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Biagio Ricciuti, Andrea De Giglio, Carmen Mecca, Cataldo Arcuri, Sabrina Marini, Giulio Metro, Sara Baglivo, Angelo Sidoni, Guido Bellezza, Lucio Crinò, Rita Chiari
Anaplastic lymphoma kinase (ALK) rearrangements represent the molecular driver of a subset of non-small cell lung cancers (NSCLCs). Despite the initial response, virtually all ALK-positive patients develop an acquired resistance to the ALK inhibitor crizotinib, usually within 12 months. Several next-generation ALK inhibitors have been developed in order to overcome crizotinib limitation, providing an unprecedented survival for this subset of patients. The aim of this review to summarize the current knowledge on ALK tyrosine kinase inhibitors (TKIs) in the treatment of advanced ALK-positive NSCLC, focusing on the role of novel ALK inhibitors in this setting...
April 17, 2018: Medical Oncology
Esther Camp, Peter J Anderson, Andrew C W Zannettino, Carlotta A Glackin, Stan Gronthos
Saethre-Chotzen syndrome (SCS), associated with TWIST-1 mutations, is characterized by premature fusion of cranial sutures. TWIST-1 haploinsufficiency, leads to alterations in suture mesenchyme cellular gene expression patterns, resulting in aberrant osteogenesis and craniosynostosis. We analyzed the expression of the TWIST-1 target, Tyrosine kinase receptor c-ros-oncogene 1 (C-ROS-1) in TWIST-1 haploinsufficient calvarial cells derived from SCS patients and calvaria of Twist-1del/+ mutant mice and found it to be highly expressed when compared to TWIST-1 wild-type controls...
April 16, 2018: Journal of Cellular Physiology
Guilherme Nader Marta, Renata Rodrigues da Cunha Colombo Bonadio, Renata Eiras Martins, Henrique Bortot Zuppani, Gilberto de Castro
The central nervous system (CNS) is a common site of disease progression in patients with non-small-cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK)-rearrangement treated with crizotinib. Cystic brain metastases (CBM) have been recently identified as one possible variant of this disease. An illustrative case report is presented along with a literature review performed in order to track relevant papers about CBM in ALK-rearranged NSCLC, including possible pathophysiology, differential diagnosis and treatment options for this condition...
2018: Ecancermedicalscience
Marta Doménech, Maria Jové, Samantha Aso, Mar Marín, Ernest Nadal
We present a 45-year-old patient diagnosed with anaplastic lymphoma kinase (ALK)-rearranged metastatic lung cancer who developed grade 4 interstitial lung disease (ILD) while on crizotinib treatment and was lately treated with brigatinib with no reappearance of ILD. To our knowledge, this is the first case report of successful treatment with brigatinib after crizotinib-induced ILD. Even though ILD secondary to brigatinib has been reported in clinical trials, no pulmonary toxicity has been seen in our patient, suggesting no crosslink lung toxicity between crizotinib and brigatinib...
May 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
C Burudpakdee, W Wong, A Seetasith, F A Corvino, W Yeh, M Gubens
OBJECTIVES: Despite improved progression-free survival, most patients treated with the first generation ALK inhibitor crizotinib ultimately experience central nervous system (CNS) progression. Brain metastases (BM) are associated with high clinical burden in patients with advanced anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC). In this study we estimate the real-world economic burden of BM in newly diagnosed ALK+ NSCLC patients and investigate whether alectinib, a second generation ALK inhibitor that delays CNS progression, may help reduce healthcare costs in patients with ALK+ NSCLC...
May 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Xiaoyan Qi, Lin Zhao, Qiuping Zhao, Qiaoxia Xu
In this study, a fast, simple and sensitive liquid chromatography-mass spectrometry method was developed for simultaneous determination of crizotinib and its major oxidative metabolite crizotinib-lactam in human plasma. The plasma samples were deproteinated by using acetonitrile containing 0.1% formic acid as precipitant whereas the chromatographic separation was obtained on a C18 column with 0.1% formic acid aqueous and acetonitrile/methanol (v:v, 1:1) as mobile phase. The mass detector was operated in positive selected reaction monitoring mode...
