Publications by authors named "Alessandro Mangogna"

41 Publications

Prognostic features of gastro-entero-pancreatic neuroendocrine neoplasms in primary and metastatic sites: Grade, mesenteric tumour deposits and emerging novelties.

J Neuroendocrinol 2021 Jun 17:e13000. Epub 2021 Jun 17.

1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Updates in classification of gastro-entero-pancreatic neuroendocrine neoplasms better reflect the biological characteristics of these tumours. In the present study, we analysed the characteristics of neuroendocrine tumours that could aid in a more precise stratification of risk groups. In addition, we have highlighted the importance of grade (re)assessment based on investigation of secondary tumour lesions. Two hundred and sixty-four cases of neuroendocrine tumours of gastro-entero-pancreatic origin from three centres were included in the study. Tumour morphology, mitotic count and Ki67 labelling index were evaluated in specimens of primary tumours, lymph node metastases and distant metastases. These variables were correlated with overall survival (OS) and relapse-free survival (RFS). Tumour stage, number of affected lymph nodes, presence of tumour deposits and synchronous/metachronous metastases were tested as possible prognostic features. Mitotic count, Ki-67 labelling index, primary tumour site, tumour stage, presence of tumour deposits and two or more affected lymph nodes were significant predictors of OS and RFS. At the same time, mitotic count and Ki-67 labelling index can be addressed as continuous variables determining prognosis. We observed a very high correlation between the measures of proliferative activity in primary and secondary tumour foci. The presence of isolated tumour deposits was identified as an important determinant of both RFS and OS for pancreatic (hazard ratio [HR] = 7.61, 95% confidence interval [CI] = 3.96-14.6, P < 0.0001 for RFS; HR = 3.28, 95% CI = 1.56-6.87, P = 0.0017 for OS) and ileal/jejunal neuroendocrine tumours (HR = 1.98, 95% CI = 1.25-3.13, P = 0.0036 for RFS and HR 2.59, 95% CI = 1.27-5.26, P = 0.009 for OS). The present study identifies the presence of mesenterial tumour deposits as an important prognostic factor for gastro-entero-pancreatic neuroendocrine tumours, provides evidence that proliferative parameters need to be treated as continuous variables and further supports the importance of grade determination in all available tumour foci.
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http://dx.doi.org/10.1111/jne.13000DOI Listing
June 2021

COVID-19 Pandemic: Huge Stress Test for Health System Could Be a Great Opportunity to Update the Workflow in a Modern Surgical Pathology.

Cancers (Basel) 2021 Jun 30;13(13). Epub 2021 Jun 30.

First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori Milano, 20133 Milan, Italy.

Background: On December 2019, an outbreak of atypical pneumonia, known as COVID-19, was identified in Wuhan, China. This disease, characterized by the rapid human-to-human transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly in more than 200 countries. Northern Italy's regions have been hit hard in terms of deaths. Here, we report the experience of the Pathology Department of the Fondazione IRCCS Istituto Nazionale Tumori (INT) in Milan, the first Italian public cancer center, in the period of the lockdown that took place in Lombardy from March to May 2020.

Method: The variation in terms of exams was calculated in two different timeframes: December 2019-February 2020 (pre-COVID-19) and March-May 2020 (COVID-19). During these periods, Turn-Around-Time (TAT) metrics released by the Lombardy Region were calculated to assess if changes applied to guarantee the safeguarding of workers affected the average diagnosis time.

Results: In the COVID-19 period, there was a decrease for all the performed exams. The most considerable decrease was observed for PAP tests (-81.6%), followed by biopsies (-48.8%), second opinions (-41.7%), and surgical (-31.5%), molecular (-29.4%) and cytological (-18.1%) tests. Measures applied within the Pathology Department, such as digital pathology, remote working, rotations and changes in operating procedures, improved the diagnostic performance as required by the guidelines of the Lombardy Region in terms of TAT. At the same time, the measures applied for the safeguarding of the personnel turned out to be feasible and did not affect the overall performance of the Pathology Department.

Conclusions: The sharp slowdown in cancer screening during the first wave of COVID-19 could seriously endanger cancer prevention in the near future.
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http://dx.doi.org/10.3390/cancers13133283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268969PMC
June 2021

Constitutive PSGL-1 Correlates with CD30 and TCR Pathways and Represents a Potential Target for Immunotherapy in Anaplastic Large T-Cell Lymphoma.

Cancers (Basel) 2021 Jun 12;13(12). Epub 2021 Jun 12.

Institute for Maternal and Child Health, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) "Burlo Garofolo", 34137 Trieste, Italy.

Due to the high expression of P-selectin glycoprotein ligand-1 (PSGL-1) in lymphoproliferative disorders and in multiple myeloma, it has been considered as a potential target for humoral immunotherapy, as well as an immune checkpoint inhibitor in T-cells. By investigating the expression of in 678 T- and B-cell samples by gene expression profiling (GEP), further supported by tissue microarray and immunohistochemical analysis, we identified anaplastic large T-cell lymphoma (ALCL) as constitutively expressing SELPLG at high levels. Moreover, GEP analysis in CD30+ ALCLs highlighted a positive correlation of with (CD30-coding gene) and T-cell receptor (TCR)-signaling genes ( and ), suggesting that the common dysregulation of TCR expression in ALCLs may be bypassed by the involvement of PSGL-1 in T-cell activation and survival. Finally, we evaluated the effects elicited by in vitro treatment with two anti-PSGL-1 antibodies (KPL-1 and TB5) on the activation of the complement system and induction of apoptosis in human ALCL cell lines. In conclusion, our data demonstrated that PSGL-1 is specifically enriched in ALCLs, altering cell motility and viability due to its involvement in CD30 and TCR signaling, and it might be considered as a promising candidate for novel immunotherapeutic approaches in ALCLs.
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http://dx.doi.org/10.3390/cancers13122958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231564PMC
June 2021

Cytoproliferative activity in colorectal poorly differentiated clusters: Biological significance in tumor setting.

