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1. Development and Multicentre Validation of the Modena Score to Predict Survival in Advanced Biliary Cancers Undergoing Second-Line Chemotherapy

Author

Salati M, Marcheselli L, Messina C, Merz V, Messina M, Carotenuto P, Caputo F, Gelsomino F, Spallanzani A, Reggaiani Bonetti L, Caramaschi S, Luppi G, Dominici M, and Ghidini M

Subjects
biliary tract cancer, chemotherapy, second-line, prognostic score, survival, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Massimiliano Salati,1,2 Luigi Marcheselli,1 Carlo Messina,3 Valeria Merz,3,4 Marco Messina,5 Pietro Carotenuto,6 Francesco Caputo,1 Fabio Gelsomino,1 Andrea Spallanzani,1 Luca Reggiani Bonetti,7 Stefania Caramaschi,7 Gabriele Luppi,1 Massimo Dominici,1 Michele Ghidini8 1Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy; 2PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy; 3Department of Medical Oncology, Santa Chiara Hospital, Trento, Italy; 4Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy; 5Oncology Unit, Fondazione San Raffaele-Giglio, Cefalu’, Palermo, Italy; 6Telethon Institute of Genetics and Medicine, Pozzuoli, 80078, Napoli, Italy; 7Pathology Section, University Hospital of Modena, Modena, Italy; 8Medical Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, ItalyCorrespondence: Massimiliano Salati, PhD Program Clinical and Experimental Medicine, University Hospital of Modena, Modena Cancer Centre, via del Pozzo 71, Modena, 41125, Italy, Tel +39/0594223808, Fax +39/0594222647, Email massimiliano.salati@unimore.itBackground: The role of second-line chemotherapy in advanced biliary cancers (ABCs) has only recently been established in phase III randomized trial and the optimal selection of patients most likely to benefit from it remains challenging.Methods: A cohort of 98 ABC treated second-line chemotherapy was used as a developmental dataset to identify covariates independently associated with overall survival (OS). Kaplan–Meier analysis was used to investigate the association between variables and OS and those retaining statistically significance were combined in a multiplexed score.Results: The following pretreatment variables were independently associated with OS: ECOG PS > 0, peritoneal disease, LDH > 430 UI/L, albumin < 3.5 gr/dL, gamma-GT > 100 UI/L, sodium < 140 mEq/L, absolute lymphocyte count < 1000/mmc, and PFS to first-line < 6 months. Based on these results, a scoring system was developed that identified three subgroups with statistically different OS: low-risk (mOS 18 months), intermediate-risk (mOS 9.4 months) and high-risk (mOS 2.9 months) (p < 0.001). The prognostic model was both internally and externally validated in a multicentre cohort of 120 ABCs.Conclusion: The Modena score is a multiplexed scoring system capable of accurately risk-stratified ABCs treated with second-line chemotherapy. Based on its reproducibility, usability and generalizability, it has the potential for assisting therapeutic decision-making in the clinic and risk-stratification in future trials.Graphical Abstract: Keywords: biliary tract cancer, chemotherapy, second-line, prognostic score, survival

Published
2022

6. Bridging the equity gap in patient education: the biliary tract cancer BABEL project

Author

Prete, MG, González Romero, F, Castro, RE, Banales, JM, Cardinale, V, Morement, H, Milne, J, Krawczyk, M, Krupa, L, Anwar, MM, Poles, ES, Merz, V, Perra, T, Porcu, A, Megdanova, V, Popova, Y, Meneses-Medina, MI, Reyes Mondragón, AL, Burguete-Torres, A, Brandão Rego, I, Magalhães, J, Liz Pimenta, J, Silva, J, João Sousa, M, Custódio, S, Costa, T, Cojocaru, FD, Drug, VL, Hassan, SU, Ain Azam, NU, Kupcinskas, J, Kreivenaite, E, Morkunas, E, Nikolaieva, O, Calvisi, D, Evert, M, Terhuja, N, Das, A, Hoang, KD, Nguyen, HH, Evseev, V, Khuntikeo, N, Abdihamid, O, Mariamidze, E, Tsiklauri, K, Koyyala, VPB, Medisetty, P, Digumarti, L, Digumarti, RR, Konkalla, VLA, Mitra, S, Sud, R, Parikh, P, Gupta, SK, Sen, S, Chanda, S, das, D, Domadia, K, Goyal, P, Goyal, S, Dhamne, N, Acharya, PV, Jain, P, Sharma, M, War, GA, Singh, SR, Dodagoudar, C, Patnaik, RS, Mashahary, SS, Paul, R, Kannan, T, Goel, V, Patnaik, N, Jajodia, A, Pasricha, S, Gupta, M, Agarwal, C, Mondal, DK, BP, A, Joga, S, Mullapally, SK, Choudhary, P, Saini, R, Selvaraju, T, Pahwa, S, Durga, G, Maheshwari, U, Dhaka, S, Lindsay, S, Omar, A, La Casta Muñoa, A, Casolino, Raffaella, and Braconi, Chiara

