bluuebunny/crossref_metadata_2025_split huggingface dataset:
Noninvasive Imaging of Tumor PD-L1 Expression Using Radiolabeled Anti–PD-L1 Antibodies
Authors: Heskamp Sandra , Hobo Willemijn , Molkenboer-Kuenen Janneke D.M. , Olive Daniel , Oyen Wim J.G. , Dolstra Harry , Boerman Otto C. 
Published: May 2015

Abstract
Antibodies that block the interaction between programmed death ligand 1 (PD-L1) and PD-1 have shown impressive antitumor activity. Patients with tumors expressing PD-L1 are most likely to respond to this treatment. The aim of our study was to develop a noninvasive imaging technique to determine tumor PD-L1 expression in vivo. This could allow selection of patients that are most likely to benefit from anti–PD-1/PD-L1 treatment and to monitor PD-L1 expression during therapy. The monoclonal antibody PD-L1.3.1 was radiolabeled with Indium-111 (111In) and characterized using PD-L1–expressing MDA-MB-231 cells. Subsequently, the optimal antibody dose and time point for imaging was determined in mice with MDA-MB-231 xenografts. Finally, SPECT/CT imaging was performed in xenograft models with different PD-L1 expression levels and tumor sections were analyzed for PD-L1 expression using IHC. The optimal antibody dose of 111In-PD-L1.3.1 (Kd = 1 nmol/L) for SPECT/CT imaging was ≤1 μg. Highest tumor-to-normal tissue contrast was obtained at days 3 and 7 after injection. 111In-PD-L1.3.1 SPECT/CT showed efficient accumulation in high PD-L1–expressing tumors (MDA-MB-231 and SK-Br-3), whereas no specific uptake was observed in tumors with low or no detectable levels of PD-L1 (SUM149, BT474, and MCF-7). SPECT/CT and autoradiography showed a very heterogeneous distribution of 111In-PD-L1.3.1 within the tumor. In conclusion, this is the first study showing the feasibility of noninvasive in vivo imaging of PD-L1 expression in tumors. 111In-PD-L1.3.1 showed efficient and specific uptake in PD-L1 expressing xenografts. This technique may enable patient selection for PD-1 and PD-L1–targeted therapy. Cancer Res; 75(14); 2928–36. ©2015 AACR.
Macrophages Regulate the Systemic Response to DNA Damage by a Cell Nonautonomous Mechanism
Authors: Geiger-Maor Anat , Guedj Avital , Even-Ram Sharona , Smith Yoav , Galun Eithan , Rachmilewitz Jacob 
Published: May 2015

Abstract
The DNA damage response (DDR) is a comprehensive and complex network of phosphorylation-mediated signaling pathways that originates endogenously from the DNA lesion and activates intrinsic DNA repair mechanisms. Here we describe a macrophage-dependent mechanism that regulates the response to DNA damage. We demonstrate that human monocytes, by releasing macrophage-derived HB-EGF, enhance DDR in neighboring cells suffering from DNA damage. Consequently, HB-EGF–treated cells exhibit higher double-strand break (DSB) rejoining and display lower levels of residual DSBs. Diethylnitrosamine (DEN) injection induce DSBs along with elevation in the number of macrophages and HB-EGF expression. Significantly, macrophage depletion or blocking HB-EGF activity results in higher levels of nonrepairable DSBs, suggesting that macrophages play a role in the resolution of DNA damage via HB-EGF. This study establishes that macrophages, acting through the activation of the EGFR cascade, constitute an important cell nonautonomous physiologic component of the DDR and points to a unique role played by immune cells in maintaining genome integrity. Cancer Res; 75(13); 2663–73. ©2015 AACR.
Classifying Cancers Based on T-cell Infiltration and PD-L1
Authors: Teng Michele W.L. , Ngiow Shin Foong , Ribas Antoni , Smyth Mark J. 
Published: May 2015

Abstract
Cancer immunotherapy may become a major treatment backbone in many cancers over the next decade. There are numerous immune cell types found in cancers and many components of an immune reaction to cancer. Thus, the tumor has many strategies to evade an immune response. It has been proposed that four different types of tumor microenvironment exist based on the presence or absence of tumor-infiltrating lymphocytes and programmed death-ligand 1 (PD-L1) expression. We review this stratification and the latest in a series of results that shed light on new approaches for rationally designing ideal combination cancer therapies based on tumor immunology. Cancer Res; 75(11); 2139–45. ©2015 AACR.
High Serum Transforming Growth Factor-β1 Levels Predict Outcome in Hepatocellular Carcinoma Patients Treated with Sorafenib
Authors: Lin Tzu-Hsuan , Shao Yu-Yun , Chan Soa-Yu , Huang Chung-Yi , Hsu Chih-Hung , Cheng Ann-Lii 
Published: May 2015

