Publications by authors named "Francesco Vasuri"

80 Publications

The power of kindness: curative treatment with metronomic combination in advanced hepatocellular carcinoma.

Anticancer Drugs 2021 Aug 16. Epub 2021 Aug 16.

Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna Pathology Unit Radiology Unit IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

The administration of approved systemic treatments for advanced hepatocellular carcinoma (HCC) is limited to patients with preserved liver function (Child-Pugh A/B7) and performance status. Conversely, metronomic chemotherapy can be safely administered to patients with poor clinical conditions and severe liver impairment. The metronomic schedule demonstrated to exert different anticancer mechanisms compared to that of the same agent administered at its standard schedule, including immune stimulation and the inhibition of angiogenesis and vasculogenesis. Nevertheless, metronomic chemotherapy is a nearly neglected option for the treatment of advanced HCC patients, even among those who cannot afford standard treatments. Herein, we report the case of a 40-year-old patient affected by HBV-HDV-related cirrhosis who was diagnosed with advanced HCC. The severe liver impairment (Child-Pugh B9) did not allow to administer first-line treatment with tyrosine kinase inhibitors so that the patient received metronomic capecitabine as upfront therapy. Due to the suspect of progressive disease at the first radiologic assessment, metronomic cyclophosphamide was added to capecitabine aiming to enhance its efficacy. After 4 months of treatment, complete tumor response, alpha-fetoprotein (AFP) normalization and the recovery of a Child-Pugh A were achieved. The patient was then able to undergo liver transplantation, and, after 18 months from the diagnosis, he is still free of disease recurrence. This experience emphasizes the reliability of metronomic capecitabine as a well-tolerated and effective treatment when patient's conditions prevent the administration of standard first-line treatments. In fact, metronomic capecitabine demonstrated its effectiveness in advanced HCC in retrospective and prospective analyses, leading to median progression-free survival and overall survival of, respectively, 6.03 and 14.47 months in phase II single-arm trial. Moreover, in consideration of the raising interest in immune-checkpoint inhibition in HCC, we believe that the immunomodulating effects of metronomic chemotherapy, either capecitabine or cyclophosphamide, warrant future trials exploring its combination with immunotherapy.
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http://dx.doi.org/10.1097/CAD.0000000000001202DOI Listing
August 2021

Adventitial Microcirculation Is a Major Target of SARS-CoV-2-Mediated Vascular Inflammation.

Biomolecules 2021 07 20;11(7). Epub 2021 Jul 20.

Pathology Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.

We report the case of a 77-year-old woman affected by coronavirus disease-19 (COVID-19) who developed an occlusive arterial disease of the lower limb requiring a left leg amputation. We studied the mechanisms of vascular damage by SARS-CoV-2 by means of a comprehensive multi-technique in situ analysis on the diseased popliteal arterial district, including immunohistochemistry (IHC), transmission electron microscopy (TEM) and miRNA analysis. At histological analyses, we observed a lymphocytic inflammatory infiltrate, oedema and endothelialitis of adventitial vasa vasorum while the media was normal and the intima had only minor changes. The vasa vasorum expressed the ACE2 receptor and factor VIII; compared with the controls, VEGFR2 staining was reduced. TEM analyses showed endothelial injury and numerous Weibel-Palade bodies in the cytoplasm. No coronavirus particle was seen. IL-6 protein and mRNA, together with miR-155-5p and miRs-27a-5p, which can target IL-6, were significantly increased compared with that in the controls. Our case report suggests an involvement of adventitial artery microcirculation by inflammation in the course of COVID-19. Without evident signs of current infection by SARS-CoV-2, endothelial cells show a spectrum of structural and functional alterations that can fuel the cardiovascular complications observed in people infected with SARS-CoV-2.
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http://dx.doi.org/10.3390/biom11071063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301851PMC
July 2021

An unusual cause of diarrhoea: case report and literature review of olmesartan-associated enteropathy.

Eur J Gastroenterol Hepatol 2021 Jul 30. Epub 2021 Jul 30.

Department of Medical and Surgical Sciences Pathology Unit, University of Bologna, Bologna, Italy.

Olmesartan is an angiotensin II receptor blocker, approved in 2002 by the Food and Drug Administration for the treatment of hypertension. During chronic therapy with olmesartan, sprue-like enteropathy can occur, being mainly characterised by non-bloody diarrhoea, weight loss and variable degrees of duodenal mucosal damage, which resolved after withdrawal of olmesartan. We hereby report the case of a 77-year-old, poli-treated male patient with a 3-month history of diarrhoea, vomiting and weight loss, associated with severe intestinal villous atrophy and lymphocytic infiltration of gastric and colonic mucosa. After extensive investigations aimed at excluding other possible causes of chronic diarrhoea, a diagnosis of olmesartan-associated enteropathy was made, which was later confirmed by clinical improvement after the discontinuation of the drug. Repeated endoscopy 8 months later showed complete healing of duodenal mucosa with normal villous architecture. Villous atrophy and lymphocytic infiltration of duodenal mucosa are the most described pathologic finding, but several cases of gastric and colonic involvement have also been reported. We, therefore, reviewed the available literature, focussing on the extent of mucosal damage throughout the whole intestine and on its possible causative factors.
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http://dx.doi.org/10.1097/MEG.0000000000002208DOI Listing
July 2021

MicroRNA profiles of human peripheral arteries and abdominal aorta in normal conditions: MicroRNAs-27a-5p, -139-5p and -155-5p emerge and in atheroma too.

Mech Ageing Dev 2021 Sep 28;198:111547. Epub 2021 Jul 28.

DIMES-Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; Subcellular Nephro-Vascular Diagnostic Program, Pathology Unit, IRCCS, Policlinico S. Orsola Hospital, Bologna, Italy.