March 28, 2018: Journal of Pharmaceutical and Biomedical Analysis
Satoshi Yoda, Jessica J Lin, Michael S Lawrence, Benjamin J Burke, Luc Friboulet, Adam Langenbucher, Leila Dardaei, Kylie Prutisto-Chang, Ibiayi Dagogo-Jack, Sergei Timofeevski, Harper Hubbeling, Justin F Gainor, Lorin A Ferris, Amanda K Riley, Krystina E Kattermann, Daria Timonina, Rebecca S Heist, A John Iafrate, Cyril H Benes, Jochen K Lennerz, Mari Mino-Kenudson, Jeffrey A Engelman, Ted W Johnson, Aaron N Hata, Alice T Shaw
The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions, ENU mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations...
April 12, 2018: Cancer Discovery
Chun-Wei Xu, Wen-Xian Wang, Yan-Ping Chen, Yu Chen, Wei Liu, Li-Hua Zhong, Fang-Fang Chen, Wu Zhuang, Zheng-Bo Song, Xiao-Hui Chen, Yun-Jian Huang, Yan-Fang Guan, Xin Yi, Tang-Feng Lv, Wei-Feng Zhu, Jian-Ping Lu, Xiao-Jiang Wang, Yi Shi, Xian-Dong Lin, Gang Chen, Yong Song
BACKGROUND: ALK rearrangement-advanced NSCLC patients respond to crizotinib. ALK rearrangement is currently determined with RT-PCR. VENTANA IHC is a standard method to identify ALK protein overexpression in NSCLC; however, VENTANA IHC has rarely been used to determine the response to crizotinib in Chinese patients with NSCLC and ALK overexpression. To better clarify the clinical implication of VENTANA IHC to detect ALK rearrangements, we conducted this study to analyze VENTANA IHC and RT-PCR in a large cohort of Chinese patients with NSCLC undergoing screening for ALK rearrangements...
April 11, 2018: Journal of Translational Medicine
Jongmin Sim, Hyunjin Kim, Jiyeon Hyeon, Yoon La Choi, Joungho Han
BACKGROUND: Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) are usually effective in lung adenocarcinoma patients with anaplastic lymphoma kinase (ALK) rearrangement. However, even after a good response to ALK-TKI therapy, most patients acquire resistance to these agents. Histological transformation is one of several suggested mechanisms of acquired resistance to ALK-TKIs. The clinicopathologic features of four patients with ALK-expressing adenocarcinoma and neuroendocrine features were analyzed...
April 9, 2018: Journal of Korean Medical Science
Prasanth Ganesan, Thanda Joshua, Shirley Sundersingh, Tenali Gnana Sagar
No abstract text is available yet for this article.
April 2018: Indian Journal of Hematology & Blood Transfusion
Francesca Iommelli, Viviana De Rosa, Cristina Terlizzi, Marcello Monti, Mariarosaria Panico, Rosa Fonti, Silvana Del Vecchio
PURPOSE: Our aim was to test whether imaging with 18 F-fluorothymidine (18 F-FLT) PET/CT was able to detect the combined effects of EGFR and MET inhibitors in oncogene-driven non-small lung cancer (NSCLC) and to elucidate the mechanisms underlying the enhanced efficacy of drug combination. EXPERIMENTAL DESIGN: NSCLC cells bearing MET amplification (H1993 and H820) were treated with EGFR and MET inhibitors either alone or in combination and then tested for cell viability and inhibition of signaling...
