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On February 23, 2018, PubMed Central Canada (PMC Canada) will be taken offline permanently. No author manuscripts will be deleted, and the approximately 2,900 manuscripts authored by Canadian Institutes of Health Research (CIHR)-funded researchers currently in the archive will be copied to the National Research Council’s (NRC) Digital Repository over the coming months. These manuscripts along with all other content will also remain publicly searchable on PubMed Central (US) and Europe PubMed Central, meaning such manuscripts will continue to be compliant with the Tri-Agency Open Access Policy on Publications.

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1.  Chemotherapy administration to breast cancer patients affects extracellular vesicles thrombogenicity and function 
Oncotarget  2017;8(38):63265-63280.
Breast cancer (BC) is the most prevalent type of malignancy in women. Extracellular vesicles (EVs) are subcellular membrane blebs that include exosomes and microparticles.
Study aims
To elucidate the effects of chemotherapy administration on BC patients’ EVs characteristics and their effects on endothelial cells (EC) functions.
Methods
EVs were isolated from the blood samples of 54 BC patients treated by chemotherapy (25 neo-adjuvant, 29 adjuvant) and from 20 healthy women (control group). Blood samples were taken before chemotherapy and on the day of last chemotherapy administration. In some patients, samples were also evaluated 24 hours after chemotherapy treatment. EVs were characterized by cell origin, thrombogenicity and cytokine content. EVs effects on coagulation, migration, apoptosis and proliferation of endothelial cells were assessed as well.
Results
Patient characteristics of the two subgroups were similar except for tumor size. Change in EV expression of BC markers, MUC1 and EpCAM, were found in patient subgroups. EC-EVs were significantly higher in both patient subgroups compared to healthy controls. Higher EVs pro-coagulant activity was found at the end of chemotherapy and a significant increase in the ratio between tissue factor (TF) and TF pathway inhibitor was documented after the first 24hours of exposure to doxorubicin treatment. Furthermore, EVs of neo-adjuvant patients obtained before chemotherapy contained more pro-angiogenic proteins, reduced endothelial cells apoptosis and increased their migration compared to EVs obtained at the same timing from adjuvant patients.
Conclusions
EVs may serve as a biomarker for chemotherapy-related thrombogenicity and may indicate vascular damage even before chemotherapy.
doi:10.18632/oncotarget.18792
PMCID: PMC5609919
breast cancer (BC); extracellular vesicles (EVs); chemotherapy; thrombogenicity; endothelial cells (EC)
2.  World Congress Integrative Medicine & Health 2017: Part one 
Brinkhaus, Benno | Falkenberg, Torkel | Haramati, Aviad | Willich, Stefan N. | Briggs, Josephine P. | Willcox, Merlin | Linde, Klaus | Theorell, Töres | Wong, Lisa M. | Dusek, Jeffrey | Wu, Darong | Eisenberg, David | Haramati, Aviad | Berger, Bettina | Kemper, Kathi | Stock-Schröer, Beate | Sützl-Klein, Hedda | Ferreri, Rosaria | Kaplan, Gary | Matthes, Harald | Rotter, Gabriele | Schiff, Elad | Arnon, Zahi | Hahn, Eckhard | Luberto, Christina M. | Martin, David | Schwarz, Silke | Tauschel, Diethard | Flower, Andrew | Gramminger, Harsha | Gupta, Hedwig H. | Gupta, S. N. | Kerckhoff, Annette | Kessler, Christian S. | Michalsen, Andreas | Kessler, Christian S. | Kim, Eun S. | Jang, Eun H. | Kim, Rana | Jan, Sae B. | Mittwede, Martin | Mohme, Wiebke | Ben-Arye, Eran | Bonucci, Massimo | Saad, Bashar | Breitkreuz, Thomas | Rossi, Elio | Kebudi, Rejin | Daher, Michel | Razaq, Samaher | Gafer, Nahla | Nimri, Omar | Hablas, Mohamed | Kienle, Gunver Sophia | Samuels, Noah | Silbermann, Michael | Bandelin, Lena | Lang, Anna-Lena | Wartner, Eva | Holtermann, Christoph | Binstock, Maxwell | Riebau, Robert | Mujkanovic, Edin | Cramer, Holger | Lauche, Romy | Michalsen, Andres | Ward, Lesley | Cramer, Holger | Irnich, Dominik | Stör, Wolfram | Burnstock, Geoffrey | Schaible, Hans-Georg | Ots, Thomas | Langhorst, Jost | Lauche, Romy | Sundberg, Tobias | Falkenberg, Torkel | Amarell, Catherina | Amarell, Catherina | Anheyer, Melanie | Eckert, Marion | Eckert, Marion | Ogal, Mercedes | Eckert, Marion | Amarell, Catherina | Schönauer, Annette | Reisenberger, Birgit | Brand, Bernhard | Anheyer, Dennis | Dobos, Gustav | Kroez, Matthias | Martin, David | Matthes, Harald | Ammendola, Aldo | Mao, Jun J. | Witt, Claudia | Yang, Yufei | Dobos, Gustav | Oritz, Miriam | Horneber, Markus | Voiß, Petra | Reisenberger, Birgit | von Rosenstiel, Alexandra | Eckert, Marion | Ogal, Mercedes | Amarell, Catharina | Anheyer, Melanie | Schad, Friedemann | Schläppi, Marc | Kröz, Matthias | Büssing, Arndt | Bar-Sela, Gil | Matthes, Harald | Schiff, Elad | Ben-Arye, Eran | Arnon, Zahi | Avshalomov, David | Attias, Samuel | Schönauer, Annette | Haramati, Aviad | Witt, Claudia | Brinkhaus, Benno | Cotton, Sian | Jong, Miek | Jong, Mats | Scheffer, Christian | Haramati, Aviad | Tauschel, Diethard | Edelhäuser, Friedrich | AlBedah, Abdullah | Lee, Myeong Soo | Khalil, Mohamed | Ogawa, Keiko | Motoo, Yoshiharu | Arimitsu, Junsuke | Ogawa, Masao | Shimizu, Genki | Stange, Rainer | Kraft, Karin | Kuchta, Kenny | Watanabe, Kenji | Bonin, D | Büssing, Arndt | Gruber, Harald | Koch, Sabine | Gruber, Harald | Pohlmann, Urs | Caldwell, Christine | Krantz, Barbara | Kortum, Ria | Martin, Lily | Wieland, Lisa S. | Kligler, Ben | Gould-Fogerite, Susan | Zhang, Yuqing | Wieland, Lisa S. | Riva, John J. | Lumpkin, Michael | Ratner, Emily | Ping, Liu | Jian, Pei | Hamme, Gesa-Meyer | Mao, Xiaosong | Chouping, Han | Schröder, Sven | Hummelsberger, Josef | Wullinger, Michael | Brodzky, Marc | Zalpour, Christoff | Langley, Julia | Weber, Wendy | Mudd, Lanay M. | Wayne, Peter | Witt, Clauda | Weidenhammer, Wolfgang | Fønnebø, Vinjar | Boon, Heather | Steel, Amie | Bugarcic, Andrea | Rangitakatu, Melisa | Steel, Amie | Adams, Jon | Sibbritt, David | Wardle, Jon | Leach, Matthew | Schloss, Janet | Dieze, Helene | Boon, Heather | Ijaz, Nadine | Willcox, Merlin | Heinrich, Michael | Lewith, George | Flower, Andrew | Graz, Bertrand | Adam, Daniela | Grabenhenrich, Linus | Ortiz, Miriam | Binting, Sylvia | Reinhold, Thomas | Brinkhaus, Benno | Andermo, Susanne | Sundberg, Tobias | Falkenberg, Torkel | Nordberg, Johanna Hök | Arman, Maria | Bhasin, Manoj | Fan, Xueyi | Libermann, Towia | Fricchione, Gregory | Denninger, John | Benson, Herbert | Berger, Bettina | Stange, Rainer | Michalsen, Andreas | Martin, David D. | Boers, Inge | Vlieger, Arine | Jong, Miek | Brinkhaus, Benno | Teut, Michael | Ullmann, Alexander | Ortiz, Miriam | Rotter, Gabriele | Binting, Sylvia | Lotz, Fabian | Roll, Stephanie | Canella, Claudia | Mikolasek, Michael | Rostock, Matthias | Beyer, Jörg | Guckenberger, Matthias | Jenewein, Josef | Linka, Esther | Six, Claudia | Stoll, Sarah | Stupp, Roger | Witt, Claudia M. | Chuang, Elisabeth | Kligler, Ben | McKee, Melissa D. | Cramer, Holger | Lauche, Romy | Klose, Petra | Lange, Silke | Langhorst, Jost | Dobos, Gustav | Chung, Vincent C. H. | Wong, Hoi L. C. | Wu, Xin Y. | Wen, Grace Y. G. | Ho, Robin S. T. | Ching, Jessica Y. L. | Wu, Justin C. Y. | Coakley, Amanda | Flanagan, Jane | Annese, Christine | Empoliti, Joanne | Gao, Zishan | Liu, Xugang | Yu, Shuguang | Yan, Xianzhong | Liang, Fanrong | Hohmann, Christoph D. | Steckhan, Nico | Ostermann, Thomas | Paetow, Arion | Hoff, Evelyn | Michalsen, Andreas | Hu, Xiao-Yang | Wu, Ruo-Han | Logue, Martin | Blonde, Clara | Lai, Lily Y. | Stuart, Beth | Flower, Andrew | Fei, Yu-Tong | Moore, Michael | Liu, Jian-Ping | Lewith, George | Hu, Xiao-Yang | Wu, Ruo-Han | Logue, Martin | Blonde, Clara | Lai, Lily Y. | Stuart, Beth | Flower, Andrew | Fei, Yu-Tong | Moore, Michael | Liu, Jian-Ping | Lewith, George | Jeitler, Michael | Zillgen, Hannah | Högl, Manuel | Steckhan, Nico | Stöckigt, Barbara | Seifert, Georg | Michalsen, Andreas | Kessler, Christian | Khadivzadeh, Talat | Bashtian, Maryam Hassanzadeh | Aval, Shapour Badiee | Esmaily, Habibollah | Kim, Jihye | Kim, Keun H. | Klocke, Carina | Joos, Stefanie | Koshak, Abdulrahman | Wie, Li | Koshak, Emad | Wali, Siraj | Alamoudi, Omer | Demerdash, Abdulrahman | Qutub, Majdy | Pushparaj, Peter | Heinrich, Michael | Kruse, Sigrid | Fischer, Isabell | Tremel, Nadine | Rosenecker, Joseph | Leung, Brenda | Takeda, Wendy | Liang, Ning | Feng, Xue | Liu, Jian-ping | Cao, Hui-juan | Luberto, Christina M. | Shinday, Nina | Philpotts, Lisa | Park, Elyse | Fricchione, Gregory L. | Yeh, Gloria | Munk, Niki | Zakeresfahani, Arash | Foote, Trevor R. | Ralston, Rick | Boulanger, Karen | Özbe, Dominik | Gräßel, Elmar | Luttenberger, Katharina | Pendergrass, Anna | Pach, Daniel | Bellmann-Strobl, Judit | Chang, Yinhui | Pasura, Laura | Liu, Bin | Jäger, Sven F. | Loerch, Ronny | Jin, Li | Brinkhaus, Benno | Ortiz, Miriam | Reinhold, Thomas | Roll, Stephanie | Binting, Sylvia | Icke, Katja | Shi, Xuemin | Paul, Friedemann | Witt, Claudia M. | Rütz, Michaela | Lynen, Andreas | Schömitz, Meike | Vahle, Maik | Salomon, Nir | Lang, Alon | Lahat, Adi | Kopylov, Uri | Ben-Horin, Shomron | Har-Noi, Ofir | Avidan, Benjamin | Elyakim, Rami | Gamus, Dorit | NG, Siew | Chang, Jessica | Wu, Justin | Kaimiklotis, John | Schumann, Dania | Buttó, Ludovica | Langhorst, Jost | Dobos, Gustav | Haller, Dirk | Cramer, Holger | Smith, Caroline | de Lacey, Sheryl | Chapman, Michael | Ratcliffe, Julie | Johnson, Neil | Lyttleton, Jane | Boothroyd, Clare | Fahey, Paul | Tjaden, Bram | van Vliet, Marja | van Wietmarschen, Herman | Jong, Miek | Tröger, Wilfried | Vuolanto, Pia | Aarva, Paulina | Sorsa, Minna | Helin, Kaija | Wenzel, Claudia | Zoderer, Iris | Pammer, Patricia | Simon, Patrick | Tucek, Gerhard | Wode, Kathrin | Henriksson, Roger | Sharp, Lena | Stoltenberg, Anna | Nordberg, Johanna Hök | Xiao-ying, Yang | Wang, Li-qiong | Li, Jin-gen | Liang, Ning | Wang, Ying | Liu, Jian-ping | Balneaves, Lynda | Capler, Rielle | Bocci, Chiara | Guffi, Marta | Paolini, Marina | Meaglia, Ilaria | Porcu, Patrizia | Ivaldi, Giovanni B. | Dragan, Simona | Bucuras, Petru | Pah, Ana M. | Badalica-Petrescu, Marius | Buleu, Florina | Hogea-Stoichescu, Gheorghe | Christodorescu, Ruxandra | Kao, Lan | Cho, Yumin | Klafke, Nadja | Mahler, Cornelia | von Hagens, Cornelia | Uhlmann, Lorenz | Bentner, Martina | Schneeweiss, Andreas | Mueller, Andreas | Szecsenyi, Joachim | Joos, Stefanie | Neri, Isabella | Ortiz, Miriam | Schnabel, Katharina | Teut, Michael | Rotter, Gabriele | Binting, Sylvia | Cree, Margit | Lotz, Fabian | Suhr, Ralf | Brinkhaus, Benno | Rossi, Elio | Baccetti, Sonia | Firenzuoli, Fabio | Monechi, Maria V. | Di Stefano, Mariella | Amunni, Gianni | Wong, Wendy | Chen, Bingzhong | Wu, Justin | Amri, Hakima | Haramati, Aviad | Kotlyanskaya, Lucy | Anderson, Belinda | Evans, Roni | Kligler, Ben | Marantz, Paul | Bradley, Ryan | Booth-LaForce, Cathryn | Zwickey, Heather | Kligler, Benjamin | Brooks, Audrey | Kreitzer, Mary J. | Lebensohn, Patricia | Goldblatt, Elisabeth | Esmel-Esmel, Neus | Jiménez-Herrera, Maria | Ijaz, Nadine | Boon, Heather | Jocham, Alexandra | Stock-Schröer, Beate | Berberat, Pascal O. | Schneider, Antonius | Linde, Klaus | Masetti, Morgana | Murakozy, Henriette | Van Vliet, Marja | Jong, Mats | Jong, Miek | Agdal, Rita | Atarzadeh, Fatemeh | Jaladat, Amir M. | Hoseini, Leila | Amini, Fatemeh | Bai, Chen | Liu, Tiegang | Zheng, Zian | Wan, Yuxiang | Xu, Jingnan | Wang, Xuan | Yu, He | Gu, Xiaohong | Daneshfard, Babak | Nimrouzi, Majid | Tafazoli, Vahid | Alorizi, Seyed M. Emami | Saghebi, Seyed A. | Fattahi, Mohammad R. | Salehi, Alireza | Rezaeizadeh, Hossein | Zarshenas, Mohammad M. | Nimrouzi, Majid | Fox, Kealoha | Hughes, John | Kostanjsek, Nenad | Espinosa, Stéphane | Lewith, George | Fisher, Peter | Latif, Abdul | Lefeber, Donald | Paske, William | Öztürk, Ali Ö. | Öztürk, Gizemnur | Boers, Inge | Tissing, Wim | Naafs, Marianne | Busch, Martine | Jong, Miek | Daneshfard, Babak | Sanaye, Mohammad R. | Dräger, Kilian | Fisher, Peter | Kreitzer, Mary J. | Evans, Roni | Leininger, Brent | Shafto, Kate | Breen, Jenny | Sanaye, Mohammad R. | Daneshfard, Babak | Simões-Wüst, Ana P. | Moltó-Puigmartí, Carolina | van Dongen, Martien | Dagnelie, Pieter | Thijs, Carel | White, Shelley | Wiesener, Solveig | Salamonsen, Anita | Stub, Trine | Fønnebø, Vinjar | Abanades, Sergio | Blanco, Mar | Masllorens, Laia | Sala, Roser | Al-Ahnoumy, Shafekah | Han, Dongwoon | He, Luzhu | Kim, Ha Yun | In Choi, Da | Alræk, Terje | Stub, Trine | Kristoffersen, Agnete | von Sceidt, Christel | Michalsen, Andreas | Bruset, Stig | Musial, Frauke | Anheyer, Dennis | Cramer, Holger | Lauche, Romy | Saha, Felix J. | Dobos, Gustav | Anheyer, Dennis | Haller, Heidemarie | Lauche, Romy | Dobos, Gustav | Cramer, Holger | Azizi, Hoda | Khadem, Nayereh | Hassanzadeh, Malihe | Estiri, Nazanin | Azizi, Hamideh | Tavassoli, Fatemeh | Lotfalizadeh, Marzieh | Zabihi, Reza | Esmaily, Habibollah | Azizi, Hoda | Shabestari, Mahmoud Mohammadzadeh | Paeizi, Reza | Azari, Masoumeh Alvandi | Bahrami-Taghanaki, Hamidreza | Zabihi, Reza | Azizi, Hamideh | Esmaily, Habibollah | Baars, Erik | De Bruin, Anja | Ponstein, Anne | Baccetti, Sonia | Di Stefano, Mariella | Rossi, Elio | Firenzuoli, Fabio | Segantini, Sergio | Monechi, Maria Valeria | Voller, Fabio | Barth, Jürgen | Kern, Alexandra | Lüthi, Sebastian | Witt, Claudia | Barth, Jürgen | Zieger, Anja | Otto, Fabius | Witt, Claudia | Beccia, Ariel | Dunlap, Corina | Courneene, Brendan | Bedregal, Paula | Passi, Alvaro | Rodríguez, Alfredo | Chang, Mayling | Gutiérrez, Soledad | Beissner, Florian | Beissner, Florian | Preibisch, Christine | Schweizer-Arau, Annemarie | Popovici, Roxana | Meissner, Karin | Beljanski, Sylvie | Belland, Laura | Rivera-Reyes, Laura | Hwang, Ula | Berger, Bettina | Sethe, Dominik | Hilgard, Dörte | Heusser, Peter | Bishop, Felicity | Al-Abbadey, Miznah | Bradbury, Katherine | Carnes, Dawn | Dimitrov, Borislav | Fawkes, Carol | Foster, Jo | MacPherson, Hugh | Roberts, Lisa | Yardley, Lucy | Lewith, George | Bishop, Felicity | Al-Abbadey, Miznah | Bradbury, Katherine | Carnes, Dawn | Dimitrov, Borislav | Fawkes, Carol | Foster, Jo | MacPherson, Hugh | Roberts, Lisa | Yardley, Lucy | Lewith, George | Bishop, Felicity | Holmes, Michelle | Lewith, George | Yardley, Lucy | Little, Paul | Cooper, Cyrus | Bogani, Patrizia | Maggini, Valentina | Gallo, Eugenia | Miceli, Elisangela | Biffi, Sauro | Mengoni, Alessio | Fani, Renato | Firenzuoli, Fabio | Brands-Guendling, Nadine | Guendling, Peter W. | Bronfort, Gert | Evans, Roni | Haas, Mitch | Leininger, Brent | Schulz, Craig | Bu, Xiangwei | Wang, J. | Fang, T. | Shen, Z. | He, Y. | Zhang, X. | Zhang, Zhengju | Wang, Dali | Meng, Fengxian | Büssing, Arndt | Baumann, Klaus | Frick, Eckhard | Jacobs, Christoph | Büssing, Arndt | Grünther, Ralph-Achim | Lötzke, Désirée | Büssing, Arndt | Jung, Sonny | Lötzke, Désirée | Recchia, Daniela R. | Robens, Sibylle | Ostermann, Thomas | Berger, Bettina | Stankewitz, Josephin | Kröz, Matthias | Jeitler, Mika | Kessler, Christian | Michalsen, Andreas | Cheon, Chunhoo | Jang, Bo H. | Ko, Seong G. | Huang, Ching W. | Sasaki, Yui | Ko, Youme | Cheshire, Anna | Ridge, Damien | Hughes, John | Peters, David | Panagioti, Maria | Simon, Chantal | Lewith, George | Cho, Hyun J. | Han, Dongwoon | Choi, Soo J. | Jung, Young S. | Im, Hyea B | Cooley, Kieran | Tummon-Simmons, Laura | Cotton, Sian | Luberto, Christina M. | Wasson, Rachel | Kraemer, Kristen | Sears, Richard | Hueber, Carly | Derk, Gwendolyn | Lill, JR | An, Ruopeng | Steinberg, Lois | Rodriguez, Lourdes Diaz | la Fuente, Francisca García-de | De la Vega, Miguel | Vargas-Román, Keyla | Fernández-Ruiz, Jonatan | Cantarero-Villanueva, Irene | Rodriguez, Lourdes Diaz | García-De la Fuente, Francisca | Jiménez-Guerrero, Fanny | Vargas-Román, Keyla | Fernández-Ruiz, Jonatan | Galiano-Castillo, Noelia | Diaz-Saez, Gualberto | Torres-Jimenez, José I. | Garcia-Gomez, Olga | Hortal-Muñoz, Luis | Diaz-Diez, Camino | Dicen, Demijon | Diezel, Helene | Adams, Jon | Steel, Amie | Wardle, Jon | Diezel, Helene | Steel, Amie | Frawley, Jane | Wardle, Jon | Broom, Alex | Adams, Jon | Dong, Fei | Yu, He | Liu, Tiegang | Ma, Xueyan | Yan, Liyi | Wan, Yuxiang | Zheng, Zian | Gu, Xiaohong | Dong, Fei | Yu, He | Wu, Liqun | Liu, Tiegang | Ma, Xueyan | Ma, Jiaju | Yan, Liyi | Wan, Yuxiang | Zheng, Zian | Zhen, Jianhua | Gu, Xiaohong | Dubois, Julie | Rodondi, Pierre-Yves | Edelhäuser, Friedrich | Schwartze, Sophia | Trapp, Barbara | Cysarz, Dirk
doi:10.1186/s12906-017-1782-4
PMCID: PMC5498855
3.  Biopsy of breast cancer metastases: patient characteristics and survival 
BMC Cancer  2017;17:7.
