Publications by authors named "Matteo Fassan"

356 Publications

Single-cell analyses reveal YAP/TAZ as regulators of stemness and cell plasticity in Glioblastoma.

Nat Cancer 2021 Feb 7;2(2):174-188. Epub 2020 Dec 7.

Department of Molecular Medicine, University of Padua, Padua, Italy.

Glioblastoma (GBM) is a devastating human malignancy. GBM stem-like cells (GSCs) drive tumor initiation and progression. Yet, the molecular determinants defining GSCs in their native state in patients remain poorly understood. Here we used single cell datasets and identified GSCs at the apex of the differentiation hierarchy of GBM. By reconstructing the GSCs' regulatory network, we identified the YAP/TAZ coactivators as master regulators of this cell state, irrespectively of GBM subtypes. YAP/TAZ are required to install GSC properties in primary cells downstream of multiple oncogenic lesions, and required for tumor initiation and maintenance in vivo in different mouse and human GBM models. YAP/TAZ act as main roadblock of GSC differentiation and their inhibition irreversibly lock differentiated GBM cells into a non-tumorigenic state, preventing plasticity and regeneration of GSC-like cells. Thus, GSC identity is linked to a key molecular hub integrating genetics and microenvironmental inputs within the multifaceted biology of GBM.
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http://dx.doi.org/10.1038/s43018-020-00150-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116831PMC
February 2021

Treatment personalization in gastrointestinal neuroendocrine tumors.

Curr Treat Options Oncol 2021 Feb 27;22(4):29. Epub 2021 Feb 27.

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

Opinion Statement: The clinical scenario of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is continuously changing due to significant improvements in the definition of their molecular landscapes and the introduction of innovative therapeutic approaches. Many efforts are currently employed in the integration of the genetics/epigenetics and clinical information. This is leading to an improvement of tumor classification, prognostic stratification and ameliorating the management of patients based on a personalized approach.
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http://dx.doi.org/10.1007/s11864-021-00825-4DOI Listing
February 2021

Synaptophysin expression in mutated advanced colorectal cancers identifies a new subgroup of tumours with worse prognosis.

Eur J Cancer 2021 Feb 16;146:145-154. Epub 2021 Feb 16.

Unit of Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. Electronic address:

Background: Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting.

Methods: We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests.

Results: Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001).

Conclusions: Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.
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http://dx.doi.org/10.1016/j.ejca.2021.01.016DOI Listing
February 2021

RAS as a positive predictive biomarker: focus on lung and colorectal cancer patients.

Eur J Cancer 2021 Feb 12;146:74-83. Epub 2021 Feb 12.

Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy.

Rat sarcoma (RAS) oncogenes have intensively been investigated during the last decades. Taking into account all human tumours, Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene is the most frequently mutated (about 22%) among the three isoforms, followed by Neuroblastoma RAS Viral Oncogene Homolog (NRAS) (8%) and Harvey Rat Sarcoma Viral Oncogene Homolog (HRAS) (3%). In the last years, careful attention has been paid on KRAS and NRAS gene mutations in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC) patients because of their prognostic and predictive roles. In particular, a large body of literature data has been generated investigating clinical outcomes of targeted treatments in NSCLC and CRC KRAS- and NRAS-mutated patients. The latest evidences are here reviewed, providing also an overview of the real-world RAS mutation testing practice across different Italian laboratories. On this basis, we propose a knowledge-based system, www.rasatlas.com, to support the healthcare personnel in the management of patients featuring RAS gene mutations in the landscape of precision oncology.
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http://dx.doi.org/10.1016/j.ejca.2021.01.015DOI Listing
February 2021

Role of next generation sequencing-based liquid biopsy in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: impact of STK11, KRAS and TP53 mutations and co-mutations on outcome.

Transl Lung Cancer Res 2021 Jan;10(1):202-220

Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy.

