Publications by authors named "Luca Mastracci"

123 Publications

Methods for restoration of ki67 antigenicity in aged paraffin tissue blocks.

Histochem Cell Biol 2021 Apr 10. Epub 2021 Apr 10.

Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, IRCCS AOU San Martino IST, Largo Rosanna Benzi, 10, 16132, Genoa, Italy.

Pathology archives are a treasure trove of paraffin embedded tissue spanning many years and covering a wide variety of tissues and diseases. The possibility of using old archival formalin fixed paraffin embedded (FFPE) tissues for diagnostic updates and research projects is a widespread need and it requires archives of stable, well-preserved samples. Immunohistochemistry performed on old archival paraffin blocks may give unreliable results, in particular for some antigens, such as Ki67. In consideration of this phenomenon, our aim is to comprehensively test and identify methods which may be used to obtain Ki67 immunohistochemical reactions of good quality from old archival FFPE blocks. Various methods were tested in order to evaluate their possible efficacy in increasing Ki67 immunointensity in a collection of 40-year-old, archival blocks including re-embedding, with deeper sectioning of tissue from the block and increasing heat-based pretreatment times (20 cases) and re-processing (20 cases). All reactions were performed using an automated immunostainer and Ki67 stained immunosections compared using a visual colour-based scale (the first immunostained section was considered as baseline). The combination of deep sectioning (1000 µM) and prolonged heat-based pretreatment (64 min) markedly increased immunoreactivity for Ki67. Re-embedding and reprocessing did not have a significant effect. Large tissue samples showed heterogeneity of Ki67 immunoexpression between the periphery of the sample and the central area. In conclusion, the study defines a useful protocol to increase antigen retrieval applicable to dated archival tissues.
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http://dx.doi.org/10.1007/s00418-021-01987-wDOI Listing
April 2021

Potential Risks of Plant Constituents in Dietary Supplements: Qualitative and Quantitative Analysis of Seeds.

Molecules 2021 Mar 4;26(5). Epub 2021 Mar 4.

Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy.

The free online trading of herbal mixtures useful for various purposes facilitates the circulation of dangerous herbs or plant parts. This is the case, for example, of the illegal trade in seeds of (), which contain alkaloids capable of inhibiting monoamine oxidase (MAO) and are therefore used in hallucinogenic preparations, such as the psychedelic drink . The precise identification of these seeds and their distinction from other very similar but not dangerous seeds are necessary for forensic purposes and represents an advance in avoiding the adulteration of mixtures. In this work, we show the qualitative identification of seeds by optical and electron microscopy and the parallel development of a real-time qPCR test, which reveals, in a species-specific manner, the presence of DNA up to quantities lower than 1 pg. In addition to the species specificity and high sensitivity, the reaction accurately quantifies the presence of seeds or parts of seeds of in complex herbal mixtures, thus giving an indication of the danger or otherwise of the product.
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http://dx.doi.org/10.3390/molecules26051368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961586PMC
March 2021

Neuroendocrine neoplasms of the appendix, colon and rectum.

Pathologica 2021 Feb;113(1):19-27

Department of Oncology, University of Turin, Orbassano, Turin, Italy.

Neuroendocrine neoplasms of the appendix, colon and rectum are classified according to the most recent WHO classification as neuroendocrine tumors (NET), neuroendocrine carcinomas (NEC) and mixed neuroendocrine-non neuroendocrine neoplasms (MiNENs). NECs and MiNENs are aggressive neoplasms requiring multimodal treatment strategies. By contrast, NETs are, in most cases, indolent lesions occurring as incidental findings in the appendix or as polyps in the rectum. While most appendiceal and rectal NETs are considered relatively non-aggressive neoplasms, a few cases, may show a more aggressive clinical course. Unfortunately, clinical/pathological characteristics to select patients at high risk of recurrence/metastases are poorly consolidated. Diagnosis is generally easy and supported by the combination of morphology and immunohistochemistry. Differential diagnostic problems are for NECs/MiNENs with poorly differentiated adenocarcinomas, when immunohistochemical neuroendocrine markers are not obviously positive, whereas for NETs they are represented by the rare appendiceal tubular and clear cell variants (which may be confused with non-neuroendocrine cancers) and rectal L-cell tumors which may be chromogranin negative and prostatic marker positive.
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http://dx.doi.org/10.32074/1591-951X-230DOI Listing
February 2021

Neuroendocrine neoplasms of the duodenum, ampullary region, jejunum and ileum.

