Publications by authors named "R Alfieri"

279 Publications

MSI Analysis in Solid and Liquid Biopsies of Gastroesophageal Adenocarcinoma Patients: A Molecular Approach.

Int J Mol Sci 2021 Jul 6;22(14). Epub 2021 Jul 6.

Immunology and Molecular Oncology, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35128 Padova, Italy.

Gastroesophageal adenocarcinoma (GEA) patients with the microsatellite instability (MSI) subtype emerged as optimal candidates for immunotherapy. To date, immunohistochemistry (IHC) is the gold standard for MSI assessment in formalin-fixed paraffin-embedded (FFPE) specimens. However, IHC, although useful for diagnostic typing, cannot be used to analyze cell-free DNA (cfDNA) in liquid biopsy, a tool that could overcome tumor heterogeneity and enable longitudinal monitoring. In order to find an alternative diagnostic method to IHC, we analyzed 86 retrospective GEAs FFPE samples with multiplex PCR. Moreover, to verify the feasibility of MSI detection in liquid biopsy, cfDNA samples of five patients that resulted in having MSI in a prospective cohort of 35 patients were evaluated by multiplex PCR, real-time PCR and droplet digital PCR (ddPCR). Analysis of FFPE showed 100% concordance between multiplex PCR and IHC (Cohen's Kappa agreement = 1). On the contrary, only ddPCR was able to detect MSI in cfDNAs of T3/T4 GEA patients. In conclusion, data highlight the molecular analysis as an optimal alternative to IHC for the diagnostic typing and suggest that the ddPCR assay can be considered as the most reliable and promising molecular approach to detect MSI in the cfDNA of GEA patients.
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http://dx.doi.org/10.3390/ijms22147244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303574PMC
July 2021

Generation and Characterization of a New Preclinical Mouse Model of EGFR-Driven Lung Cancer with MET-Induced Osimertinib Resistance.

Cancers (Basel) 2021 Jul 9;13(14). Epub 2021 Jul 9.

Oncogenic Pathways in Lung Cancer, Institut de Recherche en Cancérologie de Montpellier (IRCM)-Université de Montpellier (UM)-Institut Régional du Cancer de Montpellier (ICM), CEDEX 5, F-34298 Montpellier, France.

Despite the introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) to treat advanced lung cancer harboring EGFR-activating mutations, the prognosis remains unfavorable because of intrinsic and/or acquired resistance. We generated a new state-of-the-art mouse strain harboring the human EGFR oncogene and MET overexpression (EGFR/MET strain) that mimics the MET amplification occurring in one out of five patients with EGFR-mutated lung cancer that relapsed after treatment with osimertinib, a third-generation anti-EGFR TKI. We found that survival was reduced in EGFR/MET mice compared with mice harboring only EGFR (EGFR strain). Moreover, EGFR/MET-driven lung tumors were resistant to osimertinib, recapitulating the phenotype observed in patients. Conversely, as also observed in patients, the crizotinib (anti-MET TKI) and osimertinib combination improved survival and reduced tumor burden in EGFR/MET mice, further validating the model's value for preclinical studies. We also found that in EGFR/MET mice, MET overexpression negatively regulated EGFR activity through MIG6 induction, a compensatory mechanism that allows the coexistence of the two onco-genic events. Our data suggest that single EGFR or MET inhibition might not be a good therapeutic option for EGFR-mutated lung cancer with MET amplification, and that inhibition of both pathways should be the best clinical choice in these patients.
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http://dx.doi.org/10.3390/cancers13143441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307933PMC
July 2021

Inhibition of Human Malignant Pleural Mesothelioma Growth by Mesenchymal Stromal Cells.

Cells 2021 Jun 8;10(6). Epub 2021 Jun 8.

CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy.

Background: Malignant Pleural Mesothelioma (MPM) is an aggressive tumor that has a significant incidence related to asbestos exposure with no effective therapy and poor prognosis. The role of mesenchymal stromal cells (MSCs) in cancer is controversial due to their opposite effects on tumor growth and in particular, only a few data are reported on MSCs and MPM.

Methods: We investigated the in vitro efficacy of adipose tissue-derived MSCs, their lysates and secretome against different MPM cell lines. After large-scale production of MSCs in a bioreactor, their efficacy was also evaluated on a human MPM xenograft in mice.

Results: MSCs, their lysate and secretome inhibited MPM cell proliferation in vitro with S or G0/G1 arrest of the cell cycle, respectively. MSC lysate induced cell death by apoptosis. The efficacy of MSC was confirmed in vivo by a significant inhibition of tumor growth, similar to that produced by systemic administration of paclitaxel. Interestingly, no tumor progression was observed after the last MSC treatment, while tumors started to grow again after stopping chemotherapeutic treatment.