Abstract
Background: The TGF-β signaling pathway is crucial in the progression and metastasis of malignancies. We investigated whether the serum TGF-β1 level was related to the outcomes of patients treated with sorafenib for advanced hepatocellular carcinoma (HCC).
Experimental Design: We selected patients who had received sorafenib-containing regimens as first-line therapy for advanced HCC between 2007 and 2012. Serum TGF-β1 levels were measured and correlated with the treatment outcomes. The expression TGF-β1 and the sensitivity to sorafenib were examined in HCC cell lines.
Results:Ninety-one patients were included; 62 (68%) were hepatitis B virus surface antigen (+), and 11 (12%) were anti-hepatitis C virus (+). High (≥ median) pretreatment serum TGF-β1 levels (median 13.7 ng/mL; range, 3.0–41.8) were associated with high α-fetoprotein levels, but not with age, gender, or disease stage. Patients with high pretreatment serum TGF-β1 levels exhibited significantly shorter progression-free survival (median, 2.5 vs. 4.3 months; P = 0.022) and overall survival (median 5.6 vs. 11.6 months; P = 0.029) than did patients with low serum TGF-β1 levels. Compared with pretreatment levels, the serum TGF-β1 levels were significantly increased at disease progression (n = 29, P = 0.010). In preclinical models of HCC, higher TGF-β1 expression levels were associated with poorer sensitivity to sorafenib.
Conclusions: High pretreatment serum TGF-β1 levels were associated with poor prognoses, and increased serum TGF-β1 levels were associated with the disease progression of advanced HCC patients. TGF-β pathway may be explored as a therapeutic target for advanced HCC. Clin Cancer Res; 21(16); 3678–84. ©2015 AACR.
CCR 20th Anniversary Commentary: Expanding the Epigenetic Therapeutic Portfolio
Authors: Bates Susan E. , Robey Robert W. , Piekarz Richard L. 
Published: May 2015

Abstract
Epigenetic targets have emerged as an exciting area for drug discovery. The discovery that histone deacetylase (HDAC) inhibitors had marked anticancer activity in T-cell lymphoma gave impetus to the field. In a phase I study published in Clinical Cancer Research in March 2002, romidepsin (depsipeptide), a potent HDAC inhibitor, was found to be tolerable, with a side effect profile that was later understood to be characteristic of this class of agents. Evidence of activity in this key phase I trial provided momentum for the further study of epigenetic agents. Clin Cancer Res; 21(10); 2195–7. ©2015 AACR.
See related article by Sandor et al., Clin Cancer Res 2002;8(3) Mar 2002;718–28
CCR 20th Anniversary Commentary: Vorinostat—Gateway to Epigenetic Therapy
Authors: Kelly Wm. Kevin , Marks Paul , Richon Victoria M. 
Published: May 2015

Abstract
The study by Kelly and colleagues, published in the September 1, 2003, issue of Clinical Cancer Research, established the safety and biologic activity of the first-in-class histone deacetylase inhibitor, vorinostat, which was administered intravenously. Subsequent studies led to the development of oral vorinostat and the regulatory approval of vorinostat for cutaneous T-cell lymphomas, which opened the door for the next generation of inhibitors. Clin Cancer Res; 21(10); 2198–200. ©2015 AACR.
See related article by Kelly et al., Clin Cancer Res 2003;9(10) September 1, 2003;3578–88
Phase I Study of Pembrolizumab (MK-3475; Anti–PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors
Authors: Patnaik Amita , Kang S. Peter , Rasco Drew , Papadopoulos Kyriakos P. , Elassaiss-Schaap Jeroen , Beeram Muralidhar , Drengler Ronald , Chen Cong , Smith Lon , Espino Guillermo , Gergich Kevin , Delgado Liliana , Daud Adil , Lindia Jill A. , Li Xiaoyun Nicole , Pierce Robert H. , Yearley Jennifer H. , Wu Dianna , Laterza Omar , Lehnert Manfred , Iannone Robert , Tolcher Anthony W. 
Published: May 2015

Abstract
Purpose: This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors.
Experimental Design: In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005–10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Results: No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks' duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses ≥2 mg/kg every 3 weeks.
Conclusions: Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks. Clin Cancer Res; 21(19); 4286–93. ©2015 AACR.
See related commentary by van Elsas et al., p. 4251
Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects
Authors: Carniti Cristiana , Gimondi Silvia , Vendramin Antonio , Recordati Camilla , Confalonieri Davide , Bermema Anisa , Corradini Paolo , Mariotti Jacopo 
Published: May 2015

