17 results on '"Paolo Chiodini"'
Search Results
2. Oligo-metastatic neoPlasms from the gastro-intestinal tract: iDentIfiCaTIon of cliNical and molecular drivers: the PREDICTION study
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Alessandro Ottaiano, Antonella De Luca, Mariachiara Santorsola, Giosuè Scognamiglio, Annabella Di Mauro, Paolo Chiodini, Matilde Lambiase, Alessandra Sacco, Antonella Petrillo, Vincenza Granata, Roberta Fusco, Edoardo Mercadante, Nicola Martucci, Giuseppe De Luca, Antonello La Rocca, Egidio Celentano, Anna Crispo, Piergiacomo Di Gennaro, Fabiana Tatangelo, Gerardo Ferrara, Francesco Izzo, Andrea Belli, Renato Patrone, Paolo Delrio, Daniela Rega, Silvia De Franciscis, Paolo Muto, Vincenzo Ravo, Rossella Di Franco, Valentina Borzillo, Sara Santagata, Giuseppina Rea, Daniela Castaldo, Ugo Pace, Gianfranco De Feo, Stefania Scala, Guglielmo Nasti, and Nicola Normanno
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Oligometastatic diseases ,Colorectal cancer ,Biomarkers ,Genetics ,Prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Metastatic disease in tumors originating from the gastrointestinal tract can exhibit varying degrees of tumor burden at presentation. Some patients follow a less aggressive disease course, characterized by a limited number of metastatic sites, referred to as “oligo-metastatic disease” (OMD). The precise biological characteristics that define the oligometastatic behavior remain uncertain. In this study, we present a protocol designed to prospectively identify OMD, with the aim of proposing novel therapeutic approaches and monitoring strategies. Methods The PREDICTION study is a monocentric, prospective, observational investigation. Enrolled patients will receive standard treatment, while translational activities will involve analysis of the tumor microenvironment and genomic profiling using immunohistochemistry and next-generation sequencing, respectively. The first primary objective (descriptive) is to determine the prevalence of biological characteristics in OMD derived from gastrointestinal tract neoplasms, including high genetic concordance between primary tumors and metastases, a significant infiltration of T lymphocytes, and the absence of clonal evolution favoring specific driver genes (KRAS and PIK3CA). The second co-primary objective (analytic) is to identify a prognostic score for true OMD, with a primary focus on metastatic colorectal cancer. The score will comprise genetic concordance (> 80%), high T-lymphocyte infiltration, and the absence of clonal evolution favoring driver genes. It is hypothesized that patients with true OMD (score 3+) will have a lower rate of progression/recurrence within one year (20%) compared to those with false OMD (80%). The endpoint of the co-primary objective is the rate of recurrence/progression at one year. Considering a reasonable probability (60%) of the three factors occurring simultaneously in true OMD (score 3+), using a significance level of α = 0.05 and a test power of 90%, the study requires a minimum enrollment of 32 patients. Discussion Few studies have explored the precise genetic and biological features of OMD thus far. In clinical settings, the diagnosis of OMD is typically made retrospectively, as some patients who undergo intensive treatment for oligometastases develop polymetastatic diseases within a year, while others do not experience disease progression (true OMD). In the coming years, the identification of true OMD will allow us to employ more personalized and comprehensive strategies in cancer treatment. Trial registration ClinicalTrials.gov ID NCT05806151.