Ann Diagn Pathol 2021 Aug 16;53:151772. Epub 2021 Jun 16.

Department of Medical and Surgical Sciences for Children & Adults, Division of Pathology, University-Hospital of Modena and Reggio Emilia, Modena, Italy.

Background: Poorly differentiated clusters (PDCs) have gained a significant prognostic role in colorectal carcinomas (CRCs) being associated to high risk of lymph node metastasis, shorter survival time and poor prognosis. The knowledge in PDC biology is not completely clear.

Materials And Methods: We assessed Ki-67 LI in 45 CRCs showing ≥10 PDCs. We distinguished PDCs at the periphery of the tumor masses (pPDCs) from those within the tumor masses (cPDCs). We chose 3 cut-offs of Ki-67 labeling index (Ki-67 LI): <10%, 10-50%, and >50% of the labeled cells.

Results: Ki-67 LI in pPDCs was<10% in 37 cases (82%), 10-50% in 6 cases (13%) and >50%in 2 cases (5%); Ki-67 LI in cPDCs was<10% in 4 cases (23.5%), 10-50% in 4 (23.5%) and >50% in 9 (54%). Ki-67 LI in tumor budding foci (TBs) was <10% in 8 cases (32%), 10-50% in 8 (32%) and >50% in 9 (36%). The difference of Ki-67 LI reaches the statistical significance (p < 0.005). Ki-67 LI <10% in the pPDCs was associated with nodal metastases (pN+) (p < 0.0001), pTNM stage III and IV(p < 0.0001) and TB (p < 0.001). Ki-67 LI > 50% in cPDC was significantly associated withpT3-pT4 and advanced pTNM stages (p < 0.0001), N+ (p = 0.0001) and LVI (p < 0.05).

Conclusion: Different Ki-67 LI detected between cPDCs and pPDCs suggesting a biological difference in PDCs. An actively proliferating central tumor areas can be distinguished from the peripheral portion of the tumors in which the cells interact with the stroma acquiring invasive and metastatic potential.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151772DOI Listing
August 2021

The Ferroxidase Hephaestin in Lung Cancer: Pathological Significance and Prognostic Value.

Front Oncol 2021 19;11:638856. Epub 2021 May 19.

Department of Life Sciences, University of Trieste, Trieste, Italy.

Hephaestin (HEPH) belongs to a group of exocytoplasmic ferroxidases which contribute to cellular iron homeostasis by favouring its export. Down-regulation of HEPH expression, possibly by stimulating cell proliferation due to an increase in iron availability, has shown to correlate with poor survival in breast cancer. The lung is particularly sensitive to iron-induced oxidative stress, given the high oxygen tension present, however, HEPH distribution in lung cancer and its influence on prognosis have not been investigated yet. In this study we explored the prognostic value of HEPH and its expression pattern in the most prevalent histotypes of lung cancers, namely lung adenocarcinoma and lung squamous cell carcinoma. analyses, based on UALCAN, Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier plotter bioinformatics, revealed a significant correlation between higher levels of HEPH expression and favorable prognosis, in both cancer histotypes. Moreover, TIMER web platform showed a statistically significant association between HEPH expression and cell elements belonging to the tumor microenvironment identified as endothelial cells and a subpopulation of cancer-associated fibroblasts, further confirmed by double immunohistochemical labeling with cell type specific markers. Taken together, these data shed a light on the complex mechanisms of local iron handling lung cancer can exploit to support tumorigenesis.
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http://dx.doi.org/10.3389/fonc.2021.638856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170403PMC
May 2021

Myeloid and T-Cell Microenvironment Immune Features Identify Two Prognostic Sub-Groups in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms.

J Clin Med 2021 Apr 17;10(8). Epub 2021 Apr 17.

1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.

High-grade Gastroenteropancreatic Neuroendocrine neoplasms (H-NENs) comprehend well-differentiated tumors (NET G3) and poorly differentiated carcinomas (NEC) with proliferative activity indexes as mitotic count (MC) >20 mitoses/10 HPF and Ki-67 >20%. At present, no specific therapy for H-NENs exists and the several evidences of microenvironment involvement in their pathogenesis pave the way for tailored therapies. Forty-five consecutive cases, with available information about T-cell, immune, and non-immune markers, from surgical pathology and clinical databases of 2 Italian institutions were immunostained for Arginase, CD33, CD163 and CD66 myeloid markers. The association between features was assessed by Spearman's correlation coefficient. A unsupervised K-means algorithm was used to identify clusters of patients according to inputs of microenvironment features and the relationship between clusters and clinicopathological features, including cancer-specific survival (CSS), was analyzed. The H-NEN population was composed of 6 (13.3%) NET G3 and 39 (86.7%) NEC. Overall, significant positive associations were found between myeloid (CD33, CD163 and Arginase) and T/immune markers (CD3, CD4, CD8, PD-1 and HLA-I). Myeloid and T-cell markers CD3 and CD8 identified two clusters of patients from unsupervised K-means analysis. Cases grouped in cluster 1 with more myeloid infiltrates, T cell, HLA and expression of inhibitory receptors and ligands in the stroma (PD-1, PD-L1) had significantly better CSS than patients in cluster 2. Multivariable analysis showed that Ki-67 (>55 vs. <55, HR 8.60, CI 95% 2.61-28.33, < 0.0001) and cluster (1 vs. 2, HR 0.43, CI 95% 0.20-0.93, = 0.03) were significantly associated with survival. High grade gastroenteropancreatic neuroendocrine neoplasms can be further classified into two prognostic sub-populations of tumors driven by different tumor microenvironments and immune features able to generate the framework for evaluating new therapeutic strategies.
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http://dx.doi.org/10.3390/jcm10081741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072982PMC
April 2021

CD133 Expression in Placenta Chorioangioma Presenting as a Giant Asymptomatic Mass.

