Letizia Gnetti
@ao.pr.it
Pathology Unit
University hospital of Parma
RESEARCH INTERESTS
Lung, kidney and gastrointestinal
Scopus Publications
Scopus Publications
Gianluca Di Rienzo, Alessandro Tafuni, Umberto Maestroni, Livia Ruffini, Enrico Maria Silini, Donatello Gasparro, Francesco Paolo Pilato, and Letizia Gnetti
Siapec Servizi Srl
Summary Background Metastatic prostate adenocarcinoma is a rare event and there are few references to this topic. We report an unusual case of prostate cancer metastasis and review of contemporary literature. Moreover, we discuss the pathogenesis and the clinical aspects of this event. Case presentation A 70-year-old patient was admitted to the hospital for right scrotal pain. The ultrasound examination described an increase in testicular size, suggesting the possibility of orchiepididymitis. Past medical history reported a previous prostate adenocarcinoma. Inflammatory blood tests were normal. Importantly, PSA was 3.3 ng/ml. PET scan positivity in the scrotum raised suspicion of a relapse. Therefore, he underwent right orchiectomy. Conclusion Although metastatic prostate adenocarcinoma is rare, a correct diagnosis is of paramount importance because the therapy changes accordingly. Patients who complain of scrotal pain need to be examined accurately. Although the most common cause behind this symptom is infectious, the patient’s past medical history should be reviewed to exclude previous malignancies.
A. Leonetti, M. Verzè, R. Minari, F. Perrone, L. Gnetti, P. Bordi, M. Pluchino, R. Nizzoli, C. Azzoni, L. Bottarelli,et al.
Springer Science and Business Media LLC
A. Cavazzoni, G. Digiacomo, F. Volta, R. Alfieri, E. Giovannetti, L. Gnetti, L. Bellini, M. Galetti, C. Fumarola, G. Xu,et al.
Elsevier BV
Francesco Volta, Silvia La Monica, Alessandro Leonetti, Letizia Gnetti, Mara Bonelli, Andrea Cavazzoni, Claudia Fumarola, Maricla Galetti, Kamal Eltayeb, Roberta Minari,et al.
Springer Science and Business Media LLC
Maria Laura Schirripa, , Letizia Gnetti, Edda Emanuela Guareschi, , , and
Negah Scientific Publisher
Tadalafil is an inhibitor of the human enzyme cyclic guanosine monophosphate–specific phosphodiesterase, type 5 (PDE-5). As a mild vasodilator, it is primarily used for the treatment of erectile dysfunction, an increasingly common condition in men. It is also used for treatment of benign prostatic hyperplasia and pulmonary arterial hypertension. Adverse events of this drug are rare. Absolute contraindications include serious cardiac disease. Despite the widespread use of tadalafil, very little is known about its toxicology in forensic pathology and its association with post-mortem redistribution. This study presents a forensic case with possible contribution of tadalafil. The administration of tadalafil might act as a concurrent cause or contributing factor for lethal cardiogenic shock in people with cardiac disease.
Nicola Fusco, Mariia Ivanova, Chiara Frascarelli, Carmen Criscitiello, Bruna Cerbelli, Maria Gemma Pignataro, Angelina Pernazza, Elham Sajjadi, Konstantinos Venetis, Giulia Cursano,et al.
Elsevier BV
Isabelle Opitz, Andrea Bille, Urania Dafni, Kristiaan Nackaerts, Luca Ampollini, Marc de Perrot, Luka Brcic, Ernest Nadal, Konstantinos Syrigos, Steven G. Gray,et al.
Elsevier BV
Luigi Ventura, Letizia Gnetti, Gianluca Milanese, Maurizio Rossi, Ludovica Leo, Sara Cattadori, Mario Silva, Alessandro Leonetti, Roberta Minari, Luca Musini,et al.
Elsevier BV
Melissa Bersanelli, Letizia Gnetti, Francesco Paolo Pilato, Elena Varotti, Federico Quaini, Nicoletta Campanini, Elena Rapacchi, Roberta Camisa, Paolo Carbognani, Enrico Maria Silini,et al.