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- 2023
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3. CD39 and LDHA affects the prognostic role of NLR in metastatic melanoma patients treated with immunotherapy
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Domenico Mallardo, Mario Fordellone, Andrew White, Margaret Ottaviano, Francesca Sparano, Michael Bailey, Arianna Bianca Facchini, Sufey Ong, Piera Maiolino, Corrado Caracò, Sarah Church, Ernesta Cavalcanti, Sarah Warren, Alfredo Budillon, Alessandra Cesano, Ester Simeone, Paolo Chiodini, and Paolo Antonio Ascierto
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Melanoma ,NLR ,CD39 ,HDLA ,TGFβ ,Biomarker ,Medicine - Abstract
Abstract Background Identifying response markers is highly needed to guide the treatment strategy in patients with metastatic melanoma. Methods A retrospective study was carried out in patients with unresectable/metastatic melanoma (stage IIIb–IV), treated with anti-PD-1 in the first line setting, to better explore the role and the timing of neutrophil/lymphocyte ratio (NLR) as potential biomarker of response. The relationship of NLR with inflammation-immune mediators and the underlying negative effect of raising NLR during immunotherapy, have been investigated with transcriptomic gene analysis. Results The results confirmed previous findings that a high baseline NLR is associated with a poorer prognosis and with higher serum level of lactate dehydrogenase (LDH), regardless of the presence of brain metastases. The transcriptomic analysis showed that high baseline NLR is associated with a characteristic gene signature CCNA1, LDHA and IL18R1, which correlates with inflammation and tumorigenesis. Conversely, low baseline NLR is associated with the signature CD3, SH2D1A, ZAP70 and CD45RA, linked to the immune-activation. The genes positively associated with NLR (CD39 (ENTPD1), PTEN, MYD88, MMP9 and LDH) are involved in processes of immunosuppression, inflammation and tumor-promoting activity. Increased expression of CD39 correlated with TGFβ2, a marker of the N2 neutrophils with immunosuppressive activity. Conclusions These results suggest that increasing NLR is associated with an increased neutrophil population, with polarization to the N2 phenotype, and this process may be the basis for the negatively prognostic role of NLR.
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- 2023
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4. Biological and clinical impact of membrane EGFR expression in a subgroup of OC patients from the phase IV ovarian cancer MITO-16A/MANGO-OV2A trial
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Luca Forlani, Loris De Cecco, Vittorio Simeon, Biagio Paolini, Marina Bagnoli, Sabrina Chiara Cecere, Anna Spina, Eleonora Citeroni, Eliana Bignotti, Domenica Lorusso, Laura Arenare, Daniela Russo, Carmine De Angelis, Laura Ardighieri, Giosuè Scognamiglio, Michele Del Sesto, Germana Tognon, Daniela Califano, Clorinda Schettino, Paolo Chiodini, Francesco Perrone, Delia Mezzanzanica, Sandro Pignata, and Antonella Tomassetti
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Ovarian cancer ,Bevacizumab ,EGFR ,Immunohistochemistry ,Microarray ,Bioinformatics ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Validated prognostic biomarkers for anti-angiogenic therapy using the anti-VEGF antibody Bevacizumab in ovarian cancer (OC) patients are still an unmet clinical need. The EGFR can contribute to cancer-associated biological mechanisms in OC cells including angiogenesis, but its targeting gave disappointing results with less than 10% of OC patients treated with anti-EGFR compounds showing a positive response, likely due to a non adequate selection and stratification of EGFR-expressing OC patients. Methods EGFR membrane expression was evaluated by immunohistochemistry in a cohort of 310 OC patients from the MITO-16A/MANGO-OV2A trial, designed to identify prognostic biomarkers of survival in patients treated with first line standard chemotherapy plus bevacizumab. Statistical analyses assessed the association between EGFR and clinical prognostic factors and survival outcomes. A single sample Gene Set Enrichment-like and Ingenuity Pathway Analyses were applied to the gene expression profile of 195 OC samples from the same cohort. In an OC in vitro model, biological experiments were performed to assess specific EGFR activation. Results Based on EGFR-membrane expression, three OC subgroups of patients were identified being the subgroup with strong and homogeneous EGFR membrane localization, indicative of possible EGFR out/in signalling activation, an independent negative prognostic factor for overall survival of patients treated with an anti-angiogenic agent. This OC subgroup resulted statistically enriched of tumors of histotypes different than high grade serous lacking angiogenic molecular characteristics. At molecular level, among the EGFR-related molecular traits identified to be activated only in this patients’ subgroup the crosstalk between EGFR with other RTKs also emerged. In vitro, we also showed a functional cross-talk between EGFR and AXL RTK; upon AXL silencing, the cells resulted more sensitive to EGFR targeting with erlotinib. Conclusions Strong and homogeneous cell membrane localization of EGFR, associated with specific transcriptional traits, can be considered a prognostic biomarker in OC patients and could be useful for a better OC patients’ stratification and the identification of alternative therapeutic target/s in a personalized therapeutic approach.
