المؤلفون: Monica Niger, Federico Nichetti, Lorenzo Fornaro, Chiara Pircher, Federica Morano, Federica Palermo, Lorenza Rimassa, Tiziana Pressiani, Rossana Berardi, Andrea Casadei Gardini, Elisa Sperti, Lisa Salvatore, Davide Melisi, Francesca Bergamo, Salvatore Siena, Stefania Mosconi, Raffaella Longarini, Giuseppina Arcangeli, Salvatore Corallo, Laura Delliponti, Stefano Tamberi, Elena Fea, Giovanni Brandi, Ilario Giovanni Rapposelli, Massimiliano Salati, Paolo Baili, Rosalba Miceli, Silva Ljevar, Ilaria Cavallo, Elisa Sottotetti, Antonia Martinetti, Michele Droz Dit Busset, Carlo Sposito, Maria Di Bartolomeo, Filippo Pietrantonio, Filippo de Braud, Vincenzo Mazzaferro

المصدر: BMC Cancer, Vol 24, Iss 1, Pp 1-10 (2024)

مصطلحات موضوعية: Biliary tract cancers, Cholangiocarcinoma, Neoadjuvant chemotherapy, Cisplatin gemcitabine nabpaclitaxel, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Biliary tract cancers (BTCs) are rare and lethal cancers, with a 5-year survival inferior to 20%(1–3). The only potential curative treatment is surgical resection. However, despite complex surgical procedures that have a remarkable risk of postoperative morbidity and mortality, the 5-year survival rate after radical surgery (R0) is 20–40% and recurrence rates are up to ~ 75%(4–6). Up to ~ 40% of patients relapse within 12 months after resection, and half of these patient will recur systemically(4–6). There is no standard of care for neoadjuvant chemotherapy (NAC) in resectable BTC, but retrospective reports suggest its potential benefit (7, 8). Methods PURITY is a no-profit, multicentre, randomized phase II/III trial aimed at evaluating the efficacy of the combination of gemcitabine, cisplatin and nabpaclitaxel (GAP) as neoadjuvant treatment in patients with resectable BTC at high risk for recurrence. Primary objective of this study is to evaluate the efficacy of neoadjuvant GAP followed by surgery as compared to upfront surgery, in terms of 12-month progression-free survival for the phase II part and of progression free survival (PFS) for the phase III study. Key Secondary objectives are event free survival (EFS), relapse-free survival, (RFS), overall survival (OS), R0/R1/R2 resection rate, quality of life (QoL), overall response rate (ORR), resectability. Safety analyses will include toxicity rate and perioperative morbidity and mortality rate. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues and longitudinal ctDNA analysis are planned to identify potential biomarkers of primary resistance and prognosis. Discussion Considering the poor prognosis of resected BTC experiencing early tumor recurrence and the negative prognostic impact of R1/R2 resections, PURITY study is based on the rationale that NAC may improve R0 resection rates and ultimately patients’ outcomes. Furthermore, NAC should allow early eradication of microscopic distant metastases, undetectable by imaging but already present at the time of diagnosis and avoid mortality and morbidity associated with resection for patients with rapid progression or worsening general condition during neoadjuvant therapy. The randomized PURITY study will evaluate whether patients affected by BTC at high risk from recurrence benefit from a neoadjuvant therapy with GAP regimen as compared to immediate surgery. Trial registration PURITY is registered at ClinicalTrials.gov (NCT06037980) and EuCT(2023–503295-25–00).

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1471-2407Test

الوصول الحر: https://doaj.org/article/90a788f11b2c4f01af1f8bfb71dabb48Test

المؤلفون: Guido Giordano, Michele Milella, Matteo Landriscina, Francesca Bergamo, Giuseppe Tirino, Antonio Santaniello, Alberto Zaniboni, Enrico Vasile, Ferdinando De Vita, Giovanni Lo Re, Vanja Vaccaro, Elisa Giommoni, Donato Natale, Raffaele Conca, Daniele Santini, Luigi Maiorino, Gianni Sanna, Vincenzo Ricci, Aldo Iop, Vincenzo Montesarchio, Letizia Procaccio, Silvia Noventa, Roberto Bianco, Antonio Febbraro, Sara Lonardi, Giampaolo Tortora, Isabella Sperduti, Davide Melisi

المصدر: Cancer Medicine, Vol 13, Iss 12, Pp n/a-n/a (2024)

