72 results on '"Pina, Ziranu"'
Search Results
2. CDX-2 expression correlates with clinical outcomes in MSI-H metastatic colorectal cancer patients receiving immune checkpoint inhibitors
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Pina Ziranu, Andrea Pretta, Marta Pozzari, Antonio Maccioni, Manuela Badiali, Daniela Fanni, Eleonora Lai, Clelia Donisi, Mara Persano, Clara Gerosa, Marco Puzzoni, Fabio Bardanzellu, Rossano Ambu, Valeria Pusceddu, Marco Dubois, Giulia Cerrone, Marco Migliari, Sara Murgia, Dario Spanu, Gianluca Pretta, Valentina Aimola, Francesca Balconi, Stefania Murru, Gavino Faa, and Mario Scartozzi
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Medicine ,Science - Abstract
Abstract Immune checkpoint inhibitors (ICIs) showed efficacy in metastatic colorectal cancer (mCRC) with mismatch-repair deficiency or high microsatellite instability (dMMR-MSI-H). Unfortunately, a patient’s subgroup did not benefit from immunotherapy. Caudal-related homeobox transcription factor 2 (CDX-2) would seem to influence immunotherapy’s sensitivity, promoting the chemokine (C-X-C motif) ligand 14 (CXCL14) expression. Therefore, we investigated CDX-2 role as a prognostic-predictive marker in patients with mCRC MSI-H. We retrospectively collected data from 14 MSI-H mCRC patients treated with ICIs between 2019 and 2021. The primary endpoint was the 12-month progression-free-survival (PFS) rate. The secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and disease control rate (DCR). The PFS rate at 12 months was 81% in CDX-2 positive patients vs 0% in CDX-2 negative patients (p = 0.0011). The median PFS was not reached (NR) in the CDX-2 positive group versus 2.07 months (95%CI 2.07–10.8) in CDX-2 negative patients (p = 0.0011). Median OS was NR in CDX-2-positive patients versus 2.17 months (95% Confidence Interval [CI] 2.17–18.7) in CDX2-negative patients (p = 0.026). All CDX-2-positive patients achieved a disease response, one of them a complete response. Among CDX-2-negative patients, one achieved stable disease, while the other progressed rapidly (ORR: 100% vs 0%, p = 0.0005; DCR: 100% vs 50%, p = 0.02). Twelve patients received 1st-line pembrolizumab (11 CDX-2 positive and 1 CDX-2 negative) not reaching median PFS, while two patients (1 CDX-2 positive and 1 CDX-2 negative) received 3rd-line pembrolizumab reaching a median PFS of 10.8 months (95% CI, 10.8–12.1; p = 0.036). Although our study reports results on a small population, the prognostic role of CDX-2 in CRC seems confirmed and could drive a promising predictive role in defining the population more sensitive to immunotherapy treatment. Modulating the CDX-2/CXCL14 axis in CDX-2-negative patients could help overcome primary resistance to immunotherapy.
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- 2023
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3. CD44: A New Prognostic Marker in Colorectal Cancer?
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Pina Ziranu, Andrea Pretta, Valentina Aimola, Flaviana Cau, Stefano Mariani, Alessandra Pia D’Agata, Claudia Codipietro, Daiana Rizzo, Veronica Dell’Utri, Giorgia Sanna, Giusy Moledda, Andrea Cadoni, Eleonora Lai, Marco Puzzoni, Valeria Pusceddu, Massimo Castagnola, Mario Scartozzi, and Gavino Faa
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colorectal cancer ,CD44 ,cancer stem cells ,prognostic marker ,predictive marker ,target therapies ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Cluster of differentiation 44 (CD44) is a non-kinase cell surface glycoprotein. It is overexpressed in several cell types, including cancer stem cells (CSCs). Cells overexpressing CD44 exhibit several CSC traits, such as self-renewal, epithelial–mesenchymal transition (EMT) capability, and resistance to chemo- and radiotherapy. The role of CD44 in maintaining stemness and the CSC function in tumor progression is accomplished by binding to its main ligand, hyaluronan (HA). The HA-CD44 complex activates several signaling pathways that lead to cell proliferation, adhesion, migration, and invasion. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The different functional roles of CD44s and specific CD44v isoforms still need to be fully understood. The clinicopathological impact of CD44 and its isoforms in promoting tumorigenesis suggests that CD44 could be a molecular target for cancer therapy. Furthermore, the recent association observed between CD44 and KRAS-dependent carcinomas and the potential correlations between CD44 and tumor mutational burden (TMB) and microsatellite instability (MSI) open new research scenarios for developing new strategies in cancer treatment. This review summarises current research regarding the different CD44 isoform structures, their roles, and functions in supporting tumorigenesis and discusses its therapeutic implications.
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- 2024
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4. Prediction of Response to Anti-Angiogenic Treatment for Advanced Colorectal Cancer Patients: From Biological Factors to Functional Imaging
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Giuseppe Corrias, Eleonora Lai, Pina Ziranu, Stefano Mariani, Clelia Donisi, Nicole Liscia, Giorgio Saba, Andrea Pretta, Mara Persano, Daniela Fanni, Dario Spanu, Francesca Balconi, Francesco Loi, Simona Deidda, Angelo Restivo, Valeria Pusceddu, Marco Puzzoni, Cinzia Solinas, Elena Massa, Clelia Madeddu, Clara Gerosa, Luigi Zorcolo, Gavino Faa, Luca Saba, and Mario Scartozzi
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metastatic colorectal cancer ,angiogenesis ,anti-angiogenic treatment ,prediction of response ,biologic factors ,radiomics ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical outcomes. Nevertheless, not all patients respond to treatment and some develop resistance. Therefore, the identification of predictive factors able to predict response to angiogenesis pathway blockade is required in order to identify the best candidates to receive these agents. Unfortunately, no predictive biomarkers have been prospectively validated to date. Over the years, research has focused on biologic factors such as genetic polymorphisms, circulating biomarkers, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and microRNA. Moreover, research efforts have evaluated the potential correlation of molecular biomarkers with imaging techniques used for tumor assessment as well as the application of imaging tools in clinical practice. In addition to functional imaging, radiomics, a relatively newer technique, shows real promise in the setting of correlating molecular medicine to radiological phenotypes.
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- 2024
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5. Immunotherapy and Cancer: The Multi-Omics Perspective
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Clelia Donisi, Andrea Pretta, Valeria Pusceddu, Pina Ziranu, Eleonora Lai, Marco Puzzoni, Stefano Mariani, Elena Massa, Clelia Madeddu, and Mario Scartozzi
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immunotherapy ,AI ,multi-omics science ,biomarkers ,state of the art ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Immunotherapies have revolutionized cancer treatment approaches. Because not all patients respond positively to immune therapeutic agents, it represents a challenge for scientists who strive to understand the mechanisms behind such resistance. In-depth exploration of tumor biology, using novel technologies such as omics science, can help decode the role of the tumor immune microenvironment (TIME) in producing a response to the immune blockade strategies. It can also help to identify biomarkers for patient stratification and personalized treatment. This review aims to explore these new models and highlight their possible pivotal role in changing clinical practice.
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- 2024
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6. New Horizons in Metastatic Colorectal Cancer: Prognostic Role of CD44 Expression
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Pina Ziranu, Valentina Aimola, Andrea Pretta, Marco Dubois, Raffaele Murru, Nicole Liscia, Flaviana Cau, Mara Persano, Giulia Deias, Enrico Palmas, Francesco Loi, Marco Migliari, Valeria Pusceddu, Marco Puzzoni, Eleonora Lai, Stefano Cascinu, Gavino Faa, and Mario Scartozzi
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metastatic colorectal cancer ,biomarkers ,CD44 expression ,cancer stem cells ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: The transmembrane glycoprotein CD44, the major hyaluronan (HA) receptor, has been proven to regulate cell growth, survival, differentiation, and migration. It is therefore widely considered to be involved in carcinogenesis. Its role as a new therapeutic target in solid tumors is under evaluation in clinical trials. The prognostic value remains controversial. Here, we aimed to investigate the correlation between CD44 expression and the clinicopathological features and survival in metastatic colorectal cancer (mCRC) patients. Methods: Data from 65 mCRC patients of the Medical Oncology Unit, University Hospital and University of Cagliari were retrospectively collected from 2008 to 2021. Immunohistochemical analysis was performed at the Pathology Division, University Hospital of Cagliari on 3 μm thick sections obtained from paraffin blocks. The intensity of immunohistochemical staining was subclassified into four groups: score 0 if negative or weak membrane staining in less than 10% of tumor cells; score 1+ if weak membrane staining in at least 10% of tumor cells or moderate membrane staining in less than 10% of tumor cells; score 2+ if moderate membrane staining in at least 10% of tumor cells or intensive membrane staining in less than 10% of tumor cells; score 3+ if intense membrane staining in at least 10% of tumor cells. Based on this score, we distinguished patients into low CD44 expression (score 0, 1+, 2+) and high CD44 expression (score 3+). Statistical analysis was performed with MedCalc (survival distribution: Kaplan–Meier; survival comparison: log-rank test; association between categorical variables: Fisher’s exact test). Results: Patients’ median age was 66 years (range 49–85). Regarding CD44 expression, score was 0 in 18 patients, 1+ in 15 patients, 2+ in 18 patients, and 3+ in 14 patients. Median overall survival (mOS) was 28.1 months (95%CI: 21.3–101). CD44 overexpression (3+) was correlated with poor prognosis (p = 0.0011; HR = 0.2), with a mOS of 14.5 months (95%CI 11.7 to 35.9) versus 30.7 months (95%CI 27.8 to 101) in lower CD44 expression. Higher CD44 expression was associated with clinically poor prognostic features: age ≥ 70 years (p = 0.0166); inoperable disease (p = 0.0008); stage IV at diagnosis (p = 0.0241); BRAF mutated (p = 0.0111), high-grade tumor (p = 0.0084). Conclusions: CD44 markedly correlated with aggressive tumor behavior and contributed to the earlier progression of disease, thus suggesting its role as a novel prognostic marker and potential therapeutic target for mCRC patients.
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- 2023
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7. Liquid Biopsy-Driven Cetuximab Rechallenge Strategy in Molecularly Selected Metastatic Colorectal Cancer Patients
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Stefano Mariani, Marco Puzzoni, Riccardo Giampieri, Pina Ziranu, Valeria Pusceddu, Clelia Donisi, Mara Persano, Giovanna Pinna, Erika Cimbro, Alissa Parrino, Dario Spanu, Andrea Pretta, Eleonora Lai, Nicole Liscia, Alessio Lupi, Enrica Giglio, Grazia Palomba, Milena Casula, Marina Pisano, Giuseppe Palmieri, and Mario Scartozzi
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colorectal (colon) cancer ,epidermal growth factor receptor (EGFR) ,RAS ,liquid biopsy ,rechallenge ,cetuximab ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundRechallenge with EGFR inhibitors represents a promising strategy for patients with RAS wild type (WT) colorectal cancer (CRC) but definitive selection criteria are lacking. Recently, the RAS WT status on circulating tumor DNA (ct-DNA) emerged as a potential watershed for this strategy. Our study explored the liquid biopsy-driven cetuximab rechallenge in a RAS and BRAF WT selected population.MethodsCRC patients with RAS and BRAF WT both on tumor tissue and on ct-DNA at baseline receiving rechallenge with cetuximab were eligible for our analysis. Ct-DNA was analyzed for RAS-BRAF mutations with pyro-sequencing and nucleotide sequencing assays. Real-time PCR and droplet digital PCR were performed to confirm the RAS-BRAF mutational status.ResultsA total of 26 patients were included in our analysis. In the global population, RR was 25.0%, median overall survival (mOS) was 5.0 months, and median progression-free survival (mPFS) was 3.5 months. Previous response to anti-EGFR was associated with improved mPFS (5.0 vs. 2.0 months, HR: 0.26, p = 0.048); anti-EGFR free interval > 14 months and anti-EGFR free interval > 16 months were associated with improved mPFS (respectively 7.0 vs. 3.0 months, HR: 0.27, p = 0.013 and not reached vs. 3.0 months, HR: 0.20, p = 0.002) and with improved mOS (respectively 13.0 vs. 5.0 months, HR: 0.27, p = 0.013 and 13.0 vs. 5.0 months, HR: 0.20, p = 0.002). Previous lines >2 were correlated with improved mPFS (4.0 vs. 1.0 month, HR: 0.05, p = 0.041) and with improved mOS (7.0 vs. 1.0 month, HR: 0.045, p = 0.034). In a multiple logistic regression model, only the anti-EGFR free interval was confirmed to be a significant predictor for mOS and mPFS.ConclusionsLiquid biopsy-driven cetuximab rechallenge was confirmed to be effective. The clinical outcome was consistent with available results from phase II studies. In addition to the molecular selection through the analysis of ct-DNA for RAS, the long anti-EGFR free interval is confirmed as a prospective selection criterion for this therapeutic option.