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- 2023
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5. The number of risk factors not at target is associated with cardiovascular risk in a type 2 diabetic population with albuminuria in primary cardiovascular prevention. Post-hoc analysis of the NID-2 trial
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Ferdinando Carlo Sasso, Vittorio Simeon, Raffaele Galiero, Alfredo Caturano, Luca De Nicola, Paolo Chiodini, Luca Rinaldi, Teresa Salvatore, Miriam Lettieri, Riccardo Nevola, Celestino Sardu, Giovanni Docimo, Giuseppe Loffredo, Raffaele Marfella, Luigi Elio Adinolfi, Roberto Minutolo, and NID-2 study group Investigators
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Type 2 diabetes mellitus ,Cardiovascular risk ,Diabetes complications ,Multifactorial treatment ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Background Nephropathy in Diabetes type 2 (NID-2) study is an open-label cluster randomized clinical trial that demonstrated that multifactorial intensive treatment reduces Major Adverse Cardiac Events (MACEs) and overall mortality versus standard of care in type 2 diabetic subjects with albuminuria and no history of cardiovascular disease. Aim of the present post-hoc analysis of NID- 2 study is to evaluate whether the number of risk factors on target associates with patient outcomes. Methods Intervention phase lasted four years and subsequent follow up for survival lasted 10 years. To the aim of this post-hoc analysis, the whole population has been divided into 3 risk groups: 0–1 risk factor (absent/low); 2–3 risk factors (intermediate); 4 risk factors (high). Primary endpoint was a composite of fatal and non-fatal MACEs, the secondary endpoint was all-cause death at the end of the follow-up phase. Results Absent/low risk group included 166 patients (52.4%), intermediate risk group 128 (40.4%) and high-risk group 23 (7.3%). Cox model showed a significant higher risk of MACE and death in the high-risk group after adjustment for confounding variables, including treatment arm (HR 1.91, 95% CI 1.04–3.52, P = 0.038 and 1.96, 95%CI 1.02–3.8, P = 0,045, respectively, vs absent/low risk group). Conclusions This post-hoc analysis of the NID-2 trial indicates that the increase in the number of risk factors at target correlates with better cardiovascular-free survival in patients with type 2 diabetes at high CV risk. Clinical Trial Registration ClinicalTrials.gov number, NCT00535925. https://clinicaltrials.gov/ct2/show/NCT00535925
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- 2022
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6. The effect of DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors on cardiorenal outcomes: a network meta-analysis of 23 CVOTs
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Dario Giugliano, Miriam Longo, Simona Signoriello, Maria Ida Maiorino, Bruno Solerte, Paolo Chiodini, and Katherine Esposito
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Cardiovascular outcome trials ,DPP-4 inhibitors ,GLP-1 receptor agonists ,SGLT-2 inhibitors ,Network meta-analysis ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose co-transporter-2 (SGLT-2) inhibitors reduce cardiorenal outcomes. We performed a network meta-analysis to compare the effect on cardiorenal outcomes among GLP-1 RAs, SGLT-2 inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. Methods We searched the PUBMED, Embase and Cochrane databases for relevant studies published up until 10 December 2021. Cardiovascular and renal outcome trials reporting outcomes on GLP-1RA, SGLT-2 inhibitors and DPP-4 inhibitors in patients with or without type 2 diabetes mellitus were included. The primary outcome was major adverse cardiovascular events (MACE); other outcomes were cardiovascular and total death, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure (HHF), and renal outcome. Results Twenty-three trials enrolling a total number of 181,143 participants were included. DPP-4 inhibitors did not lower the risk of any cardiorenal outcome when compared with placebo and were associated with higher risks of MACE, HHF, and renal outcome when compared with the other two drug classes. SGLT-2 inhibitors significantly reduced cardiovascular (RR = 0.88) and total (RR = 0.87) death, as compared with DPP-4 inhibitors, while GLP-1 RA reduced total death only (RR = 0.87). The comparison between GLP-1RA and SGLT-2 inhibitors showed no difference in their risks of MACE, nonfatal MI, nonfatal stroke, CV and total death; SGLT-2 inhibitors were superior to GLP-1RA in reducing the risk of HHF and the renal outcome (24% and 22% lower risk, respectively). Only GLP-1RA reduced the risk of nonfatal stroke (RR = 0.84), as compared with placebo. There was no head-to-head trial directly comparing these antidiabetic drug classes. Conclusions SGLT-2 inhibitors and GLP-1RA are superior to DPP-4 inhibitors in reducing the risk of most cardiorenal outcomes; SGLT-2 inhibitors are superior to GLP-1RA in reducing the risk of HHF and renal events; GLP-1RA only reduced the risk of nonfatal stroke. Both SGLT-2 inhibitors and GLP-1RA should be the preferred treatment for type 2 diabetes and cardiorenal diseases.
