopic management of patients with altered gastrointestinal anatomy and percutaneous transhepatic rendezvous procedures can substantially increase success rates in selected cases.

Digital single-operator video cholangioscopy improves endoscopic management in patients with primary sclerosing cholangitis-a retrospective observational study.

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) are at a high risk of developing cholestatic liver disease and biliary cancer, and endoscopy is crucial for the complex management of these patients. AIM: To clarify the utility of recently introduced digital single-operator video cholangioscopy (SOVC) for the endoscopic management of PSC patients. METHODS: In this observational study, all patients with a history of PSC and in whom digital SOVC (using the SpyGlass DS System) was performed between 2015 and 2019 were included and retrospectively analysed. Examinations were performed at a tertiary referral centre in Germany. In total, 46 SOVCs performed in 38 patients with a history of PSC were identified. The primary endpoint was the evaluation of dominant biliary strictures using digital SOVC, and the secondary endpoints were the performance of selective guidewire passage across biliary strictures and the diagnosis and treatment of biliary stone disease in PSC patients. RESULTS: The 22 of 38 patients had a dominant biliary stricture (57.9%). In 4 of these 22 patients, a cholangiocellular carcinoma was diagnosed within the stricture (18.2%). Diagnostic evaluation of dominant biliary strictures using optical signs showed a sensitivity of 75% and a specificity of 94.4% to detect malignant strictures, whereas SOVC-guided biopsies to gain tissue for histopathological analysis showed a sensitivity of 50% and a specificity of 100%. In 13% of examinations, SOVC was helpful for guidewire passage across biliary strictures that could not be passed by conventional methods (technical success rate 100%). Biliary stone disease was observed in 17.4% of examinations; of these, in 37.5% of examinations, biliary stones could only be visualized by SOVC and not by standard fluoroscopy. Biliary stone treatment was successful in all cases (100%); 25% required SOVC-assisted electrohydraulic lithotripsy. Complications, such as postinterventional cholangitis and pancreatitis, occurred in 13% of examinations; however, no procedure-associated mortality occurred. CONCLUSION: Digital SOVC is effective and safe for the endoscopic management of PSC patients and may be regularly considered an additive tool for the complex endoscopic management of these patients.

Humoral Immune Response in IBD Patients Three and Six Months after Vaccination with the SARS-CoV-2 mRNA Vaccines mRNA-1273 and BNT162b2.

Severe acute respiratory syndrome coronovirus-2 (SARS-CoV-2) is the cause of the coronavirus disease 2019 (COVID-19) pandemic. Vaccination is considered the core approach to containing the pandemic. There is currently insufficient evidence on the efficacy of these vaccines in immunosuppressed inflammatory bowel disease (IBD) patients. The aim of this study was to investigate the humoral response in immunosuppressed IBD patients after COVID-19 mRNA vaccination. In this prospective study, IgG antibody levels (AB) against the SARS-CoV-2 receptor-binding domain (spike-protein) were quantitatively determined. For assessing the potential neutralizing capacity, a SARS-CoV-2 surrogate neutralization test (sVNT) was employed in IBD patients (n = 95) and healthy controls (n = 38). Sera were examined prior to the first/second vaccination and 3/6 months after second vaccination. Patients showed lower sVNT (%) and IgG-S (AU/mL) AB both before the second vaccination (sVNT p < 0.001; AB p < 0.001) and 3 (sVNT p = 0.002; AB p = 0.001) and 6 months (sVNT p = 0.062; AB p = 0.061) after the second vaccination. Although seroconversion rates (sVNT, IgG-S) did not differ between the two groups 3 months after second vaccination, a significant difference was seen 6 months after second vaccination (sVNT p = 0.045). Before and three months after the second vaccination, patients treated with anti-tumor necrosis factor (TNF) agents showed significantly lower AB than healthy subjects. In conclusion, an early booster shot vaccination should be discussed for IBD patients on anti-TNF therapy.

International consensus to standardise histopathological scoring for small bowel strictures in Crohn's disease.

OBJECTIVE: Effective medical therapy and validated trial outcomes are lacking for small bowel Crohn's disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion. DESIGN: Modified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures. RESULTS: In this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials. CONCLUSION: Standardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.

Loss of Mucosal p32/gC1qR/HABP1 Triggers Energy Deficiency and Impairs Goblet Cell Differentiation in Ulcerative Colitis.

