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1. Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation

Author

Grandone, E, Tiscia, G, Pesavento, R, De Laurenzo, A, Ceccato, D, Sartori, M, Mirabella, L, Cinnella, G, Mastroianno, M, Dalfino, L, Colaizzo, D, Vettor, R, Intrieri, M, Ostuni, A, Margaglione, M, Alboini, P, Antonioni, A, Aucella, F, Bochicchio, G, Carbonelli, C, Carella, M, Castori, M, Centonze, A, Ciliberti, G, Copetti, M, Corritore, M, De Cosmo, S, D'Aloiso, L, D'Errico, M, de Matthaeis, A, Del Gaudio, A, Di Giorgio, A, Giambra, V, Greco, A, Florio, L, Fontana, A, Inchingolo, V, Inglese, M, Labonia, M, La Marca, A, Latiano, T, Leone, M, Maiello, E, Mangia, A, Marciano, C, Massa, V, Massafra, S, Orciuli, G, Palladino, N, Perna, R, Piscitelli, P, Piemontese, M, Prencipe, M, Raggi, P, Rodriquenz, M, Russo, R, Sancarlo, D, Simeone, A, Trischitta, V, Zarrelli, M, Vaira, P, Vergara, D, Vescovi, A, Grandone E., Tiscia G., Pesavento R., De Laurenzo A., Ceccato D., Sartori M. T., Mirabella L., Cinnella G., Mastroianno M., Dalfino L., Colaizzo D., Vettor R., Intrieri M., Ostuni A., Margaglione M., Alboini P. E., Antonioni A., Aucella F., Bochicchio G. B., Carbonelli C., Carella M., Castori M., Centonze A., Ciliberti G., Copetti M., Corritore M., De Cosmo S., D'Aloiso L., D'Errico M. M., de Matthaeis A., Del Gaudio A., Di Giorgio A., Giambra V., Greco A., Florio L., Fontana A., Inchingolo V., Inglese M., Labonia M., La Marca A., Latiano T., Leone M., Maiello E., Mangia A., Marciano C., Massa V., Massafra S., Orciuli G., Palladino N., Perna R., Piscitelli P., Piemontese M., Prencipe M. A., Raggi P., Rodriquenz M. G., Russo R., Sancarlo D., Simeone A., Trischitta V., Zarrelli M., Vaira P., Vergara D., Vescovi A., Grandone, E, Tiscia, G, Pesavento, R, De Laurenzo, A, Ceccato, D, Sartori, M, Mirabella, L, Cinnella, G, Mastroianno, M, Dalfino, L, Colaizzo, D, Vettor, R, Intrieri, M, Ostuni, A, Margaglione, M, Alboini, P, Antonioni, A, Aucella, F, Bochicchio, G, Carbonelli, C, Carella, M, Castori, M, Centonze, A, Ciliberti, G, Copetti, M, Corritore, M, De Cosmo, S, D'Aloiso, L, D'Errico, M, de Matthaeis, A, Del Gaudio, A, Di Giorgio, A, Giambra, V, Greco, A, Florio, L, Fontana, A, Inchingolo, V, Inglese, M, Labonia, M, La Marca, A, Latiano, T, Leone, M, Maiello, E, Mangia, A, Marciano, C, Massa, V, Massafra, S, Orciuli, G, Palladino, N, Perna, R, Piscitelli, P, Piemontese, M, Prencipe, M, Raggi, P, Rodriquenz, M, Russo, R, Sancarlo, D, Simeone, A, Trischitta, V, Zarrelli, M, Vaira, P, Vergara, D, Vescovi, A, Grandone E., Tiscia G., Pesavento R., De Laurenzo A., Ceccato D., Sartori M. T., Mirabella L., Cinnella G., Mastroianno M., Dalfino L., Colaizzo D., Vettor R., Intrieri M., Ostuni A., Margaglione M., Alboini P. E., Antonioni A., Aucella F., Bochicchio G. B., Carbonelli C., Carella M., Castori M., Centonze A., Ciliberti G., Copetti M., Corritore M., De Cosmo S., D'Aloiso L., D'Errico M. M., de Matthaeis A., Del Gaudio A., Di Giorgio A., Giambra V., Greco A., Florio L., Fontana A., Inchingolo V., Inglese M., Labonia M., La Marca A., Latiano T., Leone M., Maiello E., Mangia A., Marciano C., Massa V., Massafra S., Orciuli G., Palladino N., Perna R., Piscitelli P., Piemontese M., Prencipe M. A., Raggi P., Rodriquenz M. G., Russo R., Sancarlo D., Simeone A., Trischitta V., Zarrelli M., Vaira P., Vergara D., and Vescovi A.

Abstract

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p < 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann–Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13–0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

Published
2021

3. Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation

Author

Grandone, E., Tiscia, G., Pesavento, R., De Laurenzo, A., Ceccato, D., Sartori, M. T., Mirabella, L., Cinnella, G., Mastroianno, M., Dalfino, L., Colaizzo, D., Vettor, R., Intrieri, M., Ostuni, A., Margaglione, M., Alboini, P. E., Antonioni, A., Aucella, F., Bochicchio, G. B., Carbonelli, C., Carella, M., Castori, M., Centonze, A., Ciliberti, G., Copetti, M., Corritore, M., De Cosmo, S., D'Aloiso, L., D'Errico, M. M., de Matthaeis, A., Del Gaudio, A., Di Giorgio, A., Giambra, V., Greco, A., Florio, L., Fontana, A., Inchingolo, V., Inglese, M., Labonia, M., La Marca, A., Latiano, T., Leone, M., Maiello, E., Mangia, A., Marciano, C., Massa, V., Massafra, S., Orciuli, G., Palladino, N., Perna, R., Piscitelli, P., Piemontese, M., Prencipe, M. A., Raggi, P., Rodriquenz, M. G., Russo, R., Sancarlo, D., Simeone, A., Trischitta, V., Zarrelli, M., Vaira, P., Vergara, D., Vescovi, A., Grandone, E, Tiscia, G, Pesavento, R, De Laurenzo, A, Ceccato, D, Sartori, M, Mirabella, L, Cinnella, G, Mastroianno, M, Dalfino, L, Colaizzo, D, Vettor, R, Intrieri, M, Ostuni, A, Margaglione, M, Alboini, P, Antonioni, A, Aucella, F, Bochicchio, G, Carbonelli, C, Carella, M, Castori, M, Centonze, A, Ciliberti, G, Copetti, M, Corritore, M, De Cosmo, S, D'Aloiso, L, D'Errico, M, de Matthaeis, A, Del Gaudio, A, Di Giorgio, A, Giambra, V, Greco, A, Florio, L, Fontana, A, Inchingolo, V, Inglese, M, Labonia, M, La Marca, A, Latiano, T, Leone, M, Maiello, E, Mangia, A, Marciano, C, Massa, V, Massafra, S, Orciuli, G, Palladino, N, Perna, R, Piscitelli, P, Piemontese, M, Prencipe, M, Raggi, P, Rodriquenz, M, Russo, R, Sancarlo, D, Simeone, A, Trischitta, V, Zarrelli, M, Vaira, P, Vergara, D, and Vescovi, A

