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Molecular profile of BRCA-mutated biliary tract cancers.

Gilbert Spizzo, Alberto Puccini, Joanne Xiu, Richard M Goldberg, Axel Grothey, Anthony F Shields, Sukeshi Patel Arora, Moh'd Khushmann, Mohamed E Salem, Francesca Battaglin, Yasmine Baca, Wafik S El-Deiry, Philip A Philip, Madiha Nassem, Michael Hall, John L Marshall, Florian Kocher, Arno Amann, Dominik Wolf, W Michael Korn, Heinz Lenz, Andreas Seeber,

INTRODUCTION:Prognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. BRCA mutations are known to occur in BTC but their frequency and the molecular landscape in which they are observed in distinct sites of BTC remain unknown. MATERIAL AND METHODS:Tumour samples from 1292 ... Read more >>

ESMO Open (ESMO open)
[2020, 5(3):]

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Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors.

Mohamed E Salem, J Nicholas Bodor, Alberto Puccini, Joanne Xiu, Richard M Goldberg, Axel Grothey, W Michael Korn, Anthony F Shields, William M Worrilow, Edward S Kim, Heinz-Josef Lenz, John L Marshall, Michael J Hall,

Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in ... Read more >>

Int. J. Cancer (International journal of cancer)
[2020, :]

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WRN-Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype.

Kai Zimmer, Alberto Puccini, Joanne Xiu, Yasmine Baca, Gilbert Spizzo, Heinz-Josef Lenz, Francesca Battaglin, Richard M Goldberg, Axel Grothey, Anthony F Shields, Mohamed E Salem, John L Marshall, W Michael Korn, Dominik Wolf, Florian Kocher, Andreas Seeber,

Werner syndrome gene (WRN) contributes to DNA repair. In cancer, WRN mutations (WRN-mut) lead to genomic instability. Thus, WRN is a promising target in cancers with microsatellite instability (MSI). We assessed this study to investigate the molecular profile of WRN-mut in colorectal cancer (CRC). Tumor samples were analyzed using next-generation ... Read more >>

Cancers (Basel) (Cancers)
[2020, 12(5):]

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An Emerging Landscape for Canonical and Actionable Molecular Alterations in Primary and Metastatic Prostate Cancer.

Nancy A Dawson, Matthew Zibelman, Timothy Lindsay, Rebecca A Feldman, Michelle Saul, Zoran Gatalica, W Michael Korn, Elisabeth I Heath,

Patients with prostate cancer with tumors harboring defects in DNA-repair genes (DRD) generally do not respond well to AR-directed therapy. Furthermore, canonical pathways evolve during disease progression and may affect treatment with existing therapies. Due to the limited treatment options after failure of hormonal and taxane therapy, and the tumor ... Read more >>

Mol. Cancer Ther. (Molecular cancer therapeutics)
[2020, 19(6):1373-1382]

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Comprehensive tumor profiling reveals unique molecular differences between peritoneal metastases and primary colorectal adenocarcinoma.

Matthew K Stein, Forrest W Williard, Joanne Xiu, Miriam W Tsao, Michael G Martin, Benjamin W Deschner, Paxton V Dickson, Evan S Glazer, Danny Yakoub, David Shibata, Axel F Grothey, Philip A Philip, Jimmy J Hwang, Anthony F Shields, John L Marshall, W Michael Korn, Heinz-Josef Lenz, Jeremiah L Deneve,

BACKGROUND AND OBJECTIVES:Peritoneal metastases (PM) from primary colorectal cancer (pCRC) are associated with poor outcomes; however, molecular differences are not well defined. METHODS:We compared unpaired tumor profiles of patients with pCRC and PM from Caris Life Sciences. Testing included next-generation sequencing of 592 genes, microsatellite instability (MSI) and tumor mutational ... Read more >>

J Surg Oncol (Journal of surgical oncology)
[2020, 121(8):1320-1328]

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Primary CNS lymphoma commonly expresses immune response biomarkers.

Alexander Ou, Ashley Sumrall, Surasak Phuphanich, David Spetzler, Zoran Gatalica, Joanne Xiu, Sharon Michelhaugh, Andrew Brenner, Manjari Pandey, Santosh Kesari, W Michael Korn, Sandeep Mittal, Jason Westin, Amy B Heimberger,

Background:Primary central nervous system lymphoma (PCNSL) is rare and there is limited genomic and immunological information available. Incidental clinical and radiographic responses have been reported in PCNSL patients treated with immune checkpoint inhibitors. Materials and Methods:To genetically characterize and ascertain if the majority of PCNSL patients may potentially benefit from ... Read more >>

Neurooncol Adv (Neuro-oncology advances)
[2020, 2(1):vdaa018]

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A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors.