Pathologica 2021 Feb;113(1):12-18

Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy.

Neuroendocrine neoplasms of the small intestine are some of the most frequently occurring along the gastrointestinal tract, even though their incidence is extremely variable according to specific sites. Jejunal-ileal neuroendocrine neoplasms account for about 27% of gastrointestinal NETs making them the second most frequent NET type. The aim of this review is to classify all tumors following the WHO 2019 classification and to describe their pathologic differences and peculiarities.
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http://dx.doi.org/10.32074/1591-951X-228DOI Listing
February 2021

Neuroendocrine neoplasms of the esophagus and stomach.

Pathologica 2021 Feb;113(1):5-11

Institute of Pathology, University Hospital and University of Lausanne, Switzerland.

Esophageal neuroendocrine neoplasms (E-NENs) are much rarer than other gastro-entero-pancreatic neuroendocrine neoplasms, the majority showing aggressive behavior with early dissemination and poor prognosis. Among E-NENs, exceptionally rare well differentiated neuroendocrine tumors (E-NET) and more frequent esophageal poorly differentiated neuroendocrine carcinomas (E-NEC) and mixed neuroendocrine-non neuroendocrine neoplasms (MiNEN) can be recognized. E-NECs usually exhibit a small cell morphology or mixed small and large cells. Esophageal MiNEN are composed of NEC component admixed with adenocarcinoma or squamous cell carcinoma. Gastric (G) NENs encompass a wide spectrum of entities ranging from indolent G-NETs to highly aggressive G-NECs and MiNENs. Among G-NETs, ECL-cell NETs are the most common and, although composed of histamine-producing cells, are a heterogeneous group of neoplastic proliferations showing different clinical and prognostic features depending on the patient's clinico-pathological background including the morphology of the peri-tumoral mucosa, gastrin serum levels, presence or absence of antral G-cell hyperplasia, and presence or absence of MEN1 syndrome. In general, NET associated with hypergastrinemia show a better outcome than NET not associated with hypergastrinemia. G-NECs and MiNENs are aggressive neoplasms more frequently observed in males and associated with a dismal prognosis.
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http://dx.doi.org/10.32074/1591-951X-229DOI Listing
February 2021

Hodgkin Reed-Sternberg-Like Cells in Non-Hodgkin Lymphoma.

Diagnostics (Basel) 2020 Nov 27;10(12). Epub 2020 Nov 27.

Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.

Reed-Sternberg cells (RSCs) are hallmarks of classic Hodgkin lymphoma (cHL). However, cells with a similar morphology and immunophenotype, so-called Reed-Sternberg-like cells (RSLCs), are occasionally seen in both B cell and T cell non-Hodgkin Lymphomas (NHLs). In NHLs, RSLCs are usually present as scattered elements or in small clusters, and the typical background microenviroment of cHL is usually absent. Nevertheless, in NHLs, the phenotype of RSLCs is very similar to typical RSCs, staining positive for CD30 and EBV, and often for B cell lineage markers, and negative for CD45/LCA. Due to different therapeutic approaches and prognostication, it is mandatory to distinguish between cHL and NHLs. Herein, NHL types in which RSLCs can be detected along with clinicopathological correlation are described. Moreover, the main helpful clues in the differential diagnosis with cHL are summarized.
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http://dx.doi.org/10.3390/diagnostics10121019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760963PMC
November 2020

Characterization of soluble PD-L1 in pleural effusions of mesothelioma patients: potential implications in the immune response and prognosis.

J Cancer Res Clin Oncol 2021 Feb 20;147(2):459-468. Epub 2020 Nov 20.