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- 2022
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7. Correction to: Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial
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Francesco Perrone, Maria Carmela Piccirillo, Paolo Antonio Ascierto, Carlo Salvarani, Roberto Parrella, Anna Maria Marata, Patrizia Popoli, Laurenzia Ferraris, Massimiliano M. Marrocco-Trischitta, Diego Ripamonti, Francesca Binda, Paolo Bonfanti, Nicola Squillace, Francesco Castelli, Maria Lorenza Muiesan, Miriam Lichtner, Carlo Calzetti, Nicola Duccio Salerno, Luigi Atripaldi, Marco Cascella, Massimo Costantini, Giovanni Dolci, Nicola Cosimo Facciolongo, Fiorentino Fraganza, Marco Massari, Vincenzo Montesarchio, Cristina Mussini, Emanuele Alberto Negri, Gerardo Botti, Claudia Cardone, Piera Gargiulo, Adriano Gravina, Clorinda Schettino, Laura Arenare, Paolo Chiodini, Ciro Gallo, and the TOCIVID-19 investigators, Italy
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Medicine - Published
- 2021
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8. Improvement of glycemic control and reduction of major cardiovascular events in 18 cardiovascular outcome trials: an updated meta-regression
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Maria Ida Maiorino, Miriam Longo, Lorenzo Scappaticcio, Giuseppe Bellastella, Paolo Chiodini, Katherine Esposito, and Dario Giugliano
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Cardiovascular outcome trials ,Type 2 diabetes ,DPP-4i ,GLP-1RA ,SGLT-2i ,Cardiorenal outcomes ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Background Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs. Methods An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression. Results The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P
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- 2021
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9. GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs
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Dario Giugliano, Lorenzo Scappaticcio, Miriam Longo, Paola Caruso, Maria Ida Maiorino, Giuseppe Bellastella, Antonio Ceriello, Paolo Chiodini, and Katherine Esposito
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Cardiovascular outcome trials ,Type 2 diabetes ,GLP-1RA ,Cardiorenal outcomes ,Lixisenatide ,Liraglutide ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Background A meta-analysis is presented of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RA) versus placebo on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM). Methods We did an electronic search up to June 30, 2021, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). We included data from 8 CVOTs and 60,080 patients (72.4% with established cardiovascular disease). Results GLP-1RA reduced major cardiovascular events (MACE) by 14% (HR = 0.86, 95% CI 0.79–0.94, P = 0.006) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (P = 0.127). GLP-1RA also reduced the risk of cardiovascular death by 13% (P = 0.016), nonfatal stroke by 16% (P = 0.007), hospitalization for heart failure by 10% (P = 0.023), all-cause mortality by 12% (P = 0.012), and the broad composite kidney outcome by 17% (P = 0.012), which was driven by a reduction in macroalbuminuria only (HR = 0.74, 0.67–0.82, P
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- 2021
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10. Efficacy and durability of multifactorial intervention on mortality and MACEs: a randomized clinical trial in type-2 diabetic kidney disease
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Ferdinando Carlo Sasso, Pia Clara Pafundi, Vittorio Simeon, Luca De Nicola, Paolo Chiodini, Raffaele Galiero, Luca Rinaldi, Riccardo Nevola, Teresa Salvatore, Celestino Sardu, Raffaele Marfella, Luigi Elio Adinolfi, Roberto Minutolo, and NID-2 Study Group Investigators
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Diabetic nephropathy ,Multifactorial intervention ,Intensified treatment ,CV risk factors ,Very high CV risk ,MACE ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Background Multiple modifiable risk factors for late complications in patients with diabetic kidney disease (DKD), including hyperglycemia, hypertension and dyslipidemia, increase the risk of a poor outcome. DKD is associated with a very high cardiovascular risk, which requires simultaneous treatment of these risk factors by implementing an intensified multifactorial treatment approach. However, the efficacy of a multifactorial intervention on major fatal/non-fatal cardiovascular events (MACEs) in DKD patients has been poorly investigated. Methods Nephropathy in Diabetes type 2 (NID-2) study is a multicentre, cluster-randomized, open-label clinical trial enrolling 395 DKD patients with albuminuria, diabetic retinopathy (DR) and negative history of CV events in 14 Italian diabetology clinics. Centres were randomly assigned to either Standard-of-Care (SoC) (n = 188) or multifactorial intensive therapy (MT, n = 207) of main cardiovascular risk factors (blood pressure 40/50 mg/dL for men/women and
