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Bueno, Raphael

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Bueno

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Raphael

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Bueno, Raphael
Author's Publications: search.filters.isAuthorOfPublication.07370e42-70a2-478a-a4a9-5b73ecbaaa75

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    Quantitative Clinical Staging for Patients With Malignant Pleural Mesothelioma
    (Oxford University Press, 2017) Gill, Ritu; Yeap, Beow; Bueno, Raphael; Richards, William
    Abstract Background: Analysis of the International Association for the Study of Lung Cancer (IASLC) Malignant Pleural Mesothelioma (MPM) database revealed that clinical (cTNM) staging minimally stratified survival and was discrepant with pathological (pTNM) staging. To improve prognostic classification of MPM, alternative staging models based on quantitative parameters were explored. Methods: An institutional review board–approved MPM registry was queried to identify patients with available pathological and preoperative imaging data. Qualifying patients were randomly assigned to training and test sets in a 1:2 ratio. Computed cTNM and pTNM staging (AJCC Cancer Staging Manual, 7th ed.) were compared. Quantitative image analysis included tumor volume assessed from three-dimensional reconstruction of computed tomography scans (VolCT) and maximal fissural thickness (Fmax). Survival was estimated using the Kaplan-Meier method, and the relationship with VolCT was examined by Cox regression analysis to identify optimized cut-points. Performance of cTNM and quantitative models derived was compared in the test set using Harrell’s C index. Results: A total of 472 patients met inclusion criteria. TNM staging was concordant with pathological TNM staging in 171 of 472 (36.2%), understaged in 209 (44.2%), and overstaged in 92 (19.4%) patients. The most concordant feature was involvement of interlobar fissures. A quantitative clinical staging model comprising VolCT and Fmax (c-index = 0.638, 95% confidence interval [CI] = 0.603 to 0.673) performed statistically significantly better as a prognostic classifier when compared in the test set with cTNM (c-index = 0.562, 95% CI = 0.525 to 0.599, P = .001). Conclusions: Improved prognostic performance may be achievable by quantitative clinical staging combining VolCT and Fmax, providing a cost-effective and clinically relevant surrogate for clinical TNM stage.
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    Molecular pathways and therapeutic targets in lung cancer
    (Impact Journals LLC, 2014) Shtivelman, Emma; Hensing, Thomas; Simon, George R.; Dennis, Phillip A.; Otterson, Gregory A.; Bueno, Raphael; Salgia, Ravi
    Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review.
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    Validation of a Molecular and Pathological Model for Five-Year Mortality Risk in Patients with Early Stage Lung Adenocarcinoma
    (Lippincott Williams & Wilkins, 2014) Bueno, Raphael; Hughes, Elisha; Wagner, Susanne; Gutin, Alexander S.; Lanchbury, Jerry S.; Zheng, Yifan; Archer, Michael A.; Gustafson, Corinne; Jones, Joshua T.; Rushton, Kristen; Saam, Jennifer; Kim, Edward Y.; Barberis, Massimo; Wistuba, Ignacio; Wenstrup, Richard J.; Wallace, William A.; Hartman, Anne-Renee; Harrison, David J.
    Introduction: The aim of this study was to validate a molecular expression signature [cell cycle progression (CCP) score] that identifies patients with a higher risk of cancer-related death after surgical resection of early stage (I-II) lung adenocarcinoma in a large patient cohort and evaluate the effectiveness of combining CCP score and pathological stage for predicting lung cancer mortality. Methods: Formalin-fixed paraffin-embedded surgical tumor samples from 650 patients diagnosed with stage I and II adenocarcinoma who underwent definitive surgical treatment without adjuvant chemotherapy were analyzed for 31 proliferation genes by quantitative real-time polymerase chain reaction. The prognostic discrimination of the expression score was assessed by Cox proportional hazards analysis using 5-year lung cancer-specific death as primary outcome. Results: The CCP score was a significant predictor of lung cancer-specific mortality above clinical covariates [hazard ratio (HR) = 1.46 per interquartile range (95% confidence interval = 1.12–1.90; p = 0.0050)]. The prognostic score, a combination of CCP score and pathological stage, was a more significant indicator of lung cancer mortality risk than pathological stage in the full cohort (HR = 2.01; p = 2.8 × 10−11) and in stage I patients (HR = 1.67; p = 0.00027). Using the 85th percentile of the prognostic score as a threshold, there was a significant difference in lung cancer survival between low-risk and high-risk patient groups (p = 3.8 × 10−7). Conclusions: This study validates the CCP score and the prognostic score as independent predictors of lung cancer death in patients with early stage lung adenocarcinoma treated with surgery alone. Patients with resected stage I lung adenocarcinoma and a high prognostic score may be candidates for adjuvant therapy to reduce cancer-related mortality.
