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The homeodomain-containing transcription factor pancreatic duodenal homeobox 1 (PDX-1) plays a key role in pancreatic development and β-cell function. It is a major regulator of transcription in pancreatic cells, and transactivates the insulin gene by binding to a specific DNA motif in its promoter region. Glucose also regulates insulin gene transcription through PDX-1. It has been shown that PDX-1 is required for maintaining pancreatic islet functions by activating gene expression and has a dual role in pancreatic development. It initially contributes to pancreatic formation during embryogenesis and subsequently regulates the pancreatic islet cell physiology in mature islet cells. Because of this key role in the embryologic development of the pancreas, PDX-1 expression has been investigated in pancreatic cancer cell lines and human tumors. Moreover, a few reports have described expression of PDX-1 in other human neoplasms and have investigated its potential role in differential diagnosis, but data on normal human tissues are lacking. Understanding the molecular mechanisms of pancreas formation, and especially the function of PDX-1, may contribute to the improved treatment and prevention of debilitating diseases such as diabetes, insulinomas and pancreatic carcinomas. Nevertheless, further studies are needed concerning its possible application in routine practice.

Background: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. Materials and methods: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. Results: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. Conclusions: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

Objective. [18F]Fluorodeoxyglucose (18F-FDG) PET/CT is increasingly used to assess organ involvement and response to treatment in IgG4-related disease (IgG4-RD), but clear correlations between 18F-FDG uptake and disease activity have not been established yet. We aimed to correlate the intensity and distribution of 18F-FDG uptake with validated clinical, serological and immunological parameters of IgG4-RD activity. Methods. Twenty patients with active IgG4-RD underwent a baseline 18F-FDG PET/CT. Ten patients repeated 18F-FDG PET/CT after immunosuppressive treatments. 18F-FDG tissue uptake was measured using the standardized uptake value corrected for the partial volume effect (PVC-SUV) and the total lesion glycolysis (TLG) with (TLGtot+ln) and without (TLGtot-ln) lymph nodes. Disease activity was assessed by means of clinical parameters [IgG4-RD Responder Index (RI)], serological (ESR and CRP) and immunological (serum IgG4 and circulating plasmablasts) biomarkers. The enhanced liver fibrosis score was exploited as a biomarker for fibroblast activation. Results. Thirteen (65%) patients had two or more organs affected by IgG4-RD. All patients had active IgG4-RD as defined by a median IgG4-RD RI value of 9 (range 6-15; normal < 3). Serum IgG4 and plasmablasts were elevated in 85% of patients. Circulating plasmablasts positively correlated with PVCSUV (P = 0.027), inversely correlated with TLGtot-ln (P = 0.023) and did not correlate with TLGtot+ln (P > 0.05). No statistically significant correlation was found between PVC-SUV or TLG and IgG4-RD RI, ESR, CRP, serum IgG4 or enhanced liver fibrosis score (P > 0.05). Clinical response to immunosuppressive therapies was associated with a consensual reduction of circulating plasmablasts, PVC-SUV, TLGtot+ln and TLGtot-ln values (P < 0.05 for all comparisons). Conclusions. 18F-FDG uptake of IgG4-RD lesions reflects immunological perturbations of the B cell compartment rather than fibroblast activation and extracellular matrix deposition. Conventional biomarkers of disease activity, namely IgG4-RD RI, ESR, CRP and serum IgG4 levels, do not appear to correlate with the radiometabolic activity of IgG4-RD lesions. In light of our results PET/CT represents a reliable instrument for assessing IgG4-RD activity, although lymph-node uptake deserves careful interpretation

