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JOURNAL ARTICLE
Enrico Rango, Lucia D'Antona, Giulia Iovenitti, Annalaura Brai, Arianna Mancini, Claudio Zamperini, Claudia Immacolata Trivisani, Stefano Marianelli, Anna Lucia Fallacara, Alessio Molinari, Annarita Cianciusi, Silvia Schenone, Nicola Perrotti, Elena Dreassi, Maurizio Botta
Si113, a pyrazolo[3,4-d]pyrimidine derivative, gained more attention as an anticancer agent due to its potent anticancer activity on both in vitro and in vivo hepatocellular carcinomas (HCC) and ovarian carcinoma models. But the drawback is the low water solubility which prevents its further development. In this context, we successfully overcame this limitation by synthesizing two novel prodrugs introducing the amino acid sequence D-Ala-Leu-Lys (TP). Moreover, TP sequence has a high affinity with plasmin, a protease recognized as overexpressed in many solid cancers, including HCC and ovarian carcinoma...
November 5, 2021: European Journal of Medicinal Chemistry
#22
JOURNAL ARTICLE
Harshabad Singh, Yvonne Y Li, Liam F Spurr, Atul B Shinagare, Ritika Abhyankar, Emma Reilly, Lauren K Brais, Anwesha Nag, Matthew D Ducar, Aaron R Thorner, Geoffrey I Shapiro, Rachel B Keller, Cheta Siletti, Jeffrey W Clark, Anna F Farago, Jessica J Lin, George D Demetri, Rahul Gujrathi, Matthew H Kulke, Laura E MacConaill, Azra H Ligon, Ewa Sicinska, Matthew Meyerson, Jeffrey A Meyerhardt, Andrew D Cherniack, Brian M Wolpin, Kimmie Ng, Marios Giannakis, Jason L Hornick, James M Cleary
INTRODUCTION: Receptor tyrosine kinase (RTK) fusions in colorectal cancers (CRC) are rare but potentially therapeutically relevant. We describe clinical, molecular and pathologic attributes of RTK fusion-associated CRC. METHODS: We identified all cases with RTK fusions in colorectal cancer patients seen at Dana-Farber Cancer Institute who underwent OncoPanel testing between 2013-2018. Clinical, histological and molecular features were extracted from the patient charts and molecular testing results...
January 7, 2021: Clinical Cancer Research
#23
MULTICENTER STUDY
Sara A Väyrynen, Jinming Zhang, Chen Yuan, Juha P Väyrynen, Andressa Dias Costa, Hannah Williams, Vicente Morales-Oyarvide, Mai Chan Lau, Douglas A Rubinson, Richard F Dunne, Margaret M Kozak, Wenjia Wang, Diana Agostini-Vulaj, Michael G Drage, Lauren Brais, Emma Reilly, Osama Rahma, Thomas Clancy, Jiping Wang, David C Linehan, Andrew J Aguirre, Charles S Fuchs, Lisa M Coussens, Daniel T Chang, Albert C Koong, Aram F Hezel, Shuji Ogino, Jonathan A Nowak, Brian M Wolpin
PURPOSE: Although abundant myeloid cell populations in the pancreatic ductal adenocarcinoma (PDAC) microenvironment have been postulated to suppress antitumor immunity, the composition of these populations, their spatial locations, and how they relate to patient outcomes are poorly understood. EXPERIMENTAL DESIGN: To generate spatially resolved tumor and immune cell data at single-cell resolution, we developed two quantitative multiplex immunofluorescence assays to interrogate myeloid cells (CD15, CD14, ARG1, CD33, HLA-DR) and macrophages [CD68, CD163, CD86, IFN regulatory factor 5, MRC1 (CD206)] in the PDAC tumor microenvironment...
February 15, 2021: Clinical Cancer Research
#24
JOURNAL ARTICLE
Daniele Biasci, Martin Smoragiewicz, Claire M Connell, Zhikai Wang, Ya Gao, James E D Thaventhiran, Bristi Basu, Lukasz Magiera, T Isaac Johnson, Lisa Bax, Aarthi Gopinathan, Christopher Isherwood, Ferdia A Gallagher, Maria Pawula, Irena Hudecova, Davina Gale, Nitzan Rosenfeld, Petros Barmpounakis, Elizabeta Cristina Popa, Rebecca Brais, Edmund Godfrey, Fraz Mir, Frances M Richards, Douglas T Fearon, Tobias Janowitz, Duncan I Jodrell
Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response...
