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1. Abstract GS3-07: Circulating tumor DNA (ctDNA) dynamics in patients with hormone receptor positive (HR+)/HER2 negative (HER2-) advanced breast cancer (aBC) treated in first line with ribociclib (R) and letrozole (L) in the BioItaLEE trial

Author

Giampaolo Bianchini, Luca Malorni, Grazia Arpino, Alberto Zambelli, Fabio Puglisi, Lucia Del Mastro, Marco Colleoni, Filippo Montemurro, Giulia Bianchi, Ida Paris, Giacomo Allegrini, Marina Elena Cazzaniga, Michele Orditura, Claudio Zamagni, Stefano Tamberi, Daniela Castelletti, Matteo Benelli, Maurizio Callari, Angela Santoro, and Michelino De Laurentiis

Subjects
Cancer Research, Oncology
Abstract

Background: ctDNA analysis is emerging as an attractive non-invasive approach to characterize tumor biology, describe its evolution over time, and predict treatment benefit. Here, we assessed the prognostic and predictive role of baseline and dynamic ctDNA analysis in HR+/HER2- aBC patients (pts) treated with R+L. Methods: 287 postmenopausal pts were enrolled in the BioItaLEE trial (NCT03439046). Liquid biopsies were collected at baseline (D0; n=263), day 15 of cycle 1 (D15; n=238), day 1 of cycle 2 (C2D1; n=241) and at first imaging (FI, at approximately 12 weeks; n=206). ctDNA analysis was carried out using a 533-amplicon Custom AmpliSeq HD Panel, with amplicons covering the coding exons of 39 BC-related genes (limit of detection: 0.1%). Target mutations were defined as single-nucleotide variant (SNV) or Insertion/Deletion detected at D0. When multiple target mutations were detected, the one with the highest variant allele frequency (VAF) was considered. The association between pre-treatment and on-treatment ctDNA dynamics with progression-free survival (PFS) was assessed using Multivariate Cox models. VAF clearance was defined as 100% decrease in a target mutation. Results: Median follow-up was 26.9 months and median PFS was 23.39 (20.8-NE) months. At baseline, target mutations were detected in 113 pts (43.0%), whereas 150 pts were wild-type (wt). Mean (SD) pre-treatment VAF at D0 was 11.3% (14.4). The absence of a target mutation at D0 was associated with good prognosis (HR: 0.41, 95% CI: 0.27–0.61; p Citation Format: Giampaolo Bianchini, Luca Malorni, Grazia Arpino, Alberto Zambelli, Fabio Puglisi, Lucia Del Mastro, Marco Colleoni, Filippo Montemurro, Giulia Bianchi, Ida Paris, Giacomo Allegrini, Marina Elena Cazzaniga, Michele Orditura, Claudio Zamagni, Stefano Tamberi, Daniela Castelletti, Matteo Benelli, Maurizio Callari, Angela Santoro, Michelino De Laurentiis. Circulating tumor DNA (ctDNA) dynamics in patients with hormone receptor positive (HR+)/HER2 negative (HER2-) advanced breast cancer (aBC) treated in first line with ribociclib (R) and letrozole (L) in the BioItaLEE trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS3-07.

Published
2022

2. Abstract P3-09-03: Single nucletotide polymorphisms of aromatase gene (CYP19A1) and toxicity of adjuvant aromatase inhibitors: A translational, prospective study

Author

Benedetta Conte, Chiara Molinelli, Giancarlo Bisagni, Antonio Durando, Giovanni Sanna, Stefania Gori, Ornella Garrone, Stefano Tamberi, Sabino De Placido, Francesco Schettini, Antonio Pazzola, Riccardo Ponzone, Filippo Montemurro, Gianluigi Lunardi, Rosario Notaro, Anna Turletti, Claudia Bighin, Francesca Poggio, Giulia Buzzatti, Matteo Lambertini, Luca Boni, and Lucia Del Mastro

Subjects
Cancer Research, Oncology
Abstract

Background: Extending adjuvant endocrine treatment (ET) with aromatase inhibitors (AI) to 7-10 years decreases the risk of relapse in hormone receptor-positive (HR+) breast cancer (BC). However, such benefit comes at the price of higher incidence of skeletal and cardiovascular (CV) events. Biomarkers predicting such toxicities might help clinicians in tailoring adjuvant ET to patient’s needs. We conducted a prospective study to assess whether SNPs in the gene encoding for the aromatase enzyme (CYP19A1) affect the risk of skeletal and CV events in HR+ early BC patients enrolled in the GIM4 trial. Methods: The GIM4 trial randomized HR+ BC postmenopausal patients who had been already treated with 2-3 years of adjuvant tamoxifen to either 3-2 years or 5 years of adjuvant letrozole. Four SNPs of CYP19A1 were evaluated: rs10046, rs4646, rs479292 and rs727479. SNPs were genotyped through PCR on DNA obtained from patients’ peripheral blood samples. Skeletal and CV events were assessed from randomization in the GIM4 trial to last follow-up, disease recurrence or death. Skeletal events were defined as the onset of osteoporosis or bone fractures. CV events were defined as the onset of thrombosis, embolism, stroke, myocardial infarction, hearth failure, or arrythmia. Univariate and multivariate logistic regressions were performed to evaluate the association between SNPs and skeletal and CV events. Bonferroni correction for multiplicity was used for univariate SNPs association tests, with a corrected alpha of 0.012. Only associations with an alpha level Citation Format: Benedetta Conte, Chiara Molinelli, Giancarlo Bisagni, Antonio Durando, Giovanni Sanna, Stefania Gori, Ornella Garrone, Stefano Tamberi, Sabino De Placido, Francesco Schettini, Antonio Pazzola, Riccardo Ponzone, Filippo Montemurro, Gianluigi Lunardi, Rosario Notaro, Anna Turletti, Claudia Bighin, Francesca Poggio, Giulia Buzzatti, Matteo Lambertini, Luca Boni, Lucia Del Mastro. Single nucletotide polymorphisms of aromatase gene (CYP19A1) and toxicity of adjuvant aromatase inhibitors: A translational, prospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-03.

Published
2022

3. Serum thymidine kinase activity in patients with HR-positive/HER2-negative advanced breast cancer treated with ribociclib plus letrozole: Results from the prospective BioItaLEE trial

Author

Luca Malorni, Giampaolo Bianchini, Roberta Caputo, Alberto Zambelli, Fabio Puglisi, Giulia V. Bianchi, Lucia Del Mastro, Ida Paris, Filippo Montemurro, Giacomo Allegrini, Marco Colleoni, Stefano Tamberi, Claudio Zamagni, Marina E. Cazzaniga, Michele Orditura, Valentina Guarneri, Daniela Castelletti, Matteo Benelli, Mariacristina Di Marino, Grazia Arpino, and Michelino De Laurentiis

Subjects
Cancer Research, Thymidine kinase, Oncology, Ribociclib, Letrozole, Advanced breast cancer, Biomarker
Published
2023

4. 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

Author

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

Subjects
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.

Published
2023

5. Dissecting tumor lymphocyte infiltration to predict benefit from immune-checkpoint inhibitors in metastatic colorectal cancer: lessons from the AtezoT RIBE study

Author

Roberto Moretto, Daniele Rossini, Aurélie Catteau, Carlotta Antoniotti, Mirella Giordano, Alessandra Boccaccino, Clara Ugolini, Agnese Proietti, Veronica Conca, Alboukadel Kassambara, Filippo Pietrantonio, Lisa Salvatore, Sara Lonardi, Stefano Tamberi, Emiliano Tamburini, Anello Marcello Poma, Jacques Fieschi, Gabriella Fontanini, Gianluca Masi, Jérôme Galon, and Chiara Cremolini

Subjects
Pharmacology, Cancer Research, Oncology, Immunology, Molecular Medicine, Immunology and Allergy
Abstract

BackgroundTumor immune cells influence the efficacy of immune-checkpoint inhibitors (ICIs) and many efforts aim at identifying features of tumor immune microenvironment able to predict benefit from ICIs in proficient mismatch repair (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer (mCRC).MethodsWe characterized tumor immune cell infiltrate, by assessing tumor-infiltrating lymphocytes (TILs), Immunoscore, Immunoscore-IC, and programmed death ligand-1 (PD-L1) expression in tumor samples of patients with mCRC enrolled in the AtezoTRIBE study, a phase II randomized trial comparing FOLFOXIRI/bevacizumab/atezolizumab to FOLFOXIRI/bevacizumab, with the aim of evaluating the prognostic and predictive value of these features.ResultsOut of 218 patients enrolled, 181 (83%), 77 (35%), 157 (72%) and 162 (74%) specimens were successfully tested for TILs, Immunoscore, Immunoscore-IC and PD-L1 expression, respectively, and 69 (38%), 45 (58%), 50 (32%) and 21 (13%) tumors were classified as TILs-high, Immunoscore-high, Immunoscore-IC-high and PD-L1-high, respectively. A poor agreement was observed between TILs and Immunoscore or Immunoscore-IC (K of Cohen ConclusionsThe digital evaluation of tumor immune cell infiltrate by means of Immunoscore-IC or Immunoscore identifies the subset of patients with pMMR mCRC achieving more benefit from the addition of the anti-PD-L1 to the upfront treatment. Immunoscore-IC stands as the most promising predictor of benefit from ICIs.

Published
2023

6. Association of high TUBB3 with resistance to adjuvant docetaxel-based chemotherapy in gastric cancer: translational study of ITACA-S

Author

Tiziana Pressiani, Enrico Aitini, Fabiola Cecchi, Gianni Sanna, Daniel V.T. Catenacci, Gerardo Rosati, Lorenza Landi, Hector Soto Parra, Francesca Spada, Yuan Tian, Stefano Tamberi, Elisa Giommoni, Carmine Pinto, Todd Hembrough, Luigi Cavanna, Shankar Sellappan, Antonia Martinetti, Alberto Marchet, Stefania Mosconi, Alberto Zaniboni, Alessandro Pellegrinelli, Rosalba Miceli, Francesca Pucci, Alessandra Raimondi, Paola Bolzoni, Sarit Schwartz, Filippo Pietrantonio, Maurizio Cantore, Salvatore Corallo, and Maria Di Bartolomeo

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_treatment, Leucovorin, Drug Resistance, Docetaxel, Kaplan-Meier Estimate, taxane, Translational Research, Biomedical, 0302 clinical medicine, Tubulin, Antineoplastic Combined Chemotherapy Protocols, Translational Medical Research, Adjuvant, Tumor, adjuvant therapy, General Medicine, Prognosis, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, Fluorouracil, medicine.drug, medicine.medical_specialty, Adenocarcinoma, 03 medical and health sciences, Stomach Neoplasms, Internal medicine, Biomarkers, Tumor, medicine, Adjuvant therapy, Humans, Chemotherapy, Taxane, business.industry, Cancer, class III β-tubulin, Class III β-tubulin, medicine.disease, 030104 developmental biology, Drug Resistance, Neoplasm, Neoplasm, Cisplatin, Gastric cancer, business, Biomarkers
Abstract

Background:No predictive markers for chemotherapy activity have been validated in gastric cancer (GC). The potential value of class III β-tubulin (TUBB3) as biomarker for prognosis and resistance to taxane-based therapy was reported.Methods:We analyzed GC samples of patients enrolled in the Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S), a randomized adjuvant study comparing 5-fluorouracil/leucovorin (5-FU/LV) and docetaxel-based sequential chemotherapy. TUBB3 was quantitated by selected reaction monitoring mass spectrometry and patients were stratified using a threshold of 750 attomoles per microgram (amol/µg). Cox proportional modeling and Kaplan-Meier survival analysis were used to assess the impact of TUBB3 expression on overall survival (OS) and disease-free survival.Results:Patients with TUBB3 protein levels >750 and Conclusions:The quantification of TUBB3 might be considered as a negative predictive biomarker of benefit from taxane-based therapy in GC. Studies are needed to evaluate its role in the neoadjuvant setting.

Published
2020

7. Predictive Impact of Mucinous Tumors on the Clinical Outcome in Patients with Poorly Differentiated, Stage II Colon Cancer: A TOSCA Subgroup Analysis

Author

Francesca Bergamo, Roberto Labianca, Tosca Investigators, Maria Giulia Zampino, Anna Maria Bochicchio, Francesca Galli, Fabrizio Artioli, Monica Ronzoni, Giovanni Gerardo Cardellino, Domenico Bilancia, Maurizio Cantore, Maria Di Bartolomeo, Domenico Corsi, Lorenza Rimassa, Maria Banzi, F. Galli, Eliana Rulli, Giacomo Bregni, Gerardo Rosati, Stefano Tamberi, Rodolfo Mattioli, and Paolo Marchetti

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, Population, Subgroup analysis, Adenocarcinoma, 03 medical and health sciences, Folinic acid, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Gastrointestinal Cancer, medicine, Humans, Stage (cooking), education, Neoplasm Staging, Cancer staging, education.field_of_study, business.industry, Prognosis, medicine.disease, Oxaliplatin, 030104 developmental biology, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Colonic Neoplasms, Fluorouracil, Neoplasm Recurrence, Local, business, medicine.drug
Abstract

Background Although American Society of Clinical Oncology and European Society for Medical Oncology guidelines have identified the negative prognostic factors that clinicians have to consider when treating their patients with stage II colon cancer (CC), the role of histological subtype is controversial. Subjects, Materials, and Methods The randomized, multicenter, phase III TOSCA trial compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy in 3,759 patients with high-risk stage II or stage III CC. The objective of this substudy was to evaluate the influence of histological subtypes on the impact of the treatment duration of adjuvant chemotherapy in terms of relapse-free survival (RFS) and overall survival (OS) in 85 mucinous adenocarcinoma (MUC) and 389 nonmucinous adenocarcinoma (NMUC) patients with high-risk stage II, grade 3 CC. Results A significant interaction between treatment duration and histology was observed in both RFS (p = .027) and OS (p = .017). In the subgroup of patients with MUC, worse RFS (adjusted hazard ratio [HR], 3.95; 95% confidence interval [CI], 1.03–15.17; p = .045) and OS (HR, 9.56; 95% CI, 1.14–79.98; p = .037) were detected for patients treated in the 3-month arm. No statistically significant differences were found in the subgroup of patients with NMUC. Conclusion Patients with MUC, grade 3, stage II CC require special attention and may need 6 months of oxaliplatin-based chemotherapy. Larger studies are required to assess the combined use of histology and other prognostic/predictive factors to define the administration of chemotherapy in patients with stage II CC and to improve their prognosis. Implications for Practice Although ASCO and ESMO guidelines define the prognostic factors for patients with stage II colon cancer to establish the use of adjuvant chemotherapy, the influence of histological subtypes is controversial in this population. This study underscores that patients with grade 3 mucinous adenocarcinomas may need adjuvant chemotherapy with oxaliplatin and fluoropyrimidines for a duration of 6 months rather than 3 months.

Published
2020

8. Dynamics of RAS/BRAF Mutations in cfDNA from Metastatic Colorectal Carcinoma Patients Treated with Polychemotherapy and Anti-EGFR Monoclonal Antibodies

Author

Anna Maria Rachiglio, Laura Forgione, Raffaella Pasquale, Carlo Antonio Barone, Evaristo Maiello, Lorenzo Antonuzzo, Antonino Cassata, Giuseppe Tonini, Roberto Bordonaro, Gerardo Rosati, Alberto Zaniboni, Sara Lonardi, Daris Ferrari, Giovanni Luca Frassineti, Stefano Tamberi, Salvatore Pisconti, Francesca Di Fabio, Cristin Roma, Armando Orlandi, Tiziana Latiano, Angela Damato, Giampaolo Tortora, Carmine Pinto, and Nicola Normanno

Subjects
Cancer Research, Cell-free DNA, Settore MED/06 - ONCOLOGIA MEDICA, Oncology, Liquid biopsy, Metastatic colorectal cancer, metastatic colorectal cancer, liquid biopsy, cell-free DNA, anti-EGFR therapy, Anti-EGFR therapy, digestive system diseases
Abstract

Analysis of plasma-derived cell-free DNA (cfDNA) might allow for the early identification of resistance in metastatic colorectal carcinoma (mCRC) patients receiving anti-EGFR monoclonal antibodies. We tested plasma samples from the Erbitux Metastatic Colorectal Cancer Strategy (ERMES) phase III trial of FOLFIRI+Cetuximab in first-line treatment of RAS/BRAF wild-type mCRC. Samples were collected at baseline (n = 37), at 8 weeks of treatment (n = 32), progressive disease (PD; n = 36) and 3 months after PD (n = 21). cfDNA testing was performed using the Idylla™ ctKRAS and ctNRAS-BRAF tests and the Oncomine Pan-Cancer Cell-Free Assay. Analysis of basal samples revealed RAS/BRAF mutations in 6/37 cases. A transient RAS positivity not associated with PD was observed at 8 weeks in five cases that showed no mutations at baseline and PD. The frequency of mutant cases increased at PD (33.3%) and decreased again at 3 months after PD (9.5%). The median progression-free survival (mPFS) of patients RAS/BRAF mutant at PD was 7.13 months versus 7.71 months in wild-type patients (p = 0.3892). These data confirm that the occurrence of RAS/BRAF mutations in mCRC patients receiving anti-EGFR agents is relatively frequent. However, the cfDNA dynamics of RAS mutations in patients treated with anti-EGFR agents plus polychemotherapy are complex and might not be directly associated with resistance to treatment.