Abstract
Purpose: Immune-mediated graft-versus-tumor (GVT) effects can occur after allogeneic hematopoietic stem cell transplantation (HSCT), but GVT is tightly linked to its main complication, graft-versus-host disease (GVHD). Strategies aimed at modulating GVHD, while maintaining the GVT effect, are needed to improve the cure rate of transplant. Given the emerging role of Janus-activated kinase (JAK) signaling in lymphoproliferative and myeloproliferative diseases and its established function at dictating T-cell differentiation, we postulated that JAKs might be potential therapeutic targets through a pharmacologic approach.
Experimental Design: We examined the effect of JAK1/JAK2 modulation by ruxolitinib in a mouse model of fully MHC mismatched bone marrow transplant comprising in vivo tumor inoculation.
Results: JAK1/JAK2 inhibition by ruxolitinib improved both overall survival (P = 0.03) and acute GVHD pathologic score at target organs (P ≤ 0.001) of treated mice. In addition, treatment with ruxolitinib was associated with a preserved GVT effect, as evidenced by reduction of tumor burden (P = 0.001) and increase of survival time (P = 0.01). JAK1/JAK2 inhibition did not impair the in vivo acquisition of donor T-cell alloreactivity; this observation may account, at least in part, to the preserved GVT effect. Rather, JAK1/JAK2 inhibition of GVHD was associated with the modulation of chemokine receptor expression, which may have been one factor in the reduced infiltration of donor T cells in GVHD target organs.
Conclusions: These data provide further evidence that JAK inhibition represents a new and potentially clinically relevant approach to GVHD prevention. Clin Cancer Res; 21(16); 3740–9. ©2015 AACR.
Immune Checkpoint Modulation for Non–Small Cell Lung Cancer
Authors: Soria Jean-Charles , Marabelle Aurélien , Brahmer Julie R. , Gettinger Scott 
Published: May 2015

Abstract
Therapies targeting immune checkpoints have recently shown encouraging activity in patients with heavily pretreated advanced non–small cell lung cancer (NSCLC), independently of NSCLC histology or mutational status, with low toxicity profiles when used as monotherapy. Objective response rates of approximately 20% have been reported in patients with advanced NSCLC treated with antagonist antibodies targeting the immune checkpoint, programmed death 1 (PD-1) on activated T cells, or its primary ligand, programmed death ligand 1 (PD-L1) expressed within the tumor microenvironment. Response rates appear to be higher in patients with tumor PD-L1 expression documented by immunohistochemistry, although responses have been appreciated in patients with reportedly PD-L1–negative tumor specimens. Antibodies directed against cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), another immunosuppressive T-cell signaling molecule, are also being evaluated in clinical trials, with one randomized phase II trial demonstrating improved immune-related progression-free survival in lung cancer patients when added to standard chemotherapy. Additional clinical trials are combining anti–CTLA-4 antibodies with either anti–PD-1 or anti–PD-L1 antibodies. Combinations of other immune checkpoint antagonists or agonist antibodies with anti–PD-1 or anti–PD-L1 antibodies are also being pursued. Clin Cancer Res; 21(10); 2256–62. ©2015 AACR.
See all articles in this CCR Focus section, “Progress in Lung Cancer.”
Abstract A25: Evaluation of the food environment in rural towns in eastern Washington
Authors: Ko Linda K. , Perry Cynthia , Mariscal Norma , Rodriguez Edgar , Duggan Catherine , Kratz Mario , Thompson Beti 
Published: May 2015

Abstract
Introduction: Hispanics are at increased risk for obesity, which places them at increased risk for a variety of health conditions, including cancer. Risk factors for both obesity and cancer include limited access to healthy affordable foods. This problem is especially prevalent in low-income communities such as rural towns. This study assessed the availability of healthful foods and food environment scores in two rural towns with large percentages of Hispanic residents in Eastern Washington State.
Experimental Procedures: Store inventories were collected in 14 food stores (3 grocery and 11 convenience stores) from July-August 2013 using the Nutrition Environment Measures Survey. We recorded data on availability of a variety of fresh fruits, vegetables, whole grain bread, lean ground beef, low-fat hot dogs, baked or low-fat chips, and low sugar cereal. Food environment scores were generated for stores, which consisted of a composite score of availability of healthy food, quality, and price.
Results: Convenience stores comprised 79% of food stores. Availability of specific healthful items differed between grocery and convenience stores with all the grocery stores (100%) selling at least 1 fresh fruit compared to 27% of the convenience stores. More grocery stores also had fresh vegetables (100% vs. 18%), whole grain bread (100% vs. 36%), lean ground beef (100% vs. 9%), low-fat hot dogs (100% vs. 9%), baked or low-fat chips (67% vs. 0%), and low sugar cereal (67% vs. 18%). Grocery stores, however, were slightly less likely to be stocked with 100% fruit juice (67% vs. 73%), while more stocked with diet soda (100% vs. 91%) than convenience stores. Out of a possible maximum food environment score of 62, grocery stores scored 29 while convenience stores scored 3.64.
Conclusions: Convenience stores make up a large proportion of available food sources in rural towns and have limited stocks of healthful foods. The low food environment scores of both grocery and convenience stores are indication that stores have room for improvements. Increasing the variety of healthy food offerings in food stores could be the first step in improving the food environment in rural towns.
Citation Format: Linda K. Ko, Cynthia Perry, Norma Mariscal, Edgar Rodriguez, Catherine Duggan, Mario Kratz, Beti Thompson. Evaluation of the food environment in rural towns in eastern Washington. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr A25. doi:10.1158/1538-7755.DISP13-A25
Abstract A30: Using the principles of community-based participatory research to build an office of health equity within a nationally designated cancer institute
Authors: Barrett Nadine Josann , Worthy Valarie , Boyce-Manon Xiomara , Reyes Rebecca , Banks Lamisha , Patierno Steve , Chu Claire 
Published: May 2015