November 17, 2020: Proceedings of the National Academy of Sciences of the United States of America
#25
JOURNAL ARTICLE
Chunxia Du, Annacarolina da Silva, Vicente Morales-Oyarvide, Andressa Dias Costa, Margaret M Kozak, Richard F Dunne, Douglas A Rubinson, Kimberly Perez, Yohei Masugi, Tsuyoshi Hamada, Lauren K Brais, Chen Yuan, Ana Babic, Matthew D Ducar, Aaron R Thorner, Andrew Aguirre, Matthew H Kulke, Kimmie Ng, Thomas E Clancy, Jennifer J Findeis-Hosey, Daniel T Chang, Jason L Hornick, Charles S Fuchs, Shuji Ogino, Albert C Koong, Aram F Hezel, Brian M Wolpin, Jonathan A Nowak
BACKGROUND: Insulin-like growth factor-1 receptor (IGF1R) signaling is important in pancreatic ductal adenocarcinoma (PDAC) biology, but little is known regarding IGF1R expression and patient characteristics and outcomes. METHODS: In 365 patients with resected PDAC, we evaluated IGF1R protein expression using IHC on whole-slide sections and IGF1R genomic status using next-generation sequencing. Associations of IGF1R expression, measured by H-scores incorporating staining intensity and proportion of positive tumor cells, with disease-free survival (DFS) and overall survival (OS) were evaluated in 317 and 321 patients, respectively, using Cox regression adjusting for known prognostic factors...
August 2020: Cancer Epidemiology, Biomarkers & Prevention
#26
JOURNAL ARTICLE
Rachel E Rosenblum, Cynthia K Harris, Kiwoon Joshua Baeg, Julie A Starr, Lauren K Brais, Kristen M Stashek, Stephen C Ward, Bryson W Katona, Thomas E Clancy, Juan P Wisnivesky, Matthew H Kulke, David C Metz, Michelle Kang Kim, Jennifer A Chan
OBJECTIVE: Given the lack of consensus on surveillance guidelines after pancreatic neuroendocrine tumor (PanNET) resection, we assessed outcomes in a large cohort of patients with nonmetastatic, surgically resected PanNETs. METHODS: Data of patients with PanNETs resected between 1990 and 2017 were retrospectively collected using databases at 3 academic institutions. The National Death Index was queried to determine vital status. Kaplan-Meier analysis was used to estimate recurrence-free survival (RFS) and disease-specific survival (DSS) rates...
February 2020: Pancreas
#27
JOURNAL ARTICLE
Jessica J Jalbert, Roman Casciano, Jie Meng, Lauren K Brais, Sonia J Pulgar, Anthony Berthon, Jerome Dinet, Matthew H Kulke
BACKGROUND: Although an increasing number of treatments have become available for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs), there remains little consensus on treatment sequence and its impact on health care resource use (HRU). We sought to describe treatment patterns and HRU, in a cohort of patients with metastatic GEP-NETs treated at a tertiary referral center in the U.S. MATERIALS AND METHODS: We identified patients with a well-differentiated, metastatic GEP-NET evaluated at Dana-Farber Cancer Institute between July 2003 and May 2015...
April 2020: Oncologist
#28
JOURNAL ARTICLE
Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair-Deficient Colorectal Cancer.
Carino Gurjao, David Liu, Matan Hofree, Saud H AlDubayan, Isaac Wakiro, Mei-Ju Su, Kristen Felt, Evisa Gjini, Lauren K Brais, Asaf Rotem, Michael H Rosenthal, Orit Rozenblatt-Rosen, Scott Rodig, Kimmie Ng, Eliezer M Van Allen, Steven M Corsello, Shuji Ogino, Aviv Regev, Jonathan A Nowak, Marios Giannakis
Immunotherapy with checkpoint inhibitors, such as the programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab, are effective in a variety of tumors, yet not all patients respond. Tumor microsatellite instability-high (MSI-H) has emerged as a biomarker of response to checkpoint blockade, leading to the tissue agnostic approval of pembrolizumab in MSI-H cancers. Here we describe a patient with MSI-H colorectal cancer that was treated with this immune checkpoint inhibitor and exhibited progression of disease...