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- 2021
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11. Evaluation of the diagnostic accuracy of a new point-of-care rapid test for SARS-CoV-2 virus detection
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Leonardo Miscio, Antonio Olivieri, Francesco Labonia, Gianfranco De Feo, Paolo Chiodini, Giuseppe Portella, Luigi Atripaldi, Roberto Parrella, Rodolfo Conenna, Franco Maria Buonaguro, Ernesta Cavalcanti, Paolo Ascierto, Gerardo Botti, and Attilio Bianchi
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SARS-CoV-2 ,COVID-19 ,Point-of-care rapid test ,Health surveillance ,Medicine - Abstract
Abstract Background The easy access to a quick diagnosis of coronavirus disease 2019 (COVID-19) is a key point to improve the management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to contain its spread. Up to now, laboratory real-time PCR is the standard of care, but requires a fully equipped laboratory and significant infrastructure. Consequently, new diagnostic tools are required. Methods In the present work, the diagnostic accuracy of the point-of-care rapid test "bKIT Virus Finder COVID-19" (Hyris Ltd) is evaluated by a retrospective and a prospective analysis on SARS CoV-2 samples previously assessed with an FDA “authorized for the emergency use—EUA” reference method. Descriptive statistics were used for the present study. Results Results obtained with the Hyris Kit are the same as that of standard laboratory-based real time PCR methods for all the analyzed samples. In addition, the Hyris Kit provides the test results in less than 2 h, a significantly shorter time compared to the reference methods, without the need of a fully equipped laboratory. Conclusions To conclude, the Hyris kit represents a promising tool to improve the health surveillance and to increase the capacity of SARS-CoV-2 testing.
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- 2020
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12. Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial
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Francesco Perrone, Maria Carmela Piccirillo, Paolo Antonio Ascierto, Carlo Salvarani, Roberto Parrella, Anna Maria Marata, Patrizia Popoli, Laurenzia Ferraris, Massimiliano M. Marrocco-Trischitta, Diego Ripamonti, Francesca Binda, Paolo Bonfanti, Nicola Squillace, Francesco Castelli, Maria Lorenza Muiesan, Miriam Lichtner, Carlo Calzetti, Nicola Duccio Salerno, Luigi Atripaldi, Marco Cascella, Massimo Costantini, Giovanni Dolci, Nicola Cosimo Facciolongo, Fiorentino Fraganza, Marco Massari, Vincenzo Montesarchio, Cristina Mussini, Emanuele Alberto Negri, Gerardo Botti, Claudia Cardone, Piera Gargiulo, Adriano Gravina, Clorinda Schettino, Laura Arenare, Paolo Chiodini, Ciro Gallo, and the TOCIVID-19 investigators, Italy
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COVID-19 ,Pneumonia ,Coronavirus ,Tocilizumab ,IL-6 ,Phase 2 ,Medicine - Abstract
Abstract Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P
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- 2020
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13. Preventing major adverse cardiovascular events by SGLT-2 inhibition in patients with type 2 diabetes: the role of kidney
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Dario Giugliano, Luca De Nicola, Maria Ida Maiorino, Giuseppe Bellastella, Carlo Garofalo, Paolo Chiodini, Antonio Ceriello, and Katherine Esposito
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SGLT-2 inhibitors ,Type 2 diabetes ,MACE ,Diabetic kidney disease ,Statin therapy ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Cardiovascular outcome trials (CVOTs) have demonstrated a significant reduction of major adverse cardiovascular events (MACE) in patients with type 2 diabetes (T2D) treated by SGLT-2 inhibitors. This holds true in the presence of background therapy with statins in most patients. Noteworthy, this SGLT-2 inhibitors effect is unique because, at variance with other components of cardiorenal protection, MACE prevention does not appear to be a class effect. Here, we present meta-analysis of the four key CVOTs indicating a major role of renal function in determining the extent of MACE prevention, with the benefit increasing in more severe kidney disease, that is, a high-risk condition where effectiveness of the traditional approach with statins is reduced.