مصطلحات موضوعية: FOLFIRINOX, gemcitabine, nab‐paclitaxel, pancreatic cancer, prognostic model, second‐line chemotherapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Pancreatic cancer (PC) first‐line therapy often consists of polychemotherapy regimens, but choosing a second‐line therapy after disease progression, especially following first‐line FOLFIRINOX, remains a clinical challenge. This study presents results from a large, multicenter, retrospective analysis of Italian patients with metastatic PC (mPC) treated with Nab‐paclitaxel/Gemcitabine (AG) as second or later line of treatment. Main objective of the study is to identify prognostic factors that could inform treatment decisions. Methods The study included 160 mPC patients treated with AG in 17 Italian institutions. AG was administered according to labelling dose, until disease progression, unacceptable toxicity or patient refusal. Variations in schedules, dose modifications, supportive measures, and response evaluation were determined by individual clinicians' practice. Results AG was well‐tolerated and exhibited promising clinical activity. The overall response rate (ORR) and the disease control rate (DCR) were 22.5% and 45.6%, respectively. Median progression‐free survival (PFS) and overall survival (OS) were 3.9 and 6.8 months, respectively. Among the patients who received AG as a second‐line therapy (n = 111, 66.9%), median PFS and OS were 4.2 and 7.4 months, respectively. Notably, in the 76 patients (68%) receiving AG after first‐line FOLFIRINOX, an ORR of 19.7% and a DCR of 46.0% were observed, resulting in a median PFS of 3.5 and median OS of 5.7 months. The study identified specific clinical or laboratory parameters (LDH, NLR, fasting serum glucose, liver metastases, ECOG PS, and first‐line PFS) as independent prognostic factors at multivariate level. These factors were used to create a prognostic nomogram that divided patients into three risk classes, helping to predict second‐line OS and PFS. Conclusions This study represents the largest real‐world population of mPC patients treated with AG as a second or later line of therapy. It supports the feasibility of this regimen following first‐line FOLFIRINOX, particularly in patients with specific clinical and laboratory characteristics who derived prolonged benefit from first‐line therapy.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-7634Test

الوصول الحر: https://doaj.org/article/cf916ab2ef1c4b38b23365ff3e0dccbdTest

المؤلفون: Monica Niger, Federico Nichetti, Lorenzo Fornaro, Chiara Pircher, Federica Morano, Federica Palermo, Lorenza Rimassa, Tiziana Pressiani, Rossana Berardi, Andrea Casadei Gardini, Elisa Sperti, Lisa Salvatore, Davide Melisi, Francesca Bergamo, Salvatore Siena, Stefania Mosconi, Rafaella Longarini, Giuseppina Arcangeli, Salvatore Corallo, Laura Delliponti, Stefano Tamberi, Elena Fea, Giovanni Brandi, Ilario Giovanni Rapposelli, Massimiliano Salati, Paolo Baili, Rosalba Miceli, Silva Ljevar, Ilaria Cavallo, Elisa Sottotetti, Antonia Martinetti, Michele Droz Dit Busset, Carlo Sposito, Maria Di Bartolomeo, Filippo Pietrantonio, Filippo de Braud, Vincenzo Mazzaferro

المصدر: BMC Cancer, Vol 24, Iss 1, Pp 1-2 (2024)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1471-2407Test

الوصول الحر: https://doaj.org/article/c4ad272d3a0a4894a2606455a22c0d01Test

المؤلفون: Davide Melisi, Simona Casalino, Silvia Pietrobono, Alberto Quinzii, Camilla Zecchetto, Valeria Merz

المصدر: Therapeutic Advances in Medical Oncology, Vol 16 (2024)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: The approval of novel therapeutic agents remains widely reliant on evidence derived from large phase III randomized controlled trials. Liposomal irinotecan (ONIVYDE ® ) stands out as the only drug that has demonstrated improved survival both as a first-line therapy in combination with oxaliplatin and 5-fluorouracil/leucovorin (5FU/LV) (NALIRIFOX) compared to the standard gemcitabine plus nab-paclitaxel in the NAPOLI3 trial, and as a second-line treatment in combination with 5FU/LV compared to the standard 5FU/LV in the NAPOLI1 trial. However, just as the white bear of the Dostoevsky’s paradox, the judgment of these results is invariably distracted by the intrusive thought of how different they might be if compared to similar regimens containing standard-free irinotecan as FOLFIRINOX or FOLFIRI, respectively. Here, we present and thoroughly discuss the evidence encompassing the pharmacologic, preclinical, and clinical development of liposomal irinotecan that can dispel any intrusive thoughts and foster a rational and well-considered judgment of this agent and its potential integration into the therapeutic strategies for pancreatic ductal adenocarcinoma.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1758-8359Test