Published
2022
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9. INFINITY: A multicentre, single-arm, multi-cohort, phase II trial of tremelimumab and durvalumab as neoadjuvant treatment of patients with microsatellite instability-high (MSI) resectable gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC)

Author

Filippo Pietrantonio, Alessandra Raimondi, Sara Lonardi, Sabina Murgioni, Giovanni Gerardo Cardellino, Stefano Tamberi, Antonia Strippoli, Federica Palermo, Michele Prisciandaro, Giovanni Randon, Francesca Corti, Francesca Bergamo, Floriana Nappo, Alberto Giovanni Leone, Giuseppe Leoncini, Giovanna Sabella, Kristiyana Kaneva, Carlo Sposito, Maria Di Bartolomeo, and Vincenzo Mazzaferro

Subjects
Cancer Research, Oncology
Abstract

358 Background: In resectable GAC/GEJAC, MSI status is associated with better survival and potential lack of benefit from chemotherapy. Given the high responsiveness of MSI tumors to immunotherapy, neoadjuvant or definitive dual CTLA-4/PD(L)-1 inhibition may allow omission of chemotherapy or surgery. Methods: INFINITY is a multicentre, single-arm, multi-cohort phase II trial (NCT04817826) investigating the activity and safety of tremelimumab+durvalumab as neoadjuvant (Cohort 1) or definitive (Cohort 2) treatment for MSI, mismatch repair deficient (dMMR) and EBV-negative resectable GAC/GEJAC. In Cohort 1, patients (pts) received a 12-week treatment with single high dose tremelimumab 300 mg and durvalumab 1500 mg q4 weeks (T300/D) for 3 cycles followed by surgery. The primary endpoint was pCR rate (ypT0N0) with negative ctDNA after T300/D. Secondary endpoints: disease-free survival, overall survival, quality of life. Exploratory: correlation of pCR with clinical variables, PDL-1 CPS assessed by IHC 22C3, tumor mutational burden (TMB) by Foundation One, liquid biopsies and other biomarkers. Cohort 2 investigates non operative management after same treatment regimen. Results: Overall, 18 pts with MSI/dMMR resectable cT2-4 any N GAC/GEJAC were recruited in Cohort 1. One withdrew consent and 2 achieved a complete clinical-pathological response at radiology and endoscopy (ongoing) and refused surgery. Among 15 evaluable patients, 1 had disease progression and 14 underwent resection. pCR rate was 60% (9/15) and major-complete pathological response (

Published
2023

10. Current Therapeutic Strategies in BRAF-Mutant Metastatic Colorectal Cancer

Author

Federica Gazzaneo, Giorgio Papiani, Jody Corbelli, Elisa Grassi, Stefano Tamberi, and Maria Aurelia Barbera

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, Mutant, colorectal cancer, Review, medicine.disease_cause, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, neoplasms, RC254-282, Mutation, business.industry, Microsatellite instability, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunotherapy, medicine.disease, targeted therapy, digestive system diseases, microsatellites instability, 030104 developmental biology, BRAF mutation, 030220 oncology & carcinogenesis, Colon rectal cancer, immunotherapy, business, V600E
Abstract

Around 8–12% of patients with advanced colon rectal cancer (CRC) present with BRAF alterations, in particular V600E mutation, which is associated with right-side, poorly differentiated and mucinous type tumors. The presence of BRAF mutation (BRAF-mt) has been identified as a hallmark of poor prognosis and treatment optimization in this patient subgroup is an important goal. Currently, the standard of care is an aggressive strategy involving triplet chemotherapy and anti-VEGF agents, but new therapeutic approaches are emerging. Very promising results have been obtained with targeted therapy combinations, such as anti-BRAF agents plus anti-EGFR agents. Furthermore, around 60% of BRAF-mt patients show a strong association with high microsatellite instability (MSI-H) and immune checkpoint inhibitors could represent the new standard of care for this subgroup. The focus of this review is to summarize current strategies for BRAF-mt CRC treatment and highlight new therapeutic options.

Published
2021

11. Randomized phase III trial on trabectedin (ET-743) single agent versus clinician’s choice chemotherapy in recurrent ovarian, primary peritoneal, or fallopian tube cancers of BRCA-mutated or BRCAness phenotype patients (MITO23)

Author

Giovanni Scambia, Francesco Raspagliesi, Giorgio Valabrega, Nicoletta Colombo, Carmen Pisano, Chiara Cassani, Germana Tognon, Stefano Tamberi, Giorgia Mangili, Serafina Mammoliti, Ugo De Giorgi, Filippo Greco, Anna Maria Mosconi, Enrico Breda, Grazia Artioli, Claudia Andreetta, Claudia Casanova, Rita Ceccherini, Antonio Frassoldati, and Domenica Lorusso

Subjects
Cancer Research, Oncology
Abstract

LBA5504 Background: Trabectedin demonstrated antitumor activity when administered as single agent in relapsed platinum sensitive ovarian cancer (OC), with an overall response rate (ORR) ranging from 26 to 43% and a median PFS of 5 months. In addition, trabectedin showed 39.4% RR, 4.5 months median progression free survival (PFS) and 18 months median overall survival (OS) in a single arm phase 2 trial in recurrent BRCA mutated and/or the BRCAness phenotype OC patients. Methods: In this open-label, phase III, randomized trial, we assigned recurrent OC patients harboring BRCA 1/2 mutations or with BRCAness phenotype (defined as patients who had received and responded to at least 2 previous platinum-based treatments) to receive trabectedin 1.3 mg/mq q 21d or physician’s choice chemotherapy (among carboplatin, gemcitabine, weekly paclitaxel, pegylated liposomal doxorubicine or topotecan). The primary endpoint was OS. Secondary endpoints were PFS, ORR and Duration of Response (DoR). The sample size was calculated based on the assumption that trabectedin would increase median OS from 10 to 15 months (two-sided log-rank test at the error alfa= 0.05 and a power of 80%). Medians and lifetables were computed using the Kaplan-Meier method and analyzed using the log-rank test. Cox proportional hazards model was used to assess the effect of treatment. Results: Two hundred and forty-four patients were randomized and analyzed based on the intent-to-treat principle. At a median follow up of 40 months, the median PFS was 4.4 and 4.9 months (HR= 1.03 p=0.848) and median OS was 17.9 and 15.8 months (HR=1.15 p=0.304), in the control and experimental arm, respectively. ORR was 20.2% in the group of patients receiving standard chemotherapies and 15.4% in the group of patients treated with trabectedin. No superior effect was reported for Trabectedin in the pre-specified sub-group analysis according to BRCA mutational status, type of chemotherapy and platinum-free interval. No new signal of toxicity were reported for all the chemotherapies employed. Conclusions: Trabectedin as single agent does not improve survival outcomes when compared to standard chemotherapy in BRCA mut and BRCAness phenotype OC patients. Clinical trial information: NCT02993705.

Published
2022

12. A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study final results

Author

Stefano Tamberi, Elisa Grassi, Chiara Zingaretti, Giorgio Papiani, Sara Pini, Jody Corbelli, Maria Di Bartolomeo, Filippo Pietrantonio, Giovanni Luca Frassineti, Alessandro Passardi, Fabio Gelsomino, Marina Marzola, Maria Banzi, Andrea Vincent Bonetti, Elisabetta Petracci, Chiara Carli Moretti, Isabella Banchelli, Davide Tassinari, Giampaolo Ugolini, and Oriana Nanni

Subjects
Cancer Research, Oncology
Abstract

LBA3513 Background: The combination of capecitabine plus long course radiotherapy (RT) is the standard preoperative therapy in cT3-4 cN+ rectal cancer. pathologic complete remission (pCR) can be considered as surrogate endpoint of efficacy of treatment in terms of disease-free survival (DFS). Preclinical data points heavily toward a strong synergy between RT and immune treatments. Methods: This is a prospective phase II, open label, single arm, multicentre study in patient with locally advanced rectal cancer who receive standard concomitant CT/RT therapy (825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks) followed by durvalumab (1500 mg Q4W for 3 administrations). Surgery is performed after 10-12 weeks from neoadjuvant therapy. The primary endpoint is the proportion of pCRs after at least 1 cycle of durvalumab; secondary endpoints are the proportion of clinical complete remissions (cCRs) after at least 1 cycle of durvalumab, the proportion of adverse and serious adverse events (NCI CTCAE v5.0). The sample size has been estimated by using the optimal Simon’s two-stage design assuming a null pCR proportion of 0.15 and an alternative pCR percentage of 0.30 (alpha = 0.05, power = 0.80). If more than 4 pCRs were observed in the first 19 enrolled patients, 36 additional patients were to be accrued for a total of 55 evaluable patients. The null hypothesis is rejected if ≥ 13 pCRs are observed in 55 patients. Results: Between November 2019 and August 2021, 60 patients were accrued, of which 55 were evaluable for study objectives. Fifty-two of 55 treated patients received all 3 infusions of durvalumab. After treatment, a clinical response percentage of 81.8% was observed; 3 patients had progression of disease due to local and/or metastases before surgical intervention. Eighteen patients achieved complete pathological response (32.7%), confirmed by central revision. Near complete regression, moderate and minimal regression were observed in 14 (25.5%), 9 (16.4%) and 11 (20.0%) patients respectively. Regarding toxicity, 23 patients (41.8%) had adverse events (AEs) related to durvalumab treatment. Two patients (1.8%) discontinued durvalumab for toxicity. Grade 3 AEs occurred in 4 (7.3%) patients (diarrhea, skin toxicity, transaminase increase, lipase increase and pancolitis). No Grade 4 toxicity was observed. In 20 patients (36.4%) G1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypo-thyroidism), dermatologic toxicity (skin rash) and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation). Conclusions: This study met its primary endpoint showing a promising activity of neoadjuvant chemo-radiotherapy plus durvalumab in terms of pCR rate and a safe toxicity profile. Clinical trial information: NCT04083365.

Published
2022

13. Circulating tumor DNA (ctDNA) and serum thymidine kinase 1 activity (TKa) matched dynamics in patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor 2–negative (HER2-) advanced breast cancer (ABC) treated in first-line (1L) with ribociclib (RIB) and letrozole (LET) in the BioItaLEE trial

Author

Grazia Arpino, Giampaolo Bianchini, Luca Malorni, Alberto Zambelli, Fabio Puglisi, Lucia Del Mastro, Marco Colleoni, Filippo Montemurro, Giulia Valeria Bianchi, Ida Paris, Giacomo Allegrini, Stefano Tamberi, Marina Elena Cazzaniga, Michele Orditura, Claudio Zamagni, Donatella Grasso, Matteo Benelli, Maurizio Callari, Antonina Benfante, and Michelino De Laurentiis

Subjects
Cancer Research, Oncology
Abstract

1012 Background: Independent early dynamic assessment (baseline [D0] and day 15 of first cycle [D15]) of both TKa and ctDNA was prognostic and predictive in pts with HR+, HER2− ABC treated with RIB+LET enrolled in the BioItaLEE trial (NCT03439046). Here we performed a combined analysis of these two biomarkers. Methods: 287 pts were enrolled in the study. Overall, early dynamics were assessable for both biomarkers in 241/287 pts (84.0%). Methods applied for ctDNA and TKa evaluation were previously reported. For ctDNA, samples were defined as wild type (WT) if no mutations were observed at D0 and D15, ctDNA positive (+) if with or negative (-) if without a primary target mutation at D15. Samples were TKa+ or TKa- if TKa levels were above or below the limit of detection at D15. According to ctDNA and TKa pts were classified as: WT/TKa-, WT/TKa+, ctDNA-/TKa-, ctDNA-/TKa+, ctDNA+/TKa- and ctDNA+/TKa+ and then divided into 3 main study groups (GRs) WT/TKa- (GR1, n = 126), WT/TKa+, ctDNA-/TKa-, ctDNA-/TKa+, ctDNA+/TKa- (GR2, n = 96) and ctDNA+/TKa+ (GR3, n = 19). The association between biomarkers and PFS (progression-free survival) was estimated using Kaplan-Meier analysis and multivariate Cox models with 95% confidence intervals (CIs) adjusted for clinical variables. Results: Median follow-up was 26.9 months. In multivariate Cox models both TKa dynamics and mutational tumor burden at D15 were independently predictive of PFS. Hazard ratios (HRs) were 0.37 (95% CI: 0.23-0.60; p < 0.0001) for WT vs ctDNA+ and 0.56 (95% CI: 0.32-1.00; p = 0.0506) for ctDNA- vs ctDNA+. For TKa, HR was 0.49 (95% CI: 0.30-0.80; p = 0.0040) in TKa- vs TKa+. Interestingly combining the two variables further improve prediction of outcome. HRs for TKa- vs TKa+ were 0.17 (95% CI: 0.09-0.32; p < 0.0001), 0.28 (95% CI: 0.13-0.59; p = 0.0009) and 0.44 (95% CI: 0.23-0.86; p = 0.0169) in WT, ctDNA- and ctDNA+ pts, respectively. Considering the 3 study GRs, median PFSs (95% CI) were not reached (27.89, NE), 19.58 (13.83, 23.39) and 6.65 (2.83, 12.16) months in GR1, GR2 and GR3, respectively, p < 0.001. At multivariate Cox models, HRs of GR1 and GR2 compared with GR3 were 0.17 (95% CI: 0.09-0.32; p < 0.0001) and 0.37 (95% CI: 0.20-0.67; p = 0.001) respectively. Conclusions: These findings suggest that combining the early dynamic assessment of both ctDNA and TKa may improve outcome prediction in pts treated with RIB+LET. Pts with ctDNA+/TKa+ are strongly enriched for non-responders. TKa and ctDNA capture different features of tumor biological activity and their combination warrants further evaluation in relation to other treatments, settings, and diseases. Clinical trial information: NCT03439046.

Published
2022

14. Comprehensive analysis of DNA damage repair genes reveals pathogenic variants beyond BRCA and suggests the need for extensive genetic testing in pancreatic cancer

Author

Ilaria Cangini, Valentina Arcangeli, Fabio Falcini, Stefano Tamberi, Ilario Giovanni Rapposelli, Alessandro Passardi, Giovanni Luca Frassineti, Valentina Zampiga, Giovanni Martinelli, Daniele Calistri, Martina Valgiusti, Giulia Bartolini, Mila Ravegnani, Sara Pini, and Rita Danesi

Subjects
Male, 0301 basic medicine, Gene panel, Cancer Research, DNA Repair, medicine.medical_treatment, DNA Mutational Analysis, Ataxia Telangiectasia Mutated Proteins, Synthetic lethality, Targeted therapy, 0302 clinical medicine, DNA damage repair, Medical History Taking, RC254-282, Early Detection of Cancer, Aged, 80 and over, medicine.diagnostic_test, BRCA1 Protein, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Middle Aged, Acid Anhydride Hydrolases, DNA-Binding Proteins, Oncology, 030220 oncology & carcinogenesis, Female, Fanconi Anemia Complementation Group N Protein, Adult, PALB2, Biology, 03 medical and health sciences, Pancreatic cancer, Biomarkers, Tumor, Genetics, medicine, Humans, Genetic Testing, Gene, Aged, Genetic testing, BRCA2 Protein, Research, Cancer, medicine.disease, Cancer susceptibility, Pancreatic Neoplasms, 030104 developmental biology, Rad50, Cancer research, DNA Damage
Abstract

Background Pancreatic cancer (PC) is a major cause of cancer death. In an effort to improve treatment strategies and outcomes, DNA damage repair (DDR) pathways have been introduced as a new target in PC and in other cancers, through the exploitation of synthetic lethality. Furthermore, genes involved in DDR are among the major determinants of cancer susceptibility. In addition to the well-known BRCA1 and BRCA2 genes, a plethora of other targets in the same pathways are now emerging. Methods We analyzed samples from 60 patients, affected by PC and already tested for BRCA, using a panel with 24 other cancer susceptibility genes. Results We detected 8 pathogenic or likely pathogenic mutations (13.3% of samples analyzed), 4 of which were found in non-BRCA genes (2 in ATM, 1 each in PALB2 and RAD50). Furthermore, 4 pathogenic or likely pathogenic mutations were found in patients without a personal or familial history of cancer. Conclusions Our results suggest that genetic testing with a comprehensive gene panel should be perfomed in all patients with PC, in order to allow screening for PC and other gene-related cancers in all at risk family members and to assess patients’ eligibility for emerging therapeutic options.