Atherosclerosis may starts early in life and each artery has peculiar characteristics likely affecting atherogenesis. The primary objective of the work was to underpin the microRNA (miR)-profiling differences in human normal femoral, abdominal aortic, and carotid arteries. The secondary aim was to investigate if those identified miRs, differently expressed in normal conditions, may also have a role in atherosclerotic arteries at adult ages. MiR-profiles were performed on normal tissues, revealing that aorta and carotid arteries are more similar than femoral arteries. MiRs emerging from profiling comparisons, i.e., miR-155-5p, -27a-5p, and -139-5p, were subjected to validation by RT-qPCR in normal arteries and also in pathological/atheroma counterparts, considering all the available 20 artery specimens. The three miRs were confirmed to be differentially expressed in normal femoral vs aorta/carotid arteries. Differential expression of those miRs was also observed in atherosclerotic arteries, together with some miR-target proteins, such as vimentin, CD44, E-cadherin and an additional marker SLUG. The different expression of miRs and targets/markers suggests that aorta/carotid and femoral arteries differently activate molecular drivers of pathological condition, thus conditioning the morphology of atheroma in adult life and likely suggesting the future use of artery-specific treatment to counteract atherosclerosis.
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http://dx.doi.org/10.1016/j.mad.2021.111547DOI Listing
September 2021

Expression pattern of perilipins in human brain during aging and in Alzheimer's disease.

Neuropathol Appl Neurobiol 2021 Jul 27. Epub 2021 Jul 27.

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.

Aims: Perilipins are conserved proteins that decorate intracellular lipid droplets and are essential for lipid metabolism. To date, there is limited knowledge on their expression in human brain or their involvement in brain aging and neurodegeneration. The aim of this study was to characterise the expression levels of perilipins (Plin1-Plin5) in different cerebral areas from subjects of different age, with or without signs of neurodegeneration.

Methods: We performed real-time RT-PCR, western blotting, immunohistochemistry and confocal microscopy analyses in autoptic brain samples of frontal and temporal cortex, cerebellum and hippocampus from subjects ranging from 33 to 104 years of age, with or without histological signs of neurodegeneration. To test the possible relationship between Plins and inflammation, correlation analysis with IL-6 expression was also performed.

Results: Plin2, Plin3 and Plin5, but not Plin1 and Plin4, are expressed in the considered brain areas with different intensities. Plin2 appears to be expressed more in grey matter, particularly in neurons in all the areas analysed, whereas Plin3 and Plin5 appear to be expressed more in white matter. Plin3 seems to be expressed more in astrocytes. Only Plin2 expression is higher in old subjects and patients with early tauopathy or Alzheimer's disease and is associated with IL-6 expression.

Conclusions: Perilipins are expressed in human brain but only Plin2 appears to be modulated with age and neurodegeneration and linked to an inflammatory state. We propose that the accumulation of lipid droplets decorated with Plin2 occurs during brain aging and that this accumulation may be an early marker and initial step of inflammation and neurodegeneration.
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http://dx.doi.org/10.1111/nan.12756DOI Listing
July 2021

Tissue Ki67 proliferative index expression and pathological changes in hemodialysis arteriovenous fistulae: Preliminary single-center results.

J Vasc Access 2021 Jul 24:11297298211015495. Epub 2021 Jul 24.

Department of Specialty, Diagnostic and Experimental Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Background: Arteriovenous fistula (AVF) for hemodialysis integrates outward remodeling with vessel wall thickening in response to drastic hemodynamic changes. Aim of this study is to determine the role of Ki67, a well-established proliferative marker, related to AVF, and its relationship with time-dependent histological morphologic changes.

Materials And Methods: All patients were enrolled in 1 year and stratified in two groups: (A) pre-dialysis patients submitted to first AVF and (B) patients submitted to revision of AVF. Morphological changes: neo-angiogenesis (NAG), myointimal thickening (MIT), inflammatory infiltrate (IT), and aneurysmatic fistula degeneration (AD). The time of AVF creation was recorded. A biopsy of native vein in Group A and of arterialized vein in Group B was submitted to histological and immunohistochemical (IHC) analysis. IHC for Ki67 was automatically performed in all specimens. Ki67 immunoreactivity was assessed as the mean number of positive cells on several high-power fields, counted in the hot spots.

Results: A total of 138 patients were enrolled, 69 (50.0%) Group A and 69 (50.0%) Group B. No NAG or MIT were found in Group A. Seven (10.1%) Group A veins showed a mild MIT. Analyzing the Group B, a moderate-to-severe MIT was present in 35 (50.7%), IT in 19 (27.5%), NAG in 37 (53.6%); AD was present in 10 (14.5%). All AVF of Group B with the exception of one (1.4%) showed a positivity for Ki67, with a mean of 12.31 ± 13.79 positive cells/hot spot (range 0-65). Ki67-immunoreactive cells had a subendothelial localization in 23 (33.3%) cases, a myointimal localization in SMC in 35 (50.7%) cases. The number of positive cells was significantly correlated with subendothelial localization of Ki67 ( = 0.001) and with NA ( = 0.001).

Conclusions: Native veins do not contain cycling cells. In contrast, vascular cell proliferation starts immediately after AVF creation and persists independently of the time the fistula is set up. The amount of proliferating cells is significantly associated with MIT and subendothelial localization of Ki67-immunoreactive cells, thus suggesting a role of Ki-67 index in predicting AVF failure.
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http://dx.doi.org/10.1177/11297298211015495DOI Listing
July 2021

ETS-Related Gene Expression in Healthy Femoral Arteries With Focal Calcifications.

Front Cell Dev Biol 2021 16;9:623782. Epub 2021 Jun 16.

Experimental, Diagnostic and Specialty Medicine Department (DIMES), University of Bologna, Bologna, Italy.

Bone development-related genes are enriched in healthy femoral arteries, which are more prone to calcification, as documented by the predominance of fibrocalcific plaques at the femoral location. We undertook a prospective histological study on the presence of calcifications in normal femoral arteries collected from donors. Since endothelial-to-mesenchymal transition (EndMT) participates in vascular remodeling, immunohistochemical (IHC) and molecular markers of EndMT and chondro-osteogenic differentiation were assessed. Transmission electron microscopy (TEM) was used to describe calcification at its inception. Two hundred and fourteen femoral arteries were enrolled. The mean age of the donors was 39.9 ± 12.9 years; male gender prevailed (M: 128). Histology showed a normal architecture; calcifications were found in 52 (24.3%) cases, without correlations with cardiovascular risk factors. Calcifications were seen on or just beneath the inner elastic lamina (IEL). At IHC, SLUG was increasingly expressed in the wall of focally calcified femoral arteries (FCFA). ETS-related gene (ERG), SLUG, CD44, and SOX-9 were positive in calcifications. RT-PCR showed increased levels of BPM-2, RUNX-2, alkaline phosphatase, and osteocalcin osteogenic transcripts and increased expression of the chondrogenic marker, SOX-9, in FCFA. TEM documented osteoblast-like cells adjacent to the IEL, releasing calcifying vesicles from the cell membrane. The vesicles were embedded in a proteoglycan-rich matrix and were entrapped in IEL fenestrations. In this study, ERG- and CD44-positive cell populations were found in the context of increased SLUG expression, thus supporting the participation of EndMT in FCFA; the increased transcript expression of osteochondrogenic markers, particularly SOX-9, reinforced the view that EndMT, osteochondrogenesis, and neoangiogenesis interact in the process of arterial calcification. Given its role as a transcription factor in the regulation of endothelial homeostasis, arterial ERG expression can be a clue of endothelial dysregulation and changes in IEL organization which can ultimately hinder calcifying vesicle diffusion through the IEL fenestrae. These results may have a broader implication for understanding arterial calcification within a disease context.
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http://dx.doi.org/10.3389/fcell.2021.623782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242207PMC
June 2021

