Search

Your search keyword '"Invernizzi, P"' showing total 379 results
Start Over Author "Invernizzi, P" Publication Type Electronic Resources
379 results on '"Invernizzi, P"'

1. Improvements and future perspective in diagnostic tools for neuroendocrine neoplasms

Author

Massironi, S, Franchina, M, Ippolito, D, Elisei, F, Falco, O, Maino, C, Pagni, F, Elvevi, A, Guerra, L, Invernizzi, P, Massironi S., Franchina M., Ippolito D., Elisei F., Falco O., Maino C., Pagni F., Elvevi A., Guerra L., Invernizzi P., Massironi, S, Franchina, M, Ippolito, D, Elisei, F, Falco, O, Maino, C, Pagni, F, Elvevi, A, Guerra, L, Invernizzi, P, Massironi S., Franchina M., Ippolito D., Elisei F., Falco O., Maino C., Pagni F., Elvevi A., Guerra L., and Invernizzi P.

Abstract

Introduction: Neuroendocrine neoplasms (NENs) represent a complex group of tumors arising from neuroendocrine cells, characterized by heterogeneous behavior and challenging diagnostics. Despite advancements in medical technology, NENs present a major challenge in early detection, often leading to delayed diagnosis and variable outcomes. This review aims to provide an in-depth analysis of current diagnostic methods as well as the evolving and future directions of diagnostic strategies for NENs. Area covered: The review extensively covers the evolution of diagnostic tools for NENs, from traditional imaging and biochemical tests to advanced genomic profiling and next-generation sequencing. The emerging role of technologies such as artificial intelligence, machine learning, and liquid biopsies could improve diagnostic precision, as could the integration of imaging modalities such as positron emission tomography (PET)/magnetic resonance imaging (MRI) hybrids and innovative radiotracers. Expert opinion: Despite progress, there is still a significant gap in the early diagnosis of NENs. Bridging this diagnostic gap and integrating advanced technologies and precision medicine are crucial to improving patient outcomes. However, challenges such as low clinical awareness, limited possibility of noninvasive diagnostic tools and funding limitations for rare diseases like NENs are acknowledged.

Published
2024

2. Improving predictive accuracy in primary biliary cholangitis: A new genetic risk score

Author

Gerussi, A, Cappadona, C, Bernasconi, D, Cristoferi, L, Valsecchi, M, Carbone, M, Invernizzi, P, Asselta, R, Gerussi A., Cappadona C., Bernasconi D. P., Cristoferi L., Valsecchi M. G., Carbone M., Invernizzi P., Asselta R., Gerussi, A, Cappadona, C, Bernasconi, D, Cristoferi, L, Valsecchi, M, Carbone, M, Invernizzi, P, Asselta, R, Gerussi A., Cappadona C., Bernasconi D. P., Cristoferi L., Valsecchi M. G., Carbone M., Invernizzi P., and Asselta R.

Abstract

Background and AimsGenetic variants influence primary biliary cholangitis (PBC) risk. We established and tested an accurate polygenic risk score (PRS) using these variants. MethodsData from two Italian cohorts (OldIT 444 cases, 901 controls; NewIT 255 cases, 579 controls) were analysed. The latest international genome-wide meta-analysis provided effect size estimates. The PRS, together with human leukocyte antigen (HLA) status and sex, was included in an integrated risk model. ResultsStarting from 46 non-HLA genes, 22 variants were selected. PBC patients in the OldIT cohort showed a higher risk score than controls: -.014 (interquartile range, IQR, -.023, .005) versus -.022 (IQR -.030, -.013) (p < 2.2 x 10(-16)). For genetic-based prediction, the area under the curve (AUC) was .72; adding sex increased the AUC to .82. Validation in the NewIT cohort confirmed the model's accuracy (.71 without sex, .81 with sex). Individuals in the top group, representing the highest 25%, had a PBC risk approximately 14 times higher than that of the reference group (lowest 25%; p < 10(-6)). ConclusionThe combination of sex and a novel PRS accurately discriminated between PBC cases and controls. The model identified a subset of individuals at increased risk of PBC who might benefit from tailored monitoring.

Published
2024

3. Eosinophilic esophagitis: does age matter?

Author

Massironi, S, Elvevi, A, Panceri, R, Mulinacci, G, Colella, G, Biondi, A, Invernizzi, P, Danese, S, Vespa, E, Massironi S., Elvevi A., Panceri R., Mulinacci G., Colella G., Biondi A., Invernizzi P., Danese S., Vespa E., Massironi, S, Elvevi, A, Panceri, R, Mulinacci, G, Colella, G, Biondi, A, Invernizzi, P, Danese, S, Vespa, E, Massironi S., Elvevi A., Panceri R., Mulinacci G., Colella G., Biondi A., Invernizzi P., Danese S., and Vespa E.

Abstract

Introduction: Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus with increasing prevalence worldwide. It is a multifactorial disease caused by a combination of immunologic, genetic, and environmental factors. The clinical presentation of EoE varies largely, especially between different age groups. While diagnostic criteria and therapeutic goals are similar in children and adults, there are differences in treatment, with a more cautious approach in children to avoid growth disturbances. In addition, close monitoring and follow-up are essential in children to ensure uninterrupted growth. Areas covered: A search in PubMed/MEDLINE, EMBASE, and SCOPUS databases was conducted to identify relevant studies published between January 2010 and January 2023 to give an overview of the state-of-the-art of EoE epidemiology, diagnosis, and treatment while focusing on similarities and differences between the adult and the pediatric population. Expert opinion: The current state of research indicates that while significant progress has been made in understanding and treating EoE, further research and advances are needed to optimize diagnostic strategies, tailored treatment approaches, monitoring, and follow-up, and improve long-term outcomes for patients. With further innovation, the management of EoE can become more precise and tailored, leading to better patient outcomes and improved quality of life.

Published
2024

4. Adequate versus deep response to ursodeoxycholic acid in primary biliary cholangitis: To what extent and under what conditions is normal alkaline phosphatase level associated with complication-free survival gain?

Author

Corpechot, C, Lemoinne, S, Soret, P, Hansen, B, Hirschfield, G, Gulamhusein, A, Montano-Loza, A, Lytvyak, E, Pares, A, Olivas, I, Eaton, J, Osman, K, Schramm, C, Sebode, M, Lohse, A, Dalekos, G, Gatselis, N, Nevens, F, Cazzagon, N, Zago, A, Russo, F, Floreani, A, Abbas, N, Trivedi, P, Thorburn, D, Saffioti, F, Barkai, L, Roccarina, D, Calvaruso, V, Fichera, A, Delamarre, A, Sobenko, N, Villamil, A, Medina-Morales, E, Bonder, A, Patwardhan, V, Rigamonti, C, Carbone, M, Invernizzi, P, Cristoferi, L, Van Der Meer, A, De Veer, R, Zigmond, E, Yehezkel, E, Kremer, A, Deibel, A, Bruns, T, Grosse, K, Wetten, A, Dyson, J, Jones, D, Dumortier, J, Pageaux, G, De Ledinghen, V, Chazouilleres, O, Carrat, F, Corpechot C., Lemoinne S., Soret P. -A., Hansen B., Hirschfield G., Gulamhusein A., Montano-Loza A. J., Lytvyak E., Pares A., Olivas I., Eaton J. E., Osman K. T., Schramm C., Sebode M., Lohse A. W., Dalekos G., Gatselis N., Nevens F., Cazzagon N., Zago A., Russo F. P., Floreani A., Abbas N., Trivedi P., Thorburn D., Saffioti F., Barkai L., Roccarina D., Calvaruso V., Fichera A., Delamarre A., Sobenko N., Villamil A. M., Medina-Morales E., Bonder A., Patwardhan V., Rigamonti C., Carbone M., Invernizzi P., Cristoferi L., Van Der Meer A., De Veer R., Zigmond E., Yehezkel E., Kremer A. E., Deibel A., Bruns T., Grosse K., Wetten A., Dyson J. K., Jones D., Dumortier J., Pageaux G. -P., De Ledinghen V., Chazouilleres O., Carrat F., Corpechot, C, Lemoinne, S, Soret, P, Hansen, B, Hirschfield, G, Gulamhusein, A, Montano-Loza, A, Lytvyak, E, Pares, A, Olivas, I, Eaton, J, Osman, K, Schramm, C, Sebode, M, Lohse, A, Dalekos, G, Gatselis, N, Nevens, F, Cazzagon, N, Zago, A, Russo, F, Floreani, A, Abbas, N, Trivedi, P, Thorburn, D, Saffioti, F, Barkai, L, Roccarina, D, Calvaruso, V, Fichera, A, Delamarre, A, Sobenko, N, Villamil, A, Medina-Morales, E, Bonder, A, Patwardhan, V, Rigamonti, C, Carbone, M, Invernizzi, P, Cristoferi, L, Van Der Meer, A, De Veer, R, Zigmond, E, Yehezkel, E, Kremer, A, Deibel, A, Bruns, T, Grosse, K, Wetten, A, Dyson, J, Jones, D, Dumortier, J, Pageaux, G, De Ledinghen, V, Chazouilleres, O, Carrat, F, Corpechot C., Lemoinne S., Soret P. -A., Hansen B., Hirschfield G., Gulamhusein A., Montano-Loza A. J., Lytvyak E., Pares A., Olivas I., Eaton J. E., Osman K. T., Schramm C., Sebode M., Lohse A. W., Dalekos G., Gatselis N., Nevens F., Cazzagon N., Zago A., Russo F. P., Floreani A., Abbas N., Trivedi P., Thorburn D., Saffioti F., Barkai L., Roccarina D., Calvaruso V., Fichera A., Delamarre A., Sobenko N., Villamil A. M., Medina-Morales E., Bonder A., Patwardhan V., Rigamonti C., Carbone M., Invernizzi P., Cristoferi L., Van Der Meer A., De Veer R., Zigmond E., Yehezkel E., Kremer A. E., Deibel A., Bruns T., Grosse K., Wetten A., Dyson J. K., Jones D., Dumortier J., Pageaux G. -P., De Ledinghen V., Chazouilleres O., and Carrat F.

Abstract

Background and Aims: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. Approach and Results: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7-21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7-59.9, p < 0.001) when these 2 conditions were met. Conclusions: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.

Published
2024

5. Impact of MASLD and MetALD on clinical outcomes: A meta-analysis of preliminary evidence

Author

Ciardullo, S, Mantovani, A, Morieri, M, Muraca, E, Invernizzi, P, Perseghin, G, Morieri, ML, Ciardullo, S, Mantovani, A, Morieri, M, Muraca, E, Invernizzi, P, Perseghin, G, and Morieri, ML

Abstract

A recent Delphi consensus proposed a new definition for metabolic dysfunction associated steatotic liver disease (MASLD) and introduced a disease entity called MetALD, a condition in which steatotic liver disease (SLD), metabolic dysfunction and moderate alcohol intake coexist. Given the limited available data on the prognostic implications of these disease entities, we performed a systematic review and meta-analysis of available cohort studies to evaluate the association of MASLD and MetALD with hard clinical outcomes. We included 5 studies for a total of 9 824 047 participants. Compared with participants without SLD, increased rates of all-cause mortality and incident cardiovascular disease were present for both MASLD and MetALD. Moreover, MetALD was also associated with significantly higher risks of cancer-related mortality (n = 2 studies, random-effects HR 2.10, 95% CI 1.35–3.28) and cardiovascular mortality (n = 3 studies, random-effects HR 1.17, 95% CI 1.12–1.22). Although preliminary, available evidence indicates a more unfavourable prognosis for patients with MetALD compared with those with MASLD.

Published
2024

7. Advancements in pharmacological treatment of NAFLD/MASLD: a focus on metabolic and liver-targeted interventions

Author

Ciardullo, S, Muraca, E, Vergani, M, Invernizzi, P, Perseghin, G, Ciardullo, S, Muraca, E, Vergani, M, Invernizzi, P, and Perseghin, G

Abstract

In the present narrative review, we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD). We start by reviewing the epidemiology of the condition and its close association with obesity and type 2 diabetes. We then discuss how randomized–controlled trials are performed following guidance from regulatory agencies, including differences and similarities between requirements of the US Food and Drug Administration and the European Medicine Agency. Difficulties and hurdles related to limitations of liver biopsy, a large number of screening failures in recruiting patients, as well as unpredictable response rates in the placebo group are evaluated. Finally, we recapitulate the strategies employed for potential drug treatments of this orphan condition. The first is to repurpose drugs that originally targeted T2DM and/or obesity, such as pioglitazone, glucagon-like peptide 1 receptor agonists (liraglutide and semaglutide), multi-agonists (tirzepatide and retatrutide), and sodium-glucose transporter 2 inhibitors. The second is to develop drugs specifically targeting NAFLD/MASLD. Among those, we focused on resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, as they are currently in Phase 3 of their clinical trial development. While many failures have characterized the field of pharmacological treatment of NAFLD/MASLD in the past, it is likely that approval of the first treatments is near. As occurs in many chronic conditions, combination therapy might lead to better outcomes. In the case of non-alcoholic steatohepatitis, we speculate that drugs treating underlying metabolic co-morbidities might play a bigger role in the earlier stages of disease, while liver-targeting molecules will become vital in patients with more advanced disease in terms of inflammation and fibrosis.

Published
2024

8. Any role for transarterial radioembolization in unresectable intrahepatic cholangiocarcinoma in the era of advanced systemic therapies?

Author

Elvevi, A, Laffusa, A, Elisei, F, Morzenti, S, Guerra, L, Rovere, A, Invernizzi, P, Massironi, S, Elvevi A., Laffusa A., Elisei F., Morzenti S., Guerra L., Rovere A., Invernizzi P., Massironi S., Elvevi, A, Laffusa, A, Elisei, F, Morzenti, S, Guerra, L, Rovere, A, Invernizzi, P, Massironi, S, Elvevi A., Laffusa A., Elisei F., Morzenti S., Guerra L., Rovere A., Invernizzi P., and Massironi S.