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- 2020
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14. Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: the CIFRA study protocol
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Alessandro Ottaiano, Stefania Scala, Nicola Normanno, Maria Napolitano, Monica Capozzi, Anna Maria Rachiglio, Cristin Roma, Anna Maria Trotta, Crescenzo D’Alterio, Luigi Portella, Carmela Romano, Antonino Cassata, Rossana Casaretti, Lucrezia Silvestro, Anna Nappi, Salvatore Tafuto, Antonio Avallone, Alfonso De Stefano, Mario Tamburini, Carmine Picone, Antonella Petrillo, Francesco Izzo, Raffaele Palaia, Vittorio Albino, Alfonso Amore, Andrea Belli, Ugo Pace, Massimiliano Di Marzo, Paolo Chiodini, Gerardo Botti, Gianfranco De Feo, Paolo Delrio, and Guglielmo Nasti
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Colorectal Cancer ,Antibody-dependent cell-mediated cytotoxicity ,Cetuximab ,Irinotecan ,Fluorouracule ,FcγR ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Combination of chemotherapies (fluoropirimidines, oxaliplatin and irinotecan) with biologic drugs (bevacizumab, panitumumab, cetuximab) have improved clinical responses and survival of metastatic colorectal cancer (mCRC). However, patients’ selection thorough the identification of predictive factors still represent a challange. Cetuximab (Erbitux®), a chimeric monoclonal antibody binding to the Epidermal Growth Factor Receptor (EGFR), belongs to the Immunoglobulins (Ig) grade 1 subclass able to elicite both in vitro and in vivo the Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). ADCC is the cytotoxic killing of antibody-coated target cells by immunologic effectors. The effector cells express a receptor for the Fc portion of these antibodies (FcγR); genetic polymorphisms of FcγR modify the binding affinity with the Fc of IgG1. Interestingly, the high-affinity FcγRIIIa V/V is associated with increased ADCC in vitro and in vivo. Thus, ADCC could partially account for cetuximab activity. Methods/design CIFRA is a single arm, open-label, phase II study assessing the activity of cetuximab in combination with irinotecan and fluorouracile in FcγRIIIa V/V patients with KRAS, NRAS, BRAF wild type mCRC. The study is designed with a two-stage Simon model based on a hypothetical higher response rate (+ 10%) of FcγRIIIa V/V patients as compared to previous trials (about 60%) assuming ADCC as one of the possible mechanisms of cetuximab action. The test power is 95%, the alpha value of the I-type error is 5%. With these assumptions the sample for passing the first stage is 14 patients with > 6 responses and the final sample is 34 patients with > 18 responses to draw positive conclusions. Secondary objectives include toxicity, responses’ duration, progression-free and overall survival. Furthermore, an associated translational study will assess the patients’ cetuximab-mediated ADCC and characterize the tumor microenvironment. Discussion The CIFRA study will determine whether ADCC contributes to cetuximab activity in mCRC patients selected on an innovative immunological screening. Data from the translational study will support results’ interpretation as well as provide new insights in host-tumor interactions and cetuximab activity. Trial registration The CIFRA trial (version 0.0, June 21, 2018) has been registered into the NIH-US National Library of Medicine, ClinicalTrials.gov database with the identifier number (NCT03874062).