Open Exploration Publishing
Aim: In renal cell carcinoma (RCC), tumor heterogeneity generated challenges to biomarker development and therapeutic management, often becoming responsible for primary and acquired drug resistance. This study aimed to assess the inter-tumoral, intra-tumoral, and intra-lesional heterogeneity of known druggable targets in metastatic RCC (mRCC). Methods: The RIVELATOR study was a monocenter retrospective analysis of biological samples from 25 cases of primary RCC and their paired pulmonary metastases. The biomarkers analyzed included MET, mTOR, PD-1/PD-L1 pathways and the immune context. Results: High multi-level heterogeneity was demonstrated. MET was the most reliable biomarker, with the lowest intratumor heterogeneity: the positive mutual correlation between MET expression in primary tumors and their metastases had a significantly proportional intensity (P = 0.038). The intratumor heterogeneity grade was significantly higher for the mTOR pathway proteins. Combined immunophenotypical expression patterns and their correlations with the immune context were uncovered [i.e., mTOR expression in the metastases positively correlated with PD-L1 expression in tumor-infiltrating lymphocytes (TILs), P = 0.019; MET expression was related to PD-1 expression on TILs (P = 0.041, ρ = 0.41) and peritumoral lymphocytes (RILs; P = 0.013, ρ = 0.49)], suggesting the possibility of predicting drug response or resistance to tyrosine kinase, mTOR, or immune checkpoint inhibitors. Conclusions: In mRCC, multiple and multi-level assays of potentially predictive biomarkers are needed for their reliable translation into clinical practice. The easy-to-use immunohistochemical method of the present study allowed the identification of different combined expression patterns, providing cues for planning the management of systemic treatment combinations and sequences in an mRCC patient population. The quantitative heterogeneity of the investigated biomarkers suggests that multiple intralesional assays are needed to consider the assessment reliable for clinical considerations.
Francesca Negri, Lorena Bottarelli, Giuseppe Pedrazzi, Michele Maddalo, Ludovica Leo, Gianluca Milanese, Roberto Sala, Michele Lecchini, Nicoletta Campanini, Cecilia Bozzetti,et al.
Frontiers Media SA
IntroductionThe Notch intracellular domain (NICD) and its ligands Jagged-1(Jag1), Delta-like ligand (DLL-3) and DLL4 play an important role in neoangiogenesis. Previous studies suggest a correlation between the tissue levels of NICD and response to therapy with bevacizumab in colorectal cancer (CRC). Another marker that may predict outcome in CRC is radiomics of liver metastases. The aim of this study was to investigate the expression of NICD and its ligands and the role of radiomics in the selection of treatment-naive metastatic CRC patients receiving bevacizumab.MethodsImmunohistochemistry (IHC) for NICD, Jag1 and E-cadherin was performed on the tissue microarrays (TMAs) of 111 patients with metastatic CRC treated with bevacizumab and chemotherapy. Both the intensity and the percentage of stained cells were evaluated. The absolute number of CD4+ and CD8+ lymphocytes was counted in three different high-power fields and the mean values obtained were used to determine the CD4/CD8 ratio. The positivity of tumor cells to DLL3 and DLL4 was studied. The microvascular density (MVD) was assessed in fifteen cases by counting the microvessels at 20x magnification and expressed as MVD score. Abdominal CT scans were retrieved and imported into a dedicated workstation for radiomic analysis. Manually drawn regions of interest (ROI) allowed the extraction of radiomic features (RFs) from the tumor.ResultsA positive association was found between NICD and Jag1 expression (p < 0.001). Median PFS was significantly shorter in patients whose tumors expressed high NICD and Jag1 (6.43 months vs 11.53 months for negative cases; p = 0.001). Those with an MVD score ≥5 (CD31-high, NICD/Jag1 positive) experienced significantly poorer survival. The radiomic model developed to predict short and long-term survival and PFS yielded a ROC-AUC of 0.709; when integrated with clinical and histopathological data, the integrated model improved the predictive score (ROC-AUC of 0.823).DiscussionThese results show that high NICD and Jag1 expression are associated with progressive disease and early disease progression to anti VEGF-based therapy; the preliminary radiomic analyses show that the integration of quantitative information with clinical and histological data display the highest performance in predicting the outcome of CRC patients.
