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Wenxin Luo, Panwen Tian, Yue Wang, Heng Xu, Lu Chen, Chao Tang, Yang Shu, Shouyue Zhang, Zhoufeng Wang, Jun Zhang, Li Zhang, Lili Jiang, Lunxu Liu, Guowei Che, Chenglin Guo, Hong Zhang, Jiali Wang, Weimin Li
Non-small cell lung cancer (NSCLC) has been recognized as a highly heterogeneous disease with phenotypic and genotypic diversity in each subgroup. While never-smoker patients with NSCLC have been well studied through next generation sequencing, we have yet to recognize the potentially unique molecular features of young never-smoker patients with NSCLC. In this study, we conducted whole genome sequencing (WGS) to characterize the genomic alterations of 36 never-smoker Chinese patients, who were diagnosed with lung adenocarcinoma (LUAD) at 45 years or younger...
April 18, 2018: International Journal of Cancer. Journal International du Cancer
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
Zahra Fathi, Nicholas L Syn, Jian-Guo Zhou, Raheleh Roudi
Epidemiological studies undertaken over the past decades reveal a gradual but progressive increase in the incidence and mortality attributable to lung cancer in the Islamic Republic of Iran, a sovereign state geographically situated at the crossroads of Central Eurasia and Western Asia. We identified references published in English and Persian through searches of PubMed, EMBASE, Web of Science, Scopus, and the Scientific Information Database (SID)-a specialized Iranian database, which indexes Iranian scientific journals-between inception and 15 September 2017...
April 18, 2018: Journal of Human Genetics
John Conibear, Brendan Chia, Yenting Ngai, Andrew Tom Bates, Nicholas Counsell, Rushil Patel, David Eaton, Corinne Faivre-Finn, John Fenwick, Martin Forster, Gerard G Hanna, Susan Harden, Philip Mayles, Syed Moinuddin, David Landau
INTRODUCTION: Following growing evidence to support the safety, local control (LC) and potential improvement in overall survival (OS) in patients with oligometastatic non-small cell lung cancer (NSCLC) that have been treated with local ablative therapy such as stereotactic ablative radiotherapy (SABR) and stereotactic radiosurgery (SRS), we initiate the SARON trial to investigate the impact and feasibility of adding SABR/SRS and radical radiotherapy (RRT) following standard chemotherapy on OS...
April 17, 2018: BMJ Open
Meyyappa Devan Rajagopal, Debasis Gochhait, Bheemanathi Hanuman Srinivas, Rajesh Nachiappa Ganesh, Neelaiah Siddaraju, Manju Rajaram
Primary pulmonary lymphoma is defined as clonal lymphoid proliferation affecting one or both lungs in a patient with no extrapulmonary involvement at the time of diagnosis or during the subsequent 3 months. Anaplastic large cell lymphoma (ALCL) is a rare T-cell neoplasm which occurs as two distinct clinical entities-cutaneous and systemic variant. Primary lung involvement is extremely uncommon. It can be classified on the basis of being positive or negative for ALK rearrangement which carries prognostic significance...
April 16, 2018: Diagnostic Cytopathology
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
María Verzura, Emilio Batagelj, Claudia Bagnes, Claudio Martin, Diego Enrico, Eduardo Richardet, Paola De la Iglesia
INTRODUCTION: Identification of EML4-ALK rearrangement by FISH test has become standard in advanced NSCLC patients. There is limited information about the prevalence and clinical characteristics of ALK translocation in Latin America. The aim of our study was to evaluate this lung cancer subtype features in Argentinian patients and the factibility of FISH test with different methods used for obtaining tissue samples. METHODS: Between August 2014 and February 2017, 183 non-squamous NSCLC patients were prospectively enrolled from five Argentinian institutions...
February 26, 2018: Annals of Diagnostic Pathology
Chelsea E Powell, Yang Gao, Li Tan, Katherine A Donovan, Radosław P Nowak, Amanda Loehr, Magda Bahcall, Eric S Fischer, Pasi A Janne, Rani E George, Nathanael S Gray
We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1)...
April 16, 2018: Journal of Medicinal Chemistry
H Wang, J Agulnik, G Kasymjanova, A Wang, V Cohen, D Small, C Pepe, L Sakr, P Fiset, M Auger, S Camilleri-Broet, M Alam El Din, G Chong, L van Kempen, A Spatz
Background: PD-L1 immunohistochemistry (IHC) testing is usually performed on tissue blocks from core needle biopsy or surgical resections. In this study, we assessed the feasibility of using cytology cell blocks for PD-L1 IHC assay. Methods: A total of 1419 consecutive cases of non-small cell lung cancer (NSCLC), including 371 cytology cell blocks, 809 small biopsies, and 239 surgical specimens, were included in the study. The cytology cell blocks were prepared with formalin only, methanol/alcohol only or both...
