Publications by authors named "Fiorella Calabrese"

178 Publications

Machine learning-based analysis of alveolar and vascular injury in SARS-CoV-2 acute respiratory failure.

J Pathol 2021 Feb 24. Epub 2021 Feb 24.

Department of Cardiac, Thoracic, Vascular Sciences, and Public Health, University of Padua, Medical School, Padua, Italy.

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pneumopathy is characterized by a complex clinical picture and heterogenous pathological lesions, both involving alveolar and vascular components. The severity and distribution of morphological lesions associated with SARS-CoV-2 and how they relate to clinical, laboratory, and radiological data have not yet been studied systematically. The main goals of the present study were to objectively identify pathological phenotypes and factors, that, in addition to SARS-CoV-2, may influence their occurrence. Lungs from 26 patients who died from SARS-CoV-2 acute respiratory failure were comprehensively analysed. Robust machine learning techniques were implemented to obtain a global pathological score to distinguish phenotypes with prevalent vascular or alveolar injury. The score was then analysed to assess its possible correlation with clinical, laboratory, radiological, and tissue viral data. Furthermore, an exploratory random forest algorithm was developed to identify the most discriminative clinical characteristics at hospital admission that might predict pathological phenotypes of SARS-CoV-2. Vascular injury phenotype was observed in most cases being consistently present as pure form or in combination with alveolar injury. Phenotypes with more severe alveolar injury showed significantly more frequent tracheal intubation, longer invasive mechanical ventilation, illness duration, intensive care unit, hospital stay and lower tissue viral quantity (p<0.001). Furthermore, in this phenotype, superimposed infections, tumours, and aspiration pneumonia were also more frequent (p<0.001). Random forest algorithm identified some clinical features at admission (body mass index, white blood cells, D-dimer, lymphocyte and platelet counts, fever, respiratory rate, and PaCO ) to stratify patients into different clinical clusters and potential pathological phenotypes (a web-app for score assessment has also been developed https://r-ubesp.dctv.unipd.it/shiny/AVI-Score/). In SARS-CoV-2 positive patients, alveolar injury is often associated with other factors in addition to viral infection. Identifying phenotypical patterns at admission may enable a better stratification of patients, ultimately favouring the most appropriate management. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/path.5653DOI 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

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

[Histopathological features due to the SARS-CoV-2].

Ann Pathol 2021 Feb 30;41(1):9-22. Epub 2020 Dec 30.

Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, Padova, Italie.

The infection due to the SARS-CoV-2 leads lesions mainly observed at the respiratory tract level, but not exclusively. The analyses of these lesions benefited from different autopsy studies. Thus, these lesions were observed in different organs, tissues and cells. These observations allowed us to rapidly improve the knowledge of the pathophysiological mechanisms associated with this emergent infectious disease. The virus can be detected in formalin fixed paraffin embedded tissues using immunohistochemistry, in situ hybridization, molecular biology and/or electron microscopy approaches. However, many uncertainties are still present concerning the direct role of the SARS-CoV-2 on the different lesions observed in different organs, outside the lung, such as the heart, the brain, the liver, the gastrointestinal tract, the kidney and the skin. In this context, it is pivotal to keep going to increase the different tissue and cellular studies in the COVID-19 positive patients aiming to better understanding the consequences of this new infectious disease, notably considering different epidemiological and co-morbidities associated factors. This could participate to the development of new therapeutic strategies too. The purpose of this review is to describe the main histological and cellular lesions associated with the infection due to the SARS-CoV-2.
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http://dx.doi.org/10.1016/j.annpat.2020.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773006PMC
February 2021

Lobectomy with artery reconstruction and pneumonectomy for NSCLC: a propensity score weighting study.

Ann Thorac Surg 2021 Jan 9. Epub 2021 Jan 9.

Thoracic surgery division, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Padova University Hospital, Padova Italy.

Background: The treatment of NSCLC is based, when suitable, on surgical resection. Pneumonectomy has been considered the standard surgical procedure for locally advanced lung cancers but it is associated with high mortality and morbidity rates. Reconstruction of the pulmonary artery, associated with parenchyma sparing techniques, is meant to be an alternative to pneumonectomy.

Methods: This retrospective single-centre study is based on a detailed and comprehensive analysis of the clinical and oncological data of patients treated between 2004 and 2016 through pneumonectomy or lobectomy with reconstruction of the pulmonary artery. A propensity score weighting approach, based on the pre-operative characteristics of two groups of 124 patients each was performed. The subsequent statistical analysis evaluated long and short-term clinical outcomes together with risk factors analysis.

