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Luca FABBIANI

Personale tecnico amministrativo
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto
Docente a contratto
Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze sede Policlinico

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Pubblicazioni

2023 - Can immunohistochemistry improve the pathological diagnosis of placenta accreta spectrum (PAS) disorders? [Articolo su rivista]
Losi, Lorena; Botticelli, Laura; Mancini, Luciano; Negro, Rosa; Hanspeter, Esther; Dematté, Eva; Grandi, Giovanni; Facchinetti, Fabio; Veneziano, Micaela; Malagoli, Claudia; Masini, Meris; Fabbiani, Luca; Rivasi, Francesco
abstract

Purpose: The term of placenta accreta spectrum (PAS) disorder includes all grades of abnormal placentation. It is crucial for pathologist provide standardized diagnostic assessment to evaluate the outcome of management strategies. Moreover, a correct and safe diagnosis is useful in the medico-legal field when it becomes difficult for the gynecologist to demonstrate the suitability and legitimacy of demolitive treatment. The purposes of our study were: (1) to assess histopathologic features according to the recent guidelines; (2) to determine if immunohistochemistry can be useful to identify extravillous trophoblast (EVT) and to measure the depth of infiltration into the myometrium to improve the diagnosis of PAS. Methods: The retrospective study was conducted on 30 cases of gravid hysterectomy with histopathologic diagnosis of PAS. To identify the depth of EVT, immunohistochemical stainings were performed using anti MNF116 (cytokeratins 5, 6, 8, 17, 19), actin-SM, HPL (Human Placental Lactogen), vimentin and GATA3 antibodies. Results: Our cases were graded based on the degree of invasion of the myometrium. Ten were grade 1 (33.3%), 12 grade 2 (40%) and 8 grade 3A (26.7%). EVT invasion was best seen and evident by double immunostainings with actin-SM and cytokeratins, actin-SM and HPL, actin-SM and GATA3. Conclusion: The role of pathologist is decisive to determine the different grades of PAS. A better understanding of the depth of myometrial invasion can be achieved by the use of immunohistochemistry affording an important tool to obtain reproducible grading of PAS. This purpose is crucial in the setting of postoperative quality reviews and particularly in the forensic medicine field.

2023 - Inhibition of ERK1/2 signaling prevents bone marrow fibrosis by reducing osteopontin plasma levels in a myelofibrosis mouse model [Articolo su rivista]
Bianchi, Elisa; Rontauroli, Sebastiano; Tavernari, Lara; Mirabile, Margherita; Pedrazzi, Francesca; Genovese, Elena; Sartini, Stefano; Dall'Ora, Massimiliano; Grisendi, Giulia; Fabbiani, Luca; Maccaferri, Monica; Carretta, Chiara; Parenti, Sandra; Fantini, Sebastian; Bartalucci, Niccolò; Calabresi, Laura; Balliu, Manjola; Guglielmelli, Paola; Potenza, Leonardo; Tagliafico, Enrico; Losi, Lorena; Dominici, Massimo; Luppi, Mario; Vannucchi, Alessandro Maria; Manfredini, Rossella
abstract

Clonal myeloproliferation and development of bone marrow (BM) fibrosis are the major pathogenetic events in myelofibrosis (MF). The identification of novel antifibrotic strategies is of utmost importance since the effectiveness of current therapies in reverting BM fibrosis is debated. We previously demonstrated that osteopontin (OPN) has a profibrotic role in MF by promoting mesenchymal stromal cells proliferation and collagen production. Moreover, increased plasma OPN correlated with higher BM fibrosis grade and inferior overall survival in MF patients. To understand whether OPN is a druggable target in MF, we assessed putative inhibitors of OPN expression in vitro and identified ERK1/2 as a major regulator of OPN production. Increased OPN plasma levels were associated with BM fibrosis development in the Romiplostim-induced MF mouse model. Moreover, ERK1/2 inhibition led to a remarkable reduction of OPN production and BM fibrosis in Romiplostim-treated mice. Strikingly, the antifibrotic effect of ERK1/2 inhibition can be mainly ascribed to the reduced OPN production since it could be recapitulated through the administration of anti-OPN neutralizing antibody. Our results demonstrate that OPN is a novel druggable target in MF and pave the way to antifibrotic therapies based on the inhibition of ERK1/2-driven OPN production or the neutralization of OPN activity.