BACKGROUND & AIMS: Cell differentiation in the colonic crypt is driven by a metabolic switch from glycolysis to mitochondrial oxidation. Mitochondrial and goblet cell dysfunction have been attributed to the pathology of ulcerative colitis (UC). We hypothesized that p32/gC1qR/HABP1, which critically maintains oxidative phosphorylation, is involved in goblet cell differentiation and hence in the pathogenesis of UC. METHODS: Ex vivo, goblet cell differentiation in relation to p32 expression and mitochondrial function was studied in tissue biopsies from UC patients versus controls. Functional studies were performed in goblet cell-like HT29-MTX cells in vitro. Mitochondrial respiratory chain complex V-deficient, ATP8 mutant mice were utilized as a confirmatory model. Nutritional intervention studies were performed in C57BL/6 mice. RESULTS: In UC patients in remission, colonic goblet cell differentiation was significantly decreased compared to controls in a p32-dependent manner. Plasma/serum L-lactate and colonic pAMPK level were increased, pointing at high glycolytic activity and energy deficiency. Consistently, p32 silencing in mucus-secreting HT29-MTX cells abolished butyrate-induced differentiation and induced a shift towards glycolysis. In ATP8 mutant mice, colonic p32 expression correlated with loss of differentiated goblet cells, resulting in a thinner mucus layer. Conversely, feeding mice an isocaloric glucose-free, high-protein diet increased mucosal energy supply that promoted colonic p32 level, goblet cell differentiation and mucus production. CONCLUSION: We here describe a new molecular mechanism linking mucosal energy deficiency in UC to impaired, p32-dependent goblet cell differentiation that may be therapeutically prevented by nutritional intervention.

[Acute Abdomen: Diagnostic Management]. / Akutes Abdomen: Diagnostik.

Acute abdomen is a common and sometimes dramatic clinical condition, which can be fatal if diagnosis is not made in time. A large number of diseases can cause an acute abdomen which makes a targeted and rapid diagnostic approach utterly important. The initial diagnostic approach is based on the clinical assessment (including medical history and physical examination) which allows doctors to quickly establish a suspected diagnosis with a relatively high sensitivity but a rather low specificity. Further diagnostics, including laboratory markers, imaging and - if necessary - interventional diagnostics should be initiated quickly after the first clinical assessment in order to confirm the suspected diagnosis or to further classify unclear cases. The clinical assessment is the leading diagnostic tool that determines further diagnostic approaches for patients with an acute abdomen and thus enables adequate and timely therapy.

Systematic review with meta-analysis: efficacy of balloon-assisted enteroscopy for dilation of small bowel Crohn's disease strictures.

BACKGROUND: Evidence for endoscopic balloon dilation of small intestinal strictures in Crohn's disease (CD) using balloon-assisted enteroscopy is scarce. AIM: To evaluate endoscopic balloon dilation for the treatment of small intestinal CD strictures using balloon-assisted enteroscopy. METHODS: Citations in Embase, MEDLINE, and Cochrane were systematically reviewed. In a meta-analysis of 18 studies with 463 patients and 1189 endoscopic balloon dilations, technical success was defined as the ability to dilate a stricture. Individual data were also obtained on 218 patients to identify outcome-relevant risk factors. RESULTS: In the pooled per-study analysis, technical success rate of endoscopic balloon dilation was 94.9%, resulting in short-term clinical efficacy in 82.3% of patients. Major complications occurred in 5.3% of patients. During follow-up, 48.3% of patients reported symptom recurrence, 38.8% were re-dilated and 27.4% proceeded to surgery. On the per-patient-based multivariable analysis, that patients with disease activity in the small intestine had lower short-term clinical efficacy (odds ratio 0.32; 95% confidence interval 0.14-0.73, P = 0.007). Patients with concomitant active disease in the small and/or large intestine had an increased risk to proceed toward surgery (hazard ratio 1.85; 95% confidence interval 1.09-3.13, P = 0.02 and hazard ratio 1.77; 95% confidence interval 1.34-2.34, P < 0.001). CONCLUSIONS: Balloon-assisted enteroscopy for dilatation of CD-associated small intestinal strictures has high short-term technical and clinical efficacy and low complication rates. However, up to two-thirds of patients need re-dilation or surgery.

Conversion from Standard-Release Tacrolimus to MeltDose® Tacrolimus (LCPT) Improves Renal Function after Liver Transplantation.

