Publications by authors named "Flavio Caprioli"

110 Publications

Therapies for inflammatory bowel disease do not pose additional risks for adverse outcomes of SARS-CoV-2 infection: an IG-IBD study.

Aliment Pharmacol Ther 2021 Oct 25. Epub 2021 Oct 25.

Rho (Milan), Italy.

Background: Older age and comorbidities are the main risk factors for adverse COVID-19 outcomes in patients with inflammatory bowel disease (IBD). The impact of IBD medications is still under investigation.

Aims: To assess risk factors for adverse outcomes of COVID-19 in IBD patients and use the identified risk factors to build risk indices.

Methods: Observational cohort study. Univariable and multivariable logistic regression was used to identify risk factors associated with pneumonia, hospitalisation, need for ventilatory support, and death.

Results: Of the 937 patients (446 with ulcerative colitis [UC]) evaluated, 128 (13.7%) had asymptomatic SARS-CoV-2 infection, 664 (70.8%) had a favourable course, and 135 (15.5%) had moderate or severe COVID-19. In UC patients, obesity, active disease and comorbidities were significantly associated with adverse outcomes. In patients with Crohn's disease (CD), age, obesity, comorbidities and an additional immune-mediated inflammatory disease were identified as risk factors. These risk factors were incorporated into two indices to identify patients with UC or CD with a higher risk of adverse COVID-19 outcomes. In multivariable analyses, no single IBD medication was associated with poor COVID-19 outcomes, but anti-TNF agents were associated with a lower risk of pneumonia in UC, and lower risks of hospitalisation and severe COVID-19 in CD.

Conclusion: The course of COVID-19 in patients with IBD is similar to that in the general population. IBD patients with active disease and comorbidities are at greater risk of adverse COVID-19 outcomes. IBD medications do not pose additional risks. The risk indices may help to identify patients who should be prioritised for COVID-19 re-vaccination or for therapies for SARS-CoV-2 infection.
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http://dx.doi.org/10.1111/apt.16663DOI Listing
October 2021

Human intestinal and circulating invariant natural killer T cells are cytotoxic against colorectal cancer cells via the perforin-granzyme pathway.

Mol Oncol 2021 Sep 18. Epub 2021 Sep 18.

Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.

Invariant natural killer T (iNKT) cells are lipid-specific T lymphocytes endowed with cytotoxic activities and are thus considered important in antitumor immunity. While several studies have demonstrated iNKT cell cytotoxicity against different tumors, very little is known about their cell-killing activities in human colorectal cancer (CRC). Our aim was to assess whether human iNKT cells are cytotoxic against colon cancer cells and the mechanisms underlying this activity. For this purpose, we generated stable iNKT cell lines from peripheral blood and colon specimens and used NK-92 and peripheral blood natural killer cells as cell-mediated cytotoxicity controls. In vitro cytotoxicity was assessed using a panel of well-characterized human CRC cell lines, and the cellular requirements for iNKT cell cytotoxic functions were evaluated. We demonstrated that both intestinal and circulating iNKT cells were cytotoxic against the entire panel of CRC lines, as well as against freshly isolated patient-derived colonic epithelial cancer cells. Perforin and/or granzyme inhibition impaired iNKT cell cytotoxicity, whereas T-cell receptor (TCR) signaling was a less stringent requirement for efficient killing. This study is the first evidence of tissue-derived iNKT cell cytotoxic activity in humans, as it shows that iNKT cells depend on the perforin-granzyme pathway and both adaptive and innate signal recognition for proper elimination of colon cancer cells.
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http://dx.doi.org/10.1002/1878-0261.13104DOI Listing
September 2021

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.

Clin Transl Sci 2021 Sep 15. Epub 2021 Sep 15.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Gastroenterology and Endoscopy Unit, Milan, Italy.

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 → 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.
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http://dx.doi.org/10.1111/cts.13131DOI Listing
September 2021

Surface plasmon resonance unveils important pitfalls of enzyme-linked immunoassay for the detection of anti-infliximab antibodies in patients' sera.