Results: The comparison between pneumonectomy and pulmonary artery reconstructions showed a higher 30-days (p=0.02) and 90-days (p=0.03) mortality rate in the pneumonectomy group, together with a higher incidence of major complications (p=0.004). Long term results have shown comparable outcomes, both in terms of 5-years disease free survival (52.2% in pneumonectomy vs 46.0% in pulmonary artery reconstructions, p=0.57) and overall 5-years survival (41.9% vs 35.6% respectively, p=0.57). Risk factors analysis showed that cancer specific survival was related to lymph node status (p<0.01) and absence of adjuvant therapy (p=0.04). Lymph node status also influenced the risk of recurrence (p<0.01).

Conclusions: Lobectomy with reconstruction of the pulmonary artery is a valuable and oncologically safe alternative to pneumonectomy, with lower short-term mortality and morbidity, without affecting long-term oncological results.
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http://dx.doi.org/10.1016/j.athoracsur.2020.12.029DOI Listing
January 2021

Validation of a composed COVID-19 chest radiography score: the CARE project.

ERJ Open Res 2020 Oct 26;6(4). Epub 2020 Oct 26.

Institute of Radiology, Dept of Medicine DIMED, University of Padova, Padua, Italy.

Objectives: The aim of this study was to validate a composed coronavirus disease 2019 (COVID-19) chest radiography score (CARE) based on the extension of ground-glass opacity (GG) and consolidations (Co), separately assessed, and to investigate its prognostic performance.

Methods: COVID-19-positive patients referring to our tertiary centre during the first month of the outbreak in our area and with a known outcome were retrospectively evaluated. Each lung was subdivided into three areas and a three-grade score assessing the extension of GG and Co was used. The CARE was derived from the sum of the subscores. A mixed-model ANOVA with Bonferroni correction was used to evaluate whether differences related to the referring unit (emergency room, COVID-19 wards and intensive care unit (ICU)) occurred. Logistic regression analyses were used to investigate the impact of CARE, patients' age and sex on the outcome. To evaluate the prognostic performance of CARE, receiver operating characteristic curves were computed for the entire stay and at admission only.

Results: A total of 1203 chest radiographs of 175 patients (120 males; mean age 67.81±15.5 years old) were examined. On average, each patient underwent 6.8±10.3 radiographs. Patients in ICU as well as deceased patients showed higher CARE scores (p<0.05, each). Age, Co and CARE significantly influenced the outcome (p<0.05 each). The CARE demonstrated good accuracy (area under the curve (AUC)=0.736) using longitudinal data as well as at admission only (AUC=0.740). A CARE score of 17.5 during hospitalisation showed 75% sensitivity and 69.9% specificity.

Conclusions: The CARE was demonstrated to be a reliable tool to assess the severity of pulmonary involvement at chest radiography with a good prognostic performance.
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http://dx.doi.org/10.1183/23120541.00359-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682711PMC
October 2020

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC): Lung cancer.

Lung Cancer 2020 12 4;150:221-239. Epub 2020 Sep 4.

European Cancer Organisation; Iridium Kankernetwerk and University of Antwerp, Wilrijk-Antwerp, Belgium.

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give patients, health professionals, managers and policymakers a guide to essential care throughout the patient journey. Lung cancer is the leading cause of cancer mortality and has a wide variation in treatment and outcomes in Europe. It is a major healthcare burden and has complex diagnosis and treatment challenges. Care must only be carried out in lung cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals detailed here. Such units are far from universal in European countries. To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship.
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http://dx.doi.org/10.1016/j.lungcan.2020.08.017DOI Listing
December 2020

Estimated direct costs of non-small cell lung cancer by stage at diagnosis and disease management phase: A whole-disease model.

Thorac Cancer 2021 Jan 21;12(1):13-20. Epub 2020 Nov 21.

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

Background: Non-small cell lung cancer (NSCLC) is the first cause of cancer-related death among men and the second among women worldwide. It also poses an economic threat to the sustainability of healthcare services. This study estimated the direct costs of care for patients with NSCLC by stage at diagnosis, and management phase of pathway recommended in local and international guidelines.

Methods: Based on the most up-to-date guidelines, we developed a very detailed "whole-disease" model listing the probabilities of all potentially necessary diagnostic and therapeutic actions involved in the management of each stage of NSCLC. We assigned a cost to each procedure, and obtained an estimate of the total and average per-patient costs of each stage of the disease and phase of its management.

Results: The mean expected cost of a patient with NSCLC is 21,328 € (95% C.I. -20 897-22 322). This cost is 16 291 € in stage I, 19530 € in stage II, 21938 € in stage III, 22175 € in stage IV, and 28 711 € for a Pancoast tumor. In the early stages of the disease, the main cost is incurred by surgery, whereas in the more advanced stages radiotherapy, medical therapy, treatment for progressions, and supportive care become variously more important.

Conclusions: An estimation of the direct costs of care for NSCLC is fundamental in order to predict the burden of new oncological therapies and treatments on healthcare services, and thus orient the decisions of policy-makers regarding the allocation of resources.