Published
2021

15. Tremelimumab and durvalumab combination for the non-operative management (Nom) of microsatellite instability (msi)-high resectable gastric or gastroesophageal junction cancer: The multicentre, single-arm, multi-cohort, phase ii infinity study

Author

Giovanni Gerardo Cardellino, Federica Palermo, Roberto Murialdo, Chiara Cremolini, Lorenzo Antonuzzo, Massimo Di Maio, Francesca Pucci, Giovanni Luca Frassineti, Sara Lonardi, Emiliano Tamburini, Giuseppe Aprile, Massimo Aglietta, Lorenzo Fornaro, Margherita Ratti, Stefano Tamberi, Francesco Iachetta, Carlo Sposito, Antonia Strippoli, Alessandra Raimondi, Valeria Smiroldo, Cristina Granetto, Rossana Berardi, Ferdinando De Vita, Michele Prisciandaro, Filippo Pietrantonio, Alberto Zaniboni, Vincenzo Mazzaferro, Elena Ongaro, Nicola Silvestris, Andrea Spallanzani, Maria Di Bartolomeo, Giovanni de Manzoni, Raimondi, Alessandra, Palermo, Federica, Prisciandaro, Michele, Aglietta, Massimo, Antonuzzo, Lorenzo, Aprile, Giuseppe, Berardi, Rossana, Cardellino, Giovanni G, De Manzoni, Giovanni, De Vita, Ferdinando, Di Maio, Massimo, Fornaro, Lorenzo, Frassineti, Giovanni L, Granetto, Cristina, Iachetta, Francesco, Lonardi, Sara, Murialdo, Roberto, Ongaro, Elena, Pucci, Francesca, Ratti, Margherita, Silvestris, Nicola, Smiroldo, Valeria, Spallanzani, Andrea, Strippoli, Antonia, Tamberi, Stefano, Tamburini, Emiliano, Zaniboni, Alberto, Di Bartolomeo, Maria, Cremolini, Chiara, Sposito, Carlo, Mazzaferro, Vincenzo, and Pietrantonio, Filippo

Subjects
Oncology, PD-L1, Cancer Research, medicine.medical_specialty, Durvalumab, medicine.medical_treatment, Non-operative management, Study Protocol, 03 medical and health sciences, 0302 clinical medicine, Pre-operative treatment, Internal medicine, medicine, Clinical endpoint, CTLA4, Gastric cancer, Microsatellite instability, 030212 general & internal medicine, Liquid biopsy, RC254-282, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer, medicine.disease, 030220 oncology & carcinogenesis, Cohort, Gastrectomy, business, Tremelimumab, medicine.drug
Abstract

Simple Summary The status of microsatellite instability (MSI-H) in gastric or gastroesophageal junction cancer (GC/GEJC) patients eligible for radical surgery proved to be prognostic for an improved survival outcome and predictive for poor/no benefit from the combination of adjuvant/peri-operative chemotherapy. MSI-H tumors display a high sensitivity to immunotherapy and exploratory studies showed that a pre-operative treatment with immune-checkpoint inhibitors may achieve elevated rates of pathological complete responses. The ongoing proof-of-concept INFINITY study is aimed at investigating the role of the combo-immunotherapy durvalumab plus tremelimumab as a neoadjuvant or potentially definitive treatment (avoiding surgery in case of complete clinical response) for MSI-H resectable GC/GEJC patients. Abstract In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for immunotherapy, exploratory trials showed that combination immunotherapy induces a high rate of complete pathological response (pCR), potentially achieving cancer cure without surgery. INFINITY is an ongoing phase II, multicentre, single-arm, multi-cohort trial investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant (Cohort 1) or potentially definitive (Cohort 2) treatment for MSI-high/dMMR/EBV-negative, resectable GC/GEJC. About 310 patients will be pre-screened, to enroll a total of 31 patients, 18 and 13 in Cohort 1 and 2, at 25 Italian Centres. The primary endpoint of Cohort 1 is rate of pCR (ypT0N0) and negative ctDNA after neoadjuvant immunotherapy, of Cohort 2 is 2-year complete response rate, defined as absence of macroscopic or microscopic residual disease (locally/regionally/distantly) at radiological examinations, tissue and liquid biopsy, during non-operative management without salvage gastrectomy. The ongoing INFINITY proof-of-concept study may provide evidence on immunotherapy and the potential omission of surgery in localized/locally advanced GC/GEJC patients selected for dMMR/MSI-high status eligible for radical resection.

Published
2021

16. From distress screening to uptake: An italian multicenter study of cancer patients

Author

Elisa Tiberto, Lidia Pisotti, Luigi Zerbinati, Sabrina Prati, Marina Bragagni, Flavia Foca, Silvia De Padova, Ugo De Giorgi, Luigi Grassi, Tatiana Bertelli, Ilaria Massa, Elena Meggiolaro, Federica Ruffilli, and Stefano Tamberi

Subjects
Cancer Research, medicine.medical_specialty, distress screening, cancer patients, psychosocial uptake, referral, screening policy, Referral, Distress screening, media_common.quotation_subject, Psychological intervention, Socio-culturale, Article, Psychosocial uptake, 03 medical and health sciences, 0302 clinical medicine, medicine, 030212 general & internal medicine, RC254-282, media_common, business.industry, Screening policy, Cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer patients, medicine.disease, Distress, Oncology, Telephone interview, Multicenter study, Feeling, 030220 oncology & carcinogenesis, Family medicine, business
Abstract

Simple Summary An evaluation process and adequate referrals are an important part of a distress screening program but insufficient consideration is given to referrals and uptake of available supportive services. Identifying the reasons for accepting or refusing help is needed to implement a screening-for-distress policy in a clinical cancer setting, as confirmed in the present study. It is vital to reach and motivate the highest possible number of patients to be referred to psycho-oncology services when needed. A multidisciplinary approach could help to raise awareness of the benefit of screening for distress, the implementation of which would improve uptake. Abstract Introduction: Little consideration is given to the referral and uptake of available supportive services after distress screening. However, identifying the reasons for accepting or refusing help is mandatory for implementing a screening policy. The present study explored the practical usefulness of and potential barriers to the application of distress management. Methods: 406 cancer patients were consecutively selected and asked to complete the Distress Thermometer (DT) and Problem Check List (PL). All patients with a DT score ≥6 were invited for a post-DT telephone interview with a trained psychologist. Results: The 112 patients who refused to take part were more often older, retired, at a more advanced stage of illness, and with no previous experience of psychological intervention with respect to those who accepted. Of the 78 patients with a score ≥6 who were referred to the Psycho-Oncology Service, 65.4% accepted the telephone interview. Twenty-two patients rejected the initial invitation immediately for various reasons including logistic difficulties, physical problems, and feeling embarrassed about opening up to a psychologist. Conclusions: Our study confirms that screening per sé is insufficient to deal with the problem of distress and that more emphasis should be placed on implementing referral and treatment.

Published
2021

17. AtezoTRIBE: a randomised phase II study of FOLFOXIRI plus bevacizumab alone or in combination with atezolizumab as initial therapy for patients with unresectable metastatic colorectal cancer

Author

Alessandra Boccaccino, Elisa Grassi, Federica Morano, Alfredo Falcone, Roberto Moretto, Beatrice Borelli, Sara Lonardi, Federica Marmorino, Francesca Bergamo, Filippo Pietrantonio, Patrizia Racca, Lisa Salvatore, Daniele Rossini, Stefano Tamberi, Di Stefano Brunella, Salvatore Corallo, Giuseppe Aprile, Luca Boni, Emiliano Tamburini, Giampaolo Tortora, Carlotta Antoniotti, and Chiara Cremolini

Subjects
0301 basic medicine, Oncology, Atezolizumab, Bevacizumab, Chemotherapy, FOLFOXIRI, Immune checkpoint inhibitors, Immunotherapy, Metastatic colorectal cancer, Microsatellite status, Triplet, Cancer Research, Organoplatinum Compounds, Colorectal cancer, Leucovorin, Phases of clinical research, Study Protocol, 0302 clinical medicine, Antineoplastic Agents, Immunological, FOLFOX, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, Medicine, Prospective Studies, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Italy, 030220 oncology & carcinogenesis, Microsatellite Instability, Fluorouracil, Colorectal Neoplasms, medicine.drug, medicine.medical_specialty, Antineoplastic Agents, Antibodies, Monoclonal, Humanized, lcsh:RC254-282, Drug Administration Schedule, 03 medical and health sciences, Internal medicine, Genetics, Humans, Aged, business.industry, Microsatellite instability, medicine.disease, 030104 developmental biology, Camptothecin, business
Abstract

BackgroundImmune checkpoint inhibitors (ICIs) reported remarkable achievements in several solid tumours. However, in metastatic colorectal cancer (mCRC) promising results are limited to patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-high) tumours due to their immune-enriched microenvironment. Combining cytotoxic agents and bevacizumab in mCRC with proficient mismatch repair/microsatellite stability (pMMR/MSS) could make ICIs efficacious by increasing the exposure of neoantigens, especially with highly active chemotherapy regimens, inducing immunogenic cell death, increasing the tumoral infiltration of CD8+ T-cells and reducing tumour-associated myeloid-derived suppressor cells. VEGF-blockade also plays an immunomodulatory role by inhibiting the expansion of T regulatory lymphocytes.Consistently with this rationale, a phase Ib study combined the anti-PDL-1 atezolizumab with FOLFOX/bevacizumab as first-line treatment of mCRC, irrespective of microsatellite status, and reported interesting activity and efficacy results, without safety concerns.Phase III trials led to identify FOLFOXIRI plus bevacizumab as an upfront therapeutic option in selected mCRC patients. Drawing from these considerations, the combination of atezolizumab with an intensified upfront treatment (FOLFOXIRI) and bevacizumab could be worthy of investigation.MethodsAtezoTRIBE is a prospective, open label, phase II, comparative trial in which initially unresectable and previously untreated mCRC patients, irrespective of microsatellite status, are randomized in a 1:2 ratio to receive up to 8 cycles of FOLFOXIRI/bevacizumab alone or in combination with atezolizumab, followed by maintenance with bevacizumab plus 5-fluoruracil/leucovorin with or without atezolizumab according to treatment arm until disease progression. The primary endpoint is PFS. Assuming a median PFS of 12 months for standard arm, 201 patients should be randomized in a 1:2 ratio to detect a hazard ratio of 0.66 in favour of the experimental arm. A safety run-in phase including the first 6 patients enrolled in the FOLFOXIRI/bevacizumab/atezolizumab arm was planned, and no unexpected adverse events or severe toxicities were highlighted by the Safety Monitoring Committee.DiscussionThe AtezoTRIBE study aims at assessing whether the addition of atezolizumab to an intensified chemotherapy plus bevacizumab might be an efficacious upfront strategy for the treatment of mCRC, irrespective of the microsatellite status.Trial registrationAtezoTRIBE is registered at Clinicaltrials.gov (NCT03721653), October 26th, 2018 and at EUDRACT (2017–000977-35), Februray 28th, 2017.

Published
2020

18. Pharmacokinetics, safety, and activity of trabectedin as first-line treatment in elderly patients who are affected by advanced sarcoma and are unfit to receive standard chemotherapy: A phase 2 study (TR1US study) from the Italian Sarcoma Group

Author

D. Comandini, Maurizio D'Incalci, Domenico Marra, Cristina Matteo, Giacomo Siri, Federica Grosso, Massimo Zucchetti, Marina Bergaglio, Andrea Decensi, Giovanni Grignani, Emanuela Marchesi, Emanuela Palmerini, Toni Ibrahim, Giacomo Giulio Baldi, Stefano Tamberi, Eliana Rulli, Lorenzo D'Ambrosio, Grosso F., D'Ambrosio L., Zucchetti M., Ibrahim T., Tamberi S., Matteo C., Rulli E., Comandini D., Palmerini E., Baldi G.G., DeCensi A., Bergaglio M., Marra D., Marchesi E., Siri G., D'Incalci M., and Grignani G.

Subjects
Male, Cancer Research, medicine.medical_specialty, Anthracycline, Cmax, Phases of clinical research, Antineoplastic Agents, Neutropenia, elderly, unfit patients, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Internal medicine, medicine, 80 and over, Humans, 030212 general & internal medicine, pharmacokinetic, Antineoplastic Agents, Alkylating, Trabectedin, Aged, Aged, 80 and over, business.industry, Soft tissue sarcoma, Sarcoma, advanced soft tissue sarcoma, medicine.disease, Alkylating, pharmacokinetics, trabectedin, Female, Italy, Oncology, 030220 oncology & carcinogenesis, business, medicine.drug
Abstract

Background Although elderly patients (≥70 years) represent 30% of new diagnoses of soft tissue sarcoma (STS), they are underrepresented in clinical trials and are often unfit to receive standard anthracycline-based chemotherapy. Trabectedin is registered as a second-line treatment for advanced STS and is characterized by a favorable safety profile. Methods The aim of this single-arm, phase 2 study was to investigate trabectedin (scheduled dose, 1.3-1.5 mg/m2 ) as a first-line treatment in elderly patients with advanced stage STS who are inoperable and are unfit to receive standard anthracycline-based chemotherapy. The coprimary endpoints were progression-free survival at 3 months (PFS3) and the rate of clinically limiting toxicities (CLTs). We also conducted an ancillary study on pharmacokinetics. Results Twenty-four patients (12 men and 12 women) with a median age of 79 years (interquartile range [IQR], 74-83 years) were enrolled. The histological subtype was leiomyosarcoma in 46%, liposarcoma in 33%, and other histotypes in 21%. The median number of trabectedin courses was 4 (IQR, 3-6), with 7 patients (29%) receiving ≥6 cycles. Eight patients (33%) required dose reductions. The most frequent grade 3/4 adverse events were neutropenia in 9 patients (38%), fatigue in 5 patients (21%), and aminotransferase elevation in 5 patients (21%). PFS3, median PFS, and overall survival were 71% (80% CI, 57%-81%), 4 months, and 12 months, respectively. Ten patients (42% [80% CI, 28%-57%]) experienced CLTs. Trabectedin Cmax , half-life, clearance, and distribution volume were 1.28 ng/mL (standard deviation [SD], 0.58 ng/mL), 26.70 hours (SD, 9.09 hours), 39.98 L/h/m2 (SD, 14.08 L/h/m2 ), and 1460 L/m2 (SD, 561 L/m2 ), respectively. Conclusion Trabectedin can be administered safely to elderly patients with STS who are unfit to receive anthracyclines. Pharmacokinetics in the elderly population was superimposable to historical data.

