47 results on '"Sara Manglaviti"'
Search Results
2. Real-world data to build explainable trustworthy artificial intelligence models for prediction of immunotherapy efficacy in NSCLC patients
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Arsela Prelaj, Edoardo Gregorio Galli, Vanja Miskovic, Mattia Pesenti, Giuseppe Viscardi, Benedetta Pedica, Laura Mazzeo, Achille Bottiglieri, Leonardo Provenzano, Andrea Spagnoletti, Roberto Marinacci, Alessandro De Toma, Claudia Proto, Roberto Ferrara, Marta Brambilla, Mario Occhipinti, Sara Manglaviti, Giulia Galli, Diego Signorelli, Claudia Giani, Teresa Beninato, Chiara Carlotta Pircher, Alessandro Rametta, Sokol Kosta, Michele Zanitti, Maria Rosa Di Mauro, Arturo Rinaldi, Settimio Di Gregorio, Martinetti Antonia, Marina Chiara Garassino, Filippo G. M. de Braud, Marcello Restelli, Giuseppe Lo Russo, Monica Ganzinelli, Francesco Trovò, and Alessandra Laura Giulia Pedrocchi
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non-small cell lung cancer ,immunotherapy ,machine learning ,explainable artificial intelligence ,treatment ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
IntroductionArtificial Intelligence (AI) methods are being increasingly investigated as a means to generate predictive models applicable in the clinical practice. In this study, we developed a model to predict the efficacy of immunotherapy (IO) in patients with advanced non-small cell lung cancer (NSCLC) using eXplainable AI (XAI) Machine Learning (ML) methods.MethodsWe prospectively collected real-world data from patients with an advanced NSCLC condition receiving immune-checkpoint inhibitors (ICIs) either as a single agent or in combination with chemotherapy. With regards to six different outcomes - Disease Control Rate (DCR), Objective Response Rate (ORR), 6 and 24-month Overall Survival (OS6 and OS24), 3-months Progression-Free Survival (PFS3) and Time to Treatment Failure (TTF3) - we evaluated five different classification ML models: CatBoost (CB), Logistic Regression (LR), Neural Network (NN), Random Forest (RF) and Support Vector Machine (SVM). We used the Shapley Additive Explanation (SHAP) values to explain model predictions.ResultsOf 480 patients included in the study 407 received immunotherapy and 73 chemo- and immunotherapy. From all the ML models, CB performed the best for OS6 and TTF3, (accuracy 0.83 and 0.81, respectively). CB and LR reached accuracy of 0.75 and 0.73 for the outcome DCR. SHAP for CB demonstrated that the feature that strongly influences models’ prediction for all three outcomes was Neutrophil to Lymphocyte Ratio (NLR). Performance Status (ECOG-PS) was an important feature for the outcomes OS6 and TTF3, while PD-L1, Line of IO and chemo-immunotherapy appeared to be more important in predicting DCR.ConclusionsIn this study we developed a ML algorithm based on real-world data, explained by SHAP techniques, and able to accurately predict the efficacy of immunotherapy in sets of NSCLC patients.
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- 2023
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3. Case Report: Exceptional Response to Poziotinib in Patient with Metastatic Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutation
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Arsela Prelaj, Achille Bottiglieri, Gajanan Bhat, Rocky Washington, Giuseppina Calareso, Gabriella Francesca Greco, Roberto Ferrara, Marta Brambilla, Alessandro De Toma, Mario Occhipinti, Sara Manglaviti, Alberto Soro, Monica Ganzinelli, Giuseppe Lo Russo, and Claudia Proto
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poziotinib ,NSCLC ,lung cancer ,exon 20 insertion mutation ,EGFR ,exon 20 insertion (ex20ins) ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Among the several next-generation tyrosine kinase inhibitors (TKIs) tested against uncommon EFGR alterations, poziotinib has been demonstrated to be a powerful agent for metastatic non-small-cell lung cancer (mNSCLC) with aberrations in HER2 exon 20, and FDA approval is being sought in the previously-treated population. Poziotinib has also shown activity in mNSCLC with aberrations in EGFR exon 20. Herein, we report the first published case of a patient affected by mNSCLC harbouring an EGFR exon 20 insertion (EGFRex20ins) mutation who achieved a complete response (CR) under treatment with poziotinib as part of the ZENITH20 trial. In January 2021, a former smoker 62-year-old female patient was diagnosed with relapse, after two surgeries and post-operative chemotherapy of mNSCLC, at liver and retroperitoneal nodes. Given the identification by Next Generation Sequencing (NGS) of EGFRex20ins mutation, she was enrolled in ZENITH20-cohort 5 trial, a phase 2 multicentre study aimed to assess the efficacy and safety of poziotinib in patients with EGFR or HER2 exon 20 insertion mutations. Poziotinib as first-line systemic therapy for metastatic disease was initiated at the end of January 2021 and administrated at the initial dosage of 8 mg orally twice daily (BID). The most common side effects from the beginning of the treatment included alopecia, macular skin rash, diarrhoea, xerostomia, and conjunctivitis. Due to these adverse events, poziotinib was discontinued during the first 3 months and then reduced to 6 mg orally BID in April 2021. After the dose de-escalation, the adverse events ameliorated, and the patient better tolerated the treatment without further interruption. Since the first reevaluation (after 4 weeks of therapy), the treatment with poziotinib resulted to be remarkably effective, with a partial response (PR) subsequently confirmed in May and July 2021. Then, in October 2021, a CT scan confirmed a CR, maintained with good tolerance at the last reevaluation in February 2022. Treatment is still ongoing at the same dosage. In this case, poziotinib has represented a successful and well-tolerated first-line treatment alternative to chemotherapy in this patient with EGFR exon 20 insertion mutated mNSCLC.
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- 2022
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4. Is hyperprogressive disease a specific phenomenom of immunotherapy?
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Marta Brambilla, Giuseppe Lo Russo, Roberto Ferrara, Sara Manglaviti, Marina Chiara Garassino, and Mario Occhipinti
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hyperprogressive disease ,immunotherapy ,chemotherapy-immunotherapy ,Internal medicine ,RC31-1245 - Abstract
Hyperprogressive disease (HPD) is a novel pattern of response during immunotherapy treatment. Several retrospective studies have evaluated its prevalence among various cancer types and, in particular, in non-small cell lung cancer patients, based on different definition criteria. If HPD is a just a typical phenomenon of immunotherapy is still an unsolved concern. This paper summarized the available data about HPD in other cancer treatments.
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- 2020
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5. Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications
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Claudio Vernieri, Francesca Corti, Federico Nichetti, Francesca Ligorio, Sara Manglaviti, Emma Zattarin, Carmen G. Rea, Giuseppe Capri, Giulia V. Bianchi, and Filippo de Braud
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Advanced breast cancer ,Hormone receptor-positive breast cancer ,Endocrine therapy ,mTORC1 ,PI3K ,Everolimus ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The PI3K/AKT/mTORC1 axis is implicated in hormone receptor-positive HER2-negative metastatic breast cancer (HR+ HER2− mBC) resistance to anti-estrogen treatments. Based on results of the BOLERO-2 trial, the mTORC1 inhibitor everolimus in combination with the steroidal aromatase inhibitor (AI) exemestane has become a standard treatment for patients with HR+ HER2− mBC resistant to prior non-steroidal AI therapy. In the recent SOLAR-1 trial, the inhibitor of the PI3K alpha subunit (p110α) alpelisib in combination with fulvestrant prolonged progression-free survival (PFS) when compared to fulvestrant alone in patients with PIK3CA-mutated HR+ HER2− mBC that progressed after/on previous AI treatment. Therefore, two different molecules targeting the PI3K/AKT/mTORC1 axis, namely everolimus and alpelisib, are available for patients progressing on/after previous AI treatment, but it is unclear how to optimize their use in the clinical practice. Main body of the abstract Here, we reviewed the available clinical evidence deriving from the BOLERO-2 and SOLAR-1 trials to compare efficacy and safety profiles of everolimus and alpelisib in advanced HR+ HER2− BC treatment. Adding either compound to standard endocrine therapy provided similar absolute and relative PFS advantage. In the SOLAR-1 trial, a 76% incidence of grade (G) 3 or 4 (G3/G4) adverse events was reported, while G3/G4 toxicities occurred in 42% of patients in the BOLERO-2 trial. While alpelisib was only effective in patients with PIK3CA-mutated neoplasms, retrospective analyses indicate that everolimus improves exemestane efficacy independently of PIK3CA mutational status. Conclusions Based on the available efficacy and safety data, the “new” alpelisib may be burdened by higher incidence of severe adverse events, higher costs, and anticancer efficacy that is limited to PIK3CA-mutated tumors when compared to the “old” everolimus. Therefore, the everolimus-exemestane combination remains an effective and reasonably well-tolerated therapeutic option for HR+ HER2− mBC patients progressing after/on previous AI treatment, independently of PIK3CA mutational status.
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- 2020
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6. Machine Learning Using Real-World and Translational Data to Improve Treatment Selection for NSCLC Patients Treated with Immunotherapy
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Arsela Prelaj, Mattia Boeri, Alessandro Robuschi, Roberto Ferrara, Claudia Proto, Giuseppe Lo Russo, Giulia Galli, Alessandro De Toma, Marta Brambilla, Mario Occhipinti, Sara Manglaviti, Teresa Beninato, Achille Bottiglieri, Giacomo Massa, Emma Zattarin, Rosaria Gallucci, Edoardo Gregorio Galli, Monica Ganzinelli, Gabriella Sozzi, Filippo G. M. de Braud, Marina Chiara Garassino, Marcello Restelli, Alessandra Laura Giulia Pedrocchi, and Francesco Trovo'
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non-small cell lung cancer ,immunotherapy ,biomarker ,artificial intelligence ,machine learning ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
(1) Background: In advanced non-small cell lung cancer (aNSCLC), programmed death ligand 1 (PD-L1) remains the only biomarker for candidate patients to immunotherapy (IO). This study aimed at using artificial intelligence (AI) and machine learning (ML) tools to improve response and efficacy predictions in aNSCLC patients treated with IO. (2) Methods: Real world data and the blood microRNA signature classifier (MSC) were used. Patients were divided into responders (R) and non-responders (NR) to determine if the overall survival of the patients was likely to be shorter or longer than 24 months from baseline IO. (3) Results: One-hundred sixty-four out of 200 patients (i.e., only those ones with PD-L1 data available) were considered in the model, 73 (44.5%) were R and 91 (55.5%) NR. Overall, the best model was the linear regression (RL) and included 5 features. The model predicting R/NR of patients achieved accuracy ACC = 0.756, F1 score F1 = 0.722, and area under the ROC curve AUC = 0.82. LR was also the best-performing model in predicting patients with long survival (24 months OS), achieving ACC = 0.839, F1 = 0.908, and AUC = 0.87. (4) Conclusions: The results suggest that the integration of multifactorial data provided by ML techniques is a useful tool to select NSCLC patients as candidates for IO.
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- 2022
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7. Evaluation of Drug—Drug Interactions in EGFR-Mutated Non-Small-Cell Lung Cancer Patients during Treatment with Tyrosine-Kinase Inhibitors
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Mario Occhipinti, Marta Brambilla, Giulia Galli, Sara Manglaviti, Maristella Giammaruco, Arsela Prelaj, Roberto Ferrara, Alessandro De Toma, Claudia Proto, Teresa Beninato, Emma Zattarin, Giuseppe Lo Russo, Alain Jonathan Gelibter, Maurizio Simmaco, Robert Preissner, Marina Chiara Garassino, Filippo De Braud, and Paolo Marchetti
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drug–drug interactions (DDI) ,EGFR ,tyrosine-kinase inhibitors (EGFR-TKIs) ,non-small-cell lung cancer (NSCLC) ,Drug-PIN® ,Medicine - Abstract
(1) Background. The onset of a drug–drug interaction (DDI) may affect treatment efficacy and toxicity of advanced non-small-cell lung cancer (aNSCLC) patients during epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) use. Here we present the use of Drug-PIN® (Personalized Interactions Network) software to detect DDIs in aNSCLC patients undergoing EGFR-TKIs. (2) Methods. We enrolled patients with Stage IV aNSCLC already treated with or candidates to receive EGFR-TKIs, in any line; ECOG PS 0–2; taking at least one concomitant drug. Cancer treatments, concomitant drugs, and clinical and laboratory data were collected and inserted in Drug-PIN®. (3) Results. Ninety-two patients, median age of 68.5 years (range 43–89), were included. In total, 20 clinically relevant DDIs needing medical intervention in a total of 14 patients were identified; the 14 major DDIs were related to a high-grade interaction between TKIs and SSRIs, antipsychotics, antiepileptics, H2-receptor antagonist and calcium antagonists. A negative association between statin intake and PFS was identified (p = 0.02; HR 0.281, 95% CI 0.096–0.825). (4) Conclusions. This is the first retrospective study assessing the prevalence of DDIs, the clinical need for medical intervention and the impact of concomitant drugs on EGFR-TKIs survival in aNSCLC.