Subjects
Male, Time Factors, 030204 cardiovascular system & hematology, Logistic regression, law.invention, 0302 clinical medicine, law, Risk Factors, 80 and over, 030212 general & internal medicine, Hospital Mortality, Hematology, Low-Molecular-Weight, COVID-19, Low-molecular-weight heparin, Mortality, Ventilation, Aged, Aged, 80 and over, Anticoagulants, Clinical Decision-Making, Female, Heparin, Low-Molecular-Weight, Hospitalization, Humans, Middle Aged, Protective Factors, Risk Assessment, Thromboembolism, Treatment Outcome, Blood Transfusion, Heparin, Intensive care unit, Cohort, Breathing, Cardiology and Cardiovascular Medicine, medicine.drug, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), medicine.drug_class, Low molecular weight heparin, Article, 03 medical and health sciences, Internal medicine, medicine, low-molecular-weight heparin, mortality, ventilation, aged, aged 80 and over, anticoagulants, clinical decision-making, female, low-molecular-weight, hospital mortality, hospitalization, humans, male, middle aged, protective factors, risk assessment, risk factors, thromboembolism, time factors, treatment outcome, blood transfusion, business.industry, business
Abstract

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p < 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann–Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13–0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

Published
2021

4. Correction to: Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation

Author

Grandone, E., Tiscia, G., Pesavento, R., De Laurenzo, A., Ceccato, D., Sartori, M. T., Mirabella, L., Cinnella, G., Mastroianno, M., Dalfino, L., Colaizzo, D., Vettor, R., Intrieri, M., Ostuni, A., Margaglione, M., Alboini, P. E., Antonioni, A., Aucella, F., Bochicchio, G. B., Carbonelli, C., Carella, M., Castori, M., Centonze, A., Ciliberti, G., Copetti, M., Corritore, M., De Cosmo, S., D'Aloiso, L., D'Errico, M. M., de Matthaeis, A., Del Gaudio, A., Di Giorgio, A., Giambra, V., Greco, A., Florio, L., Fontana, A., Inchingolo, V., Inglese, M., Labonia, M., La Marca, A., Latiano, T., Leone, M., Maiello, E., Mangia, A., Marciano, C., Massa, V., Massafra, S., Orciulo, G., Palladino, N., Perna, R., Piscitelli, P., Piemontese, M., Prencipe, M. A., Raggi, P., Rodriquenz, M. G., Russo, R., Sancarlo, D., Simeone, A., Trischitta, V., Zarrelli, M., Vaira, P., Vergara, D., and Vescovi, A.

Subjects
Male, 2019-20 coronavirus outbreak, medicine.medical_specialty, Time Factors, Coronavirus disease 2019 (COVID-19), medicine.drug_class, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clinical Decision-Making, Low molecular weight heparin, Risk Assessment, Risk Factors, Internal medicine, Thromboembolism, medicine, Humans, Blood Transfusion, Hospital Mortality, Aged, Aged, 80 and over, Hematology, business.industry, Correction, Anticoagulants, COVID-19, Heparin, Low-Molecular-Weight, Middle Aged, Protective Factors, CSS COVID-19 Group, Covid-19, research groups, Hospitalization, Treatment Outcome, Emergency medicine, Breathing, Female, Cardiology and Cardiovascular Medicine, business
Abstract

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann-Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13-0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

Published
2021

5. Correction to: Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation (Journal of Thrombosis and Thrombolysis, (2021), 52, 3, (772-778), 10.1007/s11239-021-02429-z)

Author

Grandone, E., Tiscia, G., Pesavento, R., De Laurenzo, A., Ceccato, D., Sartori, M. T., Mirabella, L., Cinnella, G., Mastroianno, M., Dalfino, L., Colaizzo, D., Vettor, R., Intrieri, M., Ostuni, A., Margaglione, M., Alboini, P. E., Antonioni, A., Aucella, F., Bochicchio, G. B., Carbonelli, C., Carella, M., Castori, M., Centonze, A., Ciliberti, G., Copetti, M., Corritore, M., De Cosmo, S., D'Aloiso, L., D'Errico, M. M., de Matthaeis, A., Del Gaudio, A., Di Giorgio, A., Giambra, V., Greco, A., Florio, L., Fontana, A., Inchingolo, V., Inglese, M., Labonia, M., La Marca, A., Latiano, T., Leone, M., Maiello, E., Mangia, A., Marciano, C., Massa, V., Massafra, S., Orciulo, G., Palladino, N., Perna, R., Piscitelli, P., Piemontese, M., Prencipe, M. A., Raggi, P., Rodriquenz, M. G., Russo, R., Sancarlo, D., Simeone, A., Trischitta, V., Zarrelli, M., Vaira, P., Vergara, D., and Vescovi, A.

Published
2021

6. Novel epigenetic eight-gene signature predictive of poor prognosis and msi-like phenotype in human metastatic colorectal carcinomas

Author

Condelli, Valentina, Calice, G., Cassano, A., Basso, M., Rodriquenz, M. G., Zupa, A., Maddalena, F., Crispo, F., Pietrafesa, M., Aieta, M., Sgambato, Alessandro, Tortora, Giampaolo, Zoppoli, P., Landriscina, M., Condelli V., Sgambato A. (ORCID:0000-0002-9487-4563), Tortora G. (ORCID:0000-0002-1378-4962), Condelli, Valentina, Calice, G., Cassano, A., Basso, M., Rodriquenz, M. G., Zupa, A., Maddalena, F., Crispo, F., Pietrafesa, M., Aieta, M., Sgambato, Alessandro, Tortora, Giampaolo, Zoppoli, P., Landriscina, M., Condelli V., Sgambato A. (ORCID:0000-0002-9487-4563), and Tortora G. (ORCID:0000-0002-1378-4962)

Abstract

Epigenetics is involved in tumor progression and drug resistance in human colorectal carcinoma (CRC). This study addressed the hypothesis that the DNA methylation profiling may predict the clinical behavior of metastatic CRCs (mCRCs). The global methylation profile of two human mCRC subgroups with significantly different outcome was analyzed and compared with gene expression and methylation data from The Cancer Genome Atlas COlon ADenocarcinoma (TCGA COAD) and the NCBI GENE expression Omnibus repository (GEO) GSE48684 mCRCs datasets to identify a prognostic signature of functionally methylated genes. A novel epigenetic signature of eight hypermethylated genes was characterized that was able to identify mCRCs with poor prognosis, which had a CpG-island methylator phenotype (CIMP)-high and microsatellite instability (MSI)-like phenotype. Interestingly, methylation events were enriched in genes located on the q-arm of chromosomes 13 and 20, two chromosomal regions with gain/loss alterations associated with adenoma-to-carcinoma progression. Finally, the expression of the eight-genes signature and MSI-enriching genes was confirmed in oxaliplatin-and irinotecan-resistant CRC cell lines. These data reveal that the hypermethylation of specific genes may provide prognostic information that is able to identify a subgroup of mCRCs with poor prognosis.