Medicina (Kaunas) 2021 Feb 11;57(2). Epub 2021 Feb 11.

Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, 41125 Modena, Italy.

: Placental chorioangioma is the most common benign non-trophoblastic neoplasm of the placenta. Its clinical relevance lies in the size of the tumor since larger masses cause pregnancy complications, including an unfavorable neonatal outcome. We report the case of a 34-year-old second gravida and nullipara at the 35th week of gestation, admitted to the gynecological department for antibiotic-resistant fever. The cardiotocography performed during hospitalization showed an abnormal fetal pattern. A 2250 g newborn was delivered by cesarean section. No complications were observed during childbirth and postpartum was insignificant. On gross inspection a white fleshy intraparenchymal mass blooming on the maternal surface was noted; routinely stained sections revealed features consistent with chorioangioma with vascular channels lined by inconspicuous endothelial cells immunoreactive for CD31 and CD133. Focal expression of CD133 was also observed in placental villi. CD133 expression indicated the presence of stem cells in chorioangioma, suggesting their possible role in the development of mesenchymal lesions including chorioangioma.
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http://dx.doi.org/10.3390/medicina57020162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917587PMC
February 2021

Prognostic Value of Complement Properdin in Cancer.

Front Immunol 2020 19;11:614980. Epub 2021 Jan 19.

Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, United Kingdom.

The complement system is readily triggered by the presence of damage-associated molecular patterns on the surface of tumor cells. The complement alternative pathway provides rapid amplification of the molecular stress signal, leading to complement cascade activation to deal with pathogens or malignant cells. Properdin is the only known positive regulator of the alternative pathway. In addition, properdin promotes the phagocytic uptake of apoptotic T cells by macrophages and dendritic cells without activating the complement system, thus, establishing its ability to recognize "altered-self". Dysregulation of properdin has been implicated in substantial tissue damage in the host, and in some cases, chronic unresolved inflammation. A corollary of this may be the development of cancer. Hence, to establish a correlation between properdin presence/levels in normal and cancer tissues, we performed bioinformatics analysis, using Oncomine and UALCAN. Survival analyses were performed using UALCAN and PROGgeneV2 to assess if properdin can serve as a potential prognostic marker for human lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), cervical squamous cell carcinoma (CESC), and pancreatic adenocarcinoma (PAAD). We also analyzed levels of tumor-infiltrating immune cells using TIMER, a tool for characterizing immune cell composition in cancers. We found that in LUAD and LIHC, there was a lower expression of properdin in the tumors compared to normal tissues, while no significant difference was observed in CESC and PAAD. Survival analysis demonstrated a positive association between properdin mRNA expression and overall survival in all 4 types of cancers. TIMER analysis revealed that properdin expression correlated negatively with tumor purity and positively with levels of infiltrating B cells, cytotoxic CD8 T cells, CD4 helper T cells, macrophages, neutrophils and dendritic cells in LUAD, CESC and PAAD, and with levels of B cells, CD8 T cells and dendritic cells in LIHC. Immunohistochemical analysis revealed that infiltrating immune cells were the most likely source of properdin in the tumor microenvironment. Thus, complement protein properdin shows promise as a prognostic marker in cancer and warrants further study.
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http://dx.doi.org/10.3389/fimmu.2020.614980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851055PMC
June 2021

Immunological Basis of the Endometriosis: The Complement System as a Potential Therapeutic Target.

Front Immunol 2020 11;11:599117. Epub 2021 Jan 11.

Department of Life Sciences, University of Trieste, Trieste, Italy.

Endometriosis (EM) is a chronic disease characterized by the presence and proliferation of functional endometrial glands and stroma outside the uterine cavity. Ovaries and pelvic peritoneum are the most common locations for endometrial ectopic tissue, followed by deep infiltrating EM sites. The cyclic and recurrent bleeding, the progressive fibrosis and the peritoneal adhesions of ectopic endometrial glands, may cause different symptoms depending on the origin involved. EM is a frequent clinical condition affecting around 10% of women of mainly reproductive age, as well as in post-menopausal women and adolescents, especially with uterine anomalies. The risk of developing EM depends on a complex interaction between genetic, immunological, hormonal, and environmental factors. It is largely considered to arise due to a dysfunction of immunological surveillance. In fact, women with EM exhibit altered functions of peritoneal macrophages, lymphocytes and natural killer cells, as well as levels of inflammatory mediators and growth factors in the peritoneal fluid. In EM patients, peritoneal macrophages are preponderant and highly active compared to healthy women. Peritoneal macrophages are able to regulate the events that determine the production of cytokines, prostaglandins, growth factors and complement components. Several studies have shown alteration in the regulation of the complement activation, leading to chronic inflammation characteristic of EM. Aberrant regulation/activation of the complement system has been observed in the peritoneal cavity of women affected by EM. Thus, complement inhibition may represent a new approach for the treatment of EM, given that a number of complement inhibitors are under pre-clinical and clinical development. Such an intervention may provide a broader therapeutic control of complement-mediated inflammatory damage in EM patients. This review will focus on our current understanding of the role of complement activation in EM and possible modalities available for complement-based therapy.
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http://dx.doi.org/10.3389/fimmu.2020.599117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829336PMC
June 2021

C1q-HA Matrix Regulates the Local Synthesis of Hyaluronan in Malignant Pleural Mesothelioma by Modulating HAS3 Expression.

Cancers (Basel) 2021 Jan 22;13(3). Epub 2021 Jan 22.

Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.

