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Clinical Cancer Research: An Official Journal of the American Association for Cancer Research

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https://www.readbyqxmd.com/read/28432176/a-phase-i-study-of-the-cdk4-6-inhibitor-ribociclib-lee011-in-pediatric-patients-with-malignant-rhabdoid-tumors-neuroblastoma-and-other-solid-tumors
#1
Birgit Geoerger, Franck Bourdeaut, Steven G DuBois, Matthias Fischer, James I Geller, Nicholas G Gottardo, Aurélien Marabelle, Andrew D J Pearson, Shakeel Modak, Thomas Cash, Giles W Robinson, Marlyane Motta, Alessandro Matano, Suraj G Bhansali, Jason R Dobson, Sudha Parasuraman, Susan N Chi
Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors.Experimental Design: Patients (aged 1-21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off)...
April 21, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28428193/pd-l1-expression-in-melanoma-a-quantitative-immunohistochemical-antibody-comparison
#2
Joel C Sunshine, Peter Nguyen, Genevieve Kaunitz, Tricia Cottrell, Sneha Berry, Jessica Esandrio, Haiying Xu, Aleksandra Ogurtsova, Karen R Bleich, Toby C Cornish, Evan J Lipson, Robert A Anders, Janis Taube
PD-L1 expression in the pre-treatment tumor microenvironment enriches for response to anti-PD-1/PD-L1 therapies. The purpose of this study was to quantitatively compare the performance of five monoclonal anti-PD-L1 antibodies used in recent landmark publications.  <br /><br />Experimental Design: PD-L1 immunohistochemistry (IHC) was performed on thirty-four formalin-fixed paraffin-embedded archival melanoma samples using the 5H1, SP142, 28-8, 22C3 and SP263 clones.  The percentage of total cells (including melanocytes and immune cells) demonstrating cell surface PD-L1 staining, as well as intensity measurements/H-scores, were assessed for each melanoma specimen using a computer-assisted platform...
April 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28428192/long-term-efficacy-survival-and-safety-of-177lu-dota0-tyr3-octreotate-in-patients-with-gastroenteropancreatic-and-bronchial-neuroendocrine-tumors
#3
Tessa Brabander, Wouter A Van der Zwan, Jaap Jm Teunissen, Boen L R Kam, Richard A Feelders, Wouter W de Herder, Casper H J van Eijck, Gaston J H Franssen, Eric P Krenning, Dik J Kwekkeboom
Purpose<br /> Bronchial and gastroenteropancreatic neuroendocrine tumors (NETs) are slow-growing tumors, which frequently express somatostatin receptors on their cell membranes. These receptors are targets for therapy with Lutetium-177-labeled somatostatin analogs. We have treated over 1200 patients with peptide receptor radionuclide therapy (PRRT) with (177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-DOTATATE) since the year 2000 and present the results on efficacy, survival and toxicity of this therapy. <p>Patients and methods<br /> For safety analysis, 610 patients treated with a cumulative dose of at least 100 mCi (3...
April 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28428191/the-role-of-minimal-residual-disease-testing-in-myeloma-treatment-selection-and-drug-development-current-value-and-future-applications
#4
Kenneth C Anderson, Daniel Auclair, Gary J Kelloff, Caroline C Sigman, Herve Avet-Loiseau, Ann T Farrell, Nicole J Gormley, Shaji K Kumar, Ola Landgren, Nikhil C Munshi, Michele Cavo, Faith E Davies, Alessandra Di Bacco, Jennifer S Dickey, Steven I Gutman, Howard R Higley, Mohamad A Hussein, J Milburn Jessup, Ilan R Kirsch, Richard F Little, Robert D Loberg, Jens G Lohr, Lata Mukundan, James L Omel, Trevor J Pugh, Gregory H Reaman, Michael D Robbins, A Kate Sasser, Nancy Valente, Elena Zamagni
Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10(-5)‒10(-6) cells...
April 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28428190/in-vivo-detection-of-egfrviii-in-glioblastoma-via-perfusion-magnetic-resonance-imaging-signature-consistent-with-deep-peritumoral-infiltration-the-%C3%AF-index
#5
Spyridon Bakas, Hamed Akbari, Jared Pisapia, Maria Martinez-Lage, Martin Rozycki, Saima Rathore, Nadia Dahmane, Donald M O'Rourke, Christos Davatzikos
<br />The epidermal growth factor receptor variant III (EGFRvIII) mutation has been considered a driver mutation and therapeutic target in glioblastoma, the most common and aggressive brain cancer. Currently, detecting EGFRvIII requires postoperative tissue analyses, which are ex vivo and unable to capture the tumor's spatial heterogeneity. Considering the increasing evidence of in vivo imaging signatures capturing molecular characteristics of cancer, this study aims to detect EGFRvIII in primary glioblastoma non-invasively, using routine clinically-acquired imaging...