Published
2021

9. Association of IL-8 and eNOS polymorphisms with clinical outcomes in bevacizumab-treated breast cancer patients: an exploratory analysis

Author

Di Salvatore, Mariantonietta, Lo Giudice, Loredana, Rossi, Ernesto, Santonocito, Concetta, Nazzicone, Giulia, Rodriquenz, M. G, Cappuccio, Serena, Inno, Alessandro, Fuso, Paola, Orlandi, Armando, Strippoli, Antonia, Capoluongo, Ettore Domenico, Astone, Antonio, Cassano, Alessandra, Barone, Carlo Antonio, Santonocito, Concetta (ORCID:0000-0003-3624-1386), Orlandi, Armando (ORCID:0000-0001-5253-4678), Capoluongo, Ettore Domenico (ORCID:0000-0001-9872-0572), Astone, Antonio (ORCID:0000-0001-9572-309X), Cassano, Alessandra (ORCID:0000-0002-3311-7163), Di Salvatore, Mariantonietta, Lo Giudice, Loredana, Rossi, Ernesto, Santonocito, Concetta, Nazzicone, Giulia, Rodriquenz, M. G, Cappuccio, Serena, Inno, Alessandro, Fuso, Paola, Orlandi, Armando, Strippoli, Antonia, Capoluongo, Ettore Domenico, Astone, Antonio, Cassano, Alessandra, Barone, Carlo Antonio, Santonocito, Concetta (ORCID:0000-0003-3624-1386), Orlandi, Armando (ORCID:0000-0001-5253-4678), Capoluongo, Ettore Domenico (ORCID:0000-0001-9872-0572), Astone, Antonio (ORCID:0000-0001-9572-309X), and Cassano, Alessandra (ORCID:0000-0002-3311-7163)

Abstract

BACKGROUND: The role of bevacizumab in metastatic breast cancer is controversial. Identification of predictive biomarkers could help to select patients who really benefit from it. We evaluated the association of angiogenesis-related gene polymorphisms with the treatment outcome of bevacizumab in metastatic breast cancer patients. PATIENTS AND METHODS: eNOS-786T/C and -894G/T, IL-8-251T/A genomic polymorphisms were assessed in 31 metastatic breast cancer patients treated with bevacizumab plus chemotherapy in the first-line setting. Testing for association between each polymorphism and treatment outcome was performed. RESULTS: Patients with IL-8 251 AA genotype showed a significantly lower progression-free survival in each combination comparison: "TT" vs "AA" (13 vs 8 months; p = 0.008); TT vs TA vs AA (13 vs 11 vs 8 months; p = 0.02); TT vs TA +AA (13 vs 11 months; p = 0.01); TT + TA vs AA (12 vs 8 months; p = 0.01) and a lower overall survival when compared with TT +TA genotype (26 vs 51 months, p = 0.04). Patients carrying eNOS 894 TT genotype showed a statistically significant lower progression-free survival than patients with GG genotype (11.5 vs 26.5 months; p = 0.04) with no differences in the overall survival. No association with response rate was found with any of the polymorphisms analyzed. CONCLUSION: These findings suggest that IL-8 251T/A and eNOS-894 G/T polymorphisms might have a role in predicting treatment outcome of bevacizumab in metastatic breast cancer. Our results are hypothesis generating and need to be confirmed in larger clinical trials.

Published
2016

10. Association of IL-8 and eNOS polymorphisms with clinical outcomes in bevacizumab-treated breast cancer patients: an exploratory analysis.

Author

Salvatore, M., Giudice, L., Rossi, E., Santonocito, C., Nazzicone, G., Rodriquenz, M., Cappuccio, S., Inno, A., Fuso, P., Orlandi, A., Strippoli, A., Capoluongo, E., Astone, A., Cassano, A., and Barone, C.

Abstract

Background: The role of bevacizumab in metastatic breast cancer is controversial. Identification of predictive biomarkers could help to select patients who really benefit from it. We evaluated the association of angiogenesis-related gene polymorphisms with the treatment outcome of bevacizumab in metastatic breast cancer patients. Patients and methods: eNOS-786T/C and -894G/T, IL-8-251T/A genomic polymorphisms were assessed in 31 metastatic breast cancer patients treated with bevacizumab plus chemotherapy in the first-line setting. Testing for association between each polymorphism and treatment outcome was performed. Results: Patients with IL-8 251 AA genotype showed a significantly lower progression-free survival in each combination comparison: 'TT' vs 'AA' (13 vs 8 months; p = 0.008); TT vs TA vs AA (13 vs 11 vs 8 months; p = 0.02); TT vs TA +AA (13 vs 11 months; p = 0.01); TT + TA vs AA (12 vs 8 months; p = 0.01) and a lower overall survival when compared with TT +TA genotype (26 vs 51 months, p = 0.04). Patients carrying eNOS 894 TT genotype showed a statistically significant lower progression-free survival than patients with GG genotype (11.5 vs 26.5 months; p = 0.04) with no differences in the overall survival. No association with response rate was found with any of the polymorphisms analyzed. Conclusion: These findings suggest that IL-8 251T/A and eNOS-894 G/T polymorphisms might have a role in predicting treatment outcome of bevacizumab in metastatic breast cancer. Our results are hypothesis generating and need to be confirmed in larger clinical trials. [ABSTRACT FROM AUTHOR]

Published
2016
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11. Germinal BRCA1-2 pathogenic variants (gBRCA1-2pv) and pancreatic cancer: epidemiology of an Italian patient cohort