April 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Pierre Saintigny, William N William, Jean-Philippe Foy, Vassiliki Papadimitrakopoulou, Wenhua Lang, Li Zhang, You Hong Fan, Lei Feng, Edward S Kim, Adel K El-Naggar, J Jack Lee, Li Mao, Waun Ki Hong, Mark W Lingen, Scott M Lippman
Background: We have previously shown that gene expression profiles of oral leukoplakia (OL) may improve the prediction of oral cancer (OC) risk. To identify new targets for prevention, we performed a systematic survey of transcripts associated with an increased risk of oral cancer and overexpressed in OC vs normal mucosa (NM). Methods: We used gene expression profiles of 86 patients with OL and available outcomes from a chemoprevention trial of OC and NM. MET expression was evaluated using immunohistochemistry in 120 OL patients, and its association with OC development was tested in multivariable analysis...
March 1, 2018: Journal of the National Cancer Institute
Thomas Huang, Brigitte J Engelmann, Rachael M Morgan, Kimberly J Absher, Jill M Kolesar, John L Villano
EML4-ALK alterations are more common in adenocarcinomas and are rarely found in squamous cell histology. In documented cases, the majority of EML4-ALK translocations are identified in squamous cell histology and occur in patients with no or light smoking history. We report an EML4-ALK4 translocation in a 50-year-old patient with squamous cell carcinoma and an 18 pack-year smoking history. The patient had a near complete response in the CNS to alectinib treatment. Our observation suggests that EML4-ALK genomic testing may be clinically useful in patients with heavy smoking history...
April 2, 2018: Cancer Chemotherapy and Pharmacology
Ilirjana Bajrami, Rebecca Marlow, Marieke van de Ven, Rachel Brough, Helen N Pemberton, Jessica Frankum, Feifei Song, Rumana Rafiq, Asha Konde, Dragomir B Krastev, Malini Menon, James Campbell, Aditi Gulati, Rahul Kumar, Stephen J Pettitt, Mark D Gurden, Marta Llorca Cardenosa, Irene Chong, Patrycja Gazinska, Fredrik Wallberg, Elinor J Sawyer, Lesley-Ann Martin, Mitch Dowsett, Spiros Linardopoulos, Rachael Natrajan, Colm J Ryan, Patrick W B Derksen, Jos Jonkers, Andrew N J Tutt, Alan Ashworth, Christopher J Lord
The cell adhesion glycoprotein E-cadherin (CDH1) is commonly inactivated in breast tumors. Precision medicine approaches that exploit this characteristic are not available. Using perturbation screens in breast tumor cells with CRISPR/Cas9-engineered CDH1 mutations, we identified synthetic lethality between E-cadherin deficiency and inhibition of the tyrosine kinase ROS1. Data from large-scale genetic screens in molecularly diverse breast tumor cell lines established that the E-cadherin/ROS1 synthetic lethality was not only robust in the face of considerable molecular heterogeneity but was also elicited with clinical ROS1 inhibitors, including foretinib and crizotinib...
April 2018: Cancer Discovery
Ullas Batra, Mohit Aggarwal, Parveen Jain, Pankaj Goyal, Abhishek Yadav, Udip Maheshwari, Anurag Mehta
Aims: The anaplastic lymphoma kinase (ALK) Break Apart FISH Probe Kit and Ventana anti-ALK (D5F3) CDx immunohistochemistry (IHC) assay are the Food and Drug Administration-approved companion diagnostic for targeted therapy with the ALK inhibitor crizotinib in lung cancers. The aim of this study was to assess the efficacy and safety of twice daily crizotinib tablet (250 mg) in IHC-proven echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene among Indian patients with adenocarcinoma lung in the routine clinical practice...