Key Points: SIGNIFICANT FINDINGS OF THE STUDY: The high costs of surgery make the early stages of the disease no less expensive than the advanced stages.

What This Study Adds: An estimation of the direct costs of care is fundamental in order to orient the decisions of policy-makers regarding the allocation of resources.
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http://dx.doi.org/10.1111/1759-7714.13616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779199PMC
January 2021

Combined Immunoscore for Prognostic Stratification of Early Stage Non-Small-Cell Lung Cancer.

Front Oncol 2020 25;10:564915. Epub 2020 Sep 25.

Oncology Unit 2, Istituto Oncologico Veneto IRCCS, Padua, Italy.

Background: To date, no combined immunoscore has been evaluated for prognostic stratification of early stage non-small-cell lung cancer (NSCLC). The main goal of this study was to investigate the prognostic impact of programmed death ligand 1 (PD-L1) expression and different immune cell components (CD4+, CD8+ T-lymphocytes, and CD68+ macrophages) in early stage NSCLC patients, distinguishing peritumoral (PT) and intratumoral (IT) localizations. The secondary aim was to identify a combined immunoscore to optimize the prognostic stratification of NSCLC patients.

Methods: This retrospective study included surgical specimens from consecutive chemo-naive stage II-III radically resected NSCLC patients. Immunohistochemistry was carried out to evaluate PD-L1 expression and to quantify IT and PT CD4+, CD8+ T-lymphocytes, and CD68+ macrophages. The impact of a single marker and of a combination of multiple markers on overall survival (OS) was investigated.

Results: Seventy-nine patients were included in the study. PD-L1 expression was associated with worse prognosis (3 years OS: 58% in high- compared with 67% in low-expressing tumors), even though without statistical significance. When integrating PT CD8+, CD4+, and CD68 into a combined PT immunoscore, a significant prognostic stratification of patients was obtained and confirmed at multivariate analysis (3 years OS: 86% in patients with low PT immunoscore vs. 59% in patients with high PT immunoscore, = 0.018). The integration of derived neutrophil/lymphocyte ratio (dNLR) with combined PT immunoscore improved prognostic stratification, with longer OS in patients with low PT immunoscore and low dNLR ( = 0.002).

Conclusion: The combined PT immunoscore (CD8+, CD4+, and CD68) integrated with dNLR may be a promising marker for the development of an integrated Tumor, Node, Metastasis (TNM) immunoscore.
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http://dx.doi.org/10.3389/fonc.2020.564915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544833PMC
September 2020

COVID-19 pulmonary pathology: a multi-institutional autopsy cohort from Italy and New York City.

Mod Pathol 2020 11 2;33(11):2156-2168. Epub 2020 Sep 2.

Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

SARS-CoV-2, the etiologic agent of COVID-19, is a global pandemic with substantial mortality dominated by acute respiratory distress syndrome. We systematically evaluated lungs of 68 autopsies from 3 institutions in heavily hit areas (2 USA, 1 Italy). Detailed evaluation of several compartments (airways, alveolar walls, airspaces, and vasculature) was performed to determine the range of histologic features. The cohort consisted of 47 males and 21 females with a median age of 73 years (range 30-96). Co-morbidities were present in most patients with 60% reporting at least three conditions. Tracheobronchitis was frequently present, independent from intubation or superimposed pneumonia. Diffuse alveolar damage (DAD) was seen in 87% of cases. Later phases of DAD were less frequent and correlated with longer duration of disease. Large vessel thrombi were seen in 42% of cases but platelet (CD61 positive) and/or fibrin microthrombi were present at least focally in 84%. Ultrastructurally, small vessels showed basal membrane reduplication and significant endothelial swelling with cytoplasmic vacuolization. In a subset of cases, virus was detected using different tools (immunohistochemistry for SARS-CoV-2 viral spike protein, RNA in situ hybridization, lung viral culture, and electron microscopy). Virus was seen in airway epithelium and type 2 pneumocytes. IHC or in situ detection, as well as viable form (lung culture positive) was associated with the presence of hyaline membranes, usually within 2 weeks but up to 4 weeks after initial diagnosis. COVID-19 pneumonia is a heterogeneous disease (tracheobronchitis, DAD, and vascular injury), but with consistent features in three centers. The pulmonary vasculature, with capillary microthrombi and inflammation, as well as macrothrombi, is commonly involved. Viral infection in areas of ongoing active injury contributes to persistent and temporally heterogeneous lung damage.
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http://dx.doi.org/10.1038/s41379-020-00661-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463226PMC
November 2020

Two Sorts of Microthrombi in a Patient With Coronavirus Disease 2019 and Lung Cancer.

J Thorac Oncol 2020 11 29;15(11):1782-1785. Epub 2020 Aug 29.

Anaesthesia and Intensive Care Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy.

