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https://www.readbyqxmd.com/read/28214087/targeting-the-pd-1-pd-l1-axis-in-non-small-cell-lung-cancer
#1
REVIEW
Rajiv Kumar, Dearbhaile Collins, Saoirse Dolly, Fiona McDonald, Mary E R O'Brien, Timothy A Yap
The last decade has witnessed rapid advances in the discovery and development of immune checkpoint inhibitors in cancer medicine, particularly drugs targeting programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC). The proven antitumor efficacy coupled with low rates of drug-related toxicities observed, albeit idiosyncratic, with these novel immunotherapeutics have led to the registration of multiple PD-1 and PD-L1 inhibitors, such as nivolumab, pembrolizumab, and atezolizumab, in second-line advanced NSCLC, whereas durvalumab and avelumab are in late-phase clinical testing...
December 23, 2016: Current Problems in Cancer
https://www.readbyqxmd.com/read/28213819/conditional-knockout-of-activin-like-kinase-1-alk-1-leads-to-heart-failure-without-maladaptive-remodeling
#2
Kevin J Morine, Xiaoying Qiao, Vikram Paruchuri, Mark J Aronovitz, Emily E Mackey, Lyanne Buiten, Jonathan Levine, Keshan Ughreja, Prerna Nepali, Robert M Blanton, Richard H Karas, S Paul Oh, Navin K Kapur
Activin like kinase-1 (AlK-1) mediates signaling via the transforming growth factor beta (TGFβ) family of ligands. AlK-1 activity promotes endothelial proliferation and migration. Reduced AlK-1 activity is associated with arteriovenous malformations. No studies have examined the effect of global AlK-1 deletion on indices of cardiac remodeling. We hypothesized that reduced levels of AlK-1 promote maladaptive cardiac remodeling. To test this hypothesis, we employed AlK-1 conditional knockout mice (cKO) harboring the ROSA26-CreER knock-in allele, whereby a single dose of intraperitoneal tamoxifen triggered ubiquitous Cre recombinase-mediated excision of floxed AlK-1 alleles...
February 17, 2017: Heart and Vessels
https://www.readbyqxmd.com/read/28212996/analysis-of-a-panel-of-druggable-gene-mutations-and-of-alk-and-pd-l1-expression-in-a-series-of-thymic-epithelial-tumors-tets
#3
Marcello Tiseo, Angela Damato, Lucia Longo, Fausto Barbieri, Federica Bertolini, Alessandro Stefani, Mario Migaldi, Letizia Gnetti, Roberta Camisa, Paola Bordi, Sebastiano Buti, Giulio Rossi
INTRODUCTION: Thymic epithelial tumors (TETs) are rare neoplasms with different prognosis lacking consistent molecular alterations possibly leading to targeted therapy. We collected a consecutive series of TETs aimed at investigating the mutational status of druggable genes (EGFR, c-KIT, KRAS, BRAF, PDGFR-alpha and -beta, HER2 and c-MET) and the expression of ALK and PD-L1. PATIENTS AND METHODS: One hundred twelve consecutive cases of TETs and relative clinico-pathologic features were collected...
February 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28212572/concurrent-gene-alterations-with-egfr-mutation-and-treatment-efficacy-of-egfr-tkis-in-chinese-patients-with-non-small-cell-lung-cancer
#4
Wentao Hu, Yahui Liu, Jian Chen
PURPOSE: We investigated the frequency of concurrent genes in EGFR-mutant non-small cell lung cancer patients and determined its value in predicting the efficacy of EGFR-TKIs treatment. METHODS: Three hundred and twenty patients, who harbored EGFR activating mutations and received EGFR-TKIs treatment, were examined for another eight genes including KRAS, NRAS, PIK3CA, BRAF, and HER2 mutations and ALK, ROS1, and RET fusion genes based on reverse transcription PCR...
February 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28212040/synthesis-and-speciation-dependent-properties-of-a-multimetallic-model-complex-of-nisod-that-exhibits-unique-hydrogen-bonding
#5
Ramsey A Steiner, Stephen P Dzul, Timothy L Stemmler, Todd C Harrop
The complex Na3[{Ni(II)(nmp)}3S3BTA(alk))] (1) (nmp(2-) = deprotonated form of N-(2-mercaptoethyl)picolinamide; H3S3BTA(alk) = N(1),N(3),N(5)-tris(2-mercaptoethyl)benzene-1,3,5-tricarboxamide, where H = dissociable protons), supported by the thiolate-benzenetricarboxamide scaffold (S3BTA(alk)), has been synthesized as a trimetallic model of nickel-containing superoxide dismutase (NiSOD). X-ray absorption spectroscopy (XAS) and (1)H NMR measurements on 1 indicate that the Ni(II) centers are square-planar with N2S2 coordination, and Ni-N and Ni-S distances of 1...
