Extracellular Matrix Structure and Interaction with Immune Cells in Adult Astrocytic Tumors.

The extracellular matrix (ECM) is a dynamic set of molecules produced by the cellular component of normal and pathological tissues of the embryo and adult. ECM acts as critical regulator in various biological processes such as differentiation, cell proliferation, angiogenesis, and immune control. The most frequent primary brain tumors are gliomas and by far the majority are adult astrocytic tumors (AATs). The prognosis for patients with these neoplasms is poor and the treatments modestly improves survival. In the literature, there is a fair number of studies concerning the composition of the ECM in AATs, while the number of studies relating the composition of the ECM with the immune regulation is smaller. Circulating ECM proteins have emerged as a promising biomarker that reflect the general immune landscape of tumor microenvironment and may represent a useful tool in assessing disease activity. Given the importance it can have for therapeutic and prognostic purposes, the aim of our study is to summarize the biological properties of ECM components and their effects on the tumor microenvironment and to provide an overview of the interactions between major ECM proteins and immune cells in AATs. As the field of immunotherapy in glioma is quickly expanding, we retain that current data together with future studies on ECM organization and functions in glioma will provide important insights into the tuning of immunotherapeutic approaches.

The Effects of Caloric Restriction on Inflammatory Targets in the Prostates of Aged Rats.

Numerous animal models have demonstrated that caloric restriction (CR) is an excellent tool to delay aging and increase the quality of life, likely because it counteracts age-induced oxidative stress and inflammation. The aging process can affect the prostate in three ways: the onset of benign prostatic hyperplasia, prostatitis, and prostate cancer. In this study, we used 14 aged male Sprague Dawley rats, which were allocated into two groups, at the age of 18 months old. One group was fed ad libitum (a normal diet (ND)), and the other group followed a caloric restriction diet with a 60% decrease in intake. The rats were sacrificed at the age of 24 months. By immunohistochemical (IHC) and Western blot (WB) analyses, we studied the variations between the two groups in immune inflammation and fibrosis-related markers in aged prostate tissues. Morphological examinations showed lower levels of prostatic hyperplasia and fibrosis in the CR rats vs. the ND rats. The IHC results revealed that the prostates of the CR rats exhibited a lower immune proinflammatory infiltrate level and a reduced expression of the NLRP3 inflammasome pathway, together with significantly reduced expressions of mesenchymal markers and the profibrotic factor TGFß1. Finally, by WB analysis, we observed a reduced expression of ERα, which is notoriously implicated in prostate stromal proliferation, and increased expressions of SOD1 and Hsp70, both exerting protective effects against oxidative stress. Overall, these data suggest that CR brings potential benefits to prostatic tissues as it reduces the physiological immune-inflammatory processes and the tissue remodeling caused by aging.

Superior predictive value of transmural over endoscopic severity for colectomy risk in ulcerative colitis: a multicentre prospective cohort study.

BACKGROUND AND AIMS: Endoscopic activity is associated with an increased risk of surgery in patients with ulcerative colitis [UC]. Transmural activity, as defined by Milan Ultrasound Criteria [MUC] > 6.2, reliably detects endoscopic activity in patients with UC. The present study aimed to assess in UC patients whether transmural severity is a better predictor of colectomy as compared to endoscopy. METHODS: Consecutive adult UC patients were recruited in two IBD Referral Centres and underwent colonoscopy and intestinal ultrasound in a blinded fashion. The need for colectomy was assessed at follow-up. Univariable and multivariable logistic and Cox regression analyses were performed. Receiver operating characteristic [ROC] analysis was used to compare MUC baseline values and Mayo Endoscopic Scores [MES] in predicting colectomy risk. RESULTS: Overall, 141 patients were enrolled, and 13 underwent colectomy in the follow-up period. Both MES (hazard ratio [HR]: 3.15, 95% confidence interval [CI]: 1.18-8.37, p = 0.02) and MUC [HR: 1.48, 95% CI: 1.19-1.76, p < 0.001] were associated with colectomy risk, but only MUC was independently associated with this event on multivariable analysis [HR: 1.46, 95% CI: 1.06-2.02, p = 0.02]. MUC was the only independent variable associated with colectomy risk in patients with clinically active disease (odds ratio [OR]: 1.53 [1.03-2.27], p = 0.03). MUC demonstrated higher accuracy than MES (area under ROC curve [AUROC] 0.83, 95% CI: 0.75-0.92 vs 0.71, 95% CI: 0.62-0.80) and better performance for predicting colectomy [p = 0.02]. The optimal MUC score cut-off value for predicting colectomy, as assessed by the Youden index, was 7.7. CONCLUSIONS: A superior predictive value was found for transmural vs endoscopic severity for colectomy risk in UC patients.

