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Rodabe N Amaria, Sangeetha M Reddy, Hussein A Tawbi, Michael A Davies, Merrick I Ross, Isabella C Glitza, Janice N Cormier, Carol Lewis, Wen-Jen Hwu, Ehab Hanna, Adi Diab, Michael K Wong, Richard Royal, Neil Gross, Randal Weber, Stephen Y Lai, Richard Ehlers, Jorge Blando, Denái R Milton, Scott Woodman, Robin Kageyama, Danny K Wells, Patrick Hwu, Sapna P Patel, Anthony Lucci, Amy Hessel, Jeffrey E Lee, Jeffrey Gershenwald, Lauren Simpson, Elizabeth M Burton, Liberty Posada, Lauren Haydu, Linghua Wang, Shaojun Zhang, Alexander J Lazar, Courtney W Hudgens, Vancheswaran Gopalakrishnan, Alexandre Reuben, Miles C Andrews, Christine N Spencer, Victor Prieto, Padmanee Sharma, James Allison, Michael T Tetzlaff, Jennifer A Wargo
Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses compared with adjuvant treatment1 ; however, optimal regimens have not been defined. Here we report results from a randomized phase 2 study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma ( NCT02519322 ). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs) and immune correlates of response were assessed...
October 8, 2018: Nature Medicine
Amanpreet Kaur, Brett L Ecker, Stephen M Douglass, Curtis H Kugel, Marie R Webster, Filipe V Almeida, Rajasekharan Somasundaram, James Hayden, Ehsan Ban, Hossein Ahmadzadeh, Janusz Franco-Barraza, Neelima Shah, Ian A Mellis, Frederick Keeney, Andrew Kossenkov, Hsin-Yao Tang, Xiangfan Yin, Qin Liu, Xiaowei Xu, Mitchell Fane, Patricia Brafford, Meenhard Herlyn, David W Speicher, Jennifer A Wargo, Michael T Tetzlaff, Lauren E Haydu, Arjun Raj, Vivek Shenoy, Edna Cukierman, Ashani T Weeraratna
Physical changes in skin are among the most visible signs of aging. We found that young dermal fibroblasts secrete high levels of extracellular matrix (ECM) constituents, including proteoglycans, glycoproteins and cartilage-linking proteins. The most abundantly secreted was HAPLN1, a hyaluronic and proteoglycan link protein. HAPLN1 was lost in aged fibroblasts, resulting in a more aligned ECM that promoted metastasis of melanoma cells. Reconstituting HAPLN1 inhibited metastasis in an aged microenvironment, in 3D skin reconstruction models, and in vivo...
October 2, 2018: Cancer Discovery
Michael P Smith, Sareena Rana, Jennifer Ferguson, Emily J Rowling, Keith T Flaherty, Jennifer A Wargo, Richard Marais, Claudia Wellbrock
The BRAF-kinase and the MAPK-pathway are targets of current melanoma therapies. However, MAPK-pathway inhibition results in dynamic changes of down-stream targets that can counteract inhibitor-action not only during treatment, but also in acquired resistant tumours. One such dynamic change involves the expression of the transcription factor MITF, a crucial regulator of cell survival and proliferation in untreated as well as drug-addicted acquired resistant melanoma. Tight control over MITF expression levels is required for optimal melanoma growth, and while it is well established that the MAPK-pathway regulates MITF expression, the actual mechanism is insufficiently understood...
October 1, 2018: Pigment Cell & Melanoma Research
Emily Z Keung, Alexander J Lazar, Keila E Torres, Wei-Lien Wang, Janice N Cormier, B Ashleigh Guadagnolo, Andrew J Bishop, Heather Lin, Kelly K Hunt, Justin Bird, Valerae O Lewis, Shreyaskumar R Patel, Jennifer A Wargo, Neeta Somaiah, Christina L Roland
BACKGROUND: Soft tissue sarcomas are a heterogeneous and rare group of solid tumors of mesenchymal origin that can arise anywhere in the body. Although surgical resection is the mainstay of treatment for patients with localized disease, disease recurrence is common and 5-year overall survival is poor (~ 65%). Both radiation therapy and conventional chemotherapy are used to reduce local and distant recurrence. However, the utility of radiation therapy is often limited by disease location (in the case of retroperitoneal sarcomas, for instance) while systemic therapy with conventional lines of chemotherapy offer limited efficacy and are often poorly tolerated and associated with significant toxicity...