Increased hyaluronic acid (HA) production is often associated with cancer progression. In malignant pleural mesothelioma (MPM), HA is found at elevated levels in pleural effusions and sera of patients, and it has been widely debated whether MPM cells are able to produce HA by themselves or through the release of growth factors stimulating other cells. Another key component of the MPM microenvironment is C1q, which can act as a pro-tumorigenic factor favoring cell adhesion, migration and proliferation. The aim of the current study was to prove that MPM primary cells are able to synthesize HA and to inquire the stimulus given by C1q-HA matrix to HA synthesis. We confirmed the presence of a HA coat and cable-like structures around MPM primary cells, as well as an intracellular pool, mainly localized in the cytoplasmic and perinuclear region. After evaluating HA synthase (HAS) enzymes' basal expression in MPM primary cells, we found that C1q bound to HA was able to impinge upon HA homeostasis by upregulating HAS3 both at the mRNA and the protein levels. High expression of has been correlated with a shorter life expectancy in MPM by bioinformatical analysis. These data confirmed that C1q bound to HA may exert pro-tumorigenic activity and identified HAS3 as a potential target in MPM.
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http://dx.doi.org/10.3390/cancers13030416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865933PMC
January 2021

Urinary proteomic profiles of prostate cancer with different risk of progression and correlation with histopathological features.

Ann Diagn Pathol 2021 Apr 8;51:151704. Epub 2021 Jan 8.

Department of Surgery, Medicine, Dentistry and Morphological Science with Transplant Surgery, Oncology and Regenerative Medicine Relevance, University of Modena and Reggio Emilia, via del Pozzo 71, 41124 Modena, Italy.

Prostate cancer (PCa) is the most common tumor in men with extremely variable outcome, varying from latent or indolent form to very aggressive behavior. High grade tumors, expansions exceeding the prostatic capsule into the surrounding soft tissues and spreading through lymph vascular channels, represent the most consistent unfavorable prognostic factors. However, accuracy in the prediction of the disease progression is sometimes difficult. Along with new molecular diagnostic techniques and more accurate histopathological approaches, proteomic studies challenge to identify potential biomarkers predictive of PCa progression. In our study we analyzed the urinary proteomes of 42 patients affected by PCa through two-dimensional electrophoresis associated with mass spectrometry. Proteomic profiles were correlated to histopathological features including pTNM stage and tumor differentiation in order to provide new promising markers able to define more accurately the PCa aggressiveness and driving new therapeutic approaches.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151704DOI Listing
April 2021

Multi-organ complement deposition in COVID-19 patients.

medRxiv 2021 Jan 8. Epub 2021 Jan 8.

Background: Increased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at tissue level. The mechanisms and pathways of local complement activation remain unclear.

Methods: We performed immunofluorescence analyses of autopsy specimens of lungs, kidney and liver from nine COVID-19 patients who died of acute respiratory failure. Snap-frozen samples embedded in OCT were stained with antibodies against complement components and activation products, IgG and spike protein of SARS-CoV-2.

Findings: Lung deposits of C1q, C4, C3 and C5b-9 were localized in the capillaries of the interalveolar septa and on alveolar cells. IgG displayed a similar even distribution, suggesting classical pathway activation. The spike protein is a potential target of IgG, but its uneven distribution suggests that other viral and tissue molecules may be targeted by IgG. Factor B deposits were also seen in COVID-19 lungs and are consistent with activation of the alternative pathway, whereas MBL and MASP-2 were hardly detectable. Analysis of kidney and liver specimens mirrored findings observed in the lung. Complement deposits were seen on tubules and vessels of the kidney with only mild C5b-9 staining in glomeruli, and on hepatic artery and portal vein of the liver.

Interpretation: Complement deposits in different organs of deceased COVID-19 patients caused by activation of the classical and alternative pathways support the multi-organ nature of the disease.

Funding: Grants from the Italian Ministry of Health (COVID-2020-12371808) to PLM and National Institutes of Health HL150146 to NP are gratefully acknowledged.
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http://dx.doi.org/10.1101/2021.01.07.21249116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805461PMC
January 2021

Protective and regenerative effects of a novel medical device against esophageal mucosal damage using in vitro and ex vivo models.

Biomed Pharmacother 2020 Nov 19;131:110752. Epub 2020 Sep 19.

Department of Life Sciences, University of Trieste, Trieste, Italy. Electronic address:

Gastroesophageal reflux disease (GERD) is a common digestive disorder that causes esophagitis and injuries to the esophageal mucosa. GERD symptoms are recurrent during pregnancy and their treatment is focused on lifestyle changes and nonprescription medicines. The aim of this study was to characterize the mechanism of action of a new patented medical device, an oral formulation containing hyaluronic acid, rice extract, and amino acids dispersed in a bioadhesive polymer matrix, by assessing its protective effects in in vitro and ex vivo models of esophageal mucosa damage. Acidic bile salts and pepsin cocktail (BSC) added to CP-A and COLO-680 N esophagus cells were used as an in vitro GERD model to evaluate the binding capacities, anti-inflammatory effects and reparative properties of the investigational product (IP) in comparison to a viscous control. Our results showed that the IP prevents cell permeability and tight junction dysfunction induced by BSC. Furthermore, the IP was also able to down-regulate IL-6 and IL-8 mRNA expression induced by BSC stimulation and to promote tissue repair and wound healing. The results were confirmed by ex vivo experiments in excised rat esophagi through the quantification of Evans Blue permeability assay. These experiments provided evidence that the IP is able to bind to the human esophagus cells, preventing the damage caused by gastroesophageal reflux, showing potential anti-irritative, soothing, and reparative properties.
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http://dx.doi.org/10.1016/j.biopha.2020.110752DOI Listing
November 2020

Comparison between Different Diagnostic Strategies in Low-Risk Reproductive Age and Pre-Menopausal Women Presenting Abnormal Uterine Bleeding.

Diagnostics (Basel) 2020 Oct 30;10(11). Epub 2020 Oct 30.

Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Via Dell'Istria 65/1, 34134 Trieste, Italy.