2021 - CLINICAL AND PATHOLOGICAL FEATURES OF BREAST CANCER IN PATIENTS WITH SYSTEMIC SCLEROSIS: PRELIMINARY DATA FROM THE SCLERO-BREAST STUDY [Abstract in Rivista]
Toss, Angela; Spinella, Amelia; Isca, Chrystel; Vacchi, Caterina; Ficarra, Guido; Fabbiani, Luca; Iannone, Anna; Magnani, Luca; Castrignanò, Paola; Macripo', Pierluca; Gasparini, Elisa; Piana, Simonetta; Cortesi, Laura; Maiorana, Antonino; Salvarani, Carlo; Dominici, Massimo; Giuggioli, Dilia
abstract

Systemic Sclerosis (SSc) is a chronic disease associated with a 1.5-fold increase in cancer risk, including lung cancer, hematological malignancies, and breast cancer (BC). This is a retrospective study aiming to explore the clinical and pathological features of BC developed by SSc patients. A total of 54.5% of patients developed BC before SSc (median interval: 5 years), whereas 45.5% of patients developed BC after SSc (median delay: 8 years). A total of 93.1% of patients were diagnosed with an early stage tumor. Among invasive carcinomas, 70.8% presented with a low Mib1, 8.3% with a tubular histotype, and 42.8% with a Luminal A-like phenotype. A total of 66.6% of patients underwent breast-conserving surgery and 55.5% RT. A total of 40% of patients developed interstitial lung disease after RT and 20% diffuse cutaneous SSc. The cause of death of the six deceased patients was PAH. A significant association was observed between the use of immunosuppressive therapy and diffuse skin extension, negative ACA, positive Anti-Scl-70, and interstitial lung disease, but not BC status. SSc patients developed BC at a good prognosis, suggesting a de-escalation strategy of cancer therapies. In particular, ionizing radiation and chemotherapeuticals should be limited to higher-risk cases. Finally, proper screening is mandatory in order to allow for early cancer detection in SSc patients.

2021 - Clinical and Pathological Features of Breast Cancer in Systemic Sclerosis: Results from the Sclero-Breast Study [Articolo su rivista]
Toss, Angela; Spinella, Amelia; Isca, Chrystel; Vacchi, Caterina; Ficarra, Guido; Fabbiani, Luca; Iannone, Anna; Magnani, Luca; Castrignanò, Paola; Macripò, Pierluca; Gasparini, Elisa; Piana, Simonetta; Cortesi, Laura; Maiorana, Antonino; Salvarani, Carlo; Dominici, Massimo; Giuggioli, Dilia
abstract

Systemic Sclerosis (SSc) is a chronic disease associated with a 1.5-fold increase in cancer risk, including lung cancer, hematological malignancies, and breast cancer (BC). This is a retrospective study aiming to explore the clinical and pathological features of BC developed by SSc patients. A total of 54.5% of patients developed BC before SSc (median interval: 5 years), whereas 45.5% of patients developed BC after SSc (median delay: 8 years). A total of 93.1% of patients were diagnosed with an early stage tumor. Among invasive carcinomas, 70.8% presented with a low Mib1, 8.3% with a tubular histotype, and 42.8% with a Luminal A-like phenotype. A total of 66.6% of patients underwent breast-conserving surgery and 55.5% RT. A total of 40% of patients developed interstitial lung disease after RT and 20% diffuse cutaneous SSc. The cause of death of the six deceased patients was PAH. A significant association was observed between the use of immunosuppressive therapy and diffuse skin extension, negative ACA, positive Anti-Scl-70, and interstitial lung disease, but not BC status. SSc patients developed BC at a good prognosis, suggesting a de-escalation strategy of cancer therapies. In particular, ionizing radiation and chemotherapeuticals should be limited to higher-risk cases. Finally, proper screening is mandatory in order to allow for early cancer detection in SSc patients.