Tumor Epigenetics Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genoa, Italy.

Purpose: Programmed death-ligand 1 (PD-L1) protein plays a central role in the antitumor immune response, and appears to be a predictor of prognosis and efficacy for PD-L1 and programmed death 1 (PD-1) blockade therapy. The immunoregulatory role and prognostic impact of PD-L1 soluble form (sPD-L1) have been investigated in biological fluids of patients with different tumors. In malignant pleural mesothelioma (MPM), circulating sPD-L1 has been recently reported in patients' sera, but no data are available in pleural effusions (PE). In our study, we evaluated the baseline expression levels of sPD-L1 in PE from 84 MPM patients and correlated them with PD-L1-status in matched tumors and patients' overall survival (OS).

Methods: sPD-L1 in PE was determined by ELISA and tumor PD-L1 by immunohistochemistry. Association of sPD-L1 with OS was estimated using the Cox regression model.

Results: We observed that sPD-L1 was variably expressed in all the PE and tended to be higher (by 30%) in patients with PD-L1-positive tumors (cut-off ≥ 1% stained cells) as compared to patients with PD-L1-negative tumors (geometric mean ratio = 1.28, P value = 0.288). sPD-L1 levels were significantly higher than those of sPD-1 (P value = 0.001) regardless of the MPM histotypes and they were positively correlated (r = 0.50, P value < 0.001). Moreover, high PE sPD-L1 concentrations were associated with a trend towards increased OS (hazard ratio 0.79, 95% CL 0.62-1.01, P value = 0.062).

Conclusions: Our study documents the presence of sPD-L1 in PE of MPM patients, and suggests its possible biological and prognostic role in MPM.
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http://dx.doi.org/10.1007/s00432-020-03457-7DOI Listing
February 2021

Current prognostic and predictive biomarkers for gastrointestinal tumors in clinical practice.

Pathologica 2020 Sep;112(3):248-259

Anatomic Pathology, San Martino IRCCS Hospital,, Genova, Italy.

The pathologist emerged in the personalized medicine era as a central actor in the definition of the most adequate diagnostic and therapeutic algorithms. In the last decade, gastrointestinal oncology has seen a significantly increased clinical request for the integration of novel prognostic and predictive biomarkers in histopathological reports. This request couples with the significant contraction of invasive sampling of the disease, thus conferring to the pathologist the role of governor for both proper pathologic characterization and customized processing of the biospecimens. This overview will focus on the most commonly adopted immunohistochemical and molecular biomarkers in the routine clinical characterization of gastrointestinal neoplasms referring to the most recent published recommendations, guidelines and expert opinions.
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http://dx.doi.org/10.32074/1591-951X-158DOI Listing
September 2020

Precancerous lesions of the stomach, gastric cancer and hereditary gastric cancer syndromes.

Pathologica 2020 Sep;112(3):166-185

Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy.

Gastric cancer accounts for about 6% of cancers worldwide, being the fifth most frequently diagnosed malignancy and the third leading cause of cancer related death. Gastric carcinogenesis is a multistep and multifactorial process and is the result of the complex interplay between genetic susceptibility and environmental factors. The identification of predisposing conditions and of precancerous lesions is the basis for screening programs and early stage treatment. Furthermore, although most gastric cancers are sporadic, familial clustering is observed in up to 10% of patients. Among them, hereditary cases, related to known cancer susceptibility syndromes and/or genetic causes are thought to account for 1-3% of all gastric cancers. The pathology report of gastric resections specimens therefore requires a standardized approach as well as in depth knowledge of prognostic and treatment associated factors.
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http://dx.doi.org/10.32074/1591-951X-166DOI Listing
September 2020

Gastritis: update on etiological features and histological practical approach.

Pathologica 2020 Sep;112(3):153-165

Anatomic Pathology, San Martino IRCCS Hospital, Genova, Italy.