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    Tsc1-Tp53 loss induces mesothelioma in mice, and evidence for this mechanism in human mesothelioma
    (2014) Guo, Yanan; Chirieac, Lucian; Bueno, Raphael; Pass, Harvey; Wu, Wenhao; Malinowska, Izabela A.; Kwiatkowski, David
    Mesothelioma is diagnosed in approximately 2,500 patients in the United States every year, most often arising in the pleural space, but also occurring as primary peritoneal mesothelioma. The vast majority of patients with mesothelioma die from their disease within 3 years. We developed a new mouse model of mesothelioma by bladder or intra-peritoneal injection of adenovirus Cre into mice with conditional alleles of each of Tp53 and Tsc1. Such mice began to develop malignant ascites about 6 months after injection, which was due to peritoneal mesothelioma, based on tumor morphology and immunohistochemical staining. Mesothelioma cell lines were established which showed loss of both Tsc1 and Tp53, with mTORC1 activation. Treatment of mice with malignant ascites due to mesothelioma with rapamycin led to a marked reduction in ascites, extended survival, and a 95–99% reduction in mesothelioma tumor volume, in comparison to vehicle-treated mice. To see if TSC1/TSC2 loss was a common genetic event in human mesothelioma, we examined 9 human mesothelioma cell lines, and found that 4 of 9 showed persistent activation of mTORC1 though none had loss of TSC1 or TSC2. A tissue microarray analysis of 198 human mesothelioma specimens showed that 33% of cases had reduced TSC2 expression and 60% showed activation of mTOR, indicating that mTOR activation is common in human mesothelioma and suggesting that it is a potential therapeutic target.
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    Autophagy Correlates with the Therapeutic Responsiveness of Malignant Pleural Mesothelioma in 3D Models
    (Public Library of Science, 2015) Barbone, Dario; Follo, Carlo; Echeverry, Nohemy; Gerbaudo, Victor; Klabatsa, Astero; Bueno, Raphael; Felley-Bosco, Emanuela; Broaddus, V. Courtney
    Malignant pleural mesothelioma is a highly chemoresistant solid tumor. We have studied this apoptotic resistance using in vitro and ex vivo three-dimensional models, which acquire a high level of chemoresistance that can be reduced by PI3K/mTOR inhibitors. Here, we investigate the activity of GDC-0980, a novel dual PI3K/mTOR inhibitor, which has been proposed to be effective in mesothelioma. In this work, we aimed to identify mechanisms and markers of efficacy for GDC-0980 by utilizing 3D models of mesothelioma, both in vitro multicellular spheroids and ex vivo tumor fragment spheroids grown from patient tumor samples. We found that a subset of mesothelioma spheroids is sensitive to GDC-0980 alone and to its combination with chemotherapy. Unexpectedly, this sensitivity did not correlate with the activation of the Akt/mTOR pathway. Instead, sensitivity to GDC-0980 correlated with the presence of constitutive ATG13 puncta, a feature of autophagy, a cellular program that supports cells under stress. In tumor fragment spheroids grown from 21 tumors, we also found a subset (n = 11) that was sensitive to GDC-0980, a sensitivity that also correlated with the presence of ATG13 puncta. Interference with autophagy by siRNA of ATG7, an essential autophagic protein, increased the response to chemotherapy, but only in the sensitive multicellular spheroids. In the spheroids resistant to GDC-0980, autophagy appeared to play no role. In summary, we show that GDC-0980 is effective in mesothelioma 3D models that display ATG13 puncta, and that blockade of autophagy increases their response to chemotherapy. For the first time, we show a role for autophagy in the response to chemotherapy of 3D models of mesothelioma and propose ATG13 as a potential biomarker of the therapeutic responsiveness of mesothelioma.