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- 2022
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8. Retrospective Comparative Analysis of KRAS G12C vs. Other KRAS Mutations in mCRC Patients Treated With First-Line Chemotherapy Doublet + Bevacizumab
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Riccardo Giampieri, Alessio Lupi, Pina Ziranu, Alessandro Bittoni, Andrea Pretta, Federica Pecci, Mara Persano, Enrica Giglio, Cecilia Copparoni, Sonia Crocetti, Alessandra Mandolesi, Gavino Faa, Pierpaolo Coni, Mario Scartozzi, and Rossana Berardi
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mCRC ,KRAS ,G12C ,first line ,chemotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundKRAS mutations in metastatic colorectal cancer (mCRC) define a subset of tumors that have primary resistance to anti-EGFR-based therapy. Data concerning whether different KRAS mutations may also have a prognostic value are lacking. Furthermore, novel KRAS G12C inhibitors are currently in development. The aim of our analysis was to compare response rates in patients treated with first-line chemotherapy doublet + Bevacizumab among different KRAS variants. Secondary end-points were progression free survival (PFS) and overall survival (OS).MethodsPatients with KRAS mutated mCRC treated with either FOLFIRI/FOLFOX/XELOX + Bevacizumab were eligible for enrollment. Patients whose tumor harbored NRAS mutations or that coexpressed also BRAF mutations were excluded from this retrospective analysis. Patients’ individual data were collected from patients’ records. Propensity score matching (nearest method, 1:2 ratio) was used to define the two different groups of patients for comparison (KRAS G12C mutated vs other KRAS variants). Eastern Cooperative Oncology Group Performance Status (ECOG PS), sex, metastatic site of involvement, synchronous vs metachronous metastatic disease, tumor sidedness, mucinous histology, primary tumor surgery, more than two lines of treatment for metastatic disease, and radical surgery of metastases were used as matching factors. Response rate (RR) was calculated by RECIST 1.1 criteria. Both progression free-survival and overall survival were calculated by Kaplan–Meier method. Categorical variables were compared by Fisher exact test for binomial variables and by chi-square test for all other instances. The level of statistical significance p was set at 0.05 for all tests.ResultsA total of 120 patients were assessed in the final analysis. Out of the 120 patients, 15 (12%) were KRAS G12C mutated. In the whole cohort of patients, 59/120 (49%) had partial response (PR), 42/120 (35%) had stable disease (SD), and 19/120 (16%) had progressive disease (PD) as the best response. In KRAS G12C patients, 4/15 (27%) had PR, 6/15 (40%) had SD, and the remaining 5/15 (33%) had PD as the best response. In patients with other KRAS mutations, 55/105 (52%) had PR, 37/105 (35%) had SD, and the remaining 13/105 (12%) had PD as the best response. The difference in RR between the two groups of patients was statistically significant (p=0.017). On the other hand, no difference in PFS (p=0.76) and OS (p=0.56) was observed. After matching procedures, the difference in response rates between KRAS G12C mutated patients vs the matched cohort of patients with other KRAS mutations remained statistically significant (p=0.016). KRAS G12C mutations were not associated with differences in sites of metastatic involvement, sex, and ECOG PS. On the other hand, synchronous vs metachronous metastatic disease (p=0.039), age > 75 years (p=0.043), and mucinous histology (p=0.008) were more frequent in G12C mutated tumors.ConclusionsIn our cohort of patients, it was observed that KRAS G12C mutations are associated with worse response rates compared to other KRAS variants when treated with standard chemotherapy doublet + Bevacizumab. On the other hand, both PFS and OS were not significantly different. Based on these findings, we believe that new treatment options focused on KRAS G12C inhibition should be tested mainly in first-line setting and in addition to standard chemotherapy doublet + Bevacizumab for mCRC patients, as they might “fill the gap” in response rates that was seen in our study.
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- 2021
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9. Prognostic Value of Body Mass Index in Stage II/III Colon Cancer: Posthoc Analysis From the TOSCA Trial
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Debora Basile, Gerardo Rosati, Francesca Bergamo, Silvio Ken Garattini, Maria Banzi, Maria Zampino, Silvia Bozzarelli, Paolo Marchetti, Fabio Galli, Francesca Galli, Raffaella Longarini, Alberto Zaniboni, Daris Ferrari, Sabino De Placido, Luca Giovanni Frassineti, Mario Nicolini, Saverio Cinieri, Michele Priscindiaro, Pina Ziranu, Riccardo Caccialanza, Alessandro Pastorino, Stefania Mosconi, and Giuseppe Aprile
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Oncology ,Gastroenterology - Published
- 2023
10. Influence of antidiabetic drugs on glucose metabolism and immune response in patients with metastatic pancreatic ductal adenocarcinoma receiving gemcitabine plus nab-paclitaxel as first-line treatment
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Andrea Pretta, Pina Ziranu, Riccardo Giampieri, Clelia Donisi, Erika Cimbro, Dario Spanu, Eleonora Lai, Federica Pecci, Francesca Balconi, Alessio Lupi, Marta Pozzari, Mara Persano, Sara Murgia, Valeria Pusceddu, Marco Puzzoni, Rossana Berardi, and Mario Scartozzi
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Hepatology ,Gastroenterology - Abstract
Association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated. Indeed, DM2 can be both an epiphenomenon of PDAC and a risk factor. The present study aimed to investigate the correlation between overall survival (OS) and antidiabetic drugs in patients with metastatic pancreatic ductal adenocarcinoma and DM2.Data from 232 patients were collected retrospectively from 2014 to 2021. 174 from AOU Cagliari Medical Oncology and 58 from AOU Ancona Medical Oncology. All patients received gemcitabine plus nab-paclitaxel first-line chemotherapy. We aimed to evaluate the correlation between DM2, anti-diabetic medications and overall survival. Survival distribution was assessed by Kaplan-Meier curves.Median age was 68±9, 127 (55%) were male. 138/232 (59%) patients were not affected by DM2, 94/232 (41%) were affected by DM2. 57 were insulin-treated and 37 were metformin-treated. DM2 treated patients showed an higher median overall survival (26 vs 12 months, p = 0,0002). Among DM2 patients insulin-treated and metformin-treated showed an mOS of 21 months and 33 months, respectively.Results showed a correlation between treated DM2 and higher mOS in patients with mPDAC. Limitations due to retrospective data collection must be considered. Further studies in this setting are needed.
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- 2023
11. Immune Checkpoint Inhibitors in the Treatment of HCC
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Clelia Donisi, Marco Puzzoni, Pina Ziranu, Eleonora Lai, Stefano Mariani, Giorgio Saba, Valentino Impera, Marco Dubois, Mara Persano, Marco Migliari, Andrea Pretta, Nicole Liscia, Giorgio Astara, and Mario Scartozzi
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Hepatocellular carcinoma ,immune checkpoint inhibitors ,atezolizumab ,pembrolizumab ,nivolumab ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Hepatocellular carcinoma (HCC) is the typical inflammation-induced neoplasia. It often prospers where a chronic liver disease persists, thus leading a strong rationale for immune therapy. Several immune-based treatments, including immune checkpoint inhibitors (ICI), cytokines, adoptive cell transfer, and vaccines, have been tested in the treatment of HCC. In this review, we summarize the role of the ICI in HCC patients in various sets of treatment. As for advanced HCC, the anti-Programmed cell Death protein 1 (PD1) antibodies and the anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) antibodies have been examined in patients with enthusiastic results in phase I-II-III studies. Overall, this led the Food and Drug Administration (FDA) to approve pembrolizumab, nivolumab, and nivolumab + ipilimumab in the second-line setting. The anti- Programmed Death-Ligand 1 (PDL-1) antibodies have also been evaluated. Thanks to the results obtained from phase III IMbrave study, atezolizumab + bevacizumab is now the standard of care in the first-line advanced setting of HCC. As for localized HCC, the putative immunological effect of locoregional therapies led to evaluate the combination strategy with ICI. This way, chemoembolization, ablation with radiofrequency, and radioembolization combined with ICI are currently under study. Likewise, the study of adjuvant immunotherapy following surgical resection is underway. In addition, the different ICI has been studied in combination with other ICI as well as with multikinase inhibitors and anti-angiogenesis monoclonal antibody. The evidence available suggests that combining systemic therapies and locoregional treatments with ICI may represent an effective strategy in this context.
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- 2021
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12. How to improve metastatic pancreatic ductal adenocarcinoma patients’ selection: Between clinical trials and the real-world
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Andrea, Pretta, Dario, Spanu, Stefano, Mariani, Nicole, Liscia, Pina, Ziranu, Valeria, Pusceddu, Marco, Puzzoni, Elena, Massa, Mario, Scartozzi, and Eleonora, Lai
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Oncology - Abstract
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- 2022
13. Guideline Application in Real world: multi-Institutional Based survey of Adjuvant and first-Line pancreatic Ductal adenocarcinoma treatment in Italy. Primary analysis of the GARIBALDI survey
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M. Reni, E. Giommoni, F. Bergamo, M. Milella, L. Cavanna, M.C. Di Marco, M. Spada, S. Cordio, G. Aprile, G.G. Cardellino, E. Maiello, I. Bernardini, M. Ghidini, S. Bozzarelli, M. Macchini, G. Orsi, I. De Simone, Er. Rulli, L. Porcu, V. Torri, C. Pinto, Michele Reni, Marina Macchini, Giulia Orsi, Umberto Peretti, Mariamaddalena Valente, Elisa Giommoni, Lorenzo Antonuzzo, Francesco Di Costanzo, Francesca Bergamo, Vittorina Zagonel, Sara Lonardi, Federica Buggin, Michele Milella, Silvia Palmerio, Luigi Cavanna, Camilla Di Nunzio, Maria Cristina Di Marco, Elisa Grassi, Massimiliano Spada, Marco Messina, Stefano Cordio, Francesco Avola, Giuseppe Aprile, Salvatore Pagano, Francesca Simionato, Giovanni Gerardo Cardellino, Federica Majer, Evaristo Maiello, Tiziana Pia Latiano, Cinzia Chiarazzo, Fabrizio Artioli, Giorgia Razzini, Antonella Pasqualini, Michele Ghidini, Elisa Binda, Silvia Lazzarelli, Silvia Bozzarelli, Simona Sala, Gabriele Luppi, Elisa Pettorelli, Andrea Spallanzani, Giovanni Vicario, Flavia Salmaso, Marco Basso, Nicola Silvestris, Sabina Del Curatolo, Fable Zustovich, Francesca Bongiovanni, Ciro Longobardi, Ilenia Sandi, Caterina Fontanella, Silvia Montelatici, Monica Giordano, Giovanna Luchena, Micol Gilardoni, Emiliano Tamburini, Britt Rudnas, Barbara Venturini, Barbara Merelli, Giorgia Negrini, Elio Maria Vici, Alessandra Marabese, Cristina Garetto, Paola Curcio, Saverio Cinieri, Margherita Cinefra, Pasqualinda Ferrara, Maurizio Cantore, Patrizia Morselli, Guglielmo Fumi, Agnese Isidori, Giovanni Ciccarese, Giovanni Luca Paolo Frassineti, Flavia Pagan, Vanja Vaccaro, Chiara Spoto, Marianna Ferrara, Carlo Garufi, Marta Caporale, Enrico Vasile, Francesca Salani, Elisa Barone, Rossana Berardi, Azzurra Onofri, Zelmira Ballatore, Alessandra Lucarelli, Alessandra Barucca, Amedeo Pancotti, Teresa Scipioni, Katia Bencardino, Giovanna Marrapese, Laura Idotta, Fausto Petrelli, Veronica Lonati, Anna Ceribelli, Angelo Giuli, Cristina Zannori, Maria Bassanelli, Andrea Mambrini, Laura Ginocchi, Massimo Orlandi, Luigi Celio, Monica Niger, Lavinia Biamonte, Stefano Tamberi, Alessandra Piancastelli, Giorgio Papiani, Irene Valli, Paolo Allione, Maria Giovanna Boe, Mario Scartozzi, Eleonora Lai, Annagrazia Pireddu, Pina Ziranu, Laura Demurtas, Marco Puzzoni, Stefano Mariani, Andrea Pretta, Nicole Liscia, Clementina Savastano, Valentina Malaspina, Giuseppe Tonini, Teresa Grassani, Barbara Barco, Tagliaferri Pierosandro, Domenico Ciliberto, Antonella Ierardi, Natale Daniele Calandruccio, Vincenzo Minotti, Roberta Matocci, Valter Torri, Luca Porcu, Erica Rulli, Irene De Simone, Luciano Carlucci, Eliana Rulli, Davide Poli, Paola Tonto, Francesca Scellato, Carmine Pinto, and M. Reni, E. Giommoni , F. Bergamo , M. Milella , L. Cavanna , M. C. Di Marco , M. Spada , S. Cordio , G. Aprile , G. G. Cardellino, E. Maiello, I. Bernardini, M. Ghidini, S. Bozzarelli, M. Macchini , G. Orsi , I. De Simone, Er. Rulli, L. Porcu, V. Torri & C. Pinto, GARIBALDI Study Group
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Cancer Research ,Oncology ,pancreatic adenocarcinoma, adjuvant, first line, prospective survey, adherence to guidelines - Abstract
Background: Information about the adherence to scientific societies guidelines in the ‘real-world’ therapeutic management of oncological patients are lacking. This multicenter, prospective survey was aimed to improve the knowledge relative to 2017-2018 recommendations of the Italian Association of Medical Oncology (AIOM). Patients and methods: Treatment-naive adult patients with pancreatic adenocarcinoma were enrolled. Group A received adjuvant therapy, group B received primary chemotherapy, and group C had metastatic disease. The results on patients accrued until 31 October 2019 with a mature follow-up were presented. Results: Since July 2017, 833 eligible patients of 923 (90%) were enrolled in 44 Italian centers. The median age was 69 years (range 36-89 years; 24% >75 years); 48% were female; 93% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1; group A: 16%, group B: 30%; group C: 54%; 72% Nord, 13% Center, 15% South. In group A, guidelines adherence was 68% [95% confidence interval (CI) 59% to 76%]; 53% of patients received gemcitabine and 15% gemcitabine þ capecitabine; median CA19.9 was 29 (range 0-7300; not reported 15%); median survival was 36.4 months (95% CI 27.5-47.3 months). In group B, guidelines adherence was 96% (95% CI 92% to 98%); 55% of patients received nab-paclitaxel þ gemcitabine, 27% FOLFIRINOX, 12% gemcitabine, and 3% clinical trial; median CA19.9 was 337 (range 0-20220; not reported 9%); median survival was 18.1 months (95% CI 15.6-19.9 months). In group C, guidelines adherence was 96% (95% CI 94% to 98%); 71% of patients received nabpaclitaxel þ gemcitabine, 16% gemcitabine, 8% FOLFIRINOX, and 4% clinical trial; liver and lung metastases were reported in 76% and 23% of patients, respectively; median CA19.9 value was 760 (range 0-1374500; not reported 9%); median survival was 10.0 months (95% CI 9.1-11.1 months). Conclusions: The GARIBALDI survey shows a very high rate of adherence to guidelines and survival outcome in line with the literature. CA19.9 testing should be enhanced; nutritional and psychological counseling represent an unmet need. Enrollment to assess adherence to updated AIOM guidelines is ongoing.