Background: Characterization of tumor-related genetic alterations is promising for the screening of new predictive markers in non-small cell lung cancer (NSCLC). Aim of the study was to evaluate prognostic and predictive role of most frequent tumor-associated genetic alterations detected in plasma before starting immune checkpoint inhibitors (ICIs).

Methods: Between January 2017 and October 2019, advanced NSCLC patients were prospectively screened with plasma next-generation sequencing (NGS) while included in two trials: VISION (NCT02864992), using Guardant360 test, and MAGIC (Monitoring Advanced NSCLC through plasma Genotyping during Immunotherapy: Clinical feasibility and application), using Myriapod NGS-IL 56G Assay. A control group of patients not receiving ICIs was analyzed.

Results: A total of 103 patients receiving ICIs were analyzed: median overall survival (OS) was 20.8 (95% CI: 16.7-24.9) months and median immune-related progression free disease (irPFS) 4.2 (95% CI: 2.3-6.1) months. TP53 mutations in plasma negatively affected OS both in patients treated with ICIs and in control group (P=0.001 and P=0.009), indicating a prognostic role. STK11 mutated patients (n=9) showed a trend for worse OS only if treated with ICIs. The presence of KRAS/STK11 co-mutation and KRAS/STK11/TP53 co-mutation affected OS only in patients treated with ICIs (HR =10.936, 95% CI: 2.337-51.164, P=0.002; HR =17.609, 95% CI: 3.777-82.089, P<0.001, respectively), indicating a predictive role.

Conclusions: Plasma genotyping demonstrated prognostic value of TP53 mutations and predictive value of KRAS/STK11 and KRAS/STK11/TP53 co-mutations.
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http://dx.doi.org/10.21037/tlcr-20-674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867770PMC
January 2021

miR-24-3p regulates CDX2 during intestinalization of cardiac-type epithelium in a human model of Barrett's esophagus.

Dis Esophagus 2021 Feb 9. Epub 2021 Feb 9.

Gastroesophageal Carcinogenesis Research Group, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.

Background: Cardiac-type epithelium has been proposed as the precursor of intestinal metaplasia in the development of Barrett's esophagus. Dysregulation of microRNAs (miRNAs) and their effects on CDX2 expression may contribute to intestinalization of cardiac-type epithelium. The aim of this study was to examine the possible effect of specific miRNAs on the regulation of CDX2 in a human model of Barrett's esophagus.

Methods: Microdissection of cardiac-type glands was performed in biopsy samples from patients who underwent esophagectomy and developed cardiac-type epithelium in the remnant esophagus. OpenArray™ analysis was used to compare the miRNAs profiling of cardiac-type glands with negative or fully positive CDX2 expression. CDX2 was validated as a miR-24 messenger RNA target by the study of CDX2 expression upon transfection of miRNA mimics and inhibitors in esophageal adenocarcinoma cell lines. The CDX2/miR-24 regulation was finally validated by in situ miRNA/CDX2/MUC2 co-expression analysis in cardiac-type mucosa samples of Barrett's esophagus.

Results: CDX2 positive glands were characterized by a unique miRNA profile with a significant downregulation of miR-24-3p, miR-30a-5p, miR-133a-3p, miR-520e-3p, miR-548a-1, miR-597-5p, miR-625-3p, miR-638, miR-1255b-1, and miR-1260a, as well as upregulation of miR-590-5p. miRNA-24-3p was identified as potential regulator of CDX2 gene expression in three databases and confirmed in esophageal adenocarcinoma cell lines. Furthermore, miR-24-3p expression showed a negative correlation with the expression of CDX2 in cardiac-type mucosa samples with different stages of mucosal intestinalization.

Conclusion: These results showed that miRNA-24-3p regulates CDX2 expression, and the downregulation of miRNA-24-3p was associated with the acquisition of the intestinal phenotype in esophageal cardiac-type epithelium.
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http://dx.doi.org/10.1093/dote/doab005DOI Listing
February 2021

Esophageal squamous cell carcinoma metachronous to head and neck cancers.

