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Autoimmune pancreatitis:Cornerstones and future perspectives

World Journal of Gastroenterology 2024年第8期30卷 817-832页

作者： Camilla Gallo Giulia Dispinzieri Nicola Zucchini pietro invernizzi Sara Massironi Division of Gastroenterology and Center for Autoimmune Liver Diseases Department of Medicine and SurgeryFondazione IRCCS San Gerardo dei TintoriUniversity of Milano-BicoccaMonza 20900Italy Department of Pathology Fondazione IRCCS San Gerardo dei TintoriMonza 20900Italy

Autoimmune pancreatitis(AIP)is an autoimmune subtype of chronic pancreatitis resulting from the aberrant immune response against the pancreas,leading to inflammation and fibrosis.Although AIP is rare,its incidence is increasing and is often misdiagnosed as other pancreatic diseases.AIP is commonly classified into two types.Type 1 AIP(AIP-1)is typically associated with elevated serum immunoglobulin G4(IgG4)levels and systemic manifestations,while type 2 AIP is typically a more localized form of the disease,and may coexist with other autoimmune disorders,especially inflammatory bowel diseases.Additionally,there is emerging recognition of a third type(type 3 AIP),which refers to immunotherapy-triggered AIP,although this classification is still gaining acceptance in medical literature.The clinical manifestations of AIP mainly include painless jaundice and weight loss.Elevated serum IgG4 levels are particularly characteristic of AIP-1.Diagnosis relies on a combination of clinical,laboratory,radiological,and histological findings,given the similarity of AIP symptoms to other pancreatic disorders.The mainstay of treatment for AIP is steroid therapy,which is effective in most cases.Severe cases might require additional imm-unosuppressive agents.This review aims to summarize the current knowledge of AIP,encompassing its epidemiology,etiology,clinical presentation,diagnosis,and treatment options.We also address the challenges and controversies in diagnosing and treating AIP,such as distinguishing it from pancreatic cancer and managing long-term treatment,highlighting the need for increased awareness and knowledge of this complex disease.

关键词： Autoimmunity Pancreatitis Autoimmune pancreatitis Immunoglobulin G4 Steroids Relapse

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

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World Journal of Gastrointestinal Oncology 2023年第8期15卷 1451-1460页

作者： Sara Massironi Camilla Gallo Alessandra Elvevi Marta Stegagnini Lorenzo Andrea Coltro pietro invernizzi Division of Gastroenterology Fondazione IRCCS San Gerardo dei TintoriUniversity of Milano-BicoccaSchool of MedicineMonza 20900Italy

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 detection and treatment are needed.

关键词： Atrophic gastritis Autoimmune gastritis Gastrin Gastric neuroendocrine tumors

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Endoscopic techniques for diagnosis and treatment of gastroentero-pancreatic neuroendocrine neoplasms:Where we are

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World Journal of Gastroenterology 2022年第26期28卷 3258-3273页

作者： Roberta Elisa Rossi Alessandra Elvevi Camilla Gallo Andrea Palermo pietro invernizzi Sara Massironi HPB Surgery Hepatology and Liver TransplantationENETS Center of ExcellenceFondazione IRCCS Istituto Nazionale Tumori(INTNational Cancer Institute)Milan 20133Italy Division of Gastroenterology and Center for Autoimmune Liver Diseases Department of Medicine and SurgeryUniversity of Milano-BicoccaMonza 20900Italy

BACKGROUND The correct localization of the primary tumor site and a complete histological diagnosis represent the milestones for the proper management of gastro-enteropancreatic neuroendocrine neoplasms(GEP-NENs).AIM To analyze current evidence on the role of endoscopy in the diagnosis/treatment of GEP-NENs.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 15 years,using both medical subject heading(MeSH)terms and free-language keywords:gastro-enteropancreatic neuroendocrine neoplasms;endoscopy;ultrasound endoscopy;capsule endoscopy;double-balloon enteroscopy;diagnosis;therapy;staging.RESULTS In the diagnostic setting,endoscopic ultrasonography(EUS)represents the diagnostic gold standard for pancreatic NENs and the technique of choice for the locoregional staging of gastric,duodenal and rectal NENs.The diagnosis of small bowel NENs(sbNENs)has been improved with the advent of video capsule endoscopy and double-balloon enteroscopy,which allow for direct visualization of the entire small bowel;however,data regarding the efficacy/safety of these techniques in the detection of sbNENs are scanty and often inconclusive.From a therapeutic point of view,endoscopic removal is the treatment of choice for the majority of gastric NENs(type 1/2),for well-differentiated localized nonmetastatic duodenal NENs<1 cm,confined to the submucosa layer and for<10 mm,stage T1–T2,rectal NENs.EUS-guided pancreatic locoregional ablative treatments have been proposed in recent studies with promising results in order to control symptoms or reduce tumor burden in selected patients.CONCLUSION Standard axial endoscopy and EUS still play a pivotal role in several GEP-NENs.Advanced techniques for increasing the rate of R0 resection should be reserved for high-volume referral centers.