Abnormal uterine bleeding (AUB) is a common symptom in the female population, with an estimated prevalence of 10 to 30% in fertile age and up to 90% in perimenopausal women. In most cases, AUB is due to a benign cause. However, it can also be a symptom of atypical endometrial hyperplasia or endometrial cancer, a more common disease during menopause which can also affect women in their reproductive age. Considering the high prevalence of this symptom an appropriate diagnostic algorithm is needed. Concerns about the risks, pain, and stress associated with an endometrial biopsy and its impact on the healthcare system make the choice of AUB diagnostic strategy extremely relevant. Even if the scientific community agrees on the definition of AUB, International Guidelines show some differences in the management of women of reproductive age with AUB, especially regarding the age cut-off as an independent indication for endometrial biopsy. This study compared different diagnostic strategies to identify a diagnostic pathway with high sensitivity and specificity but low impact on the health system's resources. The analysis was based on three diagnostic algorithms defined as part of the guidelines of leading scientific societies. Women of reproductive age with AUB ( = 625) and without risk of endometrial cancer were included in the study. Results showed that the best criterion to investigate AUB in women at low risk of endometrial cancer is not age cut-off but the presence or absence of focal endometrial pathology at the ultrasound and the response to the progestin therapy. This approach makes it possible to perform fewer outpatient hysteroscopic biopsies without excluding positive cases from the examination.
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http://dx.doi.org/10.3390/diagnostics10110884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692264PMC
October 2020

A Spatially Resolved Dark- versus Light-Zone Microenvironment Signature Subdivides Germinal Center-Related Aggressive B Cell Lymphomas.

iScience 2020 Oct 16;23(10):101562. Epub 2020 Sep 16.

Hematopathology Unit, European Institute of Oncology, Milan, Italy.

We applied digital spatial profiling for 87 immune and stromal genes to lymph node germinal center (GC) dark- and light-zone (DZ/LZ) regions of interest to obtain a differential signature of these two distinct microenvironments. The spatially resolved 53-genes signature, comprising key genes of the DZ mutational machinery and LZ immune and mesenchymal milieu, was applied to the transcriptomes of 543 GC-related diffuse large B cell lymphomas and double-hit (DH) lymphomas. According to the DZ/LZ signature, the GC-related lymphomas were sub-classified into two clusters. The subgroups differed in the distribution of DH cases and survival, with most DH displaying a distinct DZ-like profile. The clustering analysis was also performed using a 25-genes signature composed of genes positively enriched in the non-B, stromal sub-compartments, for the first time achieving DZ/LZ discrimination based on stromal/immune features. The report offers new insight into the GC microenvironment, hinting at a DZ microenvironment of origin in DH lymphomas.
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http://dx.doi.org/10.1016/j.isci.2020.101562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522121PMC
October 2020

Beyond Traditional Morphological Characterization of Lung Neuroendocrine Neoplasms: In Silico Study of Next-Generation Sequencing Mutations Analysis across the Four World Health Organization Defined Groups.

Cancers (Basel) 2020 Sep 24;12(10). Epub 2020 Sep 24.

1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS (Scientific Institute for Research, Hospitalization and Healthcare) Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy.

Lung neuroendocrine neoplasms (LNENs) represent a rare and heterogeneous population of lung tumors. LNENs incidence rate has increased dramatically over the past 30 years. The current World Health Organization LNENs classification (WHO 2015), distinguished four LNENs prognostic categories, according to their morphology, necrosis amount and mitotic count: typical carcinoid (TC), atypical-carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC). At present, due to their rarity and biological heterogeneity there is still no consensus on the best therapeutic approach. Next-generation-sequencing analysis showed that WHO 2015 LNENs classes, could be characterized also by specific molecular alterations: frequently mutated genes involving chromatin remodeling and generally characterized by low mutational burden (MB) are frequently detected in both TC and AC; otherwise, and tumor suppressor genes alterations and high MB are usually detected in LCNEC and SCLC. We provide an overview concerning gene mutations in each WHO 2015 LNENs class in order to report the current LNENs mutational status as potential tool to better understand their clinical outcome and to drive medical treatment.
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http://dx.doi.org/10.3390/cancers12102753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600757PMC
September 2020

Microscopic imaging of Inflammatory Bowel Disease (IBD) and Non-IBD Colitis on digital slides: The Italian Group-IBD Pathologists experience.

Pathol Res Pract 2020 Nov 29;216(11):153189. Epub 2020 Aug 29.

Institute of Pathology, ASST Spedali Civili, Brescia, Italy.

Background: The aim of the study is to report the experience of the pathologists of the Italian Group for the Study of Inflammatory Bowel Disease (IBD) (group formed by pathologists with various experience) on the morphological assessment of digital slides pertaining to IBD and Non-IBD colitis underlining the necessity to implement this tool in daily routine and its utility to share opinions on difficult cases.

Materials And Methods: Forty-eight histological slides stained with haematoxylin and eosin obtained from ileo-colorectal endoscopic biopsies were digitized using Menarini D-Sight 2.0 system, uploaded onto a website platform and shared among 40 pathologists participating in the study. Information regarding the site of biopsy was disclosed; clinical data were blinded. Each participant was committed to write a comment on microscopic features purposing diagnostic opinion. One month after the last uploaded case, a form was sent to each participant to evaluate the personal experience on digital slide sharing.

Results: Sixteen pathologists out of 40 (40%) had consistently accessed to the site,9/40 (22%) commented on all slides, a diagnostic opinion was rendered in 8 slides. Most common critical issues were: A) poor internet connection resulting in ineffective evaluation of the digital slides, B) time-consuming cases raising difficult diagnostic interpretation, C) lack of clinical history. Overall, 24 participants (60%) found the forum valuable for practical training and educational purposes.