Background
Discordance in hormone receptors (HR) and human epidermal growth factor receptor 2 (HER2) status between primary tumors and metastatic sites for breast cancer is well established. However, it is uncertain which patient-related factors lead to biopsy when metastases are suspected and whether having a biopsy impacts survival.
Methods
The medical charts of metastatic breast cancer (MBC) patients diagnosed January 2000-August 2014 were retrospectively reviewed. A biopsy was defined as a procedure where tissue was obtained and assessed for both HR and HER2. Both bivariate and multivariate analyses were performed to assess patient characteristics related to biopsy and whether having a biopsy was associated with improved survival.
Results
Of 409 patients suspected of having MBC, 165 (40%) had a biopsy, and 34% of these had discordant HR or HER2 status when compared to the initial diagnosis. In multivariate analysis, having a biopsy was associated with: recurrence in years 2010–2014, disease-free interval of > =3 years, stage 0-IIA at presentation, suspected locoregional recurrence, being HR+/HER2-, or missing HR/HER2 at diagnosis. A similar multivariate analysis revealed that having a biopsy was associated with improved survival (HR = 0.67, p = 0.002). The association of biopsy and improved survival was noted in specific subgroups: patients with missing HR and HER2 data at initial diagnosis (p = 0.001), those without metastases in liver, lung or brain (p = 0.001), and being younger than 70 years old at recurrence (p < 0.001).
Conclusions
Specific clinical factors were associated with biopsy at the time of suspected recurrence. Having a biopsy was associated with reduced mortality.
doi:10.1186/s12885-016-3014-6
PMCID: PMC5210262  PMID: 28052766
Biopsy; Breast carcinoma; Pathology; Recurrent-metastatic disease; Survival
4.  The prognostic significance of heparanase expression in metastatic melanoma 
Oncotarget  2016;7(46):74678-74685.
Background
Heparanase expression is induced in many types of cancers, including melanoma, and promotes tumor growth, angiogenesis and metastasis. However, there is insufficient data regarding heparanase expression in the metastatic lesions that are the prime target for anti-cancer therapeutics. To that end, we examined heparanase expression in metastatic melanoma and its correlation with clinical parameters.
Results
Heparanase staining was detected in 88% of the samples, and was strong in 46%. For the entire cohort of metastatic melanoma patients, no apparent correlation was found between heparanase staining intensity and survival. However, in a sub group of 46 patients diagnosed as stage IVc melanoma, strong heparanase staining was associated with reduced survival rates [hazard ratio=2.1; 95%CI 1.1-4.1, p=0.025].
Material and Methods
Paraffin sections from 69 metastatic melanomas were subjected to immunohistochemical analysis, applying anti-heparanase antibody. The clinical and pathological data, together with heparanase staining intensity, were evaluated in a logistic regression model for site of metastasis and survival. Slides were also stained for the heparanase-homolog, heparanase-2 (Hpa2).
Conclusion
Heparanase is highly expressed in metastatic melanoma and predicts poor survival of stage IVc melanoma patients, justifying the development and implementation of heparanase inhibitors as anti-cancer therapeutics.
doi:10.18632/oncotarget.12492
PMCID: PMC5342694  PMID: 27732945
heparanase; heparanase 2; melanoma; metastasis; survival
5.  Melanoma and immunotherapy bridge 2015 
Nanda, Vashisht G. Y. | Peng, Weiyi | Hwu, Patrick | Davies, Michael A. | Ciliberto, Gennaro | Fattore, Luigi | Malpicci, Debora | Aurisicchio, Luigi | Ascierto, Paolo Antonio | Croce, Carlo M. | Mancini, Rita | Spranger, Stefani | Gajewski, Thomas F. | Wang, Yangyang | Ferrone, Soldano | Vanpouille-Box, Claire | Wennerberg, Erik | Pilones, Karsten A. | Formenti, Silvia C. | Demaria, Sandra | Tang, Haidong | Wang, Yang | Fu, Yang-Xin | Dummer, Reinhard | Puzanov, Igor | Tarhini, Ahmad | Chauvin, Joe-Marc | Pagliano, Ornella | Fourcade, Julien | Sun, Zhaojun | Wang, Hong | Sanders, Cindy | Kirkwood, John M. | Chen, Tseng-hui Timothy | Maurer, Mark | Korman, Alan J. | Zarour, Hassane M. | Stroncek, David F. | Huber, Veronica | Rivoltini, Licia | Thurin, Magdalena | Rau, Tilman | Lugli, Alessandro | Pagès, Franck | Camarero, Jorge | Sancho, Arantxa | Jommi, Claudio | de Coaña, Yago Pico | Wolodarski, Maria | Yoshimoto, Yuya | Gentilcore, Giusy | Poschke, Isabel | Masucci, Giuseppe V. | Hansson, Johan | Kiessling, Rolf | Scognamiglio, Giosuè | Sabbatino, Francesco | Marino, Federica Zito | Anniciello, Anna Maria | Cantile, Monica | Cerrone, Margherita | Scala, Stefania | D’alterio, Crescenzo | Ianaro, Angela | Cirin, Giuseppe | Liguori, Giuseppina | Bott, Gerardo | Chapman, Paul B. | Robert, Caroline | Larkin, James | Haanen, John B. | Ribas, Antoni | Hogg, David | Hamid, Omid | Testori, Alessandro | Lorigan, Paul | Sosman, Jeffrey A. | Flaherty, Keith T. | Yue, Huibin | Coleman, Shelley | Caro, Ivor | Hauschild, Axel | McArthur, Grant A. | Sznol, Mario | Callahan, Margaret K. | Kluger, Harriet | Postow, Michael A. | Gordan, RuthAnn | Segal, Neil H. | Rizvi, Naiyer A. | Lesokhin, Alexander | Atkins, Michael B. | Burke, Matthew M. | Ralabate, Amanda | Rivera, Angel | Kronenberg, Stephanie A. | Agunwamba, Blessing | Ruisi, Mary | Horak, Christine | Jiang, Joel | Wolchok, Jedd | Ascierto, Paolo A. | Liszkay, Gabriella | Maio, Michele | Mandalà, Mario | Demidov, Lev | Stoyakovskiy, Daniil | Thomas, Luc | de la Cruz-Merino, Luis | Atkinson, Victoria | Dutriaux, Caroline | Garbe, Claus | Wongchenko, Matthew | Chang, Ilsung | Koralek, Daniel O. | Rooney, Isabelle | Yan, Yibing | Dréno, Brigitte | Sullivan, Ryan | Patel, Manish | Hodi, Stephen | Amaria, Rodabe | Boasberg, Peter | Wallin, Jeffrey | He, Xian | Cha, Edward | Richie, Nicole | Ballinger, Marcus | Smith, David C. | Bauer, Todd M. | Wasser, Jeffrey S. | Luke, Jason J. | Balmanoukian, Ani S. | Kaufman, David R. | Zhao, Yufan | Maleski, Janet | Leopold, Lance | Gangadhar, Tara C. | Long, Georgina V. | Michielin, Olivier | VanderWalde, Ari | Andtbacka, Robert H. I. | Cebon, Jonathan | Fernandez, Eugenio | Malvehy, Josep | Olszanski, Anthony J. | Gause, Christine | Chen, Lisa | Chou, Jeffrey | Stephen Hodi, F. | Brady, Benjamin | Mortier, Laurent | Hassel, Jessica C. | Rutkowski, Piotr | McNeil, Catriona | Kalinka-Warzocha, Ewa | Lebbé, Celeste | Ny, Lars | Chacon, Matias | Queirolo, Paola | Loquai, Carmen | Cheema, Parneet | Berrocal, Alfonso | Eizmendi, Karmele Mujika | Bar-Sela, Gil | Horak, Christine | Hardy, Helene | Weber, Jeffrey S. | Grob, Jean-Jacques | Marquez-Rodas, Ivan | Schmidt, Henrik | Briscoe, Karen | Baurain, Jean-François | Wolchok, Jedd D. | Pinto, Rosamaria | De Summa, Simona | Garrisi, Vito Michele | Strippoli, Sabino | Azzariti, Amalia | Guida, Gabriella | Guida, Michele | Tommasi, Stefania | Jacquelot, Nicolas | Enot, David | Flament, Caroline | Pitt, Jonathan M. | Vimond, Nadège | Blattner, Carolin | Yamazaki, Takahiro | Roberti, Maria-Paula | Vetizou, Marie | Daillere, Romain | Poirier-Colame, Vichnou | la Semeraro, Michaë | Caignard, Anne | Slingluff, Craig L | Sallusto, Federica | Rusakiewicz, Sylvie | Weide, Benjamin | Marabelle, Aurélien | Kohrt, Holbrook | Dalle, Stéphane | Cavalcanti, Andréa | Kroemer, Guido | Di Giacomo, Anna Maria | Maio, Michaele | Wong, Phillip | Yuan, Jianda | Umansky, Viktor | Eggermont, Alexander | Zitvogel, Laurence | Anna, Passarelli | Marco, Tucci | Stefania, Stucci | Francesco, Mannavola | Mariaelena, Capone | Gabriele, Madonna | Antonio, Ascierto Paolo | Franco, Silvestris | Roberti, María Paula | Enot, David P. | Semeraro, Michaela | Jégou, Sarah | Flores, Camila | Chen, Tseng-hui Timothy | Kwon, Byoung S. | Anderson, Ana Carrizossa | Borg, Christophe | Aubin, François | Ayyoub, Maha | De Presbiteris, Anna Lisa | Cordaro, Fabiola Gilda | Camerlingo, Rosa | Fratangelo, Federica | Mozzillo, Nicola | Pirozzi, Giuseppe | Patriarca, Eduardo J. | Caputo, Emilia | Motti, Maria Letizia | Falcon, Rosaria | Miceli, Roberta | Capone, Mariaelena | Madonna, Gabriele | Mallardo, Domenico | Carrier, Maria Vincenza | Panza, Elisabetta | De Cicco, Paola | Armogida, Chiara | Ercolano, Giuseppe | Botti, Gerardo | Cirino, Giuseppe | Sandru, Angela | Blank, Miri | Balatoni, Timea | Olasz, Judit | Farkas, Emil | Szollar, Andras | Savolt, Akos | Godeny, Maria | Csuka, Orsolya | Horvath, Szabolcs | Eles, Klara | Shoenfeld, Yehuda | Kasler, Miklos | Costantini, Susan | Capone, Francesca | Moradi, Farnaz | Berglund, Pontus | Leandersson, Karin | Linnskog, Rickard | Andersson, Tommy | Prasad, Chandra Prakash | Nigro, Cristiana Lo | Lattanzio, Laura | Wang, Hexiao | Proby, Charlotte | Syed, Nelofer | Occelli, Marcella | Cauchi, Carolina | Merlano, Marco | Harwood, Catherine | Thompson, Alastair | Crook, Tim | Bifulco, Katia | Ingangi, Vincenzo | Minopoli, Michele | Ragone, Concetta | Pessi, Antonello | Mannavola, Francesco | D’Oronzo, Stella | Felici, Claudia | Tucci, Marco | Doronzo, Antonio | Silvestris, Franco | Ferretta, Anna | Guida, Stefania | Maida, Imma | Cocco, Tiziana | Passarelli, Anna | Quaresmini, Davide | Franzese, Ornella | Palermo, Belinda | Di Donna, Cosmo | Sperduti, Isabella | Foddai, MariaLaura | Stabile, Helena | Gismondi, Angela | Santoni, Angela | Nisticò, Paola | Sponghini, Andrea P. | Platini, Francesca | Marra, Elena | Rondonotti, David | Alabiso, Oscar | Fierro, Maria T. | Savoia, Paola | Stratica, Florian | Quaglino, Pietro |  Di Monta, Gianluca | Corrado, Caracò |  Di Marzo, Massimiliano | Ugo, Marone |  Di Cecilia, Maria Luisa | Nicola, Mozzillo | Fusciello, Celeste | Marra, Antonio | Guarrasi, Rosario | Baldi, Carlo | Russo, Rosa |  Di Giulio, Giovanni | Faiola, Vincenzo | Zeppa, Pio | Pepe, Stefano | Gambale, Elisabetta | Carella, Consiglia | Di Paolo, Alessandra | De Tursi, Michele | Marra, Laura | De Murtas, Fara | Sorrentino, Valeria | Voinea, Silviu | Panaitescu, Eugenia | Bolovan, Madalina | Stanciu, Adina | Cinca, Sabin | Botti, Chiara | Aquino, Gabriella | Anniciello, Annamaria | Fortes, Cristina | Mastroeni, Simona | Caggiati, Alessio | Passarelli, Francesca | Zappalà, Alba | Capuano, Maria | Bono, Riccardo | Nudo, Maurizio | Marino, Claudia | Michelozzi, Paola | De Biasio, Valeria | Battarra, Vincenzo C. | Formenti, Silvia | Ascierto, Maria Libera | McMiller, Tracee L. | Berger, Alan E. | Danilova, Ludmila | Anders, Robert A. | Netto, George J. | Xu, Haiying | Pritchard, Theresa S. | Fan, Jinshui | Cheadle, Chris | Cope, Leslie | Drake, Charles G. | Pardoll, Drew M. | Taube, Janis M. | Topalian, Suzanne L. | Gnjatic, Sacha | Nataraj, Sarah | Imai, Naoko | Rahman, Adeeb | Jungbluth, Achim A. | Pan, Linda | Venhaus, Ralph | Park, Andrew | Lehmann, Frédéric F. | Lendvai, Nikoletta | Cohen, Adam D. | Cho, Hearn J. | Daniel, Speiser | Hirsh, Vera
Journal of Translational Medicine  2016;14(Suppl 1):65.
Table of contents
MELANOMA BRIDGE 2015
KEYNOTE SPEAKER PRESENTATIONS
Molecular and immuno-advances
K1 Immunologic and metabolic consequences of PI3K/AKT/mTOR activation in melanoma
Vashisht G. Y. Nanda, Weiyi Peng, Patrick Hwu, Michael A. Davies
K2 Non-mutational adaptive changes in melanoma cells exposed to BRAF and MEK inhibitors help the establishment of drug resistance
Gennaro Ciliberto, Luigi Fattore, Debora Malpicci, Luigi Aurisicchio, Paolo Antonio Ascierto, Carlo M. Croce, Rita Mancini
K3 Tumor-intrinsic beta-catenin signaling mediates tumor-immune avoidance
Stefani Spranger, Thomas F. Gajewski
K4 Intracellular tumor antigens as a source of targets of antibody-based immunotherapy of melanoma
Yangyang Wang, Soldano Ferrone
Combination therapies
K5 Harnessing radiotherapy to improve responses to immunotherapy in cancer
Claire Vanpouille-Box, Erik Wennerberg, Karsten A. Pilones, Silvia C. Formenti, Sandra Demaria
K6 Creating a T cell-inflamed tumor microenvironment overcomes resistance to checkpoint blockade
Haidong Tang, Yang Wang, Yang-Xin Fu
K7 Biomarkers for treatment decisions?
Reinhard Dummer
K8 Combining oncolytic therapies in the era of checkpoint inhibitors
Igor Puzanov
K9 Immune checkpoint blockade for melanoma: should we combine or sequence ipilimumab and PD-1 antibody therapy?
Michael A. Postow
News in immunotherapy
K10 An update on adjuvant and neoadjuvant therapy for melanom
Ahmad Tarhini
K11 Targeting multiple inhibitory receptors in melanoma
Joe-Marc Chauvin, Ornella Pagliano, Julien Fourcade, Zhaojun Sun, Hong Wang, Cindy Sanders, John M. Kirkwood, Tseng-hui Timothy Chen, Mark Maurer, Alan J. Korman, Hassane M. Zarour
K12 Improving adoptive immune therapy using genetically engineered T cells
David F. Stroncek
Tumor microenvironment and biomarkers
K13 Myeloid cells and tumor exosomes: a crosstalk for assessing immunosuppression?
