Immunomonitoring via ELISPOT Assay Reveals Attenuated T-Cell Immunity to CMV in Immunocompromised Liver-Transplant Patients.

Assessing immune responses to cytomegalovirus (CMV) after liver transplant in patients on immunosuppressive therapy remains challenging. In this study, employing ELISPOT assays, 52 liver-transplant recipients were evaluated for antiviral T-cell activity in peripheral blood mononuclear cells (PBMCs), measuring interferon-γ (IFN-γ) secretion upon stimulation with CMV-specific peptides (CMV peptide pool, CMV IE-1, and pp65 antigens). Parameters such as stimulation index, mean spot size, and mean spot count were measured. The study found that heightened immunosuppression, especially with prednisolone in triple therapy, significantly dampened CMV-specific immune responses. This was demonstrated by decreased IFN-γ production by CMV-specific T-cells (CMV peptide pool: p = 0.036; OR = 0.065 [95% CI: 0.005-0.840], pp65 antigen: p = 0.026; OR = 0.048 [95% CI: 0.003-0.699]). Increased immunosuppression correlated with reduced IFN-γ secretion per cell, reflected in smaller mean spot sizes for the CMV peptide pool (p = 0.019). Notably, shorter post-transplant intervals correlated with diminished antiviral T-cell IFN-γ release at two years (CMV peptide pool: p = 0.019; IE antigen: p = 0.010) and five years (CMV peptide pool: p = 0.0001; IE antigen: p = 0.002; pp65 antigen: p = 0.047), as did advancing age (pp65 antigen: p = 0.016, OR = 0.932, 95% CI: 0.881-0.987). Patients with undetectable CMV antigens had a notably higher risk of CMV reactivation within six months from blood collection, closely linked with triple immunosuppression and prednisolone use. These findings highlight the intricate interplay between immunosuppression, immune response dynamics, and CMV reactivation risk, emphasizing the necessity for tailored immunosuppressive strategies to mitigate CMV reactivation in liver-transplant recipients. It can be concluded that, particularly in the early months post-transplantation, the use of prednisolone as a third immunosuppressant should be critically reconsidered. Additionally, the use of prophylactic antiviral therapy effective against CMV in this context holds significant importance.

The role of cytoreductive surgery and HIPEC for the treatment of primary and secondary peritoneal malignancies-experience from a tertiary care center in Germany.

PURPOSE: Peritoneal surface malignancies (PSM) are commonly known to have a dismal prognosis. Over the past decades, novel techniques such as cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and pressurized intraperitoneal aerosol chemotherapy (PIPAC) have been introduced for the treatment of PSM which could improve the overall survival and quality of life of patients with PSM. The decision to proceed with CRS and HIPEC is often challenging due the complexity of the disease, the extent of the procedure, associated side effects, and potential risks. Here, we present our experience with CRS and HIPEC to add to the ongoing discussion about eligibility criteria, technical approach, and expected outcomes and contribute to the evolution of this powerful and promising tool in the multidisciplinary treatment of patients with primary and secondary PSM. METHODS: A single-center retrospective chart review was conducted and included a total of 40 patients treated with CRS and HIPEC from April 2020 to September 2022 at the University Hospital Münster Department of Surgery. All patients had histologically confirmed primary or secondary peritoneal malignancies of various primary origins. RESULTS: Our study included 22 patients with peritoneal metastases from gastric cancer (55%), 8 with pseudomyxoma peritonei (20%), 4 with mesothelioma of the peritoneum (10%), and 6 patients with PSM originating from other primary tumor locations. Median PCI at time of cytoreduction was 4 (0-25). Completeness of cytoreduction score was 0 in 37 patients (92.5%), 1 in two patients (5%), and 2 in one patient (2.5%). Median overall survival across all patients was 3.69 years. CONCLUSION: Complete cytoreduction during CRS and HIPEC can be achieved for patients with low PCI, for patients with high PCI in low-grade malignancies, and even for patients with initially high PCI in high-grade malignancies following a significant reduction of cancer burden due to extensive preoperative treatment with PIPAC and systemic chemotherapy.