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- 2023
14. Circulating tumour DNA in gastrointestinal cancer in clinical practice: Just a dream or maybe not?
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Andrea Pretta, Eleonora Lai, Clelia Donisi, Dario Spanu, Pina Ziranu, Valeria Pusceddu, Marco Puzzoni, Elena Massa, and Mario Scartozzi
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Circulating tumor DNA ,Gastrointestinal cancer ,Oncology ,Liquid biopsy ,Esophageal cancer ,Bile duct cancer ,Pancreatic cancer ,Gastric cancer ,Colorectal cancer ,Liver cancer - Abstract
The evaluation of circulating tumor DNA (ctDNA) is increasingly integrated into the management of diagnosis and treatment of gastrointestinal cancer as it represents an innovative and minimally invasive biomarker that could allow us to reach clinical needs not met yet in randomized clinical trials. Recent research provided an interesting overview of the role of circulating tumor DNA in gastric, biliary, liver, pancreatic, and colorectal cancer. Data regarding upper gastrointestinal tumors are currently not practice changing. Tumor detection rates are low in the early stages, while in advanced stages ctDNA is useful for molecular tracking evaluation. Most of the evidence comes from colorectal cancer studies, where ctDNA was evaluated both in the early and advanced stages with the post-surgery minimal residual disease assessment and the response assessment, respectively. ctDNA qualifies as a promising tool in the era of precision medicine, with potential applications in the entire management of gastrointestinal cancer patients. Further evidence is needed to establish which setting may be influenced greatly by liquid biopsy in clinical practice. ispartof: WORLD JOURNAL OF CLINICAL ONCOLOGY vol:13 issue:12 pages:980-983 ispartof: location:United States status: published
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- 2022
15. Colorectal Cancer Early Detection in Stool Samples Tracing CpG Islands Methylation Alterations Affecting Gene Expression
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Ana Florencia Vega-Benedetti, Eleonora Loi, Loredana Moi, Sandra Orrù, Pina Ziranu, Andrea Pretta, Eleonora Lai, Marco Puzzoni, Letizia Ciccone, Andrea Casadei-Gardini, Francesco Cabras, Federica Fortunato, Angelo Restivo, Luigi Zorcolo, Mario Scartozzi, and Patrizia Zavattari
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Colorectal cancer (CRC) ,CpG islands ,cancer methylation alterations ,CRC early diagnosis ,biomarkers ,GRIA4 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Colorectal cancer (CRC) is a major cause of cancer mortality. Early diagnosis is relevant for its prevention and treatment. Since DNA methylation alterations are early events in tumourigenesis and can be detected in cell-free DNA, they represent promising biomarkers for early CRC diagnosis through non-invasive methods. In our previous work, we identified 74 early altered CpG islands (CGIs) associated with genes involved in cell cross-talking and cell signalling pathways. The aim of this work was to test whether methylation-based biomarkers could be detected in non-invasive matrices. Our results confirmed methylation alterations of GRIA4 and VIPR2 in CRC tissues, using MethyLight, as well as in stool samples, using a much more sensitive technique as droplet digital PCR. Furthermore, we analysed expression levels of selected genes whose promoter CGIs were hypermethylated in CRC, detecting downregulation at mRNA and protein levels in CRC tissue for GRIA4, VIPR2, SPOCK1 and SLC6A3. Most of these genes were already lowly expressed in colon normal tissues supporting the idea that cancer DNA methylation targets genes already barely expressed in the matched normal tissues. Our study suggests GRIA4 and VIPR2 as biomarkers for early CRC diagnosis using stool samples and confirms downregulation of genes hypermethylated in CRC.
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- 2020
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16. Molecular-Biology-Driven Treatment for Metastatic Colorectal Cancer
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Eleonora Lai, Nicole Liscia, Clelia Donisi, Stefano Mariani, Simona Tolu, Andrea Pretta, Mara Persano, Giovanna Pinna, Francesca Balconi, Annagrazia Pireddu, Valentino Impera, Marco Dubois, Marco Migliari, Dario Spanu, Giorgio Saba, Silvia Camera, Francesca Musio, Pina Ziranu, Marco Puzzoni, Laura Demurtas, Valeria Pusceddu, Manuela Dettori, Elena Massa, Francesco Atzori, Mariele Dessì, Giorgio Astara, Clelia Madeddu, and Mario Scartozzi
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metastatic colorectal cancer ,molecular biomarkers ,therapeutic implications ,tailored treatment ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Metastatic CRC (mCRC) is a molecular heterogeneous disease. The aim of this review is to give an overview of molecular-driven treatment of mCRC patients. Methods: A review of clinical trials, retrospective studies and case reports was performed regarding molecular biomarkers with therapeutic implications. Results: RAS wild-type status was confirmed as being crucial for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies and for rechallenge strategy. Antiangiogenic therapies improve survival in first- and second-line settings, irrespective of RAS status, while tyrosine kinase inhibitors (TKIs) remain promising in refractory mCRC. Promising results emerged from anti-HER2 drugs trials in HER2-positive mCRC. Target inhibitors were successful for BRAFV600E mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (POLE-1) mutant patients. Data are still lacking on NTRK, RET, MGMT, and TGF-β, which require further research. Conclusion: Several molecular biomarkers have been identified for the tailored treatment of mCRC patients and multiple efforts are currently ongoing to increase the therapeutic options. In the era of precision medicine, molecular-biology-driven treatment is the key to impro patient selection and patient outcomes. Further research and large phase III trials are required to ameliorate the therapeutic management of these patients.
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- 2020
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17. From CENTRAL to SENTRAL (SErum aNgiogenesis cenTRAL): Circulating Predictive Biomarkers to Anti-VEGFR Therapy
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Riccardo Giampieri, Pina Ziranu, Bruno Daniele, Antonio Zizzi, Daris Ferrari, Sara Lonardi, Alberto Zaniboni, Luigi Cavanna, Gerardo Rosati, Mariaelena Casagrande, Nicoletta Pella, Laura Demurtas, Maria Giulia Zampino, Pietro Sozzi, Valeria Pusceddu, Domenico Germano, Eleonora Lai, Vittorina Zagonel, Carla Codecà, Michela Libertini, Marco Puzzoni, Roberto Labianca, Stefano Cascinu, and Mario Scartozzi
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colon cancer ,bevacizumab ,FGF2 ,PlGF ,VEGF ,angiogenesis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: In the last decade, a series of analyses failed to identify predictive biomarkers of resistance/susceptibility for anti-angiogenic drugs in metastatic colorectal cancer (mCRC). We conducted an exploratory preplanned analysis of serum pro-angiogenic factors (SErum aNgiogenesis-cenTRAL) in 72 mCRC patients enrolled in the phase II CENTRAL (ColorEctalavastiNTRiAlLdh) trial, with the aim to identify potential predictive factors for sensitivity/resistance to first line folinic acid-fluorouracil-irinotecan regimen (FOLFIRI) plus bevacizumab. Methods: First-line FOLFIRI/bevacizumab patients were prospectively assessed for the following circulating pro-angiogenic factors, evaluated with ELISA (enzyme-linked immunosorbent assay)-based technique at baseline and at every cycle: Vascular endothelial growth factor A (VEGF-A), hepatocyte growth factor (HGF), stromal derived factor-1 (SDF-1), placental derived growth factor (PlGF), fibroblast growth factor-2 (FGF-2), monocyte chemotactic protein-3 (MCP-3), interleukin-8 (IL-8). Results: Changes in circulating FGF-2 levels among different blood samples seemed to correlate with clinical outcome. Patients who experienced an increase in FGF-2 levels at the second cycle of chemotherapy compared to baseline, had a median Progression Free Survival (mPFS) of 12.85 vs. 7.57 months (Hazard Ratio—HR: 0.73, 95% Confidence Interval—CI: 0.43-1.27, p = 0.23). Similar results were seen when comparing FGF-2 concentrations between baseline and eight-week time point (mPFS 12.98 vs. 8.00 months, HR: 0.78, 95% CI: 0.46–1.33, p = 0.35). Conclusions: Our pre-planned, prospective analysis suggests that circulating FGF-2 levels’ early increase could be used as a marker to identify patients who are more likely to gain benefit from FOLFIRI/bevacizumab first-line therapy.
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- 2020
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18. Colorectal cancer promoter methylation alteration affects the expression of glutamate ionotropic receptor AMPA type subunit 4 alternative isoforms potentially relevant in colon tissue
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Patrizia Zavattari, Ana Florencia Vega-Benedetti, Eleonora Loi, Francesco Cabras, S. Deidda, Sandra Orrù, Mario Scartozzi, Luigi Zorcolo, Andrea Pretta, Loredana Moi, Angelo Restivo, and Pina Ziranu
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Gene isoform ,Cancer Research ,Carcinogenesis ,Colon ,Gene Expression ,AMPA receptor ,Biology ,Colorectal cancer (CRC) ,GRIA4 ,microRNA ,Gene expression ,Humans ,Protein Isoforms ,Receptors, AMPA ,Regulation of gene expression ,Promoter ,Cell Biology ,Methylation ,DNA Methylation ,DNA methylation alterations ,Gene regulation ,Gene Expression Regulation, Neoplastic ,DNA methylation ,Cancer research ,Colorectal Neoplasms ,Research Article - Abstract
DNA methylation alterations are early events during tumourigenesis, affecting genes involved in the crosstalk between cells and surroundings in colorectal cancer (CRC). Among these genes, GRIA4, Glutamate Ionotropic Receptor AMPA Type Subunit 4, displays hypermethylation in the promoter region, and is an early diagnostic biomarker. It is well known that methylation can also affect alternative transcription. The purpose of this study is to evaluate the expression, at transcript and protein level, of GRIA4 main isoforms (the canonical one and a short variant) in 23 CRC and matched normal samples, of which we previously verified the methylation status. We further predicted miRNA/transcript target interactions as a possible post-transcriptional regulation using bioinformatics tools. As expected, downregulation of both variants has been observed in tumours. Interestingly, in contrast to what observed at transcriptional level, the GluR4 protein short isoform displayed higher expression than the canonical one either in normal or tumoural tissues. This may be explained by miRNA specifically targeting the canonical isoform. Our study is the first one that shows the expression of both isoforms in colon tissues. To note, the evident expression of the short isoform suggests a functional role in intestinal cell biology.