The term IgG4-related autoimmune liver disease (AILD) refers to hepato-biliary manifestations of IgG4-related disease (IgG4-RD) including IgG4-related sclerosing cholangitis and IgG4-related pseudotumors. The association of some forms of autoimmune hepatitis to IgG4-RD remains controversial. Although autoimmune phenomena have not been clearly observed in IgG4-AILD, perturbation of the adaptive immune system and activation of the humoral response represent established pathophysiological hallmarks and potential therapeutic targets. Clinical manifestations of IgG4-AILD are virtually indistinguishable from bile duct cancer or primary sclerosing cholangitis, and are due to mass forming lesions and thickening of the biliary tract that progressively lead to biliary ducts obstruction. There are no current reliable biomarkers for IgG4-AILD and diagnosis should rely on the integration of clinical, serological, radiological, and histological findings. In analogy to most IgG4-RD manifestations, and in contrast to its major mimickers, IgG4-AILD promptly responds to glucocorticoids but frequently relapses, thus requiring long-term maintenance therapy to avoid progressive fibrosclerotic disease and liver cirrhosis. Accumulating evidence on the efficacy of B-cell depletion therapy in patients with systemic IgG4-RD is gradually changing the treatment paradigm of IgG4-AILD and biologics will be increasingly used also for gastroenterological manifestations of IgG4-RD to spare glucocorticoids and traditional immunosuppressive agents. Looking ahead, identification of reliable biomarkers and of miniinvasive strategies to obtain informative biopsies from the biliary tree represent unavoidable priorities to optimize diagnosis and management of IgG4-AILD.

Background: The pathogenetic steps leading to Covid-19 interstitial pneumonia remain to be clarified. Most postmortem studies to date reveal diffuse alveolar damage as the most relevant histologic pattern. Antemortem lung biopsy may however provide more precise data regarding the earlier stages of the disease, providing a basis for novel treatment approaches. Objectives: To ascertain the morphological and immunohistochemical features of lung samples obtained in patients with moderate Covid-19 pneumonia. Methods: Transbronchial lung cryobiopsy was carried out in 12 Covid-19 patients within 20 days of symptom onset. Results: Histopathologic changes included spots of patchy acute lung injury with alveolar type II cell hyperplasia, with no evidence of hyaline membranes. Strong nuclear expression of phosphorylated STAT3 was observed in >50% of AECII. Interalveolar capillaries showed enlarged lumen and were in part arranged in superposed rows. Pulmonary venules were characterized by luminal enlargement, thickened walls, and perivascular CD4+ T-cell infiltration. A strong nuclear expression of phosphorylated STAT3, associated with PD-L1 and IDO expression, was observed in endothelial cells of venules and interstitial capillaries. Alveolar spaces macrophages exhibited a peculiar phenotype (CD68, CD11c, CD14, CD205, CD206, CD123/IL3AR, and PD-L1). Conclusions: Morphologically distinct features were identified in early stages of Covid-19 pneumonia, with epithelial and endothelial cell abnormalities different from either classical interstitial lung diseases or diffuse alveolar damage. Alveolar type II cell hyperplasia was a prominent event in the majority of cases. Inflammatory cells expressed peculiar phenotypes. No evidence of hyaline membranes and endothelial changes characterized by IDO expression might in part explain the compliance and the characteristic pulmonary vasoplegia observed in less-advanced Covid-19 pneumonia.

Objectives IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disorder characterized by a dysregulated resolution of inflammation and wound healing response that might develop after an apoptotic insult induced by cytotoxic T lymphocytes (CTLs). Mer receptor tyrosine kinase (MerTK) and its ligand, protein S (ProS1), have a pivotal role in the resolution of inflammation, being implicated in the clearance of apoptotic cells, quenching of the immune response and development of tissue fibrosis. In the present work we aimed to investigate a possible involvement of the MerTK signalling pathway in the pathogenesis of IgG4-RD and development of tissue fibrosis. Methods MerTK and ProS1 expression patterns in IgG4-RD lesions were evaluated by immunohistochemistry and immunofluorescence studies. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were measured in the peripheral blood of IgG4-RD patients and healthy controls by flow cytometry and ELISA, respectively. Results MerTK was highly expressed by macrophages infiltrating IgG4-RD lesions. MerTK+ macrophages were more abundant in IgG4-RD than in Sjögren’s syndrome and interacted with apoptotic cells and ProS1-expressing T and B lymphocytes. Moreover, they expressed the pro-fibrotic cytokine TGF-β and their numbers declined following rituximab-induced disease remission. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were not increased in the peripheral blood of patients with IgG4-RD. Conclusions The MerTK–ProS1 axis is activated in IgG4-RD lesions, possibly leading to persistent stimulation of processes involved in the resolution of inflammation and tissue fibrosis.