Conclusions: Sharing scanned slides circulating within a dedicated forum is an effective educational tool in both IBDs and Non-IBDs colitis. Although our results demonstrated a substantial compliance of the participants, their limited participation was an objective shortcoming. Hence, further efforts are needed to encourage this potentially rewarding practice among the pathologist community.
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http://dx.doi.org/10.1016/j.prp.2020.153189DOI Listing
November 2020

Improved Prognostic Prediction in Never-Smoker Lung Cancer Patients by Integration of a Systemic Inflammation Marker with Tumor Immune Contexture Analysis.

Cancers (Basel) 2020 Jul 7;12(7). Epub 2020 Jul 7.

Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy.

Almost 25% of lung cancers (LCs) occur in never-smokers. LC inflammatory profile, based on plasma C-reactive protein levels (CRP), predicts mortality, independently by smoking-status. We hypothesized that: CRP could be associated with tumor immune contexture (TIC) in never-smokers and both these two parameters may improve their prognosis. Sixty-eight never-smokers LC patients with high or low CRP were selected. The programmed cell death protein 1 (PD-1) and its ligand (PD-L1), the human leukocyte antigens (HLA-DR and HLA-I), CD8, CD4, CD3, CD33, CD163, and CD68 were evaluated by immunohistochemistry on surgical samples given TIC evaluation. The classification model based on TIC scores was generated by Classification and Regression Tree analysis. Tumor mutational burden was evaluated by targeted next-generation sequencing. Exclusively high CRP (H-CRP) subset showed PD-L1 expression in 35% of LC as well as lower HLA-I and HLA-DR in their stromal cells. CD3, CD4, CD8, HLA-I, HLA-DR tumor cells staining were associated with a "low inflammatory profile" subset. CRP and LC immune profiles drive clinical outcome: 5-year survival 88% against 8% was associated with low and high-risk profiles ( < 0.0001). Clinical outcome prediction in never-smoker LC patients may be improved by both CRP and tumor immune contexture evaluation.
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http://dx.doi.org/10.3390/cancers12071828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408913PMC
July 2020

Zinc Oxide Exerts Anti-Inflammatory Properties on Human Placental Cells.

Nutrients 2020 Jun 18;12(6). Epub 2020 Jun 18.

Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.

Background: An aberrant and persistent inflammatory state at the fetal-maternal interface is considered as a key contributor in compromised pregnancies. Decidual endothelial cells (DECs) play a pivotal role in the control of the local decidual inflammation. The aim of the current study was to determine whether dietary supplement with zinc oxide (ZnO), due to its very low adverse effects, may be useful for modulating the inflammatory response in the first trimester of pregnancy.

Methods: The anti-inflammatory properties of ZnO in pregnancy were evaluated by in vitro tests on endothelial cells isolated from normal deciduas and on a trophoblast cell line (HTR8/Svneo). The effects of this treatment were analyzed in terms of adhesion molecule expression and inflammatory cytokine secretion, by real time-quantitative PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA).

Results: Our data showed that ZnO was able to reduce the inflammatory response of DECs, in terms of vascular cell adhesion molecule-1 (VCAM-1), interleukin (IL)-8, IL-6, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) expression induced by TNF-α stimulation. This compound exerted no effect on intracellular adhesion molecule-1 (ICAM-1) exocytosis induced by TNF-α on stimulated trophoblast cells, but significantly reduced their IL-6 expression.

Conclusion: According to these results, it can be suggested that the ZnO supplement, through its modulation of the pro-inflammatory response of DECs, can be used in pregnancy for the prevention of local decidual inflammation.
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http://dx.doi.org/10.3390/nu12061822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353449PMC
June 2020

Rituximab Plus Chemotherapy Provides No Clinical Benefit in a Peripheral T-Cell Lymphoma Not Otherwise Specified with Aberrant Expression of CD20 and CD79a: A Case Report and Review of the Literature.

Diagnostics (Basel) 2020 May 26;10(6). Epub 2020 May 26.

Pathology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University, 00189 Rome, Italy.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is the most common entity of mature T-cell neoplasms. PTCL-NOS generally has an aggressive behavior and is often refractory to standard therapy. Only a few cases of PTCL with aberrant expression of B-cell antigens have been reported so far. This phenotypic aberrancy may lead to misdiagnosis as B-cell non-Hodgkin lymphomas and eventual inappropriate patient management, whereas in an accurately diagnosed PTCL, the presence of CD20 may appear as an appealing therapeutic target. In this setting, response to anti-CD20 monoclonal antibody in combination with chemotherapy has been poorly explored. We describe the case of a 59-year-old male diagnosed by a pathological and molecular approach as PTCL-NOS with aberrant co-expression of the B-cell antigens CD20 and CD79a, which proved non-responsive to the addition of rituximab to standard polychemotherapy. This case highlights that the presence of CD20 in PTCL may be misleading in the diagnosis and also act as a lure for the clinician to adopt a rituximab-based treatment, the effectiveness of which is undefined as the molecular mechanisms underlying B-cell marker expression in PTCL.
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http://dx.doi.org/10.3390/diagnostics10060341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344438PMC
May 2020

The Extracellular Matrix Influences Ovarian Carcinoma Cells' Sensitivity to Cisplatinum: A First Step towards Personalized Medicine.

Cancers (Basel) 2020 May 7;12(5). Epub 2020 May 7.

Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.

The development of personalized therapies for ovarian carcinoma patients is still hampered by several limitations, mainly the difficulty of predicting patients' responses to chemotherapy in tumor cells isolated from peritoneal fluids. The main reason for the low predictive power of in vitro assays is related to the modification of the cancer cells' phenotype induced by the culture conditions, which results in changes to the activation state and drug sensitivity of tumor cells compared to their in vivo properties. We have defined the optimal culture conditions to set up a prognostic test to predict high-grade serous ovarian carcinoma (HGSOC) patients' responses to platinum chemotherapy. We evaluated the effects of hyaluronic acid (HA) and fibronectin matrices and the contribution of freezing/thawing processes to the cell response to platinum-based treatment, collecting spheroids from the ascitic fluids of 13 patients with stage II or III HGSOC. Our findings indicated that an efficient model used to generate predictive data for in vivo sensitivity to platinum is culturing fresh spheroids on HA, avoiding the use of previously frozen primary tumor cells. The establishment of this easy, reproducible and standardized testing method can significantly contribute to an improvement in therapeutic effectiveness, thus bringing the prospect of personalized therapy closer for ovarian carcinoma patients.
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http://dx.doi.org/10.3390/cancers12051175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281165PMC
May 2020

Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis.