Published
2020

19. 292P Serum thymidine kinase 1 activity in patients with hormone receptor positive (HR+)/HER2 negative (HER2-) advanced breast cancer (aBC) treated in first-line with ribociclib (R) and letrozole (L) in the BioItaLEE trial

Author

M. De Laurentiis, Claudio Zamagni, Michele Orditura, M. Benelli, Alberto Zambelli, D. Castelletti, M.A. Colleoni, M. Di Marino, Luca Malorni, G. Arpino, L. Del Mastro, Ida Paris, Giacomo Allegrini, Marina Elena Cazzaniga, F. Puglisi, Valentina Guarneri, Giampaolo Bianchini, Filippo Montemurro, Stefano Tamberi, and Giancarlo Bianchi

Subjects
business.industry, Letrozole, First line, Advanced breast, Cancer, Ribociclib, Hematology, medicine.disease, Oncology, Hormone receptor, Cancer research, Medicine, In patient, business, Thymidine kinase 1, medicine.drug
Published
2021

20. Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer

Author

Francovito Piantedosi, Antonio Santo, Claudia Proto, Antonio Frassoldati, Angelo Delmonte, Filippo de Marinis, Libero Ciuffreda, Enrico Cortesi, Paolo Bidoli, Graziella Pinotti, Marco Bregni, Riccardo Samaritani, Federico Cappuzzo, Lucio Crinò, Alfonso Illiano, Paola Cravero, Elisa Minenza, Giuseppe Tonini, Diana Giannarelli, Gianmauro Numico, Stefano Tamberi, Maria Giuseppina Sarobba, Francesco Grossi, Marina Chiara Garassino, Giuseppe Bronte, Crino, L, Bronte, G, Bidoli, P, Cravero, P, Minenza, E, Cortesi, E, Garassino, M, Proto, C, Cappuzzo, F, Grossi, F, Tonini, G, Sarobba, M, Pinotti, G, Numico, G, Samaritani, R, Ciuffreda, L, Frassoldati, A, Bregni, M, Santo, A, Piantedosi, F, Illiano, A, De Marinis, F, Tamberi, S, Giannarelli, D, and Delmonte, A

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, Lung Neoplasms, 0302 clinical medicine, Antineoplastic Agents, Immunological, Non-small cell lung cancer, Carcinoma, Non-Small-Cell Lung, Aged, 80 and over, education.field_of_study, Brain Neoplasms, Brain metastasis, Immune checkpoint inhibitors, Nivolumab, Non-squamous, Middle Aged, Treatment Outcome, Italy, 030220 oncology & carcinogenesis, Disease Progression, Female, Immunotherapy, medicine.symptom, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Population, Socio-culturale, Asymptomatic, 03 medical and health sciences, Internal medicine, medicine, Humans, Lung cancer, education, Cancer staging, Aged, brain metastasis, immune checkpoint inhibitors, nivolumab, non-small cell lung cancer, non-squamous, business.industry, medicine.disease, Survival Analysis, 030104 developmental biology, Expanded access, Concomitant, business
Abstract

Objectives Brain metastases are common among patients with non-squamous non-small-cell lung cancer (NSCLC) and result in a poor prognosis. Consequently, such patients are often excluded from clinical trials. In Italy an expanded access program (EAP) was used to evaluate nivolumab efficacy and safety in this subpopulation outside a clinical trial. Materials and methods In this EAP, nivolumab was available for patients with non-squamous NSCLC in progression after at least one systemic treatment for stage IIIB/IV disease. Nivolumab 3 mg/kg was administered intravenously every 2 weeks. Patients with brain metastases could be included if they were asymptomatic, neurologically stable and either off corticosteroids or on a stable or decreasing dose of ≤10 mg/day prednisone. Results 409 out of 1588 patients included had asymptomatic or controlled brain metastases. A median of 7 doses (range 1–45) were delivered. Median follow-up was 6.1 months (range 0.1–21.9). The disease control rate was 39%: 4 patients had a complete response, 64 a partial response and 96 showed stable disease. At baseline, 118 patients were on corticosteroids and 74 were undergoing concomitant radiotherapy. The median overall survival in this subpopulation was 8.6 months (95% CI: 6.4–10.8). 337 discontinued treatment for various reasons, 23 (7%) of whom due to adverse events, in line with that observed in the overall population and in previous studies. Conclusions Our results confirm that nivolumab is active in non-squamous NSCLC patients with brain metastases, despite their poor prognosis. Its safety profile is also concordant with results in the EAP overall population and in patients with other malignancies.

Published
2019

21. Assessment of Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line chemotherapy in patients with advanced HER-2 negative gastric or gastroesophageal junction cancers: The ARMANI phase III trial

Author

Marta Caporale, Salvatore Corallo, Alberto Gianluigi Luporini, Andrea Spallanzani, Michele Basso, Maria Di Bartolomeo, Mario Scartozzi, Federica Morano, Evaristo Maiello, Davide Tassinari, Andrea Bonetti, Graziella Pinotti, Filippo de Braud, Saverio Cinieri, Sergio Bracarda, Giovanni Gerardo Cardellino, Alessandro Bertolini, Claudio Verusio, Gianluca Tomasello, Hector Soto Parra, Alberto Zaniboni, Giampaolo Tortora, Samantha Di Donato, Sara Lonardi, Vincenzo Catalano, Francesco Di Costanzo, Raffaella Longarini, Libero Ciuffreda, Ferdinando De Vita, Francesco Giuliani, Maria Antista, Lorenza Rimassa, Rossana Berardi, Filippo Pietrantonio, Monica Niger, Stefano Tamberi, Lorenzo Fornaro, Giorgio V. Scagliotti, Giovanni Luca Frassineti, Di Bartolomeo, M., Niger, M., Morano, F., Corallo, S., Antista, M., Tamberi, S., Lonardi, S., Di Donato, S., Berardi, R., Scartozzi, M., Cardellino, G. G., Di Costanzo, F., Rimassa, L., Luporini, A. G., Longarini, R., Zaniboni, A., Bertolini, A., Tomasello, G., Pinotti, G., Scagliotti, G., Tortora, G., Bonetti, A., Spallanzani, A., Frassineti, G. L., Tassinari, D., Giuliani, F., Cinieri, S., Maiello, E., Verusio, C., Bracarda, S., Catalano, V., Basso, M., Ciuffreda, L., De Vita, F., Parra, H. S., Fornaro, L., Caporale, M., De Braud, F., and Pietrantonio, F.

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, Receptor, ErbB-2, medicine.medical_treatment, chemistry.chemical_compound, Study Protocol, ErbB-2, 0302 clinical medicine, Quality of life, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, Antibodies, Monoclonal, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Clinical trial, First line, Maintenance, Metastatic gastric cancer, Ramucirumab, Drug Administration Schedule, Esophagogastric Junction, Female, Humans, Maintenance Chemotherapy, Paclitaxel, Progression-Free Survival, Quality of Life, Stomach Neoplasms, Treatment Outcome, 030220 oncology & carcinogenesis, Receptor, medicine.drug, Human, medicine.medical_specialty, Antibodies, Monoclonal, Humanized, lcsh:RC254-282, Antibodies, 03 medical and health sciences, Stomach Neoplasm, Internal medicine, Genetics, medicine, Chemotherapy, Antineoplastic Combined Chemotherapy Protocol, business.industry, Oxaliplatin, Regimen, 030104 developmental biology, chemistry, business
Abstract

Platinum/fluoropyrimidine regimens are the backbone of first-line chemotherapy for advanced gastric cancer (AGC). However response rates to first line chemotherapy range from 30 to 50% and disease progression occurs after 4–6 cycles. The optimal duration of first-line therapy is still unknown and its continuation until disease progression represents the standard. However this strategy is often associated with cumulative toxicity and rapid development of drug resistance. Moreover, only about 40% of AGC pts. are eligible for second-line treatment. This is a randomized, open-label, multicenter phase III trial. It aims at assessing whether switch maintenance to ramucirumab plus paclitaxel will extend the progression-free survival (PFS) of subjects with HER-2 negative AGC who have not progressed after 3 months of a first-line with a platinum/fluoropyrimidine regimen (either FOLFOX4, mFOLFOX6 or XELOX). The primary endpoint is to compare Progression-Free Survival (PFS) of patients in ARM A (switch maintenance to ramucirumab and placlitaxel) versus ARM B (continuation of the same first-line therapy with oxaliplatin/fluoropyrimidine). Secondary endpoints are: overall survival, time-to-treatment failure, overall response rate, duration of response, percentage of patients that will receive a second line therapy according to arm treatment, safety, quality of life. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues are planned in order to identify potential biomarkers of primary resistance and prognosis. The ARMANI study estimates if patients treated with early swich with ramucirumab plus paclitaxel received benefit when compared to those treated with continuation of first line therapy. The hypothesis is that the early administration of an active, non-cross resistant second-line regimen such as ramucirumab plus paclitaxel may prolong the time in which patients are progression-free, and consequently have a better quality of life. Moreover, this strategy may rescue all those subjects that become ineligible for second-line therapy due to the rapid deterioration of health status after the first disease progression. ARMANI is registered at ClinicalTrials.gov ( NCT02934464 , October 17, 2016) and EudraCT(2016–001783-12, April 202,016).

Published
2019

22. A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study first-stage

Author

Davide Tassinari, Elisa Grassi, Dora Caruso, Maria Di Bartolomeo, Giovanni Luca Frassineti, Oriana Nanni, Carmine Pinto, Fabio Gelsomino, M. Marzola, Stefano Tamberi, Chiara Zingaretti, Maria Aurelia Barbera, Elisabetta Petracci, Isacco Montroni, Giampaolo Ugolini, Sofia Nosseir, Jody Corbelli, Chiara Carli Moretti, Andrea Bonetti, and Giorgio Papiani

Subjects
Cancer Research, medicine.medical_specialty, Durvalumab, Colorectal cancer, business.industry, medicine.medical_treatment, Urology, Phases of clinical research, medicine.disease, Capecitabine, Radiation therapy, Oncology, Concomitant, medicine, Stage (cooking), business, medicine.drug, Preoperative treatment
Abstract

3607 Background: The combination of capecitabine plus long course radiotherapy (RT) is the standard preoperative therapy in cT3-4 cN+ rectal cancer. Pathologic Complete remission (pCR) can be considered as surrogate end point of efficacy of treatment in terms of disease free survival (DFS). Preclinical data points heavily toward a strong synergy between RT and immune treatments. Methods: This is a prospective phase II, open label, single arm, multi-centre study, conducted with support from AstraZeneca, in patient with locally advanced rectal cancer who receive concomitant CT/RT therapy (825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks) followed by durvalumab (1500 mg Q4W for 3 administrations). Surgery is performed after 10-12 weeks from neoadjuvant therapy. The primary endpoint is pCR rate after at least 1 cycle of durvalumab. The sample size has been estimated by using the optimal Simon’s two-stage design. If more than 4 complete responses are observed in the first 19 enrolled patients, 36 additional patients will be accrued for a total of 55 evaluable patients. Results: Between November 2019 and July 2020, 20 patients were accrued and 19 were evaluable for study objectives, concluding the first stage of the trial. Baseline characteristics of the first 19 evaluable patients enrolled are listed in the table. All patients received 3 infusions of durvalumab; 18 patients underwent surgery after a median of 13 weeks from CHT/RT end. Five complete pathological responses (ypT0N0) were observed, allowing to proceed to the second stage. About toxicity, four patients had Grade 3-4 adverse events (AE); the most frequent G3-4 AE related to the neoadjuvant therapy were anemia (n=1), diarrhea (n=2) and neuthropenia (n=2). No grade 3 and 4 adverse events related to Durvalumab treatment were observed. Eight patients had G1-2 AE related to durvalumab, the most common being asthenia (n=2) and nausea (n=2). Conclusions: At the end of study’s first stage the preoperative treatment with radiotherapy plus capecitabine followed by durvalumab showed a safe toxicity profile and promising activity in terms of pCR rate. The second part of the trial is ongoing, and the accrual is under completion (44 patients enrolled as of 10 February 2021). Clinical trial information: NCT04083365. [Table: see text]

Published
2021

23. Ramucirumab as Second-Line Therapy in Metastatic Gastric Cancer: Real-World Data from the RAMoss Study

Author

Lorenzo Fornaro, Rosa Berenato, Gianluca Tomasello, Stefano Tamberi, Elisa Giommoni, Andrea Spallanzani, Federica Morano, Sara Lonardi, Ferdinando De Vita, Francesco Graziano, Katia Bencardino, Maria Di Bartolomeo, Raffaella Longarini, Monica Niger, Jole Ventriglia, Simone Scagnoli, Giuseppe Tirino, Salvatore Galdy, Maria Maddalena Laterza, Massimiliano Spada, Ilaria Proserpio, Lorenza Rimassa, Filippo Pietrantonio, Maria Antista, Alessandro Bertolini, Teodoro Sava, Tiziana Latiano, Alberto Zaniboni, Giordano D. Beretta, Alessandro Bittoni, Angelica Petrillo, Di Bartolomeo, M, Niger, M, Tirino, G, Petrillo, A, Berenato, R, Laterza, Mm, Pietrantonio, F, Morano, F, Antista, M, Lonardi, S, Fornaro, L, Tamberi, S, Giommoni, E, Zaniboni, A, Rimassa, L, Tomasello, G, Sava, T, Spada, M, Latiano, T, Bittoni, A, Bertolini, A, Proserpio, I, Bencardino, Kb, Graziano, F, Beretta, G, Galdy, S, Ventriglia, J, Scagnoli, S, Spallanzani, A, Longarini, R, and De Vita, F

Subjects
0301 basic medicine, Adult, Male, Cancer Research, medicine.medical_specialty, monoclonal, Neutropenia, Antibodies, Monoclonal, Humanized, Gastroenterology, Ramucirumab, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Stomach Neoplasms, Internal medicine, 80 and over, medicine, Clinical endpoint, antibodies, Humans, adult, aged, antibodies, monoclonal, humanized, female, humans, male, middle aged, neoplasm metastasis, retrospective studies, stomach neoplasms, Pharmacology (medical), Neoplasm Metastasis, Adverse effect, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Incidence (epidemiology), Antibodies, Monoclonal, Retrospective cohort study, Middle Aged, medicine.disease, Confidence interval, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Female, business
Abstract

BACKGROUND: Ramucirumab-alone or combined with paclitaxel-represents one of the main options for patients failing first-line treatment for advanced gastric cancer. OBJECTIVE: The RAMoss study aimed to evaluate the safety and efficacy profile of ramucirumab in the "real-life setting". PATIENTS AND METHODS: Patients from 25 Italian hospitals started therapy consisting of ramucirumab 8 mg/kg i.v. d1,15q28 with or without paclitaxel 80 mg/m2 i.v. d1,8,15q28. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: One hundred sixty-seven patients with disease progression on first-line therapy received ramucirumab as monotherapy (10%) or combined with paclitaxel (90%). Median treatment duration was 4 months (1-17 months). Global incidence of grade (G) 3-4 toxicity was 9.6%, and for neutropenia 5.4%; treatment was discontinued due to toxicity in 3% of patients. The most frequent adverse events (AE) were G1-2 fatigue (27.5%), G1-2 neuropathy (26.3%), and G1-2 neutropenia (14.9%). ORR was 20.2%. Stable disease was observed in 39.2% of patients, with a disease control rate of 59.4%. With a median follow-up of 11 months, median PFS was 4.3 months (95% confidence interval [CI] 4.1-4.7), whereas median OS was 8.0 months (95% CI: 7.09-8.9). In a multivariate analysis, ECOG performance status

Published
2018

24. Emerging immunotherapeutic strategies targeting telomerases in genitourinary tumors

Author

Nicola Battelli, Matteo Santoni, Francesco Carrozza, Antonio Lopez-Beltran, Francesco Piva, Marina Scarpelli, Stefano Tamberi, Liang Cheng, and Rodolfo Montironi

Subjects
0301 basic medicine, Telomerase, T cell, medicine.medical_treatment, Antineoplastic Agents, Active immunotherapy, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Medicine, Animals, Humans, Telomerase reverse transcriptase, business.industry, Antibodies, Monoclonal, Hematology, Immunotherapy, Telomere, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, business, Carcinogenesis, Urogenital Neoplasms, TEP1
Abstract

Telomerase activity and telomere length are essential for the pathogenesis of several human diseases, including genitourinary tumors. Telomerase constitutes a complex system that includes human telomerase reverse transcriptase (hTERT), human telomerase RNA component (hTR) and telomerase associated protein 1 (TEP1), which are overexpressed in tumor cells compared to normal cells and are involved in the carcinogenesis and progression of renal cell carcinoma (RCC), bladder (BC) and prostate cancer (PCa). In addition, telomerase degraded peptide fragments expressed on the surface of tumor cells lead to their recognition by immune cells. On this scenario, in vitro and in vivo studies have shown effective anti-tumor activity of hTERT-tailored strategies in genitourinary tumors, including active immunotherapy with hTERT-peptide vaccines and passive immunotherapy with hTERT-transduced T cell infusion. This review emphasizes the role of telomerase in the carcinogenesis and progression of genitourinary tumors, thus underlying the potential of emerging telomerase-tailored immunotherapies in these patients.