August 2019: Cancer Immunology Research
#29
JOURNAL ARTICLE
Annacarolina da Silva, Michaela Bowden, Sui Zhang, Yohei Masugi, Aaron R Thorner, Zachary T Herbert, Chensheng Willa Zhou, Lauren Brais, Jennifer A Chan, F Stephen Hodi, Scott Rodig, Shuji Ogino, Matthew H Kulke
OBJECTIVES: The immune environment and the potential for neuroendocrine tumors (NETs) to respond to immune checkpoint inhibitors remain largely unexplored. We assessed immune checkpoint marker expression, lymphocytic infiltrate, and associated mutational profiles in a cohort of small intestine and pancreatic NETs. METHODS: We assessed expression of PDCD1 (PD-1), CD274 (PD-L1), and PDCD1LG2 (PD-L2) in archival tissue from 64 small intestine (SINETs) and 31 pancreatic NETs (pNET)...
October 2018: Pancreas
#30
JOURNAL ARTICLE
Matthew B Yurgelun, Anu B Chittenden, Vicente Morales-Oyarvide, Douglas A Rubinson, Richard F Dunne, Margaret M Kozak, Zhi Rong Qian, Marisa W Welch, Lauren K Brais, Annacarolina Da Silva, Justin L Bui, Chen Yuan, Tingting Li, Wanwan Li, Atsuhiro Masuda, Mancang Gu, Andrea J Bullock, Daniel T Chang, Thomas E Clancy, David C Linehan, Jennifer J Findeis-Hosey, Leona A Doyle, Aaron R Thorner, Matthew D Ducar, Bruce M Wollison, Natalia Khalaf, Kimberly Perez, Sapna Syngal, Andrew J Aguirre, William C Hahn, Matthew L Meyerson, Charles S Fuchs, Shuji Ogino, Jason L Hornick, Aram F Hezel, Albert C Koong, Jonathan A Nowak, Brian M Wolpin
PURPOSE: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses. METHODS: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e...
January 2019: Genetics in Medicine: Official Journal of the American College of Medical Genetics
#31
JOURNAL ARTICLE
Andrew J Aguirre, Jonathan A Nowak, Nicholas D Camarda, Richard A Moffitt, Arezou A Ghazani, Mehlika Hazar-Rethinam, Srivatsan Raghavan, Jaegil Kim, Lauren K Brais, Dorisanne Ragon, Marisa W Welch, Emma Reilly, Devin McCabe, Lori Marini, Kristin Anderka, Karla Helvie, Nelly Oliver, Ana Babic, Annacarolina Da Silva, Brandon Nadres, Emily E Van Seventer, Heather A Shahzade, Joseph P St Pierre, Kelly P Burke, Thomas Clancy, James M Cleary, Leona A Doyle, Kunal Jajoo, Nadine J McCleary, Jeffrey A Meyerhardt, Janet E Murphy, Kimmie Ng, Anuj K Patel, Kimberly Perez, Michael H Rosenthal, Douglas A Rubinson, Marvin Ryou, Geoffrey I Shapiro, Ewa Sicinska, Stuart G Silverman, Rebecca J Nagy, Richard B Lanman, Deborah Knoerzer, Dean J Welsch, Matthew B Yurgelun, Charles S Fuchs, Levi A Garraway, Gad Getz, Jason L Hornick, Bruce E Johnson, Matthew H Kulke, Robert J Mayer, Jeffrey W Miller, Paul B Shyn, David A Tuveson, Nikhil Wagle, Jen Jen Yeh, William C Hahn, Ryan B Corcoran, Scott L Carter, Brian M Wolpin
Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data...