Humoral Immunity in Immunosuppressed IBD Patients after the Third SARS-CoV-2 Vaccination: A Comparison with Healthy Control Subjects.

INTRODUCTION: The COVID-19 pandemic is a result of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccination against COVID-19 is crucial for preventing severe illness and controlling the pandemic. This study aimed to examine how immunosuppressed patients with inflammatory bowel disease (IBD) responded to the third mRNA vaccination against SARS-CoV-2. The patients were undergoing treatments such as anti-TNF (infliximab, adalimumab), anti-α4ß7 integrin (vedolizumab), anti-IL12/23 (ustekinumab) and azathioprine (purine analog). Their responses were compared to those of healthy individuals. METHODS: In this prospective study, 81 IBD patients and 15 healthy controls were enrolled 2-4 months after receiving the third mRNA vaccination. This study measured IgG antibody levels against the SARS-CoV-2 spike protein's receptor binding domain (RBD) and assessed potential neutralization capacity using a surrogate virus neutralization test (sVNT). RESULTS: Overall, immunosuppressed IBD patients (without SARS-CoV-2 infection) exhibited significantly lower levels of anti-S-IgG (anti-RBD-IgG) and binding inhibition in the sVNT after the third vaccination compared to healthy controls. Patients under anti-TNF therapy showed notably reduced anti-S-IgG levels after the booster vaccination, in contrast to those receiving ustekinumab and azathioprine (p = 0.030, p = 0.031). IBD patients on anti-TNF therapy demonstrated significantly increased anti-S-IgG levels following prior SARS-CoV-2 infection (p = 0.020). CONCLUSION: Even after the third vaccination, immunosuppressed IBD patients exhibited diminished humoral immunity compared to healthy controls, especially those on anti-TNF therapy. Cases of penetrating infections led to considerably higher antibody levels in IBD patients under anti-TNF therapy compared to uninfected patients. Further investigation through prospective studies in immunosuppressed IBD patients is needed to determine whether this effectively safeguards against future infections or severe disease.

Impaired Humoral Immunity with Concomitant Preserved T Cell Reactivity in IBD Patients on Treatment with Infliximab 6 Month after Vaccination with the SARS-CoV-2 mRNA Vaccine BNT162b2: A Pilot Study.

Introduction: The Coronavirus Disease 2019 (COVID-19) pandemic has been caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The most important approach to prevent severe disease progression and to contain the pandemic is the use of COVID-19 vaccines. The aim of this study was to investigate the humoral and cellular response in immunosuppressed patients with inflammatory bowel disease (IBD) on treatment with anti-TNF (infliximab, adalimumab) and anti-α4ß7-Integrin (vedolizumab) 6 months after mRNA vaccination against SARS-CoV-2 compared to healthy subjects. Methods: In this prospective study, 20 IBD patients and 9 healthy controls were included 6 months after the second BNT162b2 vaccination. In addition to quantitative determination of IgG antibody levels against the SARS-CoV-2 receptor-binding domain (RBD) of the spike protein subunit S1, a SARS-CoV-2 surrogate neutralization test (sVNT) was used to assess potential neutralization capacity. SARS-CoV-2-specific T-cell responses were measured using an interferon-γ (IFN-γ) release assay (IGRA; Euroimmun Medical Laboratory Diagnostics, Lübeck, Germany). Results: S-IgG could still be detected in the majority of IBD patients 6 months after second vaccination. Compared to healthy controls, IBD patients treated with anti-TNF agents showed both lower neutralizing activity in sVNT (percent inhibition of ACE2 receptor binding by RBD protein) and lower IgG-S (AU/mL) antibody levels (AB) (sVNT: 79% vs. 2%, p < 0. 001; AB: 1018 AU/mL vs. 141 AU/mL, p = 0.025). In contrast, patients on therapy with vedolizumab showed no impairment in humoral immune response (sVNT, S-IgG) compared with healthy controls. Specific T-cellular reactivity was detected in 73% of IBD patients and in 67% of healthy controls independent of immunosuppressive therapy (anti-TNF., vedolizumab) (p = 0.189). Conclusion: Six months after BNT162b2 vaccination, this study found significantly decreased antibody levels in patients under anti-TNF therapy. IBD patients under anti-TNF and vedolizumab therapy had no impairment of T-cellular reactivity compared to healthy controls at this time point. Further studies with larger collectives for confirmation should follow.