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is recognized as the second most frequently diagnosed liver malignancy, following closely after hepatocellular carcinoma. Its incidence has seen a global upsurge in the past several years. Unfortunately, due to the lack of well-defined risk factors and limited diagnostic tools, iCCA is often diagnosed at an advanced stage, resulting in a poor prognosis. While surgery is the only potentially curative option, it is rarely feasible. Currently, there are ongoing investigations into various treatment approaches for unresectable iCCA, including conventional chemotherapies, targeted therapies, immunotherapies, and locoregional treatments. This study aims to explore the role of transarterial radioembolization (TARE) in the treatment of unresectable iCCA and provide a comprehensive review. The findings suggest that TARE is a safe and effective treatment option for unresectable iCCA, with a median overall survival (OS) of 14.9 months in the study cohort. Studies on TARE for unresectable iCCA, both as a first-line treatment (as a neo-adjuvant down-staging strategy) and as adjuvant therapy, have reported varying median response rates (ranging from 34% to 86%) and median OS (12-16 mo). These differences can be attributed to the heterogeneity of the patient population and the limited number of participants in the studies. Most studies have identified tumor burden, portal vein involvement, and the patient’s performance status as key prognostic factors. Furthermore, a phase 2 trial evaluated the combination of TARE and chemotherapy (cisplatin-gemcitabine) as a first-line therapy for locally advanced unresectable iCCA. The results showed promising outcomes, including a median OS of 22 mo and a 22% achievement in down-staging the tumor. In conclusion, TARE represents a viable treatment option for unresectable iCCA, and its combination with systemic chemotherapy has shown promising results. However, it is important to consider treatment-independe

Published
2023

9. Profiling the risk of hepatocellular carcinoma after long-term HCV eradication in patients with liver cirrhosis in the PITER cohort

Author

Kondili, L, Quaranta, M, Cavalletto, L, Calvaruso, V, Ferrigno, L, D'Ambrosio, R, Simonelli, I, Brancaccio, G, Raimondo, G, Brunetto, M, Zignego, A, Coppola, C, Iannone, A, Biliotti, E, Verucchi, G, Massari, M, Licata, A, Barbaro, F, Persico, M, Russo, F, Morisco, F, Pompili, M, Vigano, M, Puoti, M, Santantonio, T, Villa, E, Craxi, A, Chemello, L, Panetta, V, Gaeta, G, Filomia, R, Coco, B, Monti, M, Amoruso, D, Madonia, S, Ieluzzi, D, Taliani, G, Badia, L, Migliorino, G, Giorgini, A, Masarone, M, Blanc, P, Cossiga, V, De Siena, M, Tata, X, Rumi, M, Chessa, L, Lampertico, P, Ferrari, C, Gentile, I, Parruti, G, Baiocchi, L, Ciancio, A, Invernizzi, P, Federico, A, Torti, C, Morsica, G, Andreone, P, Aghemo, A, Popoli, P, Vella, S, Kondili L. A., Quaranta M. G., Cavalletto L., Calvaruso V., Ferrigno L., D'Ambrosio R., Simonelli I., Brancaccio G., Raimondo G., Brunetto M. R., Zignego A. L., Coppola C., Iannone A., Biliotti E., Verucchi G., Massari M., Licata A., Barbaro F., Persico M., Russo F. P., Morisco F., Pompili M., Vigano M., Puoti M., Santantonio T., Villa E., Craxi A., Chemello L., Panetta V., Gaeta G. B., Filomia R., Coco B., Monti M., Amoruso D. C., Madonia S., Ieluzzi D., Taliani G., Badia L., Migliorino G. M., Giorgini A., Masarone M., Blanc P., Cossiga V., De Siena M., Tata X., Rumi M. G., Chessa L., Lampertico P., Ferrari C., Gentile I., Parruti G., Baiocchi L., Ciancio A., Invernizzi P., Federico A., Torti C., Morsica G., Andreone P., Aghemo A., Popoli P., Vella S., Kondili, L, Quaranta, M, Cavalletto, L, Calvaruso, V, Ferrigno, L, D'Ambrosio, R, Simonelli, I, Brancaccio, G, Raimondo, G, Brunetto, M, Zignego, A, Coppola, C, Iannone, A, Biliotti, E, Verucchi, G, Massari, M, Licata, A, Barbaro, F, Persico, M, Russo, F, Morisco, F, Pompili, M, Vigano, M, Puoti, M, Santantonio, T, Villa, E, Craxi, A, Chemello, L, Panetta, V, Gaeta, G, Filomia, R, Coco, B, Monti, M, Amoruso, D, Madonia, S, Ieluzzi, D, Taliani, G, Badia, L, Migliorino, G, Giorgini, A, Masarone, M, Blanc, P, Cossiga, V, De Siena, M, Tata, X, Rumi, M, Chessa, L, Lampertico, P, Ferrari, C, Gentile, I, Parruti, G, Baiocchi, L, Ciancio, A, Invernizzi, P, Federico, A, Torti, C, Morsica, G, Andreone, P, Aghemo, A, Popoli, P, Vella, S, Kondili L. A., Quaranta M. G., Cavalletto L., Calvaruso V., Ferrigno L., D'Ambrosio R., Simonelli I., Brancaccio G., Raimondo G., Brunetto M. R., Zignego A. L., Coppola C., Iannone A., Biliotti E., Verucchi G., Massari M., Licata A., Barbaro F., Persico M., Russo F. P., Morisco F., Pompili M., Vigano M., Puoti M., Santantonio T., Villa E., Craxi A., Chemello L., Panetta V., Gaeta G. B., Filomia R., Coco B., Monti M., Amoruso D. C., Madonia S., Ieluzzi D., Taliani G., Badia L., Migliorino G. M., Giorgini A., Masarone M., Blanc P., Cossiga V., De Siena M., Tata X., Rumi M. G., Chessa L., Lampertico P., Ferrari C., Gentile I., Parruti G., Baiocchi L., Ciancio A., Invernizzi P., Federico A., Torti C., Morsica G., Andreone P., Aghemo A., Popoli P., and Vella S.

Abstract

Background and aims: Severe liver disease markers assessed before HCV eradication are acknowledged to usually improve after the SVR. We prospectively evaluated, in the PITER cohort, the long-term HCC risk profile based on predictors monitored after HCV eradication by direct-acting antivirals in patients with cirrhosis. Methods: HCC occurrence was evaluated by Kaplan-Meier analysis. Cox regression analysis identified the post-treatment variables associated with de-novo HCC; their predictive power was presented in a nomogram. Results: After the end of therapy (median follow-up:28.47 months), among 2064 SVR patients, 119 (5.8%) developed de-novo HCC. The HCC incidence was 1.90%, 4.21%, 6.47% at 12-, 24- and 36-months from end-of-therapy, respectively (incidence rate 2.45/100 person-years). Age, genotype 3, diabetes, platelets (PLT)≤120,000/µl and albumin ≤3.5g/dl levels were identified as pre-treatment HCC independent predictors. Adjusting for age, the post-treatment PLT≤120,000/µl (AdjHR 1.92; 95%CI:1.06-3.45) and albumin≤3.5g/dl (AdjHR 4.38; 95%CI 2.48-7.75) values were independently associated with HCC occurrence. Two different risk profiles were identified by combining long-term post-therapy evaluation of PLT ≤ vs. >120,000/µl and albumin ≤ vs. >3.5g/dl showing a significant different HCC incidence rate of 1.35 vs. 3.77/100 p-y, respectively. Conclusions: The nomogram score based on age, PLT and albumin levels after SVR showed an accurate prediction capability and may support the customizing management for early HCC detection.

Published
2023

10. Prevalence and significance of antimitochondrial antibodies in autoimmune hepatitis (AIH): Results from a large multicentre study of the International AIH Group

Author

Gatselis, N, Zachou, K, Loza, A, Cancado, E, Arinaga-Hino, T, Muratori, P, Efe, C, Floreani, A, Invernizzi, P, Takahashi, A, Takaki, A, Beretta-Piccoli, B, van Hoek, B, Lytvyak, E, Guedes, L, Purnak, T, Cazzagon, N, Lygoura, V, Arvaniti, P, Rigopoulou, E, Muratori, L, Dalekos, G, Gatselis N. K., Zachou K., Loza A. J. M., Cancado E. L. R., Arinaga-Hino T., Muratori P., Efe C., Floreani A., Invernizzi P., Takahashi A., Takaki A., Beretta-Piccoli B. T., van Hoek B., Lytvyak E., Guedes L. V., Purnak T., Cazzagon N., Lygoura V., Arvaniti P., Rigopoulou E. I., Muratori L., Dalekos G. N., Gatselis, N, Zachou, K, Loza, A, Cancado, E, Arinaga-Hino, T, Muratori, P, Efe, C, Floreani, A, Invernizzi, P, Takahashi, A, Takaki, A, Beretta-Piccoli, B, van Hoek, B, Lytvyak, E, Guedes, L, Purnak, T, Cazzagon, N, Lygoura, V, Arvaniti, P, Rigopoulou, E, Muratori, L, Dalekos, G, Gatselis N. K., Zachou K., Loza A. J. M., Cancado E. L. R., Arinaga-Hino T., Muratori P., Efe C., Floreani A., Invernizzi P., Takahashi A., Takaki A., Beretta-Piccoli B. T., van Hoek B., Lytvyak E., Guedes L. V., Purnak T., Cazzagon N., Lygoura V., Arvaniti P., Rigopoulou E. I., Muratori L., and Dalekos G. N.

Abstract

Background & Aims: Antimitochondrial antibodies (AMA) are specific markers for the diagnosis of primary biliary cholangitis (PBC) but can also be found occasionally in patients with autoimmune hepatitis (AIH). The present large multicentre cohort study assessed the prevalence and significance of AMA in AIH-patients. Methods: 123 AMA-positive AIH-patients were investigated and compared with 711 age-matched AMA-negative AIH-patients and 69 patients with AIH/PBC variant. Results: AMA prevalence in AIH-patients was 5.1% (range: 1.2%-11.8%). AMA-positivity was associated with female sex (p = 0.031) in AMA-positive AIH-patients but not with liver biochemistry, bile duct injury on liver biopsy, disease severity at baseline and response to treatment compared to AMA-negative AIH-patients. Comparing AMA-positive AIH-patients to those with AIH/PBC variant, there was no difference in disease severity. Regarding liver histology, AIH/PBC variant patients were characterized by the presence of at least one feature of bile duct damage (p<0.001). Response to immunosuppressive treatment was similar among groups. From AMA-positive AIH patients only those with evidence of non-specific bile duct injury had higher risk to progress to cirrhosis (HR=4.314, 95%CI: 2.348–7.928; p<0.001). During follow-up, AMA-positive AIH-patients had higher risk to develop histological bile duct injury (HR 4.654, 95%CI 1.829–11.840; p = 0.001). Conclusions: AMA presence is relatively common among AIH-patients, but their clinical significance seems important only when they co-exist with non-specific bile duct injury at the histological level. Therefore, a careful evaluation of liver biopsy seems of utmost importance in these patients.

Published
2023

11. Paradoxical association between dyspepsia and autoimmune chronic atrophic gastritis: Insights into mechanisms, pathophysiology, and treatment options

Author

Rossi, R, Elvevi, A, Sciola, V, Mandarino, F, Danese, S, Invernizzi, P, Massironi, S, Rossi R. E., Elvevi A., Sciola V., Mandarino F. V., Danese S., Invernizzi P., Massironi S., Rossi, R, Elvevi, A, Sciola, V, Mandarino, F, Danese, S, Invernizzi, P, Massironi, S, Rossi R. E., Elvevi A., Sciola V., Mandarino F. V., Danese S., Invernizzi P., and Massironi S.

Abstract

BACKGROUND Autoimmune gastritis (AIG) is a progressive, chronic, immune-mediated inflammatory disease characterized by the destruction of gastric parietal cells leading to hypo/anacidity and loss of intrinsic factor. Gastrointestinal symptoms such as dyspepsia and early satiety are very common, being second in terms of frequency only to anemia, which is the most typical feature of AIG. AIM To address both well-established and more innovative information and knowledge about this challenging disorder. METHODS An extensive bibliographical search was performed in PubMed to identify guidelines and primary literature (retrospective and prospective studies, systematic reviews, case series) published in the last 10 years. RESULTS A total of 125 records were reviewed and 80 were defined as fulfilling the criteria. CONCLUSION AIG can cause a range of clinical manifestations, including dyspepsia. The pathophysiology of dyspepsia in AIG is complex and involves changes in acid secretion, gastric motility, hormone signaling, and gut microbiota, among other factors. Managing dyspeptic symptoms of AIG is challenging and there are no specific therapies targeting dyspepsia in AIG. While proton pump inhibitors are commonly used to treat dyspepsia and gastroesophageal reflux disease, they may not be appropriate for AIG. Prokinetic agents, antidepressant drugs, and non-pharmacological treatments may be of help, even if not adequately evidence-based supported. A multidisciplinary approach for the management of dyspepsia in AIG is recommended, and further research is needed to develop and validate more effective therapies for dyspepsia.

Published
2023

12. Optimizing therapy in primary biliary cholangitis: Alkaline phosphatase at six months identifies one-year non-responders and predicts survival

Author

Murilloperez, C, Ioannou, S, Hassanally, I, Trivedi, P, Corpechot, C, van der Meer, A, Lammers, W, Battezzati, P, Lindor, K, Nevens, F, Kowdley, K, Bruns, T, Cazzagon, N, Floreani, A, Mason, A, Gulamhusein, A, Ponsioen, C, Carbone, M, Lleo, A, Mayo, M, Dalekos, G, Gatselis, N, Thorburn, D, Verhelst, X, Pares, A, Londono, M, Janssen, H, Invernizzi, P, Vuppalanchi, R, Hirschfield, G, Hansen, B, Levy, C, MurilloPerez C. F., Ioannou S., Hassanally I., Trivedi P. J., Corpechot C., van der Meer A. J., Lammers W. J., Battezzati P. M., Lindor K. D., Nevens F., Kowdley K. V., Bruns T., Cazzagon N., Floreani A., Mason A. L., Gulamhusein A., Ponsioen C. Y., Carbone M., Lleo A., Mayo M. J., Dalekos G. N., Gatselis N. K., Thorburn D., Verhelst X., Pares A., Londono M. -C., Janssen H. L. A., Invernizzi P., Vuppalanchi R., Hirschfield G. M., Hansen B. E., Levy C., Murilloperez, C, Ioannou, S, Hassanally, I, Trivedi, P, Corpechot, C, van der Meer, A, Lammers, W, Battezzati, P, Lindor, K, Nevens, F, Kowdley, K, Bruns, T, Cazzagon, N, Floreani, A, Mason, A, Gulamhusein, A, Ponsioen, C, Carbone, M, Lleo, A, Mayo, M, Dalekos, G, Gatselis, N, Thorburn, D, Verhelst, X, Pares, A, Londono, M, Janssen, H, Invernizzi, P, Vuppalanchi, R, Hirschfield, G, Hansen, B, Levy, C, MurilloPerez C. F., Ioannou S., Hassanally I., Trivedi P. J., Corpechot C., van der Meer A. J., Lammers W. J., Battezzati P. M., Lindor K. D., Nevens F., Kowdley K. V., Bruns T., Cazzagon N., Floreani A., Mason A. L., Gulamhusein A., Ponsioen C. Y., Carbone M., Lleo A., Mayo M. J., Dalekos G. N., Gatselis N. K., Thorburn D., Verhelst X., Pares A., Londono M. -C., Janssen H. L. A., Invernizzi P., Vuppalanchi R., Hirschfield G. M., Hansen B. E., and Levy C.

Abstract

Background and Aims: Patients with primary biliary cholangitis (PBC) and insufficient response to ursodeoxycholic acid (UDCA), currently assessed after 1 year, are candidates for second-line therapy. The aims of this study are to assess biochemical response pattern and determine the utility of alkaline phosphatase (ALP) at six months as a predictor of insufficient response. Methods: UDCA-treated patients in the GLOBAL PBC database with available liver biochemistries at one year were included. POISE criteria were used to assess response to treatment, defined as ALP <1.67 × upper limit of normal (ULN) and normal total bilirubin at one year. Various thresholds of ALP at six months were evaluated to predict insufficient response based on negative predictive value (NPV) and that with nearest to 90% NPV was selected. Results: For the study, 1362 patients were included, 1232 (90.5%) female, mean age of 54 years. The POISE criteria were met by 56.4% (n = 768) of patients at one year. The median ALP (IQR) of those who met POISE criteria compared to those who did not was 1.05 × ULN (0.82–1.33) vs. 2.37 × ULN (1.72–3.69) at six months (p <.001). Of 235 patients with serum ALP >1.9 × ULN at six months, 89% did not achieve POISE criteria (NPV) after one year of UDCA. Of those with insufficient response by POISE criteria at one year, 210 (67%) had an ALP >1.9 × ULN at six months and thus would have been identified early. Conclusions: We can identify patients for second-line therapy at six months using an ALP threshold of 1.9 × ULN, given that approximately 90% of these patients are non-responders according to POISE criteria.

Published
2023

13. Sporadic and MEN1-related gastrinoma and Zollinger–Ellison syndrome: differences in clinical characteristics and survival outcomes

Author

Massironi, S, Rossi, R, Laffusa, A, Eller-Vainicher, C, Cavalcoli, F, Zilli, A, Ciafardini, C, Sciola, V, Invernizzi, P, Peracchi, M, Massironi S., Rossi R. E., Laffusa A., Eller-Vainicher C., Cavalcoli F., Zilli A., Ciafardini C., Sciola V., Invernizzi P., Peracchi M., Massironi, S, Rossi, R, Laffusa, A, Eller-Vainicher, C, Cavalcoli, F, Zilli, A, Ciafardini, C, Sciola, V, Invernizzi, P, Peracchi, M, Massironi S., Rossi R. E., Laffusa A., Eller-Vainicher C., Cavalcoli F., Zilli A., Ciafardini C., Sciola V., Invernizzi P., and Peracchi M.