September 2018: Cancer Discovery
#32
JOURNAL ARTICLE
A Babic, N Schnure, N P Neupane, M M Zaman, N Rifai, M W Welch, L K Brais, D A Rubinson, V Morales-Oyarvide, C Yuan, S Zhang, E M Poole, B M Wolpin, M H Kulke, D A Barbie, K Wong, C S Fuchs, K Ng
OBJECTIVES: Inflammation and inflammatory conditions have been associated with pancreatic cancer risk and progression in a number of clinical, epidemiological, and animal model studies. The goal of the present study is to identify plasma markers of inflammation associated with survival of pancreatic cancer patients, and assess their joint contribution to patient outcome. METHODS: We measured circulating levels of four established markers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumor necrosis factor receptor type II (sTNF-RII), and macrophage inhibitory cytokine-1 (MIC-1)) in 446 patients enrolled in an ongoing prospective clinic-based study...
April 25, 2018: Clinical and Translational Gastroenterology
#33
JOURNAL ARTICLE
Zhi Rong Qian, Douglas A Rubinson, Jonathan A Nowak, Vicente Morales-Oyarvide, Richard F Dunne, Margaret M Kozak, Marisa W Welch, Lauren K Brais, Annacarolina Da Silva, Tingting Li, Wanwan Li, Atsuhiro Masuda, Juhong Yang, Yan Shi, Mancang Gu, Yohei Masugi, Justin Bui, Caitlin L Zellers, Chen Yuan, Ana Babic, Natalia Khalaf, Andrew Aguirre, Kimmie Ng, Rebecca A Miksad, Andrea J Bullock, Daniel T Chang, Jennifer F Tseng, Thomas E Clancy, David C Linehan, Jennifer J Findeis-Hosey, Leona A Doyle, Aaron R Thorner, Matthew Ducar, Bruce Wollison, Angelica Laing, William C Hahn, Matthew Meyerson, Charles S Fuchs, Shuji Ogino, Jason L Hornick, Aram F Hezel, Albert C Koong, Brian M Wolpin
Importance: Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few biomarkers are available to inform patient outcomes. Objective: To evaluate the alterations of the 4 main driver genes in pancreatic adenocarcinoma and patient outcomes after cancer resection. Design, Setting, and Participants: This study analyzed protein expression and DNA alterations for the KRAS, CDKN2A, SMAD4, and TP53 genes by immunohistochemistry and next-generation sequencing in formalin-fixed, paraffin-embedded tumors in 356 patients with resected pancreatic adenocarcinoma who were treated at the Dana-Farber/Brigham and Women's Cancer Center (October 26, 2002, to May 21, 2012), University of Rochester Medical Center (March 1, 2006, to November 1, 2013), or Stanford Cancer Institute (September 26, 1995, to May 22, 2013)...
March 8, 2018: JAMA Oncology
#34
JOURNAL ARTICLE
Yan Shi, Zhi Rong Qian, Sui Zhang, Wanwan Li, Yohei Masugi, Tingting Li, Jennifer A Chan, Juhong Yang, Annacarolina Da Silva, Mancang Gu, Li Liu, Tsuyoshi Hamada, Keisuke Kosumi, Trevor Dutton, Lauren K Brais, Reiko Nishihara, Charles S Fuchs, Shuji Ogino, Matthew H Kulke
OBJECTIVES: Dysregulation of the cell cycle has been observed and implicated as an etiologic factor in a range of human malignancies, but remains relatively unstudied in neuroendocrine tumors (NETs). We evaluated expression of key proteins involved in cell cycle regulation in a large cohort of NETs. METHODS: We evaluated immunohistochemical expression of CDKN1B, CDKN1A, CDKN2A, CDK2, CDK4, CDK6, cyclin D1, cyclin E1, and phosphorylated retinoblastoma protein (phospho-RB1) in a cohort of 267 patients with NETs...
November 2017: Pancreas
#35
JOURNAL ARTICLE
Michaela Bowden, Chensheng W Zhou, Sui Zhang, Lauren Brais, Ashley Rossi, Laurent Naudin, Arunthi Thiagalingam, Ewa Sicinska, Matthew H Kulke
BACKGROUND: Current diagnostic and prognostic blood-based biomarkers for neuroendocrine tumors are limited. MiRNAs have tumor-specific expression patterns, are relatively stable, and can be measured in patient blood specimens. We performed a multi-stage study to identify and validate characteristic circulating miRNAs in patients with metastatic small intestine neuroendocrine tumors, and to assess associations between miRNA levels and survival. METHODS: Using a 742-miRNA panel, we identified candidate miRNAs similarly expressed in 19 small intestine neuroendocrine tumors and matched plasma samples...