Gastric biopsies represent one of the most frequent specimens that the pathologist faces in routine activity. In the last decade or so, the landscape of gastric pathology has been changing with a significant and constant decline of -related pathologies in Western countries coupled with the expansion of iatrogenic lesions due to the use of next-generation drugs in the oncological setting. This overview will focus on the description of the elementary lesions observed in gastric biopsies and on the most recent published recommendations, guidelines and expert opinions.
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http://dx.doi.org/10.32074/1591-951X-163DOI Listing
September 2020

Neoplastic and pre-neoplastic lesions of the oesophagus and gastro-oesophageal junction.

Pathologica 2020 Sep;112(3):138-152

Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy.

Oesophageal and gastro-oesophageal junction (GOJ) neoplasms, and their predisposing conditions, may be encountered by the practicing pathologist both as biopsy samples and as surgical specimens in daily practice. Changes in incidence of oesophageal squamous cell carcinomas (such as a decrease in western countries) and in oesophageal and GOJ adenocarcinomas (such as a sharp increase in western countries) are being reported globally. New modes of treatment have changed our histologic reports as specific aspects must be detailed such as in post endoscopic resections or with regards to post neo-adjuvant therapy tumour regression grades. The main aim of this overview is therefore to provide an up-to-date, easily available and clear diagnostic approach to neoplastic and pre-neoplastic conditions of the oesophagus and GOJ, based on the most recent available guidelines and literature.
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http://dx.doi.org/10.32074/1591-951X-164DOI Listing
September 2020

Non gastro-esophageal reflux disease related esophagitis: an overview with a histologic diagnostic approach.

Pathologica 2020 Sep;112(3):128-137

Anatomic Pathology, San Martino IRCCS Hospital, Genova, Italy.

Several pathological conditions, other than gastro-esophageal reflux disease and its complications, can affect the esophagus. While some of these can present with unspecific lesions (i.e. ulcers and epithelial damage) and require clinico-pathological correlation for diagnosis (i.e. drug-induced esophagitis and corrosive esophagitis) other conditions show distinctive histological lesions which enable the pathologist to reach the diagnosis (i.e. some specific infectious esophagites and Crohn's disease). In this context eosinophilic esophagitis is the condition which has been increasingly studied in the last two decades, while lymphocytic esophagitis, a relatively new entity, still represents an enigma. This overview will focus on and describe histologic lesions which allow pathologists to differentiate between these conditions.
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http://dx.doi.org/10.32074/1591-951X-156DOI Listing
September 2020

Gastro-esophageal reflux disease and Barrett's esophagus: an overview with an histologic diagnostic approach.

Pathologica 2020 Sep;112(3):117-127

Anatomic Pathology, San Martino IRCCS Hospital, Genova, Italy.

The first part of this overview on non-neoplastic esophagus is focused on gastro-esophageal reflux disease (GERD) and Barrett's esophagus. In the last 20 years much has changed in histological approach to biopsies of patients with gastro-esophageal reflux disease. In particular, elementary histologic lesions have been well defined and modality of evaluation and grade are detailed, their sensitivity and specificity has been evaluated and their use has been validated by several authors. Also if there is not a clinical indication to perform biopsies in patient with GERD, the diagnosis of microscopic esophagitis, when biopsies are provided, can be performed by following simple rules for evaluation which allow pathologists to make the diagnosis with confidence. On the other hand, biopsies are required for the diagnosis of Barrett's esophagus. This diagnosis is the synthesis of endoscopic picture (which has to be provided with the proper description on extent and with adequate biopsies number) and histologic pattern. The current guidelines and expert opinions for the correct management of these diagnosis are detailed.
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http://dx.doi.org/10.32074/1591-951X-162DOI Listing
September 2020

The GIPAD handbook of the gastrointestinal pathologist (in the Covid-19 era).

Pathologica 2020 09;112(3):115-116

Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy.

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http://dx.doi.org/10.32074/1591-951X-160DOI Listing
September 2020

Targeted Sequencing of Sorted Esophageal Adenocarcinoma Cells Unveils Known and Novel Mutations in the Separated Subpopulations.

Clin Transl Gastroenterol 2020 09;11(9):e00202

Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.