Sci Rep 2021 07 22;11(1):14976. Epub 2021 Jul 22.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.

Measurements of serum concentrations of therapeutic antibodies and anti-drug antibodies (ADA) can support clinical decisions for the management of non-responders, optimizing the therapy. In the present study we compared the results obtained by classical ELISA and a recently proposed surface plasmon resonance (SPR)-based immunoassay, in 76 patients receiving infliximab for inflammatory bowel diseases. The two methods indicated very similar serum concentrations of the drug, but there were striking differences as regards ADA. All the sera showing ADA by ELISA (14) also showed ADA by SPR, but the absolute amounts were different, being 7-490 times higher with SPR, with no correlation. Eight patients showed ADA only with SPR, and these ADA had significantly faster dissociation rate constants than those detectable by both SPR and ELISA. The underestimation, or the lack of detection, of ADA by ELISA is likely to reflect the long incubation steps which favor dissociation of the patient's low-affinity ADA, while the commercial, high-affinity anti-infliximab antibodies used for the calibration curve do not dissociate. This problem is less important with SPR, which monitors binding in real time. The possibility offered by SPR to detect ADA in patients otherwise considered ADA-negative by ELISA could have important implications for clinicians.
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http://dx.doi.org/10.1038/s41598-021-94431-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298394PMC
July 2021

Who are the patients with Crohn's disease unsuitable to receive an anti-TNFα therapy? Results from a survey of Italian physicians and literature review.

Eur J Gastroenterol Hepatol 2021 08;33(8):1082-1090

Department of Clinical Medicine and Surgery, University of Naples 'Federico II,' Naples, Italy.

Objectives: Anti-TNFα agents have been a staple of Crohn's disease treatment for 20 years, but they have weaknesses. New treatments have more recently become available. The aim of this paper is to examine the Crohn's disease patient population for whom anti-TNF treatments are not preferred and where new mechanisms of action should be considered.

Methods: A representative sample of 100 Italian physicians with documented expertise with biological treatment of moderate-to-severe Crohn's disease were interviewed. A literature review on Crohn's disease treatment was also conducted to identify patient populations for whom anti-TNFs are unsuitable.

Results: On the basis of the interviewed physicians, about 9% of moderate-to-severe Crohn's disease patients were noneligible to anti-TNFα due to contraindication or possible risk of intolerance, while 11% had discontinued anti-TNFα treatment due to complications or intolerance/hypersensitivity. Patients with severe heart disease and at high risk of infections were more frequently considered unsuitable. The proportion of patients considered unsuitable among elderly patients and in those with recurrent infections, cancer, and other comorbidities ranged between 40 and 60%.

Conclusions: We provided additional quantitative and qualitative information to help identify patients who are less suitable to anti-TNF agents, who could benefit from newer biologic agents with different mechanisms of action.
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http://dx.doi.org/10.1097/MEG.0000000000002183DOI Listing
August 2021

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

J Gastroenterol Hepatol 2021 Jun 23. Epub 2021 Jun 23.

Gastroenterology Unit, ASST Fatebenefratelli-Sacco, L. Sacco University Hospital, Department of Biochemical and Clinical Sciences, University of Milan, Milan, Italy.

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.
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http://dx.doi.org/10.1111/jgh.15591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447454PMC
June 2021

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

Dig Liver Dis 2021 Jun 8. Epub 2021 Jun 8.

Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Via F. Sforza 35, Milan 20122, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.dld.2021.05.018DOI Listing
June 2021

Histopathology of non-IBD colitis practical recommendations from pathologists of IG-IBD Group.

Dig Liver Dis 2021 Aug 10;53(8):950-957. Epub 2021 Mar 10.

Institute of Pathology, ASST Spedali Civili, Brescia, Italy.