Jan Hendrik Rüschoff, Martina Haberecker, Zoi Tsourti, Kristiaan Nackaerts, Marc de Perrot, Luka Brcic, Ernest Nadal, Sotirios Tsimpoukis, Steven G. Gray, Luca Ampollini,et al.
Elsevier BV
Jan Hendrik Rüschoff, Martina Haberecker, Zoi Tsourti, Kristiaan Nackaerts, Marc de Perrot, Luka Brcic, Ernest Nadal, Sotirios Tsimpoukis, Steven G. Gray, Luca Ampollini,et al.
Elsevier BV
Giulia Mazzaschi, Fabiana Perrone, Roberta Minari, Michela Verzè, Cinzia Azzoni, Lorena Bottarelli, Monica Pluchino, Maria Pia Armillotta, Annalisa Ubaldi, Annalisa Altimari,et al.
Elsevier BV
Bruno Lorusso, Giuseppe Cerasoli, Angela Falco, Caterina Frati, Gallia Graiani, Denise Madeddu, Antonella Nogara, Emilia Corradini, Giovanni Roti, Elisa Cerretani,et al.
Elsevier BV
Pietro Bertoglio, Vittorio Aprile, Luigi Ventura, Maria Cattoni, Dania Nachira, Filippo Lococo, Maria Rodriguez Perez, Francesco Guerrera, Fabrizio Minervini, Giulia Querzoli,et al.
Springer Science and Business Media LLC
Abstract Objective The presence of micropapillary and solid adenocarcinoma patterns leads to a worse survival and a significantly higher tendency to recur. This study aims to assess the impact of pT descriptor combined with the presence of high-grade components on long-term outcomes in early-stage lung adenocarcinomas. Methods We retrospectively collected data of consecutive resected pT1-T3N0 lung adenocarcinoma from nine European Thoracic Centers. All patients who underwent a radical resection with lymph-node dissection between 2014 and 2017 were included. Differences in Overall Survival (OS) and Disease-Free Survival (DFS) and possible prognostic factors associated with outcomes were evaluated also after performing a propensity score matching to compare tumors containing non-high-grade and high-grade patterns. Results Among 607 patients, the majority were male and received a lobectomy. At least one high-grade histological pattern was seen in 230 cases (37.9%), of which 169 solid and 75 micropapillary. T1a-b-c without high-grade pattern had a significant better prognosis compared to T1a-b-c with high-grade pattern (p = 0.020), but the latter had similar OS compared to T2a (p = 0.277). Concurrently, T1a-b-c without micropapillary or solid patterns had a significantly better DFS compared to those with high-grade patterns (p = 0.034), and it was similar to T2a (p = 0.839). Multivariable analysis confirms the role of T descriptor according to high-grade pattern both for OS (p = 0.024; HR 1.285 95% CI 1.033–1.599) and DFS (p = 0.003; HR 1.196, 95% CI 1.054–1.344, respectively). These results were confirmed after the propensity score matching analysis. Conclusions pT1 lung adenocarcinomas with a high-grade component have similar prognosis of pT2a tumors.
Pietro Bertoglio, Luigi Ventura, Vittorio Aprile, Maria Angela Cattoni, Dania Nachira, Filippo Lococo, Maria Rodriguez Perez, Francesco Guerrera, Fabrizio Minervini, Letizia Gnetti,et al.