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- 2019
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15. Safety and efficacy of abiraterone acetate in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: an Italian multicenter 'real life' study
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Luca Cindolo, Clara Natoli, Cosimo De Nunzio, Michele De Tursi, Maurizio Valeriani, Silvana Giacinti, Salvatore Micali, Mino Rizzo, Giampaolo Bianchi, Eugenio Martorana, Marcello Scarcia, Giuseppe Mario Ludovico, Pierluigi Bove, Anastasia Laudisi, Oscar Selvaggio, Giuseppe Carrieri, Maida Bada, Pietro Castellan, Stefano Boccasile, Pasquale Ditonno, Paolo Chiodini, Paolo Verze, Vincenzo Mirone, and Luigi Schips
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Prostate cancer ,Androgen deprivation therapy ,Abiraterone acetate ,Castration-resistant prostate cancer ,Androgen receptor ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background To evaluate the safety and efficacy of abiraterone acetate (AA) in the “real life” clinical practice for men with chemotherapy-naïve metastatic castration-resistant prostate. Methods A consecutive series of patients with mCRPC in 9 Italian tertiary centres treated with AA was collected. Demographics, clinical parameters, treatment outcomes and toxicity were recorded. The Brief Pain Inventory scale Q3 was tracked and patient treatment satisfaction was evaluated. Survival curves were estimated by the method of Kaplan-Meier and Cox regression and compared by the log-rank test statistic. Results We included 145 patients (mean age 76.5y). All patients were on androgen deprivation therapy. Patients had prior radiotherapy, radical prostatectomy, both treatments or exclusive androgen deprivation therapy in 17%, 33%, 9% and 40%, respectively. 57% of the patients had a Gleason score higher more than 7 at diagnosis. 62% were asymptomatic patients. The median serum total PSA at AA start was 17 ng/mL (range 0,4–2100). The median exposure to AA was 10 months (range 1–35). The proportion of patients achieving a PSA decline ≥50% at 12 weeks was 49%. Distribution of patient satisfaction was 32% “greatly improved”, 38% “improved”, 24% “not changed”, 5.5% “worsened”. Grade 3 and 4 toxicity was recorded in 17/145 patients 11.7% (70% cardiovascular events, 30% critical elevation of AST/ALT levels). At the last follow-up, median progression free and overall survival were 17 and 26.5 months, respectively. Both outcomes significantly correlated with the presence of pain, patient satisfaction, PSA baseline and PSA decline. Conclusions The AA is effective and well tolerated in asymptomatic or slightly symptomatic mCRPC in a “real life” setting. The survival outcomes are influenced by the presence of pain, patient satisfaction, baseline PSA and PSA decline. Trial registration The study was retrospectively registered at ISRCTN as DOI: 10.1186/ISRCTN 52513758 in date April the 30th 2016.
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- 2017
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16. Improvement of glycemic control and reduction of major cardiovascular events in 18 cardiovascular outcome trials: an updated meta-regression
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Lorenzo Scappaticcio, Katherine Esposito, Giuseppe Bellastella, Maria Ida Maiorino, Paolo Chiodini, Dario Giugliano, Miriam Longo, Maiorino, M. I., Longo, M., Scappaticcio, L., Bellastella, G., Chiodini, P., Esposito, K., and Giugliano, D.
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Blood Glucose ,Male ,Time Factors ,Endocrinology, Diabetes and Metabolism ,Meta-regression ,Type 2 diabetes ,Review ,DPP-4i ,Cardiovascular outcome trials ,Glycemic control ,Risk Factors ,Cause of Death ,Stroke ,Randomized Controlled Trials as Topic ,Hazard ratio ,Cardiorenal outcome ,Middle Aged ,GLP-1RA ,Hospitalization ,Treatment Outcome ,Cardiovascular Diseases ,Female ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,MACE ,Incretins ,Risk Assessment ,Glucagon-Like Peptide-1 Receptor ,Internal medicine ,Diabetes mellitus ,medicine ,Humans ,Diseases of the circulatory (Cardiovascular) system ,Sodium-Glucose Transporter 2 Inhibitors ,Glycemic ,Aged ,Glycated Hemoglobin ,Dipeptidyl-Peptidase IV Inhibitors ,business.industry ,Cardiorenal outcomes ,SGLT-2i ,Protective Factors ,medicine.disease ,Confidence interval ,Cardiovascular outcome trial ,Diabetes Mellitus, Type 2 ,RC666-701 ,business ,Mace ,Biomarkers - Abstract
Background Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs. Methods An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression. Results The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P 2 = 45.2%, Q statistic P = 0.040). In meta-regression, there was an association between the reduction in HbA1c at the end of the trial and the HR reduction for MACE (beta = − 0.298, P = 0.007), with significant heterogeneity (I2 = 40%, Q statistic P = 0.04); this association was totally driven by the risk reduction of non-fatal stroke, which explained 100% of between-study variance (beta = − 0.531, R2 = 100%), without heterogeneity (I2 = 24%, Q statistic P = 0.206). There was no association between the reduction in HbA1c and the HR for heart failure or all-cause death. Conclusions The reduction of HbA1c in eighteen CVOTs was significantly associated with reduction of non-fatal stroke, explaining all (R2 = 100%) of the between-study variance. While the contribution of glucose lowering in some CV benefits of newer agents does not influence their indications for the patient with type 2 diabetes, it may hopefully facilitate their use.