Renal impairment is a typical side effect of tacrolimus (Tac) treatment in liver transplant (LT) recipients. One strategy to avoid renal dysfunction is to increase the concentration/dose (C/D) ratio by improving drug bioavailability. LT recipients converted from standard-release Tac to MeltDose® Tac (LCPT), a novel technological formulation, were able to reduce the required Tac dose due to higher bioavailability. Hence, we hypothesize that such a conversion increases the C/D ratio, resulting in a preservation of renal function. In the intervention group, patients were switched from standard-release Tac to LCPT. Clinical data were collected for 12 months after conversion. Patients maintained on standard-release Tac were enrolled as a control group. Twelve months after conversion to LCPT, median C/D ratio had increased significantly by 50% (p < 0.001), with the first significant increase seen 3 months after conversion (p = 0.008). In contrast, C/D ratio in the control group was unchanged after 12 months (1.75 vs. 1.76; p = 0.847). Estimated glomerular filtration rate (eGFR) had already significantly deteriorated in the control group at 9 months (65.6 vs. 70.6 mL/min/1.73 m2 at study onset; p = 0.006). Notably, patients converted to LCPT already had significant recovery of mean eGFR 6 months after conversion (67.5 vs. 65.3 mL/min/1.73 m2 at study onset; p = 0.029). In summary, conversion of LT recipients to LCPT increased C/D ratio associated with renal function improvement.

MicroRNA-320a Monitors Intestinal Disease Activity in Patients With Inflammatory Bowel Disease.

OBJECTIVES: In patients with inflammatory bowel disease (IBD), a treat-to-target treatment strategy requires tight monitoring of disease activity. Noninvasive biomarkers may help to monitor the intestinal disease activity. We demonstrated recently that peripheral microRNA (miR)-320a expression in mice follows the course of experimental colitis. The aim of this study was to evaluate the potential of miR-320a to monitor the disease activity in patients with IBD, to predict the course of disease, and to distinguish IBD from infectious colitis. METHODS: The miR-320a levels were prospectively assessed by quantitative real-time polymerase chain reaction analysis of peripheral blood samples from 40 patients with Crohn's disease (CD) and 37 patients with ulcerative colitis (UC) as well as from 19 healthy control individuals and 7 patients with infectious colitis. Disease activity was quantified by appropriate clinical disease indices and endoscopic scoring systems. RESULTS: When compared with healthy controls, miR-320a blood levels were significantly increased in patients with active CD and UC (16.1 ± 2.6 vs 2,573 ± 941; vs 434 ± 96; both P < 0.001) and patients with IBD in remission (316 ± 251 [CD] and 91 ± 29 [UC]; both P < 0.001). In patients with CD, miR-320a levels showed a strong correlation with the endoscopic disease activity (r = 0.76; P < 0.001). Similarly, in patients with UC, we detected a significantly enhanced miR-320a expression, which was highest in patients with severe endoscopic disease activity (eMayo = 0-1: 66 ± 16 vs eMayo = 2: 352 ± 102; vs eMayo = 3: 577 ± 206; both P < 0.001). Finally, miR-320a blood expression in patients with active CD and UC significantly increased compared with patients with infectious colitis (63 ± 13, P < 0.001). DISCUSSION: MiR-320a expression in peripheral blood from patients with IBD follows the clinical and endoscopic disease activities and may help to distinguish IBD from infectious colitis.

Inflammatory Bowel Disease-associated GP2 Autoantibodies Inhibit Mucosal Immune Response to Adherent-invasive Bacteria.

Adherent-invasive Escherichia coli have been suggested to play a pivotal role within the pathophysiology of inflammatory bowel disease (IBD). Autoantibodies against distinct splicing variants of glycoprotein 2 (GP2), an intestinal receptor of the bacterial adhesin FimH, frequently occur in IBD patients. Hence, we aimed to functionally characterize GP2-directed autoantibodies as a putative part of IBD's pathophysiology. Ex vivo, GP2-splicing variant 4 (GP2#4) but not variant 2 was expressed on intestinal M or L cells with elevated expression patterns in IBD patients. The GP2#4 expression was induced in vitro by tumor necrosis factor (TNF)-α. The IBD-associated GP2 autoantibodies inhibited FimH binding to GP2#4 and were decreased in anti-TNFα-treated Crohn's disease patients with ileocolonic disease manifestation. In vivo, mice immunized against GP2 before infection with adherent-invasive bacteria displayed exacerbated intestinal inflammation. In summary, autoimmunity against intestinal expressed GP2#4 results in enhanced attachment of flagellated bacteria to the intestinal epithelium and thereby may drive IBD's pathophysiology.

Serum levels of ferritin and transferrin serve as prognostic factors for mortality and survival in patients with end-stage liver disease: A propensity score-matched cohort study.