SAGE Publications
Objective: To evaluate the influence of lung adenocarcinoma second predominant pattern on the maximal standard uptake value (SUVmax) and its prognostic effect in different histologic groups. Methods: We retrospectively collected surgically resected pathologic stage I and II lung adenocarcinoma from nine European institutions. Only patients who underwent preoperative PET-CT and with available information regarding SUVmax of T (SUVmaxT) and N1 (SUVmaxN1) component were included. Results: We enrolled 344 patients with lung adenocarcinoma. SUVmaxT did not show any significant relation according to the second predominant pattern ( p = 0.139); this relationship remained nonsignificant in patients with similar predominant pattern. SUVmaxT influenced the disease-free survival in the whole cohort ( p = 0.002) and in low- and intermediate-grade predominant pattern groups ( p = 0.040 and p = 0.008, respectively). In the high-grade predominant pattern cohort and in the pathologic N1 cases, SUVmaxT lost its prognostic power. SUVmaxN1 did not show any significant correlation with predominant and second predominant patterns and did not have any prognostic impact on DFS. Conclusions: SUVmaxT is influenced only by the adenocarcinoma predominant pattern, but not by second predominant pattern. Concurrently, in high-grade predominant pattern and pN1 group the prognostic power of SUVmaxT becomes nonsignificant.
Ingrid Garajová, Rita Balsano, Valentina Donati, Letizia Gnetti, Mjriam Capula, Francesco Leonardi, Raffaele Dalla Valle, Matteo Ravaioli, Fabio Gelsomino, and Elisa Giovannetti
Ovid Technologies (Wolters Kluwer Health)
Pietro Bertoglio, Luigi Ventura, Vittorio Aprile, Maria Angela Cattoni, Dania Nachira, Filippo Lococo, Maria Rodriguez Perez, Francesco Guerrera, Fabrizio Minervini, Letizia Gnetti,et al.
Oxford University Press (OUP)
Abstract OBJECTIVES Lung cancer is increasingly diagnosed as a second cancer. Our goal was to analyse the characteristics and outcomes of early-stage resected lung adenocarcinomas in patients with previous cancers (PC) and correlations with adenocarcinoma subtypes. METHODS We retrospectively reviewed data of patients radically operated on for stage I–II lung adenocarcinoma in 9 thoracic surgery departments between 2014 and 2017. Overall survival (OS) and time to disease relapse were evaluated between subgroups. RESULTS We included 700 consecutive patients. PC were present in 260 (37.1%). Breast adenocarcinoma, lung cancer and prostate cancer were the most frequent (21.5%, 11.5% and 11.2%, respectively). No significant differences in OS were observed between the PC and non-PC groups (P = 0.378), with 31 and 75 deaths, respectively. Patients with PC had smaller tumours and were more likely to receive sublobar resection and to be operated on with a minimally invasive approach. Previous gastric cancer (P = 0.042) and synchronous PC (when diagnosed up to 6 months before lung adenocarcinoma; P = 0.044) were related, with a worse OS. Colon and breast adenocarcinomas and melanomas were significantly related to a lower incidence of high grade (solid or micropapillary, P = 0.0039, P = 0.005 and P = 0.028 respectively), whereas patients affected by a previous lymphoma had a higher incidence of a micropapillary pattern (P = 0.008). CONCLUSIONS In patients with PC, we found smaller tumours more frequently treated with minimally invasive techniques and sublobar resection, probably due to a more careful follow-up. The impact on survival is not uniform and predictable; however, breast and colon cancers and melanoma showed a lower incidence of solid or micropapillary patterns whereas patients with lymphomas had a higher incidence of a micropapillary pattern.
Fabiana Perrone, Giulia Mazzaschi, Roberta Minari, Michela Verzè, Cinzia Azzoni, Lorena Bottarelli, Rita Nizzoli, Monica Pluchino, Annalisa Altimari, Elisa Gruppioni,et al.