الوصول الحر: https://doaj.org/article/c32d3fda237b45df992f70d163f709afTest

المؤلفون: Letizia Procaccio, Valeria Merz, Morena Fasano, Vanja Vaccaro, Elisa Giommoni, Andrea Pretta, Silvia Noventa, Maria Antonietta Satolli, Guido Giordano, Clizia Zichi, Carmine Pinto, Camilla Zecchetto, Giulia Barsotti, Ferdinando De Vita, Michele Milella, Lorenzo Antonuzzo, Mario Scartozzi, Alberto Zaniboni, Rosella Spadi, Simona Casalino, Francesca Bergamo, Chiara De Toni, Davide Melisi, Sara Lonardi

المصدر: Cancer Medicine, Vol 12, Iss 13, Pp 14337-14345 (2023)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background The NAPOLI‐I trial showed better outcome of nanoliposomal irinotecan (nal‐IRI) plus 5‐fluorouracil/leucovorin (5‐FU/LV) compared to 5‐FU/LV in patients with advanced pancreatic ductal adenocarcinoma cancer (advPDAC) progressed to gemcitabine‐based therapy. This study aims to explore the real‐world efficacy and safety of 5‐FU/LV‐nal‐IRI. Methods This is a retrospective multicenter analysis including advPDAC patients receiving 5‐FU/LV‐nal‐IRI after failure of gemcitabine‐based therapy. Survival analyses were performed using Kaplan–Meier method, univariate and multivariate analyses by Cox regression. Results A total of 296 patients (median age 64.4 years, ECOG PS ≥1 in 56% of cases) were treated at 11 Italian institutions between 2016 and 2018. 34% of them underwent primary tumor resection, and 79% received gemcitabine‐nabpaclitaxel as first line. 5‐FU/LV‐nal‐IRI was administered as second‐line in 73% of cases. Objective response and disease control rate were 12% and 41%, respectively. Treatment was well tolerated with dose reductions in 50% of patients but no one permanent discontinuation; the commonest grade ≥3 toxicities were neutropenia (14%) and diarrhea (12%). Median PFS and OS from 5‐FU/LV‐nal‐IRI initiation was 3.2 and 7.1 months, respectively. Conclusions These real‐world data confirm the 5‐FU/LV‐nal‐IRI efficacy and safety in advPDAC patients progressed to gemcitabine‐based therapy, with outcomes comparable to NAPOLI‐1, even in a less‐selected population and with more modern therapeutic algorithm.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-7634Test

الوصول الحر: https://doaj.org/article/2ba909e629d843ce87c0d79ae0e1a3c6Test

المؤلفون: Serge Cedrick Toya Mbiandjeu, Angela Siciliano, Alessandro Mattè, Enrica Federti, Massimiliano Perduca, Davide Melisi, Immacolata Andolfo, Angela Amoresano, Achille Iolascon, Maria Teresa Valenti, Francesco Turrini, Michele Bovi, Arianna Pisani, Antonio Recchiuti, Domenico Mattoscio, Veronica Riccardi, Luca Dalle Carbonare, Carlo Brugnara, Narla Mohandas, Lucia De Franceschi

المصدر: Antioxidants, Vol 13, Iss 4, p 454 (2024)

مصطلحات موضوعية: oxidation, astaxanthin, nanoparticles, PLGA, red cells, UPR system, Therapeutics. Pharmacology, RM1-950

الوصف: Aging is characterized by increased oxidation and reduced efficiency of cytoprotective mechanisms. Nuclear factor erythroid-2-related factor (Nrf2) is a key transcription factor, controlling the expression of multiple antioxidant proteins. Here, we show that Nrf2−/− mice displayed an age-dependent anemia, due to the combined contributions of reduced red cell lifespan and ineffective erythropoiesis, suggesting a role of Nrf2 in erythroid biology during aging. Mechanistically, we found that the expression of antioxidants during aging is mediated by activation of Nrf2 function by peroxiredoxin-2. The absence of Nrf2 resulted in persistent oxidation and overactivation of adaptive systems such as the unfolded protein response (UPR) system and autophagy in Nrf2−/− mouse erythroblasts. As Nrf2 is involved in the expression of autophagy-related proteins such as autophagy-related protein (Atg) 4-5 and p62, we found impairment of late phase of autophagy in Nrf2−/− mouse erythroblasts. The overactivation of the UPR system and impaired autophagy drove apoptosis of Nrf2−/− mouse erythroblasts via caspase-3 activation. As a proof of concept for the role of oxidation, we treated Nrf2−/− mice with astaxanthin, an antioxidant, in the form of poly (lactic-co-glycolic acid) (PLGA)-loaded nanoparticles (ATS-NPs) to improve its bioavailability. ATS-NPs ameliorated the age-dependent anemia and decreased ineffective erythropoiesis in Nrf2−/− mice. In summary, we propose that Nrf2 plays a key role in limiting age-related oxidation, ensuring erythroid maturation and growth during aging.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2076-3921/13/4/454Test; https://doaj.org/toc/2076-3921Test