Pathologists are often called upon to diagnose colitides that differ from the two main forms of inflammatory bowel disease (IBD). These non-IBD colitides include infectious colitis, microscopic colitis, ischemic colitis, eosinophilic colitis, autoimmune enterocolitis, segmental colitis associated with diverticulosis, drug-induced colitis, radiation colitis and diversion colitis. The diagnosis of these different disease entities relies on the histopathological examination of endoscopic biopsies of the gastrointestinal tract. This paper reviews the main histomorphological characteristics of the various Non-IBD colitides.
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http://dx.doi.org/10.1016/j.dld.2021.01.026DOI Listing
August 2021

Antibiotic-associated dysbiosis affects the ability of the gut microbiota to control intestinal inflammation upon fecal microbiota transplantation in experimental colitis models.

Microbiome 2021 02 6;9(1):39. Epub 2021 Feb 6.

Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.

Background: The gut microbiota plays a central role in host physiology and in several pathological mechanisms in humans. Antibiotics compromise the composition and functions of the gut microbiota inducing long-lasting detrimental effects on the host. Recent studies suggest that the efficacy of different clinical therapies depends on the action of the gut microbiota. Here, we investigated how different antibiotic treatments affect the ability of the gut microbiota to control intestinal inflammation upon fecal microbiota transplantation in an experimental colitis model and in ex vivo experiments with human intestinal biopsies.

Results: Murine fecal donors were pre-treated with different antibiotics, i.e., vancomycin, streptomycin, and metronidazole before FMT administration to colitic animals. The analysis of the gut microbiome, fecal metabolome, and the immunophenotyping of colonic lamina propria immune cells revealed that antibiotic pre-treatment significantly influences the capability of the microbiota to control intestinal inflammation. Streptomycin and vancomycin-treated microbiota failed to control intestinal inflammation and were characterized by the blooming of pathobionts previously associated with IBD as well as with metabolites related to the presence of oxidative stress and metabolism of simple sugars. On the contrary, the metronidazole-treated microbiota retained its ability to control inflammation co-occurring with the enrichment of Lactobacillus and of innate immune responses involving iNKT cells. Furthermore, ex vivo cultures of human intestinal lamina propria mononuclear cells and iNKT cell clones from IBD patients with vancomycin pre-treated sterile fecal water showed a Th1/Th17 skewing in CD4 T-cell populations; metronidazole, on the other hand, induced the polarization of iNKT cells toward the production of IL10.

Conclusions: Diverse antibiotic regimens affect the ability of the gut microbiota to control intestinal inflammation in experimental colitis by altering the microbial community structure and microbiota-derived metabolites. Video Abstract.
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http://dx.doi.org/10.1186/s40168-020-00991-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868014PMC
February 2021

SARS-CoV-2 seroprevalence trends in healthy blood donors during the COVID-19 outbreak in Milan.

Blood Transfus 2021 05 3;19(3):181-189. Epub 2021 Feb 3.

Department of Transfusion Medicine and Haematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: The Milan metropolitan area in Northern Italy was among the most severely hit by the SARS-CoV-2 outbreak. The aim of this study was to examine the seroprevalence trends of SARS-CoV-2 in healthy asymptomatic adults, and the risk factors and laboratory correlates of positive tests.

Materials And Methods: We conducted a cross-sectional study in a random sample of blood donors, who were asymptomatic at the time of evaluation, at the beginning of the first phase (February 24 to April 8 2020; n=789). Presence of IgM/IgG antibodies against the SARS-CoV-2-Nucleocapsid protein was assessed by a lateral flow immunoassay.

Results: The test had a 100/98.3 sensitivity/specificity (n=32/120 positive/negative controls, respectively), and the IgG test was validated in a subset by an independent ELISA against the Spike protein (n=34, p<0.001). At the start of the outbreak, the overall adjusted seroprevalence of SARS-CoV-2 was 2.7% (95% CI: 0.3-6%; p<0.0001 vs 120 historical controls). During the study period, characterised by a gradual implementation of social distancing measures, there was a progressive increase in the adjusted seroprevalence to 5.2% (95% CI: 2.4-9.0; 4.5%, 95% CI: 0.9-9.2% according to a Bayesian estimate) due to a rise in IgG reactivity to 5% (95% CI: 2.8-8.2; p=0.004 for trend), but there was no increase in IgM (p=not significant). At multivariate logistic regression analysis, IgG reactivity was more frequent in younger individuals (p=0.043), while IgM reactivity was more frequent in individuals aged >45 years (p=0.002).