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    Neoadjuvant irinotecan, cisplatin, and concurrent radiation therapy with celecoxib for patients with locally advanced esophageal cancer
    (BioMed Central, 2016) Cleary, James; Mamon, Harvey; Szymonifka, Jackie; Bueno, Raphael; Choi, Noah; Donahue, Dean; Fidias, Panos M.; Gaissert, Henning; Jaklitsch, Michael; Kulke, Matthew; Lynch, Thomas P.; Mentzer, Steven; Meyerhardt, Jeffrey; Swanson, Richard; Wain, John Charles; Fuchs, Charles; Enzinger, Peter
    Background: Patients with locally advanced esophageal cancer who are treated with trimodality therapy have a high recurrence rate. Preclinical evidence suggests that inhibition of cyclooxygenase 2 (COX2) increases the effectiveness of chemoradiation, and observational studies in humans suggest that COX-2 inhibition may reduce esophageal cancer risk. This trial tested the safety and efficacy of combining a COX2 inhibitor, celecoxib, with neoadjuvant irinotecan/cisplatin chemoradiation. Methods: This single arm phase 2 trial combined irinotecan, cisplatin, and celecoxib with concurrent radiation therapy. Patients with stage IIA-IVA esophageal cancer received weekly cisplatin 30 mg/m2 plus irinotecan 65 mg/m2 on weeks 1, 2, 4, and 5 concurrently with 5040 cGy of radiation therapy. Celecoxib 400 mg was taken orally twice daily during chemoradiation, up to 1 week before surgery, and for 6 months following surgery. Results: Forty patients were enrolled with stage IIa (30 %), stage IIb (20 %), stage III (22.5 %), and stage IVA (27.5 %) esophageal or gastroesophageal junction cancer (AJCC, 5th Edition). During chemoradiation, grade 3–4 treatment-related toxicity included dysphagia (20 %), anorexia (17.5 %), dehydration (17.5 %), nausea (15 %), neutropenia (12.5 %), diarrhea (10 %), fatigue (7.5 %), and febrile neutropenia (7.5 %). The pathological complete response rate was 32.5 %. The median progression free survival was 15.7 months and the median overall survival was 34.7 months. 15 % (n = 6) of patients treated on this study developed brain metastases. Conclusions: The addition of celecoxib to neoadjuvant cisplatin-irinotecan chemoradiation was tolerable; however, overall survival appeared comparable to prior studies using neoadjuvant cisplatin-irinotecan chemoradiation alone. Further studies adding celecoxib to neoadjuvant chemoradiation in esophageal cancer are not warranted. Trial registration Clinicaltrials.gov: NCT00137852, registered August 29, 2005.
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    MET and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma
    (Public Library of Science, 2014) Kanteti, Rajani; Dhanasingh, Immanuel; Kawada, Ichiro; Lennon, Frances E.; Arif, Qudsia; Bueno, Raphael; Hasina, Rifat; Husain, Aliya N.; Vigneswaran, Wickii; Seiwert, Tanguy; Kindler, Hedy L.; Salgia, Ravi
    Malignant pleural mesothelioma (MPM) is an aggressive disease with a poor prognosis. Studies have shown that both MET and its key downstream intracellular signaling partners, PI3K and mTOR, are overexpressed in MPM. Here we determined the combinatorial therapeutic efficacy of a new generation small molecule inhibitor of MET, ARQ 197, and dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 in mesothelioma cell and mouse xenograft models. Cell viability results show that mesothelioma cell lines were sensitive to ARQ 197, NVP-BEZ235 and GDC-0980 inhibitors. The combined use of ARQ 197 with either NVP-BEZ235 or GDC-0980, was synergistic (CI<1). Significant delay in wound healing was observed with ARQ 197 (p<0.001) with no added advantage of combining it with either NVP-BEZ235 or GDC-0980. ARQ 197 alone mainly induced apoptosis (20±2.36%) that was preceded by suppression of MAPK activity, while all the three suppressed cell cycle progression. Both GDC-0980 and NVP-BEZ235 strongly inhibited activities of PI3K and mTOR as evidenced from the phosphorylation status of AKT and S6 kinase. The above observation was further substantiated by the finding that a majority of the MPM archival samples tested revealed highly active AKT. While the single use of ARQ 197 and GDC-0980 inhibited significantly the growth of MPM xenografts (p<0.05, p<0.001 respectively) in mice, the combination of the above two drugs was highly synergistic (p<0.001). Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than the use of the drugs singly in suppressing MPM tumor growth and motility and therefore merit further translational studies.