August 15, 2017: Oncotarget
#36
JOURNAL ARTICLE
Michaela Bowden, Chensheng W Zhou, Sui Zhang, Lauren Brais, Ashley Rossi, Laurent Naudin, Arunthi Thiagalingam, Ewa Sicinska, Matthew H Kulke
BACKGROUND: Current diagnostic and prognostic blood-based biomarkers for neuroendocrine tumors are limited. MiRNAs have tumor-specific expression patterns, are relatively stable, and can be measured in patient blood specimens. We performed a multi-stage study to identify and validate characteristic circulating miRNAs in patients with metastatic small intestine neuroendocrine tumors, and to assess associations between miRNA levels and survival. METHODS: Using a 742-miRNA panel, we identified candidate miRNAs similarly expressed in 19 small intestine neuroendocrine tumors and matched plasma samples...
April 7, 2017: Oncotarget
#37
JOURNAL ARTICLE
Lorenzo Botta, Giorgio Maccari, Pierpaolo Calandro, Marika Tiberi, Annalaura Brai, Claudio Zamperini, Filippo Canducci, Mario Chiariello, Rosa Martí-Centelles, Eva Falomir, Miguel Carda
AIDS-related cancer diseases are malignancies with low incidence on healthy people that affect mostly subjects already immunocompromised. The connection between HIV/AIDS and these cancers has not been established yet, but a weakened immune system is certainly the main cause. We envisaged the possibility to screen a small library of compounds synthesized in our laboratory against opportunistic tumors mainly due to HIV infection like Burkitt's Lymphoma. From cellular assays and gene expression analysis we identified two promising compounds...
June 1, 2017: Bioorganic & Medicinal Chemistry Letters
#38
JOURNAL ARTICLE
Mark Fairweather, Richard Swanson, Jiping Wang, Lauren K Brais, Trevor Dutton, Matthew H Kulke, Thomas E Clancy
BACKGROUND: Liver-directed therapies have been used to treat neuroendocrine liver metastases (NELM) for both symptomatic improvement and tumor growth control. We reviewed our experience with NELM to investigate the outcomes of available treatment modalities and to identify prognostic factors for survival. METHODS: We identified all patients with NELM, who were managed at our institution, from a prospectively collected institutional database. Overall survival (OS) was determined for each treatment modality...
August 2017: Annals of Surgical Oncology
#39
JOURNAL ARTICLE
Diana D Shi, David P Yuppa, Trevor Dutton, Lauren K Brais, Sarah L Minden, Ilana M Braun, Matthew H Kulke, Jennifer A Chan, Fremonta L Meyer
BACKGROUND: Patients with carcinoid tumors frequently could benefit from the pharmacologic treatment of depression and anxiety. However, many prescribers avoid serotonergic medications due to the theoretical risk of exacerbating carcinoid syndrome. METHODS: The authors conducted a retrospective chart review of patients with carcinoid tumors and elevated serotonin levels (as measured by 24-hour urine 5-hydroxyindoleacetic acid [5-HIAA]) at Dana-Farber/Brigham and Women's Cancer Center who initiated treatment with serotonergic antidepressants after a carcinoid diagnosis from 2003 to 2016...
March 7, 2017: Cancer
#40
JOURNAL ARTICLE
Monica Ter-Minassian, Sui Zhang, Nichole V Brooks, Lauren K Brais, Jennifer A Chan, David C Christiani, Xihong Lin, Sylvie Gabriel, Jérôme Dinet, Matthew H Kulke
Endpoints related to tumor progression are commonly used in clinical trials of novel therapeutic agents for neuroendocrine tumors (NETs). Whether improved tumor control translates into improved overall survival (OS), however, is uncertain. We assessed associations between tumor progression endpoints and OS in observational cohorts of patients with advanced neuroendocrine tumors treated with somatostatin analogs or with everolimus. We identified 440 patients with advanced NET who had received treatment with single-agent somatostatin analogs and 109 patients treated with everolimus, all of whom were treated at our institution and were evaluable for both tumor progression and survival...
February 2017: Oncologist
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