Discussion: SARS-CoV-2 infection was already circulating in Milan at the start of the outbreak. The pattern of IgM/IgG reactivity was influenced by age: IgM was more frequently detected in participants aged >45 years. By the end of April, 2.4-9.0% of healthy adults had evidence of seroconversion.
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http://dx.doi.org/10.2450/2021.0324-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092034PMC
May 2021

Milan ultrasound criteria are accurate in assessing disease activity in ulcerative colitis: external validation.

United European Gastroenterol J 2021 05 16;9(4):438-442. Epub 2021 Feb 16.

Department of Gastroenterology, Humanitas Clinical and Research Center - IRCCS, Milan, Italy.

Introduction: The aim of this study was to provide an external validation of bowel ultrasound (US) predictors of activity in ulcerative colitis (UC) and quantitative Milan Ultrasound Criteria (MUC).

Methods: Forty-three consecutive patients with UC (16 in endoscopic remission and 27 with endoscopic activity) underwent bowel US and colonoscopy in a tertiary referral inflammatory bowel disease unit.

Results: An MUC score >6.2 discriminated patients with active versus non-active UC with a sensitivity of 0.85 (95% confidence interval (CI) 0.66-0.96), specificity of 0.94 (95% CI 0.70-0.99) and an area under the curve of 0.902 (95% CI 0.772-0.971) in complete agreement with the derivation study.

Conclusion: The external validation of MUC confirms that it is an accurate tool for assessing disease activity in patients with UC.
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http://dx.doi.org/10.1177/2050640620980203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259285PMC
May 2021

Seroprevalence of SARS-CoV2 in IBD Patients Treated with Biologic Therapy.

J Crohns Colitis 2021 May;15(5):864-868

Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.

Background And Aims: A similar course of COVID-19 in patients with inflammatory bowel diseases [IBD] and in the general population has been reported. However, disease prevalence in IBD patients is presently unknown. In this prospective observational study, we aimed at determining SARS-CoV2 infection prevalence in IBD patients treated with biologic therapy.

Methods: From IBD patients under biologic therapy and recruited from three different locations in Italy and Germany, 354 sera were evaluated for antibody presence by RBD ELISA. Control groups were: i] age-matched healthy subjects tested in the same time period in Milan, Italy; ii] healthy subjects collected in the pre-COVID era; iii] IBD patients under biologic therapy collected in the pre-COVID era.

Results: Eight out of 354 patients tested positive for the anti-RBD-SARS-CoV2 IgG antibody [prevalence 2.3%]. The percentage of IgG-positive patients among those recruited from Milan was significantly higher than among those recruited from other locations [prevalence 5.4% vs 0.4%, p <0.005]. IgG-positive patients reported a significantly higher incidence of fever, anosmia, and ageusia, and were more likely to have entered into close contact with COVID-19-positive subjects before the study enrolment.

Conclusions: Seroprevalence of SARS-CoV2 in IBD patients treated with biologic therapy reflects values measured in the local general population. Specific symptoms and contact history with SARS-CoV2-infected individuals strongly increase the likelihood of SARS-CoV2 seropositivity.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717179PMC
May 2021

Activities related to inflammatory bowel disease management during and after the coronavirus disease 2019 lockdown in Italy: How to maintain standards of care.

United European Gastroenterol J 2020 12 18;8(10):1228-1235. Epub 2020 Oct 18.

Gastroenterology Unit, Mauriziano Hospital, Turin, Italy.

Background And Aims: Restructuring activities have been necessary during the lockdown phase of the coronavirus disease 2019 (COVID-19) pandemic. Few data are available on the post-lockdown phase in terms of health-care procedures in inflammatory bowel disease (IBD) care, and no data are available specifically from IBD units. We aimed to investigate how IBD management was restructured during the lockdown phase, the impact of the restructuring on standards of care and how Italian IBD units have managed post-lockdown activities.