A practical histological approach to the diagnosis of autoimmune hepatitis: experience of an Italian tertiary referral center.

Virchows Arch 2021 Jun 30. Epub 2021 Jun 30.

Pathology Unit, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, via Albertoni 15, 40138, Bologna, Italy.

Liver biopsy is crucial for the diagnosis of autoimmune hepatitis (AIH), and new reproducible histological criteria would be highly desirable, especially in acute-on-chronic cases. The aims of the present study were (i) to evaluate the AIH histopathological criteria as a function of the time and modality of AIH onset, and (ii) to validate the count of apoptotic bodies in the portal tracts as a histopathological criterion for AIH diagnosis. Sixty-five patients were retrospectively enrolled: 20 underwent biopsy for the first diagnosis and 45 had a previous histological AIH diagnosis. Biopsies were revised, and all histological variables were collected, including the lymphocytic apoptotic bodies in the portal tracts. Clinical and serological data were revised as well. First-diagnosis patients showed a higher grade of inflammation (p = 0.001), but also worse portal fibrosis (p = 0.001). The apoptotic body count was higher in first-diagnosis patients than in follow-up patients (p = 0.002), and it was strongly correlated to inflammation. Using the apoptotic body count among the simplified AIH score variables, the first-biopsy patients in the "definite" category rose from 42 to 68%. Our results confirm the histopathological criteria proposed by the literature and introduce the count of portal apoptotic bodies for the diagnosis of active AIH, especially in first biopsies without other classic features, as well as in AIH diagnostic score, albeit future studies are required to find a definite cutoff.
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http://dx.doi.org/10.1007/s00428-021-03122-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241564PMC
June 2021

MicroRNA expression profiling with a droplet digital PCR assay enables molecular diagnosis and prognosis of cancers of unknown primary.

Mol Oncol 2021 Jun 2. Epub 2021 Jun 2.

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Italy.

Metastasis is responsible for the majority of cancer-related deaths. Particularly, challenging is the management of metastatic cancer of unknown primary site (CUP), whose tissue of origin (TOO) remains undetermined even after extensive investigations and whose therapy is rather unspecific and poorly effective. Molecular approaches to identify the most probable TOO of CUPs can overcome some of these issues. In this study, we applied a predetermined set of 89 microRNAs (miRNAs) to infer the TOO of 53 metastatic cancers of unknown or uncertain origin. The miRNA expression was assessed with droplet digital PCR in 159 samples, including primary tumors from 17 tumor classes (reference set) and metastases of known and unknown origin (test set). We combined two different statistical models for class prediction to obtain the most probable TOOs: the nearest shrunken centroids approach of Prediction Analysis of Microarrays (PAMR) and the least absolute shrinkage and selection operator (LASSO) models. The molecular test was successful for all formalin-fixed paraffin-embedded samples and provided a TOO identification within 1 week from the biopsy procedure. The most frequently predicted origins were gastrointestinal, pancreas, breast, lung, and bile duct. The assay was applied also to multiple metastases from the same CUP, collected from different metastatic sites: The predictions showed a strong agreement, intrinsically validating our assay. The final CUPs' TOO prediction was compared with the clinicopathological hypothesis of primary site. Moreover, a panel of 13 miRNAs proved to have prognostic value and be associated with overall survival in CUP patients. Our study demonstrated that miRNA expression profiling in CUP samples could be employed as diagnostic and prognostic test. Our molecular analysis can be performed on request, concomitantly with standard diagnostic workup and in association with genetic profiling, to offer valuable indications about the possible primary site, thereby supporting treatment decisions.
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http://dx.doi.org/10.1002/1878-0261.13026DOI Listing
June 2021

Gastric Melanoma of Unknown Primary.

J Gastrointestin Liver Dis 2021 Mar 12;30(1):14. Epub 2021 Mar 12.

Azienda Ospedaliero-Universitaria di Bologna, Bologna; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

We describe a case of a patient with anemia referring to our Digestive Endoscopy Unit. Upper GI endoscopy revealed a polypoid lesion with an ulcerated central depression. Histopathological examination of the biopsy specimen taken during endoscopy revealed a gastric metastatic melanoma. The dermatologic inspection failed in finding the primary melanoma. The importance of endoscopic examination in the diagnostic process of metastatic patients with unknown primaries is highlited by this case.
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http://dx.doi.org/10.15403/jgld-3420DOI Listing
March 2021

Involvement of miR-30a-5p and miR-30d in Endothelial to Mesenchymal Transition and Early Osteogenic Commitment under Inflammatory Stress in HUVEC.

Biomolecules 2021 02 5;11(2). Epub 2021 Feb 5.

Laboratory of Clinical Pathology, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), St. Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy.