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- 2021
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8. Oral Capecitabine-Vinorelbine is Associated with Longer Overall Survival When Compared to Single-Agent Capecitabine in Patients with Hormone Receptor-Positive Advanced Breast Cancer
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Claudio Vernieri, Michele Prisciandaro, Federico Nichetti, Riccardo Lobefaro, Giorgia Peverelli, Francesca Ligorio, Emma Zattarin, Maria Silvia Cona, Pierangela Sepe, Francesca Corti, Sara Manglaviti, Marta Brambilla, Barbara Re, Antonino Belfiore, Giancarlo Pruneri, Luigi Celio, Gabriella Mariani, Giulia Valeria Bianchi, Licia Rivoltini, Giuseppe Capri, and Filippo de Braud
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advanced breast cancer ,chemotherapy ,capecitabine ,vinorelbine ,hormone receptor-positive breast cancer ,triple-negative breast cancer ,progression-free survival ,overall survival ,adverse events ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Single-agent capecitabine (C) is a moderately effective chemotherapeutic compound in the treatment of patients with HER2-negative metastatic breast cancer (mBC). The capecitabine-vinorelbine (CV) combination is also used due to a good tolerability profile, but no studies have demonstrated its superiority over single-agent C. Methods: We conducted a retrospective analysis to compare overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and incidence of adverse events (AEs) in patients with HER2-negative mBC treated with CV vs. single-agent C. Results: Out of 290 patients included in this study, 127 (43.8%) received single-agent C, while 163 (56.2%) patients were treated with CV. Median PFS was similar in patients treated with single-agent C or CV, while CV was associated with significantly longer OS in patients with hormone receptor-positive (HR+) BC. This OS advantage was confirmed at multivariable analysis also after propensity score-based matching of patients according to relevant clinical or tumor characteristics. When compared with single-agent C, CV was associated with higher incidence of G3/G4 and any-grade nausea/vomiting, diarrhea and increased transaminases. Conclusions: While prospective studies are needed to confirm our findings, the potential OS advantage of CV over single-agent C in HR+ mBC patients must be weighed against a significantly higher incidence of AEs.
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- 2020
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9. Circulating Fatty Acid Profile as a Biomarker for Immunotherapy in Advanced Non-Small Cell Lung Cancer
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Giulia Galli, Paola Antonia Corsetto, Claudia Proto, Giuseppe Lo Russo, Monica Ganzinelli, Eliana Rulli, Lorenzo Legramandi, Daniele Morelli, Roberto Ferrara, Arsela Prelaj, Diego Signorelli, Alessandro De Toma, Marta Brambilla, Mario Occhipinti, Sara Manglaviti, Mattia Boeri, Antonia Martinetti, Andrea Vingiani, Mario Paolo Colombo, Angela Maria Rizzo, Valter Torri, Filippo de Braud, Sabina Sangaletti, Antonio Sica, and Marina Chiara Garassino
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Pulmonary and Respiratory Medicine ,Cancer Research ,Lung Neoplasms ,Settore MED/06 - Oncologia Medica ,Fatty Acids ,Fatty acids ,Immunotherapy ,Lipid metabolism ,Membrane fluidity ,Non-small cell lung cancer ,B7-H1 Antigen ,Oncology ,Settore BIO/10 - Biochimica ,Carcinoma, Non-Small-Cell Lung ,Humans ,Inflammation Mediators ,Biomarkers - Abstract
Lipid metabolism impacts immune cell differentiation, activation, and functions, modulating inflammatory mediators, energy homeostasis, and cell membrane composition. Despite preclinical evidence, data in humans lack concerning tumors and immunotherapy (IO). We aimed at investigating the correlations between circulating lipids and the outcome of non-small cell lung cancer (NSCLC) patients treated with IO.We identified all patients with advanced NSCLC treated with IO at our Institution with available baseline plasma samples. Fatty acids (FAs) were analyzed through gas chromatography. Survival curves were estimated by the Kaplan-Meier method. Cox multivariate models were constructed through a stepwise procedure, with entry and exit P value set at .2.We identified 112 patients, mostly with performance status 1 (65.2%) and PD-L1≥1% (75.3%). Median progression-free survival (PFS) and overall survival (OS) were 2.8 and 11.0 months, respectively. Multivariable model for survival identified a positive association of circulating free (FFA) C16:0 (P .005) and esterified (EFA) C16:1 (P .030) with PFS, and a positive association of EFA C16:1 (P .001) and EFA C18:0 (P .020) with OS. EFA C16:0 was negatively associated with PFS (P .008).FFA C16:0 and FAs derived from its unsaturation (EFA C16:1) and elongation (EFA C18:0) are associated with a better outcome in NSCLC patients treated with IO. It is conceivable that the ratio among those FAs may modify membrane fluidity and receptor activity, influencing IO efficacy. These data pave the way for the investigation of lipid-modulating strategies in association with IO in NSCLC.
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- 2022
10. STYLE (NCT03449173): A Phase 2 Trial of Sunitinib in Patients With Type B3 Thymoma or Thymic Carcinoma in Second and Further Lines
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Claudia Proto, Sara Manglaviti, Giuseppe Lo Russo, Marco Musca, Giulia Galli, Martina Imbimbo, Matteo Perrino, Nadia Cordua, Eliana Rulli, Zelmira Ballatore, Alessandro Dal Maso, Antonio Chella, Andrea Sbrana, Arsela Prelaj, Roberto Ferrara, Mario Occhipinti, Marta Brambilla, Alessandro De Toma, Laura Mazzeo, Teresa Beninato, Diego Signorelli, Giacomo Massa, Francesca Gabriella Greco, Giuseppina Calareso, Daniela Miliziano, Rosa Maria Di Mauro, Giulia Mella, Alessandra Lucarelli, Angela Paggio, Francesca Galli, Valter Torri, Filippo Guglielmo Maria de Braud, Giulia Pasello, Iacopo Petrini, Rossana Berardi, Monica Ganzinelli, Marina Chiara Garassino, and Paolo Andrea Zucali
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Pulmonary and Respiratory Medicine ,Oncology - Published
- 2023
11. SARS-CoV-2 vaccine in patients with thymic epithelial tumours with and without active or pre-existing autoimmune disorders: Brief report of a TYME network safety analysis
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Federica Giugliano, Paolo A. Zucali, Giulia Galli, Zelmira Ballatore, Chiara Corti, Pamela T. Aliaga, Jacopo Uliano, Grazia Vivanet, Giuseppe Curigliano, Fabio Conforti, Paola Queirolo, Rossana Berardi, Sara Manglaviti, Giulia Apollonio, Matteo Perrino, Federica Borea, Federica D'Antonio, Marina C. Garassino, and Tommaso De Pas
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Cancer Research ,COVID-19 Vaccines ,Oncology ,SARS-CoV-2 ,Spike Glycoprotein, Coronavirus ,COVID-19 ,Humans ,Neoplasms, Glandular and Epithelial ,Thymus Neoplasms ,Autoimmune Diseases - Abstract
International guidelines recommend severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine for patients with cancer. A substantial risk of developing vaccine-related autoimmune toxicities could be hypothesised for patients with thymic epithelial tumours (TETs) due to their high risk of autoimmune disorders (ADs). Moreover, a cross-reaction between SARS-CoV-2 spike protein antibodies and various tissue proteins has been shown, and antibodies against nucleoproteins showed overlaps in the autoimmune cross-reaction with antibodies to spike protein. Due to the rarity of TETs, no data addressing this hypothesis are available.Patients with TETs who received SARS-CoV-2 vaccine, treated in 4 referral centres of the Italian Collaborative Group for ThYmic MalignanciEs (TYME) network between February 2021 and September 2021, were interviewed through a standardised 15-items questionnaire in order to describe the safety of SARS-CoV-2 vaccine in patients affected by TETs.Data from 245 doses of vaccine administered to 126 patients (41 = thymic carcinoma, 85 = thymoma; 38 with AD, of which 26 with active AD) were collected. Nine patients had a previous COVID-19-positive swab. No cases of AD reactivation or worsening of a pre-existing AD were seen in the study population. A new diagnosis of myasthenia gravis likely unrelated to the vaccine was made in two patients after the vaccination. Sixty-four patients (51%) experienced a total of 103 adverse events, all G1/G2, most commonly fatigue, new or worsening muscle pain and chills. None AE required patients' hospitalisation.SARS-CoV-2 mRNA vaccines appear to be safe in patients with TET, even in case of active or pre-existing AD.
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- 2022
12. Abstract 5506: Circulating immature neutrophils early detect hyperprogressive disease upon first-line PD-1/PD-L1 inhibitors in non-small cell lung cancer patients selecting best candidates for platinum-based chemotherapy and PD-1/PD-L1 inhibitors combinations
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Roberto Ferrara, Giuseppe Lo Russo, Chiara Maura Ciniselli, Annamaria Piva, Barbara Bassani, Elena Jachetti, Giuseppina Calareso, Valeria Duroni, Settimio Di Gregorio, Claudia Proto, Arsela Prelaj, Alessandro De Toma, Mario Occhipinti, Marta Brambilla, Sara Manglaviti, Laura Mazzeo, Arturo Rinaldi, Teresa Beninato, Monica Ganzinelli, Filippo De Braud, Marina Chiara Garassino, Paolo Verderio, Mario Paolo Colombo, and Sabina Sangaletti
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Cancer Research ,Oncology - Abstract
Background: Hyperprogressive disease (HPD) has been described in ≃14-25% of pretreated non-small cell lung cancer (NSCLC) patients upon single-agent (SA) PD-1/PD-L1 inhibitors (ICI) and has not been reported upon platinum-based chemotherapy (PCT) and ICI combinations. So far, no predictive biomarkers are available for HPD early detection. Methods: NSCLC patients treated with 1st line SA-ICI or PCT-ICI were assessed for HPD and circulating neutrophils. HPD was defined as delta tumor growth rate (TGR) >50% and/or TGR ratio ≥2. Circulating low density neutrophils (LDNs) were assessed by flow cytometry on peripheral blood mononuclear cells (PMBCs). LDNs were defined as CD66b+CD15+ cells among CD11b+ PBMCs and immature subtypes as CD10− LDNs. The LDNs predictive role was assessed by penalized model-based tests. Results: 144 NSCLC patients were included: 75 treated with SA-ICI, 69 with PCT-ICI. In the SA-ICI cohort, HPD occurred in 8 (11%) patients, while progressive disease (PD) and response or stable disease (PR/SD) occurred in 33 (44%) and 34 (45%) of patients respectively. Immature circulating CD10− LDNs were significantly higher in baseline blood samples of HPD patients [median (ME): 39.3, interquartile range (IQR): 28.7] compared to PD [ME: 7.4, IQR: 14.9, p Conclusions: Baseline circulating immature neutrophils characterize HPD upon 1st line SA-ICI and a 30.5% cut-off of immature neutrophils could select NSCLC patients to be addressed to PCT-ICI combinations. Citation Format: Roberto Ferrara, Giuseppe Lo Russo, Chiara Maura Ciniselli, Annamaria Piva, Barbara Bassani, Elena Jachetti, Giuseppina Calareso, Valeria Duroni, Settimio Di Gregorio, Claudia Proto, Arsela Prelaj, Alessandro De Toma, Mario Occhipinti, Marta Brambilla, Sara Manglaviti, Laura Mazzeo, Arturo Rinaldi, Teresa Beninato, Monica Ganzinelli, Filippo De Braud, Marina Chiara Garassino, Paolo Verderio, Mario Paolo Colombo, Sabina Sangaletti. Circulating immature neutrophils early detect hyperprogressive disease upon first-line PD-1/PD-L1 inhibitors in non-small cell lung cancer patients selecting best candidates for platinum-based chemotherapy and PD-1/PD-L1 inhibitors combinations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5506.
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- 2023
13. Prognostic role of neutrophil-to-lymphocyte ratio and EPSILoN score in advanced non-small-cell lung cancer patients treated with first-line chemo-immunotherapy
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Emma Zattarin, Sara Manglaviti, Giulia Apollonio, Teresa Beninato, Laura Mazzeo, Giacomo Massa, Achille Bottiglieri, Edoardogregorio Galli, Alessandro De Toma, Mario Occhipinti, Marta Brambilla, Roberto Ferrara, Monica Ganzinelli, Claudia Proto, Marina Chiara Garassino, Filippo de Braud, Giuseppe Lo Russo, and Arsela Prelaj
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Cancer Research ,Lung Neoplasms ,Neutrophils ,Carcinoma ,General Medicine ,first-line setting ,Prognosis ,prognostic score ,EPSILoN score ,Oncology ,neutrophil-to-lymphocyte ratio ,advanced non-small-cell lung cancer ,Carcinoma, Non-Small-Cell Lung ,Humans ,chemo-immunotherapy ,Immunotherapy ,Lymphocytes ,Non-Small-Cell Lung ,Biomarkers ,Retrospective Studies - Abstract
Patients affected by inoperable lung cancer, due to great extension or to the presence of metastases, are currently treated with intravenous drugs that act on immune system activation alone or in combination with chemotherapy as first-line treatment. The characteristics of these patients (both their medical history and their blood exams) need to be studied to find out if some of them can help clinicians to predict if they will benefit from the combination of immunotherapy with chemotherapy. The authors collected the data of patients with advanced lung cancer treated in their hospital and found out that a value calculated from their blood exams, collected before the start of treatment and a combination of values named EPSILoN score (which considers patients' clinical condition, their history of tobacco smoking, the presence of metastases in the liver and two blood exam parameters, namely the neutrophil-to-lymphocyte ratio and LDH level) can predict how their disease will evolve during first-line treatment with chemotherapy in combination with immunotherapy.