Treatment of hepatocellular carcinoma (HCC) is rapidly evolving, with many new therapeutic options, in particular, immunotherapy (IT) is acquiring a major role, even in combination regimens. Despite these promising results, an important limitation is the lack of prognostic and predictive factors that prevent provision of a tool for patient stratification in order to select the most appropriate strategy. Furthermore, response assessment can be challenging with IT due to peculiar patterns such as mixed responses or pseudoprogression. We analyzed biological and clinical features from the first 10 HCC patients treated with nivolumab in our institution. Analysis of patterns of response in CT assessment revealed complete response in pulmonary lesions, along with heterogeneous behavior in the liver and other organ lesions. Peripheral blood mononuclear cells (PBMC) analysis in the first four patients showed unique alterations in a patient with poor prognosis, both at baseline (lower percentage of effector T cells, higher percentage of natural killer T [NK/T] cells) and during treatment with nivolumab (decrease in nonclassical monocytes, increase in monocytic myeloid-derived suppressor cells [MO-MDSC]), suggesting a possible prognostic role for these features. Although obtained in a small cohort of patients, our results open a new perspective for understanding mechanisms underlying IT outcomes in HCC patients.

Neuroendocrine carcinomas of the cervix are very rare, accounting for only 1–2% of all cervical cancers and

Background: The aim of the present study was to analyze the long-term outcomes of laparoscopic and open surgery for intrahepatic cholangiocarcinoma (iCCA) in a series, collected in a tertiary referral center with a high annual volume of laparoscopic activity. Methods: Between January 2004 and June 2020, 446 liver resections (LR) were performed for iCCA: of these, 179 were performed by laparoscopic surgery (LS) and 267 with the open approach. The two groups were matched through a 1:1 propensity score using covariates representative of patient and disease characteristics. The study and control groups were compared, with specific attention given to oncological outcomes (rate of R0, depth of resection margins, overall and disease-free survival, rate, and site of recurrence). Results: The number of retrieved nodes, rate, and depth of negative resection margins were comparable between the two groups. The interval time between surgery and subsequent adjuvant treatments was significantly shorter in LS patients. No differences were shown even in the comparison between the LS and the open group in terms of median disease-free and overall survival. Moreover, the disease recurrence rate was comparable between the LS and the open groups (45.2% versus 56.7%), and the recurrence pattern was similar. Conclusions: The minimally invasive approach for iCCA was once again confirmed to be associated with advantages in terms of intraoperative and short-term outcomes, but was also proven to be oncologically non-inferior to the open counterpart. In the present study, overall and disease-free survival were found to be similar between the two approaches.

the bile duct system and pancreas show many similarities due to their anatomical proximity and common embryological origin. Consequently, preneoplastic and neoplastic lesions of the bile duct and pancreas share analogies in terms of molecular, histological and pathophysiological features. Intraepithelial neoplasms are reported in biliary tract, as biliary intraepithelial neoplasm (BilIN), and in pancreas, as pancreatic intraepithelial neoplasm (PanIN). Both can evolve to invasive carcinomas, respectively cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary neoplasms arise in biliary tract and pancreas. Intraductal papillary neoplasm of the biliary tract (IPNB) share common histologic and phenotypic features such as pancreatobiliary, gastric, intestinal and oncocytic types, and biological behavior with the pancreatic counterpart, the intraductal papillary mucinous neoplasm of the pancreas (IPMN). All these neoplastic lesions exhibit similar immunohistochemical phenotypes, suggesting a common carcinogenic process. Indeed, CCA and PDAC display similar clinic-pathological features as growth pattern, poor response to conventional chemotherapy and radiotherapy and, as a consequence, an unfavorable prognosis. The objective of this review is to discuss similarities and differences between the neoplastic lesions of the pancreas and biliary tract with potential implications on a common origin from similar stem/progenitor cells.