Switching from VEDOlizumab intravenous to subcutaneous formulation in ulcerative colitis patients in clinical remission: The SVEDO Study, an IG-IBD study.

BACKGROUND: The administration of biological drugs in inflammatory bowel diseases (IBD) is increasingly moving from intravenous to subcutaneous formulations. AIMS: To evaluate the efficacy and safety of vedolizumab subcutaneous administration after switching from intravenous administration in ulcerative colitis (UC) patients in corticosteroid-free clinical remission. METHODS: An observational, multicentre, prospective study was conducted by the Italian Group for the study of IBD (IG-IBD). UC patients in clinical remission (pMAYO < 2) not receiving steroids for > 8 months before the switch, and with at least 6 months of follow-up were included. Switch from intravenous to subcutaneous vedolizumab was defined as successful in patients not experiencing a disease flare (pMAYO ≥ 2) or needing oral steroids or stopping subcutaneous vedolizumab during the 6 months of follow-up after the switch. RESULTS: Overall, 168 patients were included. The switch was a success in 134 patients (79.8%). Vedolizumab retention rate was 88.7% at month six. C-reactive protein and faecal calprotectin values did not change after the switch (p = 0.07 and p = 0.28, respectively). Ten of the 19 patients who stopped subcutaneous formulation switched back to intravenous formulation recapturing clinical remission in 80%. Side effects were observed in 22 patients (13.1%). CONCLUSION: Effectiveness of switching from intravenous to subcutaneous vedolizumab formulation in UC patients in steroid-free clinical remission is confirmed in a real-world setting.

UMG1/CD3ε-bispecific T-cell engager redirects T-cell cytotoxicity against diffuse large B-cell lymphoma.

UMG1 is a unique epitope of CD43, not expressed by normal cells and tissues of haematopoietic and non-haematopoietic origin, except thymocytes and a minority (<5%) of peripheral blood T lymphocytes. By immunohistochemistry analysis of tissue microarray and pathology slides, we found high UMG1 expression in 20%-24% of diffuse large B-cell lymphomas (DLBCLs), including highly aggressive BCL2high and CD20low cases. UMG1 membrane expression was also found in DLBCL bone marrow-infiltrating cells and established cell lines. Targeting UMG1 with a novel asymmetric UMG1/CD3ε-bispecific T-cell engager (BTCE) induced redirected cytotoxicity against DLBCL cells and was synergistic with lenalidomide. We conclude that UMG1/CD3ε-BTCE is a promising therapeutic for DLBCLs.

An Intestinal Th17 Subset is Associated with Inflammation in Crohn's Disease and Activated by Adherent-invasive Escherichia coli.