Published
2018

25. Appropriate use of tumour biomarkers for treatment with innovative drugs: A retrospective study

Author

Maurizio Leoni, Ilaria Massa, Alessandra Piancastelli, Mattia Altini, Stefano Tamberi, Linda Valmorri, Andrea Rocca, Marina Faedi, Mattia Marri, Dino Amadori, Giovanni Luca Frassineti, Oriana Nanni, Marco Angelo Burgio, and Massimo Guidoboni

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Pathology, Colorectal cancer, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, medicine, 030212 general & internal medicine, Epidermal growth factor receptor, GiST, biology, business.industry, Cancer, Retrospective cohort study, Articles, medicine.disease, Clinical trial, 030220 oncology & carcinogenesis, biology.protein, KRAS, business
Abstract

Performing randomised clinical trials to address the clinical usefulness of predictive and prognostic tumour markers is a complex process for several reasons, and observational experiences may thus play an important role. The present study performed an observational retrospective analysis in Area Vasta Romagna, Italy, collecting information on tumour marker determination in 760 consecutive patients who started a new line of anticancer therapy between January and June 2010. The determination of well-known biomarkers was requested for all gastrointestinal stromal tumour (GIST) patients (n=13) and for almost all breast cancer patients (n=369), and targeted therapies were consequently prescribed. Conversely, Kirsten rat sarcoma viral oncogene homolog (KRAS) determination in colon cancer patients (n=177) was requested in ~50% of advanced cases, while epidermal growth factor receptor (EGFR) determination was required in slightly more than 30% of the same patients. EGFR and KRAS determinations were requested in only 15% and 7.5% of non-small cell lung cancer (NSCLC) patients (n=201), respectively. There would appear to be greater appropriateness of tumour marker determination for breast cancer and GISTs than for colon cancer and NSCLC. Resources can be further optimised by standardising tumour marker determinations in terms of the timing of requests and the consequent use of the results for tailored treatment planning.