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- 2021
19. Molecular-driven treatment for biliary tract cancer: the promising turning point
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Marco Dubois, A. Parrino, Mario Scartozzi, Pina Ziranu, E. Cimbro, Dario Spanu, Nicole Liscia, Clelia Donisi, G. Pinna, Andrea Pretta, Marco Puzzoni, Marco Migliari, Eleonora Lai, Mara Persano, Valeria Pusceddu, and Stefano Mariani
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Poor prognosis ,Biliary tract cancer ,business.industry ,Therapeutic algorithm ,Antineoplastic Agents ,medicine.disease ,Bioinformatics ,Cholangiocarcinoma ,Therapeutic approach ,Biliary Tract Neoplasms ,Isocitrate dehydrogenase ,Oncology ,Fibroblast growth factor receptor ,Humans ,Medicine ,Pharmacology (medical) ,Turning point ,Molecular Targeted Therapy ,Gallbladder cancer ,business - Abstract
Introduction In the past, targeted therapies have not shown positive results as they have been used without adequate molecular selection of patients with biliary tract cancer (BTC). This has led to an expansion of research on characteristics and molecular selection to identify new effective strategies in this setting. Improved knowledge of the molecular biology of these neoplasms has highlighted their extraordinary heterogeneity and has made it possible to identify targetable gene alterations, including fibroblast growth factor receptor (FGFR) 2 gene fusions, and isocitrate dehydrogenase (IDH) mutations. The FDA recently approved ivosidenib and pemigatinib for the treatment of BTCs. Areas covered We review data in the literature regarding targeted therapies for the treatment of BTCs, as well as on the prospects deriving from the extraordinary molecular heterogeneity of these neoplasms. Expert opinion At present, it is essential to evaluate the expression of the genetic alterations expressed by these neoplasms to offer patients an increasingly personalized therapeutic approach. Studies are needed to better define the limits and potentials of targeted therapies and their role in the therapeutic algorithm to improve the poor prognosis of these patients.
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- 2021
20. CDX-2 expression correlates with clinical outcomes in MSI-H metastatic colorectal cancer patients receiving immune checkpoint inhibitors
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Pina Ziranu, Andrea Pretta, Marta Pozzari, Antonio Maccioni, Manuela Badiali, Daniela Fanni, Eleonora Lai, Clelia Donisi, Mara Persano, Clara Gerosa, Marco Puzzoni, Fabio Bardanzellu, Rossano Ambu, Valeria Pusceddu, Marco Dubois, Giulia Cerrone, Marco Migliari, Sara Murgia, Dario Spanu, Gianluca Pretta, Valentina Aimola, Francesca Balconi, Stefania Murru, Gavino Faa, and Mario Scartozzi
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Multidisciplinary - Abstract
Immune checkpoint inhibitors (ICIs) showed efficacy in metastatic colorectal cancer (mCRC) with mismatch-repair deficiency or high microsatellite instability (dMMR-MSI-H). Unfortunately, a patient’s subgroup did not benefit from immunotherapy. Caudal-related homeobox transcription factor 2 (CDX-2) would seem to influence immunotherapy’s sensitivity, promoting the chemokine (C-X-C motif) ligand 14 (CXCL14) expression. Therefore, we investigated CDX-2 role as a prognostic-predictive marker in patients with mCRC MSI-H. We retrospectively collected data from 14 MSI-H mCRC patients treated with ICIs between 2019 and 2021. The primary endpoint was the 12-month progression-free-survival (PFS) rate. The secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and disease control rate (DCR). The PFS rate at 12 months was 81% in CDX-2 positive patients vs 0% in CDX-2 negative patients (p = 0.0011). The median PFS was not reached (NR) in the CDX-2 positive group versus 2.07 months (95%CI 2.07–10.8) in CDX-2 negative patients (p = 0.0011). Median OS was NR in CDX-2-positive patients versus 2.17 months (95% Confidence Interval [CI] 2.17–18.7) in CDX2-negative patients (p = 0.026). All CDX-2-positive patients achieved a disease response, one of them a complete response. Among CDX-2-negative patients, one achieved stable disease, while the other progressed rapidly (ORR: 100% vs 0%, p = 0.0005; DCR: 100% vs 50%, p = 0.02). Twelve patients received 1st-line pembrolizumab (11 CDX-2 positive and 1 CDX-2 negative) not reaching median PFS, while two patients (1 CDX-2 positive and 1 CDX-2 negative) received 3rd-line pembrolizumab reaching a median PFS of 10.8 months (95% CI, 10.8–12.1; p = 0.036). Although our study reports results on a small population, the prognostic role of CDX-2 in CRC seems confirmed and could drive a promising predictive role in defining the population more sensitive to immunotherapy treatment. Modulating the CDX-2/CXCL14 axis in CDX-2-negative patients could help overcome primary resistance to immunotherapy.
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- 2022
21. BRCA-mutant pancreatic ductal adenocarcinoma
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Mara Persano, Marco Dubois, Marco Puzzoni, Eleonora Lai, Marco Migliari, Stefano Mariani, S. Camera, Laura Demurtas, Andrea Pretta, Valeria Pusceddu, Pina Ziranu, Nicole Liscia, Clelia Donisi, Mario Scartozzi, S. Tolu, and Dario Spanu
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Cancer Research ,Pancreatic ductal adenocarcinoma ,endocrine system diseases ,Mutant ,Review Article ,Germline ,law.invention ,Causes of cancer ,Pathogenesis ,Breast cancer ,law ,Humans ,Medicine ,Genetic Predisposition to Disease ,Precision Medicine ,skin and connective tissue diseases ,Germ-Line Mutation ,BRCA2 Protein ,BRCA1 Protein ,business.industry ,medicine.disease ,digestive system diseases ,Pancreatic Neoplasms ,Oncology ,Mutation ,Cancer research ,Suppressor ,Female ,business ,Carcinoma, Pancreatic Ductal - Abstract
Despite continued research, pancreatic ductal adenocarcinoma (PDAC) remains one of the main causes of cancer death. Interest is growing in the role of the tumour suppressors breast cancer 1 (BRCA1) and BRCA2—typically associated with breast and ovarian cancer—in the pathogenesis of PDAC. Indeed, both germline and sporadic mutations in BRCA1/2 have been found to play a role in the development of PDAC. However, data regarding BRCA1/2-mutant PDAC are lacking. In this review, we aim to outline the specific landscape of BRCA-mutant PDAC, focusing on heritability, clinical features, differences between BRCA1 and 2 mutations and between germline and sporadic alterations, as well as established therapeutic strategies and those that are still under evaluation.
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- 2021
22. The interconnection between cellular metabolism and lymphocyte activation as a prognostic factor in patients affected by metastatic pancreatic ductal adenocarcinoma treated with gemcitabine and nab-paclitaxel as first line
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Andrea Pretta, Clelia Donisi, Riccardo Giampieri, Pina Ziranu, Erika Cimbro, Dario Spanu, Federica Pecci, Marco Migliari, Francesca Balconi, Alessio Lupi, Enrico Palmas, Giulia Deias, Benedetta Congiu, Marta Pozzari, Sara Murgia, Pusceddu Valeria, Marco Puzzoni, Eleonora Lai, Rossana Berardi, and Mario Scartozzi
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Cancer Research ,Oncology - Abstract
752 Background: Glucose and other metabolites (lactates and glutamine) in the tumor microenvironment (TME) may alter the activity of the immune system cells. Cancer cells consume glucose and its decrease in the TME affects the function of tumour-infiltrating lymphocytes (TILs). Moreover, tumor-infiltrated immunosuppressive cells and vascular endothelial cells also deplete nutrients, in the TME, enhancing an immunosuppressive environment. On the basis of the results coming from our previous works regarding lymphocytes to monocytes ratio (LMr) and diabetes, suggesting a role for each of them as predictors of better outcomes, in this study we evaluate both of them in order to establish a possible role of them as outcomes predictive factors. Methods: Data from 228 patients (pts) were collected retrospectively from 2016 to 2021: 175 from the Medical Oncology Unit of University Hospital of Cagliari; 53 from the Medical Oncology Unit, AOU Ospedali Riuniti di Ancona. All pts had stage IV disease and received gemcitabine plus nab-paclitaxel 1st line chemotherapy. Statistical analysis was performed with the MedCalc package. We aimed to evaluate the correlation between treated DM2 and lymphocytes to monocytes ratio (LMr) ≥ 4 with outcomes. Survival distribution was assessed by Kaplan-Meier curves. Multivariate analysis was performed taking into consideration the following prognostic factors: sex, ECOG-PS, LMr, NLr, LDH, Ca19.9, and metastatic sites. Results: Median age was 68 (±9), 123/228 (54%) were male, 94/232 (40,6%) were affected by DM2 (insulin or metfomin-treated) and 138 (59,4%) pts were not affected by DM2. 52/228 (23%) pts had a LMr ≥ 4, 176/228 (77%) pts had a LMr < 4. In multivariate analysis, DM2 and LM ratio ≥ 4 were found to be independent factors associated with higher overall survival. Therefore, we divided the pts into 3 groups: co-presence DM2 and LM ≥ 4 (DM+LM+); absence of DM2 and LM ≥ 4 (DM-LM-); presence of DM2 or LM ≥ 4 (DM+LM- or DM-LM+). DM+LM+ demonstrated statistically significantly higher median OS than DM+LM-/DM-LM+ and DM-LM- (not reached versus 21 versus 9 months, respectively, p < 0.0001). Furthermore, DM+LM+ showed a statistically significant better median PFS than DM+LM-/DM-LM+ and DM-LM- (11 versus 9 versus 6 months, respectively, p = 0,0036). Conclusions: Results showed a correlation between pts with DM2/LMr ≥ 4 and better outcomes. This may suggest the presence of a link between glucose metabolism and lymphocytes activation. Antidiabetic medications could promote the inhibition of Warburg effect in tumor cells, and, consequently, provide a better glucose intake to extracellular microenvironment, and immune cells, including T lymphocytes. This process leads to a higher activity of T-cells and a better treatment response. Further studies are warranted.
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- 2023
23. HOXD8 hypermethylation as a fully sensitive and specific biomarker for biliary tract cancer detectable in tissue and bile samples
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Eleonora Loi, Cesare Zavattari, Alessandro Tommasi, Loredana Moi, Matteo Canale, Agnese Po, Claudia Sabato, Ana Florencia Vega-Benedetti, Pina Ziranu, Marco Puzzoni, Eleonora Lai, Luca Faloppi, María Rullán, Juan Carrascosa, Irene Amat, Jesús M. Urman, Maria Arechederra, Carmen Berasain, Elisabetta Ferretti, Andrea Casadei-Gardini, Matías A. Avila, Sergio Alonso, Mario Scartozzi, and Patrizia Zavattari
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Homeodomain Proteins ,Cancer Research ,biomarkers ,DNA Methylation ,biliary tract cancer, methylation, biomarkers ,Biliary Tract Neoplasms ,Oncology ,biliary tract cancer ,Mutation ,Biomarkers, Tumor ,Bile ,Humans ,methylation ,Transcription Factors - Abstract
Background Biliary tract cancers (BTC) are rare but highly aggressive tumours with poor prognosis, usually detected at advanced stages. Herein, we aimed at identifying BTC-specific DNA methylation alterations. Methods Study design included statistical power and sample size estimation. A genome-wide methylation study of an explorative cohort (50 BTC and ten matched non-tumoral tissue samples) has been performed. BTC-specific altered CpG islands were validated in over 180 samples (174 BTCs and 13 non-tumoral controls). The final biomarkers, selected by a machine-learning approach, were validated in independent tissue (18 BTCs, 14 matched non-tumoral samples) and bile (24 BTCs, five non-tumoral samples) replication series, using droplet digital PCR. Results We identified and successfully validated BTC-specific DNA methylation alterations in over 200 BTC samples. The two-biomarker panel, selected by an in-house algorithm, showed an AUC > 0.97. The best-performing biomarker (chr2:176993479-176995557), associated with HOXD8, a pivotal gene in cancer-related pathways, achieved 100% sensitivity and specificity in a new series of tissue and bile samples. Conclusions We identified a novel fully efficient BTC biomarker, associated with HOXD8 gene, detectable both in tissue and bile by a standardised assay ready-to-use in clinical trials also including samples from non-invasive matrices.