The endothelial to mesenchymal transition (End-MT) can be associated with vascular calcification, by providing mesengenic progenitors. In this study, we investigated a link between End-MT and the osteogenic process and explored the involvement of miR-30a-5p and miR-30d as potential regulators of these processes. End-MT was induced in Human Umbilical Vein Endothelial Cells (HUVEC) through transforming growth factor-β1 (TGF-β1), TGFβ-3 and tumor necrosis factor-α (TNF-α), for 24 h and 6 days. End-MT mediators, mesenchymal and osteo/chondrogenic markers were analyzed through Real-Time PCR, immunofluorescence, flow cytometry and Western Blot. miR-30a-5p and miR-30d over-expression was carried out in HUVEC to explore their effects on End-MT and osteogenic differentiation. HUVEC at 24 h and 6 days gained mesenchymal morphology markers, including matrix metalloproteinase 9 (MMP-9), SLUG, VIMENTIN and α-smooth muscle actin (α-SMA), and a significant migratory potential, notably with TNF-α. After 6 days, the osteo/chondrogenic markers runt-related transcription factor 2 (RUNX-2) and SRY box transcription factor 9 (SOX-9) were upregulated. At this time point, miR-30a-5p and miR-30d decreased. Over-expression of miR-30a-5p and miR-30d affected End-MT mediators and the osteogenic potency in HUVEC, by reducing SLUG, VIMENTIN and RUNX-2. Our data suggest that End-MT represents a key link between inflammation and vascular calcification. Further, miR-30a-5p and miR-30d can regulate both the End-MT and the osteogenic processes, prompting future studies for exploring their potential use as therapeutic targets or biomarkers in vascular diseases.
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http://dx.doi.org/10.3390/biom11020226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915105PMC
February 2021

Non-Alcoholic Steatohepatitis as a Risk Factor for Intrahepatic Cholangiocarcinoma and Its Prognostic Role.

Cancers (Basel) 2020 Oct 29;12(11). Epub 2020 Oct 29.

Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, 40138 Bologna, Italy.

Non-alcoholic fatty liver disease (NAFLD) and its most aggressive form, non-alcoholic steatohepatitis (NASH), are causing a rise in the prevalence of hepatocellular carcinoma. Data about NAFLD/NASH and intrahepatic cholangiocarcinoma (iCCA) are few and contradictory, coming from population registries that do not correctly distinguish between NAFLD and NASH. We evaluated the prevalence of NAFLD and NASH in peritumoral tissue of resected iCCA ( = 180) and in needle biopsies of matched liver donors. Data of iCCA patients were subsequently analysed to compare NASH-related iCCA (Group A), iCCA arisen in a healthy liver (Group B) or in patients with classical iCCA risk factors (Group C). NASH was found in 22.5% of 129 iCCA patients without known risk factors and in 6.2% of matched controls (risk ratio 3.625, 95% confidence interval 1.723-7.626, < 0.001), while NAFLD was equally represented in both groups. The overall survival of NASH-related iCCA was inferior to that of patients with healthy liver (38.5 vs. 48.1 months, = 0.003) and similar to that of patients with known risk factors (31.9 months, = 0.948), regardless of liver fibrosis. The multivariable Cox regression confirmed NASH as a prognostic factor (hazard ratio 1.773, 95% confidence interval 1.156-2.718, = 0.009). We concluded that NASH (but not NAFLD) is a risk factor for iCCA and might affect its prognosis. Dissecting NASH from NAFLD by histology is necessary to correctly assess the actual role of these conditions. Prevention protocols for NASH patients should also consider the risk for iCCA and not only HCC. Mechanistic studies aimed to find a direct pathogenic link between NASH and iCCA could add further relevant information.
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http://dx.doi.org/10.3390/cancers12113182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692633PMC
October 2020

Standardization of conventional chemoembolization for hepatocellular carcinoma.

Ann Hepatol 2021 May-Jun;22:100278. Epub 2020 Oct 29.

Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy.

Introduction And Objectives: Conventional transarterial chemoembolization (cTACE) has several limitations due to the lack of standardization. The aim of this study was to evaluate the chemical and physical characteristics and behaviors over time of emulsions for cTACE and to assess intra- and inter-operator variabilities in the preparation processes.

Materials And Methods: This in vitro study involved evaluation of emulsions for cTACE prepared using two methods: water-in-oil (WiO) and chemotherapeutic-in-oil (CiO). Three emulsions were prepared with each method and obtained after 20, 50, and 100 pumping exchanges. A drop from each final mixture was analyzed via light microscopy (time 1) and after 5, 10, 15, and 20min since the end of preparation. After 20min, all preparations were re-mixed and new drops were re-evaluated. The intra- and inter-operator variabilities were analyzed.

Results: The mean droplet diameter decreased non-significantly when the number of pumping exchanges increased and increased significantly over time for both WiO and CiO. The droplets returned to their initial diameters after re-mixing. There were no significant differences in the intra- and inter-operator variabilities (P>0.01).

Conclusions: Any interventional radiologist, regardless of their experience, may prepare these emulsions. These data may represent a set of instructions to standardize cTACE.
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http://dx.doi.org/10.1016/j.aohep.2020.10.006DOI Listing
October 2020

Direct Antiviral Treatments for Hepatitis C Virus Have Off-Target Effects of Oncologic Relevance in Hepatocellular Carcinoma.

Cancers (Basel) 2020 Sep 19;12(9). Epub 2020 Sep 19.

Center for Applied Biomedical Research (CRBA), Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.

Background And Aims: HCV eradication by direct-acting antiviral agents (DAAs) reduces de novo hepatocellular carcinoma (HCC) incidence in cirrhosis; however, contrasting evidence about beneficial or detrimental effects still exists in patients who have already developed HCC.

Methods: we investigated whether sofosbuvir and daclatasvir modulate cell proliferation, invasion capability and gene expression (RNA-seq) in HCC-derived cell lines, hypothesizing possible off-target effects of these drugs. Results observed in HCC cell lines were validated in non-HCC cancer-derived cell lines and a preliminary series of human HCC tissues by qPCR and IHC.

Results: DAAs can affect HCC cell proliferation and migration capability by either increasing or reducing them, showing transcriptomic changes consistent with some unexpected drug-associated effects. Off-target gene modulation, mainly affecting ribosomal genes, mitochondrial functions and histones, points to epigenetics and proliferation as relevant events, consistent with matched phenotypic changes. A preliminary validation of in vitro findings was performed in a restricted cohort of HCC patients previously treated with DAAs, with immunohistochemical correlations suggesting DAA-treated HCCs to be more aggressive in terms of migration and epidermal-to-mesenchymal transition.

Conclusions: Our findings suggested the possible occurrence of off-target effects ultimately modulating cell proliferation and/or migration and potentially justified previous findings showing some instances of particularly aggressive HCC recurrence as well as reduced incidence of recurrence of HCC following treatment with DAAs.
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http://dx.doi.org/10.3390/cancers12092674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565876PMC
September 2020

Periostin, tenascin, osteopontin isoforms in long- and non-long survival patients with pancreatic cancer: a pilot study.