IFNγ-producing ex-Th17 cells ['Th1/17'] were shown to play a key pathogenic role in experimental colitis and are abundant in the intestine. Here, we identified and characterised a novel, potentially colitogenic subset of Th17 cells in the intestine of patients with Crohn's disease [CD]. Human Th17 cells expressing CCR5 ['pTh17'] co-expressed T-bet and RORC/γt and produced very high levels of IL-17, together with IFN-γ. They had a gene signature of Th17 effector cells and were distinct from established Th1/17 cells. pTh17 cells, but not Th1/17 cells, were associated with intestinal inflammation in CD, and decreased upon successful anti-TNF therapy with infliximab. Conventional CCR5[-]Th17 cells differentiated to pTh17 cells with IL-23 in vitro. Moreover, anti-IL-23 therapy with risankizumab strongly reduced pTh17 cells in the intestine. Importantly, intestinal pTh17 cells were selectively activated by adherent-invasive Escherichia coli [AIEC], but not by a commensal/probiotic E. coli strain. AIEC induced high levels of IL-23 and RANTES from dendritic cells [DC]. Intestinal CCR5+Th1/17 cells responded instead to cytomegalovirus and were reduced in ulcerative colitis [UC], suggesting an unexpected protective role. In conclusion, we identified an IL-23-inducible subset of human intestinal Th17 cells. pTh17 cells produced high levels of pro-inflammatory cytokines, were selectively associated with intestinal inflammation in CD, and responded to CD-associated AIEC, suggesting a key colitogenic role.

Safety, hesitancy of coronavirus disease 2019 vaccination and pandemic burden in patients with inflammatory bowel disease: data of a national study (ESCAPE-IBD).

BACKGROUND AND AIMS: The purpose of this study was to present data on the safety of anti- severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in a cohort of inflammatory bowel disease (IBD) patients of an ongoing multicenter study (ESCAPE-IBD) sponsored by the Italian Group for the study of Inflammatory Bowel Disease (ClinicalTrials.gov Identifier: NCT04769258). METHODS: Anti-SARS-CoV-2 vaccination was administrated to 809 IBD patients. Interviews were conducted to report adverse events related to vaccination. Of these 809, 346 patients were surveyed on the pandemic burden and the main reason for hesitancy in coronavirus disease 2019 vaccination. The chi-square test was used to compare categorical variables. Logistic regression was used to assess the relationship between disease-related characteristics and the onset of adverse events. RESULTS: About 45% of patients had at least one side effect, following the first dose (10%), the second (15%), and both doses (19%). All the adverse events were mild and lasted only a few days. Logistic regression analysis revealed that female sex ( P  < 0.001), younger age ( P  = 0.001), seroconversion ( P  = 0.002), and comorbidity ( P  < 0.001) were significantly associated with adverse events. The survey showed that the main concerns were the possibility of adverse event (33%). Almost all patients (99%) felt safer having been vaccinated at their IBD reference center. CONCLUSION: The vaccine reactions experienced in IBD patients were mostly self-limited. We found high acceptance and good safety of SARS-CoV-2 vaccination in our cohort.

The First-In-Class Anti-AXL×CD3ε Pronectin™-Based Bispecific T-Cell Engager Is Active in Preclinical Models of Human Soft Tissue and Bone Sarcomas.

Sarcomas are heterogeneous malignancies with limited therapeutic options and a poor prognosis. We developed an innovative immunotherapeutic agent, a first-in-class Pronectin™-based Bispecific T-Cell Engager (pAXL×CD3ε), for the targeting of AXL, a TAM family tyrosine kinase receptor highly expressed in sarcomas. AXL expression was first analyzed by flow cytometry, qRT-PCR, and Western blot on a panel of sarcoma cell lines. The T-cell-mediated pAXL×CD3ε cytotoxicity against sarcoma cells was investigated by flow cytometry, luminescence assay, and fluorescent microscopy imaging. The activation and degranulation of T cells induced by pAXL×CD3ε were evaluated by flow cytometry. The antitumor activity induced by pAXL×CD3ε in combination with trabectedin was also investigated. In vivo activity studies of pAXL×CD3ε were performed in immunocompromised mice (NSG), engrafted with human sarcoma cells and reconstituted with human peripheral blood mononuclear cells from healthy donors. Most sarcoma cells showed high expression of AXL. pAXL×CD3ε triggered T-lymphocyte activation and induced dose-dependent T-cell-mediated cytotoxicity. The combination of pAXL×CD3ε with trabectedin increased cytotoxicity. pAXL×CD3ε inhibited the in vivo growth of human sarcoma xenografts, increasing the survival of treated mice. Our data demonstrate the antitumor efficacy of pAXL×CD3ε against sarcoma cells, providing a translational framework for the clinical development of pAXL×CD3ε in the treatment of human sarcomas, aggressive and still-incurable malignancies.