April 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28424202/global-protease-activity-profiling-provides-differential-diagnosis-of-pancreatic-cysts
#6
Sam L Ivry, Jeremy M Sharib, Dana A Dominguez, Nilotpal Roy, Stacy E Hatcher, Michele Yip-Schneider, C Max Schmidt, Randall E Brand, Walter G Park, Matthias Hebrok, Grace Kim, Anthony J O'Donoghue, Kimberly S Kirkwood, Charles S Craik
Pancreatic cysts are estimated to be present 2-3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Missregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts.<br /><br />Experimental Design: We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples...
April 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28424201/pik3ca-mutations-contribute-to-acquired-cetuximab-resistance-in-metastatic-colorectal-cancer-patients
#7
Jian Ming Xu, Yan Wang, You-Liang Wang, Yan Wang, Tao Liu, Ming Ni, Man-Sheng Li, Li Lin, Fei-Jiao Ge, Chun Gong, Jun-Yan Gu, Ru Jia, He-Fei Wang, Yu Ling Chen, Rong-Rui Liu, Chuan-Hua Zhao, Zhao-Li Tan, Yang Jin, Yunping Zhu, Shuji Ogino, Zhi Rong Qian
<p>Mutations in KRAS are considered to be the main drivers of acquired resistance to epidermal growth factor receptor (EGFR) blockade in patients with metastatic colorectal cancer (mCRC). However, the potential roles of other genes downstream of the EGFR signaling pathway in conferring acquired resistance has not been extensively investigated.</p> <br /><br />Experimental Design: <p>Using circulating tumor DNA (ctDNA) from patients with mCRC and with acquired cetuximab resistance, we developed a targeted amplicon ultra-deep sequencing method to screen for low-abundance somatic mutations in a panel of genes that encode components of the EGFR signaling pathway...
April 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28424200/whole-exome-sequencing-of-metaplastic-breast-carcinoma-indicates-monoclonality-with-associated-ductal-carcinoma-component
#8
Bracha Avigdor, Katie Beierl, Christopher D Gocke, Daniel Zabransky, Karen Cravero, Kelly Kyker-Snowman, Berry Button, David Chu, Sarah Croessmann, Rory L Cochran, Roisin Connolly, Ben Ho Park, Ashley Cimino-Mathews, Sarah J Wheelan
Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example is metaplastic breast carcinoma, a rare but aggressive cancer with a heterogenous histology, including squamous, chondroid, and spindle cells. Metaplastic carcinomas often contain an admixed conventional ductal invasive or in situ mammary carcinoma component, and are typically triple-negative for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER-2) amplification/overexpression...
April 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28420726/intra-and-inter-observer-reproducibility-assessment-of-pd-l1-biomarker-in-non-small-cell-lung-cancer-nsclc
#9
Wendy A Cooper, Prudence A Russell, Maya Cherian, Edwina E Duhig, David Godbolt, Peter J Jessup, Christine Khoo, Connull Leslie, Annabelle Mahar, David F Moffat, Vanathi Sivasubramaniam, Céline Faure, Alena Reznichenko, Amanda Grattan, Stephen B Fox
<br />Reliable and reproducible methods for identifying PD-L1 expression on tumor cells are necessary to identify responders to anti-PD-1 therapy. We tested the reproducibility of the assessment of PD-L1 expression in non-small cell lung cancer (NSCLC) tissue samples by pathologists.<br />Experimental Design: <br />NSCLC samples were stained with PD-L1 22C3 pharmDx™ kit using the Dako Autostainer Link 48 Platform. Two sample sets of 60 samples each were designed to assess inter- and intra-observer reproducibility considering 2 cut-points for positivity: 1% or 50% of PD-L1 stained tumor cells...