Mol Biol Rep 2020 Oct 4;47(10):8235-8241. Epub 2020 Sep 4.

Department of Pharmacy and Biotechnology, Dipartimento di Farmacia e Biotecnologie)-Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Viale Ercolani 4/2, 40139, Bologna, Italy.

Pancreatic adenocarcinoma (PDAC) is the most frequent histological type of malignancy in the pancreas. Extracellular matrix (ECM), plays a critical role during the process of human carcinogenesis and the possible diversity in matricellular proteins composition of ECM may have a significant impact on the clinical course of PDAC. Aim of this paper was to evaluate the expression of three matricellular proteins, including Periostin (POSTN), Tenascin (TNS) and Osteopontin (OPN), in PDAC from long-survival (LS) and non-long survival (NLS) patients. A total of 30 PDAC were analyzed, 15 from patients that survived more than 60 months after surgery (LS) and 15 that died from the disease within 24 (NLS). RNA was extracted and OPN, TNS and POSTN mRNA levels were evaluated by qRT-PCR. LS and NLS samples showed the same type of POSTN and TN isoforms. On the contrary, OPN seems to be preferentially expressed in NLS PDAC. Moreover, OPNb and OPNc isoforms were expressed exclusively in NLS samples. In conclusion, Our data led to hypothesize a possible relationship between the expression of different isoforms of each of these proteins and the clinical outcome of patients with PDAC.
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http://dx.doi.org/10.1007/s11033-020-05763-2DOI Listing
October 2020

Pathological features and outcomes of incidental renal cell carcinoma in candidate solid organ donors.

Kidney Res Clin Pract 2020 Dec;39(4):487-494

Pathology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Background: We report the findings of a single Italian center in the evaluation of renal lesions in deceased donors from 2001 to 2017. In risk evaluation, we applied the current Italian guidelines, which include donors with small (< 4 cm, stage pT1a) renal carcinomas in the category of non-standard donors with a negligible risk of cancer transmission.

Methods: From the revision of our registries, 2,406 donors were considered in the Emilia Romagna region of Italy; organs were accepted from 1,321 individuals for a total of 3,406 organs.

Results: The evaluation of donor safety required frozen section analysis for 51 donors, in which a renal suspicious lesion was detected by ultrasound. Thirty-two primary renal tumors were finally diagnosed: 26 identified by frozen sections and 6 in discarded kidneys. The 32 tumors included 13 clear cell renal cell carcinomas (RCCs), 6 papillary RCCs, 6 angiomyolipomas, 5 oncocytomas, 1 chromophobe RCC, and 1 papillary adenoma. No cases of tumor transmission were recorded in follow-up of the recipients.

Conclusion: Donors with small RCCs can be accepted to increase the donor pool. Collaboration in a multidisciplinary setting is fundamental to accurately evaluate donor candidate risk assessment and to improve standardized protocols for surgeons and pathologists.
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http://dx.doi.org/10.23876/j.krcp.20.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770991PMC
December 2020

Sirolimus-eluting stents: opposite effects on the clonogenic cell potential on a long-term exposure.

Oncotarget 2020 Aug 4;11(31):2973-2981. Epub 2020 Aug 4.

Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Bologna University, Bologna, Italy.

We evaluated the long-term effects of sirolimus on three different cell models, cultured in physiological conditions mimicking sirolimus-eluted stent, in order to clarify the effectiveness of sirolimus in blocking cell proliferation and survival. Three cells lines (WPMY-1 myofibroblasts, HT-29 colorectal adenocarcinoma, and U2OS osteosarcoma) were selected and growth in 10 ml of Minimum Essential Medium for 5 weeks with serial dilutions of sirolimus. The number of colonies and the number of cells per colony were counted. As main result, the number of WPMY-1 surviving colonies increased in a dose-dependent manner when treated with sirolimus ( = 0.0011), while the number of U2OS colonies progressively decreased ( = 0.0011). The clonal capacity of HT-29 was not modified by the exposure to sirolimus ( = 0.6679). In conclusion sirolimus showed the well-known cytostatic effect, but with an effect on clonogenic potential different among the different cell types. In the practice, the plaque typology and composition may influence the response to sirolimus and thus the effectiveness of eluted stent.
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http://dx.doi.org/10.18632/oncotarget.27554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415404PMC
August 2020

The carotid plaque as paradigmatic case of site-specific acceleration of aging process: The microRNAs and the inflammaging contribution.

Ageing Res Rev 2020 08 28;61:101090. Epub 2020 May 28.

DIMES-Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; Interdepartmental Center - Alma Mater Research Institute on Global Challenges and Climate Change - University of Bologna, Bologna, Italy. Electronic address:

Atherosclerosis is considered a chronic inflammatory disease of arteries associated with the aging process. Many risk factors have been identified and they are mainly related to life-styles, gene-environment interactions and socioeconomic status. Carotid and coronary artery diseases are the two major atherosclerotic conditions, being the primary cause of stroke and heart attack, respectively. Nevertheless, carotid plaque assumes particular aspects not only for the specific molecular mechanisms, but also for the types of atheroma which may be associated with a better or a worst prognosis. The identification of circulating blood biomarkers able to distinguish carotid plaque types (stable or vulnerable) is a crucial step for the improvement of adequate therapeutic approaches avoiding or delaying endarterectomy in the oldest old individuals (> 80 years), a population predicted to growth in the next years. The review highlights the most recent knowledge on carotid plaque molecular mechanisms, focusing on microRNAs (miRs), as a site-specific accelerated aging within the conceptual framework of Geroscience for new affordable therapies.
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http://dx.doi.org/10.1016/j.arr.2020.101090DOI Listing
August 2020

Hypothermic Oxygenated New Machine Perfusion System in Liver and Kidney Transplantation of Extended Criteria Donors:First Italian Clinical Trial.

Sci Rep 2020 04 8;10(1):6063. Epub 2020 Apr 8.

Department of Experimental Diagnostic and Specialty Medicine, University of Bologna Sant'Orsola- Malpighi Hospital, Bologna, Italy.