Abstract

Purpose: Gastrinoma with Zollinger–Ellison syndrome (ZES) may occur sporadically (Sp) or as part of the inherited syndrome of multiple endocrine neoplasia 1 (MEN-1). Data comparing Sp and MEN-1/ZES are scanty. We aimed to identify and compare their clinical features. Methods: Consecutive patients with ZES were evaluated between 1992 and 2020 among a monocentric Italian patient cohort. Results: Of 76 MEN-1 patients, 41 had gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), 18 of whom had ZES; of 320 Sp-GEP-NEN, 19 had Sp-ZES. MEN-1/ZES patients were younger (p = 0.035) and the primary MEN-1/ZES gastrinoma was smaller than Sp-ZES (p = 0.030). Liver metastases occurred in both groups, but only Sp-ZES developed extrahepatic metastases. 13 Sp-ZES and 8 MEN-1/ZES underwent surgery. 8 Sp-ZES and 7 MEN-1/ZES received somatostatin analogs (SSAs). Median overall survival (OS) was higher in MEN-1/ZES than in Sp-ZES (310 vs 168 months, p = 0.034). At univariate-logistic regression, age at diagnosis (p = 0.01, OR = 1.1), G3 grading (p = 0.003, OR = 21.3), Sp-ZES (p = 0.02, OR = 0.3) and presence of extrahepatic metastases (p = 0.001, OR = 7.2) showed a significant association with OS. At multivariate-COX-analysis, none of the variables resulted significantly related to OS. At univariate-logistic regression, age (p = 0.04, OR = 1.0), size (p = 0.039, OR = 1.0), G3 grade (p = 0.008, OR = 14.6) and extrahepatic metastases (p = 0.005, OR = 4.6) were independently associated with progression-free survival (PFS). In multivariate-COX-analysis, only extrahepatic metastases (p = 0.05, OR = 3.4) showed a significant association with PFS. Among SSAs-treated patients, MEN-1/ZES showed better PFS (p = 0.0227). After surgery, the median PFS was 126 and 96 months in MEN-1 and Sp, respectively. Conclusion: MEN-1/ZES patients generally show better OS and PFS than Sp-ZES as well as better SSAs response.

Published
2023

14. The Emerging Role of Tumor Microenvironmental Stimuli in Regulating Metabolic Rewiring of Liver Cancer Stem Cells

Author

Correnti, M, Binatti, E, Gammella, E, Invernizzi, P, Recalcati, S, Correnti M., Binatti E., Gammella E., Invernizzi P., Recalcati S., Correnti, M, Binatti, E, Gammella, E, Invernizzi, P, Recalcati, S, Correnti M., Binatti E., Gammella E., Invernizzi P., and Recalcati S.

Abstract

Primary liver cancer (PLC) is one of the most devastating cancers worldwide. Extensive phenotypical and functional heterogeneity is a cardinal hallmark of cancer, including PLC, and is related to the cancer stem cell (CSC) concept. CSCs are responsible for tumor growth, progression, relapse and resistance to conventional therapies. Metabolic reprogramming represents an emerging hallmark of cancer. Cancer cells, including CSCs, are very plastic and possess the dynamic ability to constantly shift between different metabolic states depending on various intrinsic and extrinsic stimuli, therefore amplifying the complexity of understanding tumor heterogeneity. Besides the well-known Warburg effect, several other metabolic pathways including lipids and iron metabolism are altered in PLC. An increasing number of studies supports the role of the surrounding tumor microenvironment (TME) in the metabolic control of liver CSCs. In this review, we discuss the complex metabolic rewiring affecting liver cancer cells and, in particular, liver CSCs. Moreover, we highlight the role of TME cellular and noncellular components in regulating liver CSC metabolic plasticity. Deciphering the specific mechanisms regulating liver CSC–TME metabolic interplay could be very helpful with respect to the development of more effective and innovative combinatorial therapies for PLC treatment.

Published
2023

15. Impact of metformin on the incidence of human cholangiocarcinoma in diabetic patients: A systematic review and meta-analysis

Author

Laffusa, A, Ciaccio, A, Elvevi, A, Gallo, C, Ratti, L, Invernizzi, P, Massironi, S, Laffusa A., Ciaccio A., Elvevi A., Gallo C., Ratti L., Invernizzi P., Massironi S., Laffusa, A, Ciaccio, A, Elvevi, A, Gallo, C, Ratti, L, Invernizzi, P, Massironi, S, Laffusa A., Ciaccio A., Elvevi A., Gallo C., Ratti L., Invernizzi P., and Massironi S.

Abstract

Cholangiocarcinoma (CCA) is the second most common liver cancer. Diabetes is a well-known risk factor; however, treatment with metformin has been reported to be protective for several cancers, but data on CCA are still sparse and heterogeneous. We performed this meta-analysis to investigate the role of metformin as a potential protective factor for CCA. In this systematic review and meta-analysis, we searched PubMed/MEDLINE and EMBASE databases, from the date of inception to November 2022, for studies analyzing CCA rate in patients taking metformin. Twenty-nine articles were initially identified, of which four were eligible and included in our systematic review and meta-analysis, from which we estimated the relative risk (RR). The rate of CCA was lower for diabetic patients taking metformin than diabetic patients without metformin intake when comparing two highest quality studies [RR, 0.38; 95% confidence interval (CI), 0.290-0.508; P < 0.001], and three studies with similar inclusion criteria (RR, 0.34; 95% CI, 0.51-0.35; P < 0.001) without significant statistical heterogeneity among them (I2= 29.83%, P = 0,2326 and I2= 35.08%; P = 0.2143, respectively). Our study demonstrated a significant impact of metformin in reducing the risk of CCA by nearly 62-66% in diabetic patients taking metformin.

Published
2023

16. Artificial Intelligence and liver: Opportunities and barriers

Author

Balsano, C, Burra, P, Duvoux, C, Alisi, A, Piscaglia, F, Gerussi, A, Brunetto, M, Bonino, F, Montalti, R, Campanile, S, Persico, M, Alvaro, D, Santini, S, Invernizzi, P, Carbone, M, Masarone, M, Eccher, A, Siciliano, B, Vento, M, Ficuciello, F, Cabitza, F, Penasa, S, Donatelli, P, Balsano C., Burra P., Duvoux C., Alisi A., Piscaglia F., Gerussi A., Brunetto M. R., Bonino F., Montalti R., Campanile S., Persico M., Alvaro D., Santini S., Invernizzi P., Carbone M., Masarone M., Eccher A., Siciliano B., Vento M., Ficuciello F., Cabitza F., Penasa S., Donatelli P., Balsano, C, Burra, P, Duvoux, C, Alisi, A, Piscaglia, F, Gerussi, A, Brunetto, M, Bonino, F, Montalti, R, Campanile, S, Persico, M, Alvaro, D, Santini, S, Invernizzi, P, Carbone, M, Masarone, M, Eccher, A, Siciliano, B, Vento, M, Ficuciello, F, Cabitza, F, Penasa, S, Donatelli, P, Balsano C., Burra P., Duvoux C., Alisi A., Piscaglia F., Gerussi A., Brunetto M. R., Bonino F., Montalti R., Campanile S., Persico M., Alvaro D., Santini S., Invernizzi P., Carbone M., Masarone M., Eccher A., Siciliano B., Vento M., Ficuciello F., Cabitza F., Penasa S., and Donatelli P.

Abstract

Artificial Intelligence (AI) has recently been shown as an excellent tool for the study of the liver; however, many obstacles still have to be overcome for the digitalization of real-world hepatology. The authors present an overview of the current state of the art on the use of innovative technologies in different areas (big data, translational hepatology, imaging, and transplant setting). In clinical practice, physicians must integrate a vast array of data modalities (medical history, clinical data, laboratory tests, imaging, and pathology slides) to achieve a diagnostic or therapeutic decision. Unfortunately, machine learning and deep learning are still far from really supporting clinicians in real life. In fact, the accuracy of any technological support has no value in medicine without the support of clinicians. To make better use of new technologies, it is essential to improve clinicians’ knowledge about them. To this end, the authors propose that collaborative networks for multidisciplinary approaches will improve the rapid implementation of AI systems for developing disease-customized AI-powered clinical decision support tools. The authors also discuss ethical, educational, and legal challenges that must be overcome to build robust bridges and deploy potentially effective AI in real-world clinical settings.

Published
2023

17. Any Role for Microbiota in Cholangiocarcinoma? A Comprehensive Review

Author

Elvevi, A, Laffusa, A, Gallo, C, Invernizzi, P, Massironi, S, Elvevi A., Laffusa A., Gallo C., Invernizzi P., Massironi S., Elvevi, A, Laffusa, A, Gallo, C, Invernizzi, P, Massironi, S, Elvevi A., Laffusa A., Gallo C., Invernizzi P., and Massironi S.

Abstract

Alterations in the human microbiota have been linked to carcinogenesis in several cancers. To date, few studies have addressed the role of the microbiota in cholangiocarcinoma (CCA). Our work aims to update the knowledge about the role of the microbiota in the CCA microenvironment, and to highlight possible novel insights for the development of new diagnostic, prognostic, or even therapeutic strategies. We thus conducted a review of the literature. In recent years, great progress has been made in understanding the pathogenesis, the clinical and histological behavior, and the molecular profile of CCA. Much evidence suggests that the bile microbiota plays an essential role in biliary diseases, including CCA. Some studies have demonstrated that alterations in the qualitative and quantitative composition of the intestinal commensal bacteria lead to overall cancer susceptibility through various pathways. Other studies suggest that the gut microbiota plays a role in the pathogenesis and/or progression of CCA. The clinical implications are far-reaching, and the role of the microbiota in the CCA microenvironment may lead to considering the exciting implications of implementing therapeutic strategies that target the microbiota-immune system axis.

Published
2023

18. Use of IBD Drugs in Patients with Hepatobiliary Comorbidities: Tips and Tricks

Author

Massironi, S, Pirola, L, Mulinacci, G, Ciaccio, A, Vigano, C, Palermo, A, Zilli, A, Invernizzi, P, Danese, S, Massironi S., Pirola L., Mulinacci G., Ciaccio A., Vigano C., Palermo A., Zilli A., Invernizzi P., Danese S., Massironi, S, Pirola, L, Mulinacci, G, Ciaccio, A, Vigano, C, Palermo, A, Zilli, A, Invernizzi, P, Danese, S, Massironi S., Pirola L., Mulinacci G., Ciaccio A., Vigano C., Palermo A., Zilli A., Invernizzi P., and Danese S.

Abstract

Advanced therapies (biologic agents and small molecules) for inflammatory bowel diseases (IBD) have radically changed the management of these diseases during the last decade. Data about these drugs in patients with hepatic disorders derive mainly from real-life studies, as these conditions often represent an exclusion criterion from pivotal drug developmental trials. However, IBD patients sometimes have concomitant liver diseases. Nonalcoholic fatty liver disease is the most prevalent hepatic comorbidity, whereas viral hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis, and hepatic vascular disorders are less frequent. This review aimed at describing the real-life data about the use of advanced therapies for IBD in patients with concomitant hepatobiliary disorders. Hepatitis B virus and hepatitis C virus infections do not represent an absolute contraindication for novel IBD therapeutic agents. Data from the literature suggest a safe hepatobiliary profile of biologic agents and small molecules in the case of nonalcoholic fatty liver disease, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, and portal vein thrombosis. Consequently, although the liver disease does not affect a different therapeutic approach in patients with concomitant IBD and liver disease, a close risk/benefit analysis for each drug should be performed in these patients, especially in cirrhotic patients and in the postliver transplant setting.

Published
2023

19. Autoimmune liver diseases

Author

Scaravaglio, M, Carbone, M, Invernizzi, P, Scaravaglio M., Carbone M., Invernizzi P., Scaravaglio, M, Carbone, M, Invernizzi, P, Scaravaglio M., Carbone M., and Invernizzi P.

Published
2023

20. Incidence and prevalence of gastric neuroendocrine tumors in patients with chronic atrophic autoimmune gastritis

Author

Massironi, S, Gallo, C, Elvevi, A, Stegagnini, M, Coltro, L, Invernizzi, P, Massironi S., Gallo C., Elvevi A., Stegagnini M., Coltro L. A., Invernizzi P., Massironi, S, Gallo, C, Elvevi, A, Stegagnini, M, Coltro, L, Invernizzi, P, Massironi S., Gallo C., Elvevi A., Stegagnini M., Coltro L. A., and Invernizzi P.

Abstract

BACKGROUND The incidence of type I gastric neuroendocrine neoplasms (gNENs) has increased significantly over the past 50 years. Although autoimmune gastritis (AIG) increases the likelihood of developing gNENs, the exact incidence and prevalence of this association remain unclear. AIM To evaluate the incidence and prevalence of type I gNENs in a cohort of patients with a histological diagnosis of AIG. METHODS Patients with a histological diagnosis of AIG were enrolled between October 2020 and May 2022. Circulating levels of CgA and gastrin were assessed at enrollment. Included patients underwent regular endoscopic follow-up to detect gastric neoplastic lesions, enterochromaffin-like (ECL) cell hyperplasia, and the development of gNEN. RESULTS We included 176 patients [142 women (80.7%), median age 64 years, interquartile range (IQR) 53–71 years] diagnosed with AIG between January 1990 and June 2022. At enrollment. One hundred and sixteen patients (65.9%) had ECL hyperplasia, of whom, 29.5% had simple/linear, 30.7% had micronodular, and 5.7% had macronodular type. The median follow-up time was 5 (3–7.5) years. After 1032 person-years, 33 patients developed a total of 50 type I gNENs, with an incidence rate of 0.057 person-years, corresponding to an annual cumulative incidence of 5.7%. Circulating CgA levels did not significantly differ between AIG patients who developed gNENs and those who did not. Conversely, gastrin levels were significantly higher in AIG patients who developed gNENs [median 992 pg/mL IQR = 449–1500 vs 688 pg/mL IQR = 423–1200, P = 0.03]. Calculated gastrin sensitivity and specificity were 90.9% and 1.4%, respectively, with an overall diagnostic accuracy of 30% and a calculated area under the gastrin receiver operating characteristic curve (AUROC or AUC) of 0.53. CONCLUSION Type I gNENs are a significant complication in AIG. Gastrin’s low diagnostic accuracy prevents it from serving as a marker for early diagnosis. Effective strategies for early det

Published
2023

21. Setanaxib, a first-in-class selective NADPH oxidase 1/4 inhibitor for primary biliary cholangitis: A randomized, placebo-controlled, phase 2 trial

Author

Invernizzi, P, Carbone, M, Jones, D, Levy, C, Little, N, Wiesel, P, Nevens, F, Invernizzi P., Carbone M., Jones D., Levy C., Little N., Wiesel P., Nevens F., Invernizzi, P, Carbone, M, Jones, D, Levy, C, Little, N, Wiesel, P, Nevens, F, Invernizzi P., Carbone M., Jones D., Levy C., Little N., Wiesel P., and Nevens F.

Abstract

BackgroundPrimary biliary cholangitis (PBC) is a rare liver disease with significant unmet need for second-line/add-on treatments. Setanaxib, a NOX1/4 inhibitor, has shown anti-fibrotic effects in in vitro and animal studies. This phase 2, randomized, multicentre study investigated the efficacy and safety of setanaxib in patients with PBC. MethodsPatients with >= 6 months of ursodeoxycholic acid (UDCA) treatment were randomized 1:1:1 to oral setanaxib 400 mg once daily (OD), twice daily (BID), or placebo, in addition to UDCA for 24 weeks. Other inclusion criteria included alkaline phosphatase (ALP) >= 1.5 x ULN and gamma-glutamyl transferase (GGT) >= 1.5 x ULN. The primary endpoint was percentage change from baseline in GGT at Week 24; secondary endpoints included change from baseline in ALP, liver stiffness (LS; via transient elastography), fatigue at Week 24, and safety outcomes. p values compare setanaxib 400 mg BID and placebo groups. ResultsOf patients randomized (setanaxib 400 mg OD and BID: 38, and 36; placebo: 37), 104/111 completed Week 24. Mean (standard deviation [SD]) change in GGT to Week 24 was -4.9% (59.6%) for setanaxib 400 mg OD, -19.0% (28.9%) for setanaxib 400 mg BID, and -8.4% (21.5%) for placebo; p = .31. Patients treated with setanaxib 400 mg OD and BID showed decreased serum ALP levels from baseline to Week 24 (p = .002: setanaxib BID versus placebo). Patients treated with setanaxib 400 mg OD and BID showed mean (SD) percentage increases in LS to Week 24 of 3.3% (35.0%) and 7.9% (43.7%), versus 10.1% (33.1%) for placebo (p = .65). Changes in mean (SD) PBC-40 fatigue domain scores to Week 24 were +0.3% (24.9%) for setanaxib 400 mg OD, -9.9% (19.8%) for setanaxib 400 mg BID and +2.4% (23.1%) for placebo, p = .027. Two patients (one placebo, one setanaxib 400 mg BID) experienced serious treatment-emergent adverse events, deemed unrelated to study drug. ConclusionsThe primary endpoint was not met. However, the secondary endpoints provide

Published
2023

22. Open challenges in the management of autoimmune hepatitis

Author

Gerussi, A, Halliday, N, Carbone, M, Invernizzi, P, Thorburn, D, Gerussi A., Halliday N., Carbone M., Invernizzi P., Thorburn D., Gerussi, A, Halliday, N, Carbone, M, Invernizzi, P, Thorburn, D, Gerussi A., Halliday N., Carbone M., Invernizzi P., and Thorburn D.