Epithelial to mesenchymal transition has been suggested as a relevant contributor to pulmonary fibrosis, but how and where this complex process is triggered in idiopathic pulmonary fibrosis is not fully understood. Beta-tubulin-III (Tubβ3), ZEB1, and β-catenin are partially under the negative control of miR-200, a family of micro-RNAs playing a major role in epithelial to mesenchymal transition, that are reduced in experimental lung fibrosis and idiopathic pulmonary fibrosis. We wonder whether in situ expression of these proteins is increased in idiopathic pulmonary fibrosis, to better understand the significance of miR-200 feedback loop and epithelial to mesenchymal transition. We investigated the immunohistochemical and immunofluorescent expression and precise location of ZEB1, Tubβ3, and β-catenin in tissue samples from 34 idiopathic pulmonary fibrosis cases and 21 controls (5 normal lungs and 16 other interstitial lung diseases). In 100% idiopathic pulmonary fibrosis samples, the three proteins were concurrently expressed in fibroblastic foci, as well in damaged epithelial cells overlying these lesions and in pericytes within neo-angiogenesis areas. These results were also confirmed by immunofluorescence assay. In controls the abnormal expression of the three proteins was absent or limited. This is the first study that relates concurrent expression of Tubβ3, ZEB1, and β-catenin to abnormal epithelial and myofibroblast differentiation in idiopathic pulmonary fibrosis, providing indirect but robust evidence of miR-200 deregulation and epithelial to mesenchymal transition activation in idiopathic pulmonary fibrosis. The abnormal expression and localization of these proteins in bronchiolar fibro-proliferative lesions are unique for idiopathic pulmonary fibrosis, and might represent a disease-specific marker in challenging lung biopsies.

Context.—Pancreatic endocrine neoplasms (PENs) are diagnostically challenging tumors whose natural history is largely unknown. Histopathology allows the distinction of 2 categories: poorly differentiated high-grade carcinomas and well-differentiated neoplasms. The latter include more than 90% of PENs whose clinical behavior varies from indolent to malignant and cannot be predicted by their morphology.Objectives.—To review the literature and report on additional primary material about the clinicopathologic features, classification, staging, grading, and genetic features of PENs.Data Sources.—Literature review of relevant articles indexed in PubMed (US National Library of Medicine) and primary material from the authors' institution.Conclusions.—The diagnosis of PEN is generally easy, but unusual features may induce misdiagnosis. Immunohistochemistry solves the issue, provided that the possibility of a PEN has been considered. Morphology allows the distinction of poorly differentiated aggressive carcinomas from well-differentiated neoplasms. The World Health Organization classification criteria allow for the discernment of the latter into neoplasms and carcinomas with either benign or uncertain behavior. The recently proposed staging and grading systems hold great promise for permitting a stratification of carcinomas into clinically significant risk categories. To date, inactivation of the MEN1 gene remains the only ascertained genetic event involved in PEN genesis. It is inactivated in roughly one-third of PENs. The degree of genomic instability correlates with the aggressiveness of the neoplasm. Gene silencing by promoter methylation has been advocated, but a formal demonstration of the involvement of specific genes is still lacking. Expression profiling studies are furnishing valuable lists of mRNAs and noncoding RNAs that may advance further the research to discover novel markers and/or therapeutic targets.