Neuroendocrinology 2021 4;111(5):475-489. Epub 2020 May 4.

Unit of Pathology, Department of Medicine and Surgery and Research Center for the Study of Hereditary and Familial tumors, University of Insubria, Varese, Italy.

Background: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation.

Methods: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component.

Results: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05).

Conclusions: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.
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http://dx.doi.org/10.1159/000508376DOI Listing
May 2020

Pancreatic ductal adenocarcinoma in colonic wall: metastatic disease or cancerized pancreatic ectopic tissue?

Surg Case Rep 2020 Apr 22;6(1):80. Epub 2020 Apr 22.

Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.

We describe two unusual cases of cancerized ectopic pancreatic parenchyma within the wall of the left colon. Although the morphology of the neoplastic cells and their immunoprofile were consistent with pancreatic ductal adenocarcinoma, the detection of small foci of regular ectopic pancreatic tissue close to dysplastic glands at the periphery of the cancerized mass represented the key diagnostic features. A careful histological examination of surgical samples represents the correct approach to the diagnosis of this rare disease, mostly when total-body CT scan evaluation confirms the lack of bilio-pancreatic masses.
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http://dx.doi.org/10.1186/s40792-020-00846-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176754PMC
April 2020

Gastroblastoma in Adulthood-A Rarity among Rare Cancers-A Case Report and Review of the Literature.

Case Rep Pathol 2019 28;2019:4084196. Epub 2019 Nov 28.

First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy.

Gastroblastoma (GB) is a rare gastric epithelial-mesenchymal neoplasm, first described by Miettinen et al. So far, all reported cases described the tumor in children or young adults, and similarities with other childhood blastomas have been postulated. We report a case of GB in a 43-year-old patient with long follow up and no recurrence up to 100 months after surgery. So far, this is the second case of GB occurring in the adult age >40-year-old. Hence, GB should be considered in the differential diagnosis of microscopically comparable conditions in adults carrying a worse prognosis and different clinical approach.
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http://dx.doi.org/10.1155/2019/4084196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906822PMC
November 2019

Uterine Immunity and Microbiota: A Shifting Paradigm.

Front Immunol 2019 17;10:2387. Epub 2019 Oct 17.

Department of Life Sciences, University of Trieste, Trieste, Italy.

The female reproductive tract harbors distinct microbial communities, as in the vagina, cervical canal, uterus, and fallopian tubes. The nature of the vaginal microbiota is well-known; in contrast, the upper reproductive tract remains largely unexplored. Alteration in the uterine microbiota, which is dependent on the nutrients and hormones available to the uterus, is likely to play an important role in uterine-related diseases such as hysteromyoma, adenomyosis, and endometriosis. Uterine mucosa is an important tissue barrier whose main function is to offer protection against pathogens and other toxic factors, while maintaining a symbiotic relationship with commensal microbes. These characteristics are shared by all the mucosal tissues; however, the uterine mucosa is unique since it changes cyclically during the menstrual cycle as well as pregnancy. The immune system, besides its role in the defense process, plays crucial roles in reproduction as it ensures local immune tolerance to fetal/paternal antigens, trophoblast invasion, and vascular remodeling. The human endometrium contains a conspicuous number of immune cells, mainly Natural Killers (NK) cells, which are phenotypically distinct from peripheral cytotoxic NK, cells and macrophages. The endometrium also contains few lymphoid aggregates comprising B cell and CD8 T cells. The number and the phenotype of these cells change during the menstrual cycle. It has become evident in recent years that the immune cell phenotype and function can be influenced by microbiota. Immune cells can sense the presence of microbes through their pattern recognition receptors, setting up host-microbe interaction. The microbiota exerts an appropriately controlled defense mechanism by competing for nutrients and mucosal space with pathogens. It has recently been considered that uterus is a non-sterile compartment since it seems to possess its own microbiota. There has been an increasing interest in characterizing the nature of microbial colonization within the uterus and its apparent impact on fertility and pregnancy. This review will examine the potential relationship between the uterine microbiota and the immune cells present in the local environment.
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http://dx.doi.org/10.3389/fimmu.2019.02387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811518PMC
October 2020

Prognostic Implications of the Complement Protein C1q in Gliomas.

Front Immunol 2019 10;10:2366. Epub 2019 Oct 10.

Department of Life Sciences, University of Trieste, Trieste, Italy.

The contribution of the complement system in the pathophysiology of brain cancers has been recently considered in light of its well-known involvement in carcinogenesis. Complement system represents an important component of the inflammatory response, which acts as a functional bridge between the innate and adaptive immune response. C1q, the first recognition subcomponent of the complement classical pathway, has recently been shown to be involved in a range of pathophysiological functions that are not dependent on complement activation. C1q is expressed in the microenvironment of various types of human tumors, including melanoma, prostate, mesothelioma, and ovarian cancers, where it can exert a protective or a harmful effect on cancer progression. Despite local synthesis of C1q in the central nervous system, the involvement of C1q in glioma pathogenesis has been poorly investigated. We, therefore, performed a bioinformatics analysis, using Oncomine dataset and UALCAN database in order to assess whether the expression of the genes encoding for the three chains of C1q (, and ) could serve as a potential prognostic marker for gliomas. The obtained results were then validated using an independent glioma cohort from the Chinese Glioma Genome Atlas datasets. Our bioinformatics analysis, coupled with immunohistochemistry and fluorescence microscopy, appears to suggest a positive correlation between higher levels of C1q expression and unfavorable prognosis in a diverse grade of gliomas.
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http://dx.doi.org/10.3389/fimmu.2019.02366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795702PMC
October 2020

Gastroenteropancreatic High-Grade Neuroendocrine Neoplasms: Histology and Molecular Analysis, Two Sides of the Same Coin.