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http://dx.doi.org/10.1016/j.jtho.2020.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455572PMC
November 2020

Lung cancer biomarker testing: perspective from Europe.

Transl Lung Cancer Res 2020 Jun;9(3):887-897

The Fingerland Department of Pathology, Charles University Medical Faculty and University Hospital, Hradec Kralove, Czech Republic.

A questionnaire on biomarker testing previously used in central European countries was extended and distributed in Western and Central European countries to the pathologists participating at the Pulmonary Pathology Society meeting 26-28 June 2019 in Dubrovnik, Croatia. Each country was represented by one responder. For recent biomarkers the availability and reimbursement of diagnoses of molecular alterations in non-small cell lung carcinoma varies widely between different, also western European, countries. Reimbursement of such assessments varies widely between unavailability and payments by the health care system or even pharmaceutical companies. The support for testing from alternative sources, such as the pharmaceutical industry, is no doubt partly compensating for the lack of public health system support, but it is not a viable or long-term solution. Ideally, a structured access to testing and reimbursement should be the aim in order to provide patients with appropriate therapeutic options. As biomarker enabled therapies deliver a 50% better probability of outcome success, improved and unbiased reimbursement remains a major challenge for the future.
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http://dx.doi.org/10.21037/tlcr.2020.04.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354119PMC
June 2020

Organ Care System Lung resulted in lower apoptosis and iNOS expression in donor lungs.

Am J Transplant 2020 12 3;20(12):3639-3648. Epub 2020 Sep 3.

Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy.

Ischemia-reperfusion (IR) injury after lung transplantation is still today an important complication in up to 25% of patients. The Organ Care System (OCS) Lung, an advanced normothermic ex vivo lung perfusion system, was found to be effective in reducing primary graft dysfunction compared to standard organ care (SOC) but studies on tissue/molecular pathways that could explain these more effective clinical results are lacking. This observational longitudinal study aimed to investigate IR injury in 68 tissue specimens collected before and after reperfusion from 17 OCS and 17 SOC preserved donor lungs. Several tissue analyses including apoptosis evaluation and inducible nitric oxide synthase (iNOS) expression (by immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction) were performed. Lower iNOS expression and apoptotic index were distinctive of OCS preserved tissues at pre- and post-reperfusion times, independently from potential confounding factors. Moreover, OCS recipients had lower acute cellular rejection at the first 6-month follow-up. In conclusion, IR injury, in terms of apoptosis and iNOS expression, was less frequent in OCS- than in SOC-preserved lungs, which could eventually explain a better clinical outcome. Further studies are needed to validate our data and determine the role of iNOS expression as a predictive biomarker of the complex IR injury mechanism.
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http://dx.doi.org/10.1111/ajt.16187DOI Listing
December 2020

Pulmonary pathology and COVID-19: lessons from autopsy. The experience of European Pulmonary Pathologists.

Virchows Arch 2020 Sep 9;477(3):359-372. Epub 2020 Jul 9.

Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, Via A. Gabelli 61, 35121, Padova, Italy.

Since its initial recognition in December 2019, Coronavirus disease 19 (COVID-19) has quickly spread to a pandemic infectious disease. The causative agent has been recognized as a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily affecting the respiratory tract. To date, no vaccines are available nor any specific treatment. To limit the number of infections, strict directives have been issued by governments that have been translated into equally rigorous guidelines notably for post-mortem examinations by international and national scientific societies. The recommendations for biosafety control required during specimen collection and handling have strongly limited the practice of autopsies of the COVID-19 patients to a few adequate laboratories. A full pathological examination has always been considered an important tool to better understand the pathophysiology of diseases, especially when the knowledge of an emerging disorder is limited and the impact on the healthcare system is significant. The first evidence of diffuse alveolar damage in the context of an acute respiratory distress syndrome has now been joined by the latest findings that report a more complex scenario in COVID-19, including a vascular involvement and a wide spectrum of associated pathologies. Ancillary tools such as electron microscopy and molecular biology used on autoptic tissue samples from autopsy are also significantly contributing to confirm and/or identify new aspects useful for a deeper knowledge of the pathogenetic mechanisms. This article will review and summarize the pathological findings described in COVID-19 until now, chiefly focusing on the respiratory tract, highlighting the importance of autopsy towards a better knowledge of this disease.
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http://dx.doi.org/10.1007/s00428-020-02886-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343579PMC
September 2020

Outcome of patients with colorectal cancer undergoing lung metastases resection: a single-institution retrospective analysis.

Tumori 2021 Feb 29;107(1):46-54. Epub 2020 Jun 29.

Department of Clinical and Experimental Oncology, Medical Oncology Unit 1, Istituto Oncologico Veneto (IRCSS), Padua, Italy.