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.

How did absentee voting affect the 2020 U.S. election?

The 2020 U.S. election saw a record turnout, saw a huge increase in absentee voting, and brought unified national Democratic control­yet these facts alone do not imply that vote-by-mail increased turnout or benefited Democrats. Using new microdata on millions of individual voters and aggregated turnout data across all 50 states, this paper offers a causal analysis of the impact of absentee vote-by-mail during the COVID-19 (coronavirus disease 2019) pandemic. Focusing on natural experiments in Texas and Indiana, we find that 65-year-olds voted at nearly the same rate as 64-year-olds, despite the fact that only 65-year-olds could vote absentee without an excuse. Being just old enough to vote no-excuse absentee did not substantially increase Democratic turnout relative to Republican turnout. Voter interest appeared to be more important in driving turnout across vote modes, neutralizing the electoral impact of Democrats voting by mail at higher rates during the historic pandemic.

Vaccination against SARS-CoV-2 in Patients with Inflammatory Bowel Diseases: Where Do We Stand?

Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases (IBDs). Immunosuppressive medication is the main therapeutic approach to reducing inflammation of the gastrointestinal tract. Immunocompromised patients are more vulnerable to severe courses of illness after infection with common pathogens. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the pathogen of the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 leads to acute respiratory distress syndrome (ARDS) following severe pulmonal damage in a significant number of cases. The worldwide circulation of SARS-CoV-2 has led to major concerns about the management of IBD patients during the pandemic, as these patients are expected to be at greater risk of complications because of their underlying altered immunological condition and immunosuppressive therapies. Vaccination against SARS-CoV-2 is considered the main approach in containing the pandemic. Today, several vaccines have been shown to be highly effective in the prevention of SARS-CoV-2 infection and severe disease course in subjects without underlying conditions in respective registration studies. Patients with underlying conditions such as IBD and/or immunosuppressive therapies were not included in the registration studies, so little is known about effectiveness and safety of SARS-CoV-2 vaccination in immunocompromised IBD patients. This review provides an overview of the recent knowledge about vaccine response in IBD patients after vaccination against SARS-CoV-2.

Indications of Persistent Glycocalyx Damage in Convalescent COVID-19 Patients: A Prospective Multicenter Study and Hypothesis.

The COVID-19 pandemic is caused by the SARS CoV-2 virus and can lead to severe lung damage and hyperinflammation. In the context of COVID-19 infection, inflammation-induced degradation of the glycocalyx layer in endothelial cells has been demonstrated. Syndecan-1 (SDC-1) is an established parameter for measuring glycocalyx injury. This prospective, multicenter, observational, cross-sectional study analyzed SDC-1 levels in 24 convalescent patients that had been infected with SARS-CoV-2 with mild disease course without need of hospitalization. We included 13 age-matched healthy individuals and 10 age-matched hospitalized COVID-19 patients with acute mild disease course as controls. In convalescent COVID-19 patients, significantly elevated SDC-1 levels were detected after a median of 88 days after symptom onset compared to healthy controls, whereas no difference was found when compared to SDC-1 levels of hospitalized patients undergoing acute disease. This study is the first to demonstrate signs of endothelial damage in non-pre-diseased, convalescent COVID-19 patients after mild disease progression without hospitalization. The data are consistent with studies showing evidence of persistent endothelial damage after severe or critical disease progression. Further work to investigate endothelial damage in convalescent COVID-19 patients should follow.