January 2018: South Asian Journal of Cancer
Yi-Long Wu, James Chih-Hsin Yang, Dong-Wan Kim, Shun Lu, Jianying Zhou, Takashi Seto, Jin-Ji Yang, Noboru Yamamoto, Myung-Ju Ahn, Toshiaki Takahashi, Takeharu Yamanaka, Allison Kemner, Debasish Roychowdhury, Jolanda Paolini, Tiziana Usari, Keith D Wilner, Koichi Goto
Purpose Approximately 1% to 2% of non-small-cell lung cancers (NSCLCs) harbor a c-ros oncogene 1 ( ROS1) rearrangement. Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and MET, has shown marked antitumor activity in a small expansion cohort of patients with ROS1-positive advanced NSCLC from an ongoing phase I study. We assessed the efficacy and safety of crizotinib in the largest cohort of patients with ROS1-positive advanced NSCLC. Patients and Methods This phase II, open-label, single-arm trial enrolled East Asian patients with ROS1-positive (assessed through validated AmoyDx assay [Amoy Diagnostics, Xiamen, China] at three regional laboratories) advanced NSCLC who had received three or fewer lines of prior systemic therapies...
March 29, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Hao Wu, Chao Zeng, Yiwang Ye, Jixian Liu, Zhimin Mu, Yuancai Xie, Baokun Chen, Qiaohong Nong, Da Wu
Exosomes, released from various cell types, serve as vehicles of intercellular communication. Rearranged anaplastic lymphoma kinase (ALK) has been detected in exosomes released from cancer cells in ALK-positive non-small cell lung cancer (NSCLC), however, the functional consequence of ALK in exosomes has not been studied. This study aims to address whether exosomal ALK release is affected by stress, and whether exosomal ALK can modulate survival of recipient cells in vitro and in vivo. Exosomes, isolated from ALK-containing H3122 cells with (Exo-Apo) or without (Exo-Ctrl) irradiation treatment, were transferred to recipient H3122 cells in vitro or mouse xenograft in vivo...
March 29, 2018: Molecular Pharmaceutics
Nikolai Schleussner, Olaf Merkel, Mariantonia Costanza, Huan-Chang Liang, Franziska Hummel, Chiara Romagnani, Pawel Durek, Ioannis Anagnostopoulos, Michael Hummel, Korinna Jöhrens, Antonia Niedobitek, Patrick R Griffin, Roberto Piva, Henrike L Sczakiel, Wilhelm Woessmann, Christine Damm-Welk, Christian Hinze, Dagmar Stoiber, Bernd Gillissen, Suzanne D Turner, Eva Kaergel, Linda von Hoff, Michael Grau, Georg Lenz, Bernd Dörken, Claus Scheidereit, Lukas Kenner, Martin Janz, Stephan Mathas
Transcription factor AP-1 is constitutively activated and IRF4 drives growth and survival in ALK+ and ALK- anaplastic large cell lymphoma (ALCL). Here we demonstrate high-level BATF and BATF3 expression in ALCL. Both BATFs bind classical AP-1 motifs and interact with in ALCL deregulated AP-1 factors. Together with IRF4, they co-occupy AP-1-IRF composite elements, differentiating ALCL from non-ALCL. Gene-specific inactivation of BATFs, or global AP-1 inhibition results in ALCL growth retardation and/or cell death in vitro and in vivo...
March 28, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Yan Li, Tongtong Zhang, Jing Zhang, Wenbin Li, Pei Yuan, Puyuan Xing, Zhou Zhang, Shannon Chuai, Junling Li, Jianming Ying
INTRODUCTION: Anaplastic lymphoma kinase (ALK) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK-rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants. METHODS: Among 96 ALK-rearrangement patients treated with crizotinib, 60 patients were identified with tumor specimens that could be evaluated by next-generation sequencing (NGS)...
April 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Yubo Wang, Li Li, Rui Han, Lin Jiao, Jie Zheng, Yong He
INTRODUCTION: The efficacy of osimertinib was compromised by the development of resistance mechanisms, such as MET amplification. However, cohort studies of osimertinib resistance mechanism, and the correlation of MET and progression-free survival (PFS) after osimertinib resistance have been poorly investigated. OBJECTIVES: This study was carried out to study the acquired MET amplification after osimertinib resistance in advanced lung adenocarcinoma patients, and interrogate the correlation of clinical prognosis and MET amplification...
April 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
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