The impact of biologic therapies on extra-intestinal manifestations in inflammatory bowel disease: A multicenter study.

Introduction: Patients with inflammatory bowel disease (IBD) have a high risk of developing extra-intestinal manifestations (EIMs). We aimed to assess the cumulative incidence and clinical course of EIMs in patients treated with Vedolizumab (VDZ) and non-gut selective biologic drugs. Materials and methods: In this multicenter observational study, we enrolled 1,182 patients with IBD under biologic treatment in tertiary care centers, collecting the rate of new-onset EIMs and the clinical course of new and pre-existing EIMs since the introduction of the ongoing biologic drug (259 VDZ vs. 923 non-gut selective agents, median time 3 vs. 4 years). Results: Among 1,182 patients with IBD (median age of 46 years; 55% men) on biologics, the overall cumulative incidence of new onset EIMs was 4.1% (49/1,182), in particular 6.6% (17/259) on VDZ vs. 3.5% (32/923) on non-gut selective biologics (p = 0.02). Among 224 patients reporting new or pre-existing EIMs, those on VDZ showed a higher rate of clinical worsening compared with non-gut selective therapies (15.5 vs. 7.3%, p = 0.08). However, both showed a similar rate of modification of the therapeutic regimen. Female gender [hazard ratio (HR) 2.18], a longer course of ongoing biologic therapy (HR 1.18), ulcerative colitis (UC) (HR 1.83), and VDZ therapy (HR 1.85) were significant risk factors for developing new EIMs. Discussion: Our study suggests that the type of biologic treatment might affect the risk of developing EIMs, with a slightly higher risk in patients on gut-selective therapies. However, a similar clinical course is observed in the two groups.

IL10 Secretion Endows Intestinal Human iNKT Cells with Regulatory Functions Towards Pathogenic T Lymphocytes.

BACKGROUND AND AIMS: Invariant natural killer T [iNKT] cells perform pleiotropic functions in different tissues by secreting a vast array of pro-inflammatory and cytotoxic molecules. However, the presence and function of human intestinal iNKT cells capable of secreting immunomodulatory molecules such as IL-10 has never been reported so far. Here we describe for the first time the presence of IL10-producing iNKT cells [NKT10 cells] in the intestinal lamina propria of healthy individuals and of Crohn's disease [CD] patients. METHODS: Frequency and phenotype of NKT10 cells were analysed ex vivo from intestinal specimens of Crohn's disease [n = 17] and controls [n = 7]. Stable CD-derived intestinal NKT10 cell lines were used to perform in vitro suppression assays and co-cultures with patient-derived mucosa-associated microbiota. Experimental colitis models were performed by adoptive cell transfer of splenic naïve CD4+ T cells in the presence or absence of IL10-sufficient or -deficient iNKT cells. In vivo induction of NKT10 cells was performed by administration of short chain fatty acids [SCFA] by oral gavage. RESULTS: Patient-derived intestinal NKT10 cells demonstrated suppressive capabilities towards pathogenic CD4+ T cells. The presence of increased proportions of mucosal NKT10 cells associated with better clinical outcomes in CD patients. Moreover, an intestinal microbial community enriched in SCFA-producing bacteria sustained the production of IL10 by iNKT cells. Finally, IL10-deficient iNKT cells failed to control the pathogenic activity of adoptively transferred CD4+ T cells in an experimental colitis model. CONCLUSIONS: These results describe an unprecedentd IL10-mediated immunoregulatory role of intestinal iNKT cells in controlling the pathogenic functions of mucosal T helper subsets and in maintaining the intestinal immune homeostasis.

Agreement between real-time elastography and delayed enhancement magnetic resonance enterography on quantifying bowel wall fibrosis in Crohn's disease.