Vitamin A Plasma Levels in COVID-19 Patients: A Prospective Multicenter Study and Hypothesis.

COVID-19 is a pandemic disease that causes severe pulmonary damage and hyperinflammation. Vitamin A is a crucial factor in the development of immune functions and is known to be reduced in cases of acute inflammation. This prospective, multicenter observational cross-sectional study analyzed vitamin A plasma levels in SARS-CoV-2 infected individuals, and 40 hospitalized patients were included. Of these, 22 developed critical disease (Acute Respiratory Distress Syndrome [ARDS]/Extracorporeal membrane oxygenation [ECMO]), 9 developed severe disease (oxygen supplementation), and 9 developed moderate disease (no oxygen supplementation). A total of 47 age-matched convalescent persons that had been earlier infected with SARS-CoV-2 were included as the control group. Vitamin A plasma levels were determined by high-performance liquid chromatography. Reduced vitamin A plasma levels correlated significantly with increased levels of inflammatory markers (CRP, ferritin) and with markers of acute SARS-CoV-2 infection (reduced lymphocyte count, LDH). Vitamin A levels were significantly lower in hospitalized patients than in convalescent persons (p < 0.01). Of the hospitalized patients, those who were critically ill showed significantly lower vitamin A levels than those who were moderately ill (p < 0.05). Vitamin A plasma levels below 0.2 mg/L were significantly associated with the development of ARDS (OR = 5.54 [1.01-30.26]; p = 0.048) and mortality (OR 5.21 [1.06-25.5], p = 0.042). Taken together, we conclude that vitamin A plasma levels in COVID-19 patients are reduced during acute inflammation and that severely reduced plasma levels of vitamin A are significantly associated with ARDS and mortality.

Prone Position in Mechanically Ventilated COVID-19 Patients: A Multicenter Study.

BACKGROUND: The prone position (PP) is increasingly used in mechanically ventilated coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) patients. However, studies investigating the influence of the PP are currently lacking in these patients. This is the first study to investigate the influence of the PP on the oxygenation and decarboxylation in COVID-19 patients. METHODS: A prospective bicentric study design was used, and in mechanically ventilated COVID-19 patients, PP was indicated from a partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FIO2) ratio of <200. Patients were left prone for 16 h each. Pressure levels, FIO2, were adjusted to ensure a PaO2 greater than 60 mmHg. Blood gas analyses were performed before (baseline 0.5 h), during (1/2/5.5/9.5/13 h), and after being in the PP (1 h), the circulatory/ventilation parameters were continuously monitored, and lung compliance (LC) was roughly calculated. Responders were defined compared to the baseline value (PaO2/FIO2 ratio increase of ≥15%; partial pressure of carbon dioxide (PaCO2) decrease of ≥2%). RESULTS: 13 patients were included and 36 PP sessions were conducted. Overall, PaO2/FIO2 increased significantly in the PP (p < 0.001). Most PaO2/FIO2 responders (29/36 PP sessions, 77%) were identified 9.5 h after turning prone (14% slow responders), while most PaCO2 responders (15/36 PP sessions, 42%) were identified 13 h after turning prone. A subgroup of patients (interval intubation to PP ≥3 days) showed less PaO2/FIO2 responders (16% vs. 77%). An increase in PaCO2 and minute ventilation in the PP showed a significant negative correlation (p < 0.001). LC (median before the PP = 38 mL/cm H2O; two patients with LC >80 mL/cm H2O) showed a significant positive correlation with the 28 day survival of patients (p = 0.01). CONCLUSION: The PP significantly improves oxygenation in COVID-19 ARDS patients. The data suggest that they also benefit most from an early PP. A decrease in minute ventilation may result in fewer PaCO2 responders. LC may be a predictive outcome parameter in COVID-19 patients. TRIAL REGISTRATION: Retrospectively registered.