Sandip P Patel, Megan Othus, Young Kwang Chae, Francis J Giles, Donna E Hansel, Preet Paul Singh, Annette Fontaine, Manisha H Shah, Anup Kasi, Tareq Al Baghdadi, Marc Matrana, Zoran Gatalica, W Michael Korn, Jourdain Hayward, Christine McLeod, Helen X Chen, Elad Sharon, Edward Mayerson, Christopher W Ryan, Melissa Plets, Charles D Blanke, Razelle Kurzrock,

PURPOSE:Immune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (nonpancreatic) neuroendocrine neoplasm cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART). PATIENTS AND METHODS:We performed a prospective, open-label, ... Read more >>

Clin. Cancer Res. (Clinical cancer research : an official journal of the American Association for Cancer Research)
[2020, 26(10):2290-2296]

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Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer.

Mohamed E Salem, Francesca Battaglin, Richard M Goldberg, Alberto Puccini, Anthony F Shields, David Arguello, W Michael Korn, John L Marshall, Axel Grothey, Heinz-Josef Lenz,

BACKGROUND:The incidence of colorectal cancer (CRC), particularly left-sided tumors (LT), in adolescents and young adults (AYA) is rising. Epigenetic events appear to play an important role in tumorigenesis and cancer progression, especially in younger patients. We compared molecular features of LT to right-sided tumors (RT) in AYA. MATERIALS AND METHODS:A ... Read more >>

Oncologist (The oncologist)
[2020, 25(5):404-413]

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Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial.

Aung Naing, Deborah J Wong, Jeffrey R Infante, W Michael Korn, Raid Aljumaily, Kyriakos P Papadopoulos, Karen A Autio, Shubham Pant, Todd M Bauer, Alexandra Drakaki, Naval G Daver, Annie Hung, Navneet Ratti, Scott McCauley, Peter Van Vlasselaer, Rakesh Verma, David Ferry, Martin Oft, Adi Diab, Edward B Garon, Nizar M Tannir,

BACKGROUND:IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours. ... Read more >>

Lancet Oncol. (The Lancet. Oncology)
[2019, 20(11):1544-1555]

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Molecular Profiling of Appendiceal Adenocarcinoma and Comparison with Right-sided and Left-sided Colorectal Cancer.

Ryuma Tokunaga, Joanne Xiu, Curtis Johnston, Richard M Goldberg, Philip A Philip, Andreas Seeber, Madiha Naseem, Jae Ho Lo, Hiroyuki Arai, Francesca Battaglin, Alberto Puccini, Martin D Berger, Shivani Soni, Wu Zhang, Jimmy J Hwang, Anthony F Shields, John L Marshall, Hideo Baba, W Michael Korn, Heinz-Josef Lenz,

PURPOSE:The natural history and prognosis of appendiceal adenocarcinomas differ from those of adenocarcinomas arising in other large bowel sites. We aimed to compare the molecular profiles exhibited by appendiceal adenocarcinomas and colorectal cancers, or between the histopathologic subtypes of appendiceal adenocarcinoma. EXPERIMENTAL DESIGN:A total of 183 samples from appendiceal adenocarcinoma ... Read more >>

Clin. Cancer Res. (Clinical cancer research : an official journal of the American Association for Cancer Research)
[2019, 25(10):3096-3103]

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RARE-05. TUMOR PROFILING REVEALS EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) AND ENHANCED IMMUNE SUPPRESSION IN GLIOSARCOMAS RELATIVE TO GLIOBLASTOMA.

Christopher Dardis, Surasak Phuphanich, Nader Sanai, Joanne Xiu, Sandeep Mittal, Sharon Michelhaugh, Deepa Subramaniam, Majari Pandey, Santosh Kesari, Amy Heimberger, Zoran Gatalica, W Michael Korn, Ashley Sumrall,

AbstractBACKGROUNDGliosarcoma (GS) accounts for approximately 2% of WHO grade 4 gliomas and have a worse prognosis relative to glioblastoma (GBM). Epithelial-to-mesenchymal transition (EMT) is well recognized in a variety of tumors of ectodermal lineage. MATERIALS ANDMETHODSPatients diagnosed with either a GS (n = 44) or GBM (n = 1449) underwent ... Read more >>

Neuro-oncology (Neuro-oncology)
[2018, 20(Suppl 6):vi237-vi237]

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RARE-22. FREQUENT HIGH TUMOR MUTATIONAL BURDEN (TMB) AND PD-L1 EXPRESSION IN PRIMARY CNS LYMPHOMA (PCNSL).