الوصول الحر: https://doaj.org/article/6113bcf2028948f886726cd52fe80fabTest

المؤلفون: Simone Augustinus, Hanneke W. M. van Laarhoven, Geert A. Cirkel, Jan Willem B. de Groot, Bas Groot Koerkamp, Teresa Macarulla, Davide Melisi, Eileen M. O'Reilly, Hjalmar C. van Santvoort, Tara M. Mackay, Marc G. Besselink, Johanna W. Wilmink

المصدر: Cancers, Vol 15, Iss 23, p 5603 (2023)

مصطلحات موضوعية: expert survey, case-vignette, pancreatic cancer, asymptomatic, timing of chemotherapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Background: The use of imaging, in general, and during follow-up after resection of pancreatic cancer, is increasing. Consequently, the number of asymptomatic patients diagnosed with metastatic pancreatic cancer (mPDAC) is increasing. In these patients, palliative systemic therapy is the only tumor-directed treatment option; hence, it is often immediately initiated. However, delaying therapy in asymptomatic palliative patients may preserve quality of life and avoid therapy-related toxicity, but the impact on survival is unknown. This study aimed to gain insight into the current perspectives and clinical decision=making of experts regarding the timing of treatment initiation of patients with asymptomatic mPDAC. Methods: An online survey (13 questions, 9 case-vignettes) was sent to all first and last authors of published clinical trials on mPDAC over the past 10 years and medical oncologists of the Dutch Pancreatic Cancer Group. Inter-rater variability was determined using the Kappa Light test. Differences in the preferred timing of treatment initiation among countries, continents, and years of experience were analyzed using Fisher’s exact test. Results: Overall, 78 of 291 (27%) medical oncologists from 15 countries responded (62% from Europe, 23% from North America, and 15% from Asia–Pacific). The majority of respondents (63%) preferred the immediate initiation of chemotherapy following diagnosis. In 3/9 case-vignettes, delayed treatment was favored in specific clinical contexts (i.e., patient with only one small lung metastasis, significant comorbidities, and higher age). A significant degree of inter-rater variability was present within 7/9 case-vignettes. The recommended timing of treatment initiation differed between continents for 2/9 case-vignettes (22%), in 7/9 (77.9%) comparing the Netherlands with other countries, and based on years of experience for 5/9 (56%). Conclusions: Although the response rate was limited, in asymptomatic patients with mPDAC, immediate treatment is most often preferred. Delaying treatment until symptoms occur is considered in patients with limited metastatic disease, more comorbidities, and higher age.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/15/23/5603Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/05a757ff63264a9c9e9dabdbfe5fa8bcTest

المؤلفون: Maria Bencivenga, Lorena Torroni, Mariagiulia Dal Cero, Alberto Quinzii, Camilla Zecchetto, Valeria Merz, Simona Casalino, Francesco Taus, Silvia Pietrobono, Domenico Mangiameli, Federica Filippini, Mariella Alloggio, Claudia Castelli, Mar Iglesias, Manuel Pera, Davide Melisi

المصدر: Journal of Personalized Medicine, Vol 13, Iss 9, p 1294 (2023)

مصطلحات موضوعية: poorly cohesive, gastric cancer, YAP expression, tumor progression, Medicine

الوصف: Poorly cohesive (PC) gastric cancer (GC) is extremely aggressive in progression, and there is an urgent need to identify the molecular pathways involved. We hypothesized the essential role of the RhoA–YAP axis in these mechanisms. The present observational multicenter retrospective study included 133 patients with PC GC treated at two dedicated European surgical centers between 2004 and 2014. YAP nuclear localization was measured by immunohistochemical (IHC) analysis of tissue biopsies. The complete absence of nuclear reactivity was coded as negative expression; we considered “any positive” as low nuclear expression (>0% but p = 0.029) in patients with negative YAP (46%, 95% CI 31.1–60.0%) than in the other patients (27%, 17.5–38.1%). Moreover, when controlling for sex, age, pT, pN, and percentage of signet ring cells in the multivariable analysis, YAP expression was a significant predictor of OS (HR 2.03, 95% CI: 1.18–3.51, p = 0.011). Our results provide new insights into the role of the YAP signaling cascade, as its activation was associated with a worse prognosis in PC GC.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2075-4426/13/9/1294Test; https://doaj.org/toc/2075-4426Test