Published
2015

26. Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX

Author

Jean-François Emile, Catherine Julié, Karine Le Malicot, Come Lepage, Josep Tabernero, Enrico Mini, Gunnar Folprecht, Jean-Luc Van Laethem, Stéphanie Dimet, Camille Boulagnon-Rombi, Marc-Antoine Allard, Frédérique Penault-Llorca, Jaafar Bennouna, Pierre Laurent-Puig, Julien Taieb, Josef Thaler, Richard Greil, Johannes Gaenzer, Wolfgang Eisterer, Joerg Tschmelitsch, Felix Keil, Hellmut Samonigg, August Zabernigg, Franz Schmid, Günther Steger, Robert Steinacher, Johannes Andel, Björn Jagdt, Alois Lang, Michael Fridrik, Reinhold Függer, Friedrich Hofbauer, Ewald Woell, Dietmar Geissler, Alfred Lenauer, Manfred Prager, Geert D'Haens, Gauthier Demolin, Joseph Kerger, Guido Deboever, Gilbert Ghillebert, Marc Polus, Eric Van Cutsem, Hassan Rezaie Kalantari, Thierry Delaunoit, Jean Charles Goeminne, Marc Peeters, Philippe Vergauwe, Ghislain Houbiers, Yves Humblet, Jos Janssens, Dirk Schrijvers, Erik Vanderstraeten, Jan Vermorken, Daniel Van Daele, Michel Ferrante, Frederic Forget, Alain Hendlisz, Mette Yilmaz, Svend Erik Nielsen, Lene Vestermark, Jim Larsen, Mohamed-Ayman Zawadi, Olivier Bouche, Laurent Mineur, Jaafar Bennouna-Louridi, Louis Marie Dourthe, Marc Ychou, Eveline Boucher, Denis Pezet, Francoise Desseigne, Michel Ducreux, Patrick Texereau, Laurent Miglianico, Philippe Rougier, Serge Fratte, Charles-Briac Levache, Yacine Merrouche, Stephen Ellis, Christophe Locher, Jean-Francois Ramee, Claire Garnier, Frederic Viret, Bruno Chauffert, Isabelle Cojean-Zelek, Pierre Michel, Cedric Lecaille, Christian Borel, Jean-Francois Seitz, Denis Smith, Catherine Lombard-Bohas, Thierry Andre, Jean-Marc Gornet, Francine Fein, Marie-Aude Coulon-Sfairi, Marie-Christine Kaminsky, Jean-Paul Lagasse, Dominique Luet, Pierre-Luc Etienne, Mohamed Gasmi, Andre Vanoli, Suzanne Nguyen, Thomas Aparicio, Hervé Perrier, Noel Stremsdoerfer, Philippe Laplaige, Dominique Arsene, Dominique Auby, Laurent Bedenne, Romain Coriat, Bernard Denis, Patrick Geoffroy, Gilles Piot, Yves Becouarn, Gilbert Bordes, Gael Deplanque, Olivier Dupuis, Frederic Fruge, Rosine Guimbaud, Thierry Lecomte, Gérard Lledo, Iradej Sobhani, Amani Asnacios, Ahmed Azzedine, Christophe Desauw, Marie-Pierre Galais, Dany Gargot, You-Heng Lam, Abakar Abakar-Mahamat, Jean-Francois Berdah, Sylviane Catteau, Marie-Christine Clavero-Fabri, Jean-Francois Codoul, Jean-Louis Legoux, Denis Goldfain, Pierre Guichard, Denis Pere Verge, Jocelyne Provencal, Bruno Vedrenne, Catherine Brezault-Bonnet, Denis Cleau, Jean-Paul Desir, David Fallik, Bruno Garcia, Marie-Hélène Gaspard, Dominique Genet, Johannes Hartwig, Yves Krummel, Tamara Matysiak Budnik, Vanessa Palascak-Juif, Harizo Randrianarivelo, Yves Rinaldi, Albert Aleba, Ariane Darut-Jouve, Aimery de Gramont, Herve Hamon, Frederic Wendehenne, Axel Matzdorff, Michael Konrad Stahl, Wolfgang Schepp, Martin Burk, Lothar Mueller, Michael Geissler, Luisa Mantovani-Loeffler, Thomas Hoehler, Walter Asperger, Hendrik Kroening, Ludwig Fischer von Weikersthal, Stefan Fuxius, Matthias Groschek, Johannes Meiler, Tanja Trarbach, Jacqueline Rauh, Nicolas Ziegenhagen, Albrecht Kretzschmar, Ullrich Graeven, Arnd Nusch, Goetz von Wichert, Ralf-Dieter Hofheinz, Gerhard Kleber, Karl-Heinz Schmidt, Ursula Vehling-Kaiser, Claudia Baum, Jochen Schuette, Georg Martin Haag, Wilhelm Holtkamp, Jochen Potenberg, Tobias Reiber, Georg Schliesser, Hans-Joachim Schmoll, Wolfgang Schneider-Kappus, Wolfgang Abenhardt, Claudio Denzlinger, Jan Henning, Bartscht Marxsen, Hans Guenter Derigs, Helmut Lambertz, Ingulf Becker-Boost, Karel Caca, Christian Constantin, Thomas Decker, Henning Eschenburg, Sigrun Gabius, Holger Hebart, Albrecht Hoffmeister, Heinz-August Horst, Stephan Kremers, Malte Leithaeuser, Sebastian Mueller, Siegfried Wagner, Severin Daum, Frank Schlegel, Martina Stauch, Volker Heinemann, Evaristo Maiello, Luciano Latini, Alberto Zaniboni, Dino Amadori, Giuseppe Aprile, Sandro Barni, Rodolfo Mattioli, Andrea Martoni, Rodolfo Passalacqua, Mario Nicolini, Enzo Pasquini, Carla Rabbi, Enrico Aitini, Alberto Ravaioli, Carlo Barone, Guido Biasco, Stefano Tamberi, Angelo Gambi, Claudio Verusio, Marina Marzola, Giorgio Lelli, Corrado Boni, Stefano Cascinu, Paolo Bidoli, Massimo Vaghi, Giorgio Cruciani, Francesco Di Costanzo, Alberto Sobrero, Roberto Petrioli, Massimo Aglietta, Oscar Alabiso, Federico Capuzzo, Alfredo Falcone, Domenico Cristi Corsi, Roberto Labianca, Stefania Salvagni, Silvana Chiara, Libero Ciuffreda, Francesco Ferraù, Francesco Giuliani, Sara Lonardi, Nicola Gebbia, Giovanni Mantovani, Evaristo Sanches, Juan Carlos Mellidez, Pedro Santos, Joao Freire, Cristina Sarmento, Luis Costa, Antonio Moreira Pinto, Sergio Barroso, Jorge Espirito Santo, Fátima Guedes, Amélia Monteiro, Anabela Sa, Irene Furtado, Ramon Salazar, Enrique Aranda Aguilar, Fernando Rivera Herrero, Javier Sastre Valera, Manuel Valladares Ayerbes, Jaime Feliu Batlle, Silvia Gil, Albert Abad Esteve, Carlos Garcia-Giron, Guillermo Lopez Vivanco, Antonia Salud Salvia, Vicente Alonso Orduña, Ruth Vera Garcia, Javier Gallego, Bartomeu Massuti Sureda, Jordi Remon, Maria Jose Safont Aguilera, Luis Cirera Nogueras, Bernado Queralt Merino, Cristina Gravalos Castro, Purificacion Martinez de Prado, Carlos Pijaume Pericay, Manuel Constenla Figueiras, Inmaculada Guasch Jordan, Maria Jose Gome Reina, Amelia Lopez-Ladron Garcia, Antonio Arrivi Garcia-Ramos, Andres Cervantes, Carlos Fernandez Martos, Eugenio Marcuello Gaspar, Ines Cabezas Montero, Pilar Escudero Emperador, Ana Leon Carbonero, Manuel Gallen Castillo, Teresa Garcia Garcia, Jose Garcia Lopez, Encarnacion Gonzalez Flores, Monica Guillot Morales, Marta Llanos Muñoz, Ana López Martín, Joan Maurel, Juan Carlos Camara, Rosario Dueñas Garcia, Mercedes Salgado, Isabel Hernandez Busquier, Teresa Checa Ruiz, Adelaida Lacasta Muñoa, Miquel Nogue Aliguer, Amalia Velasco Ortiz de Taranco, Miguel Mendez Ureña, Ferran Losa Gaspa, Jose Juan Ponce, Carlos Bosch Roig, Pedro Valero Jimenez, Antonio Galan Brotons, Santiago Albiol Rodriguez, Jose Ales Martinez, Liliana Canosa Ruiz, Margarita Centelles Ruiz, John Bridgewater, Rob Glynne-Jones, Saad Tahir, Tamas Hickish, Jim Cassidy, Leslie Samuel, UE 1373 Fourrages Environnement Ruminants Lusignan, Institut National de la Recherche Agronomique ( INRA ) -Physiologie Animale et Systèmes d'Elevage ( PHASE ) -Environnement et Agronomie ( E.A. ) -Biologie et Amélioration des Plantes ( BAP ) -Fourrages Environnement Ruminants Lusignan ( FERLUS ), Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Service de Biostatistique, Fédération Francophone de la Cancérologie Digestive, FFCD, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'hépato-gastroentérologie et cancérologie digestive (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Vall d'Hebron University Hospital [Barcelona], Dpt of Internal Medicine, Section of Immunoallergology and Respiratory [Florence] Diseases, University of Florence, Carl Gustav Carus University Hospital, Erasme Hospital, Brussels, Centre Hepato-Biliaire, AP-HP Hôpital Paul Brousse, Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne ( IMoST ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ), Institut de cancérologie de l'Ouest - Nantes ( ICO Nantes ), CRLCC Paul Papin-CRLCC René Gauducheau, Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université de Nantes ( UN ), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique ( MEPPOT - U1147 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Klinikum Wels Grieskirchen, Oncology department [Salzburg], Salzburger Landesklinikum - Uniklinikum Salzburg ( SALK ), Institute of Chemical Reaction Engineering, Hamburg University of Technology, Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung ( AWI ), Department of Medical Oncology, Medical University Vienna, Department of Internal Medicine, Hospital of Steyr, Department Internal Medicine 3, Centre for Hematology and Medical Oncology, General Hospital Linz, Department Medicine LKH, Institut für Festköperfirschung, Institut des Sciences Moléculaires de Marseille ( ISM2 ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Centrale de Marseille ( ECM ) -Aix Marseille Université ( AMU ), University Hospitals Leuven [Leuven], Katholieke Universiteit Leuven ( KU Leuven ), Pharmacology and Toxicology, Ahvaz Jundishapur University of Medical Sciences, Institut de Biologie Computationnelle ( IBC ), Centre de Coopération Internationale en Recherche Agronomique pour le Développement ( CIRAD ) -Institut National de la Recherche Agronomique ( INRA ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Sciences Moléculaires ( ISM ), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique ( CNRS ), Faculty of Veterinary Medicine, Ghent University [Belgium] ( UGENT ), Medical Oncology, Antwerp University Hospital [Edegem], Recombinaison et Expression Génétique, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier de L'Ardenne (Libramont), Department of Cardiology [Sivas, Turkey], Cumhuriyet University [Sivas, Turkey], Department of Earth Sciences, Durham University, Department of Oncology, Rigshospitalet [Copenhagen], Odense Hospital, CP Kelco ApS, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Institut de Recherche en Cancérologie de Montpellier ( IRCM - U1194 Inserm - UM ), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Université du Québec à Montréal ( UQAM ), Université Panthéon-Sorbonne ( UP1 ), École nationale supérieure d'architecture de Nantes ( ENSA Nantes ), Department of Hepatogastroenterology and Oncology, Hopital Ambroise Pare, 9, Avenue Charles de Gaulle, 92104, Boulogne Cedex, France., Hôpital Ambroise Paré, CH Belfort-Montbéliard, Polyclinique Francheville, Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne ( CHU de Saint-Etienne ), Centre Hospitalier de Meaux, Service d'hématologie, Clinique Catherine de Sienne, Unité de recherche sur les Biopolymères, Interactions Assemblages ( BIA ), Institut National de la Recherche Agronomique ( INRA ), Université de la Méditerranée - Aix-Marseille 2, Centre hospitalier universitaire d'Amiens ( CHU Amiens-Picardie ), CHU Amiens-Picardie, Pôle oncologie médicale, Hôpital des Diaconesses, Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bretagne Occidentale - École de sages-femmes ( UBO UFR MSS ESF ), Université de Brest ( UBO ) -Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Service Gastro-Entérologie, CHU Besançon, Université de Franche-Comté ( UFC ) -Université de Franche-Comté ( UFC ), Centre Alexis Vautrin ( CAV ), Ecophysiologie Végétale, Agronomie et Nutritions ( EVA ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Recherche Agronomique ( INRA ), Image et ville ( IV ), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Département informatique ( INFO ), Université européenne de Bretagne ( UEB ) -Télécom Bretagne-Institut Mines-Télécom [Paris], Service de Gastro-entérologie [Avicenne], Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Agence de l'Environnement et de la Maîtrise de l'Energie - ADEME, Service d'hépato-gastroentérologie, CHU Caen-Hôpital côte de nacre, Département de Médecine, Centre hospitalier de Libourne, Service d'Hépato-Gastro-Entérologie (CHU de Dijon), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Fondation FondaMental, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor, Variabilité de réponse aux psychotropes ( VariaPsy - U1144 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ), Département d'oncologie digestive, Institut Bergonié - CRLCC Bordeaux, Hôpital St Joseph, Service de Gynécologie et d'Obstétrique ( CHU Lyon ), Hospices Civils de Lyon ( HCL ), Gastro - Entérologie et Nutrition, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Génétique, Immunothérapie, Chimie et Cancer ( GICC ), Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Université Montpellier 1 ( UM1 ), Service de gastro-entérologie - Hôpital Henri Mondor, Laboratoire Matière et Systèmes Complexes ( Laboratoire MSC ), Université Paris Diderot - Paris 7 ( UPD7 ) -UFR de Physique, France, Amériques, Espagne – Sociétés, pouvoirs, acteurs ( FRAMESPA ), Université Toulouse - Jean Jaurès ( UT2J ) -Centre National de la Recherche Scientifique ( CNRS ), Regional Hospital of Orleans, Histoire, Archéologie et littératures des Mondes chrétiens et musulmans médiévaux ( CIHAM ), École normale supérieure - Lyon ( ENS Lyon ) -Université Lumière - Lyon 2 ( UL2 ) -École des hautes études en sciences sociales ( EHESS ) -Université Jean Moulin - Lyon III ( UJML ) -Université d'Avignon et des Pays de Vaucluse ( UAPV ) -Centre National de la Recherche Scientifique ( CNRS ), Neurobiologie des signaux intercellulaires ( NSI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Dept Med Genet, Hôpital Erasme (Bruxelles), Polyclinique de Limoges - site François Chénieux [Limoges], Clinique Médicale B, CHU Strasbourg, Service de gastro-entérologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Hôpital Européen [Fondation Ambroise Paré - Marseille], Asklepios Klinikum Uckermark GmbH, DESY, Notkestr 85, D-22607 Hamburg, Germany, NASA Ames Research Center ( ARC ), Department of Chemistry, Center for Structural Biology, Vanderbilt University [Nashville], Biostatistique et Processus Spatiaux ( BIOSP ), Institute of Ecology [Jena], Friedrich-Schiller-Universität Jena, University of Rostock [Germany], Universität Stuttgart [Stuttgart], Oneonta, Zentrum für Innere Medizin, Klinikum Schwäbisch Gmünd/Stauferklinik, Physiopathologie du stress pancréatique, Institut Armand Frappier ( INRS-IAF ), Institut National de la Recherche Scientifique [Québec] ( INRS ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut Armand Frappier, Institut de Mathématiques de Marseille ( I2M ), Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Department of Computer Science [Freiburg], University of Freiburg [Freiburg], Institut für Mathematik [Berlin], Technische Universität Berlin ( TUB ), Department of Information Engineering, Computer Science and Mathematics, Università degli Studi dell'Aquila [L'Aquila] ( UNIVAQ.IT ), Department of Animal Sciences, North Carolina Agricultural and Technical State University, FEEM, Romagna Cancer Registry, IRST, Luigi Pierantoni Hospital, Observatoire sociologique du changement ( OSC ), Sciences Po-Centre National de la Recherche Scientifique ( CNRS ), Dipartimento di Chimica, Fisica e Ambiente, Università degli Studi di Udine - University of Udine [Italie], Department of Nuclear Medicine, PET/CT Centre, Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Clinica di Oncologia Medica, AO Ospedali Riuniti, Università Politecnica delle Marche [Ancona] ( UNIVPM ), Universidade Nova de Lisboa ( UNINOVA ), Ottawa Hospital Research Institute [Ottawa] ( OHRI ), Oncologia Medica, Ospedali Riuniti, Ospedale 'San Vincenzo', NIPE, CIPES, European Synchrotron Radiation Facility ( ESRF ), Departamento de Engenharia Informática, Faculdade de Engenharia [Porto] ( FEUP ), Universidade do Porto [Porto]-Universidade do Porto [Porto], 3Decide, Unité de recherche Amélioration, Génétique et Physiologie Forestières ( UAGPF ), Universidade Federal de Campina Grande [Campina Grande] ( UFCG ), Instituto de Engenharia de Sistemas e Computadores ( INESC ), Departamento de Ciências Biológicas, Universidade Regional do Cariri ( URCA Brasil ), Department of Biochemistry and Molecular Biology [Barcelona, Spain], Universitat de Barcelona ( UB ), Associated Unit to Consejo Superior de Investigaciones Científicas - CSIC [Barcelona, Spain], University of Barcelona-Institute of Biomedicine - IBUB [Barcelona, Spain], IRCELYON-Caractérisation et remédiation des polluants dans l'air et l'eau ( CARE ), Institut de recherches sur la catalyse et l'environnement de Lyon ( IRCELYON ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'analyse et d'architecture des systèmes [Toulouse] ( LAAS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Institut National Polytechnique [Toulouse] ( INP ), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier ( ICGM ICMMM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Instituto de Ciencia de Materiales de Madrid [Madrid] ( ICMM ), Interactions, Corpus, Apprentissages, Représentations ( ICAR ), École normale supérieure - Lyon ( ENS Lyon ) -Université Lumière - Lyon 2 ( UL2 ) -INRP-Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique ( CNRS ), Institut d'Investigacions Biomèdiques August Pi i Sunyer ( IDIBAPS ), North Region Cancer Registry of Portugal, UMR 5805 Environnements et Paléoenvironnements Océaniques et Continentaux ( EPOC ), Observatoire aquitain des sciences de l'univers ( OASU ), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Paediatrics and Intensive Care, Hospital Universitari Sant Joan de Deu, Laboratoire de Psychologie Sociale ( LPS ), Aix Marseille Université ( AMU ), Universitat de València ( UV ), Instituto de Cienca de Materiales de Madrid [Madrid] ( ICMM ), Biology, New Mexico State University, New Mexico State University, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Centre de recherche sur les Ions, les MAtériaux et la Photonique ( CIMAP - UMR 6252 ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Supérieure d'Ingénieurs de Caen ( ENSICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ), Institut d'Electronique et de Télécommunications de Rennes ( IETR ), Université de Nantes ( UN ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National des Sciences Appliquées - Rennes ( INSA Rennes ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ), Computer Science Department - Carnegie Mellon University, University of Pittsburgh, Laboratoire de Sciences Actuarielle et Financière ( SAF ), Université de Lyon-Université de Lyon, Instituto de Oncologia Corachan ( IDOC ), Laboratoire d'informatique de l'école normale supérieure ( LIENS ), École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ), Experimental Quantum Optics and Photonics Group, University of Strathclyde, Institut de recherches Asiatiques ( IrAsia ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Européen de Réalité Virtuelle ( CERV ), École Nationale d'Ingénieurs de Brest ( ENIB ), Sol Agro et hydrosystème Spatialisation ( SAS ), Institut National de la Recherche Agronomique ( INRA ) -AGROCAMPUS OUEST, Grenoble Institut des Neurosciences ( GIN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ), Centre de recherche cerveau et cognition ( CERCO ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire Géomatériaux et Environnement ( LGE ), Université Paris-Est Marne-la-Vallée ( UPEM ), Hôpital Ambroise Paré [AP-HP], Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre hépato-biliaire (CHB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Université de Nantes (UN), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Salzburger Landesklinikum - Uniklinikum Salzburg (SALK), Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung (AWI), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institut de Biologie Computationnelle (IBC), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University [Belgium] (UGENT), Antwerp University Hospital [Edegem] (UZA), Hillerød Hospital, Copenhagen University Hospital-Copenhagen University Hospital, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Université Paris 1 Panthéon-Sorbonne (UP1), École nationale supérieure d'architecture de Nantes (ENSA Nantes), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bretagne Occidentale - École de sages-femmes (UBO UFR MSS ESF), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Alexis Vautrin (CAV), Ecophysiologie Végétale, Agronomie et Nutritions (EVA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Recherche Agronomique (INRA), Image et ville (IV), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Département informatique (INFO), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Agence de l'Environnement et de la Maîtrise de l'Energie (ADEME), Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Libourne, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation FondaMental [Créteil], Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Service de Gynécologie et d'Obstétrique (CHU Lyon), Hospices Civils de Lyon (HCL), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1), Service de gastro-entérologie [Henri Mondor AP-HP, Créteil], Hôpital Henri Mondor-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Hôpital privé Toulon Hyères : Sainte Marguerite, Clinique des Quatre Pavillons, Lormont, France, Neurobiologie des signaux intercellulaires (NSI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), NASA Ames Research Center (ARC), Biostatistique et Processus Spatiaux (BioSP), Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], University of Rostock, State University of New York at Oneonta (SUNY Oneonta), State University of New York (SUNY), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Institut de Mathématiques de Marseille (I2M), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Klinikum Deggendorf, Technische Universität Berlin (TU), Università degli Studi dell'Aquila (UNIVAQ), North Carolina A&T State University, University of North Carolina System (UNC)-University of North Carolina System (UNC), Observatoire sociologique du changement (OSC), Sciences Po (Sciences Po)-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Università Politecnica delle Marche [Ancona] (UNIVPM), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Ottawa Hospital Research Institute [Ottawa] (OHRI), European Synchrotron Radiation Facility (ESRF), Departamento de Engenharia Informática [Porto], Faculdade de Engenharia da Universidade do Porto (FEUP), Universidade do Porto-Universidade do Porto, Universidade Federal de Campina Grande [Campina Grande] (UFCG), Instituto de Engenharia de Sistemas e Computadores (INESC), Universidade Regional do Cariri (URCA Brasil), Universitat de Barcelona (UB), IRCELYON-Catalytic and Atmospheric Reactivity for the Environment (CARE), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Interactions, Corpus, Apprentissages, Représentations (ICAR), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines (ENS LSH)-Centre National de la Recherche Scientifique (CNRS), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), UMR 5805 Environnements et Paléoenvironnements Océaniques et Continentaux (EPOC), Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Hospital Universitario de Valme, Anenida de Bellavista s/n, Sevilla 41014, Spain, Hospital Son Llatzer, Universitat de València (UV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hospital Universitari Son Espases, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Instituto de Oncologia Corachan (IDOC), Laboratoire d'informatique de l'école normale supérieure (LIENS), École normale supérieure - Paris (ENS Paris), Institut de recherches Asiatiques (IrAsia), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre Européen de Réalité Virtuelle (CERV), École Nationale d'Ingénieurs de Brest (ENIB), Sol Agro et hydrosystème Spatialisation (SAS), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche cerveau et cognition (CERCO), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Géomatériaux et Environnement (LGE), Université Paris-Est Marne-la-Vallée (UPEM), Fédération Francophone de Cancérologie Digestive (FFCD), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Recherche Agronomique (INRA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Department of Information Engineering, Computer Science and Mathematics = Dipartimento di Ingegneria e Scienze dell'Informazione e Matematica [L'Aquila] (DISIM), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département d'informatique - ENS Paris (DI-ENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), Institute of Biomedicine - IBUB [Barcelona, Spain]-University of Barcelona, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de la Recherche Agronomique (INRA)-Environnement et Agronomie (E.A.)-Biologie et Amélioration des Plantes (BAP)-Fourrages Environnement Ruminants Lusignan (FERLUS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, University of Florence (UNIFI), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique (CNRS), Ghent University [Belgium] (UGENT), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université du Québec à Montréal (UQAM), Université Panthéon-Sorbonne (UP1), Centre hospitalier universitaire d'Amiens (CHU Amiens-Picardie), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Franche-Comté (UFC)-Université de Franche-Comté (UFC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Avicenne, Optimisation Thérapeutique en Neuropsychopharmacologie (VariaPsy - U1144), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Biostatistique et Processus Spatiaux (BIOSP), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Technische Universität Berlin (TUB), Università degli Studi dell'Aquila [L'Aquila] (UNIVAQ.IT), Universidade Nova de Lisboa (NOVA), Faculdade de Engenharia [Porto] (FEUP), Unité de recherche Amélioration, Génétique et Physiologie Forestières (UAGPF), IRCELYON-Caractérisation et remédiation des polluants dans l'air et l'eau (CARE), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), Emile, J, Julie, C, Le Malicot, K, Lepage, C, Tabernero, J, Mini, E, Folprecht, G, Van Laethem, J, Dimet, S, Boulagnon-Rombi, C, Allard, M, Penault-Llorca, F, Bennouna, J, Laurent-Puig, P, Taieb, J, Bidoli, P, Emile, J. -F., Julie, C., Le Malicot, K., Lepage, C., Tabernero, J., Mini, E., Folprecht, G., Van Laethem, J. -L., Dimet, S., Boulagnon-Rombi, C., Allard, M. -A., Penault-Llorca, F., Bennouna, J., Laurent-Puig, P., Taieb, J., Thaler, J., Greil, R., Gaenzer, J., Eisterer, W., Tschmelitsch, J., Keil, F., Samonigg, H., Zabernigg, A., Schmid, F., Steger, G., Steinacher, R., Andel, J., Jagdt, B., Lang, A., Fridrik, M., Fugger, R., Hofbauer, F., Woell, E., Geissler, D., Lenauer, A., Prager, M., D'Haens, G., Demolin, G., Kerger, J., Deboever, G., Ghillebert, G., Polus, M., Van Cutsem, E., Kalantari, H. R., Delaunoit, T., Goeminne, J. C., Peeters, M., Vergauwe, P., Houbiers, G., Humblet, Y., Janssens, J., Schrijvers, D., Vanderstraeten, E., Vermorken, J., Van Daele, D., Ferrante, M., Forget, F., Hendlisz, A., Yilmaz, M., Nielsen, S. E., Vestermark, L., Larsen, J., Zawadi, M. -A., Bouche, O., Mineur, L., Bennouna-Louridi, J., Dourthe, L. M., Ychou, M., Boucher, E., Pezet, D., Desseigne, F., Ducreux, M., Texereau, P., Miglianico, L., Rougier, P., Fratte, S., Levache, C. -B., Merrouche, Y., Ellis, S., Locher, C., Ramee, J. -F., Garnier, C., Viret, F., Chauffert, B., Cojean-Zelek, I., Michel, P., Lecaille, C., Borel, C., Seitz, J. -F., Smith, D., Lombard-Bohas, C., Andre, T., Gornet, J. -M., Fein, F., Coulon-Sfairi, M. -A., Kaminsky, M. -C., Lagasse, J. -P., Luet, D., Etienne, P. -L., Gasmi, M., Vanoli, A., Nguyen, S., Aparicio, T., Perrier, H., Stremsdoerfer, N., Laplaige, P., Arsene, D., Auby, D., Bedenne, L., Coriat, R., Denis, B., Geoffroy, P., Piot, G., Becouarn, Y., Bordes, G., Deplanque, G., Dupuis, O., Fruge, F., Guimbaud, R., Lecomte, T., Lledo, G., Sobhani, I., Asnacios, A., Azzedine, A., Desauw, C., Galais, M. -P., Gargot, D., Lam, Y. -H., Abakar-Mahamat, A., Berdah, J. -F., Catteau, S., Clavero-Fabri, M. -C., Codoul, J. -F., Legoux, J. -L., Goldfain, D., Guichard, P., Verge, D. P., Provencal, J., Vedrenne, B., Brezault-Bonnet, C., Cleau, D., Desir, J. -P., Fallik, D., Garcia, B., Gaspard, M. -H., Genet, D., Hartwig, J., Krummel, Y., Budnik, T. M., Palascak-Juif, V., Randrianarivelo, H., Rinaldi, Y., Aleba, A., Darut-Jouve, A., de Gramont, A., Hamon, H., Wendehenne, F., Matzdorff, A., Stahl, M. K., Schepp, W., Burk, M., Mueller, L., Geissler, M., Mantovani-Loeffler, L., Hoehler, T., Asperger, W., Kroening, H., von Weikersthal, L. F., Fuxius, S., Groschek, M., Meiler, J., Trarbach, T., Rauh, J., Ziegenhagen, N., Kretzschmar, A., Graeven, U., Nusch, A., von Wichert, G., Hofheinz, R. -D., Kleber, G., Schmidt, K. -H., Vehling-Kaiser, U., Baum, C., Schuette, J., Haag, G. M., Holtkamp, W., Potenberg, J., Reiber, T., Schliesser, G., Schmoll, H. -J., Schneider-Kappus, W., Abenhardt, W., Denzlinger, C., Henning, J., Marxsen, B., Derigs, H. G., Lambertz, H., Becker-Boost, I., Caca, K., Constantin, C., Decker, T., Eschenburg, H., Gabius, S., Hebart, H., Hoffmeister, A., Horst, H. -A., Kremers, S., Leithaeuser, M., Mueller, S., Wagner, S., Daum, S., Schlegel, F., Stauch, M., Heinemann, V., Maiello, E., Latini, L., Zaniboni, A., Amadori, D., Aprile, G., Barni, S., Mattioli, R., Martoni, A., Passalacqua, R., Nicolini, M., Pasquini, E., Rabbi, C., Aitini, E., Ravaioli, A., Barone, C., Biasco, G., Tamberi, S., Gambi, A., Verusio, C., Marzola, M., Lelli, G., Boni, C., Cascinu, S., Bidoli, P., Vaghi, M., Cruciani, G., Di Costanzo, F., Sobrero, A., Petrioli, R., Aglietta, M., Alabiso, O., Capuzzo, F., Falcone, A., Corsi, D. C., Labianca, R., Salvagni, S., Chiara, S., Ciuffreda, L., Ferrau, F., Giuliani, F., Lonardi, S., Gebbia, N., Mantovani, G., Sanches, E., Mellidez, J. C., Santos, P., Freire, J., Sarmento, C., Costa, L., Pinto, A. M., Barroso, S., Santo, J. E., Guedes, F., Monteiro, A., Sa, A., Furtado, I., Salazar, R., Aguilar, E. A., Herrero, F. R., Valera, J. S., Ayerbes, M. V., Batlle, J. F., Gil, S., Esteve, A. A., Garcia-Giron, C., Vivanco, G. L., Salvia, A. S., Orduna, V. A., Garcia, R. V., Gallego, J., Sureda, B. M., Remon, J., Safont Aguilera, M. J., Nogueras, L. C., Merino, B. Q., Castro, C. G., de Prado, P. M., Pericay, C. P., Figueiras, M. C., Jordan, I. G., Gome Reina, M. J., Garcia, A. L. -L., Garcia-Ramos, A. A., Cervantes, A., Martos, C. F., Gaspar, E. M., Montero, I. C., Emperador, P. E., Carbonero, A. L., Castillo, M. G., Garcia, T. G., Lopez, J. G., Flores, E. G., Morales, M. G., Munoz, M. L., Martin, A. L., Maurel, J., Camara, J. C., Garcia, R. D., Salgado, M., Busquier, I. H., Ruiz, T. C., Munoa, A. L., Aliguer, M. N., de Taranco, A. V. O., Urena, M. M., Gaspa, F. L., Ponce, J. J., Roig, C. B., Jimenez, P. V., Brotons, A. G., Rodriguez, S. A., Martinez, J. A., Ruiz, L. C., Ruiz, M. C., Bridgewater, J., Glynne-Jones, R., Tahir, S., Hickish, T., Cassidy, J., and Samuel, L.