关键词： Gastro-entero-pancreatic neuroendocrine neoplasms Endoscopy Ultrasound endoscopy Capsule endoscopy Double-balloon enteroscopy Diagnosis Therapy Staging

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

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World Journal of Gastroenterology 2023年第23期29卷 3733-3747页

作者： Roberta Elisa Rossi Alessandra Elvevi Valentina Sciola Francesco Vito Mandarino Silvio Danese pietro invernizzi Sara Massironi Gastroenterology and Endoscopy Unit IRCCS Humanitas Research HospitalRozzano 20089MilanItaly Gastroenterology Unit Fondazione IRCCS San Gerardo dei TintoriMonza 20900Italy and Department of Medicine and SurgeryUniversity of Milano-BicoccaMonza 20900Italy Gastroenterology and Endoscopy Unit Fondazione IRCCS Ca’Granda Ospedale Maggiore PoliclinicoMilano 20100Italy Department of Gastroenterology and Endoscopy IRCCS Ospedale San RaffaeleMilan 20132Italy School of Medicine Vita-Salute San Raffaele UniversityMilan 20132Italy

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.

关键词： Dyspepsia Dyspeptic symptoms Gastro-intestinal symptoms Autoimmune gastritis Chronic autoimmune atrophic gastritis Treatment

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

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World Journal of Gastroenterology 2022年第11期28卷 1123-1138页

作者： Camilla Gallo Roberta Elisa Rossi Federica Cavalcoli Federico Barbaro Ivo Boškoski pietro invernizzi Sara Massironi Division of Gastroenterology and Center for Autoimmune Liver Diseases Department of Medicine and SurgeryUniversity of Milano-BicoccaEuropean Reference Network on Hepatological DiseasesSan Gerardo HospitalMonza 20900Italy Division of HPB Surgery Hepatology and Liver TransplantationDepartment of Pathophysiology and TransplantationUniversity of MilanENETS Center of ExcellenceFondazione IRCCS Istituto Nazionale Tumori(INTNational Cancer Institute)Milan 20133Italy Diagnostic and Therapeutic Endoscopy Unit Fondazione IRCCS Istituto Nazionale TumoriMilan 20133Italy Digestive Endoscopy Unit UniversitàCattolica del Sacro Cuore di RomaCenter for Endoscopic Research Therapeutics and TrainingFondazione Policlinico Universitario Agostino Gemelli IRCSSRome 00168Italy

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.

关键词： Rectal neuroendocrine tumors Endoscopy Endoscopic submucosal dissection Resectable advanced disease Systemic therapy

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

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World Journal of Hepatology 2023年第12期15卷 1284-1293页

作者： Alessandra Elvevi Alice Laffusa Federica Elisei Sabrina Morzenti Luca Guerra Antonio Rovere pietro invernizzi Sara Massironi Division of Gastroenterology and Center for Autoimmune Liver Diseases Department of Medicine and SurgeryUniversity of Milano-Bicocca and European Reference Network on Hepatological Diseases(ERN RARELIVER)Fondazione IRCCS San Gerardo dei Tintori HospitalMonza 20900Italy Department of Nuclear Medicine Fondazione IRCCS San Gerardo dei Tintori University of Milano BicoccaMonza 20900Italy Medical Physics Fondazione IRCCS San Gerardo dei TintoriMonza 20900Italy Department of Radiology and Interventional Radiology Fondazione IRCCS San Gerardo dei Tintori HospitalMonza 20900Italy

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-independent factors that can influence prognosis.Further research is necessary to identify optimal treatm

关键词： Intrahepatic cholangiocarcinoma Transarterial radioembolization Locoregional treatment Overall Survival Response rates Neo-adjuvant therapy Combined Therapies Prognostic factors

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

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World Journal of Gastroenterology 2022年第29期28卷 3767-3779页

作者： Alessandra Elvevi Elena Maria Elli Martina Luca Miki Scaravaglio Fabio Pagni Stefano Ceola Laura Ratti pietro invernizzi Sara Massironi Gastroenterology Division San Gerardo HospitalUniversity of Milano-Bicocca School of MedicineMonza 20900Italy Hematology Division and Bone Marrow Transplant Unit San Gerardo HospitalMonza 20900Italy Department of Medicine and Surgery Section of PathologySan Gerardo HospitalUniversity of Milano-Bicocca School of MedicineMonza 20900Italy

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.