April 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28420725/monitoring-daily-dynamics-of-early-tumor-response-to-targeted-therapy-by-detecting-circulating-tumor-dna-in-urine
#10
Hatim Husain, Vladislava O Melnikova, Karena Kosco, Brian Woodward, Soham More, Sandeep C Pingle, Elizabeth Weihe, Ben Ho Park, Muneesh Tewari, Mark G Erlander, Ezra E W Cohen, Scott M Lippman, Razelle Kurzrock
Purpose: Non-invasive drug biomarkers for the early assessment of tumor response can enable adaptive therapeutic decision-making and proof-of-concept studies for investigational drugs. Circulating tumor DNA (ctDNA) is released into the circulation by tumor cell turnover and has been shown to be detectable in urine. Experimental Design : We tested the hypothesis that dynamic changes in epidermal growth factor receptor (EGFR) activating (exon 19del and L858R) and resistance (T790M) mutation levels detected in urine could inform tumor response within days of therapy for advanced non-small cell lung cancer (NSCLC) patients receiving osimertinib, a second line third generation anti-EGFR tyrosine kinase inhibitor...
April 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28420724/a-zebrafish-model-discovers-a-novel-mechanism-of-stromal-fibroblast-mediated-cancer-metastasis
#11
Cai Feng Liu, Yunjian Zhang, Sharon Lim, Kayoko Hosaka, Yunlong Yang, Tatiana Pavlova, Twana Alkasalias, Johan Hartman, Lasse Jensen, Xiao-Ming Xing, Xingsheng Wang, Yong-Tian Lu, Guo Hui Nie, Yihai Cao
Purpose: Cancer metastasis can occur at the early stage of tumor development when a primary tumor at the microscopic size. In particular, the interaction of malignant cells with other cell types including cancer-associated fibroblasts (CAFs) in promoting metastasis at the early stage of tumor development remains largely unknown. Here, we investigated the role of CAFs in facilitating the initial events of cancer metastasis when primary tumors were at microscopic sizes.  <p>Experimental design: Multi-color-coded cancer cells and CAFs were co-implanted into the transparent zebrafish body and metastasis at a single cell level was monitored in living animals...
April 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28420723/mitochondrial-bax-determines-the-predisposition-to-apoptosis-in-human-aml
#12
Frank Reichenbach, Cornelius Wiedenmann, Enrico Schalk, Diana Becker, Kathrin Funk, Peter Scholz-Kreisel, Franziska Todt, Denise Wolleschak, Konstanze Dohner, Jens U Marquardt, Florian Heidel, Frank Edlich
Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death. Experimental design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort...
April 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28420722/low-tumor-mitochondrial-dna-content-is-associated-with-better-outcome-in-breast-cancer-patients-receiving-anthracycline-based-chemotherapy
#13
Marjolein J A Weerts, Antoinette Hollestelle, Anieta M Sieuwerts, John A Foekens, Stefan Sleijfer, John W M Martens
In this study, we aimed to explore whether low levels of mitochondrial DNA (mtDNA) content in the primary tumor could predict better outcome for breast cancer patients receiving anthracycline-based therapies. We hypothesized that tumor cells with low mtDNA content are more susceptible to mitochondrial damage induced by anthracyclines, and thus are more susceptible to anthracycline treatment.<br /><br />Experimental Design: We measured mtDNA content by a quantitative PCR approach in 295 primary breast tumor specimens originating from two well-defined cohorts: 174 lymph node-positive patients who received adjuvant chemotherapy and 121 patients with advanced disease who received chemotherapy as first-line palliative treatment...
April 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28420721/phase-i-study-of-fenretinide-delivered-intravenously-in-patients-with-relapsed-or-refractory-hematologic-malignancies-a-california-cancer-consortium-trial
#14
Ann Mohrbacher, Allen S Yang, Susan Groshen, Shivaani Kummar, Martin E Gutierrez, Min H Kang, Denice Tsao-Wei, C Patrick Reynolds, Edward Newman, Barry J Maurer
A phase I study was conducted to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of fenretinide delivered as an intravenous emulsion in relapsed/refractory hematologic malignancies. <br /><br />Experimental Design: Fenretinide (80 - 1810 mg/m(2)/day) was administered by continuous infusion on Days 1 - 5, in 21-day cycles, using an accelerated titration design. <br /><br />Results: Twenty-nine patients, treated with a median of three prior regimens (range, 1 to 7), were enrolled and received test drug...
April 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28420720/a-phase-i-study-of-abc294640-a-first-in-class-sphingosine-kinase-2-inhibitor-in-patients-with-advanced-solid-tumors
#15
Carolyn D Britten, Melanie B Thomas, Elizabeth Garrett-Mayer, Steven H Chin, Keisuke Shirai, Besim Ogretmen, Tricia A Bentz, Alan Brisendine, Kate Anderton, Susan L Cusack, Lynn W Maines, Yan Zhuang, Charles D Smith
Purpose:  Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and pro-inflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of ABC294640, a first-in-class orally-available inhibitor of SK2.  <p>Experimental Design:  Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid and 750 mg bid, continuously in cycles of 28 days...