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- 2022
14. Immunotherapy and chemo-immunotherapy for non–small cell lung cancer with novel actionable oncogenic driver alterations
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Laura Mazzeo, Teresa Beninato, Chiara Carlotta Pircher, Marta Brambilla, Sara Manglaviti, Alessandro De Toma, Giulia Galli, Arsela Prelaj, Roberto Ferrara, Claudia Proto, Giuseppe Lo Russo, Monica Ganzinelli, Marina Chiara Garassino, Paolo Marchetti, Filippo G. De Braud, and Mario Occhipinti
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Cancer Research ,Oncology - Abstract
9057 Background: Immune checkpoint inhibitors (IO) single agent or in combination with platinum chemotherapy (CT-IO) are standard of care for Stage IV non-small cell lung cancer (NSCLC) according to PD-L1 expression. While the efficacy of IO among patients (pts) with common EGFR and ALK alterations appears to be limited, its activity in pts with novel oncogenic drivers alterations is not well characterized. Compared to non-oncogene-addicted NSCLC, the overall response rate (ORR) seems to be similar in BRAF and c-MET altered NSCLC, lower in RET altered NSCLC, while data are less consistent in HER2 and EGFR exon 20 (EGFRex20) altered NSCLCs. Methods: From January 2016 to January 2022, we retrospectively enrolled pts with Stage IV NSCLC that received IO or combination CT– IO in any line, ECOG PS 0 - 2 and detection of MET exon 14 skipping mutations (METex14), BRAF mutations (V600E or non-V600E), RET rearrangement, HER2 point mutations (HER2mut)/exon 20 insertions (HER2ex20) or uncommon EGFR mutations (uEGFRmut)/EGFRex20. A review of clinicopathologic and molecular features and an analysis of response to combination or single-agent IO were conducted. Results: Among sixty-four pts enrolled, 20 (31%) had METex14, 19 (30%) had EGFR alterations [12 (19%) EGFRex20, 7 (11%) uEGFRmut], 8 (12%) had BRAF mutation (3 V600E and 5 non-V600E), 13(20%) had HER2 alterations [7 (11%) HER2ex20, 6 (10%) HER2mut] and 4 (6%) were RET rearranged. 43 received IO single agent and 21 received CT-IO. With a median follow up of 22 months (m), median progression free survival (mPFS) was 5.40 m (0.95 CI 4.73-6.9) overall, 6.77m in CT-IO arm (0.95 CI 5.37-NA) and 5.10m in IO arm (0.95 CI 2.60-6.7), with a trend to better mPFS for CT-IO (p 0.054). Regarding specific mutations irrespectively from treatment arm, NSCLC harboring METex14 showed a mPFS of 5.33 m (0.95 CI, 2.30-13.9), BRAF 9.9 m (0.95 CI, 6.70-NA), EGFR 4.93 m (0.95 CI, 1.80-6.9), HER2 11.4 (0.95 CI, 4.2-NA), RET 5.28 (0.95 CI, 1.42-NA). Disease control rate (DCR) was better in the CT-IO arm vs IO one in the overall population (84.2% vs 50%, p 0.013). Conclusions: Novel driver alterations seem to show a benefit from IO treatments. CT-IO seems to have a better outcome in terms of DCR. Therefore, IO-based treatment should be evaluated also in tumors harboring novel driver alterations. [Table: see text]
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- 2022
15. Immune-Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer With Uncommon Histology
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Emma Zattarin, Giuseppe Viscardi, Elisa Sottotetti, A. Prelaj, Marta Brambilla, Giulia Galli, Riccardo Lobefaro, Monica Ganzinelli, Claudia Proto, Roberto Ferrara, Rosa Maria Di Mauro, Sara Manglaviti, Diego Signorelli, Marta Bini, Mario Occhipinti, Giuseppe Lo Russo, Giulia Apollonio, Giacomo Massa, Teresa Beninato, Filippo de Braud, Alessandra Fabbri, A. Bottiglieri, M.C. Garassino, Alessandro De Toma, and Benedetta Trevisan
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Pulmonary and Respiratory Medicine ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Adenosquamous carcinoma ,medicine.medical_treatment ,Population ,Uncommon NSCLC ,Kaplan-Meier Estimate ,Gastroenterology ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,80 and over ,Humans ,ICIs ,education ,Sarcomatoid carcinoma ,Lung cancer ,Non-Small-Cell Lung ,Immune Checkpoint Inhibitors ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Aged, 80 and over ,education.field_of_study ,business.industry ,Not Otherwise Specified ,Carcinoma ,Histology ,Immunotherapy ,Middle Aged ,medicine.disease ,Survival Analysis ,immunotherapy ,lung cancer ,rare histology ,uncommon NSCLC ,Rare histology ,Oncology ,Adenocarcinoma ,Female ,business - Abstract
Immune-checkpoint inhibitors (ICIs) have significantly improved outcome of advanced non-small cell lung cancer (aNSCLC) patients. However, their efficacy remains uncertain in uncommon histologies (UH).Data from ICI treated aNSCLC patients (April,2013-January,2021) in one Institution were retrospectively collected. Univariate and multivariate survival analyses were estimated by Kaplan-Meier and Cox proportional hazards regression model, respectively. Objective response rate (ORR) and disease control rate (DCR) were assessed.Of 375 patients, 79 (21.1%) had UH: 19 (24.1%) sarcomatoid carcinoma, 15 (19.0%) mucinous adenocarcinoma, 10 (12.6%) enteric adenocarcinoma, 8 (10.1%) adenocarcinoma not otherwise specified, 7 (8.9%) large-cell neuroendocrine carcinoma, 6 (7.6%) mixed histology non-adenosquamous, 5 (6.3%) adenosquamous carcinoma, 9 (11.4%) other UH. In UH group, programmed death-ligand 1 (PD-L1)1%, 1-49%, ≥50% and unknown expression were reported in 27.8%, 22.8%, 31.7% and 17.7% patients respectively and ICI was the second/further-line in the majority of patients. After a median follow-up of 35.64 months (m), median progression-free survival (mPFS) was 2.5 m in UH [95% CI 2.2-2.9 m] versus (vs.) 2.7 m in CH [95% CI 2.3-3.2 m, P-value = .584]; median overall survival (mOS) was 8.8 m [95% CI 4.9-12.6 m] vs. 9.7 m [95% CI 8.0-11.3 m, P-value = .653]. At multivariate analyses only ECOG PS was a confirmed prognostic factor in UH. ORR and DCR were 25.3% and 40.5% in UH vs. 21.6% and 49.5% in CH [P-value = .493 and .155 respectively].No significant differences were detected between UH and CH groups. Prospective trials are needed to understand ICIs role in UH population.
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- 2022
16. Anthracycline-based and gemcitabine-based chemotherapy in the adjuvant setting for stage I uterine leiomyosarcoma: a retrospective analysis at two reference centers
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Sara Manglaviti, Nicoletta Colombo, Carlo Morosi, Roberta Sanfilippo, Rossella Bertulli, Elena Fumagalli, R. Mancari, Paola Collini, Francesco Raspagliesi, Paolo G. Casali, Chiara Fabbroni, Giorgio Bogani, and Giovanni Fucà
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Anthracycline ,medicine.medical_treatment ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Surgical oncology ,Internal medicine ,Uterine leiomyosarcoma ,Medicine ,Chemotherapy ,business.industry ,Research ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Gemcitabine ,Adjuvant chemotherapy ,Regimen ,030104 developmental biology ,030220 oncology & carcinogenesis ,business ,Adjuvant ,Cohort study ,medicine.drug - Abstract
Background Radically resected early uterine leiomyosarcoma (eULMS) is still marked by a poor prognosis. Adjuvant strategies investigated up to now have not been corroborated by controlled studies. We retrospectively reviewed the clinical outcome of eULMS patients treated with adjuvant anthracycline-based or gemcitabine-based chemotherapy at two Italian reference centers. Methods In this explorative, retrospective, cohort analysis, we included all the consecutive patients with radically resected eULMS treated at two centers between 1997 and 2017. Results A total of 109 consecutive patients were included. Sixty-six (60%) received an anthracycline-based regimen, whereas 43 (40%) received a gemcitabine-based regimen. Median disease-free survival (DFS) was 41.3 months with anthracycline-based regimens compared to 20.9 months with gemcitabine-based regimens (HR: 0.49; 95% CI: 0.30–0.80; P = 0.004). In the multivariable model, anthracycline-based regimens were independently associated with a better DFS. No difference in terms of overall survival was observed. Conclusions DFS was not the same by using an anthracycline-based or a gemcitabine-based adjuvant chemotherapy for patients with radically resected eULMS. The results of our study are in line with recent prospective controlled evidence in limb and superficial trunk soft tissue sarcomas. The role of anthracycline-based adjuvant chemotherapy should still be viewed as a research issue in eULMS.
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- 2020
17. One size does not fit all for pancreatic cancers: A review on rare histologies and therapeutic approaches
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Melissa Anna Teresa Monica, Sara Pusceddu, Sara Manglaviti, Federico Nichetti, Filippo de Braud, Vincenzo Mazzaferro, Natalie Prinzi, Maria Di Bartolomeo, Marta Brambilla, Martina Torchio, Monica Niger, Jorgelina Coppa, Maria Antista, Laura Cattaneo, Francesca Corti, and Michele Prisciandaro
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Oncology ,Pancreatoblastoma ,medicine.medical_specialty ,Pancreatic acinar cell cancer ,business.industry ,Gastroenterology ,Review ,medicine.disease ,Pancreatic adenosquamous cancer ,Pseudopapillary pancreatic cancer ,03 medical and health sciences ,0302 clinical medicine ,Rare pancreatic cancers ,Undifferentiated pancreatic cancer ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,030211 gastroenterology & hepatology ,business - Abstract
Exocrine pancreatic neoplasms represent up to 95% of pancreatic cancers (PCs) and are widely recognized among the most lethal solid cancers, with a very poor 5-year survival rate of 5%-10%. The remaining < 5% of PCs are neuroendocrine tumors that are usually characterized by a better prognosis, with a median overall survival of 3.6 years. The most common type of PC is pancreatic ductal adenocarcinoma (PDAC), which accounts for roughly 85% of all exocrine PCs. However up to 10% of exocrine PCs have rare histotypes, which are still poorly understood. These subtypes can be distinguished from PDAC in terms of pathology, imaging, clinical presentation and prognosis. Additionally, due to their rarity, any knowledge regarding these specific histotypes is mostly based on case reports and a small series of retrospective analyses. Therefore, treatment strategies are generally deduced from those used for PDAC, even if these patients are often excluded or not clearly represented in clinical trials for PDAC. For these reasons, it is essential to collect as much information as possible on the management of PC, as assimilating it with PDAC may lead to the potential mistreatment of these patients. Here, we report the most significant literature regarding the epidemiology, typical presentation, possible treatment strategies, and prognosis of the most relevant histotypes among rare PCs.
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- 2020
18. Machine Learning to Improve Treatment Selection for NSCLC Patients Treated with Immunotherapy using Real World and Translational Data
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Arsela Prelaj, Alessandra Pedrocchi, Gabriella Sozzi, Rosaria Gallucci, A. Bottiglieri, Monica Ganzinelli, Filippo de Braud, Edoardogregorio Galli, Giuseppe Lo Russo, Roberto Ferrara, Giulia Galli, Mario Occhipinti, Alessandro Robuschi, Teresa Beninato, Claudia Proto, Alessandro De Toma, Marcello Restelli, Giacomo Massa, Mattia Boeri, Marina Chiara Garassino, Emma Zattarin, Francesco Trovò, Sara Manglaviti, and Marta Brambilla
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Computer science ,business.industry ,medicine.medical_treatment ,medicine ,Immunotherapy ,Artificial intelligence ,Machine learning ,computer.software_genre ,business ,computer ,Selection (genetic algorithm) - Abstract
Introduction: In advanced Non-Small Cell Lung Cancer (NSCLC), Programmed Death Ligand 1 (PD-L1) remains the only used biomarker to candidate patients to immunotherapy (IO) with many limits. Given the complex dynamics of the immune system it is improbable that a single biomarker could be able to profile prediction with high accuracy. A promising solution cope with this complexity is provided by Artificial Intelligence (AI) and Machine Learning (ML), which are techniques able to analyse and interpret big multifactorial data. The present study aims at using AI tools to improve response and efficacy prediction in NSCLC patients treated with IO.MethodsReal world data (clinical data, PD-L1, histology, molecular, lab tests) and the blood microRNA signature classifier (MSC), which include 24 different microRNAs, were used. Patients were divided into responders (R), who obtained a complete or partial response or stable disease as best response, and non-responders (NR), who experienced progressive or hyperprogressive disease and those who died before the first radiologic evaluation. Moreover, we used the same data to determine if the overall survival of the patients was likely to be shorter or longer than 24 months from baseline IO. For A literature review and forward feature selection technique was used to extract a specific subset of the patients’ data. To develop the final predictive model, different ML methods have been tested, i.e., Feedforward Neural Network (FFNN), Logistic Regression (LR), K-nearest neighbours (K-NN), Support Vector Machines (SVM), and Random Forest (RF).Results 200 patients were included. 164 out of 200 (i.e., only those patients with PD-L1 data available) were considered in the model, 73 (44.5%) were R and 91 (55.5%) NR. Overall, the best model was the LR and included 5 features: 2 clinical features including the ECOG performance status and IO-line of therapy; 1 tissue feature such as PD-L1 tumour expression; and 2 blood features including the MSC test and the neutrophil-to-lymphocyte ratio (NLR). The model predicting R/NR of the patient achieves accuracy ACC= 0.756, F1 score F1=0.722, and Area Under the ROC Curve AUC=0.82. The use of the PD-L1 alone has an ACC=0.655. The accuracy of the ML models excluding some of the features from the model were as follow: without PD-L1 value (ACC=0.726), MSC (ACC=0.750), and both PD-L1 and MSC (ACC=0.707), i.e., considering only clinical features. At data cut-off (Nov 2020), median Overall Survival (mOS) for R was 38.5 months (m) (95%IC 23.9 - 53.1) vs 3.8 m (95%IC 2.8 - 4.7) for NR, with pConclusionsThe results suggest that the integration of multifactorial data provided by ML techniques is a useful tool to improve personalized selection of NSCLC patients candidates to IO. In particular, compared to PD-L1 alone the expected improvement was around 10%. In particular, the model shows that the higher the ECOG, NLR value, IO-line, and MSC test level the lower the response, and the higher PD-L1 the higher the response. Considering the difference in survival among R and NR groups, these results suggest that the model can also be used to indirectly predict survival. Moreover, a second model was able to predict long survival patients with good accuracy.