2021 - TERT promoter methylation and protein expression as predictive biomarkers for recurrence risk in patients with serous borderline ovarian tumours [Articolo su rivista]
Losi, Lorena; Botticelli, Laura; Garagnani, Lorella; Fabbiani, Luca; Panini, Rossana; Gallo, Graziana; Sabbatini, Roberto; Maiorana, Antonino; Benhattar, Jean
abstract

Epithelial ovarian neoplasms can be divided into three distinct clinicopathological groups: benign, malignant and borderline tumours. Borderline tumours are less aggressive than epithelial carcinomas, with an indolent clinical course and delayed recurrence. However, a subset of these cases can progress to malignancy and relapse, and death from recurrent disease can occasionally occur. Telomerase activation is a critical element in cellular immortalisation and cancer. The enzyme telomerase comprises a catalytic subunit (TERT) expressed in various types of cancers and regulated by promoter methylation mainly in epithelial tumours. The aim of this study was to investigate the promoter methylation status and the expression of TERT in 50 serous borderline tumours (SBTs) and their correlation with clinicopathological features and outcome. TERT methylation was analysed by bisulfite pyrosequencing and TERTexpression by immunohistochemistry. Methylation of TERT promoter was only observed in four SBTs. A good correlation with immunostochemistry was found: nuclear positivity for TERT expression was observed in the methylated cases, whereas no expression was detected in unmethylated tumours. One of these patients had a recurrence after 7 years and another patient died from the disease. SBTs with hypomethylated tumours and absence of TERTexpression showed a good clinical behaviour. Our study highlights the low presence of TERT methylation in SBTs, confirming that these tumours have a different biology than serous carcinomas. Furthermore, the concordance between TERT promoter methylation and TERT expression and their association with clinical outcomes leads to consider TERT alteration as a potential predictive biomarker for recurrence risk identifying patients who should undergo a careful and prolonged follow-up.

2021 - TRAIL receptors are expressed in both malignant and stromal cells in pancreatic ductal adenocarcinoma [Articolo su rivista]
Dall'Ora, Massimiliano; Rovesti, Giulia; Reggiani Bonetti, Luca; Casari, Giulia; Banchelli, Federico; Fabbiani, Luca; Veronesi, Elena; Petrachi, Tiziana; Magistri, Paolo; Di Benedetto, Fabrizio; Spallanzani, Andrea; Chiavelli, Chiara; Spano, Maria Carlotta; Maiorana, Antonino; Dominici, Massimo; Grisendi, Giulia
abstract

: This study assesses the expression of all TNF-related apoptosis-inducing ligand (TRAIL) receptors in pancreatic ductal adenocarcinoma (PDAC) tumor tissue. We aimed to include TRAIL receptor expression as an inclusion parameter in a future clinical study using a TRAIL-based therapy approach for PDAC patients. Considering the emerging influence of PDAC desmoplastic stroma on the efficacy of anti-PDAC therapies, this analysis was extended to tumor stromal cells. Additionally, we performed PDAC stroma characterization. Our retrospective cohort study (N=50) included patients with histologically confirmed PDAC who underwent surgery. The expression of TRAIL receptors (DR4, DR5, DcR1, DcR2, and OPG) in tumor and stromal cells was evaluated by immunohistochemistry (IHC). The amount of tumor stroma was assessed by anti-vimentin IHC and Mallory's trichrome staining. The prognostic impact was determined by the univariate Cox proportional hazards regression model. An extensive expression of functional receptors DR4 and DR5 and a variable expression of decoy receptors were detected in PDAC tumor and stromal cells. Functional receptors were detected also in metastatic tumor and stromal cells. A poor prognosis was associated with low or absent expression of decoy receptors in tumor cells of primary PDAC. After assessing that almost 80% of tumor mass was composed of stroma, we correlated a cellular-dense stroma in primary PDAC with reduced relapse-free survival. We demonstrated that TRAIL functional receptors are widely expressed in PDAC, representing a promising target for TRAIL-based therapies. Further, we demonstrated that a low expression of DcR1 and the absence of OPG in tumor cells, as well as a cellular-dense tumor stroma, could negatively impact the prognosis of PDAC patients.