Ashley Sumrall, Surasak Phuphanich, David Spetzler, Zoran Gatalica, Joanne Xiu, Aaron Provenzano, Andrew J. Brenner, Deepa Subramaniam, Majari Pandey, Amy Heimberger, Santosh Kesari, W Michael Korn, Sandeep Mittal,

AbstractBACKGROUNDPD-1 and PD-L1 expression has not been well-described in PCNSL. In one report of 20 PCNSL tumors, PD-1 and PD-L1 expression on tumor cells (TC), tumor-infiltrating lymphocytes (TIL), or tumor-associated macrophages (TAM) was seen in 90% (Clin Neuropathol 2014;PMID:24359606). Another report of 4 patients with relapsed PCNSL showed clinical and ... Read more >>

Neuro-oncology (Neuro-oncology)
[2018, 20(Suppl 6):vi240-vi241]

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Impact of Patient Age on Molecular Alterations of Left-Sided Colorectal Tumors.

Alberto Puccini, Heinz-Josef Lenz, John L Marshall, David Arguello, Derek Raghavan, W Michael Korn, Benjamin A Weinberg, Kelsey Poorman, Arielle L Heeke, Philip A Philip, Anthony F Shields, Richard M Goldberg, Mohamed E Salem,

BACKGROUND:The incidence of colorectal cancer (CRC) in younger patients is rising, mostly due to tumors in the descending colon and rectum. Therefore, we aimed to explore the molecular differences of left-sided CRC between younger (≤45 years) and older patients (≥65). SUBJECTS, MATERIALS, AND METHODS:In total, 1,126 CRC tumor samples from ... Read more >>

Oncologist (The oncologist)
[2019, 24(3):319-326]

Cited: 3 times

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Comparative Molecular Analyses of Esophageal Squamous Cell Carcinoma, Esophageal Adenocarcinoma, and Gastric Adenocarcinoma.

Mohamed E Salem, Alberto Puccini, Joanne Xiu, Derek Raghavan, Heinz-Josef Lenz, W Michael Korn, Anthony F Shields, Philip A Philip, John L Marshall, Richard M Goldberg,

BACKGROUND:Gastroesophageal cancers are often grouped together even though cancers that originate in the esophagus often exhibit different histological features, geographical distribution, risk factors, and clinical characteristics than those originating in the stomach. Herein, we aimed to compare the molecular characteristics of three different gastroesophageal cancer types: esophageal squamous cell carcinoma ... Read more >>

Oncologist (The oncologist)
[2018, 23(11):1319-1327]

Cited: 6 times

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Landscape of Tumor Mutation Load, Mismatch Repair Deficiency, and PD-L1 Expression in a Large Patient Cohort of Gastrointestinal Cancers.

Mohamed E Salem, Alberto Puccini, Axel Grothey, Derek Raghavan, Richard M Goldberg, Joanne Xiu, W Michael Korn, Benjamin A Weinberg, Jimmy J Hwang, Anthony F Shields, John L Marshall, Philip A Philip, Heinz-Josef Lenz,

The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair deficiency (dMMR) status, and programmed cell death-ligand 1 (PD-L1) expression. Herein, we quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal ... Read more >>

Mol. Cancer Res. (Molecular cancer research : MCR)
[2018, 16(5):805-812]

Cited: 11 times

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Genomic Landscape of Cell-Free DNA in Patients with Colorectal Cancer.

John H Strickler, Jonathan M Loree, Leanne G Ahronian, Aparna R Parikh, Donna Niedzwiecki, Allan Andresson Lima Pereira, Matthew McKinney, W Michael Korn, Chloe E Atreya, Kimberly C Banks, Rebecca J Nagy, Funda Meric-Bernstam, Richard B Lanman, AmirAli Talasaz, Igor F Tsigelny, Ryan B Corcoran, Scott Kopetz,

"Liquid biopsy" approaches analyzing cell-free DNA (cfDNA) from the blood of patients with cancer are increasingly utilized in clinical practice. However, it is not yet known whether cfDNA sequencing from large cohorts of patients with cancer can detect genomic alterations at frequencies similar to those observed by direct tumor sequencing, ... Read more >>

Cancer Discov (Cancer discovery)
[2018, 8(2):164-173]

Cited: 26 times

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Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy.