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- 2022
24. Uncovering key targets of success for immunotherapy in pancreatic cancer
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Stefano Mariani, Mario Scartozzi, Giorgio Saba, Mara Persano, Valentino Impera, Pina Ziranu, Dario Spanu, Andrea Pretta, E. Cimbro, A. Parrino, Valeria Pusceddu, Nicole Liscia, Clelia Donisi, G. Pinna, Marco Puzzoni, Marco Migliari, Marco Dubois, and Eleonora Lai
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Pharmacology ,Oncology ,medicine.medical_specialty ,Pancreatic ductal adenocarcinoma ,business.industry ,medicine.medical_treatment ,Immune checkpoint inhibitors ,Clinical Biochemistry ,Immunotherapy ,medicine.disease ,Malignancy ,Pancreatic Neoplasms ,Immune system ,Physical Barrier ,Internal medicine ,Pancreatic cancer ,Drug Discovery ,Tumor Microenvironment ,Molecular Medicine ,Medicine ,Humans ,Treatment resistance ,business ,Carcinoma, Pancreatic Ductal - Abstract
Introduction Despite available treatment options, pancreatic ductal adenocarcinoma (PDAC) is frequently lethal. Recent immunotherapy strategies have failed to yield any notable impact. Therefore, research is focussed on unearthing new drug targets and therapeutic strategies to tackle this malignancy and attain more positive outcomes for patients. Areas covered In this perspective article, we evaluate the main resistance mechanisms to immune checkpoint inhibitors (ICIs) and the approaches to circumvent them. We also offer an assessment of concluded and ongoing trials of PDAC immunotherapy. Literature research was performed on Pubmed accessible through keywords such as: 'pancreatic ductal adenocarcinoma,' 'immunotherapy,' 'immunotherapy resistance,' 'immune escape,' 'biomarkers.' Papers published between 2000 and 2021 were selected. Expert opinion The tumour microenvironment is a critical variable of treatment resistance because of its role as a physical barrier and inhibitory immune signalling. Promising therapeutic strategies appear to be a combination of immunotherapeutics with other targeted treatments. Going forward, predictive biomarkers are required to improve patient selection. Biomarker-driven trials could enhance approaches for assessing the role of immunotherapy in PDAC.
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- 2021
25. The role of immune checkpoint inhibitors in the treatment sequence of advanced gastric or gastro-esophageal junction cancer: A systematic review and meta-analysis of randomized trials
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Marco Dubois, Nicole Liscia, Oronzo Brunetti, Pina Ziranu, Eleonora Lai, Antonella Argentiero, Elena Mazza, Stefano Cascinu, Nicola Silvestris, Andrea Casadei-Gardini, and Mario Scartozzi
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Oncology ,Esophageal Neoplasms ,Stomach Neoplasms ,Humans ,Hematology ,Esophagogastric Junction ,Immune Checkpoint Inhibitors ,Randomized Controlled Trials as Topic - Abstract
This study aimed to clarify the current knowledge on the use of immunotherapy in patients with advanced gastric(G)/gastroesophageal(GEJ) cancers.A meta-analysis was done to evaluate the efficacy of immune checkpoint inhibitors(ICIs) in G/GEJ cancer both in the unselected population and in that stratified for combined positive score (CPS)≥ 1 and ≥ 10 patients.In the unselected population the result showed 21%(P 0.00001), and 29%(P 0.00001) reduction of death and progression risk for patients treated with ICIs compared without ICIs, while in CPS≥ 1 and≥ 10 populations, the result showed a death reduction of 19%(P = 0.001) and 33%(P 0.00001) respectively, and, and 23% (P 0.00001) and 43% (P 0.00001) progression risk reduction respectively, for patients treated with and without ICIs.overall survival(OS) and progression free survival(PFS) data obtained in our meta-analysis, are in favor to use ICIs in association with standard first line chemotherapy for G/GEJ cancer patients regardless to CPS status.
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- 2021
26. Lymphocyte to monocyte ratio in metastatic pancreatic ductal adenocarcinoma as a prognostic factor and its potential role in identifying a subset of patients with a favorable response to therapy
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Andrea Pretta, Dario Spanu, Riccardo Giampieri, Eleonora Lai, Erika Cimbro, Federica Pecci, Francesca Balconi, Alessio Lupi, Marta Pozzari, Sara Murgia, Fabio Bardanzellu, Antonio Maccioni, Fabiana Contu, Mara Persano, Clelia Donisi, Pusceddu Valeria, Marco Puzzoni, Pina Ziranu, Rossana Berardi, and Mario Scartozzi
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Cancer Research ,Oncology - Abstract
4153 Background: Despite the most recent therapeutic achievements, pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and response to treatments. Among the most investigated prognostic biomarkers, the lymphocyte to monocyte ratio (LMr) is gaining increasing interest in literature, mostly in hematological malignancies, breast cancer, bladder cancer, non-small cell lung cancer, colorectal cancer, and resected pancreatic adenocarcinoma. In these settings, a higher LMr allows identifying a subset of patients with a better prognosis. Our study aimed to evaluate the role of the LMr as a prognostic factor in patients affected by metastatic PDAC and to find a cut-off value able to identify a subset of patients with better prognosis and possibly susceptible to other therapeutic options. Methods: Data from 228 patients were collected retrospectively from 2014 to 2021. 175 from the Department of Medical Oncology of the University Hospital of Cagliari and 53 from the Oncology Clinic - University Hospital of Ospedali Riuniti of Ancona. All patients had metastatic PDAC and blood samples were collected before starting first-line chemotherapy. The cut-off value for LMr was calculated according to the ROC curves at 6, 12, and 18 months. Kaplan-Meier curves were then obtained for the evaluation of survivals. Finally, multivariate analysis was performed, taking into consideration the following prognostic factors: sex, ECOG-PS, NL ratio, metastatic sites, Ca19.9 and LDH. Results: The median age was 68 y.o. (range 39-84 y.o.), 123 (54%) were males. Cut off value obtained for LMR, was 4. 156 (68,4%) patients had an LMr < 4 and 72 (31,6%) patients had an LMR ≥ 4. Patients with a ratio ≥ 4 showed a statistically significant difference in terms of median overall survival compared to patients with a ratio < 4 (23 months versus 11 months, p < 0.0001). First-line median progression-free survival was also different in patients with a value greater than or equal to 4 (11 months versus 6 months, p = 0.005), suggesting a better treatment response in the first group of patients. Finally, multivariate analysis showed that LMR ≥ 4 is an independent prognostic factor for OS ( p = 0.0005). Conclusions: The results of our study show that the lymphocyte to monocyte ratio could be an important prognostic factor in patients with metastatic pancreatic ductal adenocarcinoma, although the limitations of a retrospective study should be considered. Furthermore, these findings suggest the active role of the immune response in limiting disease progression, indicating a group of patients who could benefit most from a target or combined immunotherapy treatment.
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- 2022
27. Influence of type 2 diabetes mellitus and concomitant anti-diabetic medications in patients with metastatic pancreatic ductal adenocarcinoma
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Andrea Pretta, Erika Cimbro, Riccardo Giampieri, Dario Spanu, Eleonora Lai, Federica Pecci, Francesca Balconi, Alessio Lupi, Marta Pozzari, Sara Murgia, Fabio Bardanzellu, Antonio Maccioni, Fabiana Contu, Mara Persano, Clelia Donisi, Valeria Pusceddu, Marco Puzzoni, Pina Ziranu, Rossana Berardi, and Mario Scartozzi
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Cancer Research ,Oncology - Abstract
e16301 Background: The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated. Indeed, DM2 can be both an epiphenomenon of PDAC and a risk factor. However, the data on the influence of DM2 and concomitant drug therapy in the progression of pancreatic neoplasms are conflicting. The present study aimed to investigate the correlation between overall survival (OS) and antidiabetic drugs in patients with metastatic pancreatic ductal adenocarcinoma and DM2. Methods: Data from 232 patients were collected retrospectively from 2014 to 2021. 174 from the Department of Medical Oncology of the University Hospital of Cagliari and 58 from the Department of Medical Oncology, AOU Ospedali Riuniti of Ancona. All patients had stage IV disease and received gemcitabine plus nab-paclitaxel first-line chemotherapy. Statistical analysis was performed with the MedCalc package. We aimed to evaluate the correlation between DM2, anti-diabetic medications (ADMs) and median overall survival (mOS). Survival distribution was assessed by Kaplan-Meier curves. Finally, multivariate analysis was performed, taking into consideration the following prognostic factors: sex, ECOG-PS, LDH, Ca19.9, and metastatic sites. Results: The median age was 69 y.o. (range 40-84 y.o.), 127 (54,7%) were male. All patients received first-line treatment with gemcitabine plus nab-paclitaxel. 138 (59,4%) patients were not affected by DM2, 94/232 (40,6%) were affected by DM2. Among DM2 patients, 57 (%) were insulin-treated and 37 (%) were metformin-treated. DM2 patients showed a statistically significant higher median overall survival (26 versus 11 months, 95% CI, p = 0,0002). Furthermore, among DM2 patients insulin-treated and metformin-treated showed a mOS of 21 months and 33 months, respectively (95% CI, p = 0.0002). Finally, multivariate analysis showed that treated-DM2 is an independent prognostic factor ( p = 0.03). Conclusions: The results of our study showed a correlation between DM2 on treatment (with insulin or metformin) and higher mOSin patients with metastatic PDAC. However, the limitations due to retrospective data collection must be considered. The mechanisms underlying these findings could be explained by maintaining optimal insulin concentration and good glycemic control during treatments, or by the activity of anti-diabetic medication in neoplastic tissues. However, further studies in this setting are needed.
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- 2022
28. 417P Liquid biopsy driven anti-EGFR rechallenge in metastatic colorectal cancer
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Stefano Mariani, Milena Casula, Mara Persano, Alessio Lupi, Grazia Palomba, Nicole Liscia, Marco Puzzoni, Clelia Donisi, G. Pinna, E. Cimbro, Giovannella Palmieri, Andrea Pretta, A. Parrino, Marina Pisano, Riccardo Giampieri, Eleonora Lai, Valeria Pusceddu, Enrica Giglio, M. Scartozzi, and Pina Ziranu
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Oncology ,medicine.medical_specialty ,Colorectal cancer ,business.industry ,Internal medicine ,medicine ,Hematology ,Liquid biopsy ,medicine.disease ,business - Published
- 2021
29. 407P Neoadjuvant chemo-radiotherapy response in patients affected by mismatch repair deficient (dMMR) locally advanced rectal cancer
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Mario Scartozzi, Andrea Pretta, Pina Ziranu, Mara Persano, Angelo Restivo, Marco Puzzoni, A. Parrino, Dario Spanu, Luigi Zorcolo, S. Deidda, Gavino Faa, M.A. Deidda, E. Cimbro, R. Barbara, Clelia Donisi, G. Pinna, G. Cerrone, Valeria Pusceddu, and V. Aimola
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Oncology ,medicine.medical_specialty ,Chemo-radiotherapy ,business.industry ,Colorectal cancer ,Locally advanced ,Hematology ,medicine.disease ,Internal medicine ,medicine ,DNA mismatch repair ,In patient ,business - Published
- 2021
30. 490P New horizons in metastatic colorectal cancer: Role of CD44 expression
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Eleonora Lai, Nicole Liscia, F. Sarais, Pina Ziranu, Clelia Donisi, G. Pinna, A. Parrino, Valeria Pusceddu, Marco Puzzoni, G. Cerrone, Dario Spanu, V. Aimola, Marco Dubois, Marco Migliari, Mara Persano, Stefano Mariani, Gavino Faa, E. Cimbro, Andrea Pretta, and Mario Scartozzi
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New horizons ,Oncology ,Expression (architecture) ,biology ,Colorectal cancer ,business.industry ,CD44 ,medicine ,Cancer research ,biology.protein ,Hematology ,medicine.disease ,business - Published
- 2021
31. Long Term Survival With Regorafenib: REALITY (Real Life in Italy) Trial - A GISCAD Study
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Pina Ziranu, Stefano Mariani, Floriana Nappo, Giulia Piacentini, Nicole Liscia, Sara Lonardi, Manlio Mencoboni, Alessandra Boccaccino, Veronica Conca, Roberto Labianca, Valeria Pusceddu, Alberto Zaniboni, Gemma Zucchelli, Maria Banzi, Marco Puzzoni, Eleonora Lai, Manuela Dettori, Chiara Cremolini, Saverio Cinieri, and Mario Scartozzi
- Subjects
Oncology ,medicine.medical_specialty ,Multivariate analysis ,Colorectal cancer ,Pyridines ,Logistic regression ,Liver progression ,Long term survivors ,chemistry.chemical_compound ,Internal medicine ,Regorafenib ,Multicenter trial ,medicine ,Humans ,Progression-free survival ,Retrospective Studies ,Univariate analysis ,business.industry ,Metastatic colorectal cancer ,Phenylurea Compounds ,Gastroenterology ,Tolerability ,Treatment modification ,medicine.disease ,chemistry ,business ,Colorectal Neoplasms - Abstract
Background Regorafenib is a key agent in metastatic colorectal cancer (mCRC), but no validated factors predicting longer survival are available. Patients and Methods REALITY was a retrospective multicenter trial in regorafenib-treated mCRC patients with overall survival (OS) ≥ 6 months. We aimed to assess the association between clinical parameters and outcome to define a panel identifying long term survivors among regorafenib candidates. Primary and secondary endpoints were OS and progression free survival (PFS), respectively. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; independent role of significant variables at univariate analysis: logistic regression). Results Hundred regorafenib-treated mCRC patients with OS ≥ 6 months were enrolled. Median OS was 11.5 m (95%CI:9.60-12.96); median PFS was 4.2 months (95% CI:3.43-43.03). The absence of liver progression and of dose and/or schedule changes during the first 4 cycles (mainly for good tolerability) were independently correlated at multivariate analysis with OS (Exp(b)1.8869, P= .0277and Exp(b)2.2000, P = .0313) and PFS (Exp(b)2.1583, P = .0065 and Exp(b)2.3036, P= .0169). Patients with neither of these variables had a significantly improved OS (n = 14, 20.8 months; 95% CI:12.967-55.267) versus others (n = 86, 10 months; 95% CI:8.367-12.167; HR = 0.4902, P = .0045) and PFS (11.3 months, 95%CI:4.267-35.8 vs. 3.9 months, 95% CI:3.167-43.033; HR = 0.4648, P = .0086). Conclusion These 2 factors might allow clinicians to better identify patients more likely to benefit from regorafenib. Toxicity management remains crucial.