2021 - The Interplay between HGF/c-met Axis and Nox4 in BRAF Mutated Melanoma [Articolo su rivista]
Beretti, Francesca; Farnetani, Francesca; Reggiani Bonetti, Luca; Fabbiani, Luca; Zavatti, Manuela; Maiorana, Antonino; Pellacani, Giovanni; Maraldi, Tullia
abstract

Melanoma is the leading cause of death due to cutaneous malignancy and its incidence is on the rise. Several signaling pathways, including receptor tyrosine kinases, have a role in the development and progression of melanocytic lesions and malignant melanoma. Among those, the hepatocyte growth factor (HGF)/c-met axis is emerging as a critical player because it can play a role in drug resistance. Indeed, 50% of melanoma patients present BRAF mutations, however, all responders develop resistance to the inhibitors typically within one year of treatment. Interestingly, BRAF inhibitors induce reactive oxygen species (ROS) in melanoma cells, therefore, the aim of this study was to investigate a possible interplay between HGF/c-met and ROS sources, such as NADPH oxidases (Nox).

2020 - A proof of evidence supporting abnormal immunothrombosis in severe COVID-19: naked megakaryocyte nuclei increase in the bone marrow and lungs of critically ill patients [Articolo su rivista]
Roncati, L.; Ligabue, G.; Nasillo, V.; Lusenti, B.; Gennari, W.; Fabbiani, L.; Malagoli, C.; Gallo, G.; Giovanella, S.; Lupi, M.; Salviato, T.; Paolini, A.; Costantini, M.; Trenti, T.; Maiorana, A.
abstract

Coronavirus disease 2019 (COVID-19) is a global public health emergency with many clinical facets, and new knowledge about its pathogenetic mechanisms is deemed necessary; among these, there are certainly coagulation disorders. In the history of medicine, autopsies and tissue sampling have played a fundamental role in order to understand the pathogenesis of emerging diseases, including infectious ones; compared to the past, histopathology can be now expanded by innovative techniques and modern technologies. For the first time in worldwide literature, we provide a detailed postmortem and biopsy report on the marked increase, up to 1 order of magnitude, of naked megakaryocyte nuclei in the bone marrow and lungs from serious COVID-19 patients. Most likely related to high interleukin-6 serum levels stimulating megakaryocytopoiesis, this phenomenon concurs to explain well the pulmonary abnormal immunothrombosis in these critically ill patients, all without molecular or electron microscopy signs of megakaryocyte infection.

2020 - Type 3 hypersensitivity in COVID-19 vasculitis [Articolo su rivista]
Roncati, L.; Ligabue, G.; Fabbiani, L.; Malagoli, C.; Gallo, G.; Lusenti, B.; Nasillo, V.; Manenti, A.; Maiorana, A.
abstract

Coronavirus Disease 2019 (COVID-19) is an ongoing public health emergency and new knowledge about its immunopathogenic mechanisms is deemed necessary in the attempt to reduce the death burden, globally. For the first time in worldwide literature, we provide scientific evidence that in COVID-19 vasculitis a life-threatening escalation from type 2 T-helper immune response (humoral immunity) to type 3 hypersensitivity (immune complex disease) takes place. The subsequent deposition of immune complexes inside the vascular walls is supposed to induce a severe inflammatory state and a cytokine release syndrome, whose interleukin-6 is the key myokine, from the smooth muscle cells of blood vessels.

2019 - Role of evaluating tumor‑infiltrating lymphocytes, programmed death‑1 ligand 1 and mismatch repair proteins expression in malignant mesothelioma [Articolo su rivista]
Losi, Lorena; Bertolini, Federica; Guaitoli, Giorgia; Fabbiani, Luca; Banchelli, Federico; Ambrosini-Spaltro, Andrea; Botticelli, Laura; Scurani, Letizia; Baldessari, Cinzia; Barbieri, Fausto; Cascinu, Stefano; Maiorana, Antonino
abstract