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    Fine needle aspirate flow cytometric phenotyping characterizes immunosuppressive nature of the mesothelioma microenvironment
    (Nature Publishing Group, 2016) Lizotte, Patrick H.; Jones, Robert E.; Keogh, Lauren; Ivanova, Elena; Liu, Hongye; Awad, Mark; Hammerman, Peter S.; Gill, Ritu; Richards, William; Barbie, David; Bass, Adam; Bueno, Raphael; English, Jessie M.; Bittinger, Mark; Wong, Kwok-Kin
    With the emergence of checkpoint blockade and other immunotherapeutic drugs, and the growing adoption of smaller, more flexible adaptive clinical trial designs, there is an unmet need to develop diagnostics that can rapidly immunophenotype patient tumors. The ability to longitudinally profile the tumor immune infiltrate in response to immunotherapy also presents a window of opportunity to illuminate mechanisms of resistance. We have developed a fine needle aspirate biopsy (FNA) platform to perform immune profiling on thoracic malignancies. Matching peripheral blood, bulk resected tumor, and FNA were analyzed from 13 mesothelioma patients. FNA samples yielded greater numbers of viable cells when compared to core needle biopsies. Cell numbers were adequate to perform flow cytometric analyses on T cell lineage, T cell activation and inhibitory receptor expression, and myeloid immunosuppressive checkpoint markers. FNA samples were representative of the tumor as a whole as assessed by head-to-head comparison to single cell suspensions of dissociated whole tumor. Parallel analysis of matched patient blood enabled us to establish quality assurance criteria to determine the accuracy of FNA procedures to sample tumor tissue. FNA biopsies provide a diagnostic to rapidly phenotype the tumor immune microenvironment that may be of great relevance to clinical trials.
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    31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two: National Harbor, MD, USA. 9-13 November 2016
    (BioMed Central, 2016) Ager, Casey; Reilley, Matthew; Nicholas, Courtney; Bartkowiak, Todd; Jaiswal, Ashvin; Curran, Michael; Albershardt, Tina C.; Bajaj, Anshika; Archer, Jacob F.; Reeves, Rebecca S.; Ngo, Lisa Y.; Berglund, Peter; ter Meulen, Jan; Denis, Caroline; Ghadially, Hormas; Arnoux, Thomas; Chanuc, Fabien; Fuseri, Nicolas; Wilkinson, Robert W.; Wagtmann, Nicolai; Morel, Yannis; Andre, Pascale; Atkins, Michael B.; Carlino, Matteo S.; Ribas, Antoni; Thompson, John A.; Choueiri, Toni; Hodi, F. Stephen; Hwu, Wen-Jen; McDermott, David; Atkinson, Victoria; Cebon, Jonathan S.; Fitzharris, Bernie; Jameson, Michael B.; McNeil, Catriona; Hill, Andrew G.; Mangin, Eric; Ahamadi, Malidi; van Vugt, Marianne; van Zutphen, Mariëlle; Ibrahim, Nageatte; Long, Georgina V.; Gartrell, Robyn; Blake, Zoe; Simoes, Ines; Fu, Yichun; Saito, Takuro; Qian, Yingzhi; Lu, Yan; Saenger, Yvonne M.; Budhu, Sadna; De Henau, Olivier; Zappasodi, Roberta; Schlunegger, Kyle; Freimark, Bruce; Hutchins, Jeff; Barker, Christopher A.; Wolchok, Jedd