Published
2022
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7. Bridging the equity gap in patient education: the biliary tract cancer BABEL project

Author

Casolino, Raffaella, primary, Braconi, Chiara, additional, Prete, MG, additional, González Romero, F, additional, Castro, RE, additional, Banales, JM, additional, Cardinale, V, additional, Morement, H, additional, Milne, J, additional, Krawczyk, M, additional, Krupa, L, additional, Anwar, MM, additional, Poles, ES, additional, Merz, V, additional, Perra, T, additional, Porcu, A, additional, Megdanova, V, additional, Popova, Y, additional, Meneses-Medina, MI, additional, Reyes Mondragón, AL, additional, Burguete-Torres, A, additional, Brandão Rego, I, additional, Magalhães, J, additional, Liz Pimenta, J, additional, Silva, J, additional, João Sousa, M, additional, Custódio, S, additional, Costa, T, additional, Cojocaru, FD, additional, Drug, VL, additional, Hassan, SU, additional, Ain Azam, NU, additional, Kupcinskas, J, additional, Kreivenaite, E, additional, Morkunas, E, additional, Nikolaieva, O, additional, Calvisi, D, additional, Evert, M, additional, Terhuja, N, additional, Das, A, additional, Hoang, KD, additional, Nguyen, HH, additional, Evseev, V, additional, Khuntikeo, N, additional, Abdihamid, O, additional, Mariamidze, E, additional, Tsiklauri, K, additional, Koyyala, VPB, additional, Medisetty, P, additional, Digumarti, L, additional, Digumarti, RR, additional, Konkalla, VLA, additional, Mitra, S, additional, Sud, R, additional, Parikh, P, additional, Gupta, SK, additional, Sen, S, additional, Chanda, S, additional, das, D, additional, Domadia, K, additional, Goyal, P, additional, Goyal, S, additional, Dhamne, N, additional, Acharya, PV, additional, Jain, P, additional, Sharma, M, additional, War, GA, additional, Singh, SR, additional, Dodagoudar, C, additional, Patnaik, RS, additional, Mashahary, SS, additional, Paul, R, additional, Kannan, T, additional, Goel, V, additional, Patnaik, N, additional, Jajodia, A, additional, Pasricha, S, additional, Gupta, M, additional, Agarwal, C, additional, Mondal, DK, additional, BP, A, additional, Joga, S, additional, Mullapally, SK, additional, Choudhary, P, additional, Saini, R, additional, Selvaraju, T, additional, Pahwa, S, additional, Durga, G, additional, Maheshwari, U, additional, Dhaka, S, additional, Lindsay, S, additional, Omar, A, additional, and La Casta Muñoa, A, additional

Published
2022
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10. The Origins and Spread of Domestic Horses from the Western Eurasian Steppes

