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https://www.readbyqxmd.com/read/27825636/cabozantinib-in-patients-with-advanced-ret-rearranged-non-small-cell-lung-cancer-an-open-label-single-centre-phase-2-single-arm-trial
#1
Alexander Drilon, Natasha Rekhtman, Maria Arcila, Lu Wang, Andy Ni, Melanie Albano, Martine Van Voorthuysen, Romel Somwar, Roger S Smith, Joseph Montecalvo, Andrew Plodkowski, Michelle S Ginsberg, Gregory J Riely, Charles M Rudin, Marc Ladanyi, Mark G Kris
BACKGROUND: RET rearrangements are found in 1-2% of non-small-cell lung cancers. Cabozantinib is a multikinase inhibitor with activity against RET that produced a 10% overall response in unselected patients with lung cancers. To assess the activity of cabozantinib in patients with RET-rearranged lung cancers, we did a prospective phase 2 trial in this molecular subgroup. METHODS: We enrolled patients in this open-label, Simon two-stage, single-centre, phase 2, single-arm trial in the USA if they met the following criteria: metastatic or unresectable lung cancer harbouring a RET rearrangement, Karnofsky performance status higher than 70, and measurable disease...
November 4, 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27760317/elucidation-of-the-fanconi-anemia-protein-network-in-meiosis-and-its-function-in-the-regulation-of-histone-modifications
#2
Kris G Alavattam, Yasuko Kato, Ho-Su Sin, So Maezawa, Ian J Kowalski, Fan Zhang, Qishen Pang, Paul R Andreassen, Satoshi H Namekawa
Precise epigenetic regulation of the sex chromosomes is vital for the male germline. Here, we analyze meiosis in eight mouse models deficient for various DNA damage response (DDR) factors, including Fanconi anemia (FA) proteins. We reveal a network of FA and DDR proteins in which FA core factors FANCA, FANCB, and FANCC are essential for FANCD2 foci formation, whereas BRCA1 (FANCS), MDC1, and RNF8 are required for BRCA2 (FANCD1) and SLX4 (FANCP) accumulation on the sex chromosomes during meiosis. In addition, FA proteins modulate distinct histone marks on the sex chromosomes: FA core proteins and FANCD2 regulate H3K9 methylation, while FANCD2 and RNF8 function together to regulate H3K4 methylation independently of FA core proteins...
October 18, 2016: Cell Reports
https://www.readbyqxmd.com/read/27740967/kras-mutation-is-a-significant-prognostic-factor-in-early-stage-lung-adenocarcinoma
#3
Kyuichi Kadota, Camelia S Sima, Maria E Arcila, Cyrus Hedvat, Mark G Kris, David R Jones, Prasad S Adusumilli, William D Travis
The potential clinical impact of KRAS and epidermal growth factor receptor (EGFR) mutations has been investigated in lung adenocarcinomas; however, their prognostic value remains controversial. In our study, we sought to investigate the prognostic significance of driver mutations using a large cohort of early-stage lung adenocarcinomas. We reviewed patients with pathologic early-stage, lymph node-negative, solitary lung adenocarcinoma who had undergone surgical resection (1995 to 2005; stage I/II=463/19). Tumors were classified according to the IASLC/ATS/ERS classification and genotyped by Sequenom MassARRAY system and polymerase chain reaction-based assays...
December 2016: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/27707999/a-model-of-somatic-hypermutation-targeting-in-mice-based-on-high-throughput-ig-sequencing-data
#4
Ang Cui, Roberto Di Niro, Jason A Vander Heiden, Adrian W Briggs, Kris Adams, Tamara Gilbert, Kevin C O'Connor, Francois Vigneault, Mark J Shlomchik, Steven H Kleinstein
Analyses of somatic hypermutation (SHM) patterns in B cell Ig sequences have important basic science and clinical applications, but they are often confounded by the intrinsic biases of SHM targeting on specific DNA motifs (i.e., hot and cold spots). Modeling these biases has been hindered by the difficulty in identifying mutated Ig sequences in vivo in the absence of selection pressures, which skew the observed mutation patterns. To generate a large number of unselected mutations, we immunized B1-8 H chain transgenic mice with nitrophenyl to stimulate nitrophenyl-specific λ(+) germinal center B cells and sequenced the unexpressed κ L chains using next-generation methods...