Cassie N Kline, Nancy M Joseph, James P Grenert, Jessica van Ziffle, Eric Talevich, Courtney Onodera, Mariam Aboian, Soonmee Cha, David R Raleigh, Steve Braunstein, Joseph Torkildson, David Samuel, Michelle Bloomer, Alejandra G de Alba Campomanes, Anuradha Banerjee, Nicholas Butowski, Corey Raffel, Tarik Tihan, Andrew W Bollen, Joanna J Phillips, W Michael Korn, Iwei Yeh, Boris C Bastian, Nalin Gupta, Sabine Mueller, Arie Perry, Theodore Nicolaides, David A Solomon,

Background:Molecular profiling is revolutionizing cancer diagnostics and leading to personalized therapeutic approaches. Herein we describe our clinical experience performing targeted sequencing for 31 pediatric neuro-oncology patients. Methods:We sequenced 510 cancer-associated genes from tumor and peripheral blood to identify germline and somatic mutations, structural variants, and copy number changes. Results:Genomic profiling ... Read more >>

Neuro-oncology (Neuro-oncology)
[2017, 19(5):699-709]

Cited: 49 times

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Prolonged Response to HER2-Directed Therapy in a Patient With HER2-Amplified, Rapidly Progressive Metastatic Colorectal Cancer.

Aparna Parikh, Chloe Atreya, W Michael Korn, Alan P Venook,

HER2 gene amplifications and activating mutations in the HER2 receptor tyrosine kinase are present in 4% of metastatic colorectal cancers (mCRCs). HER2-targeted therapy is not standard of care, although preclinical and clinical data suggest that patients with HER2 amplifications and/or HER2-activating mutations may benefit from HER2-directed therapy. HER2 amplifications and ... Read more >>

J Natl Compr Canc Netw (Journal of the National Comprehensive Cancer Network : JNCCN)
[2017, 15(1):3-8]

Cited: 5 times

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Bayesian Network Inference Modeling Identifies TRIB1 as a Novel Regulator of Cell-Cycle Progression and Survival in Cancer Cells.

Rina Gendelman, Heming Xing, Olga K Mirzoeva, Preeti Sarde, Christina Curtis, Heidi S Feiler, Paul McDonagh, Joe W Gray, Iya Khalil, W Michael Korn,

Molecular networks governing responses to targeted therapies in cancer cells are complex dynamic systems that demonstrate nonintuitive behaviors. We applied a novel computational strategy to infer probabilistic causal relationships between network components based on gene expression. We constructed a model comprised of an ensemble of networks using multidimensional data from ... Read more >>

Cancer Res. (Cancer research)
[2017, 77(7):1575-1585]

Cited: 7 times

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A phase 1 study combining the HER3 antibody seribantumab (MM-121) and cetuximab with and without irinotecan.

James M Cleary, Autumn J McRee, Geoffrey I Shapiro, Sara M Tolaney, Bert H O'Neil, Jeffrey D Kearns, Sara Mathews, Rachel Nering, Gavin MacBeath, Akos Czibere, Sunil Sharma, W Michael Korn,

Background HER3/EGFR heterodimers have been implicated as a mode of resistance to EGFR-directed therapies. Methods This Phase 1 trial assessed the tolerability, maximum tolerated dose (MTD) and pharmacokinetic (PK) properties of the HER-3 antibody seribantumab in combination with cetuximab (Part I) or cetuximab and irinotecan (Part II) in patients with ... Read more >>

Invest New Drugs (Investigational new drugs)
[2017, 35(1):68-78]

Cited: 1 time

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Oxaliplatin-Fluoropyrimidine Chemotherapy Plus Bevacizumab in Advanced Neuroendocrine Tumors: An Analysis of 2 Phase II Trials.

Pamela L Kunz, Raymond R Balise, Louis Fehrenbacher, Minggui Pan, Alan P Venook, George A Fisher, Margaret A Tempero, Andrew H Ko, W Michael Korn, Jimmy Hwang, Emily K Bergsland,

This study aimed to determine the safety and effectiveness of bevacizumab (B) plus FOLFOX or CAPOX in advanced neuroendocrine tumors (NETs) by performing a combined analysis of 2 separate prospective phase II studies.In the FOLFOX/B study, patients received chemotherapy without scheduled breaks in 3 cohorts: carcinoid, pancreatic NET, and poorly ... Read more >>

Pancreas (Pancreas)
[2016, 45(10):1394-1400]

Cited: 11 times

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Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology.