Introduction: Our study aimed at investigating tumor heterogeneity in esophageal adenocarcinoma (EAC) cells regarding clinical outcomes.

Methods: Thirty-eight surgical EAC cases who underwent gastroesophageal resection with lymph node dissection in 3 university centers were included. Archival material was analyzed via high-throughput cell sorting technology and targeted sequencing of 63 cancer-related genes. Low-pass sequencing and immunohistochemistry (IHC) were used to validate the results.

Results: Thirty-five of 38 EACs carried at least one somatic mutation that was absent in the stromal cells; 73.7%, 10.5%, and 10.5% carried mutations in tumor protein 53, cyclin dependent kinase inhibitor 2A, and SMAD family member 4, respectively. In addition, 2 novel mutations were found for hepatocyte nuclear factor-1 alpha in 2 of 38 cases. Tumor protein 53 gene abnormalities were more informative than p53 IHC. Conversely, loss of SMAD4 was more frequently noted with IHC (53%) and was associated with a higher recurrence rate (P = 0.015). Only through cell sorting we were able to detect the presence of hyperdiploid and pseudodiploid subclones in 7 EACs that exhibited different mutational loads and/or additional copy number amplifications, indicating the high genetic heterogeneity of these cancers.

Discussion: Selective cell sorting allowed the characterization of multiple molecular defects in EAC subclones that were missed in a significant number of cases when whole-tumor samples were analyzed. Therefore, this approach can reveal subtle differences in cancer cell subpopulations. Future studies are required to investigate whether these subclones are responsible for treatment response and disease recurrence.
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http://dx.doi.org/10.14309/ctg.0000000000000202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508445PMC
September 2020

Diagnosis of Hodgkin Lymphoma from Cell Block: A Reliable and Helpful Tool in "Selected" Diagnostic Practice.

Diagnostics (Basel) 2020 Sep 25;10(10). Epub 2020 Sep 25.

Pathology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.

Background: The diagnosis of lymphoma requires surgical specimens to perform morphological evaluation, immunohistochemical and molecular analyses. Ultrasound-guided fine needle aspiration may represent an appropriate first approach to obtain cytological samples in impalpable lesions and/or in patients unsuitable for surgical procedures. Although cytology has intrinsic limitations, the cell block method may increase the possibility of achieving an accurate diagnosis.

Methods: We retrospectively selected a total of 47 ultrasound-guided fine needle aspiration and drainage samples taken from patients with effusion and deep-seated lesions which are clinically suspicious in terms of malignancy.

Results: In 27 cases, both cell block and conventional cytology were performed: 21/27 cell blocks were adequate for the diagnosis of lymphoma and suitable for immunocytochemistry and molecular analyses vs. 12/20 samples to which only conventional cytology was applied. Moreover, in five patients we were able to make a diagnosis of Hodgkin lymphoma with the cell block (CB) technique.

Conclusions: Contrary to conventional cytology, the cell block method may allow immunocytochemistry and molecular studies providing useful information for the diagnosis and subtypization of lymphoma in patients unsuitable for surgical procedure or with deep-seated lesions or extra-nodal diseases; additionally, it is a daily, simple and helpful approach. Moreover, we describe the usefulness of cell blocks in the diagnosis of Hodgkin lymphoma.
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http://dx.doi.org/10.3390/diagnostics10100748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601842PMC
September 2020

Fibrotic progression and radiologic correlation in matched lung samples from COVID-19 post-mortems.

Virchows Arch 2021 Mar 28;478(3):471-485. Epub 2020 Sep 28.

Anatomic Pathology Unit, Department of Surgical Science and Integrated Diagnostics (DISC), University of Genova, Genova, Italy.