D.; Merghoub, Taha; Burova, Elena; Allbritton, Omaira; Hong, Peter; Dai, Jie; Pei, Jerry; Liu, Matt; Kantrowitz, Joel; Lai, Venus; Poueymirou, William; MacDonald, Douglas; Ioffe, Ella; Mohrs, Markus; Olson, William; Thurston, Gavin; Capasso, Cristian; Frascaro, Federica; Carpi, Sara; Tähtinen, Siri; Feola, Sara; Fusciello, Manlio; Peltonen, Karita; Martins, Beatriz; Sjöberg, Madeleine; Pesonen, Sari; Ranki, Tuuli; Kyruk, Lukasz; Ylösmäki, Erkko; Cerullo, Vincenzo; Cerignoli, Fabio; Xi, Biao; Guenther, Garret; Yu, Naichen; Muir, Lincoln; Zhao, Leyna; Abassi, Yama; Cervera-Carrascón, Víctor; Siurala, Mikko; Santos, João; Havunen, Riikka; Parviainen, Suvi; Hemminki, Akseli; Dalgleish, Angus; Mudan, Satvinder; DeBenedette, Mark; Plachco, Ana; Gamble, Alicia; Grogan, Elizabeth W.; Krisko, John; Tcherepanova, Irina; Nicolette, Charles; Dhupkar, Pooja; Yu, Ling; Kleinerman, Eugenie S.; Gordon, Nancy; Grenga, Italia; Lepone, Lauren; Gameiro, Sofia; Knudson, Karin M.; Fantini, Massimo; Tsang, Kwong; Hodge, James; Donahue, Renee; Schlom, Jeffrey; Evans, Elizabeth; Bussler, Holm; Mallow, Crystal; Reilly, Christine; Torno, Sebold; Scrivens, Maria; Foster, Cathie; Howell, Alan; Balch, Leslie; Knapp, Alyssa; Leonard, John E.; Paris, Mark; Fisher, Terry; Hu-Lieskovan, Siwen; Smith, Ernest; Zauderer, Maurice; Fogler, William; Franklin, Marilyn; Thayer, Matt; Saims, Dan; Magnani, John L.; Gong, Jian; Gray, Michael; Fromm, George; de Silva, Suresh; Giffin, Louise; Xu, Xin; Rose, Jason; Schreiber, Taylor H.; Gameiro, Sofia R.; Clavijo, Paul E.; Allen, Clint T.; Hodge, James W.; Tsang, Kwong Y.; Grogan, Jane; Manieri, Nicholas; Chiang, Eugene; Caplazi, Patrick; Yadav, Mahesh; Hagner, Patrick; Chiu, Hsiling; Waldman, Michelle; Klippel, Anke; Thakurta, Anjan; Pourdehnad, Michael; Gandhi, Anita; Henrich, Ian; Quick, Laura; Young, Rob; Chou, Margaret; Hotson, Andrew; Willingham, Stephen; Ho, Po; Choy, Carmen; Laport, Ginna; McCaffery, Ian; Miller, Richard; Tipton, Kimberly A.; Wong, Kenneth R.; Singson, Victoria; Wong, Chihunt; Chan, Chanty; Huang, Yuanhiu; Liu, Shouchun; Richardson, Jennifer H.; Kavanaugh, W. Michael; West, James; Irving, Bryan A.; Jaini, Ritika; Loya, Matthew; Eng, Charis; Johnson, Melissa L.; Adjei, Alex A.; Opyrchal, Mateusz; Ramalingam, Suresh; Janne, Pasi A.; Dominguez, George; Gabrilovich, Dmitry; de Leon, Laura; Hasapidis, Jeannette; Diede, Scott J.; Ordentlich, Peter; Cruickshank, Scott; Meyers, Michael L.; Hellmann, Matthew D.; Kalinski, Pawel; Zureikat, Amer; Edwards, Robert; Muthuswamy, Ravi; Obermajer, Nataša; Urban, Julie; Butterfield, Lisa H.; Gooding, William; Zeh, Herbert; Bartlett, David; Zubkova, Olga; Agapova, Larissa; Kapralova, Marina; Krasovskaia, Liudmila; Ovsepyan, Armen; Lykov, Maxim; Eremeev, Artem; Bokovanov, Vladimir; Grigoryeva, Olga; Karpov, Andrey; Ruchko, Sergey; Shuster, Alexandr; Khalil, Danny N.; Campesato, Luis Felipe; Li, Yanyun; Lazorchak, Adam S.; Patterson, Troy D.; Ding, Yueyun; Sasikumar, Pottayil; Sudarshan, Naremaddepalli; Gowda, Nagaraj; Ramachandra, Raghuveer; Samiulla, Dodheri; Giri, Sanjeev; Eswarappa, Rajesh; Ramachandra, Murali; Tuck, David; Wyant, Timothy; Leshem, Jasmin; Liu, Xiu-fen; Bera, Tapan; Terabe, Masaki; Bossenmaier, Birgit; Niederfellner, Gerhard; Reiter, Yoram; Pastan, Ira; Xia, Leiming; Xia, Yang; Hu, Yangyang; Wang, Yi; Bao, Yangyi; Dai, Fu; Huang, Shiang; Hurt, Elaine; Hollingsworth, Robert