Author

Michele Reni, M. Macchini, Maria Grazia Rodriquenz, F. Centonze, G. Tortora, I.G. Rapposelli, S. De Lorenzo, Michele Simbolo, Paola Carrera, A. Avallone, F. De Vita, S. Calzavara, C. Chiarazzo, Marina Gaule, Giulia Orsi, Alessandro Cavaliere, Margherita Ratti, L. Stuppia, M. Di Marco, C. Paratore, Michele Milella, F. de Braud, Monica Niger, Lisa Salvatore, Davide Melisi, Stefano Cascinu, L.G. Forti, G. Giordano, M.M. Valente, Massimo Falconi, U. Peretti, U. Peretti, A. Cavaliere, M. Niger, G. Tortora, M. C. Di Marco, M. G. Rodriquenz, F. Centonze, I. G. Rapposelli, G. Giordano, F. De Vita, L. Stuppia, A. Avallone, M. Ratti, C. Paratore, L. G. Forti, G. Orsi, M. M. Valente, M. Gaule, M. Macchini, P. Carrera, S. Calzavara, M. Simbolo, D. Melisi, F. De Braud, L. Salvatore, S. De Lorenzo, C. Chiarazzo, M. Falconi, S. Cascinu, M. Milella, M. Reni, Peretti, U, Cavaliere, A, Niger, M, Tortora, G, Di Marco, M C, Rodriquenz, M G, Centonze, F, Rapposelli, I G, Giordano, G, De Vita, F, Stuppia, L, Avallone, A, Ratti, M, Paratore, C, Forti, L G, Orsi, G, Valente, M M, Gaule, M, Macchini, M, Carrera, P, Calzavara, S, Simbolo, M, Melisi, D, De Braud, F, Salvatore, L, De Lorenzo, S, Chiarazzo, C, Falconi, M, Cascinu, S, Milella, M, Reni, M, Peretti, U., Cavaliere, A., Niger, M., Tortora, G., Di Marco, M. C., Rodriquenz, M. G., Centonze, F., Rapposelli, I. G., Giordano, G., De Vita, F., Stuppia, L., Avallone, A., Ratti, M., Paratore, C., Forti, L. G., Orsi, G., Valente, M. M., Gaule, M., Macchini, M., Carrera, P., Calzavara, S., Simbolo, M., Melisi, D., De Braud, F., Salvatore, L., De Lorenzo, S., Chiarazzo, C., Falconi, M., Cascinu, S., Milella, M., and Reni, M.

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Adenocarcinoma, familial cancer, Prostate cancer, Pancreatic cancer, Internal medicine, Epidemiology, Medicine, Humans, Family history, Germ-Line Mutation, Aged, Original Research, pancreatic cancer genetics, Aged, 80 and over, BRCA2 Protein, business.industry, BRCA1 Protein, Incidence (epidemiology), Middle Aged, pancreatic cancer genetic, medicine.disease, germline BRCA, epidemiology, pancreatic cancer genetics, familial cancer, Pancreatic Neoplasms, Exact test, Oncology, Italy, germline BRCA, Cohort, Female, epidemiology, business, Human
Abstract

Objective Germline BRCA1-2 pathogenic variants (gBRCApv) increase the risk of pancreatic cancer and predict for response to platinating agents and poly(ADP-ribose) polymerase inhibitors. Data on worldwide gBRCApv incidence among pancreatic ductal adenocarcinoma (PDAC) patients are sparse and describe a remarkable geographic heterogeneity. The aim of this study is to analyze the epidemiology of gBRCApv in Italian patients. Materials and methods Patients of any age with pancreatic adenocarcinoma, screened within 3 months from diagnosis for gBRCApv in Italian oncologic centers systematically performing tests without any selection. For the purposes of our analysis, breast, ovarian, pancreas, and prostate cancer in a patient's family history was considered as potentially BRCA-associated. Patients or disease characteristics were examined using the χ2 test or Fisher's exact test for qualitative variables and the Student's t-test or Mann–Whitney test for continuous variables, as appropriate. Results Between June 2015 and May 2020, 939 patients were tested by 14 Italian centers; 492 (52%) males, median age 62 years (range 28-87), 569 (61%) metastatic, 273 (29%) with a family history of potentially BRCA-associated cancers. gBRCA1-2pv were found in 76 patients (8.1%; 9.1% in metastatic; 6.4% in non-metastatic). The gBRCA2/gBRCA1 ratio was 5.4 : 1. Patients with gBRCApv were younger compared with wild-type (59 versus 62 years, P = 0.01). The gBRCApv rate was 17.1% among patients 70 years old (none out of 94 patients >73 years old). gBRCApv frequency in 845 patients, Highlights • This is the largest case series of incident PDAC patients screened for germline BRCA1-2 pathologic variants (gBRCApv). • The incidence of gBRCA1-2pv was 8.1% in the whole population; 9.1% in metastatic patients; 6.4% in non-metastatic patients. • No gBRCA1-2pv was observed over the age of 73. • These data suggest screening all PDAC patients

Published
2020

12. Immunotherapy for Biliary Tract Cancer in the Era of Precision Medicine: Current Knowledge and Future Perspectives

Author

Davide Ciardiello, Brigida Anna Maiorano, Paola Parente, Maria Grazia Rodriquenz, Tiziana Pia Latiano, Cinzia Chiarazzo, Valerio Pazienza, Luigi Pio Guerrera, Brunella Amoruso, Nicola Normanno, Giulia Martini, Fortunato Ciardiello, Erika Martinelli, Evaristo Maiello, Ciardiello, D., Maiorano, B. A., Parente, P., Rodriquenz, M. G., Latiano, T. P., Chiarazzo, C., Pazienza, V., Guerrera, L. P., Amoruso, B., Normanno, N., Martini, G., Ciardiello, F., Martinelli, E., and Maiello, E.

Subjects
QH301-705.5, Review, Target therapy, Catalysis, Inorganic Chemistry, Antineoplastic Agents, Immunological, Biomarkers, Tumor, Animals, Humans, Molecular Targeted Therapy, Physical and Theoretical Chemistry, Biology (General), Molecular Biology, QD1-999, Spectroscopy, Clinical Trials as Topic, Organic Chemistry, Precision medicine, Disease Management, General Medicine, Prognosis, Combined Modality Therapy, Computer Science Applications, Gene Expression Regulation, Neoplastic, Chemistry, Biliary Tract Neoplasms, Treatment Outcome, Biliary tract cancer, Disease Susceptibility, Immunotherapy
Abstract

Biliary tract cancers (BTC) represent a heterogeneous and aggressive group of tumors with dismal prognosis. For a long time, BTC has been considered an orphan disease with very limited therapeutic options. In recent years a better understanding of the complex molecular landscape of biology is rapidly changing the therapeutic armamentarium. However, while 40–50% of patients there are molecular drivers susceptible to target therapy, for the remaining population new therapeutic options represent an unsatisfied clinical need. The role of immunotherapy in the continuum of treatment of patients with BTC is still debated. Despite initial signs of antitumor-activity, single-agent immune checkpoint inhibitors (ICIs) demonstrated limited efficacy in an unselected population. Therefore, identifying the best partner to combine ICIs and predictive biomarkers represents a key challenge to optimize the efficacy of immunotherapy. This review provides a critical analysis of completed trials, with an eye on future perspectives and possible biomarkers of response.