Methods: A web-based online survey was conducted in two phases (April and June 2020) among the Italian Group for IBD affiliated units within the entire country. We investigated preventive measures, the possibility of continuing scheduled visits/procedures/therapies because of COVID-19 and how units resumed activities in the post-lockdown phase.

Results: Forty-two referral centres participated from all over Italy. During the COVID-19 lockdown, 36% of first visits and 7% of follow-up visits were regularly done, while >70% of follow-up scheduled visits and 5% of first visits were done virtually. About 25% of scheduled endoscopies and bowel ultrasound scans were done. More than 80% of biological therapies were done as scheduled. Compared to the pre-lockdown situation, 95% of centres modified management of outpatient activity, 93% of endoscopies, 59% of gastrointestinal ultrasounds and 33% of biological therapies. Resumption of activities after the lockdown phase may take three to six months to normalize. Virtual clinics, implementation of IBD pathways and facilities seem to be the main factors to improve care in the future.

Conclusion: Italian IBD unit restructuring allowed quality standards of care during the COVID-19 pandemic to be maintained. A return to normal appears to be feasible and achievable relatively quickly. Some approaches, such as virtual clinics and identified IBD pathways, represent a valid starting point to improve IBD care in the post-COVID-19 era.
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http://dx.doi.org/10.1177/2050640620964132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724532PMC
December 2020

Persistence of Anti-SARS-CoV-2 Antibodies in Non-Hospitalized COVID-19 Convalescent Health Care Workers.

J Clin Med 2020 Oct 1;9(10). Epub 2020 Oct 1.

Department of Experimental Oncology, European Institute of Oncology IRCCS, via Adamello 16, 20139 Milan, Italy.

Although antibody response to SARS-CoV-2 can be detected early during the infection, several outstanding questions remain to be addressed regarding the magnitude and persistence of antibody titer against different viral proteins and their correlation with the strength of the immune response. An ELISA assay has been developed by expressing and purifying the recombinant SARS-CoV-2 Spike Receptor Binding Domain (RBD), Soluble Ectodomain (Spike), and full length Nucleocapsid protein (N). Sera from healthcare workers affected by non-severe COVID-19 were longitudinally collected over four weeks, and compared to sera from patients hospitalized in Intensive Care Units (ICU) and SARS-CoV-2-negative subjects for the presence of IgM, IgG and IgA antibodies as well as soluble pro-inflammatory mediators in the sera. Non-hospitalized subjects showed lower antibody titers and blood pro-inflammatory cytokine profiles as compared to patients in Intensive Care Units (ICU), irrespective of the antibodies tested. Noteworthy, in non-severe COVID-19 infections, antibody titers against RBD and Spike, but not against the N protein, as well as pro-inflammatory cytokines decreased within a month after viral clearance. Thus, rapid decline in antibody titers and in pro-inflammatory cytokines may be a common feature of non-severe SARS-CoV-2 infection, suggesting that antibody-mediated protection against re-infection with SARS-CoV-2 is of short duration. These results suggest caution in using serological testing to estimate the prevalence of SARS-CoV-2 infection in the general population.
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http://dx.doi.org/10.3390/jcm9103188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600936PMC
October 2020

Microscopic imaging of Inflammatory Bowel Disease (IBD) and Non-IBD Colitis on digital slides: The Italian Group-IBD Pathologists experience.

Pathol Res Pract 2020 Nov 29;216(11):153189. Epub 2020 Aug 29.

Institute of Pathology, ASST Spedali Civili, Brescia, Italy.

Background: The aim of the study is to report the experience of the pathologists of the Italian Group for the Study of Inflammatory Bowel Disease (IBD) (group formed by pathologists with various experience) on the morphological assessment of digital slides pertaining to IBD and Non-IBD colitis underlining the necessity to implement this tool in daily routine and its utility to share opinions on difficult cases.