E.; Lum, Lawrence G.; Chang, Alfred E.; Wicha, Max S.; Li, Qiao; Mace, Thomas; Makhijani, Neil; Talbert, Erin; Young, Gregory; Guttridge, Denis; Conwell, Darwin; Lesinski, Gregory B.; Gonzales, Rodney JM Macedo; Huffman, Austin P.; Wang, Ximi K.; Reshef, Ran; MacKinnon, Andy; Chen, Jason; Gross, Matt; Marguier, Gisele; Shwonek, Peter; Sotirovska, Natalija; Steggerda, Susanne; Parlati, Francesco; Makkouk, Amani; Bennett, Mark K.; Emberley, Ethan; Huang, Tony; Li, Weiqun; Neou, Silinda; Pan, Alison; Zhang, Jing; Zhang, Winter; Marshall, Netonia; Marron, Thomas U.; Agudo, Judith; Brown, Brian; Brody, Joshua; McQuinn, Christopher; Farren, Matthew; Komar, Hannah; Shakya, Reena; Ludwug, Thomas; Morillon, Y. Maurice; Hammond, Scott A.; Greiner, John W.; Nath, Pulak R.; Schwartz, Anthony L.; Maric, Dragan; Roberts, David D.; Naing, Aung; Papadopoulos, Kyriakos P.; Autio, Karen A.; Wong, Deborah J.; Patel, Manish; Falchook, Gerald; Pant, Shubham; Ott, Patrick A.; Whiteside, Melinda; Patnaik, Amita; Mumm, John; Janku, Filip; Chan, Ivan; Bauer, Todd; Colen, Rivka; VanVlasselaer, Peter; Brown, Gail L.; Tannir, Nizar M.; Oft, Martin; Infante, Jeffrey; Lipson, Evan; Gopal, Ajay; Neelapu, Sattva S.; Armand, Philippe; Spurgeon, Stephen; Leonard, John P.; Sanborn, Rachel E.; Melero, Ignacio; Gajewski, Thomas F.; Maurer, Matthew; Perna, Serena; Gutierrez, Andres A.; Clynes, Raphael; Mitra, Priyam; Suryawanshi, Satyendra; Gladstone, Douglas; Callahan, Margaret K.; Crooks, James; Brown, Sheila; Gauthier, Audrey; de Boisferon, Marc Hillairet; MacDonald, Andrew; Brunet, Laura Rosa; Rothwell, William T.; Bell, Peter; Wilson, James M.; Sato-Kaneko, Fumi; Yao, Shiyin; Zhang, Shannon S.; Carson, Dennis A.; Guiducci, Cristina; Coffman, Robert L.; Kitaura, Kazutaka; Matsutani, Takaji; Suzuki, Ryuji; Hayashi, Tomoko; Cohen, Ezra E. W.; Schaer, David; Li, Yanxia; Dobkin, Julie; Amatulli, Michael; Hall, Gerald; Doman, Thompson; Manro, Jason; Dorsey, Frank Charles; Sams, Lillian; Holmgaard, Rikke; Persaud, Krishnadatt; Ludwig, Dale; Surguladze, David; Kauh, John S.; Novosiadly, Ruslan; Kalos, Michael; Driscoll, Kyla; Pandha, Hardev; Ralph, Christy; Harrington, Kevin; Curti, Brendan; Akerley, Wallace; Gupta, Sumati; Melcher, Alan; Mansfield, David; Kaufman, David R.; Schmidt, Emmett; Grose, Mark; Davies, Bronwyn; Karpathy, Roberta; Shafren, Darren; Shamalov, Katerina; Cohen, Cyrille; Sharma, Naveen; Allison, James; Shekarian, Tala; Valsesia-Wittmann, Sandrine; Caux, Christophe; Marabelle, Aurelien; Slomovitz, Brian M.; Moore, Kathleen M.; Youssoufian, Hagop; Posner, Marshall; Tewary, Poonam; Brooks, Alan D.; Xu, Ya-Ming; Wijeratne, Kithsiri; Gunatilaka, Leslie A. A.; Sayers, Thomas J.; Vasilakos, John P.; Alston, Tesha; Dovedi, Simon; Elvecrog, James; Grigsby, Iwen; Herbst, Ronald; Johnson, Karen; Moeckly, Craig; Mullins, Stefanie; Siebenaler, Kristen; SternJohn, Julius; Tilahun, Ashenafi; Tomai, Mark A.; Vogel, Katharina; Vietsch, Eveline