February 17, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28209747/pediatric-adolescent-and-young-adult-thyroid-carcinoma-harbors-frequent-and-diverse-targetable-genomic-alterations-including-kinase-fusions
#6
Pierre Vanden Borre, Alexa B Schrock, Peter M Anderson, John C Morris, Andreas M Heilmann, Oliver Holmes, Kai Wang, Adrienne Johnson, Steven G Waguespack, Sai-Hong Ignatius Ou, Saad Khan, Kar-Ming Fung, Philip J Stephens, Rachel L Erlich, Vincent A Miller, Jeffrey S Ross, Siraj M Ali
BACKGROUND: Thyroid carcinoma, which is rare in pediatric patients (age 0-18 years) but more common in adolescent and young adult (AYA) patients (age 15-39 years), carries the potential for morbidity and mortality. METHODS: Hybrid-capture-based comprehensive genomic profiling (CGP) was performed prospectively on 512 consecutively submitted thyroid carcinomas, including 58 from pediatric and AYA (PAYA) patients, to identify genomic alterations (GAs), including base substitutions, insertions/deletions, copy number alterations, and rearrangements...
February 16, 2017: Oncologist
https://www.readbyqxmd.com/read/28209203/crizotinib-associated-renal-cysts-carcs-incidence-and-patterns-of-evolution
#7
Laird B Cameron, Damian H S Jiang, Kate Moodie, Catherine Mitchell, Benjamin Solomon, Bimal Kumar Parameswaran
BACKGROUND: Novel therapeutic agents recently introduced for the treatment of cancer have several unusual side effects. An increased incidence of renal cystic lesions, often with features concerning for malignancy or infection, has been reported in patients with anaplastic lymphoma kinase (ALK) - rearranged advanced non-small cell lung cancer (NSCLC) treated with Crizotinib. Many of these lesions undergo spontaneous resolution despite developing complex features on imaging. We assess the incidence and patterns of evolution of Crizotinib Associated Renal Cysts [CARCs] at our institute and provide histopathology correlation of their benign nature...
February 16, 2017: Cancer Imaging: the Official Publication of the International Cancer Imaging Society
https://www.readbyqxmd.com/read/28203297/therapeutic-approach-to-treating-patients-with-braf-mutant-lung-cancer-latest-evidence-and-clinical-implications
#8
REVIEW
Adrianus J de Langen, Egbert F Smit
Lung adenocarcinoma is known for its high rate of somatic mutations and genomic rearrangements. The identification of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements that sensitize tumors to specific drugs has changed the therapeutic approach and prognosis in these molecularly-defined subgroups. Several other key genetic alterations have been identified, of which BRAF mutations are found in 4% of non-small cell lung cancer (NSCLC) cases. Targeted drugs against BRAF and downstream MEK were recently approved for the treatment of BRAF-positive melanoma and have entered clinical evaluation in NSCLC...
January 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28199742/genetic-analysis-and-clinicopathological-features-of-alk-rearranged-renal-cell-carcinoma-in-a-large-series-of-resected-chinese-renal-cell-carcinoma-patients-and-literature-review
#9
Wenjuan Yu, Yuewei Wang, Yanxia Jiang, Wei Zhang, Yujun Li
AIMS: Anaplastic lymphoma kinase (ALK)-rearranged renal cell carcinoma (RCC) is a rare subtype of RCC reported in recent years with 8 cases so far. The present study is focused on screening ALK-rearranged cases from a large cohort of RCCs in China to determine the frequency of ALK rearrangement and investigate the clinicopathological features and outcomes. METHODS AND RESULTS: Tissues from a total of 477 RCC patients in China were embedded into tissue microarrays for immunostaining...
February 15, 2017: Histopathology
https://www.readbyqxmd.com/read/28195686/diagnosis-of-anaplastic-lymphoma-kinase-rearrangement-in-cytological-samples-through-a-fluorescence-in-situ-hybridization-based-assay-cytological-smears-versus-cell-blocks
#10
Federica Zito Marino, Giulio Rossi, Matteo Brunelli, Maria Gabriella Malzone, Giuseppina Liguori, Giuseppe Bogina, Alessandro Morabito, Gaetano Rocco, Renato Franco, Gerardo Botti
Anaplastic lymphoma kinase (ALK) status analysis of lung cytological specimens should be successfully encouraged in routine practice because biopsy specimens are not always available. To date, the US Food and Drug Administration has approved both fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) as diagnostic tests for identifying ALK-positive patients eligible for treatment with crizotinib. Although ALK IHC is an optimal diagnostic tool, FISH becomes mandatory in equivocal cases. ALK FISH of paraffin-embedded tissue material is still the gold standard, whereas the cytological specimen assay has not yet been completely standardized...