With the aim to explore innovative tools for organ preservation, especially in marginal organs, we hereby describe a clinical trial of ex-vivo hypothermic oxygenated perfusion (HOPE) in the field of liver (LT) and kidney transplantation (KT) from Extended Criteria Donors (ECD) after brain death. A matched-case analysis of donor and recipient variables was developed: 10 HOPE-ECD livers and kidneys (HOPE-L and HOPE-K) were matched 1:3 with livers and kidneys preserved with static cold storage (SCS-L and SCS-K). HOPE and SCS groups resulted with similar basal characteristics, both for recipients and donors. Cumulative liver and kidney graft dysfunction were 10% (HOPE L-K) vs. 31.7%, in SCS group (p = 0.05). Primary non-function was 3.3% for SCS-L vs. 0% for HOPE-L. No primary non-function was reported in HOPE-K and SCS-K. Median peak aspartate aminotransferase within 7-days post-LT was significantly higher in SCS-L when compared to HOPE-L (637 vs.344 U/L, p = 0.007). Graft survival at 1-year post-transplant was 93.3% for SCS-L vs. 100% of HOPE-L and 90% for SCS-K vs. 100% of HOPE-K. Clinical outcomes support our hypothesis of machine perfusion being a safe and effective system to reduce ischemic preservation injuries in KT and in LT.
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http://dx.doi.org/10.1038/s41598-020-62979-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142134PMC
April 2020

Hypothermic Oxygenated Perfusion Versus Static Cold Storage for Expanded Criteria Donors in Liver and Kidney Transplantation: Protocol for a Single-Center Randomized Controlled Trial.

JMIR Res Protoc 2020 Mar 19;9(3):e13922. Epub 2020 Mar 19.

Department of Experimental Diagnostic and Specialty Medicine, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy.

Background: Extended criteria donors (ECD) are widely utilized due to organ shortage, but they may increase the risk of graft dysfunction and poorer outcomes. Hypothermic oxygenated perfusion (HOPE) is a recent organ preservation strategy for marginal kidney and liver grafts, allowing a redirect from anaerobic metabolism to aerobic metabolism under hypothermic conditions and protecting grafts from oxidative species-related damage. These mechanisms may improve graft function and survival.

Objective: With this study, we will evaluate the benefit of end-ischemic HOPE on ECD grafts for livers and kidneys as compared to static cold storage (SCS). The aim of the study is to demonstrate the ability of HOPE to improve graft function and postoperative outcomes of ECD kidney and liver recipients.

Methods: This is an open-label, single-center randomized clinical trial with the aim of comparing HOPE with SCS in ECD kidney and liver transplantation. In the study protocol, which has been approved by the ethics committee, 220 patients (110 liver recipients and 110 kidney recipients) will be enrolled. Livers and kidneys assigned to the HOPE group undergo machine perfusion with cold Belzer solution (4-10°C) and continuous oxygenation (partial pressure of oxygen of 500-600 mm Hg). In the control group, livers and kidneys undergoing SCS are steeped in Celsior solution and stored on ice. Using the same perfusion machine for both liver and kidney grafts, organs are perfused from the start of the back-table procedure until implantation, without increasing the cold ischemia time. For each group, we will evaluate clinical outcomes, graft function tests, histologic findings, perfusate, and the number of allocated organs. Publication of the results is expected to begin in 2021.

Results: Dynamic preservation methods for organs from high-risk donors should improve graft dysfunction after transplantation. To date, we have recruited 108 participants. The study is ongoing, and recruitment of participants will continue until January 2020.

Conclusions: The proposed preservation method should improve ECD graft function and consequently the postoperative patient outcomes.

Trial Registration: ClinicalTrials.gov NCT03837197; https://clinicaltrials.gov/ct2/show/NCT03837197 ; Archived by WebCite® at http://www.webcitation.org/76fSutT3R.

International Registered Report Identifier (irrid): DERR1-10.2196/13922.
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http://dx.doi.org/10.2196/13922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118551PMC
March 2020

Intrahepatocellular crystal storing mimicking a clinical liver disease during monoclonal gammopathy: report of a case and review of the literature.

Ultrastruct Pathol 2020 Jan 10;44(1):153-157. Epub 2020 Feb 10.

Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University, Bologna, Italy.

We present an unusual case of liver involvement in monoclonal gammopathy with generalized crystal-storing histiocytosis (G-CSH).A bone marrow storage disease was diagnosed in a 79-year-old man with monoclonal gammopathy of uncertain significance (MGUS). The patient presented with pleural effusion, an osteolytic lesion of the humerus, and an increase of aspartate transaminase and cholestatic markers that raised the clinical suspect of liver disease. A second bone marrow biopsy confirmed the diagnosis of MGUS with a histiocytic component suggestive for G-CSH.Liver biopsy showed an unremarkable histology, no significant inflammatory infiltrates, and intrasinusoidal foamy histiocytes. PAS and Masson's trichrome stains, showed, in the cytoplasm of both histiocytes and hepatocytes, rod-shaped eosinophilic crystals, which were immunoreactive for kappa light chains. Transmission electron microscopy performed on reprocessed histological sections confirmed the presence of crystals in the hepatocyte cytoplasms. Immunogold labeling intensely stained crystals for kappa light chains.To the best of our knowledge, this is the second case in which an intrahepatocellular crystal storage is described during liver involvement in G-CSH. The present case also suggests that an increase in liver serum enzymes may support the clinical diagnosis of liver CSH in a patient with MGUS.
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http://dx.doi.org/10.1080/01913123.2020.1725697DOI Listing
January 2020

MiR-30e-3p Influences Tumor Phenotype through / Axis and Predicts Sorafenib Resistance in Hepatocellular Carcinoma.

Cancer Res 2020 04 3;80(8):1720-1734. Epub 2020 Feb 3.

Center for Applied Biomedical Research, St.Orsola-Malpighi University Hospital, Bologna, Italy.