Abstract
Across the nation academic health centers, including cancer centers are establishing offices or departments focused specifically on health disparities and health equity. This movement is critical to ensure health disparities research and its dissemination, becomes an ongoing theme in the fabric of an institution. Offices or departments of this nature can often be shaped and defined based on initial funder priorities and may miss the opportunity to engage authentically with the community in the initial stages of its development. Limited practical research is available to describe the development, implementation, and initial outcomes of a new Office of Health Equity built within a NCI designated cancer institute. Using CBPR methodology, this project conducted assessments reaching over 121 diverse community members, faith leaders, cancer survivors, and caregivers from Latino, Asian, African American and medically underserved communities. Community partnerships were developed to conduct group sessions designed to describe community attitudes on cancer, clinical trials and research participation. Participants provided recommendations to collaboratively overcome barriers to accessing cancer information and care, clinical trials education and participation, and reduce cancer health disparities. Findings are reported back to the community and a full research platform and strategic plan has been developed and currently implemented with the community, survivors and practitioners. Practical methods of authentic community engagement are utilized to improve outreach and access to cancer services, clinical trials education and minority participation, ensure cancer survivors have a seamless journey throughout the cancer continuum, and to enhance cancer disparities research.
Citation Format: Nadine Josann Barrett, Valarie Worthy, Xiomara Boyce-Manon, Rebecca Reyes, Lamisha Banks, Steve Patierno, Claire Chu. Using the principles of community-based participatory research to build an office of health equity within a nationally designated cancer institute. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr A30. doi:10.1158/1538-7755.DISP13-A30
Abstract A35: Barriers faced and enablers used by community health workers in 3 underserved communities on cervical cancer screening among Haitian, Hispanic, and African American women
Authors: Rodriguez Brendaly , McCann Shelia , Carrasquillo Olveen , Kobetz Erin , Amofah Anthony , Koru-Sengul Tulay 
Published: May 2015

Abstract
As trusted members of their communities, community health workers (CHWs) have the potential to link hard-to-reach underserved populations with appropriate health care. As part of a National Cancer Institute (NCI)-funded initiative, we are examining the effectiveness of CHWs at increasing cervical cancer screening among minority women. CHWs are placed at one of three federally qualified health centers (FQHCs)/FHQC-look alike and obtain additional input from project specific Community Advisory Boards (CABs) in each community. Using a mixed methods approach consisting of quantitative recruitment data as well as key informant interviews we have identified several barriers and enablers for outreach, recruitment and retention of participants in our project. CHW characteristics facilitating study participant recruitment and retention include: personality, prior field experience, language, cultural congruence, degree of familiarity with community, ability to connect with their CAB members and degree of interaction with existing resources at their respective FQHCs (programmatic, structural, environmental and personnel). Ongoing CWH training and quality control were also important enablers of achieving our recruitment targets. Study participant characteristics such as cultural norms/beliefs, immigration status, health insurance, and economic factors (ability to meet clinic co-payments) were frequently cited as barriers. Structural/organizational characteristics of each FQHCs such as how health services are delivered, paperwork requirements, accessibility of location and tight linkages with local health departments also served as enablers and/or barriers. Lessons learned from our CHW led cervical cancer screening study can be applied to many distinct community based programs aimed at improving health care in underserved communities.
Note: This abstract was withdrawn after the Proceedings was printed and was not presented at the conference.
Citation Format: Brendaly Rodriguez, Shelia McCann, Olveen Carrasquillo, Erin Kobetz, Anthony Amofah, Tulay Koru-Sengul. Barriers faced and enablers used by community health workers in 3 underserved communities on cervical cancer screening among Haitian, Hispanic, and African American women. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr A35. doi:10.1158/1538-7755.DISP13-A35