February 14, 2017: Cancer
https://www.readbyqxmd.com/read/28194436/real-time-genomic-profiling-of-histiocytoses-identifies-early-kinase-domain-braf-alterations-while-improving-treatment-outcomes
#11
Lynn H Lee, Anjelika Gasilina, Jayeeta Roychoudhury, Jason Clark, Francis X McCormack, Joseph Pressey, Michael S Grimley, Robert Lorsbach, Siraj Ali, Mark Bailey, Philip Stephens, Jeffrey S Ross, Vincent A Miller, Nicolas N Nassar, Ashish R Kumar
Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing...
February 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28193771/ceritinib-bests-chemo-for-untreated-alk-nsclc
#12
(no author information available yet)
Patients with ALK-positive non-small cell lung cancer may soon have a new first-line treatment option in ceritinib, which outperformed chemotherapy in a phase III study. However, toxicity issues remain a problem for ceritinib, and another next-generation ALK inhibitor, alectinib, is more likely to become the drug of choice for untreated patients.
February 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28193280/functional-role-of-alk-related-signal-cascades-on-modulation-of-epithelial-mesenchymal-transition-and-apoptosis-in-uterine-carcinosarcoma
#13
H Inoue, M Hashimura, M Akiya, R Chiba, M Saegusa
BACKGROUND: Anaplastic lymphoma kinase (ALK), which is a receptor tyrosine kinase, is essentially and transiently expressed in the developing nervous system. Recently, the deregulated expression of full-length ALK has been observed in some primary solid tumors, but little is known about its involvement in the tumorigenesis of uterine carcinosarcomas (UCSs). Here we examined the functional role of the ALK gene in UCSs. METHODS: Regulation and function of the ALK gene were assessed using two endometrial carcinoma cell lines...
February 14, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28191314/diagnosis-and-treatment-of-cd20-negative-b-cell-lymphomas
#14
REVIEW
Tasleem Katchi, Delong Liu
CD20 negative B cell non-Hodgkin lymphoma (NHL) is rare and accounts for approximately 1-2% of B cell lymphomas. CD20- negative NHL is frequently associated with extranodal involvement, atypical morphology, aggressive clinical behaviour, resistance to standard chemotherapy and poor prognosis. The most common types of these include plasmablastic lymphoma, primary effusion lymphoma, large B-cell lymphoma arising from HHV8-associated multicentric Castleman's disease, and ALK+ large B cell lymphoma. This review provides an overview of the diagnostic and treatment modalities for CD20 negative B cell NHL...
2017: Biomarker Research
https://www.readbyqxmd.com/read/28189832/characteristics-and-outcomes-of-patients-with-lung-cancer-harboring-multiple-molecular-alterations-results-from-the-ifct-study-biomarkers-france
#15
Nicolas Guibert, Fabrice Barlesi, Renaud Descourt, Hervé Léna, Benjamin Besse, Michèle Beau-Faller, Jean Mosser, Eric Pichon, Jean-Philippe Merlio, L'Houcine Ouafik, François Guichard, Bénédicte Mastroianni, Lionel Moreau, Annie Wdowik, Jean-Christophe Sabourin, Antoinette Lemoine, Pascale Missy, Alexandra Langlais, Denis Moro-Sibilot, Julien Mazieres
INTRODUCTION: Little is known about the prevalence, prognosis and response to treatment of advanced non-small cell lung cancer (NSCLC) harboring multiple genomic alterations. METHODS: The French Biomarkers France database (IFCT) including 17,664 patients was used. The prevalence of multiple alterations, their associations, impact on prognosis (overall survival: OS) and their response to targeted or conventional treatments (progression free survival: PFS; objective response rate: ORR), were assessed and compared with those of patients harboring single or no mutation...