Introduction: This study was undertaken to review a single-institution cohort of patients with metastatic colorectal cancer undergoing lung resection after a multidisciplinary evaluation and to investigate the main prognostic factors for survival.

Methods: Medical records of 129 patients undergoing lung metastasectomy for colorectal cancer with curative intent from 2001 to 2017 were reviewed. Tissue samples from the primary tumor were analyzed with a multiplex genotyping system for the detection of mutations in and genes. Survival analyses were carried out by the Kaplan-Meier method. Univariate and multivariable analyses were performed using the log-rank test and the Cox regression model.

Results: Postoperative morbidity and mortality were 13.2% and 0%, respectively. At a median follow-up time of 62.5 months, median overall survival was 90.5 months and median relapse-free survival was 42.8 months. Multivariable analysis for overall survival identified synchronous versus metachronous metastatic presentation as the only prognostic factor, whereas relapse-free survival was independently associated with synchronous versus metachronous metastatic presentation, number of metastases, and postoperative chemotherapy.

Conclusions: This study shows particularly favorable survival outcomes for patients undergoing lung metastasectomy. The validity of some of the main prognostic factors was confirmed and a positive effect of postoperative chemotherapy on relapse-free survival was shown. Contrary to other reports, the presence of mutations was not associated with significant survival differences. Further studies are needed in order to clarify the interactions between molecular, clinical, and pathologic characteristics and treatment-related factors.
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http://dx.doi.org/10.1177/0300891620930793DOI Listing
February 2021

Feasibility of postmortem examination in the era of COVID-19 pandemic: the experience of a Northeast Italy University Hospital.

Virchows Arch 2020 Sep 9;477(3):341-347. Epub 2020 Jun 9.

Pathology Unit, Padua University Hospital, Padua, Italy.

With the continuous spreading of SARS-CoV-2 and increasing number of deaths worldwide, the need and appropriateness for autopsy in patients with COVID-19 became a matter of discussion. In fact, in the COVID-19 era protection of healthcare workers is a priority besides patient management. No evidence is currently available about the real risk related to the procedure as well as to the subsequent management of the samples. We herein describe the procedure that has been used to perform the first series of postmortem examinations in the COVID center of the Padua University Hospital, Padua, Italy, after the implementation of an ad hoc operating procedure, to minimize the risk of infection for pathologists and technicians. Provided that the procedure is performed in an adequate environment respecting strict biosafety rules, our data indicate that complete postmortem examination appears to be safe and will be highly informative providing useful insights into the complex disease pathogenesis.
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http://dx.doi.org/10.1007/s00428-020-02861-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282199PMC
September 2020

Immunohistochemical neuroendocrine marker expression in primary pulmonary NUT carcinoma: a diagnostic pitfall.

Histopathology 2020 09 28;77(3):508-510. Epub 2020 Jul 28.

Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Medical School, Padova, Italy.

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http://dx.doi.org/10.1111/his.14166DOI Listing
September 2020

COVID-19 pneumonia in lung transplant recipients: Report of 2 cases.

Am J Transplant 2020 10 14;20(10):2933-2937. Epub 2020 Jun 14.

Thoracic Surgery and Lung Transplant Center, Department of Cardio-Thoracic, Vascular Sciences and Public Health, Padova University-Hospital, Padova, Italy.

Coronavirus disease 2019 (COVID-19) has been declared pandemic since March 2020. In Europe, Italy was the first nation affected by this infection. We report anamnestic data, clinical features, and therapeutic management of 2 lung transplant recipients with confirmed COVID-19 pneumonia. Both patients were in good clinical condition before the infection and were receiving immunosuppression with calcineurin inhibitors (CNI), mycophenolate mofetil, and corticosteroids. Whereas mycophenolate mofetil was withdrawn in both cases, CNI were suspended only in the second patient. The first patient always maintained excellent oxygen saturation throughout hospitalization with no need for additional oxygen therapy. He was discharged with a satisfactory pulmonary function and a complete resolution of radiological and clinical findings. However, at discharge SARS-CoV-2 RNA could still be detected in the nasopharyngeal swab and in the stools. The second patient required mechanical ventilation, had a progressive deterioration of his clinical conditions, and had a fatal outcome. Further insight into SARS-CoV-2 infection is eagerly awaited to improve the outcome of transplant recipients affected by COVID-19 pneumonia.
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http://dx.doi.org/10.1111/ajt.15993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273094PMC
October 2020

Early assessment of KRAS mutation in cfDNA correlates with risk of progression and death in advanced non-small-cell lung cancer.

Br J Cancer 2020 07 7;123(1):81-91. Epub 2020 May 7.

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

Background: Liquid biopsy has the potential to monitor biological effects of treatment. KRAS represents the most commonly mutated oncogene in Caucasian non-small-cell lung cancer (NSCLC). The aim of this study was to explore association of dynamic plasma KRAS genotyping with outcome in advanced NSCLC patients.