Data on the pathology of COVID-19 are scarce; available studies show diffuse alveolar damage; however, there is scarce information on the chronologic evolution of COVID-19 lung lesions. The primary aim of the study is to describe the chronology of lung pathologic changes in COVID-19 by using a post-mortem transbronchial lung cryobiopsy approach. Our secondary aim is to correlate the histologic findings with computed tomography patterns. SARS-CoV-2-positive patients, who died while intubated and mechanically ventilated, were enrolled. The procedure was performed 30 min after death, and all lung lobes sampled. Histopathologic analysis was performed on thirty-nine adequate samples from eight patients: two patients (illness duration < 14 days) showed early/exudative phase diffuse alveolar damage, while the remaining 6 patients (median illness duration-32 days) showed progressive histologic patterns (3 with mid/proliferative phase; 3 with late/fibrotic phase diffuse alveolar damage, one of which with honeycombing). Immunohistochemistry for SARS-CoV-2 nucleocapsid protein was positive predominantly in early-phase lesions. Histologic patterns and tomography categories were correlated: early/exudative phase was associated with ground-glass opacity, mid/proliferative lesions with crazy paving, while late/fibrous phase correlated with the consolidation pattern, more frequently seen in the lower/middle lobes. This study uses an innovative cryobiopsy approach for the post-mortem sampling of lung tissues from COVID-19 patients demonstrating the progression of fibrosis in time and correlation with computed tomography features. These findings may prove to be useful in the correct staging of disease, and this could have implications for treatment and patient follow-up.
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http://dx.doi.org/10.1007/s00428-020-02934-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521863PMC
March 2021

GMP-compliant sponge-like dressing containing MSC lyo-secretome: Proteomic network of healing in a murine wound model.

Eur J Pharm Biopharm 2020 Oct 9;155:37-48. Epub 2020 Aug 9.

University of Pavia, Department of Drug Sciences, Pavia, Italy; PharmaExceed S.r.l., Pavia, Italy.

Chronic wounds account for 3% of total healthcare expenditure of developed countries; thus, innovative therapies, including Mesenchymal Stem Cells (MSCs) end their exosomes are increasingly considered, even if the activity depends on the whole secretome, made of both soluble proteins and extracellular vesicles. In this work, we prove for the first time the in vivo activity of the whole secretome formulated in a sponge-like alginate wound dressing to obtain the controlled release of bioactive substances. The product has been prepared in a public GMP-compliant facility by a scalable process; based on the murine model, treated wounds healed faster than controls without complications or infections. The treatment induced a higher acute inflammatory process in a short time and sustained the proliferative phase by accelerating fibroblast migration, granulation tissue formation, neovascularization and collagen deposition. The efficacy was substantially supported by the agreement between histological and proteomic findings. In addition to functional modules related to proteolysis, complement and coagulation cascades, protein folding and ECM remodeling, in treated skin, emerged the role of specific wound healing related proteins, including Tenascin (Tnc), Decorin (Dcn) and Epidermal growth factor receptor (EGFR). Of note, Decorin and Tenascin were also components of secretome, and network analysis suggests a potential role in regulating EGFR. Although further experiments will be necessary to characterize better the molecular keys induced by treatment, overall, our results confirm the whole secretome efficacy as novel "cell-free therapy". Also, sponge-like topical dressing containing the whole secretome, GMP- compliant and "ready-off-the-shelf", may represent a relevant point to facilitate its translation into the clinic.
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http://dx.doi.org/10.1016/j.ejpb.2020.08.003DOI Listing
October 2020

Histopathological landscape of rare oesophageal neoplasms.

World J Gastroenterol 2020 Jul;26(27):3865-3888

Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University of Padua, Padua 35121, Italy.

The landscape of neoplastic pathology of the oesophagus is dominated by malignancies of epithelial origin, in particular by oesophageal adenocarcinoma and oesophageal squamous cell carcinoma. However, several other histopathological variants can be distinguished, some associated with peculiar histopathological profiles and prognostic behaviours and frequently underrecognized in clinical practice. The aim of this review is to provide a comprehensive characterization of the main morphological and clinical features of these rare variants of oesophageal neoplastic lesions.
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http://dx.doi.org/10.3748/wjg.v26.i27.3865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385561PMC
July 2020

The Pathologic and Molecular Landscape of Esophageal Squamous Cell Carcinogenesis.