BACKGROUND: the assessment of fibrosis in Crohn's disease (CD) bowel lesions helps to guide therapeutic decisions. Real-time elastography (RTE) and delayed-enhancement magnetic resonance enterography (DE-MRE) have demonstrated good accuracy in quantifying CD-related ileal fibrosis as compared with histological examination. To date no study has compared DE-MRE and RTE. AIMS: we aimed to evaluate the agreement between RTE and DE-MRE on quantifying CD-related ileal fibrosis. METHODS: consecutive patients with ileal or ileocolonic CD underwent RTE and DE-MRE. Ileal fibrosis was quantified by calculating the strain ratio (SR) at RTE and the 70s-7 min percentage of enhancement gain (%EG) of both mucosa and submucosa at DE-MRE. A SR ≥2 was applied to define severe fibrosis. Clinically relevant outcomes occurring at follow-up were recorded. RESULTS: 40 CD patients were enrolled. A significant linear correlation was observed between SR and submucosal %EG (r = 0.594, p < 0.001). Patients with severe fibrosis (SR ≥2) had significantly higher submucosal %EG values than patients with low/moderate fibrosis (median values 26.4% vs. 9.5%, p < 0.001). During a median 43.8-month follow-up relevant disease outcomes occurred more frequently in the severe-fibrosis group (75% vs. 36%, HR 5.4, 95% CI 1.2-24.6, p = 0.029). CONCLUSIONS: the study demonstrates an excellent agreement between RTE and DE-MRE in assessing ileal fibrosis in CD.

Safety and clinical efficacy of the double switch from originator infliximab to biosimilars CT-P13 and SB2 in patients with inflammatory bowel diseases (SCESICS): A multicenter cohort study.

Data regarding double switching from originator infliximab (IFX) to IFX biosimilars in inflammatory bowel diseases (IBDs) are lacking. The purpose of this study was to evaluate the safety and efficacy of switching from originator IFX to CT-P13 and subsequently to SB2 (double switch) in patients with IBD. Patients undergoing IFX-double switch in eight Centers in Lombardy (Italy) from November 2018 to May 2019 were retrospectively analyzed. The IFX discontinuation rate, incidence and type of adverse events (AEs), and clinical remission rate were recorded. A comparison with a control group of patients with IBD single-switched from originator IFX to CT-P13 was performed, before and after an inverse probability of treatment weighting (IPTW)-based propensity score analysis. Fifty-two double-switched patients with IBD were enrolled. The 24- and 52-week proportions of patients continuing on IFX therapy following the second switch (CTP13 â†’ SB2) were 98% (95% confidence interval [CI] 94%-100%) and 90% (95% CI 81%-99%), respectively. Four patients experienced a total of five AEs, all graded 1-3 according to Common Terminology Criteria for Adverse Events (CTCAE). No infusion reactions were observed. The 24-week and follow-up end clinical remission rates following the second switch were 94% and 88%, respectively. No differences were observed in the safety and efficacy outcomes by comparing the double-switch group with a single-switch group of 66 patients with IBD; all these results were confirmed by IPTW-adjusted analysis. The study suggests both the safety and efficacy of the double switch from originator IFX to CT-P13 and SB2 in patients with IBD is maintained. This strategy may be associated with potential cost implications.

Lower incidence of COVID-19 in patients with inflammatory bowel disease treated with non-gut selective biologic therapy.

BACKGROUND AND AIM: Since the outbreak of COVID-19, concerns have been raised as to whether inflammatory bowel disease (IBD) patients under biologic therapy may be more susceptible to the disease. This study aimed to determine the incidence and outcomes of COVID-19 in a large cohort of IBD patients on biologic therapy. METHODS: This observational retrospective multicenter study collected data about COVID-19 in IBD patients on biologic therapy in Italy, between February and May 2020. The main end-points were (i) to assess both the cumulative incidence and clinical outcome of COVID-19, according to different biologic agents and (ii) to compare them with the general population and a cohort IBD patients undergoing non-biologic therapies. RESULTS: Among 1816 IBD patients, the cumulative incidence of COVID-19 was 3.9 per 1000 (7/1816) with a 57% hospitalization rate and a 29% case-fatality rate. The class of biologic agents was the only risk factor of developing COVID-19 (P = 0.01). Non-gut selective agents were associated with a lower incidence of COVID-19 cases, related symptoms, and hospitalization (P < 0.05). Compared with the general population of Lombardy, an overall lower incidence of COVID-19 was observed (3.9 vs 8.5 per 1000, P = 0.03). Compared with 565 IBD patients on non-biologic therapies, a lower rate of COVID-19 symptoms was observed in our cohort (7.5% vs 18%, P < 0.001). CONCLUSIONS: Compared with the general population, IBD patients on biologic therapy are not exposed to a higher risk of COVID-19. Non-gut selective agents are associated with a lower incidence of symptomatic disease, supporting the decision of maintaining the ongoing treatment.