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- 2021
19. 15 First-line platinum-based chemotherapy combined with PD-1/PD-L1 inhibitors (ICI) prevents hyperprogression in non-small cell lung cancer (NSCLC) patients by reducing circulating immature neutrophils
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Giuseppina Calareso, Diego Signorelli, Sara Manglaviti, Roberto Ferrara, Mario Occhipinti, Giulia Galli, Mario P. Colombo, Alessandro De Toma, Antonia Martinetti, Claudia Proto, Filippo de Braud, Monica Ganzinelli, Marta Brambilla, Arsela Prelaj, Sabina Sangaletti, Marina Chiara Garassino, Giulia Apollonio, Laura Mazzeo, Giuseppe Lo Russo, and Elena Jachetti
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Pharmacology ,Cancer Research ,Chemotherapy ,biology ,business.industry ,First line ,medicine.medical_treatment ,Immunology ,chemistry.chemical_element ,non-small cell lung cancer (NSCLC) ,medicine.disease ,Oncology ,chemistry ,PD-L1 ,Cancer research ,biology.protein ,Molecular Medicine ,Immunology and Allergy ,Medicine ,business ,Platinum ,Immature neutrophils - Abstract
BackgroundHyperprogression (HPD) has been described in ≃14–26% of NSCLC patients upon single-agent ICI1 and has not been reported upon ICI and platinum-based chemotherapy (PCT) combinations. Both high circulating neutrophils2 and senescent T-cells3 correlated with HPD, however the exact neutrophils-T-cells interplay and the role of specific neutrophils subsets in driving HPD is unknown.MethodsNSCLC patients treated with 1st line ICI as single-agent or in combination with PCT were assessed for HPD and circulating neutrophils’ phenotype. HPD required 3 assessment (2 before ICI, 1 upon ICI) and was defined as delta tumor growth rate (TGR) (TGR upon ICI – TGR before ICI) >50% and/or TGR ratio (TGR upon ICI/TGR before ICI) ≥2. Circulating low density neutrophils (LDNs) subtypes were assessed by flow cytometry on peripheral blood mononuclear cells (PMBCs). LDNs were defined as CD66b+CD15+ cells among CD11b+ PBMCs. Immature subtypes were defined as CD10- LDNs. T-cells were isolated from healthy donors and cocultured with patients‘ LDNs to characterize the neutrophils-T-cells interplay. LDNs subtypes were isolated from patients and treated in-vitro with cisplatin to assess cell death.Results46 NSCLC patients were treated with single-agent ICI and 17 with PCT+ICI (table 1). In the ICI single-agent cohort, PD and HPD occurred in 21 (41%) and 4 (9%) patients. Before ICI start, HPD patients had significantly higher median% of circulating immature CD10- LDNs neutrophils [43.5 (min 29.5; max 82.6) vs 10.3 (min 0.1; max 79.4), p=0.01] compared to PD patients (figure 1). In the ICI-PCT cohort no HPD was reported. 5 patients had baseline CD10- LDNs ≥ 43.5% (median% of CD10- LDNs in HPD patients upon single-agent ICI), 2 of them had stable disease and 3 PD upon ICI-PCT. In these 5 patients, CD10- LDNs significantly decreased during ICI-PCT compared to what observed in HPD patients upon single-agent ICI [median variation -43.4 (min -67.6, max -31.6) vs +6.9 (min -33, max +44), p= 0.03] (figure 2). After 7 days of coculture with T-cells, immature CD10- LDNs significantly reduced T-cells survival and promoted a T-cell senescent phenotype (CD28 loss, CD57 gain) impairing T-cells proliferation and increasing IFN-gamma production (figure 3). Cisplatin treatment significantly increased necrotic cell death among CD10- LDNs compared to CD10+ LDNs (figure 4).Abstract 15 Table 1Patients characteristics in the single-agent ICI and PCT+ICI cohortsAbstract 15 Figure 1Patterns of response, progression and hyperprogression to single-agent ICI and correlation with mature (CD10+) or immature (CD10-) LDNs’ subtypesAbstract 15 Figure 2Neutrophils dynamic variation upon treatment (5 patients with high baseline CD10- LDNs and PD/SD to chemo-ICI vs 4 patients with HPD upon single-agent ICI)Abstract 15 Figure 3Mature (CD10+) and immature (CD10-) LDNs in coculture with T-cells from an healthy donor differently influence CD8 and CD4 T-cells survival, proliferation, IFN-gamma production and expression of a senescent (CD28- CD57+) phenotype.Abstract 15 Figure 4Cisplatin in-vitro treatment at different concentration (1 uM and 5 uM) increases necrotic (7AAD expression) cell death preferentially of immature (CD10-) rather than mature (CD10+) LDNsConclusionsHigher baseline immature CD10- LDNs impair T-cell survival and promote T-cell senescence being a circulating biomarker of HPD upon single-agent ICI. The addition of PCT prevents HPD by inducing immature neutrophils cell death.ReferencesFerrara R, Mezquita L, Texier M, Lahmar J, Audigier-Valette C, Tessonnier L, et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with pd-1/pd-l1 inhibitors or with single-agent chemotherapy. JAMA Oncol 2018;4:1543–52. https://doi.org/10.1001/jamaoncol.2018.3676Kim Y, Kim CH, Lee HY, Lee S-H, Kim HS, Lee S, et al. Comprehensive clinical and genetic characterization of hyperprogression based on volumetry in advanced non-small cell lung cancer treated with immune checkpoint inhibitor. J Thorac Oncol 2019;14:1608–18. https://doi.org/10.1016/j.jtho.2019.05.033Ferrara R, Naigeon M, Auclin E, Duchemann B, Cassard L, Jouniaux JM, et al. Circulating T-cell immunosenescence in advanced non-small cell lung cancer patients treated with single agent PD-1/PD-L1 inhibitors or platinum-based chemotherapy. Clin Cancer Res 2020. https://doi.org/10.1158/1078-0432.CCR-20-1420.Ethics ApprovalPatients blood was obtained after signature of informed consent and within an observational prospective study (INT 22_15) approved by local Institutional Ethical Committee.
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- 2021
20. PEOPLE (NTC03447678), a phase II trial of first-line, single-agent pembrolizumab in advanced NSCLC with low PD-L1: Clinical outcomes and association with circulating immune biomarkers
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Giuseppe Lo Russo, Monica Ganzinelli, Francesco Sgambelluri, Francesca Galli, Arsela Prelaj, Sara Manglaviti, Achille Bottiglieri, Rosa Maria Di Mauro, Roberto Ferrara, Andra Diana Dumitrascu, Elisa Sottotetti, Antonia Martinetti, Alessandra Fabbri, Eliana Rulli, Filippo G. De Braud, Valter Torri, Marina Chiara Garassino, Andrea Anichini, Claudia Proto, and Roberta Mortarini
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Cancer Research ,Oncology - Abstract
9033 Background: In advanced NSCLC (aNSCLC) with PD-L1 < 50% chemo-immunotherapy is the standard of care. Although the activity of single agent pembrolizumab was reported, no biomarkers have been identified able to select patients who mostly benefit. The trial aimed to identify immune biomarkers associated with PFS in aNSCLC patients with PD-L1 levels < 50% treated with first-line pembrolizumab. Here we reported for the first time the clinical outcomes of the trial and circulating immune profiling (CIP) biomarkers correlated to PFS. Methods: This phase II trial was conducted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan. Eligible patients were previously untreated stage IIIB-IV NSCLC, EGFR and ALK wild type with PD-L1 < 50%, PS 0-2. PD-L1 was assessed with 22-C3 antibody (Dako). Patients received pembrolizumab 200 mg every 3 weeks until 35 cycles, disease progression or unacceptable toxicity. The primary endpoint was the association of immune biomarkers with PFS. OS, ORR, DCR, DoR and safety were secondary endpoints. CIP was performed by determination of absolute cell counts for 36 innate and adaptive immunity subsets through multiparametric flow cytometry on freshly isolated whole blood samples at baseline. An orthoblique principal components-based clustering approach and multivariable Cox regression model adjusted for clinical variables were used to analyse CIP variables and their correlation with clinical endpoints. Results: From May 2018 to October 2020, of 87 screened, 65 patients were enrolled. The median age was 70.9 years, most patients were male (67.7%), smoker (87.7%), non-squamous (83.1%), PDL1 + (70.8%). 12 patients (18.5%) had PS 2. During a median follow-up of 26.4 months (mo), 51 radiological progressions, 46 deaths and 60 PFS events were observed. The median PFS was 2.9 mo (95%CI 1.8 - 5.6) and the median OS was 12.1 mo (95%CI 8.7 - 17.1). The ORR was 24.1% (2 complete and 12 partial responses), DCR was 53.4% and median DoR was 14.5 mo (95%CI 6.4 - 24.9). Drug related G3-G4 adverse events were: 2 hyponatremia, 2 lipase increased, 1 pneumonitis. Out of 7 CIP clusters identified, 2 were statistically significant at multivariable analysis on 57 patients. Higher baseline counts of 8 subsets within these two clusters were associated with better PFS (HR values range: 0.88-0.98; p values range: 0.001- 0.016). The significant subsets included lymphocytes (cells expressing CD3, or CD19 or CD56, but lacking granulocyte and monocyte markers) and main NK subsets (including CD56dim CD16+, CD56dim CD16- and HLA-DR+ NK cells). Conclusions: This trial confirmed that pembrolizumab as first-line single agent is safe and active also in a subgroup of aNSCLC patients with PD-L1 < 50%. CIP biomarkers can be useful to identify patients with a favourable outcome, thus avoiding the adding toxicity of chemotherapy. Clinical trial information: NTC03447678.
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- 2022
21. PEOPLE (NTC03447678), a phase II trial to test pembrolizumab as first-line treatment in patients with advanced NSCLC with PD-L1 < 50%: A multiomics approach
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Marina Chiara Garassino, Claudia Proto, James M Dolezal, Arsela Prelaj, Luca Agnelli, Tiziana Triulzi, Alessandra Fabbri, Roberto Ferrara, Francesco Sgambelluri, Tommaso Torelli, Silvia Brich, Sara Manglaviti, Andrea Anichini, Roberta Mortarini, Giorgio Trinchieri, Giancarlo Pruneri, Filippo G. De Braud, Valter Torri, Monica Ganzinelli, and Giuseppe Lo Russo
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Cancer Research ,Oncology - Abstract
9051 Background: Chemo-immunotherapy is the standard of care for patients with advanced NSCLC and PD-L1 < 50%. Efficacy has been reported in this setting with single agent pembrolizumab, but no reliable biomarkers yet exist for selecting patients likely to respond to single agent immunotherapy. The aim of this trial was to identify potential new immune biomarkers associated with PFS in NSCLC patients with PD-L1 < 50% treated with first line pembrolizumab. Methods: Advanced EGFR and ALK wild type treatment-naïve NSCLC patients with PD-L1 < 50% were enrolled. Gene expression profile was performed using nCounter PanCancer IO 360 Panel (Nanostring) on baseline tissue. Circulating immune profiling was performed by determination of absolute cell counts with multiparametric flow cytometry on freshly isolated whole blood samples at baseline and at first radiological evaluation. Gut bacterial taxonomic abundance was obtained by shotgun metagenomic sequencing of stool sample at baseline. Pembrolizumab was administered at 200 mg flat dose every 3 weeks until 35 cycles, disease progression or unacceptable toxicity. Omics data was analyzed with sequential univariate Cox Proportional Hazards regression predicting PFS, with Benjamini-Hochberg multiple comparisons correction. Biological features significant with univariate analysis were analyzed with multivariate Least Absolute Shrinkage and Selection Operator (LASSO). Results: From May 2018 to October 2020 65 patients were enrolled. Main characteristics were: male 67.6%, smokers 87.7%, PD-L1 positive 70.8%. Median follow up and PFS were 26.4 and 2.9 months, respectively. Gene expression profile was performed in 48 patients, microbiome in 54 patients and circulating immune profiling in 56 patients at baseline and in 46 patients at first radiologic evaluation. LASSO multivariate analysis with optimal lambda of 0.28 showed high expression levels of IRF9 and COMP genes was associated with an unfavorable PFS (HR 3.03, 1.52 – 6.02, p = 0.08 and HR 1.22, 1.08 – 1.37, corrected p = 0.06, respectively). High expression levels of CD244 (HR 0.74, 0.62- 0.67, p = 0.05), PTPRC (HR 0.55, 0.38 – 0.81, p = 0.098), KLRB1 (HR 0.76, 0.66 – 0.89, p = 0.05) in tissue samples and NK cells/CD56dimCD16+ (HR 0.56, 0.41 – 0.76, p = 0.006) in peripheral blood at baseline and non classical CD14dim CD16+ monocytes (HR 0.52, 0.36 – 0.75, p = 0.004), eosinophils (CD 15+CD16-) (HR 0.62, 0.44 – 0.89, p = 0.003) lymphocytes (HR 0.28, 0.15 – 0.5, p < 0.001) in peripheral blood after first radiologic evaluation were associated to a favorable PFS. No microbiome features were selected by LASSO. Conclusions: To the best of our knowledge, this is the first prospective trial in NSCLC with PD-L1 < 50% performed with a multi-omic approach able to identify immune cell subsets and expression levels of genes associated to PFS under first line treatment with pembrolizumab. Clinical trial information: NTC03447678.