- Published
- 2021
17. Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: the CIFRA study protocol
- Author
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Francesco Izzo, Anna Maria Trotta, Vittorio Albino, Lucrezia Silvestro, Antonio Avallone, Raffaele Palaia, Gerardo Botti, Monica Capozzi, Paolo Chiodini, Rossana Casaretti, Carmine Picone, Stefania Scala, Nicola Normanno, Mario Tamburini, Andrea Belli, Crescenzo D'Alterio, Anna Maria Rachiglio, Massimiliano Di Marzo, Guglielmo Nasti, Paolo Delrio, Cristin Roma, Anna Nappi, Carmela Romano, Antonella Petrillo, Antonino Cassata, Gianfranco De Feo, Alessandro Ottaiano, Salvatore Tafuto, Maria Napolitano, Alfonso Amore, Alfonso De Stefano, Ugo Pace, Luigi Portella, Ottaiano, A., Scala, S., Normanno, N., Napolitano, M., Capozzi, M., Rachiglio, A. M., Roma, C., Trotta, A. M., D'Alterio, C., Portella, L., Romano, C., Cassata, A., Casaretti, R., Silvestro, L., Nappi, A., Tafuto, S., Avallone, A., De Stefano, A., Tamburini, M., Picone, C., Petrillo, A., Izzo, F., Palaia, R., Albino, V., Amore, A., Belli, A., Pace, U., Di Marzo, M., Chiodini, P., Botti, G., De Feo, G., Delrio, P., and Nasti, G.
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,Antibody-dependent cell-mediated cytotoxicity ,Colorectal cancer ,Phase II study ,Cetuximab ,medicine.disease_cause ,Irinotecan ,Fluorouracule ,lcsh:RC254-282 ,03 medical and health sciences ,Study Protocol ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,FcγR ,Genetics ,Medicine ,Panitumumab ,Humans ,Epidermal growth factor receptor ,neoplasms ,Colorectal Cancer ,Polymorphism, Genetic ,biology ,business.industry ,Receptors, IgG ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,digestive system diseases ,030104 developmental biology ,Treatment Outcome ,030220 oncology & carcinogenesis ,biology.protein ,KRAS ,Fluorouracil ,business ,Colorectal Neoplasms ,medicine.drug - Abstract
Background Combination of chemotherapies (fluoropirimidines, oxaliplatin and irinotecan) with biologic drugs (bevacizumab, panitumumab, cetuximab) have improved clinical responses and survival of metastatic colorectal cancer (mCRC). However, patients’ selection thorough the identification of predictive factors still represent a challange. Cetuximab (Erbitux®), a chimeric monoclonal antibody binding to the Epidermal Growth Factor Receptor (EGFR), belongs to the Immunoglobulins (Ig) grade 1 subclass able to elicite both in vitro and in vivo the Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). ADCC is the cytotoxic killing of antibody-coated target cells by immunologic effectors. The effector cells express a receptor for the Fc portion of these antibodies (FcγR); genetic polymorphisms of FcγR modify the binding affinity with the Fc of IgG1. Interestingly, the high-affinity FcγRIIIa V/V is associated with increased ADCC in vitro and in vivo. Thus, ADCC could partially account for cetuximab activity. Methods/design CIFRA is a single arm, open-label, phase II study assessing the activity of cetuximab in combination with irinotecan and fluorouracile in FcγRIIIa V/V patients with KRAS, NRAS, BRAF wild type mCRC. The study is designed with a two-stage Simon model based on a hypothetical higher response rate (+ 10%) of FcγRIIIa V/V patients as compared to previous trials (about 60%) assuming ADCC as one of the possible mechanisms of cetuximab action. The test power is 95%, the alpha value of the I-type error is 5%. With these assumptions the sample for passing the first stage is 14 patients with > 6 responses and the final sample is 34 patients with > 18 responses to draw positive conclusions. Secondary objectives include toxicity, responses’ duration, progression-free and overall survival. Furthermore, an associated translational study will assess the patients’ cetuximab-mediated ADCC and characterize the tumor microenvironment. Discussion The CIFRA study will determine whether ADCC contributes to cetuximab activity in mCRC patients selected on an innovative immunological screening. Data from the translational study will support results’ interpretation as well as provide new insights in host-tumor interactions and cetuximab activity. Trial registration The CIFRA trial (version 0.0, June 21, 2018) has been registered into the NIH-US National Library of Medicine, ClinicalTrials.gov database with the identifier number (NCT03874062).
- Published
- 2019
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