Pathol Res Pract 2021 Jan 27;219:153346. Epub 2021 Jan 27.

General Surgery Unit, Azienda Ospedaliera di Padova, Padua, Italy. Electronic address:

Background: In some HNSCC patients, a metachronous ESCC may develop. No information is available on the HNSCC-associated ESCCs microenvironment and etiology.

Methods: Among 134 ESCCs surgically treated between 2009 and 2015, a series of 6 HNSCC-associated ESCCs was collected. A series of 12 sex-, age- and stage-matched ESCCs with no previous oncological medical history was selected for comparison. Histologic assessment of intratumoral inflammatory infiltration and immunohistochemistry for CD4, CD8, CD80, PD1, PD-L1 and p53 were performed. HPV detection/genotyping was assessed by PCR single step and reverse line blot.

Results: HPV DNA was negative in all the HNSCC-associated ESCCs. In comparison to non-HNSCC-associated carcinomas, the 6 cases presented a lower lymphomonocytic infiltration, which also corresponded to a lower prevalence of CD4 + T cell infiltration and, 5/6 cases presented a PD-L1 CPS ≥ 1. All the HNSCC-associated ESCCs resulted positive for p53 immunostaining in ≥50 % of cancer cells.

Conclusion: Our study suggests that HPV infection is not an etiological factor associated to ESCC after HNSCC. On the other hand, p53 overexpression is a common finding. Moreover, our data suggest that an altered immune microenvironment, conditioned by a dysregulation in lymphomonocytic infiltration, may be a crucial factor allowing the occurrence of a metachronous ESCC.
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http://dx.doi.org/10.1016/j.prp.2021.153346DOI Listing
January 2021

Extensive molecular reclassification: new perspectives in small bowel adenocarcinoma?

Med Oncol 2021 Feb 2;38(2):17. Epub 2021 Feb 2.

Department of Medical Oncology, Università Vita-Salute San Raffaele, IRCCS-Ospedale San Raffaele, Via Olgettina 70, 20132, Milan, Italy.

SBA classification is still based on the location of the primary tumor, without genetic information. in the current study, an extensive genetic profile of SBA, was performed in order to identify and quantify targetable alterations for a future precision medicine in SBA. Clinical-pathological information for 24 patients affected by SBA were retrospectively reviewed. Whole genome analysis of the primary tumors was performed by the FOUNDATION Cdx technology. We carried out a functional enrichment analysis of the mutated genes with BioPlanet. Integrative clustering analysis revealed three distinct subtypes characterized by different genomic alterations. Cluster 1exhibited significant correlations with MSI status, high TMB, celiac disease and Jejunual site.We defined cluster 1 as "immunological subtype" (29.2% of patients). Driver mutations in this subtype suggest that 100% of patients may benefit from immunotherapy. Enrichment analysis of cluster 2 highlighted that the main affected pathway was that of homologous DNA pairing and strand exchange (16.7% of patients). We defined this cluster as "DNA Damage Repair (DDR) like". On the basis of these driver molecular alterations, 100% of patients could benefit from PARPi. Finally, Cluster 3 had no significant correlations with clinical-pathological characteristics (54.1% of patients). Enrichment analysis revealed that this cluster has remarkable similarities with CRA genomic profile, so we defined it as "Colon-like". SBA is a genetically distinct tumor entity and deep mutation heterogeneity indicates that different driver genes play a role in the biology of these tumors. The identification of clusters based on genetic profile suggest the possibility to go beyond chemotherapy in several patients.
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http://dx.doi.org/10.1007/s12032-021-01468-zDOI Listing
February 2021

Simple mucinous cyst: another potential cancer precursor in the pancreas? Case report with molecular characterization and systematic review of the literature.

Virchows Arch 2021 Jan 28. Epub 2021 Jan 28.