الوصول الحر: https://doaj.org/article/f8ecdba38aec41e786cf77b89254af02Test

المؤلفون: Valeria Merz, Domenico Mangiameli, Camilla Zecchetto, Alberto Quinzii, Silvia Pietrobono, Carlo Messina, Simona Casalino, Marina Gaule, Camilla Pesoni, Pasquale Vitale, Chiara Trentin, Michela Frisinghelli, Orazio Caffo, Davide Melisi

المصدر: Frontiers in Surgery, Vol 9 (2022)

مصطلحات موضوعية: resectable pancreatic cancer, predictive factors, neoadjuvant therapy, preoperative treatment, target therapy, molecular profiling, Surgery, RD1-811

الوصف: The mainstay treatment for patients with immediate resectable pancreatic cancer remains upfront surgery, which represents the only potentially curative strategy. Nevertheless, the majority of patients surgically resected for pancreatic cancer experiences disease relapse, even when a combination adjuvant therapy is offered. Therefore, aiming at improving disease free survival and overall survival of these patients, there is an increasing interest in evaluating the activity and efficacy of neoadjuvant and perioperative treatments. In this view, it is of utmost importance to find biomarkers able to select patients who may benefit from a preoperative therapy rather than upfront surgical resection. Defined genomic alterations and a dynamic inflammatory microenvironment are the major culprits for disease recurrence and resistance to chemotherapeutic treatments in pancreatic cancer patients. Signal transduction pathways or tumor immune microenvironment could predict early recurrence and response to chemotherapy. In the last decade, distinct molecular subtypes of pancreatic cancer have been described, laying the bases to a tailored therapeutic approach, started firstly in the treatment of advanced disease. Patients with homologous repair deficiency, in particular with mutant germline BRCA genes, represent the first subgroup demonstrating to benefit from specific therapies. A fraction of patients with pancreatic cancer could take advantage of genome sequencing with the aim of identifying possible targetable mutations. These genomic driven strategies could be even more relevant in a potentially curative setting. In this review, we outline putative predictive markers that could help in the next future in tailoring the best therapeutic strategy for pancreatic cancer patients with a potentially curable disease.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fsurg.2022.866173/fullTest; https://doaj.org/toc/2296-875XTest

الوصول الحر: https://doaj.org/article/a3bc1019d4774d3d9b135653201445c7Test

المؤلفون: Camilla Zecchetto, Alberto Quinzii, Simona Casalino, Marina Gaule, Camilla Pesoni, Valeria Merz, Silvia Pietrobono, Domenico Mangiameli, Martina Pasquato, Stefano Milleri, Simone Giacopuzzi, Maria Bencivenga, Anna Tomezzoli, Giovanni de Manzoni, Davide Melisi

المصدر: Journal of Personalized Medicine, Vol 13, Iss 3, p 508 (2023)

مصطلحات موضوعية: esophagogastric cancer, HER-2, trastuzumab resistance, FGFR3, pemigatinib, Medicine

الوصف: Trastuzumab plus chemotherapy is the standard of care for the first-line treatment of patients with HER2+ advanced esophagogastric (EG) cancer. Nevertheless, patients frequently develop resistance. In preclinical models, we identified the overexpression of Fibroblast Growth Factor Receptor (FGFR) 3 as a mechanism potentially involved in trastuzumab-acquired resistance. FGFR inhibition could be a potential mechanism as a second-line treatment. In this Simon’s two-stage phase 2, single arm study, patients with advanced EG cancer refractory to trastuzumab-containing therapies received pemigatinib, an inhibitor of FGFR. The primary end point was the 12-week progression-free survival rate. Translational analyses were performed on tissue and plasma samples. Eight patients were enrolled in the first stage. Although the 6-week disease control rate was 25%, only one patient achieved a stable disease after 12 weeks of treatment. The trial was discontinued before the second stage. Two out of six evaluable tumor samples expressed FGFR3. No FGFRs amplification was detected. HER2 amplification was lost in three out of eight patients. Three patients had an high Tumor Mutational Burden, and two of them are significantly long-term survivors. These results do not support the therapeutic efficacy of targeting FGFR in unselected patients with advanced EG cancer, who are refractory to trastuzumab-containing therapies.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2075-4426/13/3/508Test; https://doaj.org/toc/2075-4426Test

الوصول الحر: https://doaj.org/article/3f2ef8f4704e4073aec1d7f1f8a2f276Test