Veronica Huber, Licia Rivoltini
K14 Update on the SITC biomarker taskforce: progress and challenges
Magdalena Thurin
World-wide immunoscore task force: an update
K15 The immunoscore in colorectal cancer highlights the importance of digital scoring systems in surgical pathology
Tilman Rau, Alessandro Lugli
K16 The immunoscore: toward an integrated immunomonitoring from the diagnosis to the follow up of cancer’s patients
Franck Pagès
Economic sustainability of melanoma treatments: regulatory, health technology assessment and market access issues
K17 Nivolumab, the regulatory experience in immunotherapy
Jorge Camarero, Arantxa Sancho
K18 Evidence to optimize access for immunotherapies
Claudio Jommi
ORAL PRESENTATIONS
Molecular and immuno-advances
O1 Ipilimumab treatment results in CD4 T cell activation that is concomitant with a reduction in Tregs and MDSCs
Yago Pico de Coaña, Maria Wolodarski, Yuya Yoshimoto, Giusy Gentilcore, Isabel Poschke, Giuseppe V. Masucci, Johan Hansson, Rolf Kiessling
O2 Evaluation of prognostic and therapeutic potential of COX-2 and PD-L1 in primary and metastatic melanoma
Giosuè Scognamiglio, Francesco Sabbatino, Federica Zito Marino, Anna Maria Anniciello, Monica Cantile, Margherita Cerrone, Stefania Scala, Crescenzo D’alterio, Angela Ianaro, Giuseppe Cirino, Paolo Antonio Ascierto, Giuseppina Liguori, Gerardo Botti
O3 Vemurafenib in patients with BRAFV600 mutation–positive metastatic melanoma: final overall survival results of the BRIM-3 study
Paul B. Chapman, Caroline Robert, James Larkin, John B. Haanen, Antoni Ribas, David Hogg, Omid Hamid, Paolo Antonio Ascierto, Alessandro Testori, Paul Lorigan, Reinhard Dummer, Jeffrey A. Sosman, Keith T. Flaherty, Huibin Yue, Shelley Coleman, Ivor Caro, Axel Hauschild, Grant A. McArthur
O4 Updated survival, response and safety data in a phase 1 dose-finding study (CA209-004) of concurrent nivolumab (NIVO) and ipilimumab (IPI) in advanced melanoma
Mario Sznol, Margaret K. Callahan, Harriet Kluger, Michael A. Postow, RuthAnn Gordan, Neil H. Segal, Naiyer A. Rizvi, Alexander Lesokhin, Michael B. Atkins, John M. Kirkwood, Matthew M. Burke, Amanda Ralabate, Angel Rivera, Stephanie A. Kronenberg, Blessing Agunwamba, Mary Ruisi, Christine Horak, Joel Jiang, Jedd Wolchok
Combination therapies
O5 Efficacy and correlative biomarker analysis of the coBRIM study comparing cobimetinib (COBI) + vemurafenib (VEM) vs placebo (PBO) + VEM in advanced BRAF-mutated melanoma patients (pts)
Paolo A. Ascierto, Grant A. McArthur, James Larkin, Gabriella Liszkay, Michele Maio, Mario Mandalà, Lev Demidov, Daniil Stoyakovskiy, Luc Thomas, Luis de la Cruz-Merino, Victoria Atkinson, Caroline Dutriaux, Claus Garbe, Matthew Wongchenko, Ilsung Chang, Daniel O. Koralek, Isabelle Rooney, Yibing Yan, Antoni Ribas, Brigitte Dréno
O6 Preliminary clinical safety, tolerability and activity results from a Phase Ib study of atezolizumab (anti-PDL1) combined with vemurafenib in BRAFV600-mutant metastatic melanoma
Ryan Sullivan, Omid Hamid, Manish Patel, Stephen Hodi, Rodabe Amaria, Peter Boasberg, Jeffrey Wallin, Xian He, Edward Cha, Nicole Richie, Marcus Ballinger, Patrick Hwu
O7 Preliminary safety and efficacy data from a phase 1/2 study of epacadostat (INCB024360) in combination with pembrolizumab in patients with advanced/metastatic melanoma
Thomas F. Gajewski, Omid Hamid, David C. Smith, Todd M. Bauer, Jeffrey S. Wasser, Jason J. Luke, Ani S. Balmanoukian, David R. Kaufman, Yufan Zhao, Janet Maleski, Lance Leopold, Tara C. Gangadhar
O8 Primary analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma
Reinhard Dummer, Georgina V. Long, Antoni Ribas, Igor Puzanov, Olivier Michielin, Ari VanderWalde, Robert H.I. Andtbacka, Jonathan Cebon, Eugenio Fernandez, Josep Malvehy, Anthony J. Olszanski, Thomas F. Gajewski, John M. Kirkwood, Christine Gause, Lisa Chen, David R. Kaufman, Jeffrey Chou, F. Stephen Hodi
News in immunotherapy
O9 Two-year survival and safety update in patients (pts) with treatment-naïve advanced melanoma (MEL) receiving nivolumab (NIVO) or dacarbazine (DTIC) in CheckMate 066
Victoria Atkinson, Paolo A. Ascierto, Georgina V. Long, Benjamin Brady, Caroline Dutriaux, Michele Maio, Laurent Mortier, Jessica C. Hassel, Piotr Rutkowski, Catriona McNeil, Ewa Kalinka-Warzocha, Celeste Lebbé, Lars Ny, Matias Chacon, Paola Queirolo, Carmen Loquai, Parneet Cheema, Alfonso Berrocal, Karmele Mujika Eizmendi, Luis De La Cruz-Merino, Gil Bar-Sela, Christine Horak, Joel Jiang, Helene Hardy, Caroline Robert
O10 Efficacy and safety of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL) who were treated beyond progression in CheckMate 066/067
Georgina V. Long, Jeffrey S. Weber, James Larkin, Victoria Atkinson, Jean-Jacques Grob, Reinhard Dummer, Caroline Robert, Ivan Marquez-Rodas, Catriona McNeil, Henrik Schmidt, Karen Briscoe, Jean-François Baurain, F. Stephen Hodi, Jedd D. Wolchok
Tumor microenvironment and biomarkers
O11 New biomarkers for response/resistance to BRAF inhibitor therapy in metastatic melanoma
Rosamaria Pinto, Simona De Summa, Vito Michele Garrisi, Sabino Strippoli, Amalia Azzariti, Gabriella Guida, Michele Guida, Stefania Tommasi
O12 Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma and response to ipilimumab
Nicolas Jacquelot, David Enot, Caroline Flament, Jonathan M. Pitt, Nadège Vimond, Carolin Blattner, Takahiro Yamazaki, Maria-Paula Roberti, Marie Vetizou, Romain Daillere, Vichnou Poirier-Colame, Michaëla Semeraro, Anne Caignard, Craig L Slingluff Jr, Federica Sallusto, Sylvie Rusakiewicz, Benjamin Weide, Aurélien Marabelle, Holbrook Kohrt, Stéphane Dalle, Andréa Cavalcanti, Guido Kroemer, Anna Maria Di Giacomo, Michaele Maio, Phillip Wong, Jianda Yuan, Jedd Wolchok, Viktor Umansky, Alexander Eggermont, Laurence Zitvogel
O13 Serum levels of PD1- and CD28-positive exosomes before Ipilimumab correlate with therapeutic response in metastatic melanoma patients
Passarelli Anna, Tucci Marco, Stucci Stefania, Mannavola Francesco, Capone Mariaelena, Madonna Gabriele, Ascierto Paolo Antonio, Silvestris Franco
O14 Immunological prognostic factors in stage III melanomas
María Paula Roberti, Nicolas Jacquelot, David P Enot, Sylvie Rusakiewicz, Michaela Semeraro, Sarah Jégou, Camila Flores, Lieping Chen, Byoung S. Kwon, Ana Carrizossa Anderson, Caroline Robert, Christophe Borg, Benjamin Weide, François Aubin, Stéphane Dalle, Michele Maio, Jedd D. Wolchok, Holbrook Kohrt, Maha Ayyoub, Guido Kroemer, Aurélien Marabelle, Andréa Cavalcanti, Alexander Eggermont, Laurence Zitvogel
POSTER PRESENTATIONS
Molecular and immuno-advances
P1 Human melanoma cells resistant to B-RAF and MEK inhibition exhibit mesenchymal-like features
Anna Lisa De Presbiteris, Fabiola Gilda Cordaro, Rosa Camerlingo, Federica Fratangelo, Nicola Mozzillo, Giuseppe Pirozzi, Eduardo J. Patriarca, Paolo A. Ascierto, Emilia Caputo
P2 Anti-proliferative and pro-apoptotic effect of ABT888 on melanoma cell lines and its potential role in the treatment of melanoma resistant to B-RAF inhibitors
Federica Fratangelo, Rosa Camerlingo, Emilia Caputo, Maria Letizia Motti, Rosaria Falcone, Roberta Miceli, Mariaelena Capone, Gabriele Madonna, Domenico Mallardo, Maria Vincenza Carriero, Giuseppe Pirozzi and Paolo Antonio Ascierto
P3 Involvement of the L-cysteine/CSE/H2S pathway in human melanoma progression
Elisabetta Panza, Paola De Cicco, Chiara Armogida, Giuseppe Ercolano, Rosa Camerlingo, Giuseppe Pirozzi, Giosuè Scognamiglio, Gerardo Botti, Giuseppe Cirino, Angela Ianaro
P4 Cancer stem cell antigen revealing pattern of antibody variable region genes were defined by immunoglobulin repertoire analysis in patients with malignant melanoma
Beatrix Kotlan, Gabriella Liszkay, Miri Blank, Timea Balatoni, Judit Olasz, Emil Farkas, Andras Szollar, Akos Savolt, Maria Godeny, Orsolya Csuka, Szabolcs Horvath, Klara Eles, Yehuda Shoenfeld and Miklos Kasler
P5 Upregulation of Neuregulin-1 expression is a hallmark of adaptive response to BRAF/MEK inhibitors in melanoma
Debora Malpicci, Luigi Fattore, Susan Costantini, Francesca Capone, Paolo Antonio Ascierto, Rita Mancini, Gennaro Ciliberto
P6 HuR positively regulates migration of HTB63 melanoma cells
Farnaz Moradi, Pontus Berglund, Karin Leandersson, Rickard Linnskog, Tommy Andersson, Chandra Prakash Prasad
P7 Prolyl 4- (C-P4H) hydroxylases have opposing effects in malignant melanoma: implication in prognosis and therapy
Cristiana Lo Nigro, Laura Lattanzio, Hexiao Wang, Charlotte Proby, Nelofer Syed, Marcella Occelli, Carolina Cauchi, Marco Merlano, Catherine Harwood, Alastair Thompson, Tim Crook
P8 Urokinase receptor antagonists: novel agents for the treatment of melanoma
Maria Letizia Motti, Katia Bifulco, Vincenzo Ingangi, Michele Minopoli, Concetta Ragone, Federica Fratangelo, Antonello Pessi, Gennaro Ciliberto, Paolo Antonio Ascierto, Maria Vincenza Carriero
P9 Exosomes released by melanoma cell lines enhance chemotaxis of primary tumor cells