- Published
- 2021
32. The Role of p53 Expression in Patients with RAS/BRAF Wild-Type Metastatic Colorectal Cancer Receiving Irinotecan and Cetuximab as Later Line Treatment
- Author
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Angelo Paolo Dei Tos, Marco Dubois, Riccardo Giampieri, Giada Munari, Matteo Fassan, Marco Puzzoni, Marta Schirripa, Fotios Loupakis, Pina Ziranu, Stefano Mariani, Eleonora Lai, Mario Scartozzi, Nicole Liscia, Andrea Pretta, Sara Lonardi, Alberto Zaniboni, Mara Persano, Laura Demurtas, Valeria Pusceddu, Giovanni Sotgiu, Marco Migliari, and Michela Libertini
- Subjects
0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,medicine.drug_class ,Cetuximab ,Monoclonal antibody ,Irinotecan ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Pharmacology (medical) ,Epidermal growth factor receptor ,Original Research Article ,Neoplasm Metastasis ,Aged ,Response rate (survey) ,biology ,business.industry ,Hazard ratio ,Middle Aged ,medicine.disease ,digestive system diseases ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,biology.protein ,Female ,Tumor Suppressor Protein p53 ,business ,Colorectal Neoplasms ,medicine.drug - Abstract
Background Preclinical and clinical data indicate that p53 expression might modulate the activity of the epidermal growth factor receptor (EGFR), influencing response/resistance to anti-EGFR monoclonal antibodies. However, the association between p53 status and clinical outcome has not been clarified yet. Objective In our study, we evaluated the role of p53 expression in patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) receiving irinotecan/cetuximab in an exploratory and a validation cohort. Patients and Methods p53 expression was analysed in patients with RAS/BRAF wild-type mCRC receiving second-line or third-line irinotecan/cetuximab. Survival distribution was assessed by the Kaplan–Meier method, while the log-rank test was used for survival comparison. Results Among 120 patients with RAS/BRAF wild-type mCRC included in our analysis, 52 (59%) and 19 (59%) patients showed p53 overexpression in the exploratory and validation cohort, respectively. In the exploratory cohort, low p53 expression was correlated with better median progression-free survival (hazard ratio 0.39; p < 0.0001), median overall survival (hazard ratio: 0.23; p < 0.0001) and response rate (p < 0.0001). These results were confirmed by data of the validation cohort where we observed better median progression-free survival (hazard ratio: 0.48; p = 0.0399), median overall survival (hazard ratio: 0.26; p = 0.0027) and response rate (p =0.0007) in patients with p53 normal expression mCRC. Conclusions In our study, p53 overexpression was associated with anti-EGFR treatment resistance in patients with RAS/BRAF WT mCRC, as confirmed in a validation cohort. Larger studies are needed to validate the role of p53 and investigate EGFR cross-talk in these patients.
- Published
- 2021
33. Mismatch repair proteins (MMR) expression as predictive factor in locally advanced rectal cancer
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Andrea Pretta, Clelia Donisi, Mara Persano, Giovanna Pinna, Erika Cimbro, Alissa Parrino, Valentina Aimola, Dario Spanu, Giulia Cerrone, Simona Deidda, Maria Assunta Deidda, Eleonora Lai, Valeria Pusceddu, Marco Puzzoni, Pina Ziranu, Raffaele Barbara, Angelo Restivo, Luigi Zorcolo, Gavino Faa, and Mario Scartozzi
- Subjects
Cancer Research ,Oncology - Abstract
182 Background: Only few data on microsatellite instability in rectal cancer are available in literature, and dMMR role in pre-operative chemoradiotherapy response is under debate. The aim of our study was to evaluate the frequency and therapeutic implications of dMMR status in patients (pts) with locally advanced rectal cancer belonging to our Center. Methods: Data were retrospectively collected from 231 patients belonging to the Medical Oncology Unit of the University Hospital of Cagliari from 2011 to 2021. All patients were affected by locally advanced rectal adenocarcinoma (cT3-4 +/- N1-2). All patients included in the study underwent neoadjuvant chemoradiotherapy treatment with capecitabine and RT long course (total dose of Gy 50.4) and subsequently underwent total mesorectal excision (TME) followed by adjuvant chemotherapy. Mismatch repair (MMR) expression was evaluated through immunohistochemistry on surgical samples. Results: Of the 231 patients, 213 were suitable for final analyzes. Patients median age was 68 years (range 34-89). 145/201 were male and 68 were female. 66 (31%) had stage II disease and 147 (69%) had stage III disease. Considering MMR, 205/213 (96%) patients had proficient mismatch repair (pMMR), while 8/213 (4%) had dMMR. In dMMR patients defective proteins were: MSH2 in 4 patients, MLH1 and PMS2 combined in 2 patients and MSH6 in 2 patient. dMMR patients showed, unlike pMMR patients, poor or no response to chemoradiotherapy. Responses were assessed through TRG evaluation (Ryan and Dworak scoring systems) on the primary tumour. 5 patients presented a TRG-3 and 3 patients showed a TRG-4, according to Ryan score. All of them had a grade 1 regression, according to Dworak. Conclusions: The results of our study, albeit with limitations related to the retrospective nature and the limited number of dMMR cases, might indicate a correlation between microsatellite instability and little or no response to preoperative chemo-radiotherapy. It would be useful to analyze the data prospectively and further evaluate MMR as a predictor of response to combined chemo-radiotherapy.[Table: see text]
- Published
- 2022
34. P-129 Concomitant RAS and BRAF mutations: Impact on overall survival and progression free survival in metastatic colorectal cancer patients
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Mario Scartozzi, Pina Ziranu, E. Cimbro, Marco Puzzoni, Eleonora Lai, Mara Persano, A. Parrino, Marco Dubois, Marco Migliari, Valeria Pusceddu, Nicole Liscia, Clelia Donisi, G. Pinna, Andrea Pretta, and Stefano Mariani
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Colorectal cancer ,Concomitant ,Internal medicine ,Overall survival ,Medicine ,Hematology ,Progression-free survival ,business ,medicine.disease - Published
- 2021
35. Introducing immunotherapy for advanced hepatocellular carcinoma patients: Too early or too fast?
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Francesca Musio, Nicole Liscia, Marco Migliari, Andrea Casadei Gardini, Mario Scartozzi, Giorgio Astara, Clelia Donisi, G. Pinna, Pina Ziranu, Clelia Madeddu, Mara Persano, Valeria Pusceddu, S. Tolu, Valentino Impera, Stefano Mariani, S. Camera, Dario Spanu, Marco Puzzoni, Andrea Pretta, Marco Dubois, Giorgio Saba, Francesca Balconi, Eleonora Lai, Annagrazia Pireddu, Lai, Eleonora, Astara, Giorgio, Ziranu, Pina, Pretta, Andrea, Migliari, Marco, Dubois, Marco, Donisi, Clelia, Mariani, Stefano, Liscia, Nicole, Impera, Valentino, Persano, Mara, Tolu, Simona, Balconi, Francesca, Pinna, Giovanna, Spanu, Dario, Pireddu, Annagrazia, Saba, Giorgio, Camera, Silvia, Musio, Francesca, Puzzoni, Marco, Pusceddu, Valeria, Madeddu, Clelia, Casadei Gardini, Andrea, and Scartozzi, Mario
- Subjects
0301 basic medicine ,Adoptive cell transfer ,Advanced hepatocellular carcinoma ,Oncolytic virus ,Carcinoma, Hepatocellular ,medicine.medical_treatment ,Immune-related toxicity ,Cell therapy ,Immune checkpoint inhibitors ,03 medical and health sciences ,0302 clinical medicine ,Tumor Microenvironment ,Medicine ,Humans ,Immunologic Factors ,Vaccines ,business.industry ,Liver Neoplasms ,Cancer ,Antibodies, Monoclonal ,Hematology ,Immunotherapy ,medicine.disease ,digestive system diseases ,Clinical trial ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Cancer research ,Cytokines ,business ,Liver cancer - Abstract
Advanced hepatocellular carcinoma (HCC) is the most frequent liver cancer. Immunotherapy has been explored in this disease in order to improve survival outcomes. Nowadays, scientific research is focusing especially on immune checkpoint inhibitors, in particular anti-PD1, anti-PD-L1 and anti-CTLA4 monoclonal antibodies (mAbs), as single-agent or in combination with other immunotherapy agents, target therapies, anti-vascular endothelial growth factor (VEGF) and other agents targeting specific molecular pathways. Other immunotherapy strategies have been assessed or are under investigation in advanced HCC, namely cytokines, adoptive cell therapy, oncolytic virus, cancer vaccines. Each treatment presents specific efficacy and toxicity profiles, strictly related to their mechanism of action and to advanced HCC tumour microenvironment (TME). The aim of this review is to outline the state-of-the-art of immunotherapy in advanced HCC treatment, highlighting data on already investigated treatment strategies, safety and toxicity (including HBV/HCV-related HCC), and ongoing clinical trials focusing on new promising therapeutic weapons.
- Published
- 2020
36. From CENTRAL to SENTRAL (SErum aNgiogenesis cenTRAL): Circulating Predictive Biomarkers to Anti-VEGFR Therapy
- Author
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Vittorina Zagonel, Maria Giulia Zampino, Carla Codecà, Pina Ziranu, Nicoletta Pella, Gerardo Rosati, M. Libertini, Domenico Germano, Bruno Daniele, Pietro Sozzi, Luigi Cavanna, Mariaelena Casagrande, Antonio Zizzi, Roberto Labianca, Alberto Zaniboni, Sara Lonardi, Mario Scartozzi, Stefano Cascinu, Riccardo Giampieri, Eleonora Lai, Marco Puzzoni, Daris Ferrari, Laura Demurtas, Valeria Pusceddu, Giampieri, R., Ziranu, P., Daniele, B., Zizzi, A., Ferrari, D., Lonardi, S., Zaniboni, A., Cavanna, L., Rosati, G., Casagrande, M., Pella, N., Demurtas, L., Zampino, M. G., Sozzi, P., Pusceddu, V., Germano, D., Lai, E., Zagonel, V., Codeca, C., Libertini, M., Puzzoni, M., Labianca, R., Cascinu, S., and Scartozzi, M.
- Subjects
0301 basic medicine ,Oncology ,Placental growth factor ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,Circulating biomarkers ,Colorectal cancer ,FGF2 ,bevacizumab ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,Folinic acid ,angiogenesis ,0302 clinical medicine ,Internal medicine ,medicine ,Progression-free survival ,business.industry ,circulating biomarkers ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,VEGF ,Colon cancer ,Irinotecan ,Regimen ,030104 developmental biology ,colon cancer ,PlGF ,030220 oncology & carcinogenesis ,FOLFIRI ,Angiogenesis ,business ,medicine.drug - Abstract
Background: In the last decade, a series of analyses failed to identify predictive biomarkers of resistance/susceptibility for anti-angiogenic drugs in metastatic colorectal cancer (mCRC). We conducted an exploratory preplanned analysis of serum pro-angiogenic factors (SErum aNgiogenesis-cenTRAL) in 72 mCRC patients enrolled in the phase II CENTRAL (ColorEctalavastiNTRiAlLdh) trial, with the aim to identify potential predictive factors for sensitivity/resistance to first line folinic acid-fluorouracil-irinotecan regimen (FOLFIRI) plus bevacizumab. Methods: First-line FOLFIRI/bevacizumab patients were prospectively assessed for the following circulating pro-angiogenic factors, evaluated with ELISA (enzyme-linked immunosorbent assay)-based technique at baseline and at every cycle: Vascular endothelial growth factor A (VEGF-A), hepatocyte growth factor (HGF), stromal derived factor-1 (SDF-1), placental derived growth factor (PlGF), fibroblast growth factor-2 (FGF-2), monocyte chemotactic protein-3 (MCP-3), interleukin-8 (IL-8). Results: Changes in circulating FGF-2 levels among different blood samples seemed to correlate with clinical outcome. Patients who experienced an increase in FGF-2 levels at the second cycle of chemotherapy compared to baseline, had a median Progression Free Survival (mPFS) of 12.85 vs. 7.57 months (Hazard Ratio&mdash, HR: 0.73, 95% Confidence Interval&mdash, CI: 0.43-1.27, p = 0.23). Similar results were seen when comparing FGF-2 concentrations between baseline and eight-week time point (mPFS 12.98 vs. 8.00 months, HR: 0.78, 95% CI: 0.46&ndash, 1.33, p = 0.35). Conclusions: Our pre-planned, prospective analysis suggests that circulating FGF-2 levels&rsquo, early increase could be used as a marker to identify patients who are more likely to gain benefit from FOLFIRI/bevacizumab first-line therapy.