Methods: Advanced NSCLC patients were prospectively enrolled. Plasma samples were collected at baseline (T1), after 3 or 4 weeks, according to treatment schedule (T2) and at first radiological restaging (T3). Patients carrying KRAS mutation in tissue were analysed in plasma with droplet digital PCR. Semi-quantitative index of fractional abundance of mutated allele (MAFA) was used.

Results: KRAS-mutated cohort included 58 patients, and overall 73 treatments (N = 39 chemotherapy and N = 34 immune checkpoint inhibitors) were followed with longitudinal liquid biopsy. Sensitivity of KRAS detection in plasma at baseline was 48.3% (95% confidence interval (CI): 35.0-61.8). KRAS mutation at T2 was associated with increased probability of experiencing progressive disease as best radiological response (adjusted odds ratio: 7.3; 95% CI: 2.1-25.0, p = 0.0016). Increased MAFA (T1-T2) predicted shorter progression-free survival (adjusted hazard ratio (HR): 2.1; 95% CI: 1.2-3.8, p = 0.0142) and overall survival (adjusted HR: 3.2; 95% CI: 1.2-8.4, p = 0.0168).

Conclusions: Longitudinal analysis of plasma KRAS mutations correlated with outcome: its early assessment during treatment has great potentialities for monitoring treatment outcome in NSCLC patients.
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http://dx.doi.org/10.1038/s41416-020-0833-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341732PMC
July 2020

Insights into the pathogenesis of catastrophic antiphospholipid syndrome. A case report of relapsing catastrophic antiphospholipid syndrome and review of the literature on ischemic colitis.

Clin Rheumatol 2020 Apr 18;39(4):1347-1355. Epub 2019 Dec 18.

Department of Cardiac, Thoracic Vascular Sciences and Public Health, University of Padua, Padua, Italy.

We present the case of a woman with a severe clinical history of antiphospholipid syndrome and persistent positivity for lupus anticoagulant, IgG anticardiolipin and IgG anti-β2Glycoprotein I antibodies. An acute clinical onset characterized by severe abdominal pain immediately followed by circulatory shock and histological colonic small vessel thrombosis pattern pointed to a diagnosis of ischemic colitis. The subsequent rapid onset of pulmonary alveolitis and heart failure associated to subendocardial hypoperfusion led to a diagnosis of definite catastrophic antiphospholipid syndrome (CAPS). Conventional triple therapy together with a broad-spectrum preventive antibiotic therapy were quickly initiated, and the outcome was favorable. We evaluated the patients with ischemic colitis in CAPS described in the literature between 1992 and May 2019 and our CAPS case. In accordance with the "two-hit" hypothesis and on the basis of the patients' data, we would like to speculate that the colonic wall necrosis related to ischemic colitis damaged the intestinal barrier causing loss of resistance to bacteria and leading to endotoxemia and bacteremia with bacteria translocation through the circulatory stream to the lungs and heart. The bacteria acted as the priming factor which favored the binding of β2Glycoprotein I to the endothelium vessels in the colon, lungs, and heart following activation of anti-β2Glycoprotein I antibodies which attached to the domain I of β2Glycoprotein I. This was followed by complement activation which triggered the thrombotic and cytokine storm. If further clinical studies confirm this hypothesis, the treatment of CAPS could be more targeted and effective.
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http://dx.doi.org/10.1007/s10067-019-04888-5DOI Listing
April 2020

Clinical Features and Progression Pattern of Acquired T790M-positive Compared With T790M-negative EGFR Mutant Non-small-cell Lung Cancer: Catching Tumor and Clinical Heterogeneity Over Time Through Liquid Biopsy.

Clin Lung Cancer 2020 01 5;21(1):1-14.e3. Epub 2019 Aug 5.

Department of Oncology 2, Istituto Oncologico Veneto - IRCCS, Padova, Italy. Electronic address:

Background: Clinical-pathologic predictors of acquired T790M epidermal growth factor receptor (EGFR) mutation in Caucasian patients with non-small-cell lung cancer (NSCLC) progressing after first-/second-generation tyrosine kinase inhibitors (TKIs) is an open field for research. Similarly, the best time point for T790M detection by liquid or tissue biopsy after disease progression is currently matter of debate.

Patients And Methods: This is an observational study at 7 Italian centers enrolling patients with EGFR-mutant NSCLC progressing after first-/second-generation EGFR TKIs, between 2014 and 2018, aiming at comparing baseline clinical-pathologic features and progression patterns in acquired T790M-positive compared with T790M-negative cases.