Published
2022

13. Exploring biological heterogeneity and implications on novel treatment paradigm in BRAF-mutant metastatic colorectal cancer

Author

Maria Grazia Rodriquenz, Davide Ciardiello, Tiziana Pia Latiano, Brigida Anna Maiorano, Erika Martinelli, Nicola Silvestris, Fortunato Ciardiello, Evaristo Maiello, Rodriquenz, M. G., Ciardiello, D., Latiano, T. P., Maiorano, B. A., Martinelli, E., Silvestris, N., Ciardiello, F., and Maiello, E.

Subjects
Proto-Oncogene Proteins B-raf, Colonic Neoplasm, Rectal Neoplasms, Secondary resistance, Colorectal Neoplasm, Hematology, Colorectal cancer, digestive system diseases, BRAF, Targeted therapy, Oncology, V600E mutation, Non-V600E mutation, Colonic Neoplasms, Mutation, Treatment algorithm, Humans, Immunotherapy, Precision Medicine, Colorectal Neoplasms, neoplasms, Human
Abstract

Approximatively 8–15% of patients with metastatic colorectal cancer (mCRC) harbor mutation in BRAF gene. Recent advances in molecular biology enabled a better knowledge of the molecular heterogeneity within BRAF mutant (BRAFMT) CRCs, including high rate of overlapping with MSI-H status and detection of non-V600E mutations related to more favorable behavior. Treatment armamentarium has been rapidly growing in this subgroup and includes targeted combinations and immunotherapy for concomitant MSI-H patients, thereby making BRAFMT mCRC an innovative model for precision oncology. Nevertheless, duration of responses to targeted strategies remains unsatisfactory due to the development of secondary resistance, which is currently the field of major clinical research on BRAFMT mCRC. This review explores the molecular, clinical and therapeutic landscape of BRAFMT mCRC as well as an update on current treatment strategies and future perspectives in light of the heterogeneity of BRAF-mutated disease. Furthermore, a novel treatment algorithm for BRAFMT mCRC will be proposed.

Published
2021

14. Chemotherapy toxicity and activity in patients with pancreatic ductal adenocarcinoma and germline BRCA1-2 pathogenic variants (gBRCA1-2pv): a multicenter survey

Author

M. Scartozzi, Giampaolo Tortora, Giulia Orsi, Alessandro Cavaliere, Emiliano Tamburini, A.M. Militello, E. Penzo, L.G. Forti, Michele Milella, I. Bernardini, M. Macchini, Silvia Noventa, Michele Reni, M.M. Valente, Monica Niger, Stefano Cascinu, Andrea Spallanzani, K. Bencardino, M. Di Marco, Ingrid Garajová, A. Bittoni, U. Peretti, S. Mosconi, Silvia Bozzarelli, Maria Grazia Rodriquenz, C. Paratore, I.G. Rapposelli, Guido Giordano, S. De Lorenzo, Elisa Giommoni, Orsi, G., Di Marco, M., Cavaliere, A., Niger, M., Bozzarelli, S., Giordano, G., Noventa, S., Rapposelli, I. G., Garajova, I., Tortora, G., Rodriquenz, M. G., Bittoni, A., Penzo, E., De Lorenzo, S., Peretti, U., Paratore, C., Bernardini, I., Mosconi, S., Spallanzani, A., Macchini, M., Tamburini, E., Bencardino, K., Giommoni, E., Scartozzi, M., Forti, L., Valente, M. M., Militello, A. M., Cascinu, S., Milella, M., Reni, M., Orsi G., Di Marco M., Cavaliere A., Niger M., Bozzarelli S., Giordano G., Noventa S., Rapposelli I.G., Garajova I., Tortora G., Rodriquenz M.G., Bittoni A., Penzo E., De Lorenzo S., Peretti U., Paratore C., Bernardini I., Mosconi S., Spallanzani A., Macchini M., Tamburini E., Bencardino K., Giommoni E., Scartozzi M., Forti L., Valente M.M., Militello A.M., Cascinu S., Milella M., and Reni M.

Subjects
Cancer Research, medicine.medical_specialty, FOLFIRINOX, medicine.medical_treatment, pancreatic cancer, Gastroenterology, Germ Cell, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Original Research, chemotherapy toxicity, Cisplatin, Chemotherapy, Antineoplastic Combined Chemotherapy Protocol, business.industry, BRCA1 Protein, Carcinoma, Gemcitabine, Oxaliplatin, Irinotecan, Pancreatic Neoplasms, Germ Cells, Oncology, chemotherapy activity, Fluorouracil, Pancreatic Ductal, germline BRCA, chemotherapy dose intensity, Toxicity, business, medicine.drug, Human, Carcinoma, Pancreatic Ductal
Abstract

Background Germline BRCA1-2 pathogenic variants (gBRCA1-2pv)-related pancreatic ductal adenocarcinoma (PDAC) showed increased sensitivity to DNA cross-linking agents. This study aimed at exploring safety profile, dose intensity, and activity of different chemotherapy regimens in this setting. Patients and methods gBRCA1-2pv PDAC patients of any age and clinical tumor stage who completed a first course of chemotherapy were eligible. A descriptive analysis of chemotherapy toxicity, dose intensity, response, and survival outcomes was performed. Results A total of 85 gBRCA1-2pv PDAC patients treated in 21 Italian centers between December 2008 and March 2021were enrolled. Seventy-four patients were assessable for toxicity and dose intensity, 83 for outcome. Dose intensity was as follows: nab-paclitaxel 72%, gemcitabine 76% (AG); cisplatin 75%, nab-paclitaxel 73%, capecitabine 73%, and gemcitabine 65% (PAXG); fluorouracil 35%, irinotecan 58%, and oxaliplatin 64% (FOLFIRINOX). When compared with the literature, grade 3-4 neutropenia, thrombocytopenia, and diarrhea were increased with PAXG, and unmodified with AG and FOLFIRINOX. RECIST responses were numerically higher with the three- (81%) or four-drug (73%) platinum-containing regimens that outperformed AG (41%) and oxaliplatin-based doublets (56%). Carbohydrate antigen 19.9 (CA19.9) reduction >89% at nadir was reported in two-third of metastatic patients treated with triplets and quadruplets, as opposed to 33% and 45% of patients receiving oxaliplatin-based doublets or AG, respectively. All patients receiving AG experienced disease progression, with a median progression-free survival (mPFS) of 6.4 months, while patients treated with platinum-containing triplets or quadruplets had an mPFS >10.8 months. Albeit still immature, data on overall survival seemed to parallel those on PFS. Conclusions Our data, as opposed to figures expected from the literature, highlighted that platinum-based regimens provoked an increased toxicity on proliferating cells, when dose intensity was maintained, or an as-expected toxicity, when dose intensity was reduced, while no change in toxicity and dose intensity was evident with AG. Furthermore, an apparently improved outcome of platinum-based triplets or quadruplets over other regimens was observed., Highlights • Nab-paclitaxel plus gemcitabine dose intensity and toxicity were as expected from the literature. • Toxicity with platinum-based triplets was unmodified to the price of consistently reduced dose intensity. • Dose intensity for platinum-based quadruplets was preserved to the price of greater hematological toxicity and diarrhea. • RECIST and CA19.9 responses were higher with platinum-based triplets and quadruplets in metastatic patients. • Longer progression-free and overall survival were observed with platinum-based three- and four-drug regimens in stage IV (AJCC/UICC TNM 8th Edition, 2017) patients.