April 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28404599/molecular-pathways-metabolic-control-of-histone-methylation-and-gene-expression-in-cancer
#16
Thai Q Tran, Xazmin H Lowman, Mei Kong
Epigenetic alterations contribute to tumor development, progression, and therapeutic response. Many epigenetic enzymes use metabolic intermediates as cofactors to modify chromatin structure. Emerging evidence suggests that fluctuation in metabolite levels may regulate activities of these chromatin-modifying enzymes. Here we summarize recent progress in understanding the crosstalk between metabolism and epigenetic control of gene expression in cancer. We focus on how metabolic changes, due to diet, genetic mutations, or tumor microenvironment, regulate histone methylation status and consequently affect gene expression profiles to promote tumorigenesis...
April 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28400429/genomic-analysis-of-thymic-epithelial-tumors-identifies-novel-subtypes-associated-with-distinct-clinical-features
#17
Hyun-Sung Lee, Hee-Jin Jang, Rohan Shah, David Yoon, Masatsugu Hamaji, Ori Wald, Ju-Seog Lee, David J Sugarbaker, Bryan M Burt
PURPOSE To reconcile the heterogeneity of thymic epithelial tumors (TETs) and gain deeper understanding of the molecular determinants of TETs, we set out to establish a clinically relevant molecular classification system for these tumors. <p>EXPERIMENTAL DESIGN Molecular subgrouping of TETs was performed in 120 patients from The Cancer Genome Atlas using a multidimensional approach incorporating analyses of DNA mutations, mRNA expression, and somatic copy number alterations (SCNA), and validated in two independent cohorts...
April 11, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28400428/suppression-of-lymphocyte-functions-by-plasma-exosomes-correlates-with-disease-activity-in-patients-with-head-and-neck-cancer
#18
Sonja Ludwig, Theofanis Floros, Marie-Nicole Theodoraki, Chang-Sook Hong, Edwin K Jackson, Stephan Lang, Theresa L Whiteside
Purpose: Head and neck cancers (HNC) often induce profound immunosuppression which contributes to disease progression and interferes with immune-based therapies. Body fluids of HNC patients are enriched in exosomes potentially engaged in negative regulation of anti-tumor immune responses. The presence and content of exosomes derived from plasma of HNC patients are evaluated for the ability to induce immune dysfunction and influence disease activity. <p>Experimental Design: Exosomes were isolated by size-exclusion chromatography from plasma of 38 HNC patients and 14 healthy donors...
April 11, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28400427/circulating-dna-demonstrates-convergent-evolution-and-common-resistance-mechanisms-during-treatment-of-colorectal-cancer
#19
Alain R Thierry, Brice Pastor, Zhi-Qin Jiang, Anastasia Katsiampoura, Christine Parseghian, Jonathan M Loree, Michael J Overman, Cynthia Sanchez, Safia El Messaoudi, Marc Ychou, Scott Kopetz
Purpose: Liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment. <p>Experimental design: We evaluated under blinded conditions the ability of cell free DNA (cfDNA) to detect RAS/BRAF mutations in the plasma of 42 metastatic colorectal cancer patients treated on a phase Ib/II trial of FOLFOX and dasatinib, with or without cetuximab. Results: Prior to treatment, sequencing of archival tissue detected mutations in 25/42 patients (60%), while the cfDNA assay detected mutations in 37/42 patients (88%)...
April 11, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28400426/a-gene-signature-for-selecting-benefit-from-hypoxia-modification-of-radiotherapy-for-high-risk-bladder-cancer-patients
#20
Lingjian Yang, Janet Taylor, Amanda Eustace, Joely Irlam, Helen Denley, Peter J Hoskin, Jan Alsner, Francesca M Buffa, Adrian L Harris, Ananya Choudhury, Catharine M L West
Hypoxia modification improves overall survival in muscle invasive bladder cancer patients who undergo radiotherapy. There is evidence that hypoxic tumors benefit most from hypoxia modification. The study aimed to identify or derive a hypoxia gene signature that predicts benefit from hypoxia-modifying treatment in bladder cancer.<br /><br />Experimental Design: Published hypoxia signatures were tested and a new one derived by analyzing bladder cancer transcriptomic data from public databases. Tumor samples were available from the BCON phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON)...
April 11, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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