BACKGROUND: Patients with end-stage liver disease are known to suffer from a significantly high risk of mortality, but accurate prediction of the course of disease is challenging. OBJECTIVE: The study aim was to evaluate the independent prognostic and clinical importance of serum levels of ferritin and transferrin for 90-day survival of patients with liver disease. METHODS: Patients with end-stage liver disease treated during a 2-year period were enrolled retrospectively in a single-centre study. Unmatched and propensity score matching (PSM) analyses were applied. RESULTS: The study cohort comprised 286 patients with end-stage liver disease, of which 22.9% died during the observational period. High serum ferritin levels and low serum transferrin levels were associated significantly with increased 90-day mortality in the unmatched (p < 0.001) and PSM study population (p = 0.017). Serum levels of ferritin and transferrin had high prognostic capability to predict 90-day survival similar to the Model for End-stage Liver Disease. Patients with serum ferritin values >1030.5 µg/l had a 50% risk of dying within 11 days after measurement, which translated up to a 90-day mortality of 83%. CONCLUSION: Serum levels of ferritin and transferrin have independent and excellent capabilities to determine prognosis in patients with end-stage liver disease. Ferritin measurements can reliably identify those with high mortality in daily practice.

Digital single-operator video cholangioscopy in treating refractory biliary stones: a multicenter observational study.

BACKGROUND: Standard endoscopic treatment might fail to treat biliary stone disease. Here, we investigated the efficacy and safety of recently introduced digital single-operator video cholangioscopy (SOVC) for the treatment of difficult biliary stones. METHODS: Digital SOVC procedures, performed in two tertiary referral centers between 2015 and 2018, were retrospectively analyzed. Only patients with a previous failure of endoscopic standard treatment and a SOVC-based biliary stone treatment using electrohydraulic lithotripsy (EHL) or laser lithotripsy (LL) were included. The primary endpoint was to evaluate the stone removal rate per procedure and per patient. RESULTS: In total, 75 examinations with a digital SOVC-assisted biliary stone treatment, performed in 60 patients, were identified. Biliary stones were mainly located extrahepatic (64%) and less frequently intrahepatic (36%). The median stone size was 20 mm (interquartile range [IQR]: 10-25 mm) and the median stone number was 1 (IQR: 1-2). Digital SOVC-based treatment of biliary stone disease was successful in 95% of patients and 15% needed at least two treatment sessions. Evaluated per procedure, a complete stone removal was accomplished in 67% of all examinations (including initial and repeated procedures), while an incomplete stone removal was observed in 33% of cases. The per procedure analyzes revealed that the success rates for a complete stone removal were similar between LL and EHL (66% vs. 68%; p = 0.87). Complications, such as postinterventional cholangitis and pancreatitis occurred in 16% of examinations; however, except from one case, all were mild or moderate and no procedure-associated mortality occurred. CONCLUSIONS: Digital SOVC-assisted biliary stone treatment is highly effective even in cases with difficult biliary stones and might be considered the new standard of care for these patients. Furthermore, mild up to moderate complications were intermittently observed which might document the complexity of our included cases.

Histopathology Scoring Systems of Stenosis Associated With Small Bowel Crohn's Disease: A Systematic Review.

BACKGROUND & AIMS: Stenosis is a common complication of Crohn's disease (CD) that has no effective medical therapy. Development of antifibrotic agents will require testing in randomized controlled trials. Computed tomography enterography- and magnetic resonance enterography-based technologies might be used to measure outcomes in these trials. These approaches have been validated in studies of patients with symptomatic strictures who underwent imaging evaluations followed by resection with histopathologic grading of the intestinal tissue for inflammation and/or fibrosis (the reference standard). Imaging findings have correlated with findings from quantitative or semiquantitative histologic evaluation of the degree of fibromuscular stenosis and/or inflammation on the resection specimen. However, it is not clear whether histologic findings are an accurate reference standard. We performed a systematic review of all published histologic scoring systems used to assess stenosing CD. METHODS: We performed a comprehensive search of Embase and MEDLINE of studies through March 13, 2019, that used a histologic scoring system to characterize small bowel CD and assessed inflammatory and fibrotic alterations within the same adult individual. All scores fitting the criteria were included in our analysis, independent of the presence of stricturing disease, as long as inflammation and fibrosis were evaluated separately but in the same scoring system. RESULTS: We observed substantial heterogeneity among the scoring systems, which were not derived from modern principles for evaluative index development. None had undergone formal validity or reliability testing. None of the existing indices had been constructed according to accepted methods for the development of evaluative indices. Basic knowledge regarding their operating properties were lacking. Specific indices for evaluating the important pathologic component of myofibroblast hypertrophy or hyperplasia have not been proposed. CONCLUSIONS: In a systematic review of publications, we found a lack of validated histopathologic scoring systems for assessment of fibromuscular stenosis. Data that describe the operating properties of existing cross-sectional imaging techniques for stenosing CD should be questioned. Development and validation of a histopathology index is an important research priority.