Francesco Mannavola, Stella D’Oronzo, Claudia Felici, Marco Tucci, Antonio Doronzo, Franco Silvestris
P10 New insights in mitochondrial metabolic reprogramming in melanoma
Anna Ferretta, Gabriella Guida, Stefania Guida, Imma Maida, Tiziana Cocco, Sabino Strippoli, Stefania Tommasi, Amalia Azzariti, Michele Guida
P11 Lenalidomide restrains the proliferation in melanoma cells through a negative regulation of their cell cycle
Stella D’Oronzo, Anna Passarelli, Claudia Felici, Marco Tucci, Davide Quaresmini, Franco Silvestris
Combination therapies
P12 Chemoimmunotherapy elicits polyfunctional anti-tumor CD8 + T cells depending on the activation of an AKT pathway sustained by ICOS
Ornella Franzese, Belinda Palermo, Cosmo Di Donna, Isabella Sperduti, MariaLaura Foddai, Helena Stabile, Angela Gismondi, Angela Santoni, Paola Nisticò
P13 Favourable toxicity profile of combined BRAF and MEK inhibitors in metastatic melanoma patients
Andrea P. Sponghini, Francesca Platini, Elena Marra, David Rondonotti, Oscar Alabiso, Maria T. Fierro, Paola Savoia, Florian Stratica, Pietro Quaglino
P14 Electrothermal bipolar vessel sealing system dissection reduces seroma output or time to drain removal following axillary and ilio-inguinal node dissection in melanoma patients: a pilot study
Di Monta Gianluca, Caracò Corrado, Di Marzo Massimiliano, Marone Ugo, Di Cecilia Maria Luisa, Mozzillo Nicola
News in immunotherapy
P15 Clinical and immunological response to ipilimumab in a metastatic melanoma patient with HIV infection
Francesco Sabbatino, Celeste Fusciello1, Antonio Marra, Rosario Guarrasi, Carlo Baldi, Rosa Russo, Di Giulio Giovanni, Vincenzo Faiola, Pio Zeppa, Stefano Pepe
P16 Immunotherapy and hypophysitis: a case report
Elisabetta Gambale, Consiglia Carella, Alessandra Di Paolo, Michele De Tursi
Tumor microenvironment and biomarkers
P17 New immuno- histochemical markers for the differential diagnosis of atypical melanocytic lesions with uncertain malignant potential
Laura Marra, Giosuè Scognamiglio, Monica Cantile, Margherita Cerrone, Fara De Murtas, Valeria Sorrentino, Anna Maria Anniciello, Gerardo Botti
P18 Utility of simultaneous measurement of three serum tumor markers in melanoma patients
Angela Sandru, Silviu Voinea, Eugenia Panaitescu, Madalina Bolovan, Adina Stanciu, Sabin Cinca
P19 The significance of various cut-off levels of melanoma inhibitory activity in evaluation of cutaneous melanoma patients
Angela Sandru, Silviu Voinea, Eugenia Panaitescu, Madalina Bolovan, Adina Stanciu, Sabin Cinca
P20 The long noncoding RNA HOTAIR is associated to metastatic progression of melanoma and it can be identified in the blood of patients with advanced disease
Chiara Botti, Giosuè Scognamiglio, Laura Marra, Gabriella Aquino, Rosaria Falcone, Annamaria Anniciello, Paolo Antonio Ascierto, Gerardo Botti, Monica Cantile
Other
P21 The effect of Sentinel Lymph Node Biopsy in melanoma mortality: timing of dissection
Cristina Fortes, Simona Mastroeni, Alessio Caggiati, Francesca Passarelli, Alba Zappalà, Maria Capuano, Riccardo Bono, Maurizio Nudo, Claudia Marino, Paola Michelozzi
P22 Epidemiological survey on related psychopathology in melanoma
Valeria De Biasio, Vincenzo C. Battarra
IMMUNOTHERAPY BRIDGE
KEYNOTE SPEAKER PRESENTATIONS
Immunotherapy beyond melanoma
K19 Predictor of response to radiation and immunotherapy
Silvia Formenti
K20 Response and resistance to PD-1 pathway blockade: clues from the tumor microenvironment
Maria Libera Ascierto, Tracee L. McMiller, Alan E. Berger, Ludmila Danilova, Robert A. Anders, George J. Netto, Haiying Xu, Theresa S. Pritchard, Jinshui Fan, Chris Cheadle, Leslie Cope, Charles G. Drake, Drew M. Pardoll, Janis M. Taube and Suzanne L. Topalian
K21 Combination immunotherapy with autologous stem cell transplantation, protein immunization, and PBMC reinfusion in myeloma patients
Sacha Gnjatic, Sarah Nataraj, Naoko Imai, Adeeb Rahman, Achim A. Jungbluth, Linda Pan, Ralph Venhaus, Andrew Park, Frédéric F. Lehmann, Nikoletta Lendvai, Adam D. Cohen, and Hearn J. Cho
K22 Anti-cancer immunity despite T cell “exhaustion”
Speiser Daniel
Immunotherapy in oncology (I-O): data from clinical trial
K23 The Checkpoint Inhibitors for the Treatment of Metastatic Non-small Cell Lung Cancer (NSCLC)
Vera Hirsh
doi:10.1186/s12967-016-0791-2
PMCID: PMC4965835  PMID: 27461275
6.  Extraskeletal Osteosarcoma 
Objectives:
To report characteristics, treatment, and outcomes for an international cohort of patients with extraskeletal osteosarcoma (ESOS).
Materials and Methods:
Through the Rare Cancer Network, retrospective data on patients with ESOS were collected. Patient characteristics, multimodality treatment information, and survival status were analyzed.
Results:
Thirty-seven patients in 4 health care institutions were identified. Thirty-one (86%) patients had grade 3 or 4 tumors. Most patients (27 [73%]) had stage III disease. Fourteen (38%) received neoadjuvant chemotherapy or chemoradiation. Of 28 (85%) who underwent surgery, 21 (75%) had free margins achieved and 15 (41%) subsequently received adjuvant chemotherapy. At median follow-up of 45 months, 20 (55%) patients were alive, 13 (43%) of whom were disease free. Univariate analysis showed that poor overall survival was related to stage IV (P<0.001), no surgery (P<0.001), primary size >10 cm (P=0.002), and age (P=0.002). In multivariate analysis, primary size >10 cm (P=0.005) was prognostic for overall survival. For patients without metastases, univariate analysis showed disease-free survival (DFS) related to primary size >10 cm (P=0.003), surgery (P=0.004), local recurrence (P=0.003), and age (P<0.001). In multivariate analysis for DFS, primary size >10 cm (P=0.01) and older age (P<0.001) were significant for worse outcome.
Conclusions:
Multimodality treatment remains standard for localized ESOS, with indications for neoadjuvant therapy less clear. Larger tumor size and older age were prognostic of poorer DFS.
doi:10.1097/COC.0000000000000005
PMCID: PMC4892767  PMID: 24401667
extraskeletal osteosarcoma; multimodality therapy; outcome; soft-tissue sarcoma; Rare Cancer Network
7.  Treatment of Metastatic Extramammary Paget’s Disease Associated With Adnexal Adenocarcinoma, With Anti-HER2 Drugs Based on Genomic Alteration ERBB2 S310F 
The Oncologist  2014;19(9):1006-1007.
Extramammary Paget’s disease is a rare intraepithelial malignant condition affecting the apocrine gland-bearing skin. In this case, a genomic alteration, ERBB2 S310F mutation, was discovered. The ERBB2 S310F mutation seems to be a transforming mutation that should be targeted with anti-HER2 drugs. Genomic tests are justified in rare tumors.
doi:10.1634/theoncologist.2014-0054
PMCID: PMC4153459  PMID: 25085898
8.  Rapid response to vismodegib in a patient with advanced basal cell carcinoma 
JAAD Case Reports  2015;1(5):267-268.
doi:10.1016/j.jdcr.2015.06.010
PMCID: PMC4809223  PMID: 27051749
basal cell carcinoma; clinical benefit; Hedgehog signaling pathway; rapid response; vismodegib; BCC, Basal cell carcinoma
9.  Pazopanib for metastatic pulmonary epithelioid hemangioendothelioma—a suitable treatment option: case report and review of anti-angiogenic treatment options 
BMC Cancer  2015;15:402.
Background
Epithelioid hemangioendothelioma is a rare vascular tumor of borderline or low-grade malignancy. The lungs and liver are the two common primary organs affected. Metastatic disease was reported in more than 100 cases in the literature. However, no firm conclusions can be determined for recommended treatment options.
Case presentation
The current case presents a patient with metastatic pulmonary epithelioid hemangioendothelioma to the cervical and mediastinal lymph nodes, lungs and liver that has been treated with pazopanib for more than two years with PET avid complete metabolic response in the mediastinum and lungs, and long-lasting stable disease. Target therapies that block VEGFR have a logical base in this rare malignancy.
Conclusions
The current case is the first to report objective, long-lasting response to pazopanib.
doi:10.1186/s12885-015-1395-6
PMCID: PMC4437555  PMID: 25967676
Epithelioid hemangioendothelioma; Pulmonary; Pazopanib; VEGFR
10.  Complete regression of mycosis fungoides after ipilimumab therapy for advanced melanoma 
JAAD Case Reports  2015;1(2):99-100.
doi:10.1016/j.jdcr.2015.02.009
PMCID: PMC4802565  PMID: 27051697
cutaneous T-cell lymphoma; ipilimumab; melanoma; mycosis fungoides; CTCL, cutaneous T-cell lymphoma; CTLA4, cytotoxic T-lymphocyte antigen-4; MF, mycosis fungoides
11.  Expression of heparanase in soft tissue sarcomas of adults 
Background
Heparanase is an endo-β-D-glucuronidase that cleaves heparan sulfate chains of proteoglycans, resulting in the disassembly of the extracellular matrix. Heparanase has a central role in the development of various tumors, and its expression has been associated with increased tumor growth, angiogenesis and metastasis, but there is insufficient information about the function of heparanase in sarcomas.