- Published
- 2020
37. Thyroid hormones ratio is a major prognostic marker in advanced metastatic colorectal cancer: Results from the phase III randomised CORRECT trial
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Mario Scartozzi, Giuseppe Pasqualetti, Marco Puzzoni, Emmanuelle Dochy, Vittorina Zagonel, Fotios Loupakis, Fabio Monzani, Marta Schirripa, Giulia Alberti, Pina Ziranu, Sara Lonardi, and Matteo Fassan
- Subjects
Male ,0301 basic medicine ,Oncology ,Cancer Research ,Colorectal cancer ,Deiodination ,FT3/FT4 ,Refractory disease ,Regorafenib ,Survival ,Pyridines ,Thyroid Function Tests ,chemistry.chemical_compound ,0302 clinical medicine ,80 and over ,Medicine ,Neoplasm Metastasis ,Aged, 80 and over ,Tumor ,medicine.diagnostic_test ,Hazard ratio ,Middle Aged ,Prognosis ,Treatment Outcome ,030220 oncology & carcinogenesis ,Predictive value of tests ,Disease Progression ,Female ,Colorectal Neoplasms ,hormones, hormone substitutes, and hormone antagonists ,Adult ,Thyroid Hormones ,medicine.medical_specialty ,Adenocarcinoma ,Aged ,Antineoplastic Agents ,Biomarkers, Tumor ,Humans ,Phenylurea Compounds ,Predictive Value of Tests ,Retrospective Studies ,Placebo ,Thyroid function tests ,03 medical and health sciences ,Internal medicine ,Post-hoc analysis ,business.industry ,Retrospective cohort study ,medicine.disease ,030104 developmental biology ,chemistry ,business ,Biomarkers - Abstract
Free triiodothyronine (FT3)/free thyroxine (FT4) ratio is an index estimating the peripheral activity of thyroid hormones. In a previous experience, we identified a prognostic role for FT3/FT4 ratio in chemorefractory patients treated with regorafenib. Therefore, we planned this post hoc analysis of the phase III CORRECT trial of regorafenib versus placebo.Seven hundred fifty-eight out of 760 randomised patients (503 in the regorafenib and 255 in the placebo arm) were evaluable for the present analyses, based on availability of FT3 and FT4 baseline values. Co-primary objectives were to explore the predictive role of FT3/FT4 ratio in patients treated with regorafenib compared with placebo and to validate the prognostic value of FT3/FT4 ratio in the CORRECT trial.For patients randomised to regorafenib, median overall survival (OS) was 4.0, 7.5 and 9.8 months in low, intermediate and high FT3/FT4 ratio subgroups, respectively. Hazard ratio (HR) for OS was 0.40 (p 0.0001) when comparing intermediate versus low and 0.32 (p 0.0001) when comparing high versus low FT3/FT4 ratio. In the placebo arm, median OS was 3.3, 5.6 and 7.7 months, in the three subgroups. HR for OS was 0.47 (p 0.0001) when comparing intermediate versus low and 0.33 (p 0.0001) when comparing high versus low. FT3/FT4 ratio retained its association with OS in the multivariate model in both arms.While rejecting the predictive effect of baseline FT3/FT4 ratio, present data strengthen the prognostic role of the ratio, pave the way for direct clinical application, underline the need for a better biological understanding and suggest possible therapeutic implications for thyroid hormones.
- Published
- 2020
38. Retrospective survival analysis in patients with metastatic pancreatic ductal adenocarcinoma with insulin-treated type 2 diabetes mellitus
- Author
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Luca Faloppi, Valentino Impera, Eleonora Molinaro, Nicole Liscia, Giorgio Saba, Andrea Casadei Gardini, Marco Dubois, Marco Puzzoni, Giulia Rovesti, Andrea Pretta, Marco Migliari, Laura Riggi, Eleonora Lai, Francesca Musio, Giorgio Astara, Giulia Orsi, Mario Scartozzi, Kalliopi Andrikou, Stefano Cascinu, Erich Batzella, Pina Ziranu, Stefano Mariani, Mara Persano, Laura Demurtas, Valeria Pusceddu, Pretta, A., Ziranu, P., Puzzoni, M., Lai, E., Orsi, G., Liscia, N., Molinaro, E., Mariani, S., Riggi, L., Rovesti, G., Dubois, M., Migliari, M., Persano, M., Saba, G., Impera, V., Musio, F., Batzella, E., Demurtas, L., Pusceddu, V., Astara, G., Faloppi, L., Casadei Gardini, A., Andrikou, K., Cascinu, S., and Scartozzi, M.
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,insulin ,Pancreatic ductal adenocarcinoma ,type 2 diabetes mellitus ,medicine.medical_treatment ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Pancreatic cancer ,medicine ,Humans ,Hypoglycemic Agents ,Insulin ,In patient ,Public Health Surveillance ,Survival analysis ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Type 2 Diabetes Mellitus ,PDAC ,General Medicine ,Middle Aged ,medicine.disease ,Prognosis ,Survival Analysis ,Metformin ,Pancreatic Neoplasms ,antidiabetic medications ,Oncology ,Diabetes Mellitus, Type 2 ,Italy ,030220 oncology & carcinogenesis ,030211 gastroenterology & hepatology ,Female ,Insulin treated type 2 diabetes mellitus ,business ,medicine.drug ,Carcinoma, Pancreatic Ductal - Abstract
Introduction: The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated and the role of antidiabetic medications such as metformin has also been investigated. The objective of this study was to examine the association between insulin use and overall survival (OS) in patients with advanced PDAC and DM2. Methods: We retrospectively collected data from 164 patients, including an exploratory cohort of 96 patients from Medical Oncology Unit, University Hospital and University of Cagliari, Italy, and a validation cohort of 68 patients from Medical Oncology of Modena University Hospital. Patients had metastatic disease and received a first-line gemcitabine-based chemotherapy and, subsequently, a second-line fluoropyrimidines-based chemotherapy. We performed univariate analysis to evaluate correlation between long-term diabetes and overall survival. Then we performed multivariate analysis, adjusting for sex, metastatic sites, Eastern Cooperative Oncology Group Performance Status, Ca19.9 levels, N/L ratio, and lactate dehydrogenase levels at diagnosis, to confirm the independence of the variable. Results: In the exploratory cohort, DM2 was significantly associated with higher median OS at univariate analysis (16 vs 10 months; p = 0.004). This result was confirmed by validation cohort (11 months vs 6 months; p = 0.01). In multivariate analysis, insulin-treated patients compared with non diabetic patients showed a significantly increased survival of 4.6 months ( p = 0.03). Conclusions: Patients with insulin-treated metastatic PDAC showed better OS than non diabetic patients, as demonstrated by both cohorts. The correlation between OS and insulin-treated DM2 should be investigated further through a prospective clinical trial.
- Published
- 2020
39. Prognostic Value of Thyroid Hormone Ratios in Patients With Advanced Metastatic Colorectal Cancer Treated With Regorafenib: The TOREADOR Study
- Author
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Pina Ziranu, Francesca Bergamo, Alessandra Anna Prete, Fabiana Pani, Sara Lonardi, Stefano Mariotti, Marco Puzzoni, Giuseppe Pasqualetti, Laura Rumano, Sabina Murgioni, Marta Schirripa, Giulia Alberti, Mario Scartozzi, Riccardo Giampieri, Fotios Loupakis, Mario Domenico Rizzato, Fabio Monzani, Silvia Stragliotto, Valeria Pusceddu, and Vittorina Zagonel
- Subjects
Male ,0301 basic medicine ,Oncology ,Multivariate statistics ,Survival ,Pyridines ,Colorectal cancer ,Thyroid Function Tests ,chemistry.chemical_compound ,0302 clinical medicine ,Prospective Studies ,Aged, 80 and over ,Hazard ratio ,Thyroid ,Gastroenterology ,Middle Aged ,Prognosis ,Progression-Free Survival ,Deiodination ,medicine.anatomical_structure ,Italy ,030220 oncology & carcinogenesis ,Cohort ,Triiodothyronine ,Female ,Colorectal Neoplasms ,FT(3)/FT(4) ,hormones, hormone substitutes, and hormone antagonists ,Adult ,medicine.medical_specialty ,Refractory ,Antineoplastic Agents ,03 medical and health sciences ,Internal medicine ,Regorafenib ,medicine ,Humans ,Response Evaluation Criteria in Solid Tumors ,Aged ,business.industry ,Phenylurea Compounds ,medicine.disease ,Survival Analysis ,Confidence interval ,Thyroxine ,030104 developmental biology ,chemistry ,business ,Follow-Up Studies - Abstract
Background The impact of free triiodothyronine (FT3)/free thyroxine (FT4) ratio on survival in hospitalized geriatric patients was recently described. Up today, there are no data regarding the prognostic role of FT3/FT4 ratio in patients with advanced cancer. We evaluated the impact of FT3/FT4 ratio on survival in patients with refractory colorectal cancer (CRC) treated with regorafenib. Methods Patients with metastatic CRC treated with regorafenib with available clinical data and baseline measurement of FT3, FT4, and thyroid-stimulating hormone (TSH) were considered eligible. Exploratory analyses included subjects treated at Istituto Oncologico Veneto. A confirmatory analysis was planned based on FT3/FT4 ratio tertile results, and a validation cohort was built on data retrieved from University of Cagliari. Results In an exploratory cohort, the median overall survival in patients with low, intermediate, and high FT3/FT4 ratios, according to tertiles' value, was 4.8, 5.0, and 7.6 months, respectively (P = .003). The differences were significant in the multivariate model (hazard ratio, 0.43; 95% confidence interval, 0.28-0.68; P = .0003). Confirmatory results were obtained in a validation cohort, both in univariate (P = .0002) and in multivariate (hazard ratio, 0.56; 95% confidence interval, 0.36-0.88; P = .0118) models. Conclusions High baseline FT3/FT4 ratio is strongly associated to better outcome in patients with progressive metastatic CRC treated with regorafenib. Further investigations are ongoing to draw definitive conclusions regarding a potential predictive effect.
- Published
- 2018
40. Why precision medicine should be applied across the continuum of care for metastatic colorectal cancer patients
- Author
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Andrea Pretta, Pina Ziranu, Nicole Liscia, Mara Persano, P. Soro, Clelia Donisi, S. Tolu, Valentino Impera, Stefano Mariani, S. Camera, Francesca Musio, Mario Scartozzi, Laura Demurtas, Marco Puzzoni, Francesca Balconi, and Eleonora Lai
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,medicine.drug_class ,Monoclonal antibody ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Biomarkers, Tumor ,Humans ,Molecular Targeted Therapy ,Continuum of care ,Neoplasm Metastasis ,Precision Medicine ,business.industry ,General Medicine ,Continuity of Patient Care ,Precision medicine ,medicine.disease ,Survival Rate ,Treatment Outcome ,Disease Progression ,business ,Colorectal Neoplasms - Published
- 2019
41. BRAF-mutant colorectal cancer, a different breed evolving
- Author
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Pierpaolo Coni, Mario Scartozzi, Eleonora Lai, Riccardo Giampieri, Andrea Pretta, Stefano Mariani, Marco Puzzoni, Daniela Fanni, Laura Casula, Valentino Impera, Pina Ziranu, Gavino Faa, Laura Demurtas, and Valeria Pusceddu
- Subjects
0301 basic medicine ,Poor prognosis ,endocrine system diseases ,MAP Kinase Signaling System ,Colorectal cancer ,Mutant ,Mutation, Missense ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,Animals ,Humans ,Medicine ,Missense mutation ,skin and connective tissue diseases ,neoplasms ,Molecular Biology ,Pathological ,Membrane Glycoproteins ,business.industry ,Colorectal tumour ,Prognosis ,medicine.disease ,Molecular medicine ,digestive system diseases ,Breed ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,Amino Acid Substitution ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Sulfotransferases ,Colorectal Neoplasms ,business - Abstract
BRAF mutant colorectal cancer (BRAF MT CRC) is a unique category of colorectal tumour with peculiar molecular, pathological and clinical features and poor prognosis; despite recent research, BRAF mutation predictive value and standard treatment of BRAF MT CRC still have to be defined. In this review, we focused on this challenging topic. Areas covered: The potential use of BRAF mutational status among recent additional prognostic and predictive indicators and current treatment strategy in use in these patients is discussed. Moreover, implications and characteristics of new BRAF mutations other than BRAFV600E are analyzed. An in-deep outlook on the immediate future for clinical and translational research in this subgroup of patients is also presented, such as combination therapy with agents targeting the RAS/RAF/MEK/ERK pathway and standard chemotherapy in order to overcome resistance. We performed a research on Pubmed typing 'BRAF mutation', 'colorectal cancer', 'predictive and prognostic value', 'targeted therapy', 'BRAF inhibition'. Expert commentary: BRAFV600E mutation represents a strong, independent negative prognostic factor in II-III stage MSS CRC and mCRC. The best treatment still has to be identified; currently, in good performance status patients, an intensive-chemotherapy-combination remains the standard of care. Further investigations are warranted to explore new horizons to change BRAF MT mCRC outcomes.