September 24, 2018: BMC Cancer
Alexander M M Eggermont, Marka Crittenden, Jennifer Wargo
Melanoma has been the most important cancer to drive immunotherapy development of solid tumors. Since 2010, immunotherapy has been revolutionized by the concept of breaking tolerance. It represents a major paradigm shift and marks the beginning of a new era. The impact of the first immune checkpoint inhibitors, anti-CTLA-4 and anti-PD-1/anti-PD-L1, is unprecedented. In 7 years, it transformed advanced-stage melanoma into a curable disease in over 50% of patients. Another major step has been the development of the combination of BRAF inhibitors plus MEK inhibitors in the treatment of BRAF-mutant melanomas...
May 23, 2018: American Society of Clinical Oncology Educational Book
Thomas J Kandl, Oded Sagiv, Jonathan L Curry, Jing Ning, Junsheng Ma, Courtney W Hudgens, John Van Arnam, Jennifer A Wargo, Bita Esmaeli, Michael T Tetzlaff
Ocular adnexal sebaceous carcinoma (OASC) is an aggressive malignancy that frequently recurs locally and metastasizes. Surgical extirpation may produce significant aesthetic morbidity, and effective systemic therapies for locally advanced or metastatic disease are largely ineffective. Immune checkpoint inhibitors have shown efficacy in the management of several solid tumors where tumor cell PD-L1 expression correlates with improved response. To determine whether OASC might be amenable to immune checkpoint blockade, we performed comprehensive immune profiling for CD3, CD8, PD-1, FOXP3, and PD-L1 in 24 patients with primary OASC...
2018: Oncoimmunology
Shelly Kalaora, Yochai Wolf, Tali Feferman, Eilon Barnea, Erez Greenstein, Dan Reshef, Itay Tirosh, Alexandre Reuben, Sushant Patkar, Ronen Levy, Juliane Quinkhardt, Tana Omokoko, Nouar Qutob, Ofra Golani, Jianhua Zhang, Xizeng Mao, Xingzhi Song, Chantale Bernatchez, Cara Haymaker, Marie-Andrée Forget, Caitlin Creasy, Polina Greenberg, Brett W Carter, Zachary A Cooper, Steven A Rosenberg, Michal Lotem, Ugur Sahin, Guy Shakhar, Eytan Ruppin, Jennifer A Wargo, Nir Friedman, Arie Admon, Yardena Samuels
The quest for tumor-associated-antigens (TAAs) and neo-antigens is a major focus of cancer immunotherapy. Here we combine a neo-antigen prediction-pipeline and human-leukocyte-antigen (HLA)-peptidomics to identify TAAs and neo-antigens in 16 tumors derived from seven melanoma patients, and characterize their interactions with their TILs. Our investigation of the antigenic and T-cell landscapes encompassing the TAA and neo-antigen signatures, their immune reactivity, and their corresponding T-cell identities provides the first comprehensive analysis of cancer cell T-cell co-signatures, allowing us to discover remarkable antigenic and TIL similarities between metastases from the same patient...
September 12, 2018: Cancer Discovery
Richard J Schanler, Sharon L Groh-Wargo, Bridget Barrett-Reis, Robert D White, Kaashif A Ahmad, Jeffery Oliver, Geraldine Baggs, Larry Williams, David Adamkin
OBJECTIVE: To compare growth, feeding tolerance, and clinical and biochemical evaluations in human milk-fed preterm infants randomized to receive either an acidified or a nonacidified liquid human milk fortifier. STUDY DESIGN: This prospective, controlled, parallel, multicenter growth and tolerance study included 164 preterm infants (≤32 weeks of gestation, birth weight 700-1500 g) who were randomized to acidified or nonacidified liquid human milk fortifier from study day 1, the first day of fortification, through study day 29 or until hospital discharge...