Clinica Chirurgica 1 - Pancreatic and Endocrine Digestive Surgical Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, via Giustiniani, 2, 35128, Padua, Italy.

Cystic lesions of the pancreas may range from benign to precursors of pancreatic cancer. Simple mucinous cyst (SMC) is larger than 1 cm, has a gastric-type flat mucinous lining, and minimal atypia without ovarian-type stroma. We report a new case of pancreatic SMC, coupling a systematic review of the English literature mainly focused on their clinic-pathological features. We reviewed 103 cases of SMC in adults (73 women), averaging 57 (range, 26-70) years. The SMCs were located in the body-tail region of the pancreas in 60 (58%) cases, presenting as single cystic lesions in 94% of cases; 43% of patients were asymptomatic. A preoperative fine-needle aspiration of the cyst fluid detected amylase and carcinoembryonic antigen positivity in 71% and 76% of cases, respectively. Patients underwent surgery mostly for suspected malignancy; in 83% of cases, a standard pancreatic resection was performed. Mean SMC size was 4.9 (range, 1.5-12.0) cm. Mucins MUC5AC and MUC6 resulted positive in 77% and 81% of cases performed, respectively, whereas MUC2 was negative in all but one patient. The SMC from our institution was characterized by a KRAS somatic mutation. The diagnosis of SMC should be considered when a solitary pancreatic cyst larger than 1 cm is detected in asymptomatic patients. To establish a correct diagnosis, an extensive histologic/immunohistochemical analysis is essential. The presence of a KRAS mutation highlights that SMC may represent another potential pancreatic cancer precursor.
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http://dx.doi.org/10.1007/s00428-021-03029-1DOI Listing
January 2021

The Immunopathological and Histological Landscape of COVID-19-Mediated Lung Injury.

Int J Mol Sci 2021 01 19;22(2). Epub 2021 Jan 19.

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

A complete understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) physiopathology and related histopathologic lesions is necessary to improve treatment and outcome of coronavirus disease 2019 (COVID-19) patients. Many studies have focused on autopsy findings in COVID-19-related deaths to try and define any possible specific pattern. Histopathologic alterations are principally found within lungs and blood vessels, and these abnormalities also seem to have the highest clinical impact. Nevertheless, many of the morphological data collected so far are non-specific, fickle, and possibly associated with other co-existing factors. The aim of this minireview is to describe the main histopathological features related to COVID-19 and the mechanism known as "cytokine storm".
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http://dx.doi.org/10.3390/ijms22020974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835817PMC
January 2021

CKAP2L promotes non-small cell lung cancer progression through regulation of transcription elongation.

Cancer Res 2021 Jan 20. Epub 2021 Jan 20.

Cancer Research UK Manchester Institute, University of Manchester

Chromosomal instability (CIN) is a driver of clonal diversification and intra-tumor heterogeneity, providing genetic diversity that contributes to tumor progression. It is estimated that ∼80% of solid cancers, including non-small cell lung cancer (NSCLC), exhibit features of CIN, which affects tumor growth and response to therapy. However, the molecular mechanisms connecting CIN to tumor progression are still poorly understood. Through an RNAi screen performed on genes involved in CIN and overexpressed in human lung adenocarcinoma samples, we identified the cytoskeleton-associated protein 2-like (CKAP2L) as a potential oncogene that promotes lung cancer proliferation and growth in vitro and in vivo. Mechanistically, CKAP2L directly interacted with RNA Pol II and regulated transcription elongation of key genes involved in spindle assembly checkpoint, chromosome segregation, cell cycle, and E2F signaling. Furthermore, depletion of CKAP2L increased the sensitivity of NSCLC cells to alvocidib, a pan CDK inhibitor, leading to a significant reduction of cell proliferation and an increase in cell death. Altogether, these findings shed light on the molecular mechanisms through which CKAP2L, a protein involved in CIN, promotes cancer progression and suggest that its inhibition represents a novel therapeutic strategy in NSCLC.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1968DOI Listing
January 2021

Triumphs and tribulations of COVID-19 vaccines: Lessons to be learned from smallpox epidemics in the 1700s.