Functional endoscopy in neurogenic dysphagia: a feasibility study focusing on the esophageal phase of swallowing.

Background and study aims Due to demographic transition, neurogenic dysphagia has become an increasingly recognized problem. Patients suffering from dysphagia often get caught between different clinical disciplines. In this study, we implemented a defined examination protocol for evaluating the whole swallowing process by functional endoscopy. Special focus was put on the esophageal phase of swallowing. Patients and methods This prospective observational multidisciplinary study evaluated 31 consecutive patients with suspected neurogenic dysphagia by transnasal access applying an ultrathin video endoscope. Thirty-one patients with gastroesophageal reflux symptoms were used as a control group. We applied a modified approach including standardized endoscopic positions to compare our findings with fiberoptic endoscopic evaluation of swallowing and high-resolution manometry. The primary outcome measure was feasibility of functional endoscopy. Secondary outcome measures were adverse events (AEs), tolerability, and pathologic endoscopic findings. Results Functional endoscopy was successfully performed in all patients. No AEs were recorded. A variety of disorders were documented by functional endoscopy: incomplete or delayed closure of the upper esophageal sphincter in retroflex view, clearance disturbance of tubular esophagus, esophageal hyperperistalsis, and hypomotility. Analysis of results obtained with the diagnostic tools showed some discrepancies. Conclusions By interdisciplinary cooperation with additional assessment of the esophageal phase of deglutition using the innovative method of functional endoscopy, the diagnosis of neurogenic disorders including dysphagia may be significantly improved, leading to a better clinical understanding of complex dysfunctional patterns. To the best of our knowledge, this is the first study to show that a retroflex view of the ultrathin video endoscope within the esophagus can be safely performed. [NCT01995929].

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.

Bowel Preparation With Polyethylene Glycol 3350 or Fasting Only Before Peroral Single-balloon Enteroscopy: A Randomized European Multicenter Trial.

BACKGROUND: Although bowel preparation before colonoscopy and capsule endoscopy is widely evaluated and usually follows established guidelines, a standard preparation regime for peroral small bowel enteroscopy is yet to be defined.The aim of the present study was to compare small bowel preparation with polyethylene glycol (PEG) and "fasting only" (FO) before peroral single-balloon enteroscopy (SBE). STUDY: We compared small bowel preparation with PEG versus "FO" for peroral SBE in a randomized European multicenter trial. Patients' and procedural characteristics were documented and carefully analyzed. Primary endpoint was the oral intubation depth of the small bowel. A modified Boston preparation scale was used to assess bowel cleansing as a secondary endpoint. RESULTS: In total, 43 patients were enrolled in this study (FO group: n=25; PEG group: n=18). In both groups, patients' characteristics were comparable. The indications for oral enteroscopy were equally distributed in both groups (P=0.894). The oral intubation depth was significantly higher in the PEG versus the FO group (261±87 vs. 203±66 cm; P=0.019; mean±SD), while the quality of bowel preparation was equally sufficient in both groups [complete visualization of the mucosa (Boston preparation scale) 83% versus 76% (P=1.000)]. CONCLUSIONS: Small bowel preparation with PEG for SBE yields significantly deeper intubation as compared with "FO" preparation. As patient comfort and safety was similar in both groups, PEG preparation might be favored, especially if deep intubation of the small bowel is desired. For patients requiring visualization of the proximal jejunum, a FO preparation seems to be sufficient.

Distinct Disease Phenotype of Ulcerative Colitis in Patients With Coincident Primary Sclerosing Cholangitis: Evidence From a Large Retrospective Study With Matched Cohorts.