E.; Wellstein, Anton; Wythes, Martin; Crosignani, Stefano; Tumang, Joseph; Alekar, Shilpa; Bingham, Patrick; Cauwenberghs, Sandra; Chaplin, Jenny; Dalvie, Deepak; Denies, Sofie; De Maeseneire, Coraline; Feng, JunLi; Frederix, Kim; Greasley, Samantha; Guo, Jie; Hardwick, James; Kaiser, Stephen; Jessen, Katti; Kindt, Erick; Letellier, Marie-Claire; Li, Wenlin; Maegley, Karen; Marillier, Reece; Miller, Nichol; Murray, Brion; Pirson, Romain; Preillon, Julie; Rabolli, Virginie; Ray, Chad; Ryan, Kevin; Scales, Stephanie; Srirangam, Jay; Solowiej, Jim; Stewart, Al; Streiner, Nicole; Torti, Vince; Tsaparikos, Konstantinos; Zheng, Xianxian; Driessens, Gregory; Gomes, Bruno; Kraus, Manfred; Xu, Chunxiao; Zhang, Yanping; Kradjian, Giorgio; Qin, Guozhong; Qi, Jin; Xu, Xiaomei; Marelli, Bo; Yu, Huakui; Guzman, Wilson; Tighe, Rober; Salazar, Rachel; Lo, Kin-Ming; English, Jessie; Radvanyi, Laszlo; Lan, Yan; Postow, Michael; Senbabaoglu, Yasin; Gasmi, Billel; Zhong, Hong; Liu, Cailian; Hirschhorhn-Cymerman, Daniel; Zha, Yuanyuan; Malnassy, Gregory; Fulton, Noreen; Park, Jae-Hyun; Stock, Wendy; Nakamura, Yusuke; Liu, Hongtao; Ju, Xiaoming; Kosoff, Rachelle; Ramos, Kimberly; Coder, Brandon; Petit, Robert; Princiotta, Michael; Perry, Kyle; Zou, Jun; Arina, Ainhoa; Fernandez, Christian; Zheng, Wenxin; Beckett, Michael A.; Mauceri, Helena J.; Fu, Yang-Xin; Weichselbaum, Ralph R.; Lewis, Whitney; Han, Yanyan; Wu, Yeting; Yang, Chou; Huang, Jing; Wu, Dongyun; Li, Jin; Liang, Xiaoling; Zhou, Xiangjun; Hou, Jinlin; Hassan, Raffit; Jahan, Thierry; Antonia, Scott J.; Kindler, Hedy L.; Alley, Evan W.; Honarmand, Somayeh; Liu, Weiqun; Leong, Meredith L.; Whiting, Chan C.; Nair, Nitya; Enstrom, Amanda; Lemmens, Edward E.; Tsujikawa, Takahiro; Kumar, Sushil; Coussens, Lisa M.; Murphy, Aimee L.; Brockstedt, Dirk G.; Koch, Sven D.; Sebastian, Martin; Weiss, Christian; Früh, Martin; Pless, Miklos; Cathomas, Richard; Hilbe, Wolfgang; Pall, Georg; Wehler, Thomas; Alt, Jürgen; Bischoff, Helge; Geissler, Michael; Griesinger, Frank; Kollmeier, Jens; Papachristofilou, Alexandros; Doener, Fatma; Fotin-Mleczek, Mariola; Hipp, Madeleine; Hong, Henoch S.; Kallen, Karl-Josef; Klinkhardt, Ute; Stosnach, Claudia; Scheel, Birgit; Schroeder, Andreas; Seibel, Tobias; Gnad-Vogt, Ulrike; Zippelius, Alfred; Park, Ha-Ram; Ahn, Yong-Oon; Kim, Tae Min; Kim, Soyeon; Kim, Seulki; Lee, Yu Soo; Keam, Bhumsuk; Kim, Dong-Wan; Heo, Dae Seog; Pilon-Thomas, Shari; Weber, Amy; Morse, Jennifer; Kodumudi, Krithika; Liu, Hao; Mullinax, John; Sarnaik, Amod A.; Pike, Luke; Bang, Andrew; Balboni, Tracy; Taylor, Allison; Spektor, Alexander; Wilhite, Tyler; Krishnan, Monica; Cagney, Daniel; Alexander, Brian; Aizer, Ayal; Buchbinder, Elizabeth; Awad, Mark; Ghandi, Leena; Schoenfeld, Jonathan; Lessey-Morillon, Elizabeth; Ridnour, Lisa; Segal, Neil H.; Sharma, Manish; Le, Dung T.; Ferris, Robert L.; Zelenetz, Andrew D.; Levy, Ronald; Lossos, Izidore S.; Jacobson, Caron; Ramchandren, Radhakrishnan; Godwin, John; Colevas, A. Dimitrios; Meier, Roland; Krishnan, Suba; Gu, Xuemin; Neely, Jaclyn; Timmerman, John; Vanpouille-Box, Claire I.; Formenti, Silvia C.; Demaria, Sandra; Wennerberg, Erik; Mediero, Aranzazu; Cronstein, Bruce N.; Gustafson, Michael