关键词： Systemic mastocytosis Gastrointestinal involvement Gastrointestinal symptoms

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Autoimmune liver diseases

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World Journal of Gastroenterology 2008年第21期14卷 3290-3291页

作者： pietro invernizzi Ian R Mackay Division of Internal Medicine and Liver Unit San Paolo Hospital School of MedicineUniversity of MilanMilan 20142ItalyDivision of RheumatologyAllergyand Clinical ImmunologyUniversity of California at DavisDavisCAUnite States Department of Biochemistry & Molecular Biology Monash UniversityClaytonVictoria 3800Australia

The liver was one of the earliest recognized sites among autoimmune diseases yet autoimmune hepatitis,primary biliary cirrhosis,primary sclerosing cholangitis,and their overlap forms,are still problematic in diagnosis and causation.The contributions herein comprise 'pairs of articles' on clinical characteristics,and concepts of etiopathogenesis,for each of the above diseases,together with childhood autoimmune liver disease,overlaps,interpretations of diagnostic serology,and liver transplantation.This issue is timely,since we are witnessing an ever increasing applicability of immunology to a wide variety of chronic diseases,hepatic and non-hepatic,in both developed and developing countries.The 11 invited expert review articles capture the changing features over recent years of the autoimmune liver diseases,the underlying immunomolecular mechanisms of development,the potent albeit still unexplained genetic influences,the expanding repertoire of immunoserological diagnostic markers,and the increasingly effective therapeutic possibilities.

关键词：自体免疫肝疾病临床免疫学肝炎

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Experimental evidence on the immunopathogenesis of primary biliary cirrhosis

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Cellular & Molecular Immunology 2010年第1期7卷 1-10页

作者： Carlo Selmi Francesca Meda Anaid Kasangian pietro invernizzi Zhigang Tian Zhexiong Lian Mauro Podda M Eric Gershwin Department of Translational Medicine Universitàdegli Studi di MilanoMilanItaly Department of Medicine IRCCS Istituto Clinico Humanitas RozzanoMilanItaly Divisionof Rheumatology Allergyand Clinical ImmunologyUniversity of California at DavisDavisCAUSA Institute of Immunology University of Science and Technology of ChinaHefeiChina

Primary biliary cirrhosis(PBC)is a chronic cholestatic liver disease for which an autoimmune pathogenesis is supported by clinical and experimental data,including the presence of autoantibodies and autoreactive T cells.The etiology remains to be determined,yet data suggest that both a susceptible genetic background and unknown environmental factors determine disease onset.Multiple infectious and chemical candidates have been proposed to trigger the disease in a genetically susceptible host,mostly by molecular mimicry.Most recently,several murine models have been reported,including genetically determined models as well as models induced by immunization with xenobiotics and bacteria.

关键词： pathogenesis cirrhosis biliary

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Endoscopic techniques for gastric neuroendocrine tumors:An update

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World Journal of Gastrointestinal Endoscopy 2023年第3期15卷 103-113页

作者： Sara Massironi Camilla Gallo Alice Laffusa Cristina Ciuffini Clara Benedetta Conti Federico Barbaro Ivo Boskoski Marco Emilio Dinelli pietro invernizzi Gastroenterology Unit Fondazione IRCCS SanGerardo dei TintoriMonza(MB)20900Italy Interventional Endoscopy Unit Fondazione IRCCS San Gerardo dei TintoriMonza(MB)20900Italy Digestive Endoscopy Unit Fondazione Policlinico Universitario Agostino Gemelli IRCCSUniversitàCattolica del Sacro Cuore di RomaCenter for Endoscopic Research Therapeutics and Training(CERTT)Roma 00168Italy

Gastric neuroendocrine neoplasms(gNENs)are a rare type of gastric neoplasm,even if their frequency is increasing according to the latest epidemiologic revisions of the main registries worldwide.They are divided into three main subtypes,with different pathogeneses,biological behaviors,and clinical characteristics.GNEN heterogeneity poses challenges,therefore these neoplasms require different management strategies.Update the knowledge on the endoscopic treatment options to manage g-NENs.This manuscript is a narrative review of the literature.In recent years,many advances have been made not only in the knowledge of both the pathogenesis and the molecular profiling of gNENs but also in the endoscopic expertise towards innovative treatment options,which proved to be less aggressive without losing the capa-bility of being radical.The endoscopic approach is increasingly applied in the field of gastrointestinal(GI)luminal neoplasms,and this is true not only for adenocarcinomas but also for gNENs.In particular,different techniques have been described for the endoscopic removal of suspected lesions,ranging from classical polypectomy(cold or hot snare)to endoscopic mucosal resection(both with“en bloc”or piecemeal technique),endoscopic submucosal dissection,and endoscopic full-thickness resection.GNENs comprise different subtypes of neoplasms with distinct management and prognosis.New endoscopic techniques offer a wide variety of approaches for GI localized neoplasms,which demonstrated to be appropriate and effective also in the case of gNENs.Correct evaluation of size,site,morphology,and clinical context allows the choice of tailored therapy in order to guarantee a definitive treatment.

关键词： Stomach neoplasm Neuroendocrine tumors Endoscopy Endoscopic mucosal resection Endoscopic submucosal dissection

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