October 5, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27613527/a-phase-1-2-trial-of-ruxolitinib-and-erlotinib-in-patients-with-egfr-mutant-lung-adenocarcinomas-with-acquired-resistance-to-erlotinib
#5
Helena A Yu, Leslie Perez, Qing Chang, Sizhi P Gao, Mark G Kris, Gregory J Riely, Jacqueline Bromberg
INTRODUCTION: Resistance to EGFR tyrosine kinase inhibitors develops in patients with EGFR-mutant lung cancers. New treatments are needed to address resistance not mediated by EGFR T790M; preclinical evidence suggests that the Janus kinase/signal transducers and activators of transcription signaling pathway is important in acquired resistance to EGFR-directed therapy. METHODS: We evaluated the toxicity and efficacy of erlotinib and ruxolitinib in patients with EGFR-mutant lung cancers with acquired resistance to erlotinib...
September 6, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27565914/outcomes-of-chemotherapies-and-her2-directed-therapies-in-advanced-her2-mutant-lung-cancers
#6
Juliana Eng, Meier Hsu, Jamie E Chaft, Mark G Kris, Maria E Arcila, Bob T Li
Human epidermal growth factor receptor 2 (HER2, ERBB2) mutations occur in 3% of lung adenocarcinomas. While case reports and series have shown activity of HER2 targeted agents in these patients, little is known about outcomes of chemotherapies. Patients with stage IV HER2-mutant lung cancers at Memorial Sloan Kettering were reviewed. Patient demographics, types of HER2 mutations, duration of systemic treatments and survival were analyzed. We identified 38 patients with HER2-mutant lung cancers: median age 62; majority were women (n=24), never smokers (n=22), and all had adenocarcinomas...
September 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/27565909/a-phase-i-trial-of-the-hedgehog-inhibitor-sonidegib-lde225-in-combination-with-etoposide-and-cisplatin-for-the-initial-treatment-of-extensive-stage-small-cell-lung-cancer
#7
M Catherine Pietanza, Anya M Litvak, Anna M Varghese, Lee M Krug, Martin Fleisher, Jerrold B Teitcher, Andrei I Holodny, Cami S Sima, Kaitlin M Woo, Kenneth K Ng, Helen H Won, Michael F Berger, Mark G Kris, Charles M Rudin
OBJECTIVES: The Hedgehog pathway has been implicated in small cell lung cancer (SCLC) tumor initiation and progression. Pharmacologic blockade of the key Hedgehog regulator, Smoothened, may inhibit these processes. We performed a phase I study to determine the maximum tolerated dose (MTD) of sonidegib (LDE225), a selective, oral Smoothened antagonist, in combination with etoposide/cisplatin in newly diagnosed patients with extensive stage SCLC. MATERIALS AND METHODS: Patients received 4-6 21-day cycles of etoposide/cisplatin with daily sonidegib...
September 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/27548519/lung-resident-eosinophils-represent-a-distinct-regulatory-eosinophil-subset
#8
Claire Mesnil, Stéfanie Raulier, Geneviève Paulissen, Xue Xiao, Mark A Birrell, Dimitri Pirottin, Thibaut Janss, Philipp Starkl, Eve Ramery, Monique Henket, Florence N Schleich, Marc Radermecker, Kris Thielemans, Laurent Gillet, Marc Thiry, Maria G Belvisi, Renaud Louis, Christophe Desmet, Thomas Marichal, Fabrice Bureau
Increases in eosinophil numbers are associated with infection and allergic diseases, including asthma, but there is also evidence that eosinophils contribute to homeostatic immune processes. In mice, the normal lung contains resident eosinophils (rEos), but their function has not been characterized. Here, we have reported that steady-state pulmonary rEos are IL-5-independent parenchymal Siglec-FintCD62L+CD101lo cells with a ring-shaped nucleus. During house dust mite-induced airway allergy, rEos features remained unchanged, and rEos were accompanied by recruited inflammatory eosinophils (iEos), which were defined as IL-5-dependent peribronchial Siglec-FhiCD62L-CD101hi cells with a segmented nucleus...