Results: A total of 235 patients received first-line treatment with gefitinib (N = 126; 53%), erlotinib (N = 51; 22%), or afatinib (N = 58; 25%). In 120 (51%) cases, T790M was detected in liquid biopsy, tissue biopsy, or both. Age younger than 65 years (P = .037), the presence of common mutations (P = .004), and better response to first-line TKI (P = .023) were correlated with T790M positivity. T790M detection was associated with higher number of new progressing sites (P = .04), liver progression (P = .002), and a lower frequency of lung metastases (P = .027). When serial liquid biopsies were performed (N = 15), an oligoprogressive disease was correlated with a negative test outcome, whereas systemic progression was observed at the time of T790M positivity.

Conclusion: This study on a Caucasian population showed that age, type of EGFR mutation at diagnosis, response to first-line treatment, and peculiar progression pattern are associated with T790M status. Serial liquid biopsy might be useful for treatment selection, especially when tissue rebiopsy is not feasible.
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http://dx.doi.org/10.1016/j.cllc.2019.07.009DOI Listing
January 2020

Fit-For-Purpose PD-L1 Biomarker Testing For Patient Selection in Immuno-Oncology: Guidelines For Clinical Laboratories From the Canadian Association of Pathologists-Association Canadienne Des Pathologistes (CAP-ACP).

Appl Immunohistochem Mol Morphol 2019 Nov/Dec;27(10):699-714

Canadian Immunohistochemistry Quality Control.

Since 2014, programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) checkpoint inhibitors have been approved by various regulatory agencies for the treatment of multiple cancers including melanoma, lung cancer, urothelial carcinoma, renal cell carcinoma, head and neck cancer, classical Hodgkin lymphoma, colorectal cancer, gastroesophageal cancer, hepatocellular cancer, and other solid tumors. Of these approved drug/disease combinations, a subset also has regulatory agency-approved, commercially available companion/complementary diagnostic assays that were clinically validated using data from their corresponding clinical trials. The objective of this document is to provide evidence-based guidance to assist clinical laboratories in establishing fit-for-purpose PD-L1 biomarker assays that can accurately identify patients with specific tumor types who may respond to specific approved immuno-oncology therapies targeting the PD-1/PD-L1 checkpoint. These recommendations are issued as 38 Guideline Statements that address (i) assay development for surgical pathology and cytopathology specimens, (ii) reporting elements, and (iii) quality assurance (including validation/verification, internal quality assurance, and external quality assurance). The intent of this work is to provide recommendations that are relevant to any tumor type, are universally applicable and can be implemented by any clinical immunohistochemistry laboratory performing predictive PD-L1 immunohistochemistry testing.
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http://dx.doi.org/10.1097/PAI.0000000000000800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887625PMC
July 2020

Unexpected pleural finding after a fall.

Lancet Oncol 2019 10 30;20(10):e606. Epub 2019 Sep 30.

Pathological Anatomy and Thoracic Surgery, Department of Cardiac, Thoracic, Vascular Sciences and Public Health - DCTV, University of Padova Medical School, Padova, Italy. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(19)30505-4DOI Listing
October 2019

Vein Suturing Results in Worse Lung Graft Outcomes Compared to the Cuff Method.

Eur Surg Res 2019 3;60(3-4):106-116. Epub 2019 Sep 3.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy,

Background: The rat orthotopic lung transplant model is not widely used yet because of the complexity of the procedure, in particular, venous anastomosis. Here, we performed a rat orthotopic lung transplantation using either the suture (ST) or cuff (CT) method for vein anastomosis.

Objectives: To compare the vein ST and CT techniques in terms of operative time, success, recipient survival, and early histological outcomes was the objective of this study.

Methods: A total of 24 left lung transplants in rats were performed. Twelve syngeneic (Lewis to Lewis) and 12 allogeneic (Brown-Norway to Lewis) lung transplants were performed using either the vein ST or the CT procedure. Arterial and bronchial anastomoses were performed with the CT technique. Graft histological damage was evaluated 3-7 days post-transplant in all rat lungs.

Results: The surgical success rate was 75% in both the ST and CT groups. Failures related mainly to vein bleeding (n = 2 in the ST group) and thrombosis (n = 1 in the ST group; n = 2 in the CT group). Total ischemia time was longer in the ST group (122 ± 25 min in ST group vs. 83 ± 10 min in CT group, mean ± SD), due to prolonged warm ischemia time (60 ± 12 min in the ST group vs. 21 ± 5 min in the CT group, mean ± SD), reflecting the time required to complete the vein ST procedure. The prolonged warm ischemia time resulted in significantly higher vascular inflammation in syngeneic grafts (2.3 ± 1.2 ST group vs. 0 in the CT group, mean ± SD) and in increased severity of ischemia/reperfusion injury and acute graft rejection (3.6 ± 0.4 in the ST group vs. 2.6 ± 0.4 in the CT group, mean ± SD) in allogeneic lung transplants.

