Description of the Method for Evaluating Digital Endpoints in Alzheimer Disease Study : Protocol for an Exploratory, Cross-sectional Study

©Jelena Curcic, Vanessa Vallejo, Jennifer Sorinas, Oleksandr Sverdlov, Jens Praestgaard, Mateusz Piksa, Mark Deurinck, Gul Erdemli, Maximilian Bügler, Ioannis Tarnanas, Nick Taptiklis, Francesca Cormack, Rebekka Anker, Fabien Massé, William Souillard-Mandar, Nathan Intrator, Lior Molcho, Erica Madero, Nicholas Bott, Mieko Chambers, Josef Tamory, Matias Shulz, Gerardo Fernandez, William Simpson, Jessica Robin, Jón G Snædal, Jang-Ho Cha, Kristin Hannesdottir. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 10.08.2022.BACKGROUND: More sensitive and less burdensome efficacy end points are urgently needed to improve the effectiveness of clinical drug development for Alzheimer disease (AD). Although conventional end points lack sensitivity, digital technologies hold promise for amplifying the detection of treatment signals and capturing cognitive anomalies at earlier disease stages. Using digital technologies and combining several test modalities allow for the collection of richer information about cognitive and functional status, which is not ascertainable via conventional paper-and-pencil tests. OBJECTIVE: This study aimed to assess the psychometric properties, operational feasibility, and patient acceptance of 10 promising technologies that are to be used as efficacy end points to measure cognition in future clinical drug trials. METHODS: The Method for Evaluating Digital Endpoints in Alzheimer Disease study is an exploratory, cross-sectional, noninterventional study that will evaluate 10 digital technologies' ability to accurately classify participants into 4 cohorts according to the severity of cognitive impairment and dementia. Moreover, this study will assess the psychometric properties of each of the tested digital technologies, including the acceptable range to assess ceiling and floor effects, concurrent validity to correlate digital outcome measures to traditional paper-and-pencil tests in AD, reliability to compare test and retest, and responsiveness to evaluate the sensitivity to change in a mild cognitive challenge model. This study included 50 eligible male and female participants (aged between 60 and 80 years), of whom 13 (26%) were amyloid-negative, cognitively healthy participants (controls); 12 (24%) were amyloid-positive, cognitively healthy participants (presymptomatic); 13 (26%) had mild cognitive impairment (predementia); and 12 (24%) had mild AD (mild dementia). This study involved 4 in-clinic visits. During the initial visit, all participants completed all conventional paper-and-pencil assessments. During the following 3 visits, the participants underwent a series of novel digital assessments. RESULTS: Participant recruitment and data collection began in June 2020 and continued until June 2021. Hence, the data collection occurred during the COVID-19 pandemic (SARS-CoV-2 virus pandemic). Data were successfully collected from all digital technologies to evaluate statistical and operational performance and patient acceptance. This paper reports the baseline demographics and characteristics of the population studied as well as the study's progress during the pandemic. CONCLUSIONS: This study was designed to generate feasibility insights and validation data to help advance novel digital technologies in clinical drug development. The learnings from this study will help guide future methods for assessing novel digital technologies and inform clinical drug trials in early AD, aiming to enhance clinical end point strategies with digital technologies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35442.Peer reviewe

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Combining early postoperative parathyroid hormone and serum calcium levels allows for an efficacious selective post-thyroidectomy supplementation treatment