September 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27484791/molecular-and-epigenetic-features-of-melanomas-and-tumor-immune-microenvironment-linked-to-durable-remission-to-ipilimumab-based-immunotherapy-in-metastatic-patients
#9
Teofila Seremet, Alexander Koch, Yanina Jansen, Max Schreuer, Sofie Wilgenhof, Véronique Del Marmol, Danielle Liènard, Kris Thielemans, Kelly Schats, Mark Kockx, Wim Van Criekinge, Pierre G Coulie, Tim De Meyer, Nicolas van Baren, Bart Neyns
BACKGROUND: Ipilimumab (Ipi) improves the survival of advanced melanoma patients with an incremental long-term benefit in 10-15 % of patients. A tumor signature that correlates with this survival benefit could help optimizing individualized treatment strategies. METHODS: Freshly frozen melanoma metastases were collected from patients treated with either Ipi alone (n: 7) or Ipi combined with a dendritic cell vaccine (TriMixDC-MEL) (n: 11). Samples were profiled by immunohistochemistry (IHC), whole transcriptome (RNA-seq) and methyl-DNA sequencing (MBD-seq)...
2016: Journal of Translational Medicine
https://www.readbyqxmd.com/read/27432934/reply-to-j-jupp-et-al
#10
Paul J Hesketh, Kari Bohlke, Mark G Kris
No abstract text is available yet for this article.
September 20, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27099321/hiv-1-protease-reverse-transcriptase-and-integrase-variation
#11
Soo-Yon Rhee, Kris Sankaran, Vici Varghese, Mark A Winters, Christopher B Hurt, Joseph J Eron, Neil Parkin, Susan P Holmes, Mark Holodniy, Robert W Shafer
UNLABELLED: HIV-1 protease (PR), reverse transcriptase (RT), and integrase (IN) variability presents a challenge to laboratories performing genotypic resistance testing. This challenge will grow with increased sequencing of samples enriched for proviral DNA such as dried blood spots and increased use of next-generation sequencing (NGS) to detect low-abundance HIV-1 variants. We analyzed PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to characterize variation at each amino acid position, identify mutations indicating APOBEC-mediated G-to-A editing, and identify mutations resulting from selective drug pressure...
July 1, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27045139/evidence-based-policy-making-assessment-of-the-american-heart-association-s-strategic-policy-portfolio-a-policy-statement-from-the-american-heart-association
#12
Darwin R Labarthe, Larry B Goldstein, Elliott M Antman, Donna K Arnett, Gregg C Fonarow, Mark J Alberts, Laura L Hayman, Amit Khera, James F Sallis, Stephen R Daniels, Ralph L Sacco, Suhui Li, Leighton Ku, Paula M Lantz, Jennifer G Robinson, Mark A Creager, Linda Van Horn, Penny Kris-Etherton, Aruni Bhatnagar, Laurie P Whitsel
BACKGROUND: American Heart Association (AHA) public policy advocacy strategies are based on its Strategic Impact Goals. The writing group appraised the evidence behind AHA's policies to determine how well they address the association's 2020 cardiovascular health (CVH) metrics and cardiovascular disease (CVD) management indicators and identified research needed to fill gaps in policy and support further policy development. METHODS AND RESULTS: The AHA policy research department first identified current AHA policies specific to each CVH metric and CVD management indicator and the evidence underlying each policy...