BACKGROUND: Primary sclerosing cholangitis is a classical extraintestinal manifestation in patients with ulcerative colitis. However, the impact of primary sclerosing cholangitis on the disease course is incompletely understood. OBJECTIVE: This study aimed to assess the impact of primary sclerosing cholangitis on disease phenotype and its course in patients with ulcerative colitis. DESIGN: This is a retrospective study with 3:1 matched cohorts. SETTINGS: Tertiary care center's electronic database was used for data analysis from 2000 and 2018. PATIENTS: Of 782 patients with ulcerative colitis, 77 patients who had coincident primary sclerosing cholangitis were included. MAIN OUTCOME MEASURES: The primary outcomes evaluated were disease characteristics including colonic disease activity, temporal change of disease course, colorectal neoplasia, and colectomy rates. RESULTS: Disease activity during acute flares, assessed by the complete Mayo score, was significantly lower in patients with primary sclerosing cholangitis (6.2 vs 7.3; p < 0.001). In addition, disease activity in patients with primary sclerosing cholangitis was decreased, especially within the first 10 years after disease onset, and biological therapy with anti-tumor necrosis factor and anti-integrin agents was commenced less frequently (22% vs 35%; p = 0.043) and later (10-year risk: 17.4% vs 27.8%; p = 0.034). Patients with primary sclerosing cholangitis were younger at colitis diagnosis (23.3 vs 29.3 years; p < 0.001) and had more extensive disease (75% vs 46%; p < 0.001). Colorectal cancer was more frequently detected in patients with coincident primary sclerosing cholangitis (6/77 vs 16/705; p = 0.016). Colectomy rates did not differ between both groups (14.3% vs 14.5%; p = 0.56). In contrast, patients with ulcerative colitis had to undergo surgery more frequently because of therapy-refractant inflammation, whereas surgery due to neoplasia development was increased in patients with coincident primary sclerosing cholangitis (p = 0.013). LIMITATIONS: The study was limited by its retrospective design. CONCLUSION: Patients who have ulcerative colitis with coincident primary sclerosing cholangitis develop a distinct disease course characterized by an earlier disease onset and lower disease activity, but more frequent extensive disease manifestation and higher risk for colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B45. FENOTIPO DE ENFERMEDAD DISTINTIVO DE LA COLITIS ULCERATIVA EN PACIENTES CON COLANGITIS ESCLEROSANTE PRIMARIA CONCOMITANTE: EVIDENCIA DE UN ESTUDIO RETROSPECTIVO GRANDE CON COHORTES EMPAREJADAS: La colangitis esclerosante primaria es una manifestación extraintestinal clásica en pacientes con colitis ulcerativa. Sin embargo, el impacto de la colangitis esclerosante primaria en el curso de la enfermedad no es comprendido completamente.Evaluar el impacto de la colangitis esclerosante primaria en el fenotipo y curso de la enfermedad en pacientes con colitis ulcerativa.Este es un estudio retrospectivo con cohortes emparejadas 3:1.La base de datos electrónica de un centro de atención terciaria se utilizó para el análisis de datos de 2000 a 2018.782 pacientes con colitis ulcerativa, 77 padecían colangitis esclerosante primaria concomitante y fueron incluidos.Se evaluaron las características de la enfermedad, incluida la actividad de enfermedad colónica, el cambio temporal del curso de la enfermedad, la neoplasia colorrectal y las tasas de colectomía.La actividad de la enfermedad durante los brotes agudos, evaluada por la puntuación completa de Mayo, fue significativamente menor en pacientes con colangitis esclerosante primaria (6.2 vs 7.3; p < 0.001). Además, la actividad de la enfermedad en pacientes con colangitis esclerosante primaria se redujo especialmente en los primeros 10 años después del inicio de la enfermedad, y la terapia biológica con agentes anti-TNF y anti-integrina se inició con menos frecuencia (22% vs 35%; p = 0.043) y más tarde (riesgo a 10 años: 17.4% vs 27.8%; p = 0.034). Los pacientes con colangitis esclerosante primaria eran más jóvenes en el momento del diagnóstico de colitis (23.3 vs 29.3 años; p < 0.001) y tenían enfermedad más extensa (75% vs 46%; p < 0.001). El cáncer colorrectal se detectó con mayor frecuencia en pacientes con colangitis esclerosante primaria concomitante (6/77 vs 16/705; p = 0.016). Las tasas de colectomía no fueron diferentes entre ambos grupos (14.3% vs 14.5%; p = 0.56). En contraste, los pacientes con colitis ulcerativa tuvieron que someterse a cirugía con mayor frecuencia debido a inflamación refractaria a la terapia, mientras que el desarrollo de neoplasia se incrementó en pacientes con colangitis esclerosante primaria concomitante (p = 0.013).El estudio estuvo limitado por su diseño retrospectivo.Los pacientes con colitis ulcerativa con colangitis esclerosante primaria concomitante desarrollan un curso de enfermedad distintivo caracterizado por un inicio temprano de la enfermedad y una menor actividad de la enfermedad, pero con manifestación de enfermedad extensa más frecuente y un mayor riesgo de cáncer colorrectal. Vea el resumen en video en http://links.lww.com/DCR/B45.