September 5, 2018: Journal of Pediatrics
Edward J Burgess, Laura R Hoyt, Matthew J Randall, Madeleine M Mank, Joseph J Bivona, Philip L Eisenhauer, Jason W Botten, Bryan A Ballif, Ying-Wai Lam, Matthew J Wargo, Jonathan E Boyson, Jennifer L Ather, Matthew E Poynter
Studies comparing endogenous and recombinant serum amyloid A (SAA) have generated conflicting data on the proinflammatory function of these proteins. In exploring this discrepancy, we found that in contrast to commercially sourced recombinant human SAA1 (hSAA1) proteins produced in Escherichia coli , hSAA1 produced from eukaryotic cells did not promote proinflammatory cytokine production from human or mouse cells, induce Th17 differentiation, or stimulate TLR2. Proteomic analysis of E. coli -derived hSAA1 revealed the presence of numerous bacterial proteins, with several being reported or probable lipoproteins...
October 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Olivier Ethgen, Vanessa Rémy, Katherine Wargo
Immunization has been shown to be the most effective disease prevention measure of all time, apart from water purification. However, vaccination programs remain highly vulnerable to budget cuts as their benefits may not be immediately and fully identifiable. Therefore, monitoring of healthcare expenditures allocated to prevention and vaccination is critical. This letter updates our previous observation of expenditure for prevention and vaccination programs in eight European countries by adding data from 2014, where available...
July 30, 2018: Human Vaccines & Immunotherapeutics
Anu Sharma, Sumit K Subudhi, Jorge Blando, Jorge Scutti, Luis Vence, Jennifer A Wargo, James P Allison, Antoni Ribas, Padmanee Sharma
PURPOSE: CTLA-4 was the first inhibitory immune checkpoint to be identified. Two monoclonal antibodies, ipilimumab (IgG1) and tremelimumab (IgG2), which block the function of CTLA-4, have demonstrated durable clinical activity in a subset of patients with advanced solid malignancies by augmenting effector T cell-mediated immune responses. Studies in mice suggest that anti-CTLA-4 monoclonal antibodies may also selectively deplete intratumoral FOXP3+ regulatory T cells via an Fc-dependent mechanism...
July 27, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
M T Tetzlaff, J L Messina, J E Stein, X Xu, R N Amaria, C U Blank, B A van de Wiel, P M Ferguson, R V Rawson, M I Ross, A J Spillane, J E Gershenwald, R P M Saw, A C J van Akkooi, W J van Houdt, T C Mitchell, A M Menzies, G V Long, J A Wargo, M A Davies, V G Prieto, J M Taube, R A Scolyer
Background: Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment. Methods: The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy...
August 1, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Beth A Helmink, Pierre-Olivier Gaudreau, Jennifer A Wargo
Four studies recently reported in the New England Journal of Medicine highlight advances in treatment with immune checkpoint blockade across the cancer care continuum. These findings demonstrate efficacy of these agents in the treatment of early and late-stage disease, as monotherapy or in combination, and in addition to-or in place of-standard front-line therapy.
June 19, 2018: Immunity
Nora D Volkow, Eric M Wargo
No abstract text is available yet for this article.