Study aims
1) To evaluate heparanase levels in adult soft tissue sarcomas (STS); 2) To examine the correlation between heparanase levels and pathological and clinical parameters and treatment outcome.
Methods
Pathological specimens of primary or metastatic STS were subjected to immunohistochemical analysis applying an anti-heparanase antibody. The clinical and the pathological data, together with the data of heparanase levels, were evaluated in a logistic regression model for tumor recurrence and survival.
Results
One hundred and one samples were examined, 55 from primary tumors and 46 from metastatic sites. A high expression of heparanase was observed in 29 (52.7%) and 22 specimens (47.8%), respectively. There was no statistically significant difference between heparanase expressions in the primary vs. metastatic sites of tumors. Moreover, no correlation was observed between heparanase staining and tumor aggressiveness, tumor recurrence or patient survival in various groups of patients.
Conclusion
Expression of heparanase was observed in 50% of the STS, in various histological subtypes. A larger study with homogenous groups of specific sub-types of STS or stages of disease is required to validate over-expression of heparanase as a marker of disease aggressiveness.
doi:10.1186/1756-9966-33-39
PMCID: PMC4026817  PMID: 24887057
Expression; Heparanase; Recurrence; Sarcoma; Soft tissue
12.  Transforming Pain into Beauty: On Art, Healing, and Care for the Spirit 
From drawing to sculpture, poetry to journaling, and dance to music and song, the arts can have a major impact on patients' spiritual well-being and health. The arts empower patients to fulfill the basic human drive to create and give patients a sense of possibility. Through creative expression, patients regain a feeling of wholeness, individually and as part of the larger world. Although spiritual caregivers have made occasional use of the arts, it would be better for the arts to be seen as a pillar of spiritual care provision. This paper provides a model for arts-based spiritual care (chaplaincy) in oncology/hematology and elsewhere. We discuss how to match the art form intervention to the individual patient and give examples of many kinds of uniquely spiritual arts-based interventions. In life, there are occasional “caseuras,” or ruptures. Using a theoretical foundation drawn from theologian Michael Fishbane, our model of arts-based spiritual care bridges the experience of the caesura to a renewed sense of meaning, or spiritual reorientation, that can be discovered within the reality of illness. Additionally, the ambiguity and playfulness inherent to creative expression strengthen the patient's flexibility and resilience.
doi:10.1155/2014/789852
PMCID: PMC4009230  PMID: 24834099
13.  Cultural differences in spiritual care: findings of an Israeli oncologic questionnaire examining patient interest in spiritual care 
BMC Palliative Care  2014;13:19.
Background
As professional spiritual care (chaplaincy) is introduced to new cultures worldwide, it bears examining which elements of screening and care are universal and, for those elements showing cultural difference, to study them in each culture. No quantitative spiritual care patient study had previously been done in Israel. Our objectives were twofold: 1) to examine who wants spiritual care in Israel, including demographic and clinical variables, and to compare against other results worldwide to further develop universal screening protocols 2) to see what patients want from spiritual care specifically in the Israeli setting.
Methods
Self-administered patient questionnaire examining spirituality/religiosity, interest in spiritual care (subdivided by type of care), and key demographic, social, and clinical data. The study setting was an Israeli oncology center at which spiritual care had been recently introduced.
Results
Data from 364 oncology patient questionnaires found 41% interest in spiritual care, as compared to 35%-54% in American studies. Having previously been visited by a spiritual caregiver predicted patient interest in further spiritual care (AOR 2.4, 95% CI 1.2-4.6), suggesting that the new service is being well-received. Multivariate stepwise logistic regression analysis identified additional predictors of openness to receiving spiritual care: self-describing as somewhat/very spiritual vs. not spiritual (adjusted odds ratio [AOR] 3.9 and 6.3, 95% CI 1.8-8.6 and 2.6-15.1) or traditional/religious vs. secular (AOR 2.2 and 2.1, 95% CI 1.3-3.6 and 1.1-4.0); and receiving one visit a week or less from family and friends (AOR 5.6, 95% CI 2.1-15.1). These findings are in line with previous American studies, suggesting universality across cultures that could be utilized in screening. Differences in demographic data and medical condition were not significant predictors of patient interest, suggesting a cultural difference, where age and education were predictors in the American context. Levels of interest in explicitly religious or spiritual support such as prayer or addressing religious/spiritual questions were much lower than in other cultures.
Conclusions
Results illustrate the demand for and satisfaction with the new Israeli service. The cross-cultural comparison found both culture-dependent and possibly universal predictors of patient interest, and found lower interest in Israel for explicitly religious/spiritual types of support.
doi:10.1186/1472-684X-13-19
PMCID: PMC4108186  PMID: 24708816
Spiritual care; Oncology; Chaplaincy; Spiritual screening; Patient education; International; Pastoral care
14.  Barriers and challenges in integration of anthroposophic medicine in supportive breast cancer care 
SpringerPlus  2013;2:364.
In the last decade, more and more oncology centers are challenged with complementary medicine (CM) integration within supportive breast cancer care. Quality of life (QOL) improvement and attenuation of oncology treatment side effects are the core objectives of integrative CM programs in cancer care. Yet, limited research is available on the use of specific CM modalities in an integrative setting and on cancer patients’ compliance with CM consultation. Studies are especially warranted to view the clinical application of researched CM modalities, such as anthroposophic medicine (AM), a unique CM modality oriented to cancer supportive care. Our objective was to characterize consultation patterns provided by physicians trained in CM following oncology health-care practitioners’ referral of patients receiving chemotherapy. We aimed to identify characteristics of patients who consulted with AM and to explore patients’ compliance to AM treatment. Of the 341 patients consulted with integrative physicians, 138 were diagnosed with breast cancer. Following integrative physician consultation, 56 patients were advised about AM treatment and 285 about other CM modalities. Logistic multivariate regression model found that, compared with patients receiving non-anthroposophic CM, the AM group had significantly greater rates of previous CM use [EXP(B) = 3.25, 95% C.I. 1.64-6.29, p = 0.001] and higher rates of cancer recurrence at baseline (p = 0.038). Most AM users (71.4%) used a single AM modality, such as mistletoe (viscum album) injections, oral AM supplements, or music therapy. Compliance with AM modalities following physician recommendation ranged from 44% to 71% of patients. We conclude that AM treatment provided within the integrative oncology setting is feasible based on compliance assessment. Other studies are warranted to explore the effectiveness of AM in improving patients’ QOL during chemotherapy.
doi:10.1186/2193-1801-2-364
PMCID: PMC3736081  PMID: 23961426
Integrative medicine; Anthroposophic medicine; Viscum album; Quality of life; Complementary medicine; Cancer
15.  The Medical Necessity for Medicinal Cannabis: Prospective, Observational Study Evaluating the Treatment in Cancer Patients on Supportive or Palliative Care 
Background. Cancer patients using cannabis report better influence from the plant extract than from synthetic products. However, almost all the research conducted to date has been performed with synthetic products. We followed patients with a medicinal cannabis license to evaluate the advantages and side effects of using cannabis by cancer patients. Methods. The study included two interviews based on questionnaires regarding symptoms and side effects, the first held on the day the license was issued and the second 6–8 weeks later. Cancer symptoms and cannabis side effects were documented on scales from 0 to 4 following the CTCAE. The distress thermometer was used also. Results. Of the 211 patients who had a first interview, only 131 had the second interview, 25 of whom stopped treatment after less than a week. All cancer or anticancer treatment-related symptoms showed significant improvement (P < 0.001). No significant side effects except for memory lessening in patients with prolonged cannabis use (P = 0.002) were noted. Conclusion. The positive effects of cannabis on various cancer-related symptoms are tempered by reliance on self-reporting for many of the variables. Although studies with a control group are missing, the improvement in symptoms should push the use of cannabis in palliative treatment of oncology patients.
doi:10.1155/2013/510392
PMCID: PMC3730175  PMID: 23956774
16.  Suspected CNS Metastases of Askin's Tumor: Would You Irradiate the Neural Axis? 
World Journal of Oncology  2013;3(6):288-290.
We present a case of a young-adult patient who was diagnosed with Askin’s tumor, with central nervous system lesions suspected as metastases. The patient achieved complete response after chemotherapy, and the question of consolidation radiotherapy to the CNS is discussed.
doi:10.4021/wjon564w
PMCID: PMC5649808
Askin’s tumor; CNS metastases
17.  The incidence and prognostic value of HER2 overexpression and cyclin D1 expression in patients with gastric or gastroesophageal junction adenocarcinoma in Israel 
Oncology Letters  2012;5(2):559-563.
Human epidermal growth factor 2 (HER2) positivity rates for gastric or gastroesophageal junction (GEJ) adenocarcinoma have been reported at 15–25%. Cyclin D1 (BCL1) is a non-specific proliferative marker. The prognostic significance of HER2 and cyclin D1 is inconclusive, with contradictory data. The aim of this study was to evaluate the incidence of HER2 overexpression in gastric or GEJ patients. The presence of a possible correlation between HER2 status and cyclin D1 staining was assessed; both were evaluated as prognostic markers for survival. The clinical data and histological specimens of 150 consecutive patients diagnosed with gastric or GEJ adenocarcinoma, and treated at our hospital from June 2005 to March 2009, were analyzed. Pathological specimens were immunohistochemically stained for HER2. Immunoreactivity was determined according to the scoring system for gastric carcinoma. Cyclin D1 immunoreactivity was also tested. The results demonstrated that HER2 was positive in 14/150 (9.3%) patients. HER2-positive (HER2+) and HER2-negative (HER2−) patients did not differ significantly with regard to other clinicopathological parameters. In a multivariate analysis, HER2 positivity was revealed to be a poor prognosis variable (P=0.046; 95% CI, 1.03–3.58). In patients with non-metastatic disease, median survival was 59 months for HER2− and 42 months for HER2+ patients, but this difference was not significant. In patients with metastatic disease, median survival was 9.5 months and 2.5 months for HER2− and HER2+ patients, respectively (P=0.041). Cyclin D1 was not idemonstrated to be a prognostic factor and was not associated with HER2 overexpression. The rate of positive HER2 status in the current group of unselected patients with gastric and GEJ adenocarcinoma was relatively low compared with that observed in the literature. Nevertheless, HER2 positivity was associated with a poor prognosis.
doi:10.3892/ol.2012.1031
PMCID: PMC3573138  PMID: 23420289
gastric carcinoma; HER2; cyclin D1; survival; Israel
18.  Evaluation of carboplatin dosing in non-small cell lung carcinoma patients using Calvert formula and Cockroft and Gault equation for glomerular filtration rate estimation 
Oncology Letters  2012;4(5):1072-1076.