Abstract

Autoimmune hepatitis (AIH) is a rare autoimmune disease of the liver with many open questions as regards its etiopathogenesis, natural history and clinical management. The classical picture of AIH is chronic hepatitis with fluctuating elevation of serum transaminases and Immunoglobulin G levels, the presence of circulating autoantibodies and typical histological features. However, atypical presentations do occur and are not well captured by current diagnostic scores, with important consequences in terms of missed diagnoses and delayed treatments. AIH is treated with corticosteroids and immunosuppressive drugs but up to 40% of patients do not achieve full biochemical response and are at risk of progressing to cirrhosis and liver failure. Moreover, standard therapies are associated by significant side-effects which may impair the quality of life of patients living with AIH. However, advances in the understanding of the underlying immunology of AIH is raising the prospect of novel therapies and optimization of existing therapeutic approaches to reduce side-effect burdens and potentially restore immunological tolerance. In this review we outlined the clinical characteristics, etiopathogenesis and management of AIH and current challenges in the diagnosis and management of AIH and provided evidence underlying the evolution of diagnostic and clinical management protocols.

Published
2023

23. Exploring the spectrum of incidental gastric polyps in autoimmune gastritis

Author

Massironi, S, Elvevi, A, Gallo, C, Laffusa, A, Tortorella, A, Invernizzi, P, Massironi S., Elvevi A., Gallo C., Laffusa A., Tortorella A., Invernizzi P., Massironi, S, Elvevi, A, Gallo, C, Laffusa, A, Tortorella, A, Invernizzi, P, Massironi S., Elvevi A., Gallo C., Laffusa A., Tortorella A., and Invernizzi P.

Abstract

Background: Gastric polyps represent an abnormal proliferation of the gastric mucosa. Chronic atrophic autoimmune gastritis (CAAG) targets parietal cells and results in hypo-achlorhydria and hypergastrinemia, which exerts a proliferative effect on the gastric mucosa. Aims: We investigate the incidence of gastric polyps in CAAG patients. Methods: This is a single-center retrospective study examining patients with confirmed CAAG from January 1990 until June 2022. Demographic, clinical, biochemical, and serological data were collected for each included patient. The histopathological characteristics of the detected polyps were recorded. Results: A total of 176 CAAG patients were included. Eighty-nine (50.5%) had 163 incidental polyps. Seventy-six patients (85%) had 130 non-endocrine lesions, among which 118 (90.7%) were inflammatory, 6 (4.6%) adenomatous, and 4 (3%) fundic; 33 patients (37%) had gastric neuroendocrine neoplasms (gNENs), and 21 (23.6%) both; one had MALToma and one gastric adenocarcinoma. Higher circulating levels of gastrin and chromogranin A were observed among patients with polyps (median 668 vs 893 pg/ml p = 0.0237, 146 vs 207 ng/ml p = 0.0027, respectively). Conclusion: CAAG implies a high incidence of gNENs and exocrine lesions. Gastrin plays a possible trophic role on the mucosa. Further evidence is needed to validate its predictive role for increased polyp risk in CAAG.

Published
2023

24. Corrigendum to: “Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆” [J Hepatol (2020) 505–515, (S0168827820302130), (10.1016/j.jhep.2020.04.003)]

Author

Anstee Q. M., Anstee, Q, Darlay, R, Cockell, S, Meroni, M, Govaere, O, Tiniakos, D, Burt, A, Bedossa, P, Palmer, J, Liu, Y, Aithal, G, Allison, M, Yki-Jarvinen, H, Vacca, M, Dufour, J, Invernizzi, P, Prati, D, Ekstedt, M, Kechagias, S, Francque, S, Petta, S, Bugianesi, E, Clement, K, Ratziu, V, Schattenberg, J, Valenti, L, Day, C, Cordell, H, Daly, A, Anstee Q. M., Darlay R., Cockell S., Meroni M., Govaere O., Tiniakos D., Burt A. D., Bedossa P., Palmer J., Liu Y. -L., Aithal G. P., Allison M., Yki-Jarvinen H., Vacca M., Dufour J. -F., Invernizzi P., Prati D., Ekstedt M., Kechagias S., Francque S., Petta S., Bugianesi E., Clement K., Ratziu V., Schattenberg J. M., Valenti L., Day C. P., Cordell H. J., Daly A. K., Anstee Q. M., Anstee, Q, Darlay, R, Cockell, S, Meroni, M, Govaere, O, Tiniakos, D, Burt, A, Bedossa, P, Palmer, J, Liu, Y, Aithal, G, Allison, M, Yki-Jarvinen, H, Vacca, M, Dufour, J, Invernizzi, P, Prati, D, Ekstedt, M, Kechagias, S, Francque, S, Petta, S, Bugianesi, E, Clement, K, Ratziu, V, Schattenberg, J, Valenti, L, Day, C, Cordell, H, Daly, A, Anstee Q. M., Darlay R., Cockell S., Meroni M., Govaere O., Tiniakos D., Burt A. D., Bedossa P., Palmer J., Liu Y. -L., Aithal G. P., Allison M., Yki-Jarvinen H., Vacca M., Dufour J. -F., Invernizzi P., Prati D., Ekstedt M., Kechagias S., Francque S., Petta S., Bugianesi E., Clement K., Ratziu V., Schattenberg J. M., Valenti L., Day C. P., Cordell H. J., and Daly A. K.

Abstract

In this article we used data from the Understanding Society study as part of our control group. While we did explain that the data was provided by Understanding Society in the paper, we did not include the statement they required for use of these data which is the following: “Understanding Society: The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen and the genome-wide scan data were analysed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website https://www.understandingsociety.ac.uk/.” We apologise for any inconvenience caused.

Published
2023

25. Geographical region and clinical outcomes of patients with primary biliary cholangitis from Western Europe

Author

Murillo Perez, C, Gerussi, A, Trivedi, P, Corpechot, C, Van Der Meer, A, Maria Battezzati, P, Lindor, K, Nevens, F, Kowdley, K, Bruns, T, Cazzagon, N, Floreani, A, Tanaka, A, Ma, X, Mason, A, Gulamhusein, A, Ponsioen, C, Carbone, M, Lleo, A, Mayo, M, Dalekos, G, Gatselis, N, Thorburn, D, Verhelst, X, Pares, A, Janssen, H, Hirschfield, G, Hansen, B, Invernizzi, P, Lammers, W, Murillo Perez C. F., Gerussi A., Trivedi P. J., Corpechot C., Van Der Meer A. J., Maria Battezzati P., Lindor K. D., Nevens F., Kowdley K. V., Bruns T., Cazzagon N., Floreani A., Tanaka A., Ma X., Mason A. L., Gulamhusein A., Ponsioen C. Y., Carbone M., Lleo A., Mayo M. J., Dalekos G. N., Gatselis N. K., Thorburn D., Verhelst X., Pares A., Janssen H. L. A., Hirschfield G. M., Hansen B. E., Invernizzi P., Lammers W. J., Murillo Perez, C, Gerussi, A, Trivedi, P, Corpechot, C, Van Der Meer, A, Maria Battezzati, P, Lindor, K, Nevens, F, Kowdley, K, Bruns, T, Cazzagon, N, Floreani, A, Tanaka, A, Ma, X, Mason, A, Gulamhusein, A, Ponsioen, C, Carbone, M, Lleo, A, Mayo, M, Dalekos, G, Gatselis, N, Thorburn, D, Verhelst, X, Pares, A, Janssen, H, Hirschfield, G, Hansen, B, Invernizzi, P, Lammers, W, Murillo Perez C. F., Gerussi A., Trivedi P. J., Corpechot C., Van Der Meer A. J., Maria Battezzati P., Lindor K. D., Nevens F., Kowdley K. V., Bruns T., Cazzagon N., Floreani A., Tanaka A., Ma X., Mason A. L., Gulamhusein A., Ponsioen C. Y., Carbone M., Lleo A., Mayo M. J., Dalekos G. N., Gatselis N. K., Thorburn D., Verhelst X., Pares A., Janssen H. L. A., Hirschfield G. M., Hansen B. E., Invernizzi P., and Lammers W. J.

Abstract

Background and aims The are geographic variations in the incidence and prevalence of primary biliary cholangitis (PBC). The aim was to explore whether clinical outcomes of patients within Western Europe differ according to geographical region. Methods Ursodeoxycholic acid-treated patients from European centers from the Global PBC database diagnosed from 1990 onwards were included. Patients with a time lag > 1 year from diagnosis to start of follow-up were excluded. Differences in baseline characteristics were studied according to North/South and East/West, whereas outcomes (transplant-free survival and decompensation) were studied with center latitude and longitude. Cox regression analyses were adjusted for age, sex, diagnosis year, biochemical markers, and cirrhosis as a time-dependent covariate. Results One thousand eight hundred seventy-eight patients were included, and there were no geographical differences in age or sex, with a mean age of 54 years and 89% female patients. Those in North Europe were more often of a moderately advanced/advanced Rotterdam biochemical stage (28.4%) compared with South Europe (20.6%). Additionally, they exhibited higher median alkaline phosphatase (2.0 ×ULN vs. 1.4 ×ULN) and transaminases. In multivariable analysis, there was a significant interaction between center latitude and longitude for decompensation (P < 0.001) and a trend for transplant-free survival, in which the Northwestern area demonstrated an increased risk for poor outcomes as compared to the reference (Paris). Conclusion We describe geographic variations in outcomes for patients across Europe from specialist centers in the Global PBC Study Group. Further study is important to explore the potential individual, environmental, and healthcare-related factors that may be contributors.

Published
2023

26. Corrigendum to: “An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs” [J Hepatol 75 (2021) 572-581, (S0168827821003342), (10.1016/j.jhep.2021.04.055)]

Author

Cordell H. J., Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byan, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Cordell H. J., Fryett J. J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S. -S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B. D., Atkinson E. J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M. A. R., Sun D., Jones D. E., Flack S., Spicer A., Mulcahy V. L., Byan J., Han Y., Sandford R. N., Lazaridis K. N., Amos C. I., Hirschfield G. M., Seldin M. F., Invernizzi P., Siminovitch K. A., Ma X., Nakamura M., Mells G. F., Cordell H. J., Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byan, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Cordell H. J., Fryett J. J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S. -S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B. D., Atkinson E. J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M. A. R., Sun D., Jones D. E., Flack S., Spicer A., Mulcahy V. L., Byan J., Han Y., Sandford R. N., Lazaridis K. N., Amos C. I., Hirschfield G. M., Seldin M. F., Invernizzi P., Siminovitch K. A., Ma X., Nakamura M., and Mells G. F.

Abstract

It has come to our attention that while we explained that data for the control group in our study was provided by Understanding Society, we did not include the required statement for use of these data, which is the following: “Understanding Society: The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen and the genome-wide scan data were analysed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website https://www.understandingsociety.ac.uk/.” We apologise for any inconvenience caused.

Published
2023

27. Predictors of serious adverse events and non-response in cirrhotic patients with primary biliary cholangitis treated with obeticholic acid

Author

De Vincentis, A, D'Amato, D, Cristoferi, L, Gerussi, A, Malinverno, F, Lleo, A, Colapietro, F, Marra, F, Galli, A, Fiorini, C, Coco, B, Brunetto, M, Niro, G, Cotugno, R, Saitta, C, Cozzolongo, R, Losito, F, Giannini, E, Labanca, S, Marzioni, M, Marconi, G, Morgando, A, Pellicano, R, Vanni, E, Cazzagon, N, Floreani, A, Chessa, L, Morelli, O, Muratori, L, Pellicelli, A, Pompili, M, Ponziani, F, Tortora, A, Rosina, F, Russello, M, Cannavo, M, Simone, L, Storato, S, Vigano, M, Abenavoli, L, D'Anto, M, De Gasperi, E, Distefano, M, Scifo, G, Zolfino, T, Calvaruso, V, Cuccorese, G, Palitti, V, Sacco, R, Bertino, G, Frazzetto, E, Alvaro, D, Mulinacci, G, Palermo, A, Scaravaglio, M, Terracciani, F, Galati, G, Ronca, V, Zuin, M, Claar, E, Izzi, A, Picardi, A, Invernizzi, P, Vespasiani-Gentilucci, U, Carbone, M, Feletti, V, Mussetto, A, Venere, R, Bernaccioni, G, Graciella Pigozzi, M, Fagiuoli, S, Terreni, N, Pozzoni, P, Baiocchi, L, Grassi, G, Vinci, M, Bellia, V, Boldizzoni, R, Casella, S, Omazzi, B, Poggi, G, De Vincentis A., D'Amato D., Cristoferi L., Gerussi A., Malinverno F., Lleo A., Colapietro F., Marra F., Galli A., Fiorini C., Coco B., Brunetto M., Niro G. A., Cotugno R., Saitta C., Cozzolongo R., Losito F., Giannini E. G., Labanca S., Marzioni M., Marconi G., Morgando A., Pellicano R., Vanni E., Cazzagon N., Floreani A., Chessa L., Morelli O., Muratori L., Pellicelli A., Pompili M., Ponziani F., Tortora A., Rosina F., Russello M., Cannavo M., Simone L., Storato S., Vigano M., Abenavoli L., D'Anto M., De Gasperi E., Distefano M., Scifo G., Zolfino T., Calvaruso V., Cuccorese G., Palitti V. P., Sacco R., Bertino G., Frazzetto E., Alvaro D., Mulinacci G., Palermo A., Scaravaglio M., Terracciani F., Galati G., Ronca V., Zuin M., Claar E., Izzi A., Picardi A., Invernizzi P., Vespasiani-Gentilucci U., Carbone M., Feletti V., Mussetto A., Venere R., Bernaccioni G., Graciella Pigozzi M., Fagiuoli S., Terreni N., Pozzoni P., Baiocchi L., Grassi G., Vinci M., Bellia V., Boldizzoni R., Casella S., Omazzi B., Poggi G., De Vincentis, A, D'Amato, D, Cristoferi, L, Gerussi, A, Malinverno, F, Lleo, A, Colapietro, F, Marra, F, Galli, A, Fiorini, C, Coco, B, Brunetto, M, Niro, G, Cotugno, R, Saitta, C, Cozzolongo, R, Losito, F, Giannini, E, Labanca, S, Marzioni, M, Marconi, G, Morgando, A, Pellicano, R, Vanni, E, Cazzagon, N, Floreani, A, Chessa, L, Morelli, O, Muratori, L, Pellicelli, A, Pompili, M, Ponziani, F, Tortora, A, Rosina, F, Russello, M, Cannavo, M, Simone, L, Storato, S, Vigano, M, Abenavoli, L, D'Anto, M, De Gasperi, E, Distefano, M, Scifo, G, Zolfino, T, Calvaruso, V, Cuccorese, G, Palitti, V, Sacco, R, Bertino, G, Frazzetto, E, Alvaro, D, Mulinacci, G, Palermo, A, Scaravaglio, M, Terracciani, F, Galati, G, Ronca, V, Zuin, M, Claar, E, Izzi, A, Picardi, A, Invernizzi, P, Vespasiani-Gentilucci, U, Carbone, M, Feletti, V, Mussetto, A, Venere, R, Bernaccioni, G, Graciella Pigozzi, M, Fagiuoli, S, Terreni, N, Pozzoni, P, Baiocchi, L, Grassi, G, Vinci, M, Bellia, V, Boldizzoni, R, Casella, S, Omazzi, B, Poggi, G, De Vincentis A., D'Amato D., Cristoferi L., Gerussi A., Malinverno F., Lleo A., Colapietro F., Marra F., Galli A., Fiorini C., Coco B., Brunetto M., Niro G. A., Cotugno R., Saitta C., Cozzolongo R., Losito F., Giannini E. G., Labanca S., Marzioni M., Marconi G., Morgando A., Pellicano R., Vanni E., Cazzagon N., Floreani A., Chessa L., Morelli O., Muratori L., Pellicelli A., Pompili M., Ponziani F., Tortora A., Rosina F., Russello M., Cannavo M., Simone L., Storato S., Vigano M., Abenavoli L., D'Anto M., De Gasperi E., Distefano M., Scifo G., Zolfino T., Calvaruso V., Cuccorese G., Palitti V. P., Sacco R., Bertino G., Frazzetto E., Alvaro D., Mulinacci G., Palermo A., Scaravaglio M., Terracciani F., Galati G., Ronca V., Zuin M., Claar E., Izzi A., Picardi A., Invernizzi P., Vespasiani-Gentilucci U., Carbone M., Feletti V., Mussetto A., Venere R., Bernaccioni G., Graciella Pigozzi M., Fagiuoli S., Terreni N., Pozzoni P., Baiocchi L., Grassi G., Vinci M., Bellia V., Boldizzoni R., Casella S., Omazzi B., and Poggi G.