Published
2021

15. Gene copy number and post-transductional mechanisms regulate TRAP1 expression in human colorectal carcinomas

Author

Michele Aieta, Luciana Possidente, Valentina Condelli, Matteo Landriscina, Francesca Maddalena, Pietro Zoppoli, Michele Pietrafesa, Valeria Li Bergolis, Franca Esposito, Maria Grazia Rodriquenz, Giulia Vita, Pietrafesa, M., Maddalena, F., Possidente, L., Condelli, V., Zoppoli, P., Li Bergolis, V., Rodriquenz, M. G., Aieta, M., Vita, G., Esposito, F., and Landriscina, M.

Subjects
Adult, Male, Proteomics, Gene Dosage, Colorectal Neoplasm, Article, Catalysis, TRAP1, lcsh:Chemistry, Inorganic Chemistry, Downregulation and upregulation, Heat shock protein, medicine, Humans, Gene silencing, HSP90 Heat-Shock Proteins, Copy-number variation, Physical and Theoretical Chemistry, lcsh:QH301-705.5, Molecular Biology, Spectroscopy, Aged, Aged, 80 and over, Polysomy, Messenger RNA, GSNOR, biology, Copy number variation, Organic Chemistry, General Medicine, Middle Aged, medicine.disease, Hsp90, S-nitrosylation, Computer Science Applications, Gene Expression Regulation, Neoplastic, Colorectal carcinoma, HSP90 Heat-Shock Protein, lcsh:Biology (General), lcsh:QD1-999, TRAP1 Gene, Cancer research, biology.protein, Female, Colorectal Neoplasms, Human
Abstract

Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a heat shock protein 90 (HSP90) molecular chaperone overexpressed in 60&ndash, 70% human colorectal carcinomas (CRCs) and the co-upregulation of TRAP1 and associated 6-related proteins identifies metastatic CRCs with poor prognosis. Since the molecular mechanisms responsible for TRAP1 regulation are still unknown, the significance of TRAP1 gene copy number (CN) and the role of post-transductional protein modifications were addressed. TRAP1 gene aneuploidy accounted for 34.5% of cases in a cohort of 58 human CRCs and TRAP1 CN correlated with its mRNA and protein expression, suggesting that transcriptional mechanisms are responsible for TRAP1 upregulation. Furthermore, the analysis of the National Cancer Institute&rsquo, s Clinical Proteomic Tumor Analysis Consortium/The Cancer Genome Atlas (CPTAC/TCGA) CRC database showed that TRAP1 polysomy significantly correlates with lymph node involvement. However, a subgroup of tumors showed TRAP1 protein levels independent from its CN. Of note, a direct correlation was observed between TRAP1 protein levels and the expression of S-nitrosoglutathione reductase (GSNOR), a denitrosylase involved in the regulation of protein S-nitrosylation. Furthermore, CRC cell lines exposed to hypoxia or dichloroacetate treatment showed the downregulation of TRAP1 upon GSNOR silencing and this resulted in increased TRAP1 mono/polyubiquitination. These data suggest that transcriptional and post-transductional mechanisms account for TRAP1 expression in human CRCs and GSNOR protects TRAP1 from S-nitrosylation and consequent proteasome degradation mostly in conditions of stress.

Published
2020

16. Novel Epigenetic Eight-Gene Signature Predictive of Poor Prognosis and MSI-Like Phenotype in Human Metastatic Colorectal Carcinomas

Author

Michele A. Basso, Francesca Maddalena, Fabiana Crispo, Giampaolo Tortora, Alessandra Cassano, Michele Pietrafesa, Valentina Condelli, Giovanni Calice, Maria Grazia Rodriquenz, Angela Zupa, Alessandro Sgambato, Matteo Landriscina, Pietro Zoppoli, Michele Aieta, Condelli, V., Calice, G., Cassano, A., Basso, M., Rodriquenz, M. G., Zupa, A., Maddalena, F., Crispo, F., Pietrafesa, M., Aieta, M., Sgambato, A., Tortora, G., Zoppoli, P., and Landriscina, M.

Subjects
0301 basic medicine, Cancer Research, Prognosi, CIMP status, Biology, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, Settore MED/04 - PATOLOGIA GENERALE, Gene signature, medicine, CIMP statu, Epigenetics, neoplasms, Gene, Microsatellite instability, Methylation, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, Promoter methylation, medicine.disease, Phenotype, digestive system diseases, MSI-like signature, Colorectal carcinoma, 030104 developmental biology, Oncology, Tumor progression, 030220 oncology & carcinogenesis, MSI-like signa-ture, DNA methylation, Cancer research
Abstract

Simple Summary The global methylation profile of two human metastatic colorectal carcinoma subgroups with significantly different outcomes (primary-resistant versus drug-sensitive tumors) was analyzed and compared with the gene expression and methylation data from The Cancer Genome Atlas COlon ADenocarcinoma (TCGA COAD) metastatic colorectal carcinoma dataset with the aim to identify a prognostic signature of functionally methylated genes. A novel epigenetic eight-gene signature, with hypermethylation of the promoter regions, was identified and validated for its capacity to predict poor outcome, which had a CpG-island methylator phenotype (CIMP)-high status and microsatellite instability (MSI)-like phenotype. Abstract Epigenetics is involved in tumor progression and drug resistance in human colorectal carcinoma (CRC). This study addressed the hypothesis that the DNA methylation profiling may predict the clinical behavior of metastatic CRCs (mCRCs). The global methylation profile of two human mCRC subgroups with significantly different outcome was analyzed and compared with gene expression and methylation data from The Cancer Genome Atlas COlon ADenocarcinoma (TCGA COAD) and the NCBI GENE expression Omnibus repository (GEO) GSE48684 mCRCs datasets to identify a prognostic signature of functionally methylated genes. A novel epigenetic signature of eight hypermethylated genes was characterized that was able to identify mCRCs with poor prognosis, which had a CpG-island methylator phenotype (CIMP)-high and microsatellite instability (MSI)-like phenotype. Interestingly, methylation events were enriched in genes located on the q-arm of chromosomes 13 and 20, two chromosomal regions with gain/loss alterations associated with adenoma-to-carcinoma progression. Finally, the expression of the eight-genes signature and MSI-enriching genes was confirmed in oxaliplatin- and irinotecan-resistant CRC cell lines. These data reveal that the hypermethylation of specific genes may provide prognostic information that is able to identify a subgroup of mCRCs with poor prognosis.