Materials And Methods: Forty-eight histological slides stained with haematoxylin and eosin obtained from ileo-colorectal endoscopic biopsies were digitized using Menarini D-Sight 2.0 system, uploaded onto a website platform and shared among 40 pathologists participating in the study. Information regarding the site of biopsy was disclosed; clinical data were blinded. Each participant was committed to write a comment on microscopic features purposing diagnostic opinion. One month after the last uploaded case, a form was sent to each participant to evaluate the personal experience on digital slide sharing.

Results: Sixteen pathologists out of 40 (40%) had consistently accessed to the site,9/40 (22%) commented on all slides, a diagnostic opinion was rendered in 8 slides. Most common critical issues were: A) poor internet connection resulting in ineffective evaluation of the digital slides, B) time-consuming cases raising difficult diagnostic interpretation, C) lack of clinical history. Overall, 24 participants (60%) found the forum valuable for practical training and educational purposes.

Conclusions: Sharing scanned slides circulating within a dedicated forum is an effective educational tool in both IBDs and Non-IBDs colitis. Although our results demonstrated a substantial compliance of the participants, their limited participation was an objective shortcoming. Hence, further efforts are needed to encourage this potentially rewarding practice among the pathologist community.
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http://dx.doi.org/10.1016/j.prp.2020.153189DOI Listing
November 2020

Prognostic Role of Mismatch Repair Status, Histotype and High-Risk Pathologic Features in Stage II Small Bowel Adenocarcinomas.

Ann Surg Oncol 2021 Feb 5;28(2):1167-1177. Epub 2020 Aug 5.

Unit of Pathology, Cervello Hospital, Palermo, Italy.

Background: Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer.

Patients And Methods: In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability.

Results: We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status.

Conclusions: Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.
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http://dx.doi.org/10.1245/s10434-020-08926-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801310PMC
February 2021

Probiotic Lactobacillus and Bifidobacterium Strains Counteract Adherent-Invasive (AIEC) Virulence and Hamper IL-23/Th17 Axis in Ulcerative Colitis, but Not in Crohn's Disease.

Cells 2020 08 1;9(8). Epub 2020 Aug 1.

Department of Biosciences, Università degli Studi di Milano, 20133 Milan, Italy.

Hypersecretion of proinflammatory cytokines and dysregulated activation of the IL-23/Th17 axis in response to intestinal microbiota dysbiosis are key factors in the pathogenesis of inflammatory bowel diseases (IBD). In this work, we studied how and strains affect AIEC-LF82 virulence mechanisms and the consequent inflammatory response linked to the CCR6-CCL20 and IL-23/Th17 axes in Crohn's disease (CD) and ulcerative colitis (UC) patients. All and strains significantly reduced the LF82 adhesion and persistence within HT29 intestinal epithelial cells, inhibiting IL-8 secretion while not affecting the CCR6-CCL20 axis. Moreover, they significantly reduced LF82 survival within macrophages and dendritic cells, reducing the secretion of polarizing cytokines related to the IL-23/Th17 axis, both in healthy donors (HD) and UC patients. In CD patients, however, only Bbr8 strain was able to slightly reduce the LF82 persistence within dendritic cells, thus hampering the IL-23/Th17 axis. In addition, probiotic strains were able to modulate the AIEC-induced inflammation in HD, reducing TNF-α and increasing IL-10 secretion by macrophages, but failed to do so in IBD patients. Interestingly, the probiotic strains studied in this work were all able to interfere with the IL-23/Th17 axis in UC patients, but not in CD patients. The different interaction mechanisms of probiotic strains with innate immune cells from UC and CD patients compared to HD suggest that testing on CD-derived immune cells may be pivotal for the identification of novel probiotic strains that could be effective also for CD patients.
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http://dx.doi.org/10.3390/cells9081824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464949PMC
August 2020

Fogging IBD Management: An Unusual Case of IBD Flare-up During the COVID-19 Outbreak.

Inflamm Bowel Dis 2020 09;26(10):e128-e129

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.