Cancers (Basel) 2020 Aug 4;12(8). Epub 2020 Aug 4.

Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy.

Esophageal squamous cell carcinoma represents the most common histotype of epithelial neoplasm occurring within esophageal mucosa worldwide. Despite the comprehensive molecular characterization of this entity, to date no significant targeted therapy has been introduced into clinical practice. In this review, we describe the molecular landscape of esophageal squamous cell carcinoma based on the most recent literature. Moreover, we focus on other rare variants and on the relationship with head and neck squamous cell carcinomas.
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http://dx.doi.org/10.3390/cancers12082160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465394PMC
August 2020

Lung fibrosis: an undervalued finding in COVID-19 pathological series.

Lancet Infect Dis 2021 04 28;21(4):e72. Epub 2020 Jul 28.

Anatomic Pathology Unit, Policlinico San Martino Hospital, Genova, Italy.

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http://dx.doi.org/10.1016/S1473-3099(20)30582-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386839PMC
April 2021

Fasting-mimicking diet and hormone therapy induce breast cancer regression.

Nature 2020 07 15;583(7817):620-624. Epub 2020 Jul 15.

IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.
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http://dx.doi.org/10.1038/s41586-020-2502-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881940PMC
July 2020

Recurrent Leiomyosarcoma of the Small Bowel: A Case Series.

Anticancer Res 2020 Jul;40(7):4199-4204

Department of General Surgery, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, University of Genoa, Genoa, Italy.

Background/aim: Leiomyosarcoma is an extremely rare, small bowel neoplasm (2% of all gastrointestinal tumours). Early diagnosis is challenging due to the slow growth of the cancer. The biological behaviour of this group of tumours is aggressive, and the first-line treatment is surgical resection.

Patients And Methods: This is a report of 4 cases of small bowel leiomyosarcoma that were treated in the last ten years at Hospital San Martino: one involving the jejunum and three involving the ileum (age range=69-86 years). Three patients underwent surgical resection and one was treated with chemotherapy.

Results: All patients who were eligible for surgery underwent radical resection with R0 margins. Mean overall survival was 33 months (range=8-84 months).

Conclusion: Specific guidelines for small bowel leiomyosarcoma do not currently exist and these rare cases should be discussed in a multidisciplinary context. The first treatment approach is surgery, and in some cases, multivisceral resection may be needed to obtain free margins, even in recurrent cases.
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http://dx.doi.org/10.21873/anticanres.14420DOI Listing
July 2020

Circulating exosomal microRNAs as potential biomarkers of hepatic injury and inflammation in a murine model of glycogen storage disease type 1a.

Dis Model Mech 2020 09 18;13(9). Epub 2020 Sep 18.

Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy

Most patients affected by glycogen storage disease type 1a (GSD1a), an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α), develop renal and liver complications, including the development of hepatocellular adenoma/carcinoma. The purpose of this study was to identify potential biomarkers of the pathophysiology of the GSD1a-affected liver. To this end, we used the plasma exosomes of a murine model of GSD1a, the LS- mouse, to uncover the modulation in microRNA expression associated with the disease. The microRNAs differentially expressed between LS- and wild-type mice, LS- mice with hepatocellular adenoma and LS- mice without adenoma, and LS- mice with amyloidosis and LS- mice without amyloidosis were identified. Pathway analysis demonstrated that the target genes of the differentially expressed microRNA were significantly enriched for the insulin signaling pathway, glucose and lipid metabolism, Wnt/β-catenin, telomere maintenance and hepatocellular carcinoma, and chemokine and immune regulation signaling pathways. Although some microRNAs were common to the different pathologic conditions, others were unique to the cancerous or inflammatory status of the animals. Therefore, the altered expression of several microRNAs is correlated with various pathologic liver states and might help to distinguish them during the progression of the disease and the development of late GSD1a-associated complications.
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http://dx.doi.org/10.1242/dmm.043364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520457PMC
September 2020

Erratum: Benelli, R., et al. Aspartate-β-Hydroxylase: A Promising Target to Limit the Local Invasiveness of Colorectal Cancer. , , 971.