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- 2022
22. 1236P Poziotinib in NSCLC harbouring EGFR or HER2 exon 20 insertion mutation
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Sara Manglaviti, Emma Zattarin, Rosaria Gallucci, Claudia Proto, Roberto Ferrara, A. De Toma, Teresa Beninato, Arsela Prelaj, Giulia Galli, M.C. Garassino, Giulia Apollonio, Valter Torri, E. Galli, Monica Ganzinelli, A. Bottiglieri, Marta Brambilla, G. Lo Russo, R. Di Mauro, F. de Braud, and M. Occhipinti
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Exon ,Oncology ,business.industry ,Cancer research ,Poziotinib ,Medicine ,Hematology ,Insertion ,business - Published
- 2021
23. Poziotinib for EGFR and HER2 exon 20 insertion mutation in advanced NSCLC: Results from the expanded access program
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A. Bottiglieri, Federico Nichetti, Alessandro De Toma, Claudia Proto, Gabriella Francesca Greco, Riccardo Lobefaro, Rosaria Gallucci, Mario Occhipinti, Marina Chiara Garassino, A. Prelaj, Giulia Galli, Roberto Ferrara, Monica Ganzinelli, Alice Labianca, Filippo de Braud, Sara Manglaviti, Giuseppe Viscardi, Marta Brambilla, Valter Torri, Giuseppe Lo Russo, Nicoletta Zilembo, and Diego Signorelli
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Adult ,Compassionate Use Trials ,Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Time Factors ,Receptor, ErbB-2 ,EGFR ,Antineoplastic Agents ,Exon 20 insertion mutation ,NSCLC ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,HER2 ,medicine ,Mucositis ,Humans ,Progression-free survival ,exon 20 insertion mutation ,poziotinib ,Lung cancer ,Protein Kinase Inhibitors ,Aged ,Pneumonitis ,Aged, 80 and over ,business.industry ,Poziotinib ,Exons ,Middle Aged ,medicine.disease ,Rash ,Progression-Free Survival ,ErbB Receptors ,Mutagenesis, Insertional ,030104 developmental biology ,030220 oncology & carcinogenesis ,Expanded access ,Toxicity ,Disease Progression ,Quinazolines ,Female ,medicine.symptom ,business - Abstract
Background The treatment of metastatic non–small-cell lung cancer (mNSCLC) patients with EGFR/HER2 exon 20 insertion mutation (i-mut) remains an unmet clinical need. Poziotinib, a new generation tyrosine kinase inhibitor, is currently under investigation as a potential targeted therapy. This compassionate study of its use aims to describe the activity/toxicity of poziotinib in mNSCLC with EGFR/HER2-exon-20-i-mut. Patients and methods NSCLC patients who were treated either with EGFR or HER2 exon 20-i-mut within an expanded access program were included in this study. Poziotinib (16 mg or less) was administrated orally quaque die (QD). The primary end-point was the overall response rate (ORR) assessed by central review using RECIST v1.1, and secondary end-points were median progression free survival (PFS), disease control rate (DCR), median overall survival (OS) and toxicity. Results The median age of all the 30 patients was 58 years (25–80 years), most of them were females (73%); ECOG 0–1 (83%), EGFR i-mut (73%) and pre-treated (83%). 73% started with poziotinib at a dose of 16 mg. At data cut-off, 22 of 33 patients (73%) experienced a progress in the disease and 12 of 30 (40%) died. Median PFS was 5.6 months (95% CI: 3.6–6.7 months) and the mOS 9.5 months (95% CI: 5.3 – not-reached months). The ORR was 30% (EGFR/HER2: 23/50%) and DCR 80%. G3 AEs were reported in 66% of the patients and were found with skin rash (50%), diarrhoea (17.6%), mucositis (7%) and paronychia (3%). G5, possibly associated with pneumonitis might also have occurred. Conclusions Poziotinib exhibited effects in mNSCLC patients with EGFR/HER2-exon 20-i-mut. The toxicity rate was high leading to frequent dose interruption and reduction, thereby reducing mPFS in patients with good ORR/DCR. ZENITH20 trial is now being used to evaluate the low dose and new scheduled dose (e.g. bis in die (BID)).
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- 2021
24. 1311P The role of inflammatory biomarkers in advanced non-small cell lung cancer patients treated with chemo-immunotherapy
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Sara Manglaviti, Claudia Proto, Giulia Galli, Laura Mazzeo, Mario Occhipinti, Monica Ganzinelli, F. de Braud, Giacomo Massa, Giulia Apollonio, Roberto Ferrara, A. De Toma, Elena Galli, Emma Zattarin, A. Prelaj, Marta Brambilla, G. Lo Russo, Teresa Beninato, A. Bottiglieri, and M.C. Garassino
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Oncology ,business.industry ,Cancer research ,Medicine ,Hematology ,Non small cell ,business ,Lung cancer ,medicine.disease ,Inflammatory biomarkers ,Chemo immunotherapy - Published
- 2021
25. Is hyperprogressive disease a specific phenomenom of immunotherapy?
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Roberto Ferrara, Mario Occhipinti, Giuseppe Lo Russo, Sara Manglaviti, Marta Brambilla, and Marina Chiara Garassino
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0301 basic medicine ,Oncology ,lcsh:Internal medicine ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Cancer therapy ,Tumor therapy ,Immunotherapy ,Disease ,hyperprogressive disease ,03 medical and health sciences ,chemotherapy-immunotherapy ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,immunotherapy ,medicine ,lcsh:RC31-1245 ,business - Abstract
Hyperprogressive disease (HPD) is a novel pattern of response during immunotherapy treatment. Several retrospective studies have evaluated its prevalence among various cancer types and, in particular, in nonsmall cell lung cancer patients, based on different definition criteria. If HPD is a just a typical phenomenon of immunotherapy is still an unsolved concern. This paper summarized the available data about HPD in other cancer treatments. Hyperprogressive disease (HPD) is a novel pattern of response during immunotherapy treatment. Several retrospective studies have evaluated its prevalence among various cancer types and, in particular, in non-small cell lung cancer patients, based on different definition criteria. If HPD is a just a typical phenomenon of immunotherapy is still an unsolved concern. This paper summarized the available data about HPD in other cancer treatments.
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- 2020
26. 133P Drug-drug interactions (DDIs) in non-small cell lung cancer during chemotherapy-immunotherapy treatment
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Claudia Proto, Giulia Galli, Marta Brambilla, M. Occhipinti, G. Lo Russo, Arsela Prelaj, Alain Gelibter, Sara Manglaviti, Roberto Ferrara, Teresa Beninato, A. De Toma, Piero Marchetti, Maurizio Simmaco, Emma Zattarin, and Marina Chiara Garassino
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Pulmonary and Respiratory Medicine ,Drug ,Oncology ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,media_common.quotation_subject ,Immunotherapy ,medicine.disease ,Internal medicine ,medicine ,Non small cell ,business ,Lung cancer ,media_common - Published
- 2021
27. Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications
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Sara Manglaviti, Filippo de Braud, Giuseppe Capri, Carmen G. Rea, Claudio Vernieri, Giulia Bianchi, Francesca Ligorio, Federico Nichetti, Francesca Corti, and Emma Zattarin
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Oncology ,Receptor, ErbB-2 ,Review ,PI3K ,Alpelisib ,chemistry.chemical_compound ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Exemestane ,Surgical oncology ,Antineoplastic Combined Chemotherapy Protocols ,Multicenter Studies as Topic ,Prospective Studies ,Efficacy comparisons ,Neoplasm Metastasis ,mTORC1 ,Randomized Controlled Trials as Topic ,0303 health sciences ,Clinical Trials as Topic ,Hormone receptor-positive breast cancer ,Standard treatment ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Metastatic breast cancer ,Treatment Outcome ,030220 oncology & carcinogenesis ,Advanced breast cancer ,Female ,PIK3CA mutations ,Patient Safety ,medicine.drug ,Endocrine therapy ,medicine.medical_specialty ,Breast Neoplasms ,Mechanistic Target of Rapamycin Complex 1 ,lcsh:RC254-282 ,03 medical and health sciences ,Breast cancer ,Internal medicine ,medicine ,Humans ,Everolimus ,Adverse effect ,neoplasms ,030304 developmental biology ,Retrospective Studies ,Fulvestrant ,business.industry ,medicine.disease ,Androstadienes ,chemistry ,business ,Proto-Oncogene Proteins c-akt - Abstract
Background The PI3K/AKT/mTORC1 axis is implicated in hormone receptor-positive HER2-negative metastatic breast cancer (HR+ HER2− mBC) resistance to anti-estrogen treatments. Based on results of the BOLERO-2 trial, the mTORC1 inhibitor everolimus in combination with the steroidal aromatase inhibitor (AI) exemestane has become a standard treatment for patients with HR+ HER2− mBC resistant to prior non-steroidal AI therapy. In the recent SOLAR-1 trial, the inhibitor of the PI3K alpha subunit (p110α) alpelisib in combination with fulvestrant prolonged progression-free survival (PFS) when compared to fulvestrant alone in patients with PIK3CA-mutated HR+ HER2− mBC that progressed after/on previous AI treatment. Therefore, two different molecules targeting the PI3K/AKT/mTORC1 axis, namely everolimus and alpelisib, are available for patients progressing on/after previous AI treatment, but it is unclear how to optimize their use in the clinical practice. Main body of the abstract Here, we reviewed the available clinical evidence deriving from the BOLERO-2 and SOLAR-1 trials to compare efficacy and safety profiles of everolimus and alpelisib in advanced HR+ HER2− BC treatment. Adding either compound to standard endocrine therapy provided similar absolute and relative PFS advantage. In the SOLAR-1 trial, a 76% incidence of grade (G) 3 or 4 (G3/G4) adverse events was reported, while G3/G4 toxicities occurred in 42% of patients in the BOLERO-2 trial. While alpelisib was only effective in patients with PIK3CA-mutated neoplasms, retrospective analyses indicate that everolimus improves exemestane efficacy independently of PIK3CA mutational status. Conclusions Based on the available efficacy and safety data, the “new” alpelisib may be burdened by higher incidence of severe adverse events, higher costs, and anticancer efficacy that is limited to PIK3CA-mutated tumors when compared to the “old” everolimus. Therefore, the everolimus-exemestane combination remains an effective and reasonably well-tolerated therapeutic option for HR+ HER2− mBC patients progressing after/on previous AI treatment, independently of PIK3CA mutational status.
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- 2020
28. Oral Capecitabine-Vinorelbine is Associated with Longer Overall Survival When Compared to Single-Agent Capecitabine in Patients with Hormone Receptor-Positive Advanced Breast Cancer
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Francesca Ligorio, Gabriella Mariani, Sara Manglaviti, Federico Nichetti, Marta Brambilla, Luigi Celio, Emma Zattarin, Barbara Re, Antonino Belfiore, Riccardo Lobefaro, Maria Silvia Cona, Francesca Corti, Giorgia Peverelli, Pierangela Sepe, Michele Prisciandaro, Filippo de Braud, Giulia Bianchi, Giuseppe Capri, Claudio Vernieri, Licia Rivoltini, and Giancarlo Pruneri
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Cancer Research ,medicine.medical_specialty ,overall survival ,Vinorelbine ,chemotherapy ,Gastroenterology ,lcsh:RC254-282 ,Article ,Capecitabine ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,030212 general & internal medicine ,Progression-free survival ,Prospective cohort study ,Adverse effect ,Triple-negative breast cancer ,advanced breast cancer ,hormone receptor-positive breast cancer ,business.industry ,capecitabine ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Metastatic breast cancer ,adverse events ,vinorelbine ,Oncology ,Tolerability ,030220 oncology & carcinogenesis ,triple-negative breast cancer ,business ,progression-free survival ,medicine.drug - Abstract
Background: Single-agent capecitabine (C) is a moderately effective chemotherapeutic compound in the treatment of patients with HER2-negative metastatic breast cancer (mBC). The capecitabine-vinorelbine (CV) combination is also used due to a good tolerability profile, but no studies have demonstrated its superiority over single-agent C. Methods: We conducted a retrospective analysis to compare overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and incidence of adverse events (AEs) in patients with HER2-negative mBC treated with CV vs. single-agent C. Results: Out of 290 patients included in this study, 127 (43.8%) received single-agent C, while 163 (56.2%) patients were treated with CV. Median PFS was similar in patients treated with single-agent C or CV, while CV was associated with significantly longer OS in patients with hormone receptor-positive (HR+) BC. This OS advantage was confirmed at multivariable analysis also after propensity score-based matching of patients according to relevant clinical or tumor characteristics. When compared with single-agent C, CV was associated with higher incidence of G3/G4 and any-grade nausea/vomiting, diarrhea and increased transaminases. Conclusions: While prospective studies are needed to confirm our findings, the potential OS advantage of CV over single-agent C in HR+ mBC patients must be weighed against a significantly higher incidence of AEs.