Author

Librado, P., Khan, N., Fages, A., Kusliy, M. A., Suchan, T., Tonasso-Calvière, L., Schiavinato, S., Alioglu, D., Fromentier, A., Perdereau, A., Aury, J. -M., Gaunitz, C., Chauvey, L., Seguin-Orlando, A., Der Sarkissian, C., Southon, J., Shapiro, B., Tishkin, A. A., Kovalev, A. A., Alquraishi, S., Alfarhan, A. H., Al-Rasheid, K. A. S., Seregély, T., Klassen, L., Iversen, R., Bignon-Lau, O., Bodu, P., Olive, M., Castel, J. -C., Boudadi-Maligne, M., Alvarez, N., Germonpré, M., Moskal-del Hoyo, M., Wilczyński, J., Pospuła, S., Lasota-Kuś, A., Tunia, K., Nowak, M., Rannamäe, E., Saarma, U., Boeskorov, G., Lōugas, L., Kyselý, R., Peške, L., Bălășescu, A., Dumitrașcu, V., Dobrescu, R., Gerber, D., Kiss, V., Szécsényi-Nagy, A., Mende, B. G., Gallina, Z., Somogyi, K., Kulcsár, G., Gál, E., Bendrey, R., Allentoft, M. E., Sirbu, G., Dergachev, V., Shephard, H., Tomadini, N., Grouard, S., Kasparov, A., Basilyan, A. E., Anisimov, M. A., Nikolskiy, P. A., Pavlova, E. Y., Pitulko, V., Brem, G., Wallner, B., Schwall, C., Keller, M., Kitagawa, K., Bessudnov, A. N., Bessudnov, A., Taylor, W., Magail, J., Gantulga, J. -O., Bayarsaikhan, J., Erdenebaatar, D., Tabaldiev, K., Mijiddorj, E., Boldgiv, B., Tsagaan, T., Pruvost, M., Olsen, S., Makarewicz, C. A., Valenzuela Lamas, S., Albizuri Canadell, S., Nieto Espinet, A., Iborra, M. P., Lira Garrido, J., Rodríguez González, E., Celestino, S., Olària, C., Arsuaga, J. L., Kotova, N., Pryor, A., Crabtree, P., Zhumatayev, R., Toleubaev, A., Morgunova, N. L., Kuznetsova, T., Lordkipanize, D., Marzullo, M., Prato, O., Bagnasco Gianni, G., Tecchiati, U., Clavel, B., Lepetz, S., Davoudi, H., Mashkour, M., Berezina, N. Y., Stockhammer, P. W., Krause, J., Haak, W., Morales-Muñiz, A., Benecke, N., Hofreiter, M., Ludwig, A., Graphodatsky, A. S., Peters, J., Kiryushin, K. Y., Iderkhangai, T. -O., Bokovenko, N. A., Vasiliev, S. K., Seregin, N. N., Chugunov, K. V., Plasteeva, N. A., Baryshnikov, G. F., Petrova, E., Sablin, M., Ananyevskaya, E., Logvin, A., Shevnina, I., Logvin, V., Kalieva, S., Loman, V., Kukushkin, I., Merz, I., Merz, V., Sakenov, S., Varfolomeyev, V., Usmanova, E., Zaibert, V., Arbuckle, B., Belinskiy, A. B., Kalmykov, A., Reinhold, S., Hansen, S., Yudin, A. I., Vybornov, A. A., Epimakhov, A., Berezina, N. S., Roslyakova, N., Kosintsev, P. A., Kuznetsov, P. F., Anthony, D., Kroonen, G. J., Kristiansen, K., Wincker, P., Outram, A., Orlando, L., Librado, P., Khan, N., Fages, A., Kusliy, M. A., Suchan, T., Tonasso-Calvière, L., Schiavinato, S., Alioglu, D., Fromentier, A., Perdereau, A., Aury, J. -M., Gaunitz, C., Chauvey, L., Seguin-Orlando, A., Der Sarkissian, C., Southon, J., Shapiro, B., Tishkin, A. A., Kovalev, A. A., Alquraishi, S., Alfarhan, A. H., Al-Rasheid, K. A. S., Seregély, T., Klassen, L., Iversen, R., Bignon-Lau, O., Bodu, P., Olive, M., Castel, J. -C., Boudadi-Maligne, M., Alvarez, N., Germonpré, M., Moskal-del Hoyo, M., Wilczyński, J., Pospuła, S., Lasota-Kuś, A., Tunia, K., Nowak, M., Rannamäe, E., Saarma, U., Boeskorov, G., Lōugas, L., Kyselý, R., Peške, L., Bălășescu, A., Dumitrașcu, V., Dobrescu, R., Gerber, D., Kiss, V., Szécsényi-Nagy, A., Mende, B. G., Gallina, Z., Somogyi, K., Kulcsár, G., Gál, E., Bendrey, R., Allentoft, M. E., Sirbu, G., Dergachev, V., Shephard, H., Tomadini, N., Grouard, S., Kasparov, A., Basilyan, A. E., Anisimov, M. A., Nikolskiy, P. A., Pavlova, E. Y., Pitulko, V., Brem, G., Wallner, B., Schwall, C., Keller, M., Kitagawa, K., Bessudnov, A. N., Bessudnov, A., Taylor, W., Magail, J., Gantulga, J. -O., Bayarsaikhan, J., Erdenebaatar, D., Tabaldiev, K., Mijiddorj, E., Boldgiv, B., Tsagaan, T., Pruvost, M., Olsen, S., Makarewicz, C. A., Valenzuela Lamas, S., Albizuri Canadell, S., Nieto Espinet, A., Iborra, M. P., Lira Garrido, J., Rodríguez González, E., Celestino, S., Olària, C., Arsuaga, J. L., Kotova, N., Pryor, A., Crabtree, P., Zhumatayev, R., Toleubaev, A., Morgunova, N. L., Kuznetsova, T., Lordkipanize, D., Marzullo, M., Prato, O., Bagnasco Gianni, G., Tecchiati, U., Clavel, B., Lepetz, S., Davoudi, H., Mashkour, M., Berezina, N. Y., Stockhammer, P. W., Krause, J., Haak, W., Morales-Muñiz, A., Benecke, N., Hofreiter, M., Ludwig, A., Graphodatsky, A. S., Peters, J., Kiryushin, K. Y., Iderkhangai, T. -O., Bokovenko, N. A., Vasiliev, S. K., Seregin, N. N., Chugunov, K. V., Plasteeva, N. A., Baryshnikov, G. F., Petrova, E., Sablin, M., Ananyevskaya, E., Logvin, A., Shevnina, I., Logvin, V., Kalieva, S., Loman, V., Kukushkin, I., Merz, I., Merz, V., Sakenov, S., Varfolomeyev, V., Usmanova, E., Zaibert, V., Arbuckle, B., Belinskiy, A. B., Kalmykov, A., Reinhold, S., Hansen, S., Yudin, A. I., Vybornov, A. A., Epimakhov, A., Berezina, N. S., Roslyakova, N., Kosintsev, P. A., Kuznetsov, P. F., Anthony, D., Kroonen, G. J., Kristiansen, K., Wincker, P., Outram, A., and Orlando, L.