MDPI AG
Introduction: BRAF mutation involved 2–4% of lung adenocarcinoma. Differences in clinicopathologic features and patient outcome exist between V600E and non-V600E BRAF mutated NSCLC. Thus, we sought to assess the frequency and clinical relevance of BRAF mutations in a real-life population of advanced-NSCLC, investigating the potential prognostic significance of distinct genetic alterations. Materials and Methods: The present multicenter Italian retrospective study involved advanced BRAF mutant NSCLC. Complete clinicopathologic data were evaluated for BRAF V600E and non-V600E patients. Results: A total of 44 BRAFmut NSCLC patients were included (V600E, n = 23; non-V600E, n = 21). No significant differences in survival outcome and treatment response were documented, according to V600E vs. non-V600E mutations, although a trend towards prolonged PFS was observed in the V600E subgroup (median PFS = 11.3 vs. 6.0 months in non-V600E). In the overall population, ECOG PS and age significantly impacted on OS, while bone lesions were associated with shorter PFS. Compared to immunotherapy, first-line chemotherapy was associated with longer OS in the overall population, and especially in the BRAF V600E subtype. Conclusions: Here, we report on real-life data from a retrospective cohort of advanced-NSCLC harboring BRAF alterations. Our study offers relevant clues on survival outcome, therapeutic response, and clinicopathologic correlations of BRAF-mutant NSCLC.
Francesca Negri, Lorena Bottarelli, Gian Luigi de’ Angelis, and Letizia Gnetti
MDPI AG
Mutations in KRAS are among the most frequent aberrations in cancer, including colon cancer. KRAS direct targeting is daunting due to KRAS protein resistance to small molecule inhibition. Moreover, its elevated affinity to cellular guanosine triphosphate (GTP) has made the design of specific drugs challenging. Indeed, KRAS was considered ‘undruggable’. KRASG12C is the most commonly mutated variant of KRAS in non-small cell lung cancer. Currently, the achievements obtained with covalent inhibitors of this variant have given the possibility to assess the best therapeutic approach to KRAS-driven tumors. Mutation-related biochemical assets and the tissue of origin are expected to influence responses to treatment. Further attempts to obtain mutant-specific KRAS (KRASG12C) switch-II covalent inhibitors are ongoing and the results are promising. Drugs targeted to block KRAS effector pathways could be combined with direct KRAS inhibitors, immunotherapy or T cell-targeting approaches in KRAS-mutant tumors. The development of valuable combination regimens will be essential against potential mechanisms of resistance that may arise during treatment.
Roberta Minari, Samuel Valentini, Denise Madeddu, Andrea Cavazzoni, Silvia La Monica, Costanza Anna Maria Lagrasta, Roberto Bertorelli, Veronica De Sanctis, Paola Fassan, Cinzia Azzoni,et al.
Elsevier BV
Francesca Trentini, Giulia Mazzaschi, Gianluca Milanese, Claudio Pavone, Denise Madeddu, Letizia Gnetti, Caterina Frati, Bruno Lorusso, Costanza Anna Maria Lagrasta, Roberta Minari,et al.
SAGE Publications
Background: Radiomics has emerged as a noninvasive tool endowed with the potential to intercept tumor characteristics thereby predicting clinical outcome. In a recent study on resected non-small cell lung cancer (NSCLC), we identified highly prognostic computed tomography (CT)–derived radiomic features (RFs), which in turn were able to discriminate hot from cold tumor immune microenvironment (TIME). We aimed at validating a radiomic model capable of dissecting specific TIME profiles bearing prognostic power in resected NSCLC. Methods: The validation cohort included 31 radically resected NSCLCs clinicopathologically matched with the training set (n = 69). TIME was classified in hot and cold according to a multiparametric immunohistochemical analysis involving PD-L1 score and incidence of immune effector phenotypes among tumor infiltrating lymphocytes (TILs). High-throughput radiomic features (n = 841) extracted from CT images were correlated to TIME parameters to ultimately define prognostic classes. Results: We confirmed PD-1 to CD8 ratio as best predictor of clinical outcome among TIME characteristics. Significantly prolonged overall survival (OS) was observed in patients carrying hot (median OS not reached) vs cold (median OS 22 months; hazard ratio 0.28, 95% confidence interval 0.09–0.82; p = 0.015) immune background, thus validating the prognostic impact of these two TIME categories in resected NSCLC. Importantly, in the validation setting, three out of eight previously identified RFs sharply distinguishing hot from cold TIME were endorsed. Among signature-related RFs, Wavelet-HHH_gldm_HighGrayLevelEmphasis highly performed as descriptor of hot immune contexture (area under the receiver operating characteristic curve 0.94, 95% confidence interval 0.81–1.00; p = 0.01). Conclusion: Radiomics may decipher specific TIME profiles providing a noninvasive prognostic approach in resected NSCLC and an exploitable predictive strategy in advanced cases.