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- 2020
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29. 1388P Poziotinib in advanced NSCLC with EGFR or HER2 exon 20 insertion mutation: Initial results from a single site expanded access program
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Marina Chiara Garassino, Francesca Greco, Claudia Proto, M. Occhipinti, A. Bottiglieri, Giulia Galli, Giuliano Molino, Arsela Prelaj, Riccardo Lobefaro, Marta Brambilla, G. Lo Russo, Diego Signorelli, Nicoletta Zilembo, Roberto Ferrara, Alice Labianca, Rosaria Gallucci, A. De Toma, Sara Manglaviti, Giuseppe Viscardi, and Valter Torri
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Exon ,Oncology ,business.industry ,Single site ,Expanded access ,Cancer research ,Medicine ,Poziotinib ,Hematology ,Insertion ,business - Published
- 2020
30. Retreatment With Anti-EGFR Antibodies in Metastatic Colorectal Cancer Patients: A Multi-institutional Analysis
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Alessandra Boccaccino, Chiara Cremolini, Michele Prisciandaro, Maria Bensi, Alfredo Falcone, Marco Maria Germani, Filippo Pagani, Daniele Rossini, Marta Schirripa, Roberto Moretto, Nicole Liscia, Mario Scartozzi, Daniele Santini, Filippo Pietrantonio, Raffaella Vivolo, Antonio Pellino, Sara Manglaviti, Lisa Salvatore, Fotios Loupakis, and Emanuela Dell'Aquila
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Oncology ,Male ,Colorectal cancer ,Disease ,0302 clinical medicine ,Stable Disease ,Antineoplastic Agents, Immunological ,Antineoplastic Combined Chemotherapy Protocols ,Aged, 80 and over ,biology ,Gastroenterology ,Middle Aged ,Prognosis ,Progression-Free Survival ,ErbB Receptors ,Prior Therapy ,Italy ,030220 oncology & carcinogenesis ,Retreatment ,030211 gastroenterology & hepatology ,Female ,Antibody ,Chemorefractory metastatic colorectal cancer ,Circulating tumor DNA ,Liquid biopsy ,Rechallenge ,Resistance and sensitivity to anti-EGFR ,Colorectal Neoplasms ,Adult ,medicine.medical_specialty ,Clinical Decision-Making ,Disease-Free Survival ,03 medical and health sciences ,Young Adult ,Internal medicine ,medicine ,Humans ,Response Evaluation Criteria in Solid Tumors ,Aged ,Retrospective Studies ,business.industry ,Patient Selection ,Reproducibility of Results ,medicine.disease ,Regimen ,Drug Resistance, Neoplasm ,biology.protein ,Feasibility Studies ,business ,Progressive disease - Abstract
Background On the basis of retrospective analyses and phase 2 studies, metastatic colorectal cancer patients whose disease responded to a first-line regimen containing an anti–epidermal growth factor receptor (EGFR) agent may experience benefit from anti-EGFR readministration in later therapy lines. While the analysis of circulating tumor DNA seems a promising tool to select the best candidates for this strategy, identifying clinical predictors of anti-EGFR sensitivity would be useful to drive treatment choices in daily practice. Patients and Methods A real-life database of 5530 patients treated at 6 institutions was queried. Included were patients who were retreated with anti-EGFRs, who had RAS/BRAF wild-type–status tissue samples, who had received a first-line anti-EGFR–based regimen with at least stable disease as best response, and who had received at least one further line of therapy before anti-EGFR retreatment. The association with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of variables potentially related to anti-EGFR sensitivity was investigated. Results A total of 86 patients were identified. The ORR during anti-EGFR retreatment was 19.8%; median PFS and OS were 3.8 and 10.2 months, respectively. No significant association of clinical features of anti-EGFR sensitivity with ORR, PFS, and OS was observed. Among the 56 patients with a time from the last anti-EGFR administration to first-line progressive disease of 2 prior therapy lines and a longer anti-EGFR–free interval were associated with higher ORR, but not with longer PFS or OS. Conclusion Clinical features we deemed surrogates of anti-EGFR sensitivity were not reliable predictors of benefit from anti-EGFR retreatment.
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- 2019
31. P40.08 Bone-Targeted Agents Improve Survival in High Bone Tumor Burden Advanced Non-Small-Cell-Lung Cancer Patients Treated With PD-(L)1 Inhibitors
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M.C. Garassino, Marta Bini, Giuseppe Viscardi, F. de Braud, Roberto Ferrara, Giulia Apollonio, Mario Occhipinti, Claudia Proto, Sara Manglaviti, Diego Signorelli, A. Prelaj, Monica Ganzinelli, E. Zecca, Laura Mazzeo, Marta Brambilla, G. Lo Russo, Elena Galli, Teresa Beninato, Alice Labianca, Giulia Galli, Emma Zattarin, and A. De Toma
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Tumor burden ,Non small cell ,Lung cancer ,medicine.disease ,business - Published
- 2021
32. P40.19 Efficacy and Toxicity of Third-Line Chemotherapy in Advanced Non-Small Cell Lung Cancer
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Emma Zattarin, Marta Brambilla, G. Lo Russo, M.C. Garassino, Teresa Beninato, Giulia Galli, Claudia Proto, Marta Bini, Elena Galli, F. de Braud, A. Prelaj, A. Bottiglieri, Sara Manglaviti, Monica Ganzinelli, Giacomo Massa, Giulia Apollonio, C. Sposetti, A. De Toma, Roberto Ferrara, and Mario Occhipinti
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Third line chemotherapy ,business.industry ,Internal medicine ,Toxicity ,medicine ,Non small cell ,business ,Lung cancer ,medicine.disease - Published
- 2021
33. 1327P Impact of bone targeted agents (BTA) in advanced non-small cell lung cancer (aNSCLC) patients (pts) with high bone tumor burden (HBTB) treated with PD(L)1 inhibitors (ICIs)
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Emma Zattarin, Marta Bini, E. Zecca, E. Galli, Sara Manglaviti, Alice Labianca, Giulia Apollonio, Roberto Ferrara, A. De Toma, Giulia Galli, Giuseppe Viscardi, Arsela Prelaj, F. de Braud, M.C. Garassino, Claudia Proto, Teresa Beninato, Diego Signorelli, Marta Brambilla, G. Lo Russo, and M. Occhipinti
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Tumor burden ,Hematology ,Non small cell ,Lung cancer ,medicine.disease ,business - Published
- 2021
34. Abstract 1669: Immunometabolism of circulating neutrophils in hyperprogressive disease (HPD) upon first-line PD-1/PD-L1 inhibitors (ICI) alone or in combination with platinum-based chemotherapy (PCT) in non-small cell lung cancer (NSCLC) patients (pts)
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Giuseppe Lo Russo, Roberto Ferrara, Giulia Galli, Mario P. Colombo, Sestina Maria Spanò, Mario Occhipinti, Alessandro De Toma, Claudia Proto, Diego Signorelli, Giuseppina Calareso, Sabrina Sangaletti, Marina Chiara Garassino, Filippo de Braud, Sara Manglaviti, Giuliano Molino, Francesca Greco, Alice Labianca, Elena Jachetti, Marta Brambilla, Antonia Martinetti, Marta Bini, Arsela Prelaj, Monica Ganzinelli, and Teresa Beninato
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Cancer Research ,Chemotherapy ,medicine.medical_specialty ,biology ,medicine.diagnostic_test ,business.industry ,CD3 ,medicine.medical_treatment ,non-small cell lung cancer (NSCLC) ,CD28 ,Cancer ,medicine.disease ,Peripheral blood mononuclear cell ,Gastroenterology ,Flow cytometry ,Oncology ,PD-L1 ,Internal medicine ,medicine ,biology.protein ,business - Abstract
Background: HPD has been described in 14-26% of NSCLC pts upon single agent ICI and correlates with poor survival. Currently, HPD occurrence has not been explored upon ICI-PCT and biomarkers of HPD are lacking. Although high circulating neutrophils (Ns) correlated with HPD in NSCLC pts, the role of specific Ns subsets is unknown. Methods: NSCLC pts treated with 1st line ICI as single agent or in combination with PCT were assessed for HPD and circulating Ns' phenotype. Tumor response was evaluated by RECIST 1.1. HPD required 3 assessment (2 before ICI, 1 upon ICI) and was defined as delta tumor growth rate (TGR) (TGR upon ICI - TGR before ICI) >50% and/or TGR ratio (TGR upon ICI/TGR before ICI) ≥2. Circulating low density Ns (LDNs) subtypes were assessed by flow cytometry (FC) on peripheral blood mononuclear cells (PBMCs). LDNs were defined as CD66b+CD15+ cells among CD11b+ PBMCs. Immature subtypes were defined as CD10- LDNs. Fatty acids (FA) (bodipy-palmitate) uptake was assessed by FC. T-cells of healthy donors were isolated and activated in vitro with CD3/CD28 beads in presence or not of pts' Ns to characterize their interplay. Results: Of 63 NSCLC pts, 22% had PD-L1 on tumor cells ≥50%. In the ICI single agent cohort (N=46), PD and HPD occurred in 21 (41%) and 4 (9%) pts, respectively. Before ICI start, HPD pts had significantly higher median percentage (%) of circulating immature CD10- LDNs [43.5 (min 29.5; max 82.6) vs 10.3 (min 0.1; max 79.4), p=0.01] compared to PD pts. In the ICI-PCT cohort (N=17), PD occurred in 4 (23%) pts, no HPD was reported. 5 pts had baseline CD10- LDNs ≥ 43.5% (median % of CD10- LDNs in HPD pts upon single agent ICI), 2 of them had SD and 3 PD upon ICI-PCT. In these 5 pts, CD10- LDNs significantly decreased during ICI-PCT compared to what observed in HPD pts during single agent ICI [median variation -43.4 (min -67.6, max -31.6) vs +6.9 (min -33, max +44), p= 0.03]. CD10- LDNs did not impair T-cells proliferation and IFNγ production, measured after 7 days of coculture but significantly reduced T-cell survival compared to CD10+LDNs. Baseline metabolic profile assessment showed that immature CD10- LDNs had a predominant lipid metabolism with a higher FA uptake [bodipy-palmitate mean florescence intensity (MFI) ± standard deviation (SD): 46754±11562] compared to lymphocytes [bodipy-palmitate MFI ±SD: 11542±405]. Conclusion: Higher baseline immature CD10- LDNs is a circulating biomarker of HPD upon single agent ICI. The addition of PCT prevents HPD reducing the immature Ns subset. The FA metabolism of immature LDNs does not affect T-cells proliferation/activation but reduces T-cells survival, suggesting that these two processes are differently regulated and that immature Ns reduce T-cells life span by metabolic competition. Citation Format: Roberto Ferrara, Elena Jachetti, Giuseppina Calareso, Marta Brambilla, Giuseppe Lo Russo, Claudia Proto, Arsela Prelaj, Diego Signorelli, Giulia Galli, Alessandro De Toma, Mario Occhipinti, Sara Manglaviti, Alice Labianca, Monica Ganzinelli, Sestina Maria Spanò, Giuliano Molino, Antonia Martinetti, Francesca Gabriella Greco, Marta Bini, Teresa Beninato, Filippo de Braud, Mario Paolo Colombo, Marina Chiara Garassino, Sabrina Sangaletti. Immunometabolism of circulating neutrophils in hyperprogressive disease (HPD) upon first-line PD-1/PD-L1 inhibitors (ICI) alone or in combination with platinum-based chemotherapy (PCT) in non-small cell lung cancer (NSCLC) patients (pts) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1669.
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- 2021
35. Evaluation of Drug—Drug Interactions in EGFR-Mutated Non-Small-Cell Lung Cancer Patients during Treatment with Tyrosine-Kinase Inhibitors
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Claudia Proto, Giulia Galli, Alessandro De Toma, M.C. Garassino, Emma Zattarin, Roberto Ferrara, Sara Manglaviti, Maurizio Simmaco, Marta Brambilla, Mario Occhipinti, Teresa Beninato, A. Prelaj, Maristella Giammaruco, Alain Gelibter, Filippo de Braud, Paolo Marchetti, Giuseppe Lo Russo, and Robert Preissner
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Drug ,Oncology ,medicine.medical_specialty ,Statin ,medicine.drug_class ,EGFR ,media_common.quotation_subject ,tyrosine-kinase inhibitors (EGFR-TKIs) ,non-small-cell lung cancer (NSCLC) ,Medicine (miscellaneous) ,non-small cell lung cancer (NSCLC) ,Article ,03 medical and health sciences ,0302 clinical medicine ,drug–drug interactions (DDI) ,Internal medicine ,medicine ,Lung cancer ,Drug-PIN® ,030304 developmental biology ,media_common ,0303 health sciences ,business.industry ,Cancer ,drug-drug interactions (DDI) ,drug-PIN (R) ,Retrospective cohort study ,medicine.disease ,Concomitant drug ,respiratory tract diseases ,030220 oncology & carcinogenesis ,Concomitant ,Medicine ,business - Abstract
(1) Background. The onset of a drug–drug interaction (DDI) may affect treatment efficacy and toxicity of advanced non-small-cell lung cancer (aNSCLC) patients during epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) use. Here we present the use of Drug-PIN® (Personalized Interactions Network) software to detect DDIs in aNSCLC patients undergoing EGFR-TKIs. (2) Methods. We enrolled patients with Stage IV aNSCLC already treated with or candidates to receive EGFR-TKIs, in any line, ECOG PS 0–2, taking at least one concomitant drug. Cancer treatments, concomitant drugs, and clinical and laboratory data were collected and inserted in Drug-PIN®. (3) Results. Ninety-two patients, median age of 68.5 years (range 43–89), were included. In total, 20 clinically relevant DDIs needing medical intervention in a total of 14 patients were identified, the 14 major DDIs were related to a high-grade interaction between TKIs and SSRIs, antipsychotics, antiepileptics, H2-receptor antagonist and calcium antagonists. A negative association between statin intake and PFS was identified (p = 0.02, HR 0.281, 95% CI 0.096–0.825). (4) Conclusions. This is the first retrospective study assessing the prevalence of DDIs, the clinical need for medical intervention and the impact of concomitant drugs on EGFR-TKIs survival in aNSCLC.