Abstract

Background & Aims: Obeticholic acid (OCA) has recently been restricted in patients with primary biliary cholangitis (PBC) with “advanced cirrhosis” because of its narrow therapeutic index. We aimed to better define the predicting factors of hepatic serious adverse events (SAEs) and non-response in cirrhotic patients undergoing OCA therapy. Methods: Safety and efficacy of treatment were evaluated in a cohort of consecutive PBC cirrhotic patients started with OCA. OCA response was evaluated according to the Poise criteria. Risk factors for hepatic SAEs and non-response were reported as risk ratios (RR) with 95% confidence intervals (CIs). Results: One hundred PBC cirrhotics were included, 97 Child-Pugh class A and 3 class B. Thirty-one had oesophageal varices and 5 had a history of ascites. Thirty-three per cent and 32% of patients achieved a biochemical response at 6 and 12 months respectively. Male sex (adjusted-RR 1.75, 95%CI 1.42–2.12), INR (1.37, 1.00–1.87), Child-Pugh score (1.79, 1.28–2.50), MELD (1.17, 1.04–1.30) and bilirubin (1.83, 1.11–3.01) were independently associated with non-response to OCA. Twenty-two patients discontinued OCA within 12 months: 10 for pruritus, 9 for hepatic SAEs (5 for jaundice and/or ascitic decompensation; 4 for upper digestive bleeding). INR (adjusted-RR 1.91, 95%CI 1.10–3.36), lower albumin levels (0.18, 0.06–0.51), Child-Pugh score (2.43, 1.50–4.04), history of ascites (3.5, 1.85–6.5) and bilirubin (1.30, 1.05–1.56), were associated with hepatic SAEs. A total bilirubin≥1.4 mg/dl at baseline was the most accurate biochemical predictor of hepatic SAEs under OCA. Conclusions: An accurate baseline assessment is crucial to select cirrhotic patients who can benefit from OCA. Although OCA is effective in one third of cirrhotics, bilirubin level ≥1.4 mg/dl should discourage from its use.

Published
2022

28. Primary Sclerosing Cholangitis and Amyloid A Amyloidosis: Association or Coincidence?

Author

Lacetera, R, Roggero, L, Vercelloni, P, Uzzo, M, Carbone, M, Invernizzi, P, L'Imperio, V, Pieruzzi, F, Sinico, R, Lacetera R., Roggero L., Vercelloni P., Uzzo M., Carbone M., Invernizzi P., L'Imperio V., Pieruzzi F., Sinico R. A., Lacetera, R, Roggero, L, Vercelloni, P, Uzzo, M, Carbone, M, Invernizzi, P, L'Imperio, V, Pieruzzi, F, Sinico, R, Lacetera R., Roggero L., Vercelloni P., Uzzo M., Carbone M., Invernizzi P., L'Imperio V., Pieruzzi F., and Sinico R. A.

Abstract

AA amyloidosis may complicate several chronic inflammatory conditions. From a clinical point of view, causality between inflammatory pathology and AA amyloidosis can be assumed because of the data described in the literature; some of the best known include rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and chronic infections. Singles cases of inflammatory diseases have been found at AA amyloidosis. Causality becomes more plausible if at least two different cases with AA amyloidosis are both found to have the same rare inflammatory disease. We describe the case of a patient with primary sclerosing cholangitis (PSC) with development of AA amyloidosis conditioning a nephrotic syndrome, likely secondary to failure to control the chronic inflammatory process. Only two cases in the literature describe the association of this rare disease and the appearance of AA amyloidosis. The treatment of AA amyloidosis consists in treating the underlying inflammatory disorder; to date, few effective treatments are available for PSC. Therefore, and in view of the limited data in the literature, we believe it is important to describe its association.

Published
2022

29. Recognition and inhibition of SARS-CoV-2 by humoral innate immunity pattern recognition molecules

Author

Stravalaci, M, Pagani, I, Paraboschi, E, Pedotti, M, Doni, A, Scavello, F, Mapelli, S, Sironi, M, Perucchini, C, Varani, L, Matkovic, M, Cavalli, A, Cesana, D, Gallina, P, Pedemonte, N, Capurro, V, Clementi, N, Mancini, N, Invernizzi, P, Bayarri-Olmos, R, Garred, P, Rappuoli, R, Duga, S, Bottazzi, B, Uguccioni, M, Asselta, R, Vicenzi, E, Mantovani, A, Garlanda, C, Stravalaci M., Pagani I., Paraboschi E. M., Pedotti M., Doni A., Scavello F., Mapelli S. N., Sironi M., Perucchini C., Varani L., Matkovic M., Cavalli A., Cesana D., Gallina P., Pedemonte N., Capurro V., Clementi N., Mancini N., Invernizzi P., Bayarri-Olmos R., Garred P., Rappuoli R., Duga S., Bottazzi B., Uguccioni M., Asselta R., Vicenzi E., Mantovani A., Garlanda C., Stravalaci, M, Pagani, I, Paraboschi, E, Pedotti, M, Doni, A, Scavello, F, Mapelli, S, Sironi, M, Perucchini, C, Varani, L, Matkovic, M, Cavalli, A, Cesana, D, Gallina, P, Pedemonte, N, Capurro, V, Clementi, N, Mancini, N, Invernizzi, P, Bayarri-Olmos, R, Garred, P, Rappuoli, R, Duga, S, Bottazzi, B, Uguccioni, M, Asselta, R, Vicenzi, E, Mantovani, A, Garlanda, C, Stravalaci M., Pagani I., Paraboschi E. M., Pedotti M., Doni A., Scavello F., Mapelli S. N., Sironi M., Perucchini C., Varani L., Matkovic M., Cavalli A., Cesana D., Gallina P., Pedemonte N., Capurro V., Clementi N., Mancini N., Invernizzi P., Bayarri-Olmos R., Garred P., Rappuoli R., Duga S., Bottazzi B., Uguccioni M., Asselta R., Vicenzi E., Mantovani A., and Garlanda C.

Abstract

The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in coronavirus disease 2019 (COVID-19). The present study was designed to conduct a systematic investigation of the interaction of human humoral fluid-phase pattern recognition molecules (PRMs) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of 12 PRMs tested, the long pentraxin 3 (PTX3) and mannose-binding lectin (MBL) bound the viral nucleocapsid and spike proteins, respectively. MBL bound trimeric spike protein, including that of variants of concern (VoC), in a glycan-dependent manner and inhibited SARS-CoV-2 in three in vitro models. Moreover, after binding to spike protein, MBL activated the lectin pathway of complement activation. Based on retention of glycosylation sites and modeling, MBL was predicted to recognize the Omicron VoC. Genetic polymorphisms at the MBL2 locus were associated with disease severity. These results suggest that selected humoral fluid-phase PRMs can play an important role in resistance to, and pathogenesis of, COVID-19, a finding with translational implications.

Published
2022

30. Rectal neuroendocrine tumors: Current advances in management, treatment, and surveillance

Author

Gallo, C, Invernizzi, P, Massironi, S, Rossi, R, Cavalcoli, F, Barbaro, F, Boskoski, I, Gallo C., Invernizzi P., Massironi S., Rossi R. E., Cavalcoli F., Barbaro F., Boskoski I., Gallo, C, Invernizzi, P, Massironi, S, Rossi, R, Cavalcoli, F, Barbaro, F, Boskoski, I, Gallo C., Invernizzi P., Massironi S., Rossi R. E., Cavalcoli F., Barbaro F., and Boskoski I.

Abstract

Rectal neuroendocrine neoplasms (r-NENs) are considered among the most frequent digestive NENs, together with small bowel NENs. Their incidence has increased over the past few years, and this is probably due to the widespread use of endoscopic screening for colorectal cancer and the advanced endoscopic procedures available nowadays. According to the current European Neuroendocrine Tumor Society (ENETS) guidelines, well-differentiated r-NENs smaller than 10 mm should be endoscopically removed in view of their low risk of local and distant invasion. R-NENs larger than 20 mm are candidates for surgical resection because of their high risk of distant spreading and the involvement of the muscularis propria. There is an area of uncertainty regarding tumors between 10 and 20 mm, in which the metastatic risk is intermediate and the endoscopic treatment can be challenging. Once removed, the indications for surveillance are scarce and poorly codified by international guidelines, therefore in this paper, a possible algorithm is proposed.

Published
2022

31. Duodenal Gastric Metaplasia and Duodenal Neuroendocrine Neoplasms: More Than a Simple Coincidence?

Author

Massironi, S, Rossi, R, Milanetto, A, Andreasi, V, Campana, D, Nappo, G, Partelli, S, Gallo, C, Scaravaglio, M, Zerbi, A, Panzuto, F, Pasquali, C, Falconi, M, Invernizzi, P, Massironi S., Rossi R. E., Milanetto A. C., Andreasi V., Campana D., Nappo G., Partelli S., Gallo C., Scaravaglio M., Zerbi A., Panzuto F., Pasquali C., Falconi M., Invernizzi P., Massironi, S, Rossi, R, Milanetto, A, Andreasi, V, Campana, D, Nappo, G, Partelli, S, Gallo, C, Scaravaglio, M, Zerbi, A, Panzuto, F, Pasquali, C, Falconi, M, Invernizzi, P, Massironi S., Rossi R. E., Milanetto A. C., Andreasi V., Campana D., Nappo G., Partelli S., Gallo C., Scaravaglio M., Zerbi A., Panzuto F., Pasquali C., Falconi M., and Invernizzi P.

Abstract

Background: Duodenal gastric metaplasia (DGM) is considered a precancerous lesion. No data are available regarding its possible role as a risk factor for duodenal neuroendocrine neoplasms (dNENs). Aims: To assess the prevalence of DGM in a cohort of dNENs. Methods: Subgroup analysis of a retrospective study including dNEN patients who underwent surgical resection between 2000 and 2019 and were observed at eight Italian tertiary referral centers. Results: 109 dNEN patients were evaluated. Signs of DGM associated with the presence of dNEN were reported in 14 patients (12.8%). Among these patients, nine (64.4%) had a dNEN of the superior part of the duodenum, one (7.1%) a periampullary lesion, three (21.4%) a dNEN located in the second portion of the duodenum, with a different localization distribution compared to patients without DGM (p = 0.0332). Ten were G1, three G2, and in one patient the Ki67 was not available. In the group with DGM, six patients (35.7%) were classified at stage I, five (28.6%) at stage II, three (21.4%) at stage III, and no one at stage IV. In the group without DGM, 20 patients (31%) were at stage I, 15 (15%) at stage II, 42 (44%) at stage III, and 19 (20%) at stage IV (p = 0.0236). At the end of the study, three patients died because of disease progression. Conclusions: our findings might suggest that DGM could represent a feature associated with the occurrence of dNEN, especially for forms of the superior part of the duodenum, which should be kept in mind in the endoscopic follow up of patients with DGM. Interestingly, dNEN inside DGM showed a more favorable staging, with no patients in stage IV. The actual relationship and the clinical relevance of this possible association require further clarification.

Published
2022

32. Continuous clinical remission with biologics in ulcerative colitis: the 'AURORA' comparison study

Author

Cassinotti, A, Mezzina, N, De Silvestri, A, Di Paolo, D, Lenti, M, Bezzio, C, Stradella, D, Mauri, M, Zadro, V, Ricci, C, Casini, V, Radice, E, Massari, A, Maconi, G, Saibeni, S, Caprioli, F, Tari, R, Fichera, M, Cortelezzi, C, Parravicini, M, Tinelli, C, Testoni, P, Pace, F, Segato, S, Invernizzi, P, Occhipinti, P, Manes, G, Di Sabatino, A, Pastorelli, L, Vecchi, M, Ardizzone, S, Cassinotti A., Mezzina N., De Silvestri A., Di Paolo D., Lenti M. V., Bezzio C., Stradella D., Mauri M., Zadro V., Ricci C., Casini V., Radice E., Massari A., Maconi G., Saibeni S., Caprioli F., Tari R., Fichera M., Cortelezzi C. C., Parravicini M., Tinelli C., Testoni P. A., Pace F., Segato S., Invernizzi P., Occhipinti P., Manes G., Di Sabatino A., Pastorelli L., Vecchi M., Ardizzone S., Cassinotti, A, Mezzina, N, De Silvestri, A, Di Paolo, D, Lenti, M, Bezzio, C, Stradella, D, Mauri, M, Zadro, V, Ricci, C, Casini, V, Radice, E, Massari, A, Maconi, G, Saibeni, S, Caprioli, F, Tari, R, Fichera, M, Cortelezzi, C, Parravicini, M, Tinelli, C, Testoni, P, Pace, F, Segato, S, Invernizzi, P, Occhipinti, P, Manes, G, Di Sabatino, A, Pastorelli, L, Vecchi, M, Ardizzone, S, Cassinotti A., Mezzina N., De Silvestri A., Di Paolo D., Lenti M. V., Bezzio C., Stradella D., Mauri M., Zadro V., Ricci C., Casini V., Radice E., Massari A., Maconi G., Saibeni S., Caprioli F., Tari R., Fichera M., Cortelezzi C. C., Parravicini M., Tinelli C., Testoni P. A., Pace F., Segato S., Invernizzi P., Occhipinti P., Manes G., Di Sabatino A., Pastorelli L., Vecchi M., and Ardizzone S.

Abstract

Objectives Comparative trials among biological drugs for the treatment of ulcerative colitis (UC) provided conflicting results. After patent expire of infliximab originator, adalimumab, infliximab biosimilar, golimumab and vedolizumab have been approved in Italy. We compared the efficacy of these four biologics in UC according to the concept of continuous clinical remission (CCR). Methods In a retrospective, multicentre study, all UC patients treated with adalimumab, infliximab biosimilar, golimumab or vedolizumab between 2014 and 2019 were included. All drugs were compared to each other according to the 1-year CCR rate, defined as Mayo partial score ≤2, with bleeding subscore = 0, without any relapse or optimization with dose escalation, topical treatments or steroid use after first clinical remission. Results Four-hundred sixteen patients (adalimumab = 90, infliximab biosimilar = 105, golimumab = 79, vedolizumab = 142) were included. CCR was achieved in similar percentages among the groups (33%, 37%, 28%, 37%, respectively). All drugs were equivalent in biologic-naive patients, while vedolizumab was better than a second anti-TNF in prior anti-TNF agent failures. No differences were found according to type of adverse events or severe adverse events. Conclusions Based on a strict definition of clinical remission, all biologics appear equally effective at 1 year. Changing to vedolizumab is more effective than switching to another anti-TNF in TNF failures.

Published
2022

33. Decreased CD57 expression of natural killer cells enhanced cytotoxicity in patients with primary sclerosing cholangitis

Author

Liu, B, Yang, G, Sun, Y, Tomiyama, T, Zhang, W, Leung, P, He, X, Dhaliwal, S, Invernizzi, P, Gershwin, M, Bowlus, C, Liu B., Yang G. -X., Sun Y., Tomiyama T., Zhang W., Leung P. S. C., He X. -S., Dhaliwal S., Invernizzi P., Gershwin M. E., Bowlus C. L., Liu, B, Yang, G, Sun, Y, Tomiyama, T, Zhang, W, Leung, P, He, X, Dhaliwal, S, Invernizzi, P, Gershwin, M, Bowlus, C, Liu B., Yang G. -X., Sun Y., Tomiyama T., Zhang W., Leung P. S. C., He X. -S., Dhaliwal S., Invernizzi P., Gershwin M. E., and Bowlus C. L.