- Published
- 2018
42. 459P Dynamic changes of pro-angiogenic factors during FOLFIRI-aflibercept treatment: Interim analysis of DISTINCTIVE trial
- Author
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Sabina Murgioni, Pina Ziranu, S. Cherri, Mario Scartozzi, Valeria Smiroldo, G. Rosati, A. Cappetta, M.G. Zampino, Fabio Gelsomino, Clelia Madeddu, S. Lonardi, Cristina Morelli, L. Mascia, M.A. Palladino, Eleonora Lai, Veronica Conca, M. Squadroni, R. Bollina, Stefania Mosconi, and G. Barsotti
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,FOLFIRI ,Hematology ,business ,Interim analysis ,Aflibercept ,medicine.drug - Published
- 2021
43. 467P Monocyte to red blood cells ratio (MRR): an innovative haematologic prognostic parameter in FOLFIRI-aflibercept treated patients: A subgroup analysis from the DISTINCTIVE trial
- Author
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S. Cherri, M. Squadroni, V. Flaminio, Pina Ziranu, Andrea Spallanzani, M.A. Palladino, Sabina Murgioni, Clelia Madeddu, L. Mascia, G. Rosati, M.C. De Grandis, Eleonora Lai, G. Piacentini, Debora Basile, Valeria Smiroldo, S. Di Bella, M.G. Zampino, Veronica Conca, Mario Scartozzi, and Francesca Bergamo
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Monocyte ,Subgroup analysis ,Hematology ,medicine.anatomical_structure ,Internal medicine ,FOLFIRI ,Medicine ,business ,Aflibercept ,medicine.drug - Published
- 2021
44. Correction to: Angiogenesis Genotyping and Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Receiving Sorafenib: The ALICE‑2 Study
- Author
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Cosmo Damiano Gadaleta, Eva Galizia, Andrea Casadei Gardini, Giorgia Marisi, Stefano Cascinu, Marco Puzzoni, Pina Ziranu, Caterina Vivaldi, Riccardo Giampieri, Eleonora Lai, Maristella Bianconi, Paola Ulivi, Laura Demurtas, Nicola Battelli, Nicola Silvestris, Luca Faloppi, Mario Scartozzi, Cristian Loretelli, Gianluca Masi, and Alfredo Falcone
- Subjects
Oncology ,Sorafenib ,Cancer Research ,medicine.medical_specialty ,Angiogenesis ,business.industry ,medicine.disease ,Internal medicine ,Hepatocellular carcinoma ,medicine ,Pharmacology (medical) ,In patient ,business ,Genotyping ,medicine.drug - Published
- 2020
45. PD-5 Retrospective comparative analysis of K-ras G12C vs other K-ras mutations in metastatic colorectal cancer patients treated with first-line chemotherapy doublet + bevacizumab
- Author
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Federica Pecci, Mara Persano, Pina Ziranu, Alessandra Mandolesi, Enrica Giglio, Alessio Lupi, Andrea Pretta, Riccardo Giampieri, Alessandro Bittoni, R. Berardi, Sonia Crocetti, and Mario Scartozzi
- Subjects
Oncology ,medicine.medical_specialty ,Bevacizumab ,business.industry ,Colorectal cancer ,Internal medicine ,medicine ,Hematology ,First line chemotherapy ,business ,medicine.disease ,medicine.drug - Published
- 2021
46. P-128 Influence of anti-diabetic medications on the outcomes of patients with pancreatic ductal adenocarcinoma and type 2 diabetes mellitus
- Author
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Andrea Pretta, A. Parrino, Marco Dubois, Mario Scartozzi, Marco Migliari, Pina Ziranu, Eleonora Lai, Nicole Liscia, E. Cimbro, Clelia Donisi, G. Pinna, Marco Puzzoni, Mara Persano, Stefano Mariani, and Valeria Pusceddu
- Subjects
medicine.medical_specialty ,Pancreatic ductal adenocarcinoma ,Oncology ,business.industry ,Internal medicine ,medicine ,Type 2 Diabetes Mellitus ,Hematology ,business ,Gastroenterology - Published
- 2021
47. P-127 Lymphocyte to monocyte ratio as a prognostic factor in stage IV pancreatic ductal adenocarcinoma naive patients before gemcitabine-nab-paclitaxel chemotherapy
- Author
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A. Parrino, Andrea Pretta, Pina Ziranu, Mario Scartozzi, Marco Puzzoni, E. Cimbro, Mara Persano, Eleonora Lai, Stefano Mariani, Nicole Liscia, Clelia Donisi, G. Pinna, Marco Dubois, Valeria Pusceddu, and Marco Migliari
- Subjects
Chemotherapy ,Prognostic factor ,Pancreatic ductal adenocarcinoma ,business.industry ,medicine.medical_treatment ,Monocyte ,Lymphocyte ,Hematology ,Gemcitabine ,Therapy naive ,medicine.anatomical_structure ,Oncology ,medicine ,Cancer research ,Stage iv ,business ,medicine.drug - Published
- 2021
48. Liquid biopsy-driven anti-EGFR rechallenge in patients with metastatic colorectal cancer
- Author
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Valentino Impera, Francesca Musio, Grazia Palomba, Mario Scartozzi, S. Tolu, Marina Pisano, Pina Ziranu, Anna Grazia Pireddu, Milena Casula, Mara Persano, Nicole Liscia, Clelia Donisi, G. Pinna, Stefano Mariani, Eleonora Lai, Marco Puzzoni, Giuseppe Palmieri, Andrea Pretta, Laura Demurtas, and Valeria Pusceddu
- Subjects
Cancer Research ,Oncology ,Colorectal cancer ,business.industry ,Cancer research ,Wild type ,medicine ,In patient ,Liquid biopsy ,medicine.disease ,business ,EGFR inhibitors - Abstract
3577 Background: The rechallenge with EGFR inhibitors represents an emerging strategy for anti-EGFR pre-treated patients with RAS wild type colorectal cancer (CRC). Unfortunately definitive selection criteria for anti-EGFR rechallenge in this setting are lacking. Very recently RAS wild type status on circulating tumor DNA (ct-DNA) at the time of rechallenge along with already known clinical criteria emerged as a potential watershed for this strategy. In the present study we explored liquid biopsy-driven anti-EGFR rechallenge strategy in the clinical practice for patients with metastatic colorectal cancer. Methods: Ct-DNA from RAS and BRAF wild type metastatic CRC patients previously treated with an anti-EGFR containing therapy was analyzed for RAS/BRAF mutations with the aim to evaluate the rechallenge strategy with anti-EGFR. The ct-DNA was analyzed for RAS-BRAF mutations using pyro-sequencing (PyroMark Q24 MDx Workstation) and nucleotide sequencing (Genetic Analyzer ABI3130) assays. Real-time PCR (Idylla) and droplet digital PCR (QX200 System) were performed to confirm the RAS-BRAF mutation status. Several clinical variables including previous response to anti EGFR containing therapy, tumor sidedness and anti-EGFR free interval were evaluated in relation to outcome. Tumor response evaluation was performed according to RECIST 1.1. Differences between categorical variables were evaluated using the Fisher’s exact test. Survival probability over time was estimated by the Kaplan–Meier method. Significant differences in the probability of survival between the strata were evaluated by log-rank test. Results: Twenty patients were included in the study. All patients were tested for RAS-BRAF mutations in ct-DNA. Fourteen patients (70%) showed a RAS-BRAF WT molecular profile, six patients (30%) showed a KRAS mutation. All the patients with ct-DNA RAS-BRAF WT profile underwent rechallenge with anti-EGFR. In details 11 patients (78.6%) underwent irinotecan+ cetuximab treatment, whereas 3 patients (21.4%) underwent panitumumab monotherapy. As for the outcome results to the rechallenge strategy, the median OS was 7 months (95% CI 5.0 to 13.0), the median PFS was 3 months (95% CI 2.0 to 6.0), the ORR was 27.3% with a DCR of 54.5%. Among the clinical variables evaluated as putative predictive/prognostic factors, previous response to anti-EGFR treatment was related to a not statistically significant improved OS (12 months vs 5 months HR:0.19 p: 0.06) and to a statistically significant improved ORR (75% vs 0% p:0.03). Conclusions: The rechallenge strategy with anti-EGFR confirmed to be feasible in clinical practice. The clinical outcome resulted consistent with the literature data. In addition to the molecular selection through the analysis of ct-DNA for RAS, previous response to anti EGFR treatment is confirmed as a prospective selection criteria for this therapeutic option.
- Published
- 2021
49. Phase 2 study of second-line FOLFIRI-aflibercept in prospectively stratified, RAS wild type, anti-EGFR resistant, metastatic colorectal cancer patients: The DISTINCTIVE trial
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Pina Ziranu, Luigi Mascia, Gerardo Rosati, Alberto Zaniboni, Eleonora Lai, Clelia Madeddu, Sabina Murgioni, Giordano D. Beretta, Luigi Cavanna, Valeria Smiroldo, Mario Scartozzi, Sara Lonardi, Cristina Morelli, Fabio Gelsomino, Veronica Conca, Silvia Della Torre, Giuseppe Aprile, Fotios Loupakis, Stefania Mosconi, and M. Giulia Zampino
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Oncology ,Cancer Research ,medicine.medical_specialty ,Second line treatment ,business.industry ,Colorectal cancer ,Wild type ,Phases of clinical research ,medicine.disease ,Second line ,Internal medicine ,FOLFIRI ,Medicine ,business ,Aflibercept ,medicine.drug - Abstract
e15503 Background: Data on anti-angiogenic second line treatment in RAS wild type (wt) metastatic colorectal cancer (mCRC) patients (pts) progressing after first-line anti-EGFR drug are lacking and no validated biomarkers are available. We present the pre-planned interim analysis of the DISTINCTIVE trial (NCT04252456), a biologically enriched, prospectively stratified phase 2 study assessing the aflibercept use in this setting. Methods: RAS wt mCRC pts progressing after first line oxaliplatin-based + anti-EGFR therapy and candidates for second-line FOLFIRI/aflibercept are eligible for the DISTINCTIVE trial. Pts are prospectively allocated to a favorable (F) or unfavorable (U) prognostic group, according to Elisa-assessed baseline (BL) VEGFR2 plasma levels (PL). Other circulating angiogenic factors are evaluated at BL, first tumor assessment (TA1) and disease progression (PD). Primary endpoint is overall survival (OS) according to VEGFR2 levels. Secondary endpoints are OS, progression free survival (PFS), response rate, safety and angiogenic factors levels. Statistical analysis is performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; multivariate analysis: logistic regression). Sample size: 151 pts (one-sided test, α: 0.1, β: 0.2). Results: From 04/2018 to 06/2020, 73 pts were enrolled. Complete data from 44 pts were available for interim analysis. 33 pts (75%) achieved DCR (26 pts/59% SD, 7 pts/16% PR). Globally, median OS was 11.9 months (m) (95%CI 10 – 14.2). 24 (54.5%) pts were prospectively assigned to F group (VEGFR2 PL > 4 ng/ml) and 20 (45.5%) to U group (VEGFR2 PL ≤4 ng/ml). OS in F group was 13.1 m (95%CI 9.6 – 14.2) vs 11.9 m (95%CI 6.8 – 11.9) in U group (HR 0.76 p = 0.6218). PFS was 9.8 m [95%CI 5.7 – 24.2] in F group vs 4.2 m [95%CI 2.5 – 14.2] in U group (HR 0.41 p = 0.0105). We also found preliminary correlation with PD as shown in table. Conclusions: Interim analysis showed high activity of FOLFIRI/aflibercept in RAS WT anti-EGFR pretreated mCRC pts. VEGFR2 showed promising ability to predict aflibercept efficacy. Our data on circulating angiogenic biomarkers are likely to further compose the landscape of anti-angiogenic activity in mCRC pts. Clinical trial information: NCT04252456. [Table: see text]
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- 2021
50. Effective combinatorial immunotherapy for castration-resistant prostate cancer: new future chance?
- Author
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Pina Ziranu, Francesco Atzori, Marco Puzzoni, Laura Demurtas, Giorgio Astara, and Mario Scartozzi
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Cancer Research ,Oncology ,Radiology, Nuclear Medicine and imaging - Published
- 2017
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