Neuroendocrinology 2020 27;110(7-8):616-629. Epub 2019 Sep 27.

1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy,

Background: In gastroenteropancreatic (GEP) high-grade neuroendocrine neoplasms (H-NENs), Ki-67 threshold of 55% defines three prognosis subclasses: neuroendocrine tumor (NET) G3, neuroendocrine carcinoma (NEC) <55%, and NEC ≥55%. We investigated whether the molecular profiling of H-NENs differs among these subcategories and evaluated potential therapeutic targets, including PD-L1.

Methods: In GEP-NEN patients, we evaluated: (i) 55% threshold for Ki-67 labeling index for further stratifying NEC and (ii) immunoreactivity and gene mutations by immunohistochemistry and targeted next-generation sequencing (T-NGS).

Results: Fifteen NETs G3 and 39 NECs were identified. Ki-67 labeling index was <55% in 9 NECs and ≥55% in 30 NECs. Gene mutations by NGS (TP53, 32.9%; KRAS, 5.5%; BRAF, 4.1%) were detected in 46.6% NENs, significantly enriched in NEC ≥55% (76.7%) compared to NEC <55% (55.6%) or NET (20.0%). PD-L1 staining in tumor-infiltrating lymphocytes was observed in NEC ≥55% (36.7%; p = 0.03). Median OS was 4.3 years in NET G3, 1.8 years in NEC <55%, and 0.7 years in NEC ≥55% (p <0.0001); it was 2.3 years with NGS wild-type, 0.7 years with ≥1 mutation (p <0.0001), 0.8 years in PD-L1-positive patients, and 1.7 years in PD-L1-negative subjects (p = 0.0004). In multivariate analysis, only the proposed subclassification approach yielded statistically significant differences between groups (NEC <55% vs. NET G3, HR 14.1, 95% CI 2.2-89.8, p = 0.005; NEC ≥55% vs. NET G3, HR 25.8, 95% CI 3.9-169, p = 0.0007).

Conclusions: These findings identify NEC ≥55% as a biologically and prognostically distinct subtype and pave the way for more personalized treatment.
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http://dx.doi.org/10.1159/000503722DOI Listing
July 2021

Biopsy or bio-spy? The role of fine-needle aspiration cytology in pancreatic tuberculosis.

Int J Mycobacteriol 2019 Jul-Sep;8(3):309-310

Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.

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http://dx.doi.org/10.4103/ijmy.ijmy_103_19DOI Listing
October 2019

Evaluation of the Interplay Between the Complement Protein C1q and Hyaluronic Acid in Promoting Cell Adhesion.

J Vis Exp 2019 06 15(148). Epub 2019 Jun 15.

Department of Life Sciences, University of Trieste;

It has been increasingly demonstrated that the tumor microenvironment plays an active role in neoplasia growth and metastasis. Through different pathways, tumor cells can efficiently recruit stromal, immune and endothelial cells by secreting stimulatory factors, chemokines and cytokines. In turn, these cells can alter the signaling properties of the microenvironment by releasing growth-promoting signals, metabolites and extracellular matrix components to sustain high proliferation and metastatic competence. In this context, we identify that the complement component C1q, highly expressed locally by a range of human malignant tumors, upon interacting with the extracellular matrix hyaluronic acid, strongly affects the behavior of primary cells isolated from human tumor specimens. Here, we describe a method to test how C1q bound to hyaluronic acid (HA) impacts tumor cell adhesion, underlying the fact that the biological properties of key components of the extracellular matrix (in this case HA) can be shaped by bioactive signals toward tumor progression.
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http://dx.doi.org/10.3791/58688DOI Listing
June 2019

Poorly differentiated clusters (PDC) in colorectal cancer: Does their localization in tumor matter?

Ann Diagn Pathol 2019 Aug 17;41:106-111. Epub 2019 Jun 17.

Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy. Electronic address:

Poorly differentiated clusters (PDC) are aggregates of at least five neoplastic cells lacking evidence of glandular differentiation. By definition, they can be present at the invasive front (peripheral PDC or pPDC) and within the tumor stroma (central PDC or cPDC). In colorectal cancer (CRC), PDC are considered adverse prognosticators and seem to reflect epithelial mesenchymal transition (EMT). In this study, we have investigated the immuno-expression of two EMT-related proteins, E-cadherin and β-catenin, in PDC of primary CRCs and matched liver metastases. pPDC always showed nuclear β-catenin staining and diffusely reduced/absence of E-cadherin expression as opposed cPDC which showed nuclear β-catenin immunoreactivity and E-cadherin expression in about 50% of cases. In addition, the pattern of β-catenin and E-cadherin expression differed between PDC and the main tumor, and between primary CRC and liver metastasis (LM), in a percentage of cases. A discordant pattern of β-catenin and E-cadherin expression between pPDC and cPDC, between main tumor and cPDC, and between primary CRC and LM, confirms that EMT is a dynamic and reversible process in CRC. On the overall, this suggests that pPDC and cPDC are biologically different. We may advocate that PDC develop at the tumor center (cPDC) and then some of them migrate towards the tumor periphery while progressively completing EMT process (pPDC). Based on these results, PDC presence and counting may have different prognostic relevance if the assessment is done at the invasive front of the tumor or in the intratumor stroma.
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http://dx.doi.org/10.1016/j.anndiagpath.2019.06.008DOI Listing
August 2019
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