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- 2021
36. 184P Bone-targeted agents (BTA) improve survival in advanced non-small cell lung cancer (aNSCLC) patients (pts) with high bone tumor burden (HBTB) treated with PD-(L)-1 inhibitors (ICIs)
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Monica Ganzinelli, Diego Signorelli, Giulia Galli, F. de Braud, M. Occhipinti, A. De Toma, Claudia Proto, Marina Chiara Garassino, Giuseppe Viscardi, Marta Bini, Sara Manglaviti, Alice Labianca, Arsela Prelaj, E. Zecca, Teresa Beninato, Marta Brambilla, G. Lo Russo, Roberto Ferrara, and Emma Zattarin
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Tumor burden ,Non small cell ,business ,Lung cancer ,medicine.disease - Published
- 2021
37. MGMT methylation in metastatic pancreatic cancer (mPAC): A single center experience
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M. Marcuzzo, M. Di Bartolomeo, Federico Nichetti, Sara Pusceddu, F. de Braud, Giorgia Peverelli, Alessandra Raimondi, Marta Brambilla, Federica Perrone, Michele Prisciandaro, Sara Manglaviti, Filippo Pietrantonio, Giancarlo Pruneri, Martina Torchio, Federica Morano, Filippo Pagani, Elena Tamborini, Maria Antista, and Monica Niger
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Oncology ,medicine.medical_specialty ,Temozolomide ,Formalin fixed paraffin embedded ,business.industry ,O-6-methylguanine-DNA methyltransferase ,Hematology ,Single Center ,Internal medicine ,Metastatic pancreatic cancer ,medicine ,Enhanced sensitivity ,Mgmt methylation ,business ,neoplasms ,Pcr analysis ,medicine.drug - Abstract
Background Metastatic pancreatic cancer (mPAC) is a devastating disease with few therapeutic options. O6-methylguanine-DNA methyltransferase (MGMT) is a key DNA repair gene and there are reports of MGMT alterations in various gastrointestinal cancers, including colorectal cancer and mPAC. Low MGMT expression by immunohistochemistry (IHC) and MGMT promoter methylation ultimately result in diminished DNA-repair of O6-alkylguanine adducts and enhanced sensitivity to alkylating agents, such as temozolomide (TMZ). This report presents data on MGMT testing mPAC pts admitted at our center. Methods Formalin-fixed paraffin-embedded (FFPE) tissue samples were examined via methyl specific PCR (EZ DNA Methylation-Gold™ KIT), to assess MGMT promoter methylation, and IHC, to assess protein expression. Furthermore, Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®” and “Oncomine BRCA Research Assay”) and PCR analysis of microsatellite instability (MSI) were performed. Results Archived FFPE tissue sections obtained from 90 pts admitted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from October 2017 to April 2019 were analyzed. At the time of this report, 60 samples (66%) had adequate tissue for extended analyses. As expected, 55 (92%) pts had KRAS mutations, while ATM, CDKN2A mutations and microsatellite instability (MSI) were found in 3 (5%), 4( 6%) and 2 (3%) pts, respectively. MGMT promoter methylation was found in 21 pts (35%), of which 13 (61%) had low/negative MGMT protein expression. Of note, amongst MGMT methylated pts, there were 5 (23%) BRCA1/2 somatic mutant and 2 (9%) MSI, suggesting possible genomic instability. Conclusions MGMT is a prognostic and predictive marker in glioblastomas and there is an increasing evidence in its role in metastatic CRC, with phase II studies showing a response rate of 10% in chemorefractory pts with MGMT methylation treated with TMZ. In our single center experience, MGMT methylation was found in 35% of patients with mPAC. This data warrant further prospective confirmation; nevertheless, considering the growing interest in the role of DNA-damage response genes in mPAC, there is definitely a rationale in investigating MGMT methylation as a predictive and prognostic biomarker in mPAC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure F. Morano: Honoraria (self): Servier. F. Pietrantonio: Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: Lilly; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Bayer; Advisory / Consultancy: Servier; Research grant / Funding (institution): BMS. F.G.M. De Braud: Advisory / Consultancy: TizianaLife Sciences; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy: Novartis; Advisory / Consultancy: Servier; Advisory / Consultancy: Pharm Research Associated; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Advisory / Consultancy: Amgen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Octimet Oncology; Advisory / Consultancy: Incyte; Advisory / Consultancy: Teofarma; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: EMD Serono; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: AstraZeneca. M. Di Bartolomeo: Advisory / Consultancy: Lilly; Advisory / Consultancy: Servier; Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.
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- 2019
38. Abstract PO-065: Artificial intelligence to improve selection for NSCLC patients treated with immunotherapy
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Mario Occhipinti, Roberto Ferrara, Gabriella Sozzi, Mattia Boeri, Mavis Mensah, Marcello Restelli, Giulia Galli, Alessandro Robuschi, Marta Bini, Claudia Proto, Marina Chiara Garassino, Francesco Trovò, Alessandro De Toma, Filippo de Braud, Giuseppe Lo Russo, Nicoletta Zilembo, Marta Brambilla, Sara Manglaviti, Alice Labianca, Arsela Prelaj, Alessandra Pedrocchi, Monica Ganzinelli, and Teresa Beninato
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Internal medicine ,Medicine ,Immunotherapy ,business ,Selection (genetic algorithm) - Abstract
Introduction In advanced Non-Small Cell Lung Cancer (aNSCLC), Programmed Death Ligand 1 (PD-L1) remains the only used biomarker to candidate patients (pts) to immunotherapy (IO) even if its predictive accuracy is not satisfactory. Indeed, given the complex dynamics underlying the cross-talk between the tumor and its microenvironment, it is unlikely that a single biomarker could be able to profile prediction with high precision. Artificial Intelligence (AI) and machine learning (ML) are techniques able to analyze and interpret big data, which cope with this complexity. The present study aims at using AI tools to improve response and efficacy prediction in aNSCLC pts treated with IO. Methods A classification task to determine if a pt is likely to benefit from IO was formulated using complete clinical data, PD-L1, histology, molecular data, and the blood microRNA signature classifier (MSC), which include 24 different microRNAs. Pts were divided into responders (R), who obtained a partial response or stable disease as best response, and non-R, who experienced progressive disease. A forward feature selection technique based on the Akaike Information Criterion was used to extract a specific subset of the pts data, being the most informative ones for the task. To develop the final predictive model, different ML methods have been tested: K-nearest neighbors, Logistic Regression, Kernel Support Vector Machines, Feedforward Neural Network, and Random Forest. Results Of 164 enrolled pts, 73 (44.5%) were R and 91 (55.5%) non-R. At data cut-off (Nov 2020), median Overall Survival (mOS) was 10.1 (95%IC 7.0 - 13.2) months (m). mOS for R pts was 38.5 m (95%IC 23.9 - 53.1) vs 3.8 m (95%IC 2.8 - 4.7) of non-R, p Citation Format: Arsela Prelaj, Mattia Boeri, Alessandro Robuschi, Claudia Proto, Giuseppe Lo Russo, Roberto Ferrara, Giulia Galli, Alessandro De Toma, Marta Brambilla, Mario Occhipinti, Sara Manglaviti, Alice Labianca, Teresa Beninato, Marta Bini, Mavis Mensah, Monica Ganzinelli, Nicoletta Zilembo, Filippo de Braud, Gabriella Sozzi, Marcello Restelli, Alessandra Pedrocchi, Marina Chiara Garassino, Francesco Trovo. Artificial intelligence to improve selection for NSCLC patients treated with immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-065.
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- 2021
39. Risk of disease progression (PD) following discontinuation of BRAF±MEK targeted therapies for reasons other than PD in patients (pts) with metastatic or unresectable melanoma
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Francesca Corti, Lorenza Di Guardo, Carolina Cimminiello, Michele Del Vecchio, Giovanni Randon, Marta Bini, Irene Vetrano, Sara Manglaviti, Emma Zattarin, Alessandra Raimondi, Ilaria Bisogno, and Filippo de Braud
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Oncology ,Cancer Research ,medicine.medical_specialty ,Metastatic melanoma ,business.industry ,Melanoma ,Disease progression ,medicine.disease ,Discontinuation ,BRAF V600E ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Toxicity ,medicine ,In patient ,business ,030215 immunology - Abstract
10053 Background: In pts with metastatic melanoma bearing BRAF V600E/K mutations BRAF V600±MEK inhibitors are administered until PD/unacceptable toxicity. In patients achieving durable responses, outcomes following discontinuation for reasons other than PD are largely unknown. Methods: We identified all patients who interrupted BRAF±MEK inhibitors for reasons other than PD after complete (CR) or partial response (PR) from a clinical dataset of patients with BRAF mutated metastatic/unresectable melanoma treated with targeted therapy at a single Institution. Results: We included 24 pts. Fifteen (62.5%) and 9 (37.5%) pts were treated respectively with BRAF inhibitor monotherapy and BRAF+MEK inhibitor combination. All pts had normal baseline LDH and ECOG PS0, 2 (8%) pts had brain metastases and 15 (62.5%) had multi-organ metastatic involvement. Dose reduction was required for 12 (50%) pts. Median treatment duration was 59 (12-88) months. Causes of discontinuation were unacceptable toxicity (19 pts-79%) and consent withdrawal (5 pts-21%). At the time of discontinuation, 17 (71%) and 7 (29%) pts had achieved respectively CR and PR. At a median follow up of 31 (8-59) months after treatment discontinuation, 9 (37.5%) pts had experienced PD. Median time to PD after treatment discontinuation was 9 (3-16) months. At time of PD, 2 (22%) pts displayed involvement of new organ sites. Risk of PD following discontinuation was respectively 31% and 45% at 12 and 24 months. Neither baseline characteristics nor treatment duration and time to best response influenced risk of PD; we found a non-significant trend towards higher risk of relapse for patients interrupting treatment with residual disease compared to those who interrupted treatment after achieving CR [HR 3.3; 95%CI (0.8–14.1); log-rank p = 0.081]. After PD, 6 pts received BRAF+MEK inhibitors with a response rate of 100% and 3/6 pts achieving CR. Conclusions: In a subset of patients with favorable prognostic characteristics and retained sensitivity to BRAF±MEK inhibitors, treatment discontinuation was associated with relevant risk of relapse with about one third of pts experiencing PD within one year. Biomarker studies are needed to identify pts who might safely discontinue therapy due to sustained toxicity, especially after achieving CR.
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- 2020
40. Update of NGS analysis of Italian survey of second tumors in patients with diagnosis of GIST (gastrointestinal stromal tumor)
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Margherita Nannini, Laura Papi, Giovanni Vancheri, Giovanni Grignani, Sara Manglaviti, Giovannella Palmieri, Alessandro Mazzocca, Giulia Meoni, Silvia Gasperoni, Angela Stefania Ribecco, Lorenzo Tofani, Francesca Castiglione, Margaret Ottaviano, Francesco Tolomeo, Agnese Paderi, Bruno Vincenzi, Tommaso Adragna, Elena Fumagalli, Enrico Mini, and Margherita Vannucchi
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Oncology ,Cancer Research ,medicine.medical_specialty ,GiST ,business.industry ,GIST - Gastrointestinal stromal tumor ,Second primary cancer ,digestive system diseases ,Internal medicine ,medicine ,In patient ,business ,neoplasms - Abstract
e23518 Background: In patients with GIST, literature reports a risk of second primary tumors between 4.5% and 33% with different distribution in the worldwide. The network of 7 italian EURACAN centers has collected clinical and molecular features of GIST patients with second primary tumors. Methods: We reviewed the clinical characteristics of 201 patients with GIST and second primary tumors in order to evaluate association between risk of dead and each possible factor, using Kaplan meier curve, log-rank test and Cox model for Hazard Ratio and it’s interval Confidence 95% estimation. Furthermore, NGS analysis ( 56 gene onco panel) in 72 patients with GIST was performed. Results: On the basis of the significant correlation previously observed between the Miettinen risk criteria of GIST (low/very low) and the incidence of second primary tumors (gastrointestinal tumors),P < 0.001 (Abstr 11032 ASCO 2019), we observed in these patients a median age of diagnosis of GIST of 68, with prevalent gastric site localization ( KIT exon 11 mutation), NF1 and Lynch (kit/pdgfra WT) syndromes in the low risk subgroup. The more frequent site of second epithelial tumor in gastrointestinal tract was the colon followed by gastric, pancreatic and biliary tract. In patients with GIST with low-very low risk according Miettinen classification, after a median follow-up period of 25 years, we have observed that the gastroenteric site of second tumors occurrence is significantly related to the survival (p < .0003). In the NGS analysis of the GIST we observed the pathogenetic somatic mutations in the following genes: BRCA 2 (p.Thr2125fs), but germline test negative, TP53 (p.Arg192*,p.Gly244Ser,p.His168Leu), RET (p.Lys120Asn, p.His168Leu, p.Thr930Met ), NRAS (p.Gly134Asp), CTNNB1 (p.Ser45Phe), MSH6 (P.Ala164Val), SMARCB1 (p.Arg192), VHL (p.Gly93Val), PTEN(p.Val158Ile, p.Asn323fs), STK1I (p.Arg40Cys), SMO (p.Glu194Lys), EGFR (p.Gly721Asp), ATM (p.Asp2708Asn), ERBB4 (p.Asn181Ile). Conclusions: In our analysis patients with GIST (low-very low classes according to Miettinen) have significant risk to death because of second primary tumors in gastrointestinal tract. Specific attention to gastrointestinal screening during the follow-up of GIST (low and very low risk) is required.