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.

Percutaneous-transhepatic-endoscopic rendezvous procedures are effective and safe in patients with refractory bile duct obstruction.

Background: Percutaneous-transhepatic-endoscopic rendezvous procedures (PTE-RVs) are rescue approaches used to facilitate biliary drainage. Objective: The objective of this article is to evaluate the safety and the technical success of PTE-RVs in comparison with those of percutaneous transhepatic cholangiographies (PTCs). Methods: Percutaneous procedures performed over a 10-year period were retrospectively analyzed in a single-center cohort. Examinations were performed because of a previous or expected failure of standard endoscopic methods including endoscopic retrograde cholangiography (ERC) or balloon-assisted ERC to achieve biliary access. Results: In total, 553 percutaneous procedures including 163 PTE-RVs and 390 PTCs were performed. Overall, 71.3% of the patients suffered from malignant disease with pancreas-carcinoma (32.8%) and cholangio-carcinoma (19.0%) as the most frequent, while 28.7% of the patients suffered from benign disease. Many patients had a postoperative change in bowel anatomy (50.8%).PTC had a higher technical success rate (89.7%); however, the technical success rate of PTE-RVs was still high (80.4%; p < 0.003). Overall complications occurred in 23.5% of all procedures. Significantly fewer complications occurred after performing PTE-RVs than after PTCs (16.6% vs 26.4%; p = 0.037). Conclusion: Beside a high technical efficacy of PTE-RVs, significantly fewer complications occur following PTE-RVs than following PTCs; thus, PTE-RV should be preferred over PTC alone in selected patients.

Digital single-operator cholangioscopy: a useful tool for selective guidewire placements across complex biliary strictures.

BACKGROUND: Treatment of biliary strictures is challenging. Digital single-operator cholangioscopes (SOCs) equipped with an improved imaging quality, were recently introduced and may be useful for selective guidewire placement in difficult biliary strictures. METHODS: A total of 167 digital SOC procedures performed between 2015 and 2018 were retrospectively analyzed for successful guidewire placements across biliary strictures. Only cases with previous failed conventional guidewire placement approaches were included. RESULTS: In total, 30 examinations with a digital SOC-assisted guidewire placement across biliary strictures, performed in 23 patients, were identified. In 52% of all patients, the stricture was benign with post-liver-transplant strictures (75%) as the most frequent finding; in 48% of all patients the stricture was malignant with cholangiocellular carcinoma as the most frequent type (64%). Guidewire placement was successful in 21 of 30 procedures (70%). According to a subgroup analysis, digital SOC-assisted guidewire placements were significantly more successful in patients with benign strictures than those in patients with malignant strictures (88.2% vs. 46.2%; p = 0.02). Furthermore, the technical success rate tended to be increased in cases of initial examinations (78.3%) than in patients with repeated examinations (42.9%; p = 0.15). Adverse events, such as post-interventional pancreatitis or cholangitis as well as severe bleeding occurred in 16.7% of all examinations. CONCLUSIONS: Digital SOC-assisted guidewire placements have high technical success rates, especially in benign biliary strictures. This technique can help to avoid more invasive procedures such as percutaneous transhepatic or endoscopic ultrasound-guided biliary drainage.