Jaffer A Ajani, Thomas A D'Amico, Khaldoun Almhanna, David J Bentrem, Joseph Chao, Prajnan Das, Crystal S Denlinger, Paul Fanta, Farhood Farjah, Charles S Fuchs, Hans Gerdes, Michael Gibson, Robert E Glasgow, James A Hayman, Steven Hochwald, Wayne L Hofstetter, David H Ilson, Dawn Jaroszewski, Kimberly L Johung, Rajesh N Keswani, Lawrence R Kleinberg, W Michael Korn, Stephen Leong, Catherine Linn, A Craig Lockhart, Quan P Ly, Mary F Mulcahy, Mark B Orringer, Kyle A Perry, George A Poultsides, Walter J Scott, Vivian E Strong, Mary Kay Washington, Benny Weksler, Christopher G Willett, Cameron D Wright, Debra Zelman, Nicole McMillian, Hema Sundar,

Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of death from cancer in the world. Several advances have been made in the staging procedures, imaging techniques, and treatment approaches. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer provide an evidence- ... Read more >>

J Natl Compr Canc Netw (Journal of the National Comprehensive Cancer Network : JNCCN)
[2016, 14(10):1286-1312]

Cited: 155 times

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A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-amplified solid tumor malignancies.

Amy Jo Chien, Alyson Cockerill, Craig Fancourt, Emmett Schmidt, Mark M Moasser, Hope S Rugo, Michelle E Melisko, Andrew H Ko, R Katie Kelley, W Michael Korn, Laura J Esserman, Laura van't Veer, Christina Yau, Denise M Wolf, Pamela N Munster,

Akt plays a key role in the aggressive pathogenesis of HER2+ malignancies, suggesting that Akt-inhibitors may be of therapeutic value in the treatment of HER2+ tumors. Preclinical studies demonstrate synergy between MK-2206, a selective allosteric Akt-inhibitor, with paclitaxel and trastuzumab. We aimed to evaluate the safety of this combination in ... Read more >>

Breast Cancer Res. Treat. (Breast cancer research and treatment)
[2016, 155(3):521-530]

Cited: 9 times

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A Multicenter, Open-Label Phase II Clinical Trial of Combined MEK plus EGFR Inhibition for Chemotherapy-Refractory Advanced Pancreatic Adenocarcinoma.

Andrew H Ko, Tanios Bekaii-Saab, Jessica Van Ziffle, Olga M Mirzoeva, Nancy M Joseph, AmirAli Talasaz, Peter Kuhn, Margaret A Tempero, Eric A Collisson, R Kate Kelley, Alan P Venook, Elizabeth Dito, Anna Ong, Sharvina Ziyeh, Ryan Courtin, Regina Linetskaya, Sanaa Tahiri, W Michael Korn,

PURPOSE:On the basis of preclinical evidence of synergistic activity between MEK and EGFR inhibitors in pancreatic ductal adenocarcinoma (PDAC), we evaluated the safety and efficacy of selumetinib, a MEK1/2 inhibitor, plus erlotinib in patients with previously treated advanced PDAC. EXPERIMENTAL DESIGN:In this single-arm phase II trial, eligible patients received the ... Read more >>

Clin. Cancer Res. (Clinical cancer research : an official journal of the American Association for Cancer Research)
[2016, 22(1):61-68]

Cited: 30 times

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Esophageal and esophagogastric junction cancers, version 1.2015.

Jaffer A Ajani, Thomas A D'Amico, Khaldoun Almhanna, David J Bentrem, Stephen Besh, Joseph Chao, Prajnan Das, Crystal Denlinger, Paul Fanta, Charles S Fuchs, Hans Gerdes, Robert E Glasgow, James A Hayman, Steven Hochwald, Wayne L Hofstetter, David H Ilson, Dawn Jaroszewski, Kory Jasperson, Rajesh N Keswani, Lawrence R Kleinberg, W Michael Korn, Stephen Leong, A Craig Lockhart, Mary F Mulcahy, Mark B Orringer, James A Posey, George A Poultsides, Aaron R Sasson, Walter J Scott, Vivian E Strong, Thomas K Varghese, Mary Kay Washington, Christopher G Willett, Cameron D Wright, Debra Zelman, Nicole McMillian, Hema Sundar, ,

Esophageal cancer is the sixth most common cause of cancer deaths worldwide. Adenocarcinoma is more common in North America and Western European countries, originating mostly in the lower third of the esophagus, which often involves the esophagogastric junction (EGJ). Recent randomized trials have shown that the addition of preoperative chemoradiation ... Read more >>

J Natl Compr Canc Netw (Journal of the National Comprehensive Cancer Network : JNCCN)
[2015, 13(2):194-227]

Cited: 124 times

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