May 3, 2016: Circulation
https://www.readbyqxmd.com/read/26964771/phase-ii-study-of-a-non-platinum-containing-doublet-of-paclitaxel-and-pemetrexed-with-bevacizumab-as-initial-therapy-for-patients-with-advanced-lung-adenocarcinomas
#13
M C Pietanza, Matthew D Hellmann, John J Fiore, Stephanie Smith-Marrone, Ethan M Basch, Lawrence H Schwartz, Michelle S Ginsberg, Marwan Shouery, Samantha K Newman, Mary Shaw, Lauren J Rogak, Alex E Lash, Patrick Hilden, Mark G Kris
INTRODUCTION: Many patients with lung cancers cannot receive platinum-containing regimens owing to comorbid medical conditions. We designed the PPB (paclitaxel, pemetrexed, and bevacizumab) regimen to maintain or improve outcomes while averting the unique toxicities of platinum-based chemotherapies. METHODS: We enrolled patients with untreated, advanced lung adenocarcinomas with measurable disease and no contraindications to bevacizumab. Participants received paclitaxel, 90 mg/m(2), pemetrexed, 500 mg/m(2), and bevacizumab, 10 mg/kg, every 14 days for 6 months and continued to receive pemetrexed and bevacizumab every 14 days until progression or unacceptable toxicity...
June 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/26898325/large-cell-neuroendocrine-carcinoma-of-the-lung-clinico-pathologic-features-treatment-and-outcomes
#14
Jarushka Naidoo, Maria L Santos-Zabala, Tunc Iyriboz, Kaitlin M Woo, Camelia S Sima, John J Fiore, Mark G Kris, Gregory J Riely, Piro Lito, Afsheen Iqbal, Stephen Veach, Stephanie Smith-Marrone, Inderpal S Sarkaria, Lee M Krug, Charles M Rudin, William D Travis, Natasha Rekhtman, Maria C Pietanza
BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) accounts for approximately 3% of lung cancers. Pathologic classification and optimal therapies are debated. We report the clinicopathologic features, treatment and survival of a series of patients with stage IV LCNEC. MATERIALS AND METHODS: Cases of pathologically-confirmed stage IV LCNEC evaluated at Memorial Sloan Kettering Cancer Center from 2006 to 2013 were identified. We collected demographic, treatment, and survival data...
January 21, 2016: Clinical Lung Cancer
https://www.readbyqxmd.com/read/26730601/serum-biomarkers-associated-with-clinical-outcomes-fail-to-predict-brain-metastases-in-patients-with-stage-iv-non-small-cell-lung-cancers
#15
Bob T Li, Emil Lou, Meier Hsu, Helena A Yu, Jarushka Naidoo, Marjorie G Zauderer, Camelia Sima, Melissa L Johnson, Mariza Daras, Lisa M DeAngelis, Martin Fleisher, Mark G Kris, Christopher G Azzoli
BACKGROUND: Lung cancers account for the majority of brain metastases which pose major therapeutic challenges. Biomarkers prognosticating for the development of brain metastases in patients with non-small cell lung cancers (NSCLC) may improve personalized care. Six serum proteomic biomarkers were previously investigated at Memorial Sloan Kettering but their associations with brain metastases were unknown. METHODS: Serum NSE, CYFRA 21-1, ProGRP, SCC-Ag, TIMP1, and HE4 by ELISA-based proteomic assays were prospectively collected from consecutive patients with stage IV NSCLC...
2016: PloS One
https://www.readbyqxmd.com/read/26724474/adaptive-neoadjuvant-chemotherapy-guided-by-18-f-fdg-pet-in-resectable-non-small-cell-lung-cancers-the-neoscan-trial
#16
Jamie E Chaft, Mark Dunphy, Jarushka Naidoo, William D Travis, Matthew Hellmann, Kaitlin Woo, Robert Downey, Valerie Rusch, Michelle S Ginsberg, Christopher G Azzoli, Mark G Kris
INTRODUCTION: Although perioperative chemotherapy improves survival in patients with resectable lung cancers, systemic recurrence remains common. Neoadjuvant chemotherapy permits response assessment and an opportunity to switch treatment regimens. Response measured by fludeoxyglucose ((18)F-FDG) positron emission tomography (PET) correlates with clinical outcomes better than computed tomography (CT) does. This trial assessed PET-measured response rate to alternative chemotherapy in patients with a suboptimal PET response after two cycles of neoadjuvant chemotherapy...