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- 2020
41. 146P Safety and metabolic effects of fasting-mimicking diet in breast cancer patients
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Alessandra Raimondi, Claudio Vernieri, Giancarlo Bianchi, Federico Nichetti, Emma Zattarin, Licia Rivoltini, Sara Manglaviti, Francesca Ligorio, Giuseppe Capri, and F. de Braud
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Oncology ,medicine.medical_specialty ,Breast cancer ,business.industry ,Metabolic effects ,Internal medicine ,medicine ,Hematology ,business ,medicine.disease - Published
- 2020
42. Is MGMT methylation a new therapeutic target for biliary tract cancer?
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F. de Braud, Elena Tamborini, Federica Morano, Federico Nichetti, Arianna Ottini, Filippo Pietrantonio, Martina Torchio, Marta Brambilla, Monica Niger, Giorgia Peverelli, Giancarlo Pruneri, Federica Perrone, Sara Pusceddu, M. Marcuzzo, M. Di Bartolomeo, Sara Manglaviti, Maria Antista, and Filippo Pagani
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Oncology ,medicine.medical_specialty ,Biliary tract cancer ,Heterogeneous group ,business.industry ,Mgmt expression ,Hematology ,Protein expression ,Internal medicine ,Promoter methylation ,medicine ,Enhanced sensitivity ,Prognostic biomarker ,Mgmt methylation ,business - Abstract
Background Biliary Tract Cancers (BTC) are a devastating and molecularly heterogeneous group of diseases, with significant differences between intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and Gall bladder (GB) cancer. O6-methylguanine-DNA methyltransferase (MGMT) is a key DNA repair gene, responsible of alkyl groups’ elimination from the O6-position of guanine. Reductions in MGMT expression and MGMT promoter methylation result in diminished DNA-repair of O6-alkylguanine adducts and enhanced sensitivity to alkylating agents, such as temozolomide (TMZ). This alterations have been described in BTC in small reports with variable frequencies. Here we present data on MGMT methylation tested in BTC pts admitted at our center. Methods MGMT promoter methylation was studied via methyl specific PCR (EZ DNA Methylation-Gold™ KIT), while protein expression was assessed with immunohistochemistry (IHC). Formalin-fixed paraffin-embedded (FFPE) tissue samples were also examined using Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®”). Results Archived FFPE tissue sections from 100 pts admitted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from October 2017 to February 2019 were analyzed. Amongst the 89 samples with adequate tissue, 73% were ICC, 16% were ECC and 8 % were GC. 34 pts (38%) had MGMT promoter methylation, while low/negative MGMT protein expression was found in 45 pts (50%). MGMT methylation was identified in 38% of ICC, 26% of ECC and 62% of GC. As expected, we identified IDH1/2 mutations in 15%, all affected by ICC. Of note, amongst MGMT methylated pts, there were 4 pts (11%) with concomitant IDH1/2 mutations, which are reported to be associated with CpG Island Methylator Phenotype. Conclusions MGMT is a prognostic and predictive marker in glioblastomas and there is an increasing evidence in its role in gastrointestinal cancer, with phase II studies showing a response rate of 10% in chemorefractory MGMT- methylated colorectal cancer treated with TMZ. In our single center experience, MGMT methylation was found in 38% of patients with BTC. This data warrant further confirmation, but there is a growing interest in novel targeted therapies exploiting the role of MGMT methylation as a predictive and prognostic biomarker in BTC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure F. Morano: Honoraria (institution): Servier. F. Pietrantonio: Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Amgen; Honoraria (institution), Advisory / Consultancy: EMD Serono; Honoraria (institution), Advisory / Consultancy: Sanofi; Honoraria (institution), Advisory / Consultancy: Bayer; Honoraria (institution), Advisory / Consultancy: Servier; Research grant / Funding (self): BMS. M. Di Bartolomeo: Honoraria (institution), Advisory / Consultancy: Eli Lilly; Honoraria (institution), Advisory / Consultancy: Servier; Travel / Accommodation / Expenses: Roche. F.G.M. De Braud: Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Servier; Advisory / Consultancy: Pharm Research Associated; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: ACCMED; Advisory / Consultancy: Incyte; Advisory / Consultancy: Teofarma; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: EMD Serono; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Fondazione Menarini; Speaker Bureau / Expert testimony: MSD. All other authors have declared no conflicts of interest.
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- 2019
43. safety analysis for near rectilinear orbit close approach rendezvous in the circular restricted three-body problem
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Sara Manglaviti
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- 2017
44. Impact of age on safety and efficacy of first-line FOLFOXIRI/bevacizumab in mCRC: A pooled analysis of TRIBE and TRIBE2 studies
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Mariaelena Casagrande, Alberto Zaniboni, Alfredo Falcone, Emanuela Dell'Aquila, Federica Urbano, Gemma Zucchelli, Giuseppe Aprile, Gianluca Tomasello, Giacomo Allegrini, Daniele Rossini, Angela Buonadonna, Carlotta Antoniotti, Sabina Murgioni, Chiara Cremolini, Federica Marmorino, Sara Lonardi, Beatrice Borelli, Sara Manglaviti, Monica Ronzoni, and Giuliana Ritorto
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Oncology ,Cancer Research ,medicine.medical_specialty ,FOLFOXIRI ,Bevacizumab ,business.industry ,First line ,ECOG Performance Status ,Tribe (biology) ,Pooled analysis ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
3536 Background: FOLFOXIRI/bevacizumab is a valuable upfront option in mCRC based on results of phase III TRIBE and TRIBE2 studies: 1187 pts aged 18–70 years with ECOG performance status (PS) ≤ 2 or between 71–75 years with an ECOG PS of 0 were randomized to receive first-line FOLFOXIRI/bevacizumab or a doublet (FOLFIRI in TRIBE and mFOLFOX6 in TRIBE2)/bevacizumab. Here, we aimed at assessing the effect of the intensification of the upfront chemotherapy (triplet versus doublet) in terms of safety and efficacy in pts aged < 70 versus 70-75. Methods: Subgroup analyses for ORR, PFS, G3/4 overall adverse events (AEs), chemo-related and bevacizumab-related AEs were performed according to baseline age. Results: 182 (15%) out of 1187 pts were 70-75 years old (97 in the FOLFOXIRI/bevacizumab and 85 in the doublets/bevacizumab arms). The benefit provided by the intensification of the upfront chemotherapy was independent of the age subgroup in terms of both ORR (p for interaction = 0.684) and PFS (p for interaction = 0.634). The risk of overall and chemo-related G3/4 AEs was increased with the triplet independently of age (p for interaction = 0.736 and 0.790), while no difference in bevacizumab-related AEs was observed in both subgroups (p for interaction = 0.566). In the overall population, as compared to younger pts, those aged 70-75 were more susceptible to overall G3/4 AEs (70% vs 57%, p = 0.001). In the FOLFOXIRI/bevacizumab arm a higher incidence of G3/4 diarrhea (27% vs 17%, p = 0.016) and febrile neutropenia (16% vs 6% p = 0.001) and a lower incidence of all grade nausea (51% vs 65%, p = 0.009) and vomiting (26% vs 44% p = 0.001) were reported among elderly pts. Conclusions: The activity and efficacy of FOLFOXIRI/bevacizumab are confirmed among selected pts between 70 and 75 years old, with a relative increase in the risk of chemo-related AEs similar to that of younger pts. However, elderly pts are more susceptible to experience AEs independently of the treatment arm. Considering the increased incidence of febrile neutropenia and diarrhea with FOLFOXIRI/bevacizumab, the use of G-CSF as primary prophylaxis or an initial dose reduction of irinotecan and 5-fluorouracil might be considered in this population.
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- 2019
45. Exploiting DNA repair alterations in metastatic pancreatic cancer (mPAC): Is MGMT methylation a new therapeutic target?
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Maria Di Bartolomeo, Elena Tamborini, Maria Antista, Monica Niger, Sara Pusceddu, Arianna Ottini, Alessandra Raimondi, Matteo Marcuzzo, Federica Morano, Filippo de Braud, Federica Perrone, Martina Torchio, Giovanni Randon, Michele Prisciandaro, Filippo Pagani, Federico Nichetti, Giancarlo Pruneri, Sara Manglaviti, Giorgia Peverelli, and Filippo Pietrantonio
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Cancer Research ,Poor prognosis ,Methyltransferase ,DNA repair ,business.industry ,digestive system diseases ,Oncology ,Metastatic pancreatic cancer ,Overall survival ,Cancer research ,Medicine ,Mgmt methylation ,business ,neoplasms - Abstract
e15770 Background: Metastatic pancreatic cancer (mPAC) has a poor prognosis, with few therapeutic options and an overall survival (OS) at 5 years < 5%. O6-methylguanine-DNA methyltransferase ( MGMT) is a key DNA repair gene, responsible of alkyl groups’ elimination from the O6-position of guanine. Its promoter methylation results in diminished DNA-repair of O6-alkylguanine adducts and enhanced sensitivity to alkylating agents, such as temozolomide (TMZ). Of note, both reductions in MGMT expression and MGMT promoter methylation are described in a variety of gastrointestinal malignancies, including colorectal cancer (CRC). Here we present data on MGMT methylation tested in mPAC pts treated at our center. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were examined using Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®” and “Oncomine BRCA Research Assay”) and PCR analysis of microsatellite instability (MSI). Furthermore, the exploratory analysis of MGMT status was performed via methyl specific PCR (EZ DNA Methylation-Gold™ KIT) to assess promoter methylation, and immunohistochemistry (IHC) was done to assess protein expression. Results: Archived FFPE tissue sections obtained from 60 pts treated at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from October 2017 to December 2018 were analyzed. 47 samples (78%) had adequate tissue for extended analyses. As expected, 44 (93%) pts had KRAS mutations, while ATM, CDKN2A mutations and microsatellite instability (MSI) were found in 3 pts (6%), respectively. MGMT promoter methylation was identified in 14 pts (29%), with low/negative MGMT protein expression in 7 (14%). Interestingly, amongst MGMT methylated pts, there were 3 (21%) BRCA1/2 somatic mutant and 1 (7%) MSI, suggesting possible genomic instability. Conclusions: MGMT is a prognostic and predictive marker in glioblastomas and there is an increasing evidence in its role in metastatic CRC, with phase II studies showing a response rate of 10% in chemorefractory pts with MGMT methylation treated with TMZ. In our single center experience, MGMT methylation was found in 29% of patients with mPAC. This data warrant further prospective confirmation, but there is definitely a growing interest in the role of MGMT methylation as a predictive and prognostic biomarker in mPAC.
- Published
- 2019
46. Italian survey of second tumors in patients with diagnosis of GIST (gastrointestinal stromal tumor)
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Sara Fancelli, Lorenzo Tofani, Margaret Ottaviano, Maria Abbondanza Pantaleo, Giovannella Palmieri, Lorenzo D'Ambrosio, Lorena Incorvaia, Silvia Gasperoni, Giuseppe Badalamenti, Luca Messerini, Giovanni Grignani, Giulia Meoni, Margherita Nannini, Enrico Caliman, Agnese Paderi, Enrico Mini, Bruno Vincenzi, Elena Fumagalli, Sara Manglaviti, and Alessandro Mazzocca
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Oncology ,business.industry ,Mesenchymal stem cell ,medicine ,GIST - Gastrointestinal stromal tumor ,Digestive tract ,In patient ,business ,neoplasms ,digestive system diseases - Abstract
11032 Background: GISTs are the most common mesenchymal tumors of the digestive tract. As of recent, new links are being made between GISTS and secondary malignancies. However, whether the coexistence of GISTs with other tumors is stochastic, or the result of related pathogenetic mechanisms is still unknown. Methods: We retrospectively reviewed clinical and molecular features from all GIST patients with second tumors treated in seven Italian GIST reference centers. Qualitative variables were compared using the Fisher exact test. Results: Clinical data of 184 patients with diagnosis of GIST were evaluated. Median age at diagnosis was 66 years, KIT exon 11 resulted the most frequent mutation (73%) while seven patients (3.8%) had a genetic syndrome. The most common primary GIST localizations were stomach (54%) and small intestine (33%). Second tumors arose mostly from gastrointestinal and genitourinary tract. Fourtythree patients had two primary tumors other than GIST and five patients had three other primary malignancies. According to Miettinen criteria, 45% of non-metastatic patients at diagnosis belong to low or very low-risk classes. We highlighted a significant correlation (P=0.002) between risk class and second/third tumor localization, with considerably high percentage of GI second malignancies in low/very low risk GISTs (table). Conclusions: The high frequency of second/third tumors reported in low and very low GIST calls for a careful follow-up also in these patients. Furthermore, this population requires further genetic investigation, NGS analysis is ongoing. [Table: see text]
- Published
- 2019
47. Impact of age and gender on safety and efficacy of first-line FOLFOXIRI/bevacizumab in mCRC a pooled analysis of TRIBE and TRIBE2 studies
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Giacomo Allegrini, Monica Ronzoni, Gianluca Masi, A. Falcone, Daniele Rossini, G. Aprile, C. Cremolini, G. Tomasello, Angela Buonadonna, Roberto Moretto, Beatrice Borelli, Sara Manglaviti, S. Lonardi, Mariaelena Casagrande, Federica Marmorino, Gemma Zucchelli, A. Zaniboni, G. Ritorto, Emanuela Dell'Aquila, Federica Urbano, Carlotta Antoniotti, and Sabina Murgioni
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Age and gender ,FOLFOXIRI ,Pooled analysis ,Oncology ,Bevacizumab ,business.industry ,First line ,medicine ,Hematology ,Tribe (biology) ,business ,medicine.drug ,Demography
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