Abstract

Domestication of horses fundamentally transformed long-range mobility and warfare1. However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling2–4 at Botai, Central Asia around 3500 bc3. Other longstanding candidate regions for horse domestication, such as Iberia5 and Anatolia6, have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 bc, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association7 between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 bc8,9 driving the spread of Indo-European languages10. This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium bc Sintashta culture11,12. © 2021, The Author(s).

Published
2021

13. 63P Multicentre match-paired analysis of advanced biliary cancer (ABC) long-term survivors: The BILONG study

Author

Caputo, F., primary, Gelsomino, F., additional, Spallanzani, A., additional, Pettorelli, E., additional, Benatti, S., additional, Ghidini, M., additional, Grizzi, G., additional, Ratti, M., additional, Merz, V., additional, Messina, C., additional, Tonelli, R., additional, Luppi, G., additional, Melisi, D., additional, Dominici, M., additional, and Salati, M., additional

Published
2020
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14. 57P Third-line chemotherapy in advanced biliary cancers (ABC): Pattern of care, treatment outcome and prognostic factors from a multicenter study

Author

Rizzo, A., primary, Salati, M., additional, Merz, V., additional, Messina, C., additional, Ricci, A.D., additional, Palloni, A., additional, Frega, G., additional, De Lorenzo, S., additional, Caputo, F., additional, Gelsomino, F., additional, Spallanzani, A., additional, Mollica, V., additional, Abbati, F., additional, Carotenuto, P., additional, Pettorelli, E., additional, Benatti, S., additional, Luppi, G., additional, Melisi, D., additional, Dominici, M., additional, and Brandi, G., additional