April 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/26723242/her2-amplification-and-her2-mutation-are-distinct-molecular-targets-in-lung-cancers
#17
Bob T Li, Dara S Ross, Dara L Aisner, Jamie E Chaft, Meier Hsu, Severine L Kako, Mark G Kris, Marileila Varella-Garcia, Maria E Arcila
INTRODUCTION: Human epidermal growth factor receptor 2 gene (HER2 [also known as ERBB2]) alterations have been identified as oncogenic drivers and potential therapeutic targets in lung cancers. The molecular associations of HER2 gene amplification, mutation, and HER2 protein overexpression in lung cancers have not been distinctly defined. To explore these associations, Memorial Sloan Kettering Cancer Center and the University of Colorado combined their data on HER2 alterations in lung cancers...
March 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/26695526/role-of-race-in-oncogenic-driver-prevalence-and-outcomes-in-lung-adenocarcinoma-results-from-the-lung-cancer-mutation-consortium
#18
Conor E Steuer, Madhusmita Behera, Lynne Berry, Sungjin Kim, Michael Rossi, Gabriel Sica, Taofeek K Owonikoko, Bruce E Johnson, Mark G Kris, Paul A Bunn, Fadlo R Khuri, Edward B Garon, Suresh S Ramalingam
BACKGROUND: The discovery of oncogenic drivers has ushered in a new era for lung cancer, but the role of these mutations in different racial/ethnic minorities has been understudied. The Lung Cancer Mutation Consortium 1 (LCMC1) database was investigated to evaluate the frequency and impact of oncogenic drivers in lung adenocarcinomas in the racial/ethnic minority patient population. METHODS: Patients with metastatic lung adenocarcinomas from 14 US sites were enrolled in the LCMC1...
March 1, 2016: Cancer
https://www.readbyqxmd.com/read/26673800/a-novel-crizotinib-resistant-solvent-front-mutation-responsive-to-cabozantinib-therapy-in-a-patient-with-ros1-rearranged-lung-cancer
#19
Alexander Drilon, Romel Somwar, Jacob P Wagner, Nadeem A Vellore, Christopher A Eide, Matthew S Zabriskie, Maria E Arcila, Jaclyn F Hechtman, Lu Wang, Roger S Smith, Mark G Kris, Gregory J Riely, Brian J Druker, Thomas O'Hare, Marc Ladanyi, Monika A Davare
PURPOSE: Rearranged ROS1 is a crizotinib-sensitive oncogenic driver in lung cancer. The development of acquired resistance, however, poses a serious clinical challenge. Consequently, experimental and clinical validation of resistance mechanisms and potential second-line therapies is essential. EXPERIMENTAL DESIGN: We report the discovery of a novel, solvent-front ROS1(D2033N) mutation in a patient with CD74-ROS1-rearranged lung adenocarcinoma and acquired resistance to crizotinib...
May 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26644527/symptom-monitoring-with-patient-reported-outcomes-during-routine-cancer-treatment-a-randomized-controlled-trial
#20
RANDOMIZED CONTROLLED TRIAL
Ethan Basch, Allison M Deal, Mark G Kris, Howard I Scher, Clifford A Hudis, Paul Sabbatini, Lauren Rogak, Antonia V Bennett, Amylou C Dueck, Thomas M Atkinson, Joanne F Chou, Dorothy Dulko, Laura Sit, Allison Barz, Paul Novotny, Michael Fruscione, Jeff A Sloan, Deborah Schrag
PURPOSE: There is growing interest to enhance symptom monitoring during routine cancer care using patient-reported outcomes, but evidence of impact on clinical outcomes is limited. METHODS: We randomly assigned patients receiving routine outpatient chemotherapy for advanced solid tumors at Memorial Sloan Kettering Cancer Center to report 12 common symptoms via tablet computers or to receive usual care consisting of symptom monitoring at the discretion of clinicians...
February 20, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
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