Virchows Arch 2021 Jan 12. Epub 2021 Jan 12.

Department of Molecular Medicine, Microbiology Unit, University of Padua, Padua, Italy.

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http://dx.doi.org/10.1007/s00428-021-03020-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801227PMC
January 2021

Next-Generation Sequencing in Tumor Diagnosis and Treatment.

Diagnostics (Basel) 2020 Nov 17;10(11). Epub 2020 Nov 17.

Department of Public Health, University of Naples Federico II, 80131 Naples, Italy.

Next-Generation Sequencing (NGS) allows for the sequencing of multiple genes at a very high depth of coverage [...].
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http://dx.doi.org/10.3390/diagnostics10110962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698429PMC
November 2020

SRC and PIM1 as potential co-targets to overcome resistance in MET deregulated non-small cell lung cancer.

Transl Lung Cancer Res 2020 Oct;9(5):1810-1821

Pangaea Oncology, Laboratory of Molecular Biology, Coyote Research Group, Quirón-Dexeus University Institute, Barcelona, Spain.

Background: The role of MET alterations in non-small cell lung cancer (NSCLC) is increasing and several targeted agents are under evaluation. MET exon 14 skipping mutations and MET amplifications are associated with potential sensitivity to MET inhibition, though resistance mechanisms are emerging. In MET addicted cells, MET inhibition leads to activation of proviral integration site for Moloney murine leukemia virus-1 (PIM1). PIM1 and proto-oncogene tyrosine-protein kinase Src (SRC) can regulate the expression of receptor tyrosine kinases (RTKs), potentially inducing resistance to MET inhibition through cross-activation.

Methods: We evaluated the activity of class I-II MET inhibitors, the SRC inhibitor dasatinib, and pan-PIM inhibitors in four MET addicted cell lines. We assessed the effect of the dual MET/PIM and MET/SRC inhibition on cell viability and at the protein level. We evaluated RNA expression profiles of the cell lines. Advanced NSCLCs were also screened for MET alterations.

Results: All cell lines were sensitive to class I-II MET inhibitors. All cell lines were resistant to single PIM and SRC inhibition. Dual MET/PIM inhibition was synergistic or additive in MET amplified cell lines and dual MET/SRC inhibition was highly synergistic in all MET addicted cell lines. The addition of an SRC inhibitor partially prevents the RTKs cross-activation. MET alterations were found in 9 out of 97 evaluable samples (9.3%); median overall survival in MET altered patients was 5 months (95% CI, 3 m-NA).

Conclusions: We identified a potential role of PIM inhibition in MET amplified tumors and of SRC inhibition in MET addicted tumors. Potential applications of this new treatment strategy warrant further evaluation.
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http://dx.doi.org/10.21037/tlcr-20-681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653128PMC
October 2020

EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers.

Gut 2020 Nov 16. Epub 2020 Nov 16.

Department of Medicine, Royal Marsden Hospital NHS Trust, London, UK

Objective: Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785).

Design: CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients.

Results: amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from -amplified aGEA.

Conclusion: CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials.
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http://dx.doi.org/10.1136/gutjnl-2020-322658DOI Listing
November 2020

Histology of the spleen in immune thrombocytopenia: clinical-pathological characterization and prognostic implications.

Eur J Haematol 2021 Feb 2;106(2):281-289. Epub 2020 Dec 2.

Surgical Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy.

Objective: Immune thrombocytopenia (ITP) is an acquired disorder, characterized by immune-mediated platelet destruction. The spleen plays a key pathogenic role in ITP and splenectomy is a valuable second-line therapy for this disease. Little is known on ITP spleen histology and response to splenectomy is unpredictable. This study aims to characterize ITP spleen histology and assess possible predictors of splenectomy outcome.