The molecular background of hepatocellular carcinoma (HCC) is highly heterogeneous, and biomarkers predicting response to treatments are an unmet clinical need. We investigated miR-30e-3p contribution to HCC phenotype and response to sorafenib, as well as the mutual modulation of pathway, in HCC tissues and preclinical models. MiR-30e-3p was downregulated in human and rat HCCs, and its downregulation associated with mutations. contributed to miR-30e-3p biogenesis, and was identified among its target genes, establishing an miR-30e-3p// feedforward loop and accounting for miR-30e-3p dual role based on status. , , and were demonstrated as miR-30e-3p additional targets mediating its contribution to stemness and malignant features. In a preliminary cohort of patients with HCC treated with sorafenib, increased miR-30e-3p circulating levels predicted the development of resistance. In conclusion, molecular background dictates miR-30e-3p dual behavior in HCC. Mdm2 targeting plays a predominant tumor suppressor function in wild-type contexts, whereas other targets such as , , and gain relevance and mediate miR-30e-3p oncogenic role in nonfunctional backgrounds. Increased circulating levels of miR-30e-3p predict the development of sorafenib resistance in a preliminary series of patients with HCC and deserve future investigations. SIGNIFICANCE: The dual role of miR-30e-3p in HCC clarifies how the molecular context dictates the tumor suppressor or oncogenic function played by miRNAs.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0472DOI Listing
April 2020

Predictors of survival in malignant aortic tumors.

J Vasc Surg 2020 05 17;71(5):1771-1780. Epub 2019 Dec 17.

Vascular Surgery, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Policlinico Sant'Orsola-Malpighi, Bologna, Italy.

Objective: Malignant aortic tumors (MATs) are exceedingly rare, and a comprehensive review of clinical and therapeutic aspects is lacking in the literature. The aim of this study was to analyze all known cases of MATs and to identify predictors of patients' survival.

Methods: All patients diagnosed with an aortic tumor treated in a single center along with all case reports and reviews available in the literature through a specific PubMed search using keywords such as "malignant" and "aorta" or "aortic," "tumor," or "sarcoma" or "angiosarcoma" were analyzed. The tumor's primary location, clinical presentation, histologic subtype, and treatment choice were examined. Survival at 1 year, 3 years, and 5 years and the possible preoperative and operative outcome predictors were evaluated using Kaplan-Meier analysis with a log-rank test and by Cox regression for multivariate analysis.

Results: In addition to the 5 cases treated in our center, 218 other cases of MAT were reported in the literature from 1873 to 2017. The mean age of the patients was 60.1 ± 11.9 years, and the male to female ratio was 1.59:1. The median overall survival from diagnosis was 8 (7-9) months; 1-, 3-, and 5-year survival rates were 26%, 7.6%, and 3.5%, respectively. Chronic hypertension (P = .03), fever (P = .03), back pain (P = .01), asthenia (P = .04), and signs of peripheral embolization (P = .007) were significant predictors of a poor result. Histologic subtypes had a different impact on survival, with no statistical significance. Compared with other treatment strategies, combined surgical-medical therapy had the best impact on the median survival rate (surgical-medical, 12 [8-24] months; medical, 8 [5-10] months; surgical 7 [2-16] months; no treatment, 2 [0.5-15] months; P = .001). Analyzing exclusively medical approaches, chemotherapy and radiotherapy had the best impact on median survival rate compared with untreated patients (chemotherapy-radiotherapy, 18 [10-26] months; radiotherapy, 16 [8-20] months; chemotherapy, 10 [7-24] months; no medical treatment, 6 [2-16] months; P = .005); these data were not sustained by multivariate analysis.

Conclusions: Aortic tumors are a malignant pathologic condition with a short survival rate after initial diagnosis. Survival is further diminished in the presence of clinical factors such as hypertension, fever, back pain, asthenia, and signs of peripheral embolization. Combined surgical and medical treatment, particularly with chemotherapy and radiotherapy, has shown the highest survival rate.
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http://dx.doi.org/10.1016/j.jvs.2019.09.030DOI Listing
May 2020

Pd-ligand 1 is expressed in inflammatory cells but not in neoplastic cells in hepatocellular carcinoma: An immunohistochemical study.

Acta Histochem 2020 Jan 22;122(1):151468. Epub 2019 Nov 22.

Pathology Unit, S.Orsola Malpighi University Hospital, Bologna, Italy. Electronic address:

Nowadays, the major limit to the immunohistochemical (IHC) analysis of tissue PD-L1 is the high variability of the monoclonal antibodies commercially available. Aims of the present paper are to assess the best clone and the most suitable scoring for PD-L1 IHC determination on human hepatocellular carcinoma (HCC) among three commercially available clones, and to evaluate which PD-L1 clone is the best in predicting HCC aggressiveness in vivo. We built a tissue microarray (TMA) with 60 retrospective HCC cases, including the correspondent non-tumoral tissue. IHC was automatically performed using the following anti-PD-L1 clones: 28.8, SP142, and SP263. As results, we did not find any immunoreactivity for PD-L1 in both neoplastic and normal hepatocytes included in the TMA using the three antibodies. Positivity for PD-L1 was exclusively seen in inflammatory cells within the HCC tissue and in cirrhotic parenchyma. When a gold standard was assessed, the sensitivity of SP142, 28.8 and SP263 was 46 %, 54 % and 85 % respectively. Using the SP263 clone, the absolute number of PD-L1-positive inflammatory cells in the HCC cores was paired with the number of PD-L1-positive inflammatory cells in the corresponding non-tumoral tissue (P = 0.001). Finally, using SP263, the mean number of PD-L1-positive cells was 11.3 ± 12.6 in HCC from deceased patients, versus 4.7 ± 5.2 in alive patients (p = 0.039). SP263 is the most sensitive clone for PD-L1 IHC tissue determination in HCC, as well as the best antibody for the assessment of its biological behavior.
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http://dx.doi.org/10.1016/j.acthis.2019.151468DOI Listing
January 2020

Pathobiological and Radiological Approach For Hepatocellular Carcinoma Subclassification.

Sci Rep 2019 10 14;9(1):14749. Epub 2019 Oct 14.

Pathology Unit, S. Orsola University Hospital, Bologna, Italy.

Many advances have been made in the imaging diagnosis and in the histopathological evaluation of HCC. However, the classic imaging and histopathological features of HCC are still inadequate to define patient's prognosis. We aimed to find the link between new proposed morphovascular patterns of hepatocellular carcinoma (HCC) and magnetic resonance imaging (MRI) features to identify pre-operatory markers of biologically aggressive HCC. Thirty-nine liver nodules in 22 patients were consecutively identified. Histopathological analysis and immunohistochemistry for CD34 and Nestin were performed to identify the four different HCC morphovascular patterns. MRI was performed using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid. Three out of four morphovascular HCC patterns showed peculiar MRI features: in particular Pattern D (solid aggressive HCCs with CD34+/Nestin+ new-formed arteries) were isointense on T1-WI in 83% of cases and hyperintense on T2-WI in 50%. Five histologically-diagnosed HCC were diagnosed as non-malignant nodules on MRI due to their early vascularization and low aggressiveness (Pattern A). The comparison between histology and MRI confirms that a subclassification of HCC is possible in a pre-operatory setting. MRI seems to reinforce once more the identity of the different morphovascular HCC patterns and the possibility to pre-operatively identify HCCs with features of biological aggressiveness.
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http://dx.doi.org/10.1038/s41598-019-51303-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791846PMC
October 2019

Different histological types of active intraplaque calcification underlie alternative miRNA-mRNA axes in carotid atherosclerotic disease.