February 9, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28189201/co-clinical-quantitative-tumor-volume-imaging-in-alk-rearranged-nsclc-treated-with-crizotinib
#16
Mizuki Nishino, Adrian G Sacher, Leena Gandhi, Zhao Chen, Esra Akbay, Andriy Fedorov, Carl F Westin, Hiroto Hatabu, Bruce E Johnson, Peter Hammerman, Kwok-Kin Wong
PURPOSE: To evaluate and compare the volumetric tumor burden changes during crizotinib therapy in mice and human cohorts with ALK-rearranged non-small-cell lung cancer (NSCLC). METHODS: Volumetric tumor burden was quantified on serial imaging studies in 8 bitransgenic mice with ALK-rearranged adenocarcinoma treated with crizotinib, and in 33 human subjects with ALK-rearranged NSCLC treated with crizotinib. The volumetric tumor burden changes and the time to maximal response were compared between mice and humans...
March 2017: European Journal of Radiology
https://www.readbyqxmd.com/read/28188721/pd-l1-over-expression-is-associated-with-a-poor-prognosis-in-asian-non-small-cell-lung-cancer-patients
#17
Haifeng Xia, Ji Shen, Fang Hu, Shaomu Chen, Haitao Huang, Yaozeng Xu, Haitao Ma
BACKGROUND: The prognostic role of programmed cell death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) remains controversial. This meta-analysis was conducted to clarify the association of PD-L1 with survival in NSCLC patients. METHODS: Relevant studies were collected from PubMed, Embase and Web of Science. Only studies in which PD-L1 expression was detected by immunohistochemical staining in NSCLC patients correlated with patient survival data were included...
February 7, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28185914/therapeutic-strategies-and-mechanisms-of-drug-resistance-in-anaplastic-lymphoma-kinase-alk-rearranged-lung-cancer
#18
REVIEW
Ryohei Katayama
Anaplastic lymphoma kinase (ALK) gene encoding the receptor tyrosine kinase ALK is expressed as a fusion gene in a variety of carcinomas. The expression of ALK is nearly undetectable in adults, and its activation is normally regulated by its ligands, FAM150A/B. However, ALK gene rearrangements result in different ALK fusion proteins that are constitutively expressed via the active promoter of fusion partner genes. ALK fusion proteins dimerize in a ligand-independent manner and lead to the dysregulation of cell proliferation via abnormal constitutive activation of ALK tyrosine kinase...
February 6, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28183714/dichotomous-alk-ihc-is-a-better-predictor-for-alk-inhibition-outcome-than-traditional-alk-fish-in-advanced-non-small-cell-lung-cancer
#19
Anthonie van der Wekken, Rianne Pelgrim, Nils 't Hart, Naomi Werner, Mirjam Mastik, Lizza Hendriks, Erik Hfm van der Heijden, Monika Looijen-Salamon, A Joop de Langen, Jeske Staal-van den Brekel, Sietske Riemersma, Ben E van den Borne, Ernst-Jan M Speel, Anne-Marie C Dingemans, T Jeroen N Hiltermann, Anke van den Berg, Wim Timens, Ed Schuuring, Harry Jm Groen
ALK rearrangement detection using fluorescence in situ hybridization (FISH) is the standard test to identify non-small cell lung carcinoma (NSCLC) patients eligible for treatment with ALK inhibitors. Recently ALK protein expression in resectable NSCLC showed predictive value. We evaluated tumor response rate and survival after crizotinib treatment of advanced NSCLC patients with ALK activation using both dichotomous immunohistochemical staining (IHC) and FISH. Design Stage IV NSCLC patients treated with crizotinib were selected...
February 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28183697/safety-and-antitumor-activity-of-the-multi-targeted-pan-trk-ros1-and-alk-inhibitor-entrectinib-rxdx-101-combined-results-from-two-phase-1-trials-alka-372-001-and-startrk-1
#20
Alexander Drilon, Salvatore Siena, Sai-Hong Ignatius Ou, Manish Patel, Myung Ju Ahn, Jeeyun Lee, Todd M Bauer, Anna F Farago, Jennifer J Wheler, Stephen V Liu, Robert Doebele, Laura Giannetta, Giulio Cerea, Giovanna Marrapese, Michele Schirru, Alessio Amatu, Katia Bencardino, Laura Palmeri, Andrea Sartore-Bianchi, Angelo Vanzulli, Sara Cresta, Silvia Damian, Matteo Duca, Elena Ardini, Gang Li, Jason Christiansen, Karey Kowalski, Ann Johnson, Rupal Patel, David Luo, Edna Chow-Maneval, Zachary Hornby, Pratik S Multani, Alice T Shaw, Filippo G De Braud
Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two Phase 1 studies in patients with advanced or metastatic solid tumors, including patients with active CNS disease. Here we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the RP2D...
February 9, 2017: Cancer Discovery
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