Methods: A series of 23 ITP spleens were retrospectively assessed for the following histological parameters: density of lymphoid follicles (LFs), marginal zones (MZs), T helper and cytotoxic T cells; presence of reactive germinal centers (GCs); width of perivascular T cell sheaths; and red pulp features. Clinical and histological data were matched with postsplenectomy platelet counts to assess their prognostic relevance.

Results: Three histological patterns were documented: a hyperplastic white pulp pattern, a non-activated white pulp pattern (lacking GCs), and a white pulp-depleted pattern. Poor surgical responses were associated with presplenectomy high-dose steroid administration, autoimmune comorbidities and low T follicular helper cell density. The combination of such parameters stratified patients into different splenectomy response groups. The removal of accessory spleens was also associated with better outcome.

Conclusion: ITP spleens are histologically heterogeneous and clinical-pathological parameters may help predict the splenectomy outcome.
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http://dx.doi.org/10.1111/ejh.13547DOI 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

Malignant epithelial/exocrine tumors of the pancreas.

Pathologica 2020 Sep;112(3):210-226

Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.

Pancreatic malignant exocrine tumors represent the most important cause of cancer-related death for pancreatic neoplasms. The most common tumor type in this category is represented by pancreatic ductal adenocarcinoma (PDAC), an ill defined, stroma-rich, scirrhous neoplasm with glandular differentiation. Here we present the relevant characteristics of the most important PDAC variants, namely adenosquamous carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, signet ring carcinoma, medullary carcinoma and hepatoid carcinoma. The other categories of malignant exocrine tumors, characterized by fleshy, stroma-poor, circumscribed neoplasms, include acinar cell carcinoma (pure and mixed), pancreatoblastoma, and solid pseudopapillary neoplasms. The most important macroscopic, histologic, immunohistochemical and molecular hallmarks of all these tumors, highlighting their key diagnostic/pathological features are presented. Lastly, standardized indications regarding gross sampling and how to compile a formal pathology report for pancreatic malignant exocrine tumors will be provided.
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http://dx.doi.org/10.32074/1591-951X-167DOI Listing
September 2020

Inflammatory and tumor-like lesions of the pancreas.

Pathologica 2020 Sep;112(3):197-209

Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.

Inflammatory/tumor-like lesions of the pancreas represent a heterogeneous group of diseases that can variably involve the pancreatic gland determining different signs and symptoms. In the category of inflammatory/tumor-like lesions of the pancreas, the most important entities are represented by chronic pancreatitis, which includes alcoholic, obstructive and hereditary pancreatitis, paraduodenal (groove) pancreatitis, autoimmune pancreatitis, lymphoepithelial cyst, pancreatic hamartoma and intrapancreatic accessory spleen. An in-depth knowledge of such diseases is essential, since they can cause severe morbidity and may represent a potential life-threatening risk for patients. Furthermore, in some cases the differential diagnosis with malignant tumors may be challenging. Herein we provide a general overview of all these categories, with the specific aim of highlighting their most important clinic-pathological hallmarks to be used in routine diagnostic activities and clinical practice.
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http://dx.doi.org/10.32074/1591-951X-168DOI 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

Multi-center real-world comparison of the fully automated Idylla™ microsatellite instability assay with routine molecular methods and immunohistochemistry on formalin-fixed paraffin-embedded tissue of colorectal cancer.

Virchows Arch 2020 Nov 10. Epub 2020 Nov 10.

Departments of Pathology and Molecular Genetics, Hospital U Arnau de Vilanova and Hospital U de Bellvitge, University of Lleida, IRBLLEIDA, IDIBELL, CIBERONC, Av. Alcalde Rovira Roure, 80 25198, Lleida, Spain.