Therapeutic afucosylated monoclonal antibody and bispecific T-cell engagers for T-cell acute lymphoblastic leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a poor cure rate for relapsed/resistant patients. Due to the lack of T-cell restricted targetable antigens, effective immune-therapeutics are not presently available and the treatment of chemo-refractory T-ALL is still an unmet clinical need. To develop novel immune-therapy for T-ALL, we generated an afucosylated monoclonal antibody (mAb) (ahuUMG1) and two different bispecific T-cell engagers (BTCEs) against UMG1, a unique CD43-epitope highly and selectively expressed by T-ALL cells from pediatric and adult patients. METHODS: UMG1 expression was assessed by immunohistochemistry (IHC) on a wide panel of normal tissue microarrays (TMAs), and by flow cytometry on healthy peripheral blood/bone marrow-derived cells, on 10 different T-ALL cell lines, and on 110 T-ALL primary patient-derived cells. CD43-UMG1 binding site was defined through a peptide microarray scanning. ahuUMG1 was generated by Genetic Glyco-Engineering technology from a novel humanized mAb directed against UMG1 (huUMG1). BTCEs were generated as IgG1-(scFv)2 constructs with bivalent (2+2) or monovalent (2+1) CD3ε arms. Antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP) and redirected T-cell cytotoxicity assays were analysed by flow cytometry. In vivo antitumor activity of ahUMG1 and UMG1-BTCEs was investigated in NSG mice against subcutaneous and orthotopic xenografts of human T-ALL. RESULTS: Among 110 T-ALL patient-derived samples, 53 (48.1%) stained positive (24% of TI/TII, 82% of TIII and 42.8% of TIV). Importantly, no expression of UMG1-epitope was found in normal tissues/cells, excluding cortical thymocytes and a minority (<5%) of peripheral blood T lymphocytes. ahUMG1 induced strong ADCC and ADCP on T-ALL cells in vitro, which translated in antitumor activity in vivo and significantly extended survival of treated mice. Both UMG1-BTCEs demonstrated highly effective killing activity against T-ALL cells in vitro. We demonstrated that this effect was specifically exerted by engaged activated T cells. Moreover, UMG1-BTCEs effectively antagonized tumor growth at concentrations >2 log lower as compared with ahuUMG1, with significant mice survival advantage in different T-ALL models in vivo. CONCLUSION: Altogether our findings, including the safe UMG1-epitope expression profile, provide a framework for the clinical development of these innovative immune-therapeutics for this still orphan disease.

miR-21 antagonism abrogates Th17 tumor promoting functions in multiple myeloma.

Multiple myeloma (MM) is tightly dependent on inflammatory bone marrow microenvironment. IL-17 producing CD4+ T cells (Th17) sustain MM cells growth and osteoclasts-dependent bone damage. In turn, Th17 differentiation relies on inflammatory stimuli. Here, we investigated the role of miR-21 in Th17-mediated MM tumor growth and bone disease. We found that early inhibition of miR-21 in naive T cells (miR-21i-T cells) impaired Th17 differentiation in vitro and abrogated Th17-mediated MM cell proliferation and osteoclasts activity. We validated these findings in NOD/SCID-g-NULL mice, intratibially injected with miR-21i-T cells and MM cells. A Pairwise RNAseq and proteome/phosphoproteome analysis in Th17 cells demonstrated that miR-21 inhibition led to upregulation of STAT-1/-5a-5b, STAT-3 impairment and redirection of Th17 to Th1/Th2 like activated/polarized cells. Our findings disclose the role of miR-21 in pathogenic Th17 activity and open the avenue to the design of miR-21-targeting strategies to counteract microenvironment dependence of MM growth and bone disease.