Quantitative Phase Imaging Using Digital Holographic Microscopy Reliably Assesses Morphology and Reflects Elastic Properties of Fibrotic Intestinal Tissue.

Intestinal strictures are a frequent complication in patients with Crohn's Disease (CD) and the presence of fibrosis within strictures impacts the therapeutic treatment approach. Here, we evaluate quantitative phase imaging (QPI) using digital holographic microscopy (DHM) for the evaluation of fibrosis within CD strictures. 30 full thickness resection specimens were obtained from non-stenotic and stenotic tissue areas of 15 CD patients. Cryostat sections were analyzed by DHM to measure the spatial distribution of the refractive index (RI) to quantify tissue density. Complementary, histopathological evaluation of H&E staining and immunofluorescence (IF) targeting fibrosis markers served as the gold standard. Moreover, tissue stiffness was evaluated by elastography. RI values assessed by DHM were significantly higher in stenotic compared to non-stenotic tissue areas (p < 0.001). Histopathological analysis using H&E staining and IF confirmed the elevated expression of fibrosis markers in stenotic compared to non-stenotic tissue (all p < 0.001). The RI retrieved by DHM strongly correlated with the amount of fibrosis as determined by IF (p < 0.001; R2 = 0.48). Furthermore, elastography detected a significantly higher tissue stiffness in stenotic as compared to non-stenotic tissue sections (p < 0.001). In conclusion, QPI using DHM accurately assesses fibrotic properties of CD-associated strictures and may improve the characterization of CD strictures.

Target-Specific Fluorescence-Mediated Tomography for Non-Invasive and Dynamic Assessment of Early Neutrophil Infiltration in Murine Experimental Colitis.

The role of neutrophils in the pathogenesis of inflammatory bowel disease (IBD) is still only incompletely understood. Here, we evaluated target-specific fluorescence-mediated tomography (FMT) for visualization of neutrophil infiltration in murine experimental DSS-induced colitis. Colitis was assessed using clinical, endoscopic, and histopathological parameters. Intestinal neutrophil infiltration was determined at day 0, 4, and 10 by targeted FMT after injection of a neutrophil-specific fluorescence-labelled monoclonal antibody (Gr-1). Complementary, immunofluorescence tissue sections with Gr-1 and ELISA-based assessment of tissue myeloperoxidase (MPO) served as the gold standard for the quantification of neutrophil infiltration. Colitic animals showed decreasing body weight, presence of fecal occult blood, and endoscopic signs of inflammation. FMT revealed a significantly increased level of fluorescence only four days after colitis induction as compared to pre-experimental conditions (pmol tracer 73.2 ± 18.1 versus 738.6 ± 80.7; p < 0.05), while neither body weight nor endoscopic assessment showed significant changes at this early time. Confirmatory, post-mortem immunofluorescence studies and measurements of tissue MPO confirmed the presence of increased neutrophil infiltration in colitic mice compared to controls. Concluding, Gr-1 targeted FMT can detect early colonic infiltration of neutrophils in experimental colitis even before clinical symptoms or endoscopic alterations occur. Therefore, FMT might be an important tool for repetitive and non-invasive monitoring of inflammatory cell infiltrate in intestinal inflammation.

Endoscopic Radiofrequency Ablation Prolongs Survival of Patients with Unresectable Hilar Cholangiocellular Carcinoma - A Case-Control Study.

The life expectancy of unresectable hilar cholangiocellular carcinomas (CCCs) is very limited and endoscopic radiofrequency ablation (ERFA) of the biliary tract may prolong survival. Our single-center-study retrospectively analysed all CCC cases, in whom ERFAs of the biliary tract were performed between 2012 and 2017 and compared these to historical control cases who received the standard treatment of sole stent application. ERFA was performed in 32 patients with malignant biliary strictures that were mainly caused by Bismuth III and IV hilar CCCs (66%). 14 of these patients received repeated ERFAs, for an overall performance of 54 ERFAs. Stents were applied after examination of all patients (100%). Adverse events occurred in 18.5% of examinations. Case-control analysis revealed that the survival time of cases with unresectable Bismuth type III and IV hilar CCCs (n = 20) treated with combined ERFA and stent application significantly increased compared to controls (n = 22) treated with sole stent application (342 +/- 57 vs. 221 +/- 26 days; p = 0.046). In conclusion, ERFA therapy significantly prolonged survival in patients with unresectable Bismuth type III and IV hilar CCC. As an effective and safe method, ERFA should be considered as a palliative treatment for all these patients.