August 7, 2018: Annals of Internal Medicine
M Farah, P Nagarajan, J L Curry, Z Tang, T-B Kim, P P Aung, C A Torres-Cabala, A K Eterovic, J A Wargo, V G Prieto, M T Tetzlaff
Spitzoid neoplasms pose diagnostic difficulties because their morphology is not consistently predictive of their biological potential. Recent advances in the molecular characterization of these tumours provides a framework by which they can now begin to be categorized. In particular, spitzoid lesions with ALK rearrangement have been specifically associated with a characteristic plexiform growth pattern of intersecting fascicles of amelanotic spindled melanocytes. We report the case of an 87-year-old man with a 3-cm nodule on his mid-upper back comprised of an intradermal proliferation of fusiform amelanotic melanocytes arranged in intersecting fascicles with occasional peritumoral clefts...
June 13, 2018: British Journal of Dermatology
Marie-Andrée Forget, Cara Haymaker, Kenneth R Hess, Yuzhong Jeff Meng, Caitlin Creasy, Tatiana Karpinets, Orenthial J Fulbright, Jason Roszik, Scott E Woodman, Young Uk Kim, Donastas Sakellariou-Thompson, Ankit Bhatta, Arely Wahl, Esteban Flores, Shawne T Thorsen, René J Tavera, Renjith Ramachandran, Audrey M Gonzalez, Christopher L Toth, Seth Wardell, Rahmatu Mansaray, Vruti Patel, Destiny Joy Carpio, Carol Vaughn, Chantell M Farinas, Portia G Velasquez, Wen-Jen Hwu, Sapna P Patel, Michael A Davies, Adi Diab, Isabella C Glitza, Hussein Tawbi, Michael K Wong, Suzanne Cain, Merrick I Ross, Jeffrey E Lee, Jeffrey E Gershenwald, Anthony Lucci, Richard Royal, Janice N Cormier, Jennifer A Wargo, Laszlo G Radvanyi, Carlos A Torres-Cabala, Rameen Beroukhim, Patrick Hwu, Rodabe N Amaria, Chantale Bernatchez
Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. Patients and Methods: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival...
September 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
J Dako, J Buzzard, M Jain, R Pandey, S Groh-Wargo, P Shekhawat
BACKGROUND: Necrotizing Enterocolitis (NEC) is a multifactorial condition where PRBC transfusion is associated with necrotizing enterocolitis (TANEC) in about a third of all cases of NEC. We have investigated the role of feeding practices in incidence of TANEC. We sought to compare infants diagnosed with TANEC versus infants diagnosed with classic NEC and investigated the effects of a standardized slow enteral feeding (SSEF) protocol on TANEC incidence as well as the effects of SSEF on growth of infants with NEC...
2018: Journal of Neonatal-perinatal Medicine
Wilson M Compton, Eric M Wargo
No abstract text is available yet for this article.
June 5, 2018: Annals of Internal Medicine
Anna Maria Hibbs, Kristie Ross, Leigh Ann Kerns, Carol Wagner, Mamta Fuloria, Sharon Groh-Wargo, Teresa Zimmerman, Nori Minich, Curtis Tatsuoka
Importance: Black infants born preterm face high rates of recurrent wheezing throughout infancy. Vitamin D supplementation has the potential to positively or negatively affect wheezing through modulation of the pulmonary and immune systems. Objective: To assess the effectiveness of 2 vitamin D dosing strategies in preventing recurrent wheezing. Design, Setting, and Participants: A randomized clinical trial enrolled 300 black infants born at 28 to 36 weeks' gestation between January 2013 and January 2016 at 4 sites in the United States, and followed them up through March 2017...
May 22, 2018: JAMA: the Journal of the American Medical Association
Miles C Andrews, Alexandre Reuben, Vancheswaran Gopalakrishnan, Jennifer A Wargo
Cancer research has seen unprecedented advances over the past several years, with tremendous insights gained into mechanisms of response and resistance to cancer therapy. Central to this has been our understanding of crosstalk between the tumor and the microenvironment, with the recognition that complex interactions exist between tumor cells, stromal cells, overall host immunity, and the environment surrounding the host. This is perhaps best exemplified in cancer immunotherapy, where numerous studies across cancer types have illuminated our understanding of the genomic and immune factors that shape responses to therapy...
2018: Frontiers in Immunology
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