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, Medizin, Leucovorin, Prospective cohort study, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, FOLFOX, Organoplatinum Compounds/therapeutic use, Antineoplastic Combined Chemotherapy Protocols, tudy, Lymphocytes, Prospective Studies, Leucovorin/therapeutic use, Middle Aged, Prognosis, 3. Good health, Colorectal carcinoma, Fluorouracil, 030220 oncology & carcinogenesis, Predictive value of tests, Colonic Neoplasms, Biomarker (medicine), Lymphocytes/pathology, Female, Adjuvant, medicine.drug, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Fluorouracil/therapeutic use, Biomarkers, Tumor/analysis, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Predictive Value of Tests, Biomarker, Immune response, Internal medicine, medicine, Biomarkers, Tumor, Humans, Survival analysis, Aged, business.industry, medicine.disease, Survival Analysis, Surgery, 030104 developmental biology, Prospective cohort&nbsp, Multivariate Analysis, Colonic Neoplasms/diagnosis, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, business
Abstract

IF 6.029; International audience; BackgroundThe prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use.Patients and methodsAccording to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data.ResultsAmong the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients.ConclusionAlthough this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients.

Published
2017

27. Assessment of ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line chemotherapy in patients (pts) with advanced HER2-negative gastric or gastroesophageal junction cancers: The ARMANI phase III trial

Author

Federica Morano, Filippo Pietrantonio, Elisa Giommoni, Gianluca Tomasello, Filippo de Braud, Francesco Giuliani, Giovanni Gerardo Cardellino, Salvatore Corallo, Maria Di Bartolomeo, Giovanni Luca Frassineti, Sara Lonardi, Ferdinando De Vita, Graziella Pinotti, Rossana Berardi, Mario Scartozzi, Lorenza Rimassa, Maria Pia Brizzi, Samantha Di Donato, Monica Niger, and Stefano Tamberi

Subjects
Oncology, Cancer Research, medicine.medical_specialty, business.industry, HER2 negative, Advanced gastric cancer, Gastroesophageal Junction, Ramucirumab, chemistry.chemical_compound, Paclitaxel, chemistry, Internal medicine, Medicine, In patient, First line chemotherapy, business
Abstract

TPS4151 Background: Platinum/fluoropyrimidine regimens are the backbone of first-line therapy for advanced gastric cancer (AGC). The optimal duration of first-line therapy is still unknown and its continuation until disease progression represents the standard. However this strategy is often associated with cumulative toxicity and rapid development of drug resistance. Moreover, only 40% of AGC pts are eligible for second-line treatment. This study aims at assessing whether switch maintenance to ramucirumab plus paclitaxel will extend the progression-free survival (PFS) of subjects with HER-2 negative AGC who have not progressed after a first-line with a platinum/fluoropyrimidine regimen. The hypothesis is that the early administration of an active, non-cross resistant regimen may delay disease progression and, consequently, improve pts’ quality of life. This strategy may also rescue all those subjects that become ineligible for a second-line therapy due to the rapid clinical deterioration. Methods: This is a randomized, open-label, multicenter, phase III trial. Eligibility criteria are: unresectable/metastatic HER-2 negative AGC or gastroesophageal junction (GEJ) cancer; ECOG PS 0-1; measurable and/or evaluable disease by RECIST v1.1; no progression after 3 months of therapy with either FOLFOX4, mFOLFOX6 or XELOX . The primary endpoint is to compare PFS of pts in ARM A (continuation of the same first-line therapy with oxaliplatin/fluoropyrimidine) versus ARM B (switch maintenance to ramucirumab and placlitaxel). Secondary endpoints are: overall survival, time-to-treatment failure, overall response rate, duration of response, percentage of pts receiving a second-line therapy per treatment arm, safety and quality of life. Exploratory analyses to identify primary resistance and prognosis biomarkers are planned, including Next-Generation Sequencing (NGS) on archival tumor tissues. The ARMANI study is sponsored by the Fondazione IRCCS Istituto Nazionale dei Tumori and it is ongoing at 29 Italian centers with a planned population of 280 pts. Clinical trial information: NCT02934464.

Published
2019

28. Analysis of liquid biopsies from metastatic colorectal carcinoma (mCRC) patients (pts) enrolled in the ERMES clinical trial

Author

Carmine Pinto, Sara Lonardi, Giuseppe Tonini, Nicola Normanno, Giovanni Luca Frassineti, Raffaella Pasquale, A. Cassata, Carlo Barone, Evaristo Maiello, Laura Forgione, Gerardo Rosati, Anna Maria Rachiglio, Roberto Bordonaro, Francesca Di Fabio, Francesco Di Costanzo, Alberto Zaniboni, Emiliano Tamburini, Salvatore Pisconti, Stefano Tamberi, and Daris Ferrari

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Response to therapy, business.industry, Colorectal cancer, fungi, food and beverages, Disease, medicine.disease, Clinical trial, 03 medical and health sciences, ERMES, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Medicine, Biomarker (medicine), Liquid biopsy, business, Tissue biopsy
Abstract

e15507Background: Liquid biopsy is an alternative to tissue biopsy for biomarker testing. In addition, it can be used to monitor the response to therapy and the molecular evolution of the disease. ...

Published
2018

29. Pharmacokinetic study of trabectedin administered as 24-hour infusion in elderly patients with advanced soft tissue sarcoma (STS) treated according to the TR1US ISG study

Author

D. Marra, Giovanni Grignani, Emanuela Marchesi, M. D'Incalci, Mariella Ferrari, Toni Ibrahim, Stefano Tamberi, Luca Porcu, Massimo Zucchetti, and Federica Grosso

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, business.industry, Soft tissue sarcoma, medicine.disease, Surgery, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Pharmacokinetics, 030220 oncology & carcinogenesis, Internal medicine, Medicine, business, Trabectedin, medicine.drug
Published
2016

30. Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin as first-line treatment for patients with ovarian cancer: the MITO-2 randomized phase III trial

Author

Francesco Perrone, Giovanni Scambia, Alessandro Morabito, Vanda Salutari, Francesco Legge, Enrico Aitini, Stefano Greggi, Paolo Scollo, Alberto Ravaioli, Roberto Sorio, Laura Scaltriti, L. Frigerio, Antonella Savarese, Donato Natale, Gabriella Ferrandina, Carmela Pisano, Alba A. Brandes, Massimo Di Maio, Antonio Febbraro, Enrico Breda, Ciro Gallo, Alessandra Vernaglia Lombardi, Maria Rosaria Valerio, Vittorio Gebbia, Pietro Del Medico, Pietro Musso, Stefano Tamberi, Domenica Lorusso, Sandro Pignata, Antonella Ferro, Pignata, S, Scambia, G, Ferrandina, G, Savarese, A, Sorio, R, Breda, E, Gebbia, V, Musso, P, Frigerio, L, Del Medico, P, Lombardi, Av, Febbraro, A, Scollo, P, Ferro, A, Tamberi, S, Brandes, A, Ravaioli, A, Valerio, Mr, Aitini, E, Natale, D, Scaltriti, L, Greggi, S, Pisano, C, Lorusso, D, Salutari, V, Legge, F, Di Maio, M, Morabito, A, Gallo, Ciro, Perrone, F., Pignata, S., Scambia, G., Ferrandina, G., Savarese, A., Sorio, R., Breda, E., Gebbia, V., Musso, P., Frigerio, L., Del Medico, P., Lombardi, A., Febbraro, A., Scollo, P., Ferro, A., Tamberi, S., Brandes, A., Ravaioli, A., Valerio, M., Aitini, E., Natale, D., Scaltriti, L., Greggi, S., Pisano, C., Lorusso, D., Salutari, V., Legge, F., Di Maio, M., Morabito, A., Gallo, C., and Perrone, F

Subjects
Oncology, Adult, Cancer Research, medicine.medical_specialty, Settore MED/06 - Oncologia Medica, medicine.medical_treatment, Antineoplastic Agents, Polyethylene Glycol, Disease-Free Survival, law.invention, Carboplatin, Polyethylene Glycols, Antineoplastic Agent, chemistry.chemical_compound, Randomized controlled trial, law, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Doxorubicin, Aged, Ovarian Neoplasms, Chemotherapy, Antineoplastic Combined Chemotherapy Protocol, business.industry, Ovarian Neoplasm, Area under the curve, Cancer, Middle Aged, medicine.disease, Surgery, Settore MED/40 - GINECOLOGIA E OSTETRICIA, chemistry, Paclitaxel, Quality of Life, Female, business, Ovarian cancer, Human, medicine.drug
Abstract

Purpose Carboplatin/paclitaxel is the standard first-line chemotherapy for patients with advanced ovarian cancer. Multicentre Italian Trials in Ovarian Cancer-2 (MITO-2), an academic multicenter phase III trial, tested whether carboplatin/pegylated liposomal doxorubicin (PLD) was more effective than standard chemotherapy. Patients and Methods Chemotherapy-naive patients with stage IC to IV ovarian cancer (age ≤ 75 years; Eastern Cooperative Oncology Group performance status ≤ 2) were randomly assigned to carboplatin area under the curve (AUC) 5 plus paclitaxel 175 mg/m2 or to carboplatin AUC 5 plus PLD 30 mg/m2, every 3 weeks for six cycles. Primary end point was progression-free survival (PFS). With 632 events in 820 enrolled patients, the study would have 80% power to detect a 0.80 hazard ratio (HR) of PFS. Results Eight hundred twenty patients were randomly assigned. Disease stages III and IV were prevalent. Occurrence of PFS events substantially slowed before obtaining the planned number. Therefore, in concert with the Independent Data Monitoring Committee, final analysis was performed with 556 events, after a median follow-up of 40 months. Median PFS times were 19.0 and 16.8 months with carboplatin/PLD and carboplatin/paclitaxel, respectively (HR, 0.95; 95% CI, 0.81 to 1.13; P = .58). Median overall survival times were 61.6 and 53.2 months with carboplatin/PLD and carboplatin/paclitaxel, respectively (HR, 0.89; 95% CI, 0.72 to 1.12; P = .32). Carboplatin/PLD produced a similar response rate but different toxicity (less neurotoxicity and alopecia but more hematologic adverse effects). There was no relevant difference in global quality of life after three and six cycles. Conclusion Carboplatin/PLD was not superior to carboplatin/paclitaxel, which remains the standard first-line chemotherapy for advanced ovarian cancer. However, given the observed CIs and the different toxicity, carboplatin/PLD could be considered an alternative to standard therapy.

Published
2011

31. EGFR and K-ras mutations along the spectrum of pulmonary epithelial tumors of the lung and elaboration of a combined clinicopathologic and molecular scoring system to predict clinical responsiveness to EGFR inhibitors

Author

Fabrizio Luppi, Emmanuela Meschiari, Mario Bavieri, Annamaria Cadioli, Alberto Cavazza, Stefano Tamberi, Alessandro Marchioni, Bruno Murer, Giuliana Sartori, Lucia Longo, Alessandro Sgambato, Mario Migaldi, Giulio Rossi, Fausto Barbieri, Sartori, G, Cavazza, A, Sgambato, A, Marchioni, A, Barbieri, F, Longo, L, Bavieri, M, Murer, B, Meschiari, E, Tamberi, S, Cadioli, A, Luppi, F, Migaldi, M, and Rossi, G

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Lung Neoplasms, Adolescent, Antineoplastic Agents, Neuroendocrine tumors, medicine.disease_cause, Polymerase Chain Reaction, K-ra, Sex Factors, Growth factor receptor, Risk Factors, medicine, Humans, Epidermal growth factor receptor, Neoplasms, Glandular and Epithelial, Child, Lung, Protein Kinase Inhibitors, EGFR inhibitors, Cancer, Aged, Retrospective Studies, Aged, 80 and over, Mutation, biology, Smoking, Infant, Anatomical pathology, General Medicine, Middle Aged, medicine.disease, Immunohistochemistry, respiratory tract diseases, ErbB Receptors, Genes, ras, Drug Resistance, Neoplasm, Child, Preschool, Cancer research, biology.protein, Adenocarcinoma, Female, Epidermal growth factor receptor * EGFR * K-ras * Histotype * Lung * Cancer * Score
Abstract

We tested 418 neoplasms along the whole spectrum of primary lung tumor histotypes for epidermal growth factor receptor (EGFR) and K-ras mutations. Clinicopathologic data from 154 patients undergoing treatment with EGFR tyrosine kinase inhibitors (TKIs) were retrospectively studied. A scoring system assigning a score for each positive or negative characteristic (+1, female sex, nonsmoking status, adenocarcinoma histotype, Asian ethnicity, and EGFR mutation; −1, current smoker and K-ras mutation; and 0, male sex, ex-smoker, nonadenocarcinoma histotype, and no mutations) was elaborated and tested with EGFR-TKI response. Salivary gland–type, mucin-rich, and neuroendocrine tumors do not harbor EGFR mutations. A subset of nonmucinous adenocarcinomas, not necessarily of the bronchioloalveolar type, is related to EGFR mutations. Three probability groups significantly correlating with response to EGFR-TKIs were identified. Of note, the addition of molecular results did not significantly change the predictive value obtained by the combination of clinicopathologic characteristics alone in this scoring system. K-ras mutations, significantly associated with the mucin-secreting type of adenocarcinoma, consistently predict lack of response in white patients.

Published
2009

32. P-023 eNOS polymorphisms in relation to outcome in advanced HCC patients receiving sorafenib

Author

R.R. Salvatore, Giovanni Luca Frassineti, Francesco Giuseppe Foschi, Stefano Tamberi, Andrea Casadei Gardini, Luca Faloppi, and M. Giorgia

Subjects
Sorafenib, Oncology, medicine.medical_specialty, biology, business.industry, Hematology, biology.organism_classification, Nitric oxide synthase, Enos, Internal medicine, Cancer research, biology.protein, Medicine, business, medicine.drug
Published
2015

33. eNOS polymorphisms in relation to outcome in advanced HCC patients receiving sorafenib

Author

Andrea Casadei Gardini, Francesco Giuseppe Foschi, Emanuela Scarpi, Giorgia Marisi, Paola Ulivi, Luca Faloppi, Elena Tenti, Emiliano Tamburini, Stefano Cascinu, Stefano Tamberi, Giovanni Luca Frassineti, and Mario Scartozzi

Subjects
Sorafenib, medicine.medical_specialty, Cancer Research, biology, business.industry, biology.organism_classification, medicine.disease, Nitric oxide, Vascular endothelial growth factor, chemistry.chemical_compound, Real-time polymerase chain reaction, Endocrinology, chemistry, Oncology, Enos, Internal medicine, Hepatocellular carcinoma, Cancer cell, medicine, Cancer research, business, Receptor, medicine.drug
Abstract

230 Background: Cancer cells adapt to hypoxic microenvironment through the activation of many molecules, including endothelial nitric oxide synthase (eNOS). Sorafenib, by blocking the vascular endothelial growth factor receptors (VEGFRs), induces an inhibition of eNOS activity with a consequent decrease of the production of nitric oxide (NO). NO is associated with an increase of tumor angiogenesis, tumor invasion and metastasis formation. In our study we analysed the role of eNOS polymorphisms in relation to clinical outcome in patients with hepatocellular carcinoma treated with sorafenib. Methods: From a database of 257 patients diagnosed with hepatocellular carcinoma from 2004 to 2014, we selected 54 patients who received sorafenib. Peripheral blood samples or FFPE tumor tissues were available for DNA extraction and genotyping analysis. Three eNOS polymorphisms (eNOS +894 G/T, eNOS VNTR 27bp 4a/b, eNOS -786 C/T) were analyzed by direct sequencing or Real Time PCR method. We analyzed 21 patients for the VNTR 4a/b polymorphism and 32 patients for -786 C/T polymorphism. All the candidate genotypes were evaluated to identify a potential correlation with overall survival (OS) (log-rank test). Results: With regard to eNOS VNTR it was observed that patients carrying the b allele (5 repetitions of 27bp) both in homozygosity (4bb) and in heterozygosity (4ab) were associated with a better OS. The variants 4aa (4 repeats of 27bp in homozygosity), 4ab and 4bb, were associated with a median OS of 5.7, 13.9 and 23.6 months, respectively (p = 0.016). For eNOS-786 the presence of the T allele both in homozygosity (TT) and in heterozygosity(TC) was associated with a statistically significant longer OS with respect to patients with CC genotype (15.6 versus 13.9 months, respectively, p = 0.031). No correlations were observed in relation to PFS (p = 0.494). Conclusions: eNOS VNTR and eNOS -786 could represent prognostic markers in patients with advanced hepatocellular carcinoma treated with sorafenib.