Published
2021

17. Lenvatinib for the treatment of renal cell carcinoma

Author

Navid Sobhani, Giandomenico Roviello, Silvia Paola Corona, Daniele Generali, Anna Maria Mileo, Maria Grazia Rodriquenz, Marco Imperatori, Raffaele Conca, Giovanni Bozza, Anna Ianza, Michele Aieta, Roviello, G., Corona, S., Bozza, G., Aieta, M., Generali, D., Rodriquenz, M. G., Mileo, A. M., Imperatori, M., Ianza, A., Conca, R., and Sobhani, N.

Subjects
0301 basic medicine, Vascular Endothelial Growth Factor A, PDGFRα, VEGF receptors, Quinoline, Angiogenesis Inhibitors, urologic and male genital diseases, chemistry.chemical_compound, 0302 clinical medicine, Renal cell carcinoma, Antineoplastic Combined Chemotherapy Protocols, Pharmacology (medical), Receptor, biology, Phenylurea Compounds, VEGFR1–3, c-KIT, FGFR1–4, Lenvatinib, RET, Animals, Carcinoma, Renal Cell, Everolimus, Humans, Kidney Neoplasms, Protein Kinase Inhibitors, Quinolines, Kidney Neoplasm, General Medicine, Vascular endothelial growth factor, Vascular endothelial growth factor A, Everolimu, 030220 oncology & carcinogenesis, medicine.drug, Angiogenesis Inhibitor, Human, Phenylurea Compound, VEGFR1-3, FGFR1-4, Protein Kinase Inhibitor, 03 medical and health sciences, medicine, Pharmacology, Antineoplastic Combined Chemotherapy Protocol, business.industry, Animal, Carcinoma, Renal Cell, medicine.disease, 030104 developmental biology, chemistry, biology.protein, Cancer research, business
Abstract

Introduction: Renal cell carcinoma (RCC) accounts for 2–3% of all solid tumors. Expression of the receptor for the vascular endothelial growth factor (VEGF) is one of the most common features of RCC. Areas covered: Lenvatinib is a novel multi-kinase inhibitor that has been studied in several solid tumors. It has shown promising results in the treatment of RCC, especially when combined with everolimus, In this review, we summarize the available data of lenvatinib for the treatment of advanced/metastatic renal cell carcinoma. Expert opinion: Lenvatinib in combination with everolimus has provided encouraging results in both clinical and laboratory investigations showing that blocking angiogenesis and the mTOR signalling pathway could be a remarkable approach for treating RCC. As an additive to this type of approach it would be interesting in future clinical settings testing also the combination of lenvatinib and everolimus with immune-therapy.

Published
2018

18. Chemotherapy toxicity and activity in patients with pancreatic ductal adenocarcinoma and germline BRCA1-2 pathogenic variants (gBRCA1-2pv): a multicenter survey.

Author

Orsi G, Di Marco M, Cavaliere A, Niger M, Bozzarelli S, Giordano G, Noventa S, Rapposelli IG, Garajova I, Tortora G, Rodriquenz MG, Bittoni A, Penzo E, De Lorenzo S, Peretti U, Paratore C, Bernardini I, Mosconi S, Spallanzani A, Macchini M, Tamburini E, Bencardino K, Giommoni E, Scartozzi M, Forti L, Valente MM, Militello AM, Cascinu S, Milella M, and Reni M

Subjects
Antineoplastic Combined Chemotherapy Protocols adverse effects, BRCA1 Protein genetics, Cisplatin therapeutic use, Germ Cells, Humans, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal genetics, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics
Abstract

Background: Germline BRCA1-2 pathogenic variants (gBRCA1-2pv)-related pancreatic ductal adenocarcinoma (PDAC) showed increased sensitivity to DNA cross-linking agents. This study aimed at exploring safety profile, dose intensity, and activity of different chemotherapy regimens in this setting., Patients and Methods: gBRCA1-2pv PDAC patients of any age and clinical tumor stage who completed a first course of chemotherapy were eligible. A descriptive analysis of chemotherapy toxicity, dose intensity, response, and survival outcomes was performed., Results: A total of 85 gBRCA1-2pv PDAC patients treated in 21 Italian centers between December 2008 and March 2021were enrolled. Seventy-four patients were assessable for toxicity and dose intensity, 83 for outcome. Dose intensity was as follows: nab-paclitaxel 72%, gemcitabine 76% (AG); cisplatin 75%, nab-paclitaxel 73%, capecitabine 73%, and gemcitabine 65% (PAXG); fluorouracil 35%, irinotecan 58%, and oxaliplatin 64% (FOLFIRINOX). When compared with the literature, grade 3-4 neutropenia, thrombocytopenia, and diarrhea were increased with PAXG, and unmodified with AG and FOLFIRINOX. RECIST responses were numerically higher with the three- (81%) or four-drug (73%) platinum-containing regimens that outperformed AG (41%) and oxaliplatin-based doublets (56%). Carbohydrate antigen 19.9 (CA19.9) reduction >89% at nadir was reported in two-third of metastatic patients treated with triplets and quadruplets, as opposed to 33% and 45% of patients receiving oxaliplatin-based doublets or AG, respectively. All patients receiving AG experienced disease progression, with a median progression-free survival (mPFS) of 6.4 months, while patients treated with platinum-containing triplets or quadruplets had an mPFS >10.8 months. Albeit still immature, data on overall survival seemed to parallel those on PFS., Conclusions: Our data, as opposed to figures expected from the literature, highlighted that platinum-based regimens provoked an increased toxicity on proliferating cells, when dose intensity was maintained, or an as-expected toxicity, when dose intensity was reduced, while no change in toxicity and dose intensity was evident with AG. Furthermore, an apparently improved outcome of platinum-based triplets or quadruplets over other regimens was observed., Competing Interests: Disclosure MN reports travel expenses from Celgene; speaker honorarium from Accademia della Medicina; and consultant honoraria from EMD Serono. IG serves on the advisory board of Amgen, Takeda, and Eisai. GT reports travel expenses and personal honoraria for advisory boards from Celgene, Merck, AstraZeneca, Servier, and BMS. SC reports travel expenses and personal honoraria for the following companies: Amgen, Bayer, Eli Lilly, and Servier (as speaker); Amgen, Eli Lilly, Bayer, Baxter, Merck Sharp & Dohme (MSD), Servier (on advisory boards). Amgen, Baxter, Eli Lilly, Celgene, Novartis, and MSD (as consultant); receiving research grant from Celgene and Eisai. MM reports personal honoraria as speaker or consultant for the following companies: AstraZeneca, MSD, Boehringer Ingelheim, Pfizer, EUSA Pharma, Merck-Serono, Novartis, Roche, Ipsen, and Mylan. MR reports travel expenses and personal honoraria for advisory boards from Celgene, Merck, AstraZeneca, Baxalta (2016), Baxter, Sanofi (2017), Servier, Shire, Eli Lilly, Pfizer (2016), Novocure (2016), and Novartis (2016); personal honoraria for steering committee work for AstraZeneca, and nonremunerated steering committee activities for Boston Pharmaceuticals. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2021
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19. Germinal BRCA1-2 pathogenic variants (gBRCA1-2pv) and pancreatic cancer: epidemiology of an Italian patient cohort.