Michela Verzè, Roberta Minari, Letizia Gnetti, Paola Bordi, Alessandro Leonetti, Agnese Cosenza, Leonarda Ferri, Maria Majori, Massimo De Filippo, Sebastiano Buti,et al.
MDPI AG
In order to study alternatives at the tissue biopsy to study EGFR status in NSCLC patients, we evaluated three different liquid biopsy platforms (plasma, urine and exhaled breath condensate, EBC). We also reviewed the literature of the cfDNA biological sources other than plasma and compared our results with it about the sensitivity to EGFR mutation determination. Twenty-two EGFR T790M-mutated NSCLC patients in progression to first-line treatment were enrolled and candidate to osimertinib. Plasma, urine and EBC samples were collected at baseline and every two months until progression. Molecular analysis of cfDNA was performed by ddPCR and compared to tissue results. At progression NGS analysis was performed. The EGFR activating mutation detection reached a sensitivity of 58 and 11% and for the T790M mutation of 45 and 10%, in plasma and urine samples, respectively. Any DNA content was recovered from EBC samples. Considering the plasma monitoring study, the worst survival was associated with positive shedding status; both plasma and urine molecular progression anticipated the radiological worsening. Our results confirmed the role of plasma liquid biopsy in testing EGFR mutational status, but unfortunately, did not evidence any improvement from the combination with alternative sources, as urine and EBC.
Giulia Mazzaschi, Alessandro Leonetti, Roberta Minari, Letizia Gnetti, Federico Quaini, Marcello Tiseo, and Francesco Facchinetti
Springer Science and Business Media LLC
The quest for immunotherapy (IT) biomarkers is an element of highest clinical interest in both solid and hematologic tumors. In non-small-cell lung cancer (NSCLC) patients, besides PD-L1 expression evaluation with its intrinsic limitations, tissue and circulating parameters, likely portraying the tumor and its stromal/immune counterparts, have been proposed as potential predictors of IT responsiveness. STK11 mutations have been globally labeled as markers of IT resistance. After a thorough literature review, STK11 mutations condition the prognosis of NSCLC patients receiving ICI-containing regimens, implying a relevant biological and clinical significance. On the other hand, waiting for prospective and solid data, the putative negative predictive value of STK11 inactivation towards IT is sustained by less evidence. The physiologic regulation of multiple cellular pathways performed by STK11 likely explains the multifaceted modifications in tumor cells, stroma, and tumor immune microenvironment (TIME) observed in STK11 mutant lung cancer, particularly explored in the molecular subgroup of KRAS co-mutation. IT approaches available thus far in NSCLC, mainly represented by anti-PD-1/PD-L1 inhibitors, are not promising in the case of STK11 inactivation. Perceptive strategies aimed at modulating the TIME, regardless of STK11 status or specifically addressed to STK11-mutated cases, will hopefully provide valid therapeutic options to be adopted in the clinical practice.
Francesca Negri, Letizia Gnetti, Giuseppe Pedrazzi, Enrico Maria Silini, and Camillo Porta
Future Medicine Ltd
Background: Alpha-fetoprotein (AFP) is the only biomarker with proven prognostic value in advanced hepatocellular carcinoma. Preliminary data indicate crosstalk between AFP and VEGF signaling. Methods: The authors looked at 69 patients with advanced hepatocellular carcinoma who were previously tested for VEGFR2 expression, had available baseline AFP serum concentrations and were treated with sorafenib within clinical trials. Results: Shorter progression-free survival and overall survival were associated with increased AFP level and elevated VEGFR2 staining. At multivariate analysis of AFP level was the only independent prognostic factor for progression-free survival and overall survival. Conclusion: The authors' study confirms the adverse prognostic role of elevated baseline AFP and also suggests a possible role of AFP in primary resistance to sorafenib therapy.