The tumor immune microenvironment (TME) and immune checkpoints have been reported to serve a role in the pathogenesis of malignant mesothelioma (MM) and treatment outcome. Additionally, mismatch Repair (MMR) deficiency appears to enhance the response to checkpoints blockade in several tumors. The aim of the present study was to analyze programmed death‑1 ligand 1 (PD‑L1) expression in MM and to characterize the TME. This could help to understand the immune response, and evaluate its prognostic and predictive values. We also investigated MMR protein expression. We retrospectively analyzed 55 mesotheliomas to determine PD‑L1, CD4+, CD8+, mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and PMS1 homolog 2, mismatch repair system component (PMS2) expression. We used an immunoscore (1+, 2+ and 3+) to evaluate tumor‑infiltrating lymphocytes (TILs). TILs were observed in all but two samples (53/55); the majority had an immunoscore 1+ (30/53), while 2+/3+ was reported for 23/53 samples. A predominance of CD8+ was highlighted in 8 cases (15%). PD‑L1 expression of ≥1% on tumor cells was displayed in 40 cases; in 9 of these, ≥50% expression was reported. Of note, alterations in MMR staining was not observed. In addition, survival analysis revealed that epithelioid subtype was associated with better prognosis. We observed a trend towards poorer prognosis for ≥50% PD‑L1 expression on tumor cells, lower immunoscore (1+) and CD8+ TIL predominance. The present study highlighted the importance of exploring the TME and the standardization of PD‑L1 assessment guidelines to apply in the field of immunotherapy.

2018 - Distinct DNA Methylation Profiles in Ovarian Tumors: Opportunities for Novel Biomarkers [Articolo su rivista]
Losi, Lorena; Fonda, Sergio; Saponaro, Sara; Chelbi, Sonia T.; Cesare, Lancellotti; Gozzi, Gaia; Loredana, Alberti; Fabbiani, Luca; Laura, Botticelli; Jean, Benhattar
abstract

Aberrant methylation of multiple promoter CpG islands could be related to the biology of ovarian tumors and its determination could help to improve treatment strategies. DNA methylation profiling was performed using the Methylation Ligation-dependent Macroarray (MLM), an array-based analysis. Promoter regions of 41 genes were analyzed in 102 ovarian tumors and 17 normal ovarian samples. An average of 29% of hypermethylated promoter genes was observed in normal ovarian tissues. This percentage increased slightly in serous, endometrioid, and mucinous carcinomas (32%, 34%, and 45%, respectively), but decreased in germ cell tumors (20%). Ovarian tumors had methylation profiles that were more heterogeneous than other epithelial cancers. Unsupervised hierarchical clustering identified four groups that are very close to the histological subtypes of ovarian tumors. Aberrant methylation of three genes (BRCA1, MGMT, and MLH1), playing important roles in the different DNA repair mechanisms, were dependent on the tumor subtype and represent powerful biomarkers for precision therapy. Furthermore, a promising relationship between hypermethylation of MGMT, OSMR, ESR1, and FOXL2 and overall survival was observed. Our study of DNA methylation profiling indicates that the different histotypes of ovarian cancer should be treated as separate diseases both clinically and in research for the development of targeted therapies.

2016 - Promoter Methylation and Down-regulated Expression of the TBX15 Gene in Ovarian Carcinoma [Articolo su rivista]
Gozzi, Gaia; Chelbi, Sonia T; Manni, Paola; Alberti, Loredana; Fonda, Sergio; Saponaro, Sara; Fabbiani, Luca; Rivasi, Francesco; Benhattar, Jean; Losi, Lorena
abstract

TBX15 is a gene involved in the development of mesodermal derivatives. As the ovaries and the female reproductive system are of mesodermal origin, the aim of the present study was to determine the methylation status of the TBX15 gene promoter and the expression levels of TBX15 in ovarian carcinoma, which is the most lethal and aggressive type of gynecological tumor, in order to determine the role of TBX15 in the pathogenesis of ovarian carcinoma. This alteration could be used to predict tumor development, progression, recurrence and therapeutic effects. The study was conducted on 80 epithelial ovarian carcinoma and 17 control cases (normal ovarian and tubal tissues). TBX15 promoter methylation was first determined by pyrosequencing following bisulfite modification, then by cloning and sequencing, in order to obtain information about the epigenetic haplotype. Immunohistochemical analysis was performed to evaluate the correlation between the methylation and protein expression levels. Data revealed a statistically significant increase of the TBX15 promoter region methylation in 82% of the tumor samples and in various histological subtypes. Immunohistochemistry showed an inverse correlation between methylation levels and the expression of the TBX15 protein. Furthermore, numerous tumor samples displayed varying degrees of intratumor heterogeneity. Thus, the present study determined that ovarian carcinoma typically expresses low levels of TBX15 protein, predominantly due to an epigenetic mechanism. This may have a role in the pathogenesis of ovarian carcinoma independent of the histological subtype.