Cancers (Basel) 2020 05 13;12(5). Epub 2020 May 13.

SSD Oncologia Molecolare e Angiogenesi, IRCCS Ospedale Policlinico San Martino, largo Rosanna Benzi 10, 16132 Genova, Italy.

The authors wish to make the following corrections to this paper [...].
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http://dx.doi.org/10.3390/cancers12051226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281291PMC
May 2020

Brentuximab-related apoptotic colopathy.

Pathology 2020 06 25;52(4):483-484. Epub 2020 Apr 25.

Anatomic Pathology, Ospedale Policlinico San Martino IRCCS, Genova, Italy; Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Genova, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.pathol.2020.02.011DOI Listing
June 2020

Phenotypic characterization of tumor CTLA-4 expression in melanoma tissues and its possible role in clinical response to Ipilimumab.

Clin Immunol 2020 06 25;215:108428. Epub 2020 Apr 25.

IEO, Division of Medical Oncology for Melanoma, Sarcoma, and Rare Tumors, European Institute of Oncology IRCCS, Milan, Italy.

The expression of the immune checkpoint molecule CTLA-4 has been almost exclusively studied in the T cell lineage, but increasing evidence has shown its expression on tumors with implications for immunotherapy. To date, the degree of expression of CTLA-4 on tumor cells as a predictive biomarker of response to immune checkpoint inhibitors has not been studied. In this report, we analyzed this issue in melanoma patients treated with CTLA-4 inhibitor Ipilimumab (IPI). We show that the level of CTLA-4 expression on melanoma cells is higher than that on tumor infiltrating lymphocytes (TIL) and it is associated with clinical response to IPI therapy supporting the idea of its possible role as a predictive biomarker.
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http://dx.doi.org/10.1016/j.clim.2020.108428DOI Listing
June 2020

Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, and .

Cancers (Basel) 2020 04 19;12(4). Epub 2020 Apr 19.

Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genova, Italy.

The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and better define the role of candidate genes. We characterized 273 and negative probands through a custom-designed targeted gene panel that included and Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes ( and ), including two novel variants in and 4 in . We also found four deleterious and five likely deleterious variants in (3.3%). Thus, including potentially deleterious variants in increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.
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http://dx.doi.org/10.3390/cancers12041007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226507PMC
April 2020

Aspartate-β-Hydroxylase: A Promising Target to Limit the Local Invasiveness of Colorectal Cancer.

Cancers (Basel) 2020 Apr 14;12(4). Epub 2020 Apr 14.

SSD Oncologia Molecolare e Angiogenesi, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy.

Colorectal cancer's (CRC) ability to invade local tissues and lymph nodes and generate distant metastases is the key for TNM classification. Aspartate-β-hydroxylase (ASPH), a transmembrane protein that catalyzes Notch receptors and ligand activation, is involved in tumor invasion. Because Notch is involved in gut homeostasis, it could be a target for CRC therapy. ASPH mRNA and protein expression, promoter methylation and gene copy numbers were evaluated using the TCGA and CPTAC human CRC datasets. Using digital pathology, ASPH was scored in the luminal area (LM), center tumor (CT) and invasive margin (IM) of 100 human CRCs. The effect of ASPH targeting on invasiveness and viability was tested by siRNA knockdown and small molecule inhibitors (SMI). Bioinformatics analysis showed increased expression of ASPH mRNA and protein in CRC, paired with a decreased methylation profile. ASPH genetic gain or amplification was frequent (56%), while deletion was rare (0.03%). Digital pathology analysis showed that ASPH exerted its pathological activity in the invasive margin of the tumor, affecting invasive front morphology, tumor budding and patients' overall survival. In vitro, ASPH targeting by siRNA or SMI reduced cell invasion and growth and caused Notch-1 downregulation. This study demonstrates that ASPH targeting by specific inhibitors could improve CRC treatment strategies.
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http://dx.doi.org/10.3390/cancers12040971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226058PMC
April 2020