BACKGROUND: Optimal treatment protocol to prevent symptomatic hypocalcemia following total thyroidectomy is still matter of debate. We prospectively evaluated the efficacy of a selective supplementation protocol based on both early postoperative intact parathyroid hormone (iPTH) and serum calcium levels. METHODS: Two hundred thirty consecutive patients were divided in three different groups of treatment according to iPTH levels 4 h after total thyroidectomy (4 h-iPTH) and serum calcium levels in the first postoperative day (1PO-Ca): group A (4 h-iPTH > 10 pg/ml, 1PO-Ca 65 8.5 mg/dl), no treatment; group B (4 h-iPTH > 10 pg/ml, 1PO-Ca < 8.5 mg/dl), oral calcium (OC) 3 g per day; and group C (4 h-iPTH 64 10 pg/ml), OC 3 g + calcitriol (VD) 1 \u3bcg per day. Development of biochemical and/or symptomatic hypocalcemia was evaluated. RESULTS: Fifty-nine patients (25.6%) had subnormal 4 h-iPTH levels ( 6410 pg/ml) (group C). Among patients with normal 4 h-iPTH levels, 25 (10.9%) had subnormal 1PO-Ca (<8.5 mg/dl) (group B). The remaining 146 patients (63.5%) had normal 4 h-iPTH and 1PO-Ca levels (group A). One patient in group A, 2 in group B, and 18 in group C developed biochemical hypocalcemia. Only one patient in group C experienced major symptoms. Treatment was discontinued within 1 month in all the patients in group B. At a mean follow-up of 303 days, five patients in group C were still under supplementation treatment. CONCLUSION: The proposed supplementation protocol seems efficacious in preventing symptomatic hypocalcemia. It could allow a safe and early discharge of most patients, thus avoiding the constraints and the costs of routine supplementation

Melanoma and immunotherapy bridge 2015

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 Hirs

Melanoma and immunotherapy bridge 2015

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 Hirs

Melanoma and immunotherapy bridge 2015 : Naples, Italy. 1-5 December 2015

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 Hirs

Global variations in heart failure etiology, management, and outcomes

Importance: Most epidemiological studies of heart failure (HF) have been conducted in high-income countries with limited comparable data from middle- or low-income countries. Objective: To examine differences in HF etiology, treatment, and outcomes between groups of countries at different levels of economic development. Design, Setting, and Participants: Multinational HF registry of 23 341 participants in 40 high-income, upper–middle-income, lower–middle-income, and low-income countries, followed up for a median period of 2.0 years. Main Outcomes and Measures: HF cause, HF medication use, hospitalization, and death. Results: Mean (SD) age of participants was 63.1 (14.9) years, and 9119 (39.1%) were female. The most common cause of HF was ischemic heart disease (38.1%) followed by hypertension (20.2%). The proportion of participants with HF with reduced ejection fraction taking the combination of a β-blocker, renin-angiotensin system inhibitor, and mineralocorticoid receptor antagonist was highest in upper–middle-income (61.9%) and high-income countries (51.1%), and it was lowest in low-income (45.7%) and lower–middle-income countries (39.5%) (P &lt; .001). The age- and sex- standardized mortality rate per 100 person-years was lowest in high-income countries (7.8 [95% CI, 7.5-8.2]), 9.3 (95% CI, 8.8-9.9) in upper–middle-income countries, 15.7 (95% CI, 15.0-16.4) in lower–middle-income countries, and it was highest in low-income countries (19.1 [95% CI, 17.6-20.7]). Hospitalization rates were more frequent than death rates in high-income countries (ratio = 3.8) and in upper–middle-income countries (ratio = 2.4), similar in lower–middle-income countries (ratio = 1.1), and less frequent in low-income countries (ratio = 0.6). The 30-day case-fatality rate after first hospital admission was lowest in high-income countries (6.7%), followed by upper–middle-income countries (9.7%), then lower–middle-income countries (21.1%), and highest in low-income countries (31.6%). The proportional risk of death within 30 days of a first hospital admission was 3- to 5-fold higher in lower–middle-income countries and low-income countries compared with high-income countries after adjusting for patient characteristics and use of long-term HF therapies. Conclusions and Relevance: This study of HF patients from 40 different countries and derived from 4 different economic levels demonstrated differences in HF etiologies, management, and outcomes. These data may be useful in planning approaches to improve HF prevention and treatment globally