Conclusions: These data demonstrated for the first time that MSCs, both through paracrine and cell-to-cell interaction mechanisms, induced a significant inhibition of human mesothelioma growth. Since the prognosis for MPM patients is poor and the options of care are limited to chemotherapy, MSCs could provide a potential new therapeutic approach for this malignancy.
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http://dx.doi.org/10.3390/cells10061427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227879PMC
June 2021

Immunotherapeutic Approaches in Malignant Pleural Mesothelioma.

Cancers (Basel) 2021 Jun 4;13(11). Epub 2021 Jun 4.

Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignant disease affecting the mesothelium, commonly associated to asbestos exposure. The current therapeutic actions, based on cisplatin/pemetrexed treatment, are limited due to the late stage at which most patients are diagnosed and to the intrinsic chemo-resistance of the tumor. Another relevant point is the absence of approved therapies in the second line setting following progression of MPM after chemotherapy. Considering the poor prognosis of the disease and the fact that the incidence of this tumor is expected to increase in the next decade, novel therapeutic approaches are urgently needed. In the last few years, several studies have investigated the efficacy and safety of immune-checkpoint inhibitors (ICIs) in the treatment of unresectable advanced MPM, and a number of trials with immunotherapeutic agents are ongoing in both first line and second line settings. In this review, we describe the most promising emerging immunotherapy treatments for MPM (ICIs, engineered T cells to express chimeric antigen receptors (CARs), dendritic cells (DCs) vaccines), focusing on the biological and immunological features of this tumor as well as on the issues surrounding clinical trial design.
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http://dx.doi.org/10.3390/cancers13112793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200040PMC
June 2021

Chemoradiotherapy followed by Active Surveillance Versus Standard Esophagectomy for Esophageal Cancer: A Systematic Review and Individual Patient Data Meta-Analysis.

Ann Surg 2021 May 11. Epub 2021 May 11.

*Department of Surgery, Erasmus MC - University Medical Center, Rotterdam, the Netherlands †Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ‡Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America §University of Lille, Department of Digestive and Oncological Surgery, Claude Huriez University Hospital, F-59000 Lille, France ¶Division of Upper Gastro-Intestinal Surgery, Department of Surgery, Humanitas University, Humanitas Clinical and Research Center-IRCCS, Milan, Italy ||Department of Oncological Surgery, Veneto Institute of Oncology (IOV-IRCCS), Padua, Italy **Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea ††Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea ‡‡Department of Surgery, Connolly Hospital, Dublin, Ireland §§Department of Public Health, Erasmus MC - University Medical Center, Rotterdam, the Netherlands.

Objective: To compare overall survival of patients with a clinically complete response (cCR) undergoing active surveillance versus standard esophagectomy.

Summary Background Data: One-third of patients with esophageal cancer have a pathologically complete response in the resection specimen after neoadjuvant chemoradiotherapy. Active surveillance may be of benefit in patients with cCR, determined with diagnostics during response evaluations after chemoradiotherapy.

Methods: A systematic review and meta-analysis was performed comparing overall survival between patients with cCR after chemoradiotherapy undergoing active surveillance versus standard esophagectomy. Authors were contacted to supply individual patient data. Overall and progression free survival were compared using random effects meta-analysis of randomized or propensity score matched data. Locoregional recurrence rate was assessed. The study-protocol was registered (PROSPERO:CRD42020167070).

Results: Seven studies were identified comprising 788 patients, of which after randomization or propensity score matching yielded 196 active surveillance and 257 standard esophagectomy patients. All authors provided individual patient data. The risk of all-cause mortality for active surveillance was 1.08 (95%Confidence Interval (CI):0.62-1.87,p = 0.75) after intention-to-treat analysis and 0.93 (95%CI:0.56-1.54,p = 0.75) after per-protocol analysis. The risk of progression or all-cause mortality for active surveillance was 1.14 (95%CI:0.83-1.58,p = 0.36). Five-year locoregional recurrence rate during active surveillance was 40% (95%CI:26%-59%). 95% of active surveillance patients undergoing postponed esophagectomy for locoregional recurrence had radical resection.

Conclusions: Overall survival was comparable in patients with cCR after chemoradiotherapy undergoing active surveillance or standard esophagectomy. Diagnostic followup is mandatory in active surveillance and postponed esophagectomy should be offered to operable patients in case of locoregional recurrence.
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http://dx.doi.org/10.1097/SLA.0000000000004930DOI Listing
May 2021
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