Blue-light imaging compared with high-definition white light for real-time histology prediction of colorectal polyps less than 1 centimeter: a prospective randomized study.

BACKGROUND AND AIMS: Blue-light imaging (BLI) is a new chromoendoscopy technique, potentially useful for differentiating neoplastic from nonneoplastic lesions. The present study was aimed at comparing BLI with high-definition white light (HDWL) in the real-time histology prediction of colon polyps <10 mm. METHODS: Consecutive outpatients undergoing colonoscopy with the ELUXEO 7000 endoscopy platform and 760 series video colonoscopes (Fujifilm Co, Tokyo, Japan) who had at least 1 polyp <10 mm were randomized to BLI or HDWL for polyp characterization. The accuracy of high-confidence real-time histology prediction (adenoma vs not adenoma) by either BLI or HDWL for polyps <10 mm (primary end-point) and diminutive (≤5 mm) polyps was calculated, along with sensitivity, specificity, and positive and negative predictive values, with histopathology as the reference standard. RESULTS: A total of 483 polyps were detected in 245 randomized patients (125 and 120 in the BLI and HDWL arms, respectively). A total of 358 were diminutive, and 283 were adenomas. Overall, 222 (85.7%) and 193 (86.1%) polyps were characterized with high confidence by BLI and HDWL, respectively (P = .887), with an overall accuracy of 92% and 84%, respectively (P = .011). The accuracy was significantly higher by BLI than HDWL, also for diminutive polyps (92% vs 83%; P = .008). When BLI was used, the negative predictive value for diminutive rectosigmoid polyps was 88%, and the post-polypectomy surveillance interval was correctly attributed in 85.7% and 93.7% of patients, respectively, according to U.S. and European guidelines. CONCLUSION: BLI was superior to HDWL for the real-time prediction of histology in polyps <10 mm. A BLI-dedicated classification might further improve the endoscopist performance. (Clinical trial registration number: NCT03274115.).

Deregulation of SGK1 in Ulcerative Colitis: A Paradoxical Relationship Between Immune Cells and Colonic Epithelial Cells.

BACKGROUND: Inflammatory bowel disease (IBD) is due to the interaction of genetic and environmental factors that trigger an unbalanced immune response ultimately resulting in the peculiar inflammatory reaction. Experimental models of IBD point to a role of T-cell-derived cytokines (Th17) and to SGK1 as mediator of the Th17 switch. We hypothesize that SGK1, a salt inducible kinase, directs lymphocytic behavior and tissue damage. METHODS: Eleven controls and 32 ulcerative colitis (UC) patients were randomized according to endoscopic Mayo score. Mucosal biopsies from different intestinal tracts were analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction to check the expression of disease markers including SGK1. Peripheral blood mononuclear cells (PBMCs) from patients and controls were analyzed by fluorescence-activated cell sorting. Finally, an in vitro cell model was developed to test the hypothesis. RESULTS: SGK1 mRNA and protein expression in lesional areas of UC patients were lower than in normal peri-lesional areas of the same patients and in normal tissues of healthy controls. SGK1 expression was increased in PBMCs from UC patients, particularly in the CD4+ cell population, enriched in Th17 cells. IL17/IL13 was increased in patients and correlated with SGK1 expression. Genetically engineered Jurkat cells confirmed the effect of SGK1 overexpression on viability of RKO cells. CONCLUSIONS: These observations suggest a pathogenic mechanism whereby SGK1 overexpression in CD4+ T cells induces the secretion of the inflammatory cytokines IL17 and IL13, which downregulate the expression of SGK1 in target tissues. Our data suggest a novel hypothesis in the pathogenesis of UC, integrating colonic epithelial cells and lymphocytes.