Cold versus hot snare endoscopic resection of large non-pedunculated colorectal polyps (randomized-controlled German CHRONICLE-trial)

Background and aims Endoscopic mucosal resection (EMR) is standard therapy for non-pedunculated colorectal polyps ≥20mm. Recently, it has been suggested that polyp resection without current (cold resection) may be superior to the standard technique using cutting/coagulation current (hot resection) by reducing adverse events (AE), but evidence from a randomized trial is missing. Methods In this randomized-controlled multicentric trial involving 19 centers, non-pedunculated colorectal polyps ≥20mm were randomly assigned to cold or hot EMR. Primary outcome was major AE (perforation or post-endoscopic bleeding). Among secondary outcomes major AE subcategories, postpolypectomy-syndrome and residual adenoma were most relevant. Results Between 2021 and 2023, 396 polyps in 363 patients (48.2% female) were enrolled for the intention-to-treat analysis. Major AE occurred in 1.0 % in the cold and in 7.9% in the hot group (p=0.001; Odds ratio [OR] 0.12 [95%-CI: 0.03-0.54]). Rates for perforation and post-endoscopic bleeding were significantly lower in the cold group with 0% vs. 3.9% (p=0.007) and 1.0% vs. 4.4% (p=0.040). Postpolypectomy-syndrome occurred with similar frequency (3.1% vs. 4.4%, p=0.490). After cold resection, residual adenoma was found more frequently, with 23.7% vs. 13.8% (p=0.020; OR 1.94 [95%-CI: 1.12-3.38]). In multivariable analysis, lesion diameter of ≥4cm was an independent predictor both for major AE (OR 3.37) and residual adenoma (OR 2.47), and high-grade dysplasia/cancer for residual adenoma (OR 2.92). Conclusion Cold resection of large non-pedunculated colorectal polyps appears considerably safer than hot EMR, however at the cost of a higher residual adenoma rate. Further studies have to confirm to which extent polyp size and histology can determine an individualized approach (Trial number: DRKS00025170)

HIV-Induced T-Cell Activation/Exhaustion in Rectal Mucosa Is Controlled Only Partially by Antiretroviral Treatment

Peripheral blood T-cells from untreated HIV-1-infected patients exhibit reduced immune responses, usually associated with a hyperactivated/exhausted phenotype compared to HAART treated patients. However, it is not clear whether HAART ameliorates this altered phenotype of T-cells in the gastrointestinal-associated lymphoid tissue (GALT), the main site for viral replication. Here, we compared T-cells from peripheral blood and GALT of two groups of chronically HIV-1-infected patients: untreated patients with active viral replication, and patients on suppressive HAART. We characterized the T-cell phenotype by measuring PD-1, CTLA-4, HLA-DR, CD25, Foxp3 and granzyme A expression by flow cytometry; mRNA expression of T-bet, GATA-3, ROR-γt and Foxp3, and was also evaluated in peripheral blood mononuclear cells and rectal lymphoid cells. In HIV-1+ patients, the frequency of PD-1+ and CTLA-4+ T-cells (both CD4+ and CD8+ T cells) was higher in the GALT than in the blood. The expression of PD-1 by T-cells from GALT was higher in HIV-1-infected subjects with active viral replication compared to controls. Moreover, the expression per cell of PD-1 and CTLA-4 in CD4+ T-cells from blood and GALT was positively correlated with viral load. HAART treatment decreased the expression of CTLA-4 in CD8+ T cells from blood and GALT to levels similar as those observed in controls. Frequency of Granzyme A+ CD8+ T-cells in both tissues was low in the untreated group, compared to controls and HAART-treated patients. Finally, a switch towards Treg polarization was found in untreated patients, in both tissues. Together, these findings suggest that chronic HIV-1 infection results in an activated/exhausted T-cell phenotype, despite T-cell polarization towards a regulatory profile; these alterations are more pronounced in the GALT compared to peripheral blood, and are only partiality modulated by HAART

Extracellular Vesicles from Steatotic Hepatocytes Provoke Pro-Fibrotic Responses in Cultured Stellate Cells