The aim of this study was to evaluate the reliability of the Cockroft and Gault (CG) equation for glomerular filtration rate (GFR) estimation in carboplatin dosing based on the Calvert formula. The records of 117 patients with advanced non-small cell lung carcinoma treated with carboplatin were retrospectively analyzed. Theoretical carboplatin doses derived from the Calvert formula using the CG equation were calculated for each chemotherapy cycle. Fluctuations in the theoretical carboplatin doses were analyzed, and discrepancies between actual carboplatin doses prescribed by the physician and theoretical doses were assessed. It was found that, compared with the first-cycle dose, subsequent theoretical doses were more than 10% higher in 79/320 cycles (24.7%) and more than 10% lower in 53/320 cycles (16.6%; P=0.015). A body mass index greater than or equal to 30 was associated with a tendency for increased CG-estimated GFR during subsequent chemotherapy cycles (P=0.009). Physicians tended to lower the prescribed dose (32.2% of the cycles) by using a higher serum creatinine (Scr) level for dose calculation than was actually measured. We concluded that Calvert formula-derived carboplatin doses fluctuate widely during repeated cycles when actual Scr is used for CG-estimated GFR. The measurement of 24-h creatinine clearance is advised as an alternative in selected patients with reduction in serum creatinine observed during treatments.
doi:10.3892/ol.2012.869
PMCID: PMC3499615  PMID: 23162654
Cockroft and Gault; glomerular filtration rate; body mass index; carboplatin; lung cancer
19.  Postoperative chemotherapy in gastric cancer, consisting of etoposide, doxorubicin and cisplatin, followed by radiotherapy with concomitant cisplatin: A feasibility study 
Oncology Letters  2012;3(5):1154-1158.
The prognosis following surgical treatment of gastric carcinoma (GC) or gastroesophageal junction (GEJ) adenocarcinoma remains poor. Although adjuvant chemo-radiotherapy with 5-fluorouracil has been shown to be beneficial, a high rate of distant failure has been reported. Thus, the toxicity profile and efficacy of an intensified chemo-radiotherapy regimen following complete or near-complete resection of GC was evaluated. Patients who underwent surgery for GC were eligible for evaluation. Treatment consisted of four cycles of modified EAP: etoposide 100 mg/m2, days 1–3; cisplatin 27 mg/m2, days 1–3; and adriamycin 40 mg/m2, day 1; every 21 days, followed by a course of radiotherapy (45 Gy; 1.8 Gy/fr) combined with weekly cisplatin 40 mg/m2. In total, 40 patients were included in the analysis. Median follow-up was 34 months from the onset of chemotherapy. Microscopic stage IV disease and/or R1 resection were found in 11 patients. For these patients, the median progression-free survival was 6.5 months, and overall survival 9.5 months, compared to 25 and 54 months, respectively, for the remaining 29 patients. In the latter subgroup, longer disease-free survival was associated with average dose intensity of >90% for the four cycles of EAP. The predominant grade 3–4 toxicities during EAP-chemotherapy were hematological adverse events. Nevertheless, the rate of severe non-hematologic toxicity reached 60%. There was one toxicity-related mortality. During the chemo-radiotherapy course, 39% of patients experienced grade 3–4 non-hematologic toxicities. It was concluded that the high toxicity rate of this regimen does not justify further evaluation of this postoperative protocol. Chemo-radiotherapy for R1 or pathological microscopic M1 patients does not appear to be justified.
doi:10.3892/ol.2012.617
PMCID: PMC3389679  PMID: 22783410
gastric cancer; adjuvant chemo-radiotherapy; cisplatin; adriamycin; etoposide
20.  Reflections on Palliative Care from the Jewish and Islamic Tradition 
Spiritual care is a vital part of holistic patient care. Awareness of common patient beliefs will facilitate discussions about spirituality. Such conversations are inherently good for the patient, deepen the caring staff-patient-family relationship, and enhance understanding of how beliefs influence care decisions. All healthcare providers are likely to encounter Muslim patients, yet many lack basic knowledge of the Muslim faith and of the applications of Islamic teachings to palliative care. Similarly, some of the concepts underlying positive Jewish approaches to palliative care are not well known. We outline Jewish and Islamic attitudes toward suffering, treatment, and the end of life. We discuss our religions' approaches to treatments deemed unnecessary by medical staff, and consider some of the cultural reasons that patients and family members might object to palliative care, concluding with specific suggestions for the medical team.
doi:10.1155/2012/693092
PMCID: PMC3235784  PMID: 22203878
21.  DNA Methyltransferase 1 and 3B Activate BAG-1 Expression via Recruitment of CTCFL/BORIS and Modulation of Promoter Histone Methylation 
Cancer research  2008;68(8):2726-2735.
In a previous genomic analysis, using somatic methyltransferase (DNMT) knockout cells, we showed that hypomethylation decreased the expression of as many genes as were observed to increase, suggesting a previously unknown mechanism for epigenetic regulation. To address this idea, the expression of the BAG family genes was used as a model. These genes were used because their expression was decreased in DNMT1−/−, DNMT3B−/−, and double knockout cells and increased in DNMT1-overexpressing and DNMT3B-overexpressing cells. Chromatin immunoprecipitation analysis of the BAG-1 promoter in DNMT1-overexpressing or DNMT3B-overexpressing cells showed a permissive dimethyl-H3-K4/dimethyl-H3-K9 chromatin status associated with DNA-binding of CTCFL/BORIS, as well as increased BAG-1 expression. In contrast, a nonpermissive dimethyl-H3-K4/dimethyl-H3-K9 chromatin status was associated with CTCF DNA-binding and decreased BAG-1 expression in the single and double DNMT knockout cells. BORIS short hairpin RNA knockdown decreased both promoter DNA-binding, as well as BAG-1 expression, and changed the dimethyl-H3-K4/dimethyl-H3-K9 ratio to that characteristic of a nonpermissive chromatin state. These results suggest that DNMT1 and DNMT3B regulate BAG-1 expression via insulator protein DNA-binding and chromatin dynamics by regulating histone dimethylation.
doi:10.1158/0008-5472.CAN-07-6654
PMCID: PMC2733164  PMID: 18413740
22.  BAT3 and SET1A Form a Complex with CTCFL/BORIS To Modulate H3K4 Histone Dimethylation and Gene Expression▿ †  
Molecular and Cellular Biology  2008;28(21):6720-6729.
Chromatin status is characterized in part by covalent posttranslational modifications of histones that regulate chromatin dynamics and direct gene expression. BORIS (brother of the regulator of imprinted sites) is an insulator DNA-binding protein that is thought to play a role in chromatin organization and gene expression. BORIS is a cancer-germ line gene; these are genes normally present in male germ cells (testis) that are also expressed in cancer cell lines as well as primary tumors. This work identifies SET1A, an H3K4 methyltransferase, and BAT3, a cochaperone recruiter, as binding partners for BORIS, and these proteins bind to the upstream promoter regions of two well-characterized procarcinogenic genes, Myc and BRCA1. RNA interference (RNAi) knockdown of BAT3, as well as SET1A, decreased Myc and BRCA1 gene expression but did not affect the binding properties of BORIS, but RNAi knockdown of BORIS prevented the assembly of BAT3 and SET1A at the Myc and BRCA1 promoters. Finally, chromatin analysis suggested that BORIS and BAT3 exert their effects on gene expression by recruiting proteins such as SET1A that are linked to changes in H3K4 dimethylation. Thus, we propose that BORIS acts as a platform upon which BAT3 and SET1A assemble and exert effects upon chromatin structure and gene expression.
doi:10.1128/MCB.00568-08
PMCID: PMC2573239  PMID: 18765639
23.  A randomized, double-blind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate/severe, chronic cancer pain 
Palliative Medicine  2012;26(1):50-60.
Objective: An examination of whether oxycodone/naloxone prolonged-release tablets (OXN PR) can improve constipation and maintain analgesia, compared with oxycodone prolonged-release tablets (OxyPR) in patients with moderate/severe cancer pain.
Methods: Randomized, double-blind, active-controlled, double-dummy, parallel-group study in which 185 patients were randomized to receive up to 120 mg/day of OXN PR or OxyPR over 4 weeks. Efficacy assessments included Bowel Function Index (BFI), Brief Pain Inventory Short-Form (BPI-SF), laxative and rescue medication use. Quality of life (QoL) and safety assessments were conducted.
Results: After 4 weeks, mean BFI score was significantly lower with OXN PR; mean total laxative intake was 20% lower with OXN PR. Mean BPI-SF scores were similar for both treatments and the average rate of analgesic rescue medication use was low and comparable. QoL assessments were stable and comparable with greater improvements in constipation-specific QoL assessments with OXN PR. Overall, rates of adverse drug reactions were similar.
Conclusions: OXN PR provides superior bowel function in cancer pain patients, compared with OxyPR, without compromising analgesic efficacy or safety. This study confirms that OXN PR is well tolerated and efficacious in cancer pain patients and results are in line with those seen in non-malignant pain patients.
doi:10.1177/0269216311418869
PMCID: PMC3255516  PMID: 21937568
Analgesia; constipation; naloxone; neoplasms; oxycodone; pain

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