Abstract

Background/aims: Primary sclerosing cholangitis (PSC) is a chronic inflammatory biliary disease for which the immunopathological basis remains an enigma. Natural killer (NK) cells are key components of innate immunity and seemingly play diversified roles in different autoimmune disorders (AIDs). The aim of this study was to determine the role of NK cells in the pathogenesis of PSC. Methods: The frequency and phenotype of circulating NK cells in a large cohort of patients with PSC and healthy controls (HCs) were systematically examined. In addition, the functional capacity of NK cells including cytotoxicity and cytokine production was studied. Results: The frequency of CD3−CD56dimCD16+ (defined as CD56dim) NK cells in PSC patients was significantly lower in comparison to HCs. CD56dim NK cells from PSC displayed a more immature phenotype including high expression of the natural killing receptor NKp46 and downregulation of the highly differentiated NK cell marker CD57. Interestingly, the reduction of CD57 expression of NK cells was associated with the disease severity of PSC. In addition, PSC CD56dim NK cells exhibited increased CD107a degranulation and cytolytic activity toward target cells compared with HCs. Further analysis demonstrated that CD57−CD56dim NK cells from PSC had elevated expression of NKp46, NKp30, IL-2 receptor, and KLRG1 and higher cytotoxic capacity as compared to CD57+CD56dim NK cells. Conclusions: Our data demonstrate that the differentiation of PSC NK cells is dysregulated with enhanced cytotoxic activity. This change is likely to be functionally involved in pathogenesis and disease progression, deducing the potential of NK-directed immunotherapy for PSC.

Published
2022

34. Management of asymptomatic sporadic non-functioning pancreatic neuroendocrine neoplasms no larger than 2 cm: Interim analysis of prospective ASPEN trial

Author

Partelli, S, Massironi, S, Zerbi, A, Niccoli, P, Kwon, W, Landoni, L, Panzuto, F, Tomazic, A, Bongiovanni, A, Kaltsas, G, Sauvanet, A, Bertani, E, Mazzaferro, V, Caplin, M, Armstrong, T, Weickert, M, Ramage, J, Segelov, E, Butturini, G, Staettner, S, Cives, M, Frilling, A, Moulton, C, He, J, Boesch, F, Selberheer, A, Twito, O, Castaldi, A, De Angelis, C, Gaujoux, S, Holzer, K, Wilson, C, Almeamar, H, Vigia, E, Muffatti, F, Luca, M, Lania, A, Ewald, J, Kim, H, Salvia, R, Rinzivillo, M, Smid, A, Gardini, A, Tsoli, M, Hentic, O, Colombo, S, Citterio, D, Toumpanakis, C, Ramsey, E, Randeva, H, Srirajaskanthan, R, Croagh, D, Regi, P, Gasteiger, S, Invernizzi, P, Ridolfi, C, Giovannini, M, Jang, J, Bassi, C, Falconi, M, Partelli S., Massironi S., Zerbi A., Niccoli P., Kwon W., Landoni L., Panzuto F., Tomazic A., Bongiovanni A., Kaltsas G., Sauvanet A., Bertani E., Mazzaferro V., Caplin M., Armstrong T., Weickert M. O., Ramage J., Segelov E., Butturini G., Staettner S., Cives M., Frilling A., Moulton C. A., He J., Boesch F., Selberheer A., Twito O., Castaldi A., De Angelis C. G., Gaujoux S., Holzer K., Wilson C. H., Almeamar H., Vigia E., Muffatti F., Luca M., Lania A., Ewald J., Kim H., Salvia R., Rinzivillo M., Smid A., Gardini A., Tsoli M., Hentic O., Colombo S., Citterio D., Toumpanakis C., Ramsey E., Randeva H. S., Srirajaskanthan R., Croagh D., Regi P., Gasteiger S., Invernizzi P., Ridolfi C., Giovannini M., Jang J. -Y., Bassi C., Falconi M., Partelli, S, Massironi, S, Zerbi, A, Niccoli, P, Kwon, W, Landoni, L, Panzuto, F, Tomazic, A, Bongiovanni, A, Kaltsas, G, Sauvanet, A, Bertani, E, Mazzaferro, V, Caplin, M, Armstrong, T, Weickert, M, Ramage, J, Segelov, E, Butturini, G, Staettner, S, Cives, M, Frilling, A, Moulton, C, He, J, Boesch, F, Selberheer, A, Twito, O, Castaldi, A, De Angelis, C, Gaujoux, S, Holzer, K, Wilson, C, Almeamar, H, Vigia, E, Muffatti, F, Luca, M, Lania, A, Ewald, J, Kim, H, Salvia, R, Rinzivillo, M, Smid, A, Gardini, A, Tsoli, M, Hentic, O, Colombo, S, Citterio, D, Toumpanakis, C, Ramsey, E, Randeva, H, Srirajaskanthan, R, Croagh, D, Regi, P, Gasteiger, S, Invernizzi, P, Ridolfi, C, Giovannini, M, Jang, J, Bassi, C, Falconi, M, Partelli S., Massironi S., Zerbi A., Niccoli P., Kwon W., Landoni L., Panzuto F., Tomazic A., Bongiovanni A., Kaltsas G., Sauvanet A., Bertani E., Mazzaferro V., Caplin M., Armstrong T., Weickert M. O., Ramage J., Segelov E., Butturini G., Staettner S., Cives M., Frilling A., Moulton C. A., He J., Boesch F., Selberheer A., Twito O., Castaldi A., De Angelis C. G., Gaujoux S., Holzer K., Wilson C. H., Almeamar H., Vigia E., Muffatti F., Luca M., Lania A., Ewald J., Kim H., Salvia R., Rinzivillo M., Smid A., Gardini A., Tsoli M., Hentic O., Colombo S., Citterio D., Toumpanakis C., Ramsey E., Randeva H. S., Srirajaskanthan R., Croagh D., Regi P., Gasteiger S., Invernizzi P., Ridolfi C., Giovannini M., Jang J. -Y., Bassi C., and Falconi M.

Published
2022

35. Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls

Author

Murillo Perez, C, Fisher, H, Hiu, S, Kareithi, D, Adekunle, F, Mayne, T, Malecha, E, Ness, E, van der Meer, A, Lammers, W, Trivedi, P, Battezzati, P, Nevens, F, Kowdley, K, Bruns, T, Cazzagon, N, Floreani, A, Mason, A, Pares, A, Londono, M, Invernizzi, P, Carbone, M, Lleo, A, Mayo, M, Dalekos, G, Gatselis, N, Thorburn, D, Verhelst, X, Gulamhusein, A, Janssen, H, Smith, R, Flack, S, Mulcahy, V, Trauner, M, Bowlus, C, Lindor, K, Corpechot, C, Jones, D, Mells, G, Hirschfield, G, Wason, J, Hansen, B, Sturgess, R, Healey, C, Gunasekera, A, Kallis, Y, Wright, G, Mathialahan, T, Evans, R, Gasem, J, Ramanaden, D, Ward, E, Bhalme, M, Southern, P, Maggs, J, Yousif, M, Srivastava, B, Foxton, M, Collins, C, Prasad, Y, Porras-Perez, F, Yapp, T, Patel, M, Ede, R, Carte, M, Koss, K, Sattianayagam, P, Grimley, C, Tidbury, J, Mansour, D, Beckley, M, Hollywood, C, Ramag, J, Gordon, H, Ridpath, J, Grover, B, Abouda, G, Rees, I, Narain, M, Salam, I, Banim, P, Das, D, Matthews, H, Mohammed, F, Jones, R, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Hutchinson, J, Gupta, P, Shah, A, Saha, S, Pollock, K, Barclay, S, Mcdonald, N, Rushbrook, S, Przemioslo, R, Millar, A, Mitchell, S, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Cramp, M, Aspinal, R, Booth, J, Williams, E, Hussaini, H, Christie, J, Chaudhry, T, Mann, S, Ala, A, Maltby, J, Corbett, C, Singhal, S, Hoeroldt, B, Butterworth, J, Douglas, A, Sinha, R, Panter, S, Shearman, J, Bray, G, Roberts, M, Forton, D, Taylor, N, Jafar, W, Cowan, M, Ch'Ng, C, Rahman, M, Wesley, E, Jain, S, Mandal, A, Wright, M, Gordon, F, Unitt, E, Austin, A, Palegwala, A, Vemala, V, Higham, A, Fraser, J, Li, A, Ramakrishnan, S, King, A, Whalley, S, Gee, I, Keld, R, Fellows, H, Gotto, J, Millson, C, Murillo Perez C. F., Fisher H., Hiu S., Kareithi D., Adekunle F., Mayne T., Malecha E., Ness E., van der Meer A. J., Lammers W. J., Trivedi P. J., Battezzati P. M., Nevens F., Kowdley K. V., Bruns T., Cazzagon N., Floreani A., Mason A. L., Pares A., Londono M. -C., Invernizzi P., Carbone M., Lleo A., Mayo M. J., Dalekos G. N., Gatselis N. K., Thorburn D., Verhelst X., Gulamhusein A., Janssen H. L. A., Smith R., Flack S., Mulcahy V., Trauner M., Bowlus C. L., Lindor K. D., Corpechot C., Jones D., Mells G., Hirschfield G. M., Wason J., Hansen B. E., Sturgess R., Healey C., Gunasekera A., Kallis Y., Wright G., Mathialahan T., Evans R., Gasem J., Ramanaden D., Ward E., Bhalme M., Southern P., Maggs J., Yousif M., Srivastava B., Foxton M., Collins C., Prasad Y., Porras-Perez F., Yapp T., Patel M., Ede R., Carte M., Koss K., Sattianayagam P., Grimley C., Tidbury J., Mansour D., Beckley M., Hollywood C., Ramag J., Gordon H., Ridpath J., Grover B., Abouda G., Rees I., Narain M., Salam I., Banim P., Das D., Matthews H., Mohammed F., Jones R., Sen S., Bird G., Prince M., Prasad G., Kitchen P., Hutchinson J., Gupta P., Shah A., Saha S., Pollock K., Barclay S., McDonald N., Rushbrook S., Przemioslo R., Millar A., Mitchell S., Davis A., Naqvi A., Lee T., Ryder S., Collier J., Cramp M., Aspinal R., Booth J., Williams E., Hussaini H., Christie J., Chaudhry T., Mann S., Ala A., Maltby J., Corbett C., Singhal S., Hoeroldt B., Butterworth J., Douglas A., Sinha R., Panter S., Shearman J., Bray G., Roberts M., Forton D., Taylor N., Jafar W., Cowan M., Ch'ng C. L., Rahman M., Wesley E., Jain S., Mandal A., Wright M., Trivedi P., Gordon F., Unitt E., Austin A., Palegwala A., Vemala V., Higham A., Fraser J., Li A., Ramakrishnan S., King A., Whalley S., Gee I., Keld R., Fellows H., Gotto J., Millson C., Murillo Perez, C, Fisher, H, Hiu, S, Kareithi, D, Adekunle, F, Mayne, T, Malecha, E, Ness, E, van der Meer, A, Lammers, W, Trivedi, P, Battezzati, P, Nevens, F, Kowdley, K, Bruns, T, Cazzagon, N, Floreani, A, Mason, A, Pares, A, Londono, M, Invernizzi, P, Carbone, M, Lleo, A, Mayo, M, Dalekos, G, Gatselis, N, Thorburn, D, Verhelst, X, Gulamhusein, A, Janssen, H, Smith, R, Flack, S, Mulcahy, V, Trauner, M, Bowlus, C, Lindor, K, Corpechot, C, Jones, D, Mells, G, Hirschfield, G, Wason, J, Hansen, B, Sturgess, R, Healey, C, Gunasekera, A, Kallis, Y, Wright, G, Mathialahan, T, Evans, R, Gasem, J, Ramanaden, D, Ward, E, Bhalme, M, Southern, P, Maggs, J, Yousif, M, Srivastava, B, Foxton, M, Collins, C, Prasad, Y, Porras-Perez, F, Yapp, T, Patel, M, Ede, R, Carte, M, Koss, K, Sattianayagam, P, Grimley, C, Tidbury, J, Mansour, D, Beckley, M, Hollywood, C, Ramag, J, Gordon, H, Ridpath, J, Grover, B, Abouda, G, Rees, I, Narain, M, Salam, I, Banim, P, Das, D, Matthews, H, Mohammed, F, Jones, R, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Hutchinson, J, Gupta, P, Shah, A, Saha, S, Pollock, K, Barclay, S, Mcdonald, N, Rushbrook, S, Przemioslo, R, Millar, A, Mitchell, S, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Cramp, M, Aspinal, R, Booth, J, Williams, E, Hussaini, H, Christie, J, Chaudhry, T, Mann, S, Ala, A, Maltby, J, Corbett, C, Singhal, S, Hoeroldt, B, Butterworth, J, Douglas, A, Sinha, R, Panter, S, Shearman, J, Bray, G, Roberts, M, Forton, D, Taylor, N, Jafar, W, Cowan, M, Ch'Ng, C, Rahman, M, Wesley, E, Jain, S, Mandal, A, Wright, M, Gordon, F, Unitt, E, Austin, A, Palegwala, A, Vemala, V, Higham, A, Fraser, J, Li, A, Ramakrishnan, S, King, A, Whalley, S, Gee, I, Keld, R, Fellows, H, Gotto, J, Millson, C, Murillo Perez C. F., Fisher H., Hiu S., Kareithi D., Adekunle F., Mayne T., Malecha E., Ness E., van der Meer A. J., Lammers W. J., Trivedi P. J., Battezzati P. M., Nevens F., Kowdley K. V., Bruns T., Cazzagon N., Floreani A., Mason A. L., Pares A., Londono M. -C., Invernizzi P., Carbone M., Lleo A., Mayo M. J., Dalekos G. N., Gatselis N. K., Thorburn D., Verhelst X., Gulamhusein A., Janssen H. L. A., Smith R., Flack S., Mulcahy V., Trauner M., Bowlus C. L., Lindor K. D., Corpechot C., Jones D., Mells G., Hirschfield G. M., Wason J., Hansen B. E., Sturgess R., Healey C., Gunasekera A., Kallis Y., Wright G., Mathialahan T., Evans R., Gasem J., Ramanaden D., Ward E., Bhalme M., Southern P., Maggs J., Yousif M., Srivastava B., Foxton M., Collins C., Prasad Y., Porras-Perez F., Yapp T., Patel M., Ede R., Carte M., Koss K., Sattianayagam P., Grimley C., Tidbury J., Mansour D., Beckley M., Hollywood C., Ramag J., Gordon H., Ridpath J., Grover B., Abouda G., Rees I., Narain M., Salam I., Banim P., Das D., Matthews H., Mohammed F., Jones R., Sen S., Bird G., Prince M., Prasad G., Kitchen P., Hutchinson J., Gupta P., Shah A., Saha S., Pollock K., Barclay S., McDonald N., Rushbrook S., Przemioslo R., Millar A., Mitchell S., Davis A., Naqvi A., Lee T., Ryder S., Collier J., Cramp M., Aspinal R., Booth J., Williams E., Hussaini H., Christie J., Chaudhry T., Mann S., Ala A., Maltby J., Corbett C., Singhal S., Hoeroldt B., Butterworth J., Douglas A., Sinha R., Panter S., Shearman J., Bray G., Roberts M., Forton D., Taylor N., Jafar W., Cowan M., Ch'ng C. L., Rahman M., Wesley E., Jain S., Mandal A., Wright M., Trivedi P., Gordon F., Unitt E., Austin A., Palegwala A., Vemala V., Higham A., Fraser J., Li A., Ramakrishnan S., King A., Whalley S., Gee I., Keld R., Fellows H., Gotto J., and Millson C.

Abstract

Background & Aims: The Primary Biliary Cholangitis (PBC) Obeticholic Acid (OCA) International Study of Efficacy (POISE) randomized, double-blind, placebo-controlled trial demonstrated that OCA reduced biomarkers associated with adverse clinical outcomes (ie, alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase) in patients with PBC. The objective of this study was to evaluate time to first occurrence of liver transplantation or death in patients with OCA in the POISE trial and open-label extension vs comparable non-OCA–treated external controls. Methods: Propensity scores were generated for external control patients meeting POISE eligibility criteria from 2 registry studies (Global PBC and UK-PBC) using an index date selected randomly between the first and last date (inclusive) on which eligibility criteria were met. Cox proportional hazards models weighted by inverse probability of treatment assessed time to death or liver transplantation. Additional analyses (Global PBC only) added hepatic decompensation to the composite end point and assessed efficacy in patients with or without cirrhosis. Results: During the 6-year follow-up, there were 5 deaths or liver transplantations in 209 subjects in the POISE cohort (2.4%), 135 of 1381 patients in the Global PBC control (10.0%), and 281 of 2135 patients in the UK-PBC control (13.2%). The hazard ratios (HRs) for the primary outcome were 0.29 (95% CI, 0.10–0.83) for POISE vs Global PBC and 0.30 (95% CI, 0.12–0.75) for POISE vs UK-PBC. In the Global PBC study, HR was 0.20 (95% CI, 0.03–1.22) for patients with cirrhosis and 0.31 (95% CI, 0.09–1.04) for those without cirrhosis; HR was 0.42 (95% CI, 0.21–0.85) including hepatic decompensation. Conclusions: Patients treated with OCA in a trial setting had significantly greater transplant-free survival than comparable external control patients.