Microsatellite instability (MSI) is present in 15-20% of primary colorectal cancers. MSI status is assessed to detect Lynch syndrome, guide adjuvant chemotherapy, determine prognosis, and use as a companion test for checkpoint blockade inhibitors. Traditionally, MSI status is determined by immunohistochemistry or molecular methods. The Idylla™ MSI Assay is a fully automated molecular method (including automated result interpretation), using seven novel MSI biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2) and not requiring matched normal tissue. In this real-world global study, 44 clinical centers performed Idylla™ testing on a total of 1301 archived colorectal cancer formalin-fixed, paraffin-embedded (FFPE) tissue sections and compared Idylla™ results against available results from routine diagnostic testing in those sites. MSI mutations detected with the Idylla™ MSI Assay were equally distributed over the seven biomarkers, and 84.48% of the MSI-high samples had ≥ 5 mutated biomarkers, while 98.25% of the microsatellite-stable samples had zero mutated biomarkers. The concordance level between the Idylla™ MSI Assay and immunohistochemistry was 96.39% (988/1025); 17/37 discordant samples were found to be concordant when a third method was used. Compared with routine molecular methods, the concordance level was 98.01% (789/805); third-method analysis found concordance for 8/16 discordant samples. The failure rate of the Idylla™ MSI Assay (0.23%; 3/1301) was lower than that of referenced immunohistochemistry (4.37%; 47/1075) or molecular assays (0.86%; 7/812). In conclusion, lower failure rates and high concordance levels were found between the Idylla™ MSI Assay and routine tests.
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http://dx.doi.org/10.1007/s00428-020-02962-xDOI Listing
November 2020

The Tumor Microenvironment of Primitive and Metastatic Breast Cancer: Implications for Novel Therapeutic Strategies.

Int J Mol Sci 2020 Oct 30;21(21). Epub 2020 Oct 30.

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

Breast cancer evolves thanks to a dense and close interaction with the surrounding tumor microenvironment (TME). Fibroblasts, leukocytes, blood and lymphatic endothelial cells and extracellular matrix are the constituents of this entity, and they synergistically play a pivotal role in all of the stages of breast cancer development, from its onset to its metastatic spread. Moreover, it has been widely demonstrated that variations to the TME can correspond to prognosis variations. Breast cancer not only modulates the transformation of the environment within the mammary gland, but the same process is observed in metastases as well. In this minireview, we describe the features of TME within the primitive breast cancer, throughout its evolution and spread into the main metastatic sites.
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http://dx.doi.org/10.3390/ijms21218102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662409PMC
October 2020

Duodenal Histological Findings and Risk of Coeliac Disease in Subjects with Autoimmune Atrophic Gastritis: A Retrospective Evaluation.

Digestion 2020 Oct 19:1-7. Epub 2020 Oct 19.

Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.

Background And Aim: Autoimmune atrophic gastritis (AAG) is characterized by a variable spectrum of gastric and extra-gastric symptoms and has been associated with other autoimmune diseases. It is still unknown whether AAG patients have a higher risk of coeliac disease (CeD) or of any other particular duodenal histological damage. Our study aimed at evaluating the duodenal histological findings and the risk of CeD in patients with AAG, with and without other concurrent autoimmune diseases.

Methods: We retrospectively collected all the histological findings of the adult patients undergoing upper gastrointestinal endoscopy with concurrent duodenal and gastric biopsies at our gastroenterology unit between 2015 and 2018 and who were regularly followed up at our centre. Date of endoscopy evaluation, endoscopy indication, data on previous CeD diagnosis and on other autoimmune-associated diseases, and a description of histological diagnosis were recorded.

Results: Of the 2,423 evaluated endoscopies, 209 patients had an AAG diagnosis (8.6%). One hundred thirty-nine patients, aged 57.4 (standard deviation 13.2) years, were regularly followed up at our centre and were included. Of them, 4 subjects had a previous diagnosis of CeD and one had CeD diagnosis at index endoscopy. Additionally, 8 patients had an isolated increase of intraepithelial lymphocytes (IELs, 6%) and 2 villous atrophy with a normal IEL count. The risk of CeD in AAG was not modulated by the presence of other concurrent autoimmune diseases.