Published
2020
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15. Plasmatic CXCL8 is a marker for TGFß-activated kinase 1 (TAK1) activation which may predict resistance to nanoliposomal irinotecan (nal-IRI) in gemcitabine-refractory pancreatic cancer (PC) patients

Author

Merz, V., primary, Zecchetto, C., additional, Santoro, R., additional, Simionato, F., additional, Piro, G., additional, Sabbadini, F., additional, Cavaliere, A., additional, Casalino, S., additional, Auriemma, A., additional, and Melisi, D., additional

Published
2019
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17. Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling

Author

Carbone, C, primary, Piro, G, additional, Gaianigo, N, additional, Ligorio, F, additional, Santoro, R, additional, Merz, V, additional, Simionato, F, additional, Zecchetto, C, additional, Falco, G, additional, Conti, G, additional, Kamga, P T, additional, Krampera, M, additional, Di Nicolantonio, F, additional, De Franceschi, L, additional, Scarpa, A, additional, Tortora, G, additional, and Melisi, D, additional

Published
2017
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18. A circulating TH2 cytokines profile predicts survival in patients with resectable pancreatic adenocarcinoma

Author

Melisi, D., primary, Piro, G., additional, Simionato, F., additional, Carbone, C., additional, Frizziero, M., additional, Malleo, G., additional, Zanini, S., additional, Casolino, R., additional, Santoro, R., additional, Mina, M.M., additional, Zecchetto, C., additional, Merz, V., additional, Scarpa, A., additional, Bassi, C., additional, and Tortora, G., additional

Published
2017
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20. 248 Fibroblast Growth Factor Receptor (FGFR)3 sustains acquired resistance to trastuzumab in gastric cancer patients

Author

Piro, G., primary, Carbone, C., additional, Cataldo, I., additional, Di Nicolantonio, F., additional, Giacopuzzi, S., additional, Boschi, F., additional, Zanotto, M., additional, Merz, V., additional, Mina, M.M., additional, Sbarbati, A., additional, De Manzoni, G., additional, Scarpa, A., additional, Tortora, G., additional, and Melisi, D., additional

Published
2015
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21. TAK1-regulated expression of BIRC3 predicts resistance to preoperative chemoradiotherapy in oesophageal adenocarcinoma patients

Author

Piro, G, primary, Giacopuzzi, S, additional, Bencivenga, M, additional, Carbone, C, additional, Verlato, G, additional, Frizziero, M, additional, Zanotto, M, additional, Mina, M M, additional, Merz, V, additional, Santoro, R, additional, Zanoni, A, additional, De Manzoni, G, additional, Tortora, G, additional, and Melisi, D, additional

Published
2015
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24. Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling

Author

Carbone, C, Piro, G, Gaianigo, N, Ligorio, F, Santoro, R, Merz, V, Simionato, F, Zecchetto, C, Falco, G, Conti, G, Kamga, P T, Krampera, M, Di Nicolantonio, F, De Franceschi, L, Scarpa, A, Tortora, G, and Melisi, D

Abstract

Background:Solid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions.Methods:We studied the role of factors secreted by two adipogenic model systems from primary human bone marrow stromal cells (hBMSCs) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS),Results:We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPOCM) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSCCM) from two different healthy donors. Several genes coding for soluble modulators of the non-canonical WNT signaling pathway, including FRZB, SFRP2, RSPO1, WNT5A and 5B were significantly overexpressed in fully differentiated adipocytes than in their respective in hBMSC. ADIPOCMinduced the overexpression and the nuclear translocation of the Frizzled family member receptor tyrosine kinase-like orphan receptor (Ror) 2 in HPDE and HPDE/KRAS cells. Vantictumab, an anti-Frizzled monoclonal antibody, reduced ROR2 nuclear translocation and in turn the EMT and aggressiveness in HPDE and HPDE/KRAS cells.Conclusions:We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer.

Published
2018
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