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http://dx.doi.org/10.1093/ibd/izaa184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546026PMC
September 2020

A Novel Genetic Variant Mapping on the Genomic Region Targeted by Mongersen Is Associated with Crohn's Disease.

Biomedicines 2020 Jul 22;8(8). Epub 2020 Jul 22.

Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.

Background: Down-regulation of Smad7 with a specific Smad7 antisense (AS) oligonucleotide-containing oral drug (Mongersen) was effective in pre-clinical studies and initial clinical trials in Crohn's disease (CD) patients. A recent phase 3 trial was discontinued due to an apparent inefficacy of the drug, but factors contributing to the failure of this study remain unknown. Here, we analysed the frequency in CD of rs144204026 C/T single nucleotide polymorphism (SNP), which maps on the corresponding region targeted by the Smad7 AS contained in the Mongersen formulation and examined whether such a variant allele affects the ability of Smad7 AS to knockdown Smad7.

Methods: rs144204026 SNP frequency was evaluated in two independent Italian cohorts of Crohn's disease patients and normal controls. Genotyping was performed by allelic discrimination assay. expression was evaluated in or heterozygous PBMCs treated with Smad7 AS.

Results: No TT genotype was seen in CD patients and controls. Heterozygous genotype was more frequent in CD patients of both cohort 1 (11/235, 4.68%) and cohort 2 (8/122, 6.56%) as compared to controls (6/363, 1.65%; = 0.029 and = 0.01 respectively). Overall, a statistically significant association was observed between the T variant allele and CD patients' susceptibility ( = 0.008; OR = 3.28, 95%CI: 1.3-8.3). Smad7 AS down-regulated RNA independently of the presence of the variant allele.

Conclusions: This is the first study to show an association between rs144204026 SNP and CD patients. Data indicate that such a variant does not negatively influence the in vitro inhibitory effect of Smad7 AS on Smad7.
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http://dx.doi.org/10.3390/biomedicines8080234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460430PMC
July 2020

Use of biosimilars in inflammatory bowel diseases: A survey among the clinicians members of the Italian Group for the Study of Inflammatory Bowel Disease (IGIBD).

Dig Liver Dis 2020 08 29;52(8):928-930. Epub 2020 Jun 29.

IBD Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy.

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http://dx.doi.org/10.1016/j.dld.2020.06.020DOI Listing
August 2020

The Role of Gut Microbiota Biomodulators on Mucosal Immunity and Intestinal Inflammation.

Cells 2020 05 16;9(5). Epub 2020 May 16.

Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, 20139 Milan, Italy.

Alterations of the gut microbiota may cause dysregulated mucosal immune responses leading to the onset of inflammatory bowel diseases (IBD) in genetically susceptible hosts. Restoring immune homeostasis through the normalization of the gut microbiota is now considered a valuable therapeutic approach to treat IBD patients. The customization of microbe-targeted therapies, including antibiotics, prebiotics, live biotherapeutics and faecal microbiota transplantation, is therefore considered to support current therapies in IBD management. In this review, we will discuss recent advancements in the understanding of host-microbe interactions in IBD and the basis to promote homeostatic immune responses through microbe-targeted therapies. By considering gut microbiota dysbiosis as a key feature for the establishment of chronic inflammatory events, in the near future it will be suitable to design new cost-effective, physiologic, and patient-oriented therapeutic strategies for the treatment of IBD that can be applied in a personalized manner.
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http://dx.doi.org/10.3390/cells9051234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291275PMC
May 2020

Outcomes of COVID-19 in 79 patients with IBD in Italy: an IG-IBD study.

Gut 2020 07 30;69(7):1213-1217. Epub 2020 Apr 30.

IBD Center, Gastroenterology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy.

Objectives: COVID-19 has rapidly become a major health emergency worldwide. Patients with IBD are at increased risk of infection, especially when they have active disease and are taking immunosuppressive therapy. The characteristics and outcomes of COVID-19 in patients with IBD remain unclear.