Conclusions: We support the screening of all AAG patients with CeD autoantibodies. Findings of isolated IEL or villous atrophy are not exclusively related to CeD.
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http://dx.doi.org/10.1159/000510354DOI Listing
October 2020

The immune receptor CD300e negatively regulates T cell activation by impairing the STAT1-dependent antigen presentation.

Sci Rep 2020 10 5;10(1):16501. Epub 2020 Oct 5.

Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35131, Padova, Italy.

CD300e is a surface receptor, expressed by myeloid cells, involved in the tuning of immune responses. CD300e engagement was reported to provide the cells with survival signals, to trigger the expression of activation markers and the release of pro-inflammatory cytokines. Hence, CD300e is considered an immune activating receptor. In this study, we demonstrate that the ligation of CD300e in monocytes hampers the expression of the human leukocyte antigen (HLA) class II, affecting its synthesis. This effect, which is associated with the transcription impairment of the signal transducer and activator of transcription 1 (STAT1), overcomes the capacity of interferon gamma (IFN-γ) to promote the expression of the antigen-presenting molecules. Importantly, the decreased expression of HLA-II on the surface of CD300e-activated monocytes negatively impacts their capacity to activate T cells in an antigen-specific manner. Notably, unlike in vitro- differentiated macrophages which do not express CD300e, the immune receptor is expressed by tissue macrophages. Taken together, our findings argue against the possibility that this molecule should be considered an activating immune receptor sensu stricto. Moreover, our results support the notion that CD300e might be a new player in the regulation of the expansion of T cell-mediated responses.
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http://dx.doi.org/10.1038/s41598-020-73552-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536427PMC
October 2020

Histological assessment of gastric pseudopyloric metaplasia: Intra- and inter-observer consistency.

Dig Liver Dis 2021 Jan 28;53(1):61-65. Epub 2020 Sep 28.

Department of Medicine, Michael E. DeBakey VA Medical Center, Baylor College of Medicine Houston, TX, USA.

Background: The histological spectrum of oxyntic mucosal atrophy (a major determinant of gastric cancer risk) includes pseudopyloric metaplasia (PPM), which histological assessment has been regarded as unreliable. PPM consistently expresses Trefoil-Factor 2 (TFF2), which is histochemically detecteble (TFF2-IHC).

Aims: Intra- and inter-observer consistency in assessing PPM was examined using both hematoxylin & eosin (H&E) and TFF2-IHC.

Materials And Methods: Seventy-four oxyntic biopsy samples obtained from autoimmune gastritis were considered. Two serial histological sections obtained from the paraffin-embedded tissue-samples were stained with H&E and TFF2-IHC. Three pathologists (Alpha, Beta, Gamma) independently scored PPM by both staining and the Intra- and inter-observer consistency (H&E versus TFF2-IHC) was calculated using k-statistics and/or Spearman's coefficient.

Results: Based on H&E-stain versus TFF2-IHC, intra-observer consistency in PPM assessement was ranked as consistently "good" (k-values: Alpha=0.79; Beta=0.78; Gamma=0.75). Based on H&E, the overall PPM inter-observer consistency among the 3 observers was ranked as "good" (k=0.77) (the inter-observer consistency for pairs of observers was as follows: Alpha versus Beta k=0.88; Alpha versus Gamma k=0.87; Beta versus Gamma k=0.80). Based on TFF2-IHC, the overall PPM inter-observer agreement was ranked as "excellent" (k=0.91) (the inter-observer consistency for pairs of observers was as follows: Alpha versus Beta k=1; Alpha versus Gamma k=0.91; Beta versus Gamma k=0.91).

Conclusion: Relying on either H&E staining or TFF2-IHC, pathologists assess PPM consistently.
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http://dx.doi.org/10.1016/j.dld.2020.09.003DOI Listing
January 2021