Author

Peretti U, Cavaliere A, Niger M, Tortora G, Di Marco MC, Rodriquenz MG, Centonze F, Rapposelli IG, Giordano G, De Vita F, Stuppia L, Avallone A, Ratti M, Paratore C, Forti LG, Orsi G, Valente MM, Gaule M, Macchini M, Carrera P, Calzavara S, Simbolo M, Melisi D, De Braud F, Salvatore L, De Lorenzo S, Chiarazzo C, Falconi M, Cascinu S, Milella M, and Reni M

Subjects
Adult, Aged, Aged, 80 and over, Female, Germ-Line Mutation, Humans, Italy epidemiology, Male, Middle Aged, Adenocarcinoma epidemiology, Adenocarcinoma genetics, BRCA1 Protein genetics, BRCA2 Protein genetics, Pancreatic Neoplasms epidemiology, Pancreatic Neoplasms genetics
Abstract

Objective: Germline BRCA1-2 pathogenic variants (gBRCApv) increase the risk of pancreatic cancer and predict for response to platinating agents and poly(ADP-ribose) polymerase inhibitors. Data on worldwide gBRCApv incidence among pancreatic ductal adenocarcinoma (PDAC) patients are sparse and describe a remarkable geographic heterogeneity. The aim of this study is to analyze the epidemiology of gBRCApv in Italian patients., Materials and Methods: Patients of any age with pancreatic adenocarcinoma, screened within 3 months from diagnosis for gBRCApv in Italian oncologic centers systematically performing tests without any selection. For the purposes of our analysis, breast, ovarian, pancreas, and prostate cancer in a patient's family history was considered as potentially BRCA-associated. Patients or disease characteristics were examined using the χ 2 test or Fisher's exact test for qualitative variables and the Student's t-test or Mann-Whitney test for continuous variables, as appropriate., Results: Between June 2015 and May 2020, 939 patients were tested by 14 Italian centers; 492 (52%) males, median age 62 years (range 28-87), 569 (61%) metastatic, 273 (29%) with a family history of potentially BRCA-associated cancers. gBRCA1-2pv were found in 76 patients (8.1%; 9.1% in metastatic; 6.4% in non-metastatic). The gBRCA2/gBRCA1 ratio was 5.4 : 1. Patients with gBRCApv were younger compared with wild-type (59 versus 62 years, P = 0.01). The gBRCApv rate was 17.1% among patients <40 years old, 10.4% among patients 41-50 years old, 9.2% among patients 51-60 years old, 6.7% among patients aged 61-70 years, and 6.2% among patients >70 years old (none out of 94 patients >73 years old). gBRCApv frequency in 845 patients <74 years old was 9%. Patients with/without a family history of potentially BRCA-associated tumors had 14%/6% mutations., Conclusion: Based on our findings of a gBRCApv incidence higher than expected in a real-life series of Italian patients with incident PDAC, we recommend screening all PDAC patients <74 years old, regardless of family history and stage, due to the therapeutic implications and cancer risk prevention in patients' relatives., Competing Interests: Disclosure MR reports travel expenses and personal honoraria for Advisory Boards from Celgene, Merck, Astra-Zeneca, Baxalta (2016), Baxter, Sanofi (2017), Servier, Shire, Eli Lilly, Pfizer (2016), Novocure (2016), and Novartis (2016), personal honoraria for steering committee work for AstraZeneca, and non-remunerated steering committee activities for Boston Pharmaceuticals. MF reports travel expenses and personal honoraria for Advisory Boards from Celgene, Novartis, Advanced Accelerators Applications, and Ipsen. SC reports travel expenses and personal honoraria for the following companies. Speaker: Amgen, Bayer, Eli Lilly, Servier. Advisory Boards: Amgen, Eli Lilly, Bayer, Baxter, Merck Sharp & Dohme (MSD), Servier. Consultant: Amgen, Baxter, Eli Lilly, Celgene, Novartis, MSD. Research grant: Celgene, Eisai. GT: Travel expenses and personal honoraria for Advisory Boards from Celgene, Merck, Astra-Zeneca, Servier. LS reports travel expenses and personal honoraria for Advisory Boards from Merck-Serono, Celgene, Roche, Sanofi, Servier, Bayer, Astra-Zeneca, Amgen. DM reports research grants and personal fees for consulting from Incyte Corporation; research grants and personal fees for consulting from Shire, Evotec, and iOnctura; research grants from Celgene, and personal fees for consulting from Eli Lilly and Baxter. FDV reports travel expenses and personal honoraria for Advisory Boards: Roche, Amgen, Celgene, Eli Lilly, Servier. MDM reports travel expenses and personal honoraria for Advisory Boards from Celgene. GG reports travel expenses and personal honoraria for Advisory Boards from Celgene (2016–2017–2018), Sanofi (2016–2018), Servier (2019). FDB reports personal honoraria for: Consultant Advisory Board: Ignyta, Bristol-Myers Squibb (BMS), Daiichi Sankyo, Pfizer, Octimet Oncology, Incyte, Teofarma, Pierre Fabre, Roche, EMD Serono, Sanofi, NMS Nerviano Medical Science, Pharm Research Associated (UK) Ltd; Speaker: BMS, Roche, MSD, Ignyta, Bayer, ACCMED, Dephaforum S.r.l., Nadirex, Merck, Biotechspert Ltd, PriME Oncology, Pfizer, Servier, Celgene, Tesaro, Loxo Oncology Inc., Sanofi, Healthcare Research & Pharmacoepidemiology. MN reports travel expenses from Celgene and personal honoraria for Advisory Board from EMD Serono. All the other authors have declared no conflicts of interest. Patient consent Before testing, all patients signed an informed consensus statement that was revised and approved by a local ethics committee and allowed, for genetic testing, and data collection, and analysis and elaboration. Data were irreversibly anonymized before entering into the database. Data availability statement Data are available upon reasonable request., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2021
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