Published
2015

34. Effect of metformin on clinical outcome in advanced HCC patients receiving sorafenib

Author

Stefano Tamberi, Nicola Silvestris, Gianluca Masi, Emanuela Scarpi, Caterina Vivaldi, Stefano Cascinu, Andrea Casadei Gardini, Dino Amadori, Francesco Giuseppe Foschi, Mario Scartozzi, Giorgia Marisi, Giovanni Luca Frassineti, Paola Ulivi, and Luca Faloppi

Subjects
musculoskeletal diseases, Sorafenib, Oncology, Cancer Research, medicine.medical_specialty, business.industry, musculoskeletal, neural, and ocular physiology, Type 2 Diabetes Mellitus, Retrospective cohort study, macromolecular substances, medicine.disease, digestive system diseases, Metformin, nervous system, Hepatocellular carcinoma, Internal medicine, Medicine, business, medicine.drug
Abstract

e15156 Background: Several studies reported an association between type 2 diabetes mellitus (DM2) and hepatocellular carcinoma (HCC). Data from several retrospective studies and meta-analysis have ...

Published
2015

35. MITO-11: A randomized multicenter phase II trial testing the addition of pazopanib to weekly paclitaxel in platinum-resistant or -refractory advanced ovarian cancer (AOC)

Author

Daniela Sambataro, Sabrina Chiara Cecere, Giovanni Scambia, Vanda Salutari, Stefano Tamberi, Marilena Di Napoli, Francesco Perrone, Saverio Cinieri, Michele Orditura, Carmela Pisano, Maria Carmela Piccirillo, Pierluigi Benedetti Panici, Ciro Gallo, Gennaro Daniele, Sandro Pignata, Valentina Arcangeli, Anna Maria Mosconi, Stefania Bartolini, Francesco Raspagliesi, and Domenica Lorusso

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Advanced ovarian cancer, business.industry, Weekly paclitaxel, Pharmacology, Pazopanib, Refractory, Internal medicine, medicine, business, Platinum resistant, medicine.drug
Abstract

5503^ Background: few drugs are available for patients (pts) with platinum resistant or refractory AOC; their efficacy is scanty. Evidence on antiangiogenic drugs efficacy in AOC is increasing. Paz...

Published
2014

36. KRAS, BRAF and PIK3CA Status in Squamous Cell Anal Carcinoma (SCAC)

Author

Andrea Casadei Gardini, Giovanni Luca Frassineti, Massimo Giannini, Angela Ragazzini, Alassandro Passardi, Dino Amadori, Wainer Zoli, Laura Capelli, Paola Ulivi, Eva Freier, Emanuela Scarpi, Stefano Tamberi, Casadei Gardini, Andrea, Capelli, Laura, Ulivi, Paola, Giannini, Massimo, Freier, Eva, Tamberi, Stefano, Scarpi, Emanuela, Passardi, Alassandro, Zoli, Wainer, Ragazzini, Angela, Amadori, Dino, and Frassinet, Giovanni Luca

Subjects
Genetics and Molecular Biology (all), Male, Viral Diseases, Pathology, Epidemiology, medicine.medical_treatment, DNA Mutational Analysis, lcsh:Medicine, medicine.disease_cause, Biochemistry, Phosphatidylinositol 3-Kinases, Exon, Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), Gastrointestinal Cancers, Medicine and Health Sciences, lcsh:Science, Human papillomavirus 16, Mutation, Multidisciplinary, Cancer Risk Factors, Middle Aged, Anus Neoplasms, Infectious Diseases, Oncology, Research Design, Fluorouracil, Carcinoma, Squamous Cell, Female, KRAS, Cancer Epidemiology, Research Article, medicine.drug, Proto-Oncogene Proteins B-raf, Human Papillomavirus Infection, medicine.medical_specialty, Clinical Research Design, Class I Phosphatidylinositol 3-Kinases, Mitomycin, Genetic Causes of Cancer, Sexually Transmitted Diseases, Antineoplastic Agents, Gastroenterology and Hepatology, Biology, Research and Analysis Methods, Proto-Oncogene Proteins p21(ras), Proto-Oncogene Proteins, Gastrointestinal Tumors, Genetics, Cancer Genetics, medicine, Humans, Anal cancer, neoplasms, Aged, Neoplasm Staging, Retrospective Studies, Clinical Genetics, Papillomavirus Infections, lcsh:R, Biology and Life Sciences, Cancers and Neoplasms, Retrospective cohort study, medicine.disease, Axons, digestive system diseases, Radiation therapy, Gamma Rays, ras Proteins, Cancer research, lcsh:Q, Carcinogenesis
Abstract

Anti-EGFR therapy appears to be a potential treatment option for squamous cell anal carcinoma (SCAC). KRAS mutation is a rare event in SCAC, indicating the absence of the principal mechanism of resistance to this type of therapy. However, no information is available from the literature regarding the status of BRAF or PIK3CA in this cancer type. We analysed KRAS, BRAF and PIK3CA status in SCAC patients in relation to the clinical-pathological characteristics of patients and to the presence of the human papilloma virus (HPV). One hundred and three patients were treated with the Nigro scheme for anal cancer from March 2001 to August 2012. Fifty patients were considered for the study as there was insufficient paraffinembedded tumour tissue to perform molecular analysis the remaining 53. DNA was extracted from paraffin-embedded sections. KRAS, BRAF and PIK3CA gene status and HPV genotype were evaluated by pyrosequencing. KRAS and BRAF genes were wild-type in all cases. Conversely, PIK3CA gene was found to be mutated in 11 (22%) cases. In particular, 8 mutations occurred in exon 9 and 3 in exon 20 of the PIK3CA gene. These findings suggest that SCAC could potentially respond to an anti-EGFR drug. PIK3CA mutation may be involved in the process of carcinogenesis in some cases of SCAC. © 2014 Casadei Gardini et al.

Published
2014

37. Mucoepidermoid carcinoma of the lung, response to EGFR inhibitors, EGFR and K-RAS mutations, and differential diagnosis

Author

Alberto Cavazza, Giulio Rossi, Giuliana Sartori, Antonio Rossi, and Stefano Tamberi

Subjects
Pulmonary and Respiratory Medicine, Oncology, Cancer Research, medicine.medical_specialty, Mutation, Lung, business.industry, Adenosquamous carcinoma, respiratory system, medicine.disease, medicine.disease_cause, respiratory tract diseases, medicine.anatomical_structure, Mucoepidermoid carcinoma, Internal medicine, medicine, Carcinoma, Differential diagnosis, Lung cancer, business, EGFR inhibitors
Abstract

Mucoepidermoid carcinoma (MEC) of the lung needs to be carefully distinguished from other lung tumors with similar features, particularly from adenosquamous carcinoma, this latter tumor frequently showing EGFR mutations. In contrast with the data reported by Han et al in the last July issue of Lung Cancer, neither EGFR nor K-RAS mutations were observed in MEC from caucasian patients.

Published
2009

38. KRAS, BRAF, PIK3CA, and human papilloma virus (HPV) status in squamous cell anal carcinoma (SCAC)

Author

Giovanni Luca Frassineti, Daniele Calistri, Martina Valgiusti, Andrea Casadei Gardini, Massimo Giannini, Stefano Tamberi, Paola Rosetti, Maurizio Puccetti, Dino Amadori, Laura Capelli, Alessandro Passardi, Luca Saragoni, Paola Ulivi, and Eva Freier

Subjects
Human papilloma virus, Cancer Research, Oncology, business.industry, Cancer research, Squamous Cell Anal Carcinoma, Medicine, KRAS, business, medicine.disease_cause, neoplasms, Hpv status
Abstract

e15055 Background: In literature three studies have described KRAS status in SCAC: they analyzed 139 patients, only 1, 4% were mutated. In this study we analyzed BRAF and PIK3CA status. The evaluation of these two genes is important for predicting the response to anti-EGFR drugs. There is one study that values the positivity of HPV in SCAC. This study with few patients shows that the positivity of HPV16 is predictive for improvement of progression free survival (PFS). Methods: 79 patients were treated for anal cancer at the Oncology center of Forlì, Ravenna and Faenza in the last ten years. Up to now we analyzed 29 patients (9 with relapse of disease). DNA was extracted from paraffin-embedded sections and KRAS, BRAF and PIK3CA gene status were assessed by Pyrosequencing methodology, using 3 different kits: anti-EGFR MoAb response (KRAS status), anti-EGFR MoAb response (BRAF status), and anti- EGFR MoAb response (PIK3CA status) (Diatech, Jesi, Ancona, Italy). Reactions were run on a PyroMark Q96 ID (Qiagen). The presence and genotyping of Human Papilloma Virus (HPV) were assessed using the AMPLIQUALITY HPV-HS Bio and AMPLIQUALITY HPV-Type (AB ANALITICA, Padova, Italy) kit. Results: KRAS and BRAF genes were wild-type in all cases. Conversely, PIK3CA gene resulted mutated in 9 of 31 cases (28.1%). In particular, 7 mutations occurred in exon 9 (4 E454K and 3 E542K) and 2 in exon 20 (H1047R and H1047L) of the PIK3CA gene. Patients without relapse of disease were positive in 94% of cases for HPV16 and in 40% for mutation of PIK3CA. Patients with relapse of disease were positive in 70% of cases for HPV16 and 37,5% for mutation of PIK3CA. Conclusions: KRAS and BRAF genes were wild type in 100% of cases. This study demonstrates that the SCAC could potentially respond to an anti-EGFR drug.The mutation of PIK3CA does not seem to be predictive for response to treatment. Positivity for HPV16 seems predictive for PFS and overall survival. Furthermore, the study shows that PIK3CA mutation may contribute to carcinogenesis in some cases of this tumor. In addition, patients with a mutation of PI3K could have benefit from specific drugs that inhibit this kinase.

Published
2013

39. A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer (PANDORA)

Author

Oriana Nanni, Carmine Pinto, M. Marzola, Maria Di Bartolomeo, Giovanni Luca Frassineti, Maria Aurelia Barbera, Jody Corbelli, Chiara Carli Moretti, Andrea Bonetti, Stefano Cascinu, Elisa Grassi, Giorgio Papiani, G. Ugolini, Stefano Tamberi, Chiara Zingaretti, Isacco Montroni, Giulio Rossi, and Ilaria Panzini

Subjects
Cancer Research, medicine.medical_specialty, Durvalumab, business.industry, Colorectal cancer, medicine.medical_treatment, Standard treatment, Phases of clinical research, medicine.disease, Capecitabine, Radiation therapy, Oncology, Concomitant, medicine, Radiology, business, medicine.drug, Preoperative treatment
Abstract

TPS259 Background: The standard treatment for cT3-4 N0-1 rectal cancer is preoperative chemo-radiation therapy (CT/RT). The combination of capecitabine plus long course radiotherapy (RT) is standard therapy in this setting. Pathologic Complete remission (pCR) can be considered as surrogate end point of efficacy of treatment in terms of disease free survival (DFS). Clinical complete remission (cCR) is an important endpoint for “wait and see” strategy. In the PACIFIC trial in non-small cell lung cancer the patients were treated with durvalumab maintenance after CT/RT with advantage in progression free survival. Preclinical data points heavily toward a strong synergy between RT and immune treatments. Furthermore, a systemic effect of RT is possible when enhanced by targeted immune treatments. Methods: This is a prospective phase II, open label, single arm, multi-centre study to evaluate the activity of an innovative sequence in operable rectal cancer: standard concomitant CT/RT therapy with 825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks followed by 1500 mg Q4W durvalumab for 3 administration. After 9-10 weeks from neoadjuvant therapy will be performed re-staging with CT and MRI scan. Surgery will be performed at week 10-12 from the end of CT/RT. Primary Objective: pCR rate, defined as a TRG 3-4 according to DWORAK criteria. Secondary Objectives: Safety of treatment with durvalumab; cCR rate after durvalumab treatment before surgery and DFS. cCR will be evaluated with clinical, endoscopic and radiological assessment to look for evidence of residual disease. DFS will be evaluated during a follow up of 5 years. Exploratory Objective: Biological translational analysis of tumor biomarkers will be performed on the endoscopy biopsy done at the diagnosis and on the biopsy performed after the CT/RT prior to treatment with durvavalumab. We hypothesize that the addition of durvalumab after standard CT/RT for the treatment of locally advanced rectal cancer may improve the pathological response rate and we have planned to enlist 60 patients in 7 centers with an enrollment period of 12 months, already underway. Clinical trial information: NCT04083365.

40. Real time contrast enhanced ultrasonography in detection of liver metastases from gastrointestinal cancer

Author

Francesco Corradi, Giampaolo Ugolini, Mikaela Mancini, Luigi Bolondi, Fabio Fornari, R. Righini, Fabio Piscaglia, Alberto Bazzocchi, F. Giangregorio, Bruno Cola, Stefano Tamberi, P. Pini, Piscaglia F, Corradi F, Mancini M, Giangregorio F, Tamberi S, Ugolini G, Cola B, Bazzocchi A, Righini R, Pini P, Fornari F, and Bolondi L

Subjects
Adult, Male, medicine.medical_specialty, Cancer Research, Real-Time Contrast-Enhanced Ultrasonography, Contrast Media, lcsh:RC254-282, Sensitivity and Specificity, X ray computed, Surgical oncology, Genetics, Medicine, Humans, Gastrointestinal cancer, Aged, Gastrointestinal Neoplasms, Ultrasonography, Aged, 80 and over, Oncology, business.industry, Liver Neoplasms, Follow up studies, Image enhancement, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Image Enhancement, Female, Imaging technique, Radiology, business, Tomography, X-Ray Computed, Contrast-enhanced ultrasound, Follow-Up Studies, Research Article
Abstract

Background Contrast enhanced ultrasound (CEUS) is an imaging technique which appeared on the market around the year 2000 and proposed for the detection of liver metastases in gastrointestinal cancer patients, a setting in which accurate staging plays a significant role in the choice of treatment. Methods A total of 109 patients with colorectal (n = 92) or gastric cancer prospectively underwent computed tomography (CT) scan and conventional US evaluation followed by real time CEUS. A diagnosis of metastases was made by CT or, for lesions not visibile at CT, the diagnosis was achieved by histopathology or by a malignant behavior during follow-up. Results Of 109 patients, 65 were found to have metastases at presentation. CEUS improved sensitivity in metastatic livers from 76.9% of patients (US) to 95.4% (p <0.01), while CT scan reached 90.8% (p = n.s. vs CEUS, p < 0.01 vs US). CEUS and CT were more sensitive than US also for detection of single lesions (87 with US, 122 with CEUS, 113 with CT). In 15 patients (13.8%), CEUS revealed more metastases than CT, while CT revealed more metastases than CEUS in 9 patients (8.2%) (p = n.s.). Conclusion CEUS is more sensitive than conventional US in the detection of liver metastases and could be usefully employed in the staging of patients with gastrointestinal cancer. Findings at CEUS and CT appear to be complementary in achieving maximum sensitivity.

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