Hepatic steatosis and chronic hepatocyte damage ultimately lead to liver fibrosis. Key pathophysiological steps are the activation and transdifferentiation of hepatic stellate cells. We assessed the interplay between hepatocytes and hepatic stellate cells under normal and steatotic conditions. We hypothesized that hepatocyte-derived extracellular vesicles (EVs) modify the phenotype of stellate cells. By high speed centrifugation, EVs were isolated from conditioned media of the hepatocellular carcinoma cell line HepG2 under baseline conditions (C-EVs) or after induction of steatosis by linoleic and oleic acids for 24 h (FA-EVs). Migration of the human stellate cell line TWNT4 and of primary human stellate cells towards the respective EVs and sera of MAFLD patients were investigated using Boyden chambers. Phenotype alterations after incubation with EVs were determined by qRT-PCR, Western blotting and immunofluorescence staining. HepG2 cells released more EVs after treatment with fatty acids. Chemotactic migration of TWNT4 and primary hepatic stellate cells was increased, specifically towards FA-EVs. Prolonged incubation of TWNT4 cells with FA-EVs induced expression of proliferation markers and a myofibroblast-like phenotype. Though the expression of the collagen type 1 alpha 1 gene did not change after FA-EV treatment, expression of the myofibroblast markers, e.g., alpha-smooth-muscle-cell actin and TIMP1, was significantly increased. We conclude that EVs from steatotic hepatocytes can influence the behavior, phenotypes and expression levels of remodeling markers of stellate cells and guides their directed migration. These findings imply EVs as operational, intercellular communicators in the pathophysiology of steatosis-associated liver fibrosis and might represent a novel diagnostic parameter and therapeutic target

Flow chart of the Meta-Analysis of <i>5-HTTLPR</i> polymorphisms and Post-traumatic Stress Disorder (PTSD).

<p>Adapted from Sagoo GS, Little J, Higgins JP, Systematic Reviews of Genetic Association Studies. Human Genome Epidemiology Network. PLOS Med 2009; 6(3): e28 doi: e28 10.1371/journal.pmed.1000028 and Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097.</p

Analyses of publication bias by the Egger test.

<p>SE: Standard error; T: T-test; df: Degrees of freedom. BFM: Biallelic Frequency Model; BDM: Biallelic Dominant Model; BRM: Biallelic Recessive Model; TFM: Triallelic Frequency Model; TDM: Triallelic Dominant Model; TRM: Triallelic Recessive Model.</p

Forest plot of <i>5-HTTLPR</i> biallelic recessive model (<i>SS</i> vs <i>L</i>+) and Post-traumatic Stress Disorder (PTSD).

<p>Forest plot of <i>5-HTTLPR</i> biallelic recessive model (<i>SS</i> vs <i>L</i>+) and Post-traumatic Stress Disorder (PTSD).</p

Description of the quality characteristics of the included and excluded studies in the Meta-Analysis of <i>5-HTTLPR</i> polymorphisms and Post-traumatic Stress Disorder (PTSD).

$<p>Representativeness of cases included all eligible cases with outcome of interest over a defined period of time, all cases in a defined catchment area, all cases in a defined hospital or clinic, group of hospitals, health maintenance organization, or an appropriate sample of those cases (e.g. random sample).</p>#<p>Representativeness of controls assesses whether the control series used in the study is derived from the same population as the cases and essentially would have been cases had the outcome been present and included community and clinical controls within the same community or hospitalized population as cases.</p>&<p>If Yes, the % of the different ethnics groups are provided in brackets.AS: Asiatic. EA: Euro-American; AA: Afro-Americans; Af: African; Eu: Europeans.</p>†<p>HWE: Hardy-Weinberg Equilibrium; ‡TQS: Total Quality Score.</p

Funnel plots of <i>5-HTTLPR</i> polymorphisms and Post-traumatic Stress Disorder (PTSD) to assess publication bias.

<p><b>White circles</b> represent each of the included studies. <b>Black circles</b> represent the new effect estimated to achieve symmetry.</p