Design: This Italian prospective observational cohort study enrolled consecutive patients with an established IBD diagnosis and confirmed COVID-19. Data regarding age, sex, IBD (type, treatments and clinical activity), other comorbidities (Charlson Comorbidity Index (CCI)), signs and symptoms of COVID-19 and therapies were compared with COVID-19 outcomes (pneumonia, hospitalisation, respiratory therapy and death).

Results: Between 11 and 29 March 2020, 79 patients with IBD with COVID-19 were enrolled at 24 IBD referral units. Thirty-six patients had COVID-19-related pneumonia (46%), 22 (28%) were hospitalised, 7 (9%) required non-mechanical ventilation, 9 (11%) required continuous positive airway pressure therapy, 2 (3%) had endotracheal intubation and 6 (8%) died. Four patients (6%) were diagnosed with COVID-19 while they were being hospitalised for a severe flare of IBD. Age over 65 years (p=0.03), UC diagnosis (p=0.03), IBD activity (p=0.003) and a CCI score >1 (p=0.04) were significantly associated with COVID-19 pneumonia, whereas concomitant IBD treatments were not. Age over 65 years (p=0.002), active IBD (p=0.02) and higher CCI score were significantly associated with COVID-19-related death.

Conclusions: Active IBD, old age and comorbidities were associated with a negative COVID-19 outcome, whereas IBD treatments were not. Preventing acute IBD flares may avoid fatal COVID-19 in patients with IBD. Further research is needed.
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http://dx.doi.org/10.1136/gutjnl-2020-321411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242872PMC
July 2020

A fatal case of COVID-19 pneumonia occurring in a patient with severe acute ulcerative colitis.

Gut 2020 06 3;69(6):1148-1149. Epub 2020 Apr 3.

Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

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http://dx.doi.org/10.1136/gutjnl-2020-321183DOI Listing
June 2020

Immunological Variables Associated With Clinical and Endoscopic Response to Vedolizumab in Patients With Inflammatory Bowel Diseases.

J Crohns Colitis 2020 Sep;14(9):1190-1201

Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

Background And Aims: Vedolizumab [VDZ] is a monoclonal antibody directed against the α4β7 integrin heterodimer, approved for patients with inflammatory bowel diseases [IBD]. This study aimed at identifying immunological variables associated with response to vedolizumab in patients with ulcerative colitis [UC] and Crohn's disease [CD].

Methods: This is a phase IV explorative prospective interventional trial. IBD patients received open-label VDZ at Weeks 0, 2, 6, and 14. Patients with a clinical response at Week 14 were maintained with VDZ up to Week 54. At Weeks 0 and 14, their peripheral blood was obtained and endoscopy with biopsies was performed. The Week 14 clinical response and remission, Week 54 clinical remission, and Week 14 endoscopic response were evaluated as endpoints of the study. The expression of surface markers, chemokine receptors, and α4β7 heterodimer in peripheral blood and lamina propria lymphocytes was assessed by flow cytometry. A panel of soluble mediators was assessed in sera at baseline and at Week 14 by 45-plex.

Results: A total of 38 IBD patients [20 UC, 18 CD] were included in the study. At Week 14, the clinical response and remission rates were 87% and 66%, respectively. Higher baseline levels of circulating memory Th1 cells were strongly associated with clinical response at Week 14 [p = 0.0001], whereas reduced baseline levels of lamina propria memory Th17 and Th1/17 cells were associated with endoscopic response. Immunological clusters were found to be independently associated with vedolizumab outcomes at multivariable analysis. A panel of soluble markers, including IL17A, TNF, CXCL1, CCL19 for CD and G-CSF and IL7 for UC, associated with vedolizumab-induced Week 54 clinical remission.

Conclusions: The results of this exploratory study uncovered a panel of circulating and mucosal immunological variables associated with response to treatment with vedolizumab.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa035DOI Listing
September 2020

PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.

Mod Pathol 2020 07 17;33(7):1398-1409. Epub 2020 Feb 17.

Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy.

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1 immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1 cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1 microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.
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http://dx.doi.org/10.1038/s41379-020-0497-0DOI Listing
July 2020
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