Published
2022

36. Primary biliary cholangitis: perception and expectation of illness

Author

Floreani, A, Scaffidi, M, Coco, B, Giannini, E, Labanca, S, Bonaiuto, E, De Martin, S, Invernizzi, P, Carbone, M, Alvaro, D, Bragazzi, M, Calvaruso, V, Cossiga, V, Cazzagon, N, Floreani A., Scaffidi M., Coco B., Giannini E. G., Labanca S., Bonaiuto E., De Martin S., Invernizzi P., Carbone M., Alvaro D., Bragazzi M. C., Calvaruso V., Cossiga V., Cazzagon N., Floreani, A, Scaffidi, M, Coco, B, Giannini, E, Labanca, S, Bonaiuto, E, De Martin, S, Invernizzi, P, Carbone, M, Alvaro, D, Bragazzi, M, Calvaruso, V, Cossiga, V, Cazzagon, N, Floreani A., Scaffidi M., Coco B., Giannini E. G., Labanca S., Bonaiuto E., De Martin S., Invernizzi P., Carbone M., Alvaro D., Bragazzi M. C., Calvaruso V., Cossiga V., and Cazzagon N.

Abstract

An important tool to explore personal experience of symptoms, treatment and clinical outcome is stratification of illness perception in patients affected by PBC. Aim: To assess the perception of illness in a cohort of Italian patients with PBC. Methods: Between June and December 2019, a specific questionnaire was administered to a pool of 210 patients from 7 tertiary Italian centers, in order to identify and assess the patient's past history, symptoms and their impact on the quality of life, follow-up, treatment and perceived satisfaction of patients toward the provided care. Results: Fatigue, pruritus, and abdominal discomfort and sicca syndrome were present in 50.4%, 45%, 30.4% and 28.5% of patients, fatigue having the most impacting the daily-life. After a consultation with a specialist, the diagnosis of PBC was met within 18 months for 143 patients. Patients were mostly concerned about possible health problems that occur and in 25% of cases, symptoms had a negative impact on their life. Eighty percent of patients said they were satisfied with efficacy and tolerability of treatment, while 26% requested an improvement in the relationship with the specialist. Conclusions: The results highlight the importance of both promoting timely referral to the specialist and facilitating communication between healthcare professionals and patients.

Published
2022

37. Clinical challenge for gastroenterologists–Gastrointestinal manifestations of systemic mastocytosis: A comprehensive review

Author

Elvevi, A, Elli, E, Luca, M, Scaravaglio, M, Pagni, F, Ceola, S, Ratti, L, Invernizzi, P, Massironi, S, Elvevi A., Elli E. M., Luca M., Scaravaglio M., Pagni F., Ceola S., Ratti L., Invernizzi P., Massironi S., Elvevi, A, Elli, E, Luca, M, Scaravaglio, M, Pagni, F, Ceola, S, Ratti, L, Invernizzi, P, Massironi, S, Elvevi A., Elli E. M., Luca M., Scaravaglio M., Pagni F., Ceola S., Ratti L., Invernizzi P., and Massironi S.

Abstract

Mastocytosis is a rare and heterogeneous disease characterized by various clinical and biological features that affect different prognoses and treatments. The disease is usually divided into 2 principal categories: cutaneous and systemic disease (SM). Clinical features can be related to mast cell (MC) mediator release or pathological MC infiltration. SM is a disease often hard to identify, and the diagnosis is based on clinical, biological, histological, and molecular criteria with different specialists involved in the patient’s clinical work-up. Among all manifestations of the disease, gastrointestinal (GI) symptoms are common, being present in 14%-85% of patients, and can significantly impair the quality of life. Here we review the data regarding GI involvement in SM, in terms of clinical presentations, histological and endoscopic features, the pathogenesis of GI symptoms, and their treatment.

Published
2022

38. A quantitative MRCP-derived score for medium-term outcome prediction in primary sclerosing cholangitis

Author

Cristoferi, L, Porta, M, Bernasconi, D, Leonardi, F, Gerussi, A, Mulinacci, G, Palermo, A, Gallo, C, Scaravaglio, M, Stucchi, E, Maino, C, Ippolito, D, D'Amato, D, Ferreira, C, Nardi, A, Banerjee, R, Valsecchi, M, Antolini, L, Corso, R, Sironi, S, Fagiuoli, S, Invernizzi, P, Carbone, M, Cristoferi, L., Porta, M., Bernasconi, D. P., Leonardi, F., Gerussi, A., Mulinacci, G., Palermo, A., Gallo, C., Scaravaglio, M., Stucchi, E., Maino, C., Ippolito, D., D'Amato, D., Ferreira, C., Nardi, A., Banerjee, R., Valsecchi, M. G., Antolini, L., Corso, R., Sironi, S., Fagiuoli, S., Invernizzi, P., Carbone, M., Cristoferi, L, Porta, M, Bernasconi, D, Leonardi, F, Gerussi, A, Mulinacci, G, Palermo, A, Gallo, C, Scaravaglio, M, Stucchi, E, Maino, C, Ippolito, D, D'Amato, D, Ferreira, C, Nardi, A, Banerjee, R, Valsecchi, M, Antolini, L, Corso, R, Sironi, S, Fagiuoli, S, Invernizzi, P, Carbone, M, Cristoferi, L., Porta, M., Bernasconi, D. P., Leonardi, F., Gerussi, A., Mulinacci, G., Palermo, A., Gallo, C., Scaravaglio, M., Stucchi, E., Maino, C., Ippolito, D., D'Amato, D., Ferreira, C., Nardi, A., Banerjee, R., Valsecchi, M. G., Antolini, L., Corso, R., Sironi, S., Fagiuoli, S., Invernizzi, P., and Carbone, M.

Published
2022

39. New insights on the role of human leukocyte antigen complex in primary biliary cholangitis

Author

Mulinacci, G, Palermo, A, Gerussi, A, Asselta, R, Gershwin, M, Invernizzi, P, Mulinacci G., Palermo A., Gerussi A., Asselta R., Gershwin M. E., Invernizzi P., Mulinacci, G, Palermo, A, Gerussi, A, Asselta, R, Gershwin, M, Invernizzi, P, Mulinacci G., Palermo A., Gerussi A., Asselta R., Gershwin M. E., and Invernizzi P.

Abstract

Primary Biliary Cholangitis (PBC) is a rare autoimmune cholangiopathy. Genetic studies have shown that the strongest statistical association with PBC has been mapped in the human leukocyte antigen (HLA) locus, a highly polymorphic area that mostly contribute to the genetic variance of the disease. Furthermore, PBC presents high variability throughout different population groups, which may explain the different geoepidemiology of the disease. A major role in defining HLA genetic contribution has been given by genome-wide association studies (GWAS) studies; more recently, new technologies have been developed to allow a deeper understanding. The study of the altered peptides transcribed by genetic alterations also allowed the development of novel therapeutic strategies in the context of immunotolerance. This review summarizes what is known about the immunogenetics of PBC with a focus on the HLA locus, the different distribution of HLA alleles worldwide, and how HLA modifications are associated with the pathogenesis of PBC. Novel therapeutic strategies are also outlined.

Published
2022

40. GWAS and autoimmunity: What have we learned and what next

Author

Gerussi, A, Soskic, B, Asselta, R, Invernizzi, P, Gershwin, M, Gerussi A., Soskic B., Asselta R., Invernizzi P., Gershwin M. E., Gerussi, A, Soskic, B, Asselta, R, Invernizzi, P, Gershwin, M, Gerussi A., Soskic B., Asselta R., Invernizzi P., and Gershwin M. E.

Abstract

Autoimmune diseases are common conditions characterized by loss of tolerance, female predominance and a remarkable heterogeneity among different populations. Most often they are polygenic and several genetic loci have been linked with the risk of developing autoimmune diseases. However, causal inference is difficult. When the genomic revolution began there were high hopes of translating fast genetic analyses to the bedside but this has proven to be challenging. Nonetheless, over the last decade, fine-mapping strategies have greatly improved; one of the most significant research lines focuses on the in vivo and ex vivo definition of the effect of genetic variants within the target tissues and within specific subpopulations of immune cells that are involved in the disease pathogenesis. This strategy also includes the longitudinal tracking of a large number of immunophenotypes in many individuals to build a large reference atlas for variant characterization. In this review, we discuss the results obtained by GWAS in autoimmune diseases and review recent advances in fine mapping strategies. More importantly, we discuss gaps and future directions.

Published
2022

41. The Role of Epigenetics in Primary Biliary Cholangitis

Author

Gerussi, A, Paraboschi, E, Cappadona, C, Caime, C, Binatti, E, Cristoferi, L, Asselta, R, Invernizzi, P, Gerussi A., Paraboschi E. M., Cappadona C., Caime C., Binatti E., Cristoferi L., Asselta R., Invernizzi P., Gerussi, A, Paraboschi, E, Cappadona, C, Caime, C, Binatti, E, Cristoferi, L, Asselta, R, Invernizzi, P, Gerussi A., Paraboschi E. M., Cappadona C., Caime C., Binatti E., Cristoferi L., Asselta R., and Invernizzi P.

Abstract

Primary Biliary Cholangitis (PBC) is a rare autoimmune disease of the liver, affecting mostly females. There is evidence that epigenetic changes have a pathogenic role in PBC. Epigenetic modifications are related to methylation of CpG DNA islands, post-translational modifications of histone proteins, and non-coding RNAs. In PBC, there are data showing a dysregulation of all these levels, especially in immune cells. In addition, epigenetics seems to be involved in complex phenomena such as X monosomy or abnormalities in the process of X chromosome inactivation, which have been reported in PBC and appear to influence its sex imbalance and pathogenesis. We review here historical data on epigenetic modifications in PBC, present new data, and discuss possible links among X-chromosome abnormalities at a genetic and epigenetic level, PBC pathogenesis, and PBC sex imbalance.

Published
2022

42. X marks the spot in autoimmunity

Author

Gerussi, A, Caime, C, Binatti, E, Cappadona, C, Cristoferi, L, Asselta, R, Gershwin, M, Invernizzi, P, Gerussi A., Caime C., Binatti E., Cappadona C., Cristoferi L., Asselta R., Gershwin M. E., Invernizzi P., Gerussi, A, Caime, C, Binatti, E, Cappadona, C, Cristoferi, L, Asselta, R, Gershwin, M, Invernizzi, P, Gerussi A., Caime C., Binatti E., Cappadona C., Cristoferi L., Asselta R., Gershwin M. E., and Invernizzi P.

Abstract

Introduction: Autoimmune diseases mostly affect females. Besides hormones, several factors related to chromosome X have been called in action to explain this sex predominance. Areas covered: This paper provides an overview on the role of chromosome X (chrX) in explaining why females have higher susceptibility to autoimmunity. The work outlines some essential concepts regarding chrX inactivation, escape from chrX inactivation and the evolutionary history of chrX. In addition, we will discuss the concept of gene escape in immune cells, with examples related to specific X-linked genes and autoimmune diseases. Expert opinion: There is growing evidence that many genes present on chrX escape inactivation, and some of them have significant immune-mediated functions. In immune cells of female individuals the escape of these genes is not constant, but the knowledge of the mechanisms controlling this plasticity are not completely understood. Future studies aimed at the characterization of these modifications at single-cell resolution, together with conformational 3D studies of the inactive X chromosome, will hopefully help to fill this gap of knowledge.

Published
2022

43. The Role of Macrophages in Liver Fibrosis: New Therapeutic Opportunities

Author

Binatti, E, Gerussi, A, Barisani, D, Invernizzi, P, Binatti E., Gerussi A., Barisani D., Invernizzi P., Binatti, E, Gerussi, A, Barisani, D, Invernizzi, P, Binatti E., Gerussi A., Barisani D., and Invernizzi P.

Abstract

Chronic inflammation is the hallmark of fibrotic disorders and is characterized by the activation of immune cells in the damaged tissues. Macrophages have emerged as central players in the fibrotic process since they initiate, sustain and amplify the inflammatory reaction. As regards the liver, distinct populations of phagocytic cells, like Kupffer cells and monocyte‐derived macrophages, are indisputably key cells implicated in the pathogenesis of several chronic liver diseases. In this review, we summarize the current knowledge on the origin, role and functions of macrophages in fibrotic conditions, with a specific focus on liver fibrosis; then, we discuss some innovative therapeutic strategies targeting macrophages in fibrotic liver diseases.

Published
2022

44. SARS-CoV-2 vaccination and risk of severe COVID-19 outcomes in patients with autoimmune hepatitis

Author

Efe, C, Tascilar, K, Gerussi, A, Bolis, F, Lammert, C, Ebik, B, Stattermayer, A, Cengiz, M, Gokce, D, Cristoferi, L, Peralta, M, Massoumi, H, Montes, P, Cerda, E, Rigamonti, C, Yapali, S, Adali, G, Caliskan, A, Balaban, Y, Eren, F, Eskazan, T, Barutcu, S, Lytvyak, E, Zazueta, G, Kayhan, M, Heurgue-Berlot, A, De Martin, E, Yavuz, A, Biyik, M, Narro, G, Duman, S, Hernandez, N, Gatselis, N, Aguirre, J, Idilman, R, Silva, M, Mendizabal, M, Atay, K, Guzelbulut, F, Dhanasekaran, R, Montano-Loza, A, Dalekos, G, Ridruejo, E, Invernizzi, P, Wahlin, S, Efe C., Tascilar K., Gerussi A., Bolis F., Lammert C., Ebik B., Stattermayer A. F., Cengiz M., Gokce D. T., Cristoferi L., Peralta M., Massoumi H., Montes P., Cerda E., Rigamonti C., Yapali S., Adali G., Caliskan A. R., Balaban Y., Eren F., Eskazan T., Barutcu S., Lytvyak E., Zazueta G. M., Kayhan M. A., Heurgue-Berlot A., De Martin E., Yavuz A., Biyik M., Narro G. C., Duman S., Hernandez N., Gatselis N. K., Aguirre J., Idilman R., Silva M., Mendizabal M., Atay K., Guzelbulut F., Dhanasekaran R., Montano-Loza A. J., Dalekos G. N., Ridruejo E., Invernizzi P., Wahlin S., Efe, C, Tascilar, K, Gerussi, A, Bolis, F, Lammert, C, Ebik, B, Stattermayer, A, Cengiz, M, Gokce, D, Cristoferi, L, Peralta, M, Massoumi, H, Montes, P, Cerda, E, Rigamonti, C, Yapali, S, Adali, G, Caliskan, A, Balaban, Y, Eren, F, Eskazan, T, Barutcu, S, Lytvyak, E, Zazueta, G, Kayhan, M, Heurgue-Berlot, A, De Martin, E, Yavuz, A, Biyik, M, Narro, G, Duman, S, Hernandez, N, Gatselis, N, Aguirre, J, Idilman, R, Silva, M, Mendizabal, M, Atay, K, Guzelbulut, F, Dhanasekaran, R, Montano-Loza, A, Dalekos, G, Ridruejo, E, Invernizzi, P, Wahlin, S, Efe C., Tascilar K., Gerussi A., Bolis F., Lammert C., Ebik B., Stattermayer A. F., Cengiz M., Gokce D. T., Cristoferi L., Peralta M., Massoumi H., Montes P., Cerda E., Rigamonti C., Yapali S., Adali G., Caliskan A. R., Balaban Y., Eren F., Eskazan T., Barutcu S., Lytvyak E., Zazueta G. M., Kayhan M. A., Heurgue-Berlot A., De Martin E., Yavuz A., Biyik M., Narro G. C., Duman S., Hernandez N., Gatselis N. K., Aguirre J., Idilman R., Silva M., Mendizabal M., Atay K., Guzelbulut F., Dhanasekaran R., Montano-Loza A. J., Dalekos G. N., Ridruejo E., Invernizzi P., and Wahlin S.