Conclusions: The vein ST technique is a more time-consuming procedure than the CT method and the prolonged anastomosis time has a deleterious impact on transplant outcomes. These findings suggest that warm ischemia time - one of the modifiable transplant factors - should be considered a major risk factor in lung transplantation, particularly in the setting of donation after cardiac death.
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http://dx.doi.org/10.1159/000501805DOI Listing
March 2020

Predictors of behaviour in solitary fibrous tumours of the pleura surgically resected: Analysis of 107 patients.

J Surg Oncol 2019 Sep 16;120(4):761-767. Epub 2019 Jul 16.

Thoracic Surgery Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University Hospital of Padova, Padova, Italy.

Objectives: Gold standard therapy for solitary fibrous tumour of the pleura is complete surgical resection. Aims of this retrospective study are to evaluate oncological and surgical outcomes and to verify the clinical reliability of prognostic scores presented in literature.

Methods: Study population: 107 patients surgically treated between 1972 and 2018. Male/female ratio: 1/2.45; median age at surgery: 60 years (range, 19-80); peduncle lesions 69.8%; visceral pleura origin 72.9%; benign histology 73.8%; median diameter 8 cm (range 1 to 35, 27 cases giant [≥15 cm]).

Results: After a median follow up of 7 years, 12 patients had recurrence. By multivariate analysis, malignant histology (P = .03; HR, 4.17; 95% CI, 1.15-15.06), origin from parietal pleura (P  = .03; HR, 3.90; 95% CI, 1.08-14.09), England (P = .002; HR, 1.98; 95% CI, 1.28-3.07), Diebold (P = .008; HR, 1.96; 95% CI, 1.20-3.22) and Tapias (P = .003; HR, 1.75; 95% CI, 1.20-2.53) scores were found independent significant predictors of relapse. Giant tumours were associated with open surgery (P = .003), origin from parietal pleura (P = .011) and intraoperative bleeding (P > .001). Overall 10-year disease-free survival (DFS) rate was 81%. Predictors of worst DFS were parietal pleura origin (P = .002), malignant histology (P = .006) and all the prognostic scores.

Conclusions: Malignant histology and origin from parietal pleura were significant predictors of tumour recurrence and worst DFS. The use of current scoring systems can help to predict clinical behaviour. Patients with higher risk of relapse can benefit from closer follow up, prolonged over 10 years.
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http://dx.doi.org/10.1002/jso.25634DOI Listing
September 2019

Airway Histopathology of Adolescent Survivors of Bronchopulmonary Dysplasia.

J Pediatr 2019 08 7;211:215-218. Epub 2019 May 7.

Department of Woman's and Child's Health - University Hospital of Padova, Padova, Italy. Electronic address:

Long-term survivors of bronchopulmonary dysplasia develop chronic obstructive lung disease. Herein we report in vivo histopathology from bronchial biopsies of 3 adolescent survivors of severe bronchopulmonary dysplasia. Thickened basement membranes with lymphocytic infiltrates and signs of immature neoangiogenesis in the absence of T-helper lymphocytes or eosinophils suggest the presence of an ongoing active airway process.
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http://dx.doi.org/10.1016/j.jpeds.2019.04.006DOI Listing
August 2019

A Nonsmoker Man in His 40s With a Diagnosis of Genetic-Related Idiopathic Pulmonary Fibrosis (Surfactant-Protein C Gene Mutation).

Chest 2019 04;155(4):e91-e96

Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy. Electronic address:

A nonsmoker man in his 40s underwent bilateral lung transplantation with a referral diagnosis of genetic-related idiopathic pulmonary fibrosis (IPF). The patient had no medical history in childhood and early adulthood, nor was there a family history of IPF. His nonsmoker father presented with lung cancer at 59 years of age. The patient was a professional brass instrument player; he had started playing at 9 years of age, and he was recently playing 3 to 4 h per day. He had a 7-year clinical history of chronic cough and shortness of breath. Bilateral fine crackles were present at clinical examination. There was no digital clubbing. Data had been collected since 2015: no clinical or immunologic signs of connective tissue disease were evident, including autoantibodies for myositis or anti-synthetase syndrome. Chest radiograph showed diffuse interstitial lung disease. Results of pulmonary function tests yielded a restrictive pattern with decreased FVC and decreased total lung capacity (69% and 47% of predicted, respectively). The FEV/FVC ratio was 86%, and carbon monoxide transfer coefficient was 36% of predicted. BAL cellular analysis consisted of macrophages (66%), lymphocytes (19%; CD4/CD8 ratio, 0.16), neutrophils (10%), and eosinophils (5%).
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http://dx.doi.org/10.1016/j.chest.2018.12.015DOI Listing
April 2019

Thymic Carcinoma With Thyroid Transcription Factor-1 Expression: An Insidious Pitfall.

J Thorac Oncol 2019 Apr;14(4):e68-e70

Thoracic Surgery Unit, Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2018.09.030DOI Listing
April 2019