Safety, diagnostic accuracy and therapeutic efficacy of digital single-operator cholangioscopy.

BACKGROUND: Digital single-operator cholangioscopes (digital SOCs), equipped with an improved image quality, have been recently introduced. OBJECTIVE: The aim of this study is to evaluate the safety and diagnostic and therapeutic efficacy of digital SOCs (Spyglass™ DS). METHODS: Sixty-seven digital SOC procedures performed between 2015 and 2017 were retrospectively analyzed. RESULTS: The most frequent indications for examination were indeterminate biliary strictures (61.2%) and biliary stone disease (23.9%). In 25 patients (37.3), visual findings predicted malignancy with a sensitivity of 88.9%, a specificity of 97.6%, a positive predictive value (PPV) of 96.0% and a negative predictive value (NPV) of 92.9%. For histological analysis, forceps biopsies were performed in 29 patients (43.2%). Compared with visual findings, forceps biopsies yield a lower diagnostic efficacy in diagnosing malignancy (sensitivity 62.5%, specificity 90.0%, PPV 90.9%, NPV 60.0%). Therapeutic interventions were performed in 19 patients with a technical success rate of 89.4%. Adverse events were observed in 17 patients (25.4%). Of these, 11 patients (16.4%) suffered from severe adverse events (pancreatitis, cholangitis or major bleeding), which led to a prolonged hospital stay. CONCLUSION: Digital SOCs have excellent diagnostic and therapeutic efficacies, but are accompanied by high rates of adverse events; therefore, physicians should use digital SOCs in carefully selected cases.

Syndecan-4 Modulates Epithelial Gut Barrier Function and Epithelial Regeneration in Experimental Colitis.

Background: The transmembrane heparan sulfate proteoglycan Syndecan-4 (Sdc4) plays an important role in the regulation of various inflammatory disorders. However, the involvement of Sdc4 in intestinal inflammation remains unknown. Therefore, we assessed the impact of Sdc4 deficiency on experimental colitis and epithelial wound healing in vitro and in vivo. Methods: Dextran sulfate sodium (DSS)-induced colitis was monitored in wild type and Sdc4-deficient (Sdc4-/-) mice by assessment of body weight, histology, inflammatory cellular infiltration, and colon length. Syndecan-4 expression was measured by immunohistochemistry, Western blot, and quantitative real-time PCR. Epithelial permeability was evaluated by Evans blue measurements, Western blot, and immunohistological analysis of tight junction protein expression. Impact of Sdc4 on epithelial wound healing was determined by scratch assay in vitro and by colonoscopy following mechanical wounding in vivo. Results: In Sdc4-/- mice, colitis-like symptoms including severe weight loss, shortened colon length, histological damage, and invasion of macrophages and granulocytes were markedly aggravated compared with wild type (WT) animals. Moreover, colonic epithelial permeability in Sdc4-/- mice was enhanced, while tight junction protein expression decreased. Furthermore, Sdc4-/- colonic epithelial cells had lower cell proliferation and migration rates which presented in vivo as a prolonged intestinal wound healing phenotype. Strikingly, in WT animals, Sdc4 expression was reduced during colitis and was elevated during recovery. Conclusions: The loss of Sdc4 aggravates the course of experimental colitis, potentially through impaired epithelial cell integrity and regeneration. In view of the development of current treatment approaches involving Sdc4 inhibition for inflammatory disorders like arthritis, particular caution should be taken in case of adverse gastrointestinal side-effects.