Abstract

Background: Data regarding outcome of Coronavirus disease 2019 (COVID-19) in vaccinated patients with autoimmune hepatitis (AIH) are lacking. We evaluated the outcome of COVID-19 in AIH patients who received at least one dose of Pfizer- BioNTech (BNT162b2), Moderna (mRNA-1273) or AstraZeneca (ChAdOx1-S) vaccine. Patients and methods: We performed a retrospective study on AIH patients with COVID-19. The outcomes of AIH patients who had acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection after at least one dose of COVID-19 vaccine were compared to unvaccinated patients with AIH. COVID-19 outcome was classified according to clinical state during the disease course as: (i) no hospitalization, (ii) hospitalization without oxygen supplementation, (iii) hospitalization with oxygen supplementation by nasal cannula or mask, (iv) intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v) ICU admission with invasive mechanical ventilation or (vi) death, and data was analyzed using ordinal logistic regression. Results: We included 413 (258 unvaccinated and 155 vaccinated) patients (81%, female) with a median age of 52 (range: 17–85) years at COVID-19 diagnosis. The rates of hospitalization were (36.4% vs. 14.2%), need for any supplemental oxygen (29.5% vs. 9%) and mortality (7% vs. 0.6%) in unvaccinated and vaccinated AIH patients with COVID-19. Having received at least one dose of SARS-CoV-2 vaccine was associated with a significantly lower risk of worse COVID-19 severity, after adjusting for age, sex, comorbidities and presence of cirrhosis (adjusted odds ratio [aOR] 0.18, 95% confidence interval [CI], 0.10–0.31). Overall, vaccination against SARS-CoV-2 was associated with a significantly lower risk of mortality from COVID-19 (aOR 0.20, 95% CI 0.11–0.35). Conclusions: SARS-CoV-2 vaccination significantly reduced the risk of COVID-19 severity and mortality in patients with AIH.

Published
2022

45. Genetics of Primary Biliary Cholangitis

Author

Gerussi, A, Asselta, R, Invernizzi, P, Gerussi A., Asselta R., Invernizzi P., Gerussi, A, Asselta, R, Invernizzi, P, Gerussi A., Asselta R., and Invernizzi P.

Published
2022

46. Role of ductular reaction and ductular–canalicular junctions in identifying severe primary biliary cholangitis

Author

Overi, D, Carpino, G, Cristoferi, L, Onori, P, Kennedy, L, Francis, H, Zucchini, N, Rigamonti, C, Vigano, M, Floreani, A, D'Amato, D, Gerussi, A, Venere, R, Alpini, G, Glaser, S, Alvaro, D, Invernizzi, P, Gaudio, E, Cardinale, V, Carbone, M, Overi D., Carpino G., Cristoferi L., Onori P., Kennedy L., Francis H., Zucchini N., Rigamonti C., Vigano M., Floreani A., D'Amato D., Gerussi A., Venere R., Alpini G., Glaser S., Alvaro D., Invernizzi P., Gaudio E., Cardinale V., Carbone M., Overi, D, Carpino, G, Cristoferi, L, Onori, P, Kennedy, L, Francis, H, Zucchini, N, Rigamonti, C, Vigano, M, Floreani, A, D'Amato, D, Gerussi, A, Venere, R, Alpini, G, Glaser, S, Alvaro, D, Invernizzi, P, Gaudio, E, Cardinale, V, Carbone, M, Overi D., Carpino G., Cristoferi L., Onori P., Kennedy L., Francis H., Zucchini N., Rigamonti C., Vigano M., Floreani A., D'Amato D., Gerussi A., Venere R., Alpini G., Glaser S., Alvaro D., Invernizzi P., Gaudio E., Cardinale V., and Carbone M.

Abstract

Background & Aims: Primary biliary cholangitis (PBC) is a chronic cholangiopathy characterised by immuno-mediated injury of interlobular bile ducts leading to intrahepatic cholestasis and progressive liver fibrosis. PBC histology is characterised by portal inflammation, progressive fibrosis, ductopenia, and the appearance of the so-called ductular reaction. The aim of the present study was to investigate the pathogenetic relevance of ductular reaction in PBC. Methods: Liver biopsies were collected from naïve people with PBC (N = 87). Clinical–serological parameters were obtained at diagnosis and after 1 year of ursodeoxycholic acid (UDCA) treatment. Histological staging was performed on all slides according to multiple scoring systems and criteria for PBC. Liver samples were obtained from Mdr2−/− mice treated with or without UDCA. Samples were processed for histology, immunohistochemistry, and immunofluorescence. Results: Ductular reaction in people with PBC correlated with the disease stage and liver fibrosis, but not with disease activity; an extensive ductular reaction correlated with serum alkaline phosphatase levels at diagnosis, response to UDCA, and individuals’ estimated survival, independently from other histological parameters, including disease stage. In people with PBC, reactive ductules were associated with the establishment of junctions with bile canaliculi and with fibrogenetic cell activation. Consistently, in a mouse model of intrahepatic cholestasis, UDCA treatment was effective in reducing ductular reaction and fibrosis and increasing ductular–canalicular junctions. Conclusions: Extensive ductular reaction outlines a severe histologic phenotype in PBC and is associated with an inadequate therapy response and a worse estimated prognosis. Lay summary: In people affected by primary biliary cholangitis (PBC), the histological appearance of extensive ductular reaction identifies individuals at risk of progressive fibrosis. Ductular reaction at dia

Published
2022

47. Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581] (Journal of Hepatology (2021) 75(3) (572–581), (S0168827821003342), (10.1016/j.jhep.2021.04.055))

Author

Cordell H. J., Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byun, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Tanaka, A, Takikawa, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Kawata, K, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Tarocchi, M, Cordell H. J., Fryett J. J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S. -S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B. D., Atkinson E. J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M. A. R., Sun D., Jones D. E., Flack S., Spicer A., Mulcahy V. L., Byun J., Han Y., Sandford R. N., Lazaridis K. N., Amos C. I., Hirschfield G. M., Seldin M. F., Invernizzi P., Siminovitch K. A., Ma X., Nakamura M., Mells G. F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P. L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P. M., Benedetti A., Bragazzi M. C., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L. S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G. A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Tanaka A., Takikawa H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Kawata K., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L. A., Overton J. D., Reid J. G., Shuldiner A., Beechert C., Forsythe C., Fuller E. D., Gu Z., Lattari M., Lopez A., Schleicher T. D., Padilla M. S., Toledo K., Widom L., Wolf S. E., Pradhan M., Manoochehri K., Ulloa R. H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E. K., Salerno W., Staples J. C., Jones M. B., Mitnaul L. J., Sturgess R., Healey C., Yeoman A., Gunasekera A. V. J., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J. A., Gorard D. A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M. R., Collins C. E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M. J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I. R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H. M., Ridpath J., Ngatchu T., Bob Grover V. P., Shidrawi R. G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M. A., Curtis H., Matthews H. C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M. I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N. N., Gupta P., Shah A., Evans C. D. J., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S. T., McDonald N., Bathgate A. J., Palmer K., Dillon J. F., Rushbrook S. M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T. J. W., Ryder S., Collier J., Klass H., Cramp M. E., Sharer N., Aspinall R., Ghosh D., Douds A. C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C. L., Rahman M., Whatley G. C. A., Wesley E., Mandal A., Jain S., Pereira S. P., Wright M., Trivedi P., Gordon F. H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A. D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S. J., Bell A., Wong V. S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., Tarocchi M., Cordell H. J., Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byun, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Tanaka, A, Takikawa, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Kawata, K, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Tarocchi, M, Cordell H. J., Fryett J. J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S. -S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B. D., Atkinson E. J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M. A. R., Sun D., Jones D. E., Flack S., Spicer A., Mulcahy V. L., Byun J., Han Y., Sandford R. N., Lazaridis K. N., Amos C. I., Hirschfield G. M., Seldin M. F., Invernizzi P., Siminovitch K. A., Ma X., Nakamura M., Mells G. F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P. L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P. M., Benedetti A., Bragazzi M. C., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L. S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G. A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Tanaka A., Takikawa H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Kawata K., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L. A., Overton J. D., Reid J. G., Shuldiner A., Beechert C., Forsythe C., Fuller E. D., Gu Z., Lattari M., Lopez A., Schleicher T. D., Padilla M. S., Toledo K., Widom L., Wolf S. E., Pradhan M., Manoochehri K., Ulloa R. H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E. K., Salerno W., Staples J. C., Jones M. B., Mitnaul L. J., Sturgess R., Healey C., Yeoman A., Gunasekera A. V. J., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J. A., Gorard D. A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M. R., Collins C. E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M. J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I. R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H. M., Ridpath J., Ngatchu T., Bob Grover V. P., Shidrawi R. G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M. A., Curtis H., Matthews H. C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M. I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N. N., Gupta P., Shah A., Evans C. D. J., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S. T., McDonald N., Bathgate A. J., Palmer K., Dillon J. F., Rushbrook S. M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T. J. W., Ryder S., Collier J., Klass H., Cramp M. E., Sharer N., Aspinall R., Ghosh D., Douds A. C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C. L., Rahman M., Whatley G. C. A., Wesley E., Mandal A., Jain S., Pereira S. P., Wright M., Trivedi P., Gordon F. H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A. D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S. J., Bell A., Wong V. S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., and Tarocchi M.

Abstract

It has come to our attention that the name of one of the authors in our manuscript was incorrectly spelled ‘Jinyoung Byan’; the correct spelling is ‘Jinyoung Byun’ as in the author list above. In addition, the excel files of the supplementary tables were not included during the online publication of our article. These have now been made available online. We apologize for any inconvenience caused.

Published
2022

48. Vanishing bile duct syndrome following pembrolizumab infusion: case report and review of the literature

Author

Gemelli, M, Carbone, M, Abbate, M, Mancin, M, Zucchini, N, Colonese, F, Invernizzi, P, Bidoli, P, Cortinovis, D, Gemelli M., Carbone M., Abbate M. I., Mancin M., Zucchini N., Colonese F., Invernizzi P., Bidoli P., Cortinovis D., Gemelli, M, Carbone, M, Abbate, M, Mancin, M, Zucchini, N, Colonese, F, Invernizzi, P, Bidoli, P, Cortinovis, D, Gemelli M., Carbone M., Abbate M. I., Mancin M., Zucchini N., Colonese F., Invernizzi P., Bidoli P., and Cortinovis D.

Abstract

Plain language summary Immunotherapy has demonstrated high efficacy in lung cancer and is commonly used in clinical practice. Despite the good tolerability, severe immune-related adverse events may occur, requiring hospitalization and possibly leading to death. We present a case of vanishing bile duct syndrome (a rare and potentially lethal condition characterized by progressive destruction of small bile ducts) which arose a few days after the first pembrolizumab infusion. Laboratory tests and radiological imaging were performed to orient diagnosis and monitor disease; a histological sample was required for vanishing bile duct syndrome diagnosis. High-dose steroid therapy and immunosuppressors were administered, with scarce efficacy. Prompt recognition and management of similar conditions is crucial to avoid fatal events. Further studies are needed to investigate new drugs for steroid-refractory conditions.

Published
2022

49. E. coli and the etiology of human PBC: Antimitochondrial antibodies and spreading determinants

Author

Yang, Y, Choi, J, Chen, Y, Invernizzi, P, Yang, G, Zhang, W, Shao, T, Jordan, F, Nemeria, N, Coppel, R, Ridgway, W, Kurth, M, Ansari, A, Leung, P, Gershwin, M, Yang Y., Choi J., Chen Y., Invernizzi P., Yang G., Zhang W., Shao T. -H., Jordan F., Nemeria N., Coppel R. L., Ridgway W. M., Kurth M., Ansari A. A., Leung P. S. C., Gershwin M. E., Yang, Y, Choi, J, Chen, Y, Invernizzi, P, Yang, G, Zhang, W, Shao, T, Jordan, F, Nemeria, N, Coppel, R, Ridgway, W, Kurth, M, Ansari, A, Leung, P, Gershwin, M, Yang Y., Choi J., Chen Y., Invernizzi P., Yang G., Zhang W., Shao T. -H., Jordan F., Nemeria N., Coppel R. L., Ridgway W. M., Kurth M., Ansari A. A., Leung P. S. C., and Gershwin M. E.

Abstract

Background and Aims: The increased frequency of urinary tract infections in patients with primary biliary cholangitis (PBC) and the cross-reactivity between the lipoyl domains (LD) of human pyruvate dehydrogenase complex (hPDC-E2) and Escherichia coli PDC-E2 (ePDC-E2) have long suggested a role of E. coli in causality of PBC. This issue, however, has remained speculative. We hypothesized that by generating specific constructs of human and E. coli PDC-E2, we would be able to assess the specificity of autoantibody responses and define whether exposure to E. coli in susceptible hosts is the basis for the antimitochondrial antibody (AMA) response. Approach and Results: Importantly, the reactivity of hPDC-E2 LD (hPDC-E2LD) affinity-purified antibodies against hPDC-E2LD could only be removed by prior absorption with hPDC-E2LD and not ePDC-E2, suggesting the presence of unique human PDC-E2 epitopes distinct from E. coli PDC-E2. To identify the autoepitope(s) present in hPDC-E2LD, a more detailed study using a variety of PDC-E2 constructs was tested, including the effect of lipoic acid (LA) on ePDC-E2 conformation and AMA recognition. Individual recombinant ePDCE2 LD domains LD1, LD2 and LD3 did not react with either AMA or antibodies to LA (anti-LA), but in contrast, anti-LA was readily reactive against purified recombinant LD1, LD2, and LD3 expressed in tandem (LP); such reactivity increased when LP was precultured with LA. Moreover, when the three LD (LD1, LD2, LD3) domains were expressed in tandem in pET28a or when LD1 was expressed in another plasmid pGEX, they were lipoylated and reactive to PBC sera. Conclusions: In conclusion, our data are consistent with an exposure to E. coli that elicits specific antibody to ePDC-E2 resulting in determinant spreading and the classic autoantibody to hPDC-E2LD. We argue this is the first step to development of human PBC.

Published
2022

50. Somatostatin analogs in patients with Zollinger Ellison syndrome (ZES): an observational study

Author

Massironi, S, Cavalcoli, F, Elvevi, A, Quatrini, M, Invernizzi, P, Massironi S., Cavalcoli F., Elvevi A., Quatrini M., Invernizzi P., Massironi, S, Cavalcoli, F, Elvevi, A, Quatrini, M, Invernizzi, P, Massironi S., Cavalcoli F., Elvevi A., Quatrini M., and Invernizzi P.

Abstract

Purpose: Zollinger Ellison syndrome (ZES) is a rare syndrome caused by gastrin hypersecretion from a gastrinoma. Gastrinoma treatment has two goals: the control of acid hypersecretion and the control of tumor growth. While therapy for the syndrome is univocally based on proton pump inhibitors, the one for disease control is still debated. We here aimed at evaluating the role of somatostatin analogs (SSAs) in the control of tumor progression in a series of ZES patients. Methods: A retrospective analysis of a prospectively collected database of ZES patients, followed and managed from 1990 to 2019, was performed. The patients’ clinical, pathological, treatment, and follow-up data were analyzed. Data regarding SSAs therapy start, dosage, duration, and side effects were collected. Results: 33 patients with ZES were diagnosed. Fourteen patients (42%) had a grade 1 (G1) neuroendocrine neoplasm (NEN), five had G2 (15%), none had G3. Fifteen patients (45%) had metastatic disease. Overall, 12 (36%) underwent SSAs therapy. The median treatment duration was 36 months. Eight patients (67%) had a sustained response to SSAs, four (33%) showed an early progression, with a significant difference in terms of PFS between the patients with early and late progression (84 vs 2 months, p = 0.004). No differences in terms of OS and PFS were observed between the treated and non-treated patients, despite the proportion of metastatic patients was greater in the SSAs-treated group (75% vs 29% in the non-treated group, p = 0.01). Conclusion: Present data support the use of SSAs in ZES, considering that gastrinoma is mainly a well-differentiated low-grade tumor (G1 or G2), with a high expression of somatostatin receptors.

Published
2022

Catalog

Books, media, physical & digital resources
See catalog results