P.; DiCostanzo, AriCeli; Wheatley, Courtney; Kim, Chul-Ho; Bornschlegl, Svetlana; Gastineau, Dennis A.; Johnson, Bruce D.; Dietz, Allan B.; MacDonald, Cameron; Bucsek, Mark; Qiao, Guanxi; Hylander, Bonnie; Repasky, Elizabeth; Turbitt, William J.; Xu, Yitong; Mastro, Andrea; Rogers, Connie J.; Withers, Sita; Wang, Ziming; Khuat, Lam T.; Dunai, Cordelia; Blazar, Bruce R.; Longo, Dan; Rebhun, Robert; Grossenbacher, Steven K.; Monjazeb, Arta; Murphy, William J.; Rowlinson, Scott; Agnello, Giulia; Alters, Susan; Lowe, David; Scharping, Nicole; Menk, Ashley V.; Whetstone, Ryan; Zeng, Xue; Delgoffe, Greg M.; Santos, Patricia M.; Shi, Jian; Delgoffe, Greg; Nagasaka, Misako; Sukari, Ammar; Byrne-Steele, Miranda; Pan, Wenjing; Hou, Xiaohong; Brown, Brittany; Eisenhower, Mary; Han, Jian; Collins, Natalie; Manguso, Robert; Pope, Hans; Shrestha, Yashaswi; Boehm, Jesse; Haining, W. 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    Publication
    Gender-Specific Molecular and Clinical Features Underlie Malignant Pleural Mesothelioma
    (American Association for Cancer Research (AACR), 2016-01-15) De Rienzo, Assunta; Archer, Michael A.; Yeap, Beow; Dao, Nhien; Sciaranghella, Daniele; Sideris, Antonios C.; Zheng, Yifan; Holman, Alexander G.; Wang, Yaoyu E.; Dal Cin, Paola; Fletcher, Jonathan; Rubio, Renee; Croft, Larry; Quackenbush, John; Sugarbaker, Peter E.; Munir, Kiara J.; Battilana, Jesse R.; Gustafson, Corinne; Chirieac, Lucian; Ching, Soo Meng; Wong, James; Tay, Liang Chung; Rudd, Stephen; Hercus, Robert; Sugarbaker, David J.; Richards, William; Bueno, Raphael
    Malignant pleural mesothelioma (MPM) is an aggressive cancer that occurs more frequently in men, but is associated with longer survival in women. Insight into the survival advantage of female patients may advance the molecular understanding of MPM and identify therapeutic interventions that will improve the prognosis for all MPM patients. In this study, we performed whole-genome sequencing of tumor specimens from 10 MPM patients and matched control samples to identify potential driver mutations underlying MPM. We identified molecular differences associated with gender and histology. Specifically, single-nucleotide variants of BAP1 were observed in 21% of cases, with lower mutation rates observed in sarcomatoid MPM (p<0.001). Chromosome 22q loss was more frequently associated with the epithelioid than that non-epitheliod histology (p=0.037), whereas CDKN2A deletions occurred more frequently in non-epithelioid subtypes among men (p=0.021) and were correlated with shorter overall survival for the entire cohort (p=0.002) and for men (p=0.012). Furthermore, women were more likely to harbor TP53 mutations (p=0.004). Novel mutations were found in genes associated with the integrin-linked kinase pathway, including MYH9 and RHOA. Moreover, expression levels of BAP1, MYH9, and RHOA were significantly higher in non-epithelioid tumors, and were associated with significant reduction in survival of the entire cohort and across gender subgroups. Collectively, our findings indicate that diverse mechanisms highly related to gender and histology appear to drive MPM.