April 12, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Leena Gandhi, Delvys Rodríguez-Abreu, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Flávia De Angelis, Manuel Domine, Philip Clingan, Maximilian J Hochmair, Steven F Powell, Susanna Y-S Cheng, Helge G Bischoff, Nir Peled, Francesco Grossi, Ross R Jennens, Martin Reck, Rina Hui, Edward B Garon, Michael Boyer, Belén Rubio-Viqueira, Silvia Novello, Takayasu Kurata, Jhanelle E Gray, John Vida, Ziwen Wei, Jing Yang, Harry Raftopoulos, M Catherine Pietanza, Marina C Garassino
Background First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. Methods In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy...
April 16, 2018: New England Journal of Medicine
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
Daichi Fujimoto, Hiroshige Yoshioka, Yuki Kataoka, Takeshi Morimoto, Young Hak Kim, Keisuke Tomii, Tadashi Ishida, Masataka Hirabayashi, Satoshi Hara, Manabu Ishitoko, Yasushi Fukuda, Moon Hee Hwang, Naoki Sakai, Motonari Fukui, Hitoshi Nakaji, Mitsunori Morita, Tadashi Mio, Takehiro Yasuda, Takakazu Sugita, Toyohiro Hirai
INTRODUCTION: Nivolumab has been shown to be effective and safe in previously treated patients with advanced non-small cell lung cancer (NSCLC). However, little is known regarding its performance in real-world (i.e., non-trial) settings. Furthermore, nivolumab efficacy is unknown in patients who are ineligible for clinical trials or who are categorized into small subgroups in such trials. METHODS: We conducted a 15-center, observational, retrospective cohort study of patients with advanced NSCLC who received nivolumab monotherapy between January and December 2016...
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
Bryan D Choi, Ganesh M Shankar, Ahilan Sivaganesan, Laura A Van Beaver, Kevin Oh, John H Shin
STUDY DESIGN: A retrospective cohort study. OBJECTIVE: We performed a retrospective study of patients treated at our institution over the last 7 years to ascertain whether gene expression signatures in patients with advanced metastatic disease are associated with survival, when the disease has progressed to the spine. SUMMARY OF BACKGROUND DATA: Spinal metastases are a major cause of morbidity in patients with cancer. Molecular profiling strategies to characterize lung cancer have identified several genetic biomarkers that may lead to more effective prognostication...
April 12, 2018: Spine
Nicolas Foos, Carolin Seuring, Robin Schubert, Anja Burkhardt, Olof Svensson, Alke Meents, Henry N Chapman, Max H Nanao
Specific radiation damage can be used to determine phases de novo from macromolecular crystals. This method is known as radiation-damage-induced phasing (RIP). One limitation of the method is that the dose of individual data sets must be minimized, which in turn leads to data sets with low multiplicity. A solution to this problem is to use data from multiple crystals. However, the resulting signal can be degraded by a lack of isomorphism between crystals. Here, it is shown that serial synchrotron crystallography in combination with selective merging of data sets can be used to determine high-quality phases for insulin and thaumatin, and that the increased multiplicity can greatly enhance the success rate of the experiment...
April 1, 2018: Acta Crystallographica. Section D, Structural Biology
Xianyong Jiang, Daobin Zhou
No abstract text is available yet for this article.
April 12, 2018: Blood
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
Konstantinos Syrigos, Oraianthi Fiste, Andriani Charpidou, Dimitra Grapsa
The presence of circulating tumor cells (CTCs) in the peripheral blood of cancer patients was first described in the second half of the 19th century, but research interest in their potential clinical utility has intensified and greatly expanded only in recent years. Herein, we summarize and critically discuss current knowledge on CTC count as a predictor of survival in lung cancer, and comment on the existing challenges and future perspectives in this field. The majority of data published to date, including the results of almost all large cohorts, are strongly supportive of the value of CTC enumeration as a predictor of survival, mainly in advanced/metastatic non-small and small cell lung cancer (NSCLC and SCLC, respectively)...
May 2018: Critical Reviews in Oncology/hematology
Chaohong Chen, Zhifeng He, Deyao Xie, Liangcheng Zheng, Tianhao Zhao, Xinbo Zhang, Dezhi Cheng
Anaplastic lymphoma kinase (ALK) has been regarded as an essential target for the treatment of non-small cell lung cancer (NSCLC). However, the emergence of G1202R solvent front mutation that confer resistance to the drugs were reported for the first as well as the second generation ALK inhibitors. It was supposed that the G1202R solvent front mutation might hinder the drug binding. In this study, a different fact could be clarified by multiple molecular modeling methodologies through a structural analogue of ceritinib (compound 10, Cpd-10) that is reported to be a potent inhibitor against the G1202R mutation...
April 12, 2018: Journal of Physical Chemistry. B
Anna W LaVigne, David M Meredith, David R D'Adamo, Danielle N Margalit
We present a challenging case of a previously healthy 23-year-old man who developed an inflammatory myofibroblastic tumour of the hard palate, harbouring a rearrangement of the anaplastic lymphoma kinase (ALK) locus. Despite surgical intervention, radiotherapy and ALK-inhibition therapy, the tumour recurred locally and metastasised to regional lymph nodes, and the patient passed away roughly 9 months after diagnosis from local progression. The rapid progression of this patient's disease and its resistance to treatment demonstrate the potentially aggressive clinical course of inflammatory myofibroblastic tumours...
April 11, 2018: BMJ Case Reports
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