Virchows Arch 2020 Feb 10;476(2):307-316. Epub 2019 Sep 10.

Clinical and Surgical Pathology, Department of Specialty, Diagnostic and Experimental Medicine, S.Orsola-Malpighi Hospital, University of Bologna, via Massarenti 9, 40138, Bologna, Italy.

Arterial calcification is an actively regulated process, with different morphological manifestations. Micro-RNAs emerged as potential regulators of vascular calcification; they may become novel diagnostic tools and be used for a finest staging of the carotid plaque progression. The present study aimed at characterizing the different miRNA-mRNA axes in carotid plaques according to their histological patterns of calcification. Histopathological analysis was performed on 124 retrospective carotid plaques, with clinical data and preoperatory angio-CT. miRNA analysis was carried out with microfluidic cards. Real-time PCR was performed for selected miRNAs validation and for RUNX-2 and SOX-9 mRNA levels. CD31, CD68, SMA, and SOX-9 were analyzed by immunohistochemistry. miRNA levels on HUVEC cells were analyzed for confirming results under in vitro osteogenic conditions. Histopathological analysis revealed two main calcification subtypes of plaques: calcific cores (CC) and protruding nodules (PN). miRNA array and PCR validation of miR-1275, miR-30a-5p, and miR-30d indicated a significant upregulation of miR-30a-5p and miR-30d in the PN plaques. Likewise, the miRNA targets RUNX-2 and SOX-9 resulted poorly expressed in PN plaques. The inverse correlation between miRNA and RUNX-2 levels was confirmed on osteogenic-differentiated HUVEC. miR-30a-5p and miR-30d directly correlated with calcification extension and thickness at angio-CT imaging. Our study demonstrated the presence of two distinct morphological subtypes of calcification in carotid atheromatous plaques, supported by different miRNA signatures, and by different angio-CT features. These results shed the light on the use of miRNA as novel diagnostic markers, suggestive of plaque evolution.
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http://dx.doi.org/10.1007/s00428-019-02659-wDOI Listing
February 2020

Immunomorphology and molecular biology of mixed primary liver cancers: is Nestin a marker of intermediate-cell carcinoma?

Histopathology 2020 Jan 29;76(2):265-274. Epub 2019 Oct 29.

Pathology Unit, S.Orsola Malpighi Hospital, Bologna University, Bologna, Italy.

Aims: Primary mixed liver cancers (PLCs), combined hepatocellular-cholangiocellular (cHCC-CC) and intermediate-cell carcinomas are rare tumours characterised by different molecular mechanisms. Nestin is a marker of progenitor cells with a promising application in human tumours. The aims of the present paper are (i) to determine the expression of Nestin in mixed PLCs; and (ii) to correlate the PLC immunoprofile with the gene expression in each tumour component.

Methods And Results: We selected 28 mixed PLCs, 13 (46.4%) cHCC-CC and 15 (53.6%) intermediate-cell carcinomas. The immunohistochemistry panel consisted of keratin 7, keratin 19, CD56 and Nestin. Next-generation sequencing analysis was performed on 17 cases (27 specimens) using a multi-gene custom panel. The differentiated HCC and CC components of cHCC-CC were negative for Nestin in all cases. The intermediate areas of cHCC-CC were immunoreactive for Nestin in 92.3% of cases, for CD56 in 76.9% and for K7/K19 in all cases. The immunoprofile of the intermediate-cell carcinomas showed 73.3% of cases positive for Nestin and 66.7% for CD56. TP53 and TERT were the most frequently mutated genes (31.3% and 17.6% of samples, respectively). Mutations were also found in IDH1, IDH2, PIK3CA and NRAS genes. Intermediate and HCC areas of cHCC-CC seemed to share the same mutational profile, and both harboured different mutations than the CC component.

Conclusions: According to our preliminary data, Nestin was not expressed by hepatocellular or cholangiocellular-cell components, but was expressed by most of the intermediate cells in PLCs, and therefore could be considered in the differential diagnosis of PLCs, together with mutational profile.
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http://dx.doi.org/10.1111/his.13966DOI Listing
January 2020

Histological Evidence of Diabetic Kidney Disease Precede Clinical Diagnosis.

Am J Nephrol 2019 5;50(1):29-36. Epub 2019 Jun 5.

Department of Experimental, Diagnostic and Specialty Medicine, Nephrology, Dialysis and Renal Transplant Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy,

Background: In the absence of a histological diagnosis, persistent albuminuria is globally accepted as the main diagnostic criteria for diabetic kidney disease (DKD).

Methods: In the present retrospective study, we evaluated data from an Italian cohort of 42 deceased diabetic donors (mainly with type 2 diabetes). Using the kidney biopsies obtained at the time of donation to evaluate single or double allocation based on Karpinski score, we determined the prevalence of histological lesions attributable to diabetes.

Results: All 42 donors presented with proteinuria in the normal range and an estimated glomerular filtration rate (eGFR) (chronic kidney disease [CKD]-EPI) >60 mL/min/1.73 m2. A kidney biopsy was available for 36 patients; of these, one was not interpretable and 32 showed histopathological lesions consistent with DKD and encompassing all histological classes. Thus, we found a relatively high proportion of histologically proven DKD that had been clinically undiagnosed, as none of the patient had significant proteinuria and eGFR <60 mL/min/1.73 m2.

Conclusions: The data we present here support the need to implement routine kidney biopsies in normoalbuminuric diabetic subjects in the early stages of CKD. Such strategy may help to improve risk stratification in diabetic patients and guide therapeutic decisions during the early stages of the disease.
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http://dx.doi.org/10.1159/000500353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691362PMC
August 2020
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