Annotated high citation abstracts

11879110

Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution.
C Arden Pope, Richard T Burnett, Michael J Thun, Eugenia E Calle, Daniel Krewski, Kazuhiko Ito, George D Thurston
(Department of Economics, Brigham Young University, 142 FOB, Provo, UT 84602, USA. cap3@email.byu.edu)
JAMA

associations have_been found between day-to-day particulate_air pollution and increased_risk of various adverse health outcomes including cardiopulmonary mortality however studies of health effects of long-term particulate_air pollution have_been less conclusive to assess the relationship_between long-term exposure to fine_particulate air_pollution and all-cause lung cancer and cardiopulmonary mortality vital_status and cause of death data were collected by the american cancer society as part of the cancer prevention ii study an ongoing_prospective mortality study which enrolled approximately_million adults in participants_completed questionnaire detailing individual risk factor data age_sex race weight height smoking_history education marital_status diet alcohol_consumption and occupational_exposures the risk factor data for approximately adults were linked with air_pollution data for metropolitan_areas throughout the united_states and combined with vital_status and cause of death data through_december all-cause lung cancer and cardiopulmonary mortality fine_particulate and sulfur oxide--related pollution were associated with all-cause lung cancer and cardiopulmonary mortality each 10-microg/m elevation in fine_particulate air_pollution was associated with approximately and increased_risk of all-cause cardiopulmonary and lung cancer mortality respectively measures of coarse particle fraction and total_suspended particles were not consistently associated with mortality long-term exposure to combustion-related fine_particulate air_pollution is an_important environmental risk factor for cardiopulmonary and

11784875

Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
Joan H Schiller, David Harrington, Chandra P Belani, Corey Langer, Alan Sandler, James Krook, Junming Zhu, David H Johnson
(University of Wisconsin Hospital and Clinics, Madison, USA.)
N. Engl. J. Med.

we_conducted randomized study to determine_whether any of three chemotherapy_regimens was superior to cisplatin and paclitaxel in patients with advanced_non-small-cell lung cancer total of patients with advanced_non-small-cell lung cancer were randomly_assigned to reference regimen of cisplatin and paclitaxel or to one of three experimental regimens cisplatin and gemcitabine cisplatin and docetaxel or carboplatin and paclitaxel the response_rate for all eligible patients was percent with median_survival of months percent_confidence interval to 1-year_survival rate of percent_percent confidence_interval to percent and 2-year_survival rate of percent_percent confidence_interval to percent the response_rate and survival did_not differ_significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the three experimental regimens treatment with cisplatin and gemcitabine was associated with significantly_longer time to the progression of disease than was treatment with cisplatin and paclitaxel but was more_likely to cause grade or renal toxicity in percent of patients vs percent of those treated with cisplatin_plus paclitaxel patients with performance_status of had significantly_lower rate of survival than did those with performance_status of or none of four chemotherapy_regimens offered significant advantage_over the others in the treatment of advanced_non-small-cell lung cancer

12748244

Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected].
Masahiro Fukuoka, Seiji Yano, Giuseppe Giaccone, Tomohide Tamura, Kazuhiko Nakagawa, Jean-Yves Douillard, Yutaka Nishiwaki, Johan Vansteenkiste, Shinzoh Kudoh, Danny Rischin, Richard Eek, Takeshi Hora ...
(Fourth Department of Internal Medicine, Kinki University School of Medicine, 377-2 Ohnohigashi Osakasayama, Osaka 589, Japan. mfukuoka@med.kindai.ac.jp)
J. Clin. Oncol.

to evaluate the efficacy and tolerability of two doses of gefitinib_iressa zd1839_astrazeneca wilmington_de novel epidermal_growth factor_receptor tyrosine_kinase inhibitor in patients with pretreated advanced_non-small-cell lung cancer nsclc this was randomized_double-blind parallel-group multicenter_phase ii_trial two_hundred ten patients with advanced_nsclc who were previously_treated with one or two chemotherapy_regimens at_least one containing platinum were randomly_assigned to receive_either 250-mg or 500-mg oral doses of gefitinib once_daily efficacy was similar for the and 500-mg/d groups objective tumor response_rates were confidence_interval ci to and ci to among evaluable patients symptom_improvement rates were ci to and ci to median_progression-free survival times were and months and median overall_survival times were and months respectively symptom improvements were recorded for mg/d and mg/d of patients with tumor response adverse_events aes at both dose levels were generally_mild grade or and consisted_mainly of skin_reactions and diarrhea drug-related_toxicities were more_frequent in the higher-dose_group withdrawal due to drug-related aes was and for patients receiving gefitinib and mg/d respectively gefitinib showed clinically_meaningful antitumor_activity and provided symptom_relief as second and third-line_treatment in these patients at mg/d gefitinib had favorable ae profile gefitinib_mg/d is an_important novel treatment_option for patients with pretreated

15329413

EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.
William Pao, Vincent Miller, Maureen Zakowski, Jennifer Doherty, Katerina Politi, Inderpal Sarkaria, Bhuvanesh Singh, Robert Heelan, Valerie Rusch, Lucinda Fulton, Elaine Mardis, Doris Kupfer, Richard ...
(Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. paow@mskcc.org)
Proc. Natl. Acad. Sci. U.S.A.

somatic_mutations in the tyrosine_kinase tk_domain of the epidermal_growth factor_receptor egfr gene are reportedly associated with sensitivity of lung cancers to gefitinib_iressa kinase_inhibitor in-frame_deletions occur in exon whereas point_mutations occur_frequently in codon exon we found from sequencing the egfr_tk domain that of gefitinib-sensitive tumors had similar types of alterations no mutations were found in eight gefitinib-refractory tumors five of seven tumors sensitive to erlotinib_tarceva related kinase_inhibitor for which the clinically_relevant target is undocumented had analogous somatic_mutations as_opposed to none of erlotinib-refractory tumors because most mutation-positive tumors were adenocarcinomas from patients who_smoked cigarettes in lifetime_never smokers we screened egfr_exons 2-28 in adenocarcinomas resected from untreated never_smokers seven tumors had tk_domain mutations in contrast to of non-small_cell lung cancers resected from untreated former or current_smokers immunoblotting of lysates from cells transiently_transfected with various egfr constructs demonstrated that compared to wild-type protein an exon_deletion mutant induced diminished levels of phosphotyrosine whereas the phosphorylation at tyrosine of an exon point mutant was inhibited at 10-fold_lower concentrations of drug collectively_these data show_that adenocarcinomas from never_smokers comprise distinct_subset of lung cancers frequently containing mutations within the tk_domain of egfr that are associated with gefitinib and erlotinib sensitivity

15210113

Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis.
Jing Yang, Sendurai A Mani, Joana Liu Donaher, Sridhar Ramaswamy, Raphael A Itzykson, Christophe Come, Pierre Savagner, Inna Gitelman, Andrea Richardson, Robert A Weinberg
(Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.)
Cell

metastasis is multistep_process during which cancer cells disseminate from the site of primary tumors and establish secondary tumors in distant_organs in search for key_regulators of metastasis in murine breast tumor model we have found that the transcription_factor twist master_regulator of embryonic morphogenesis plays_an essential_role in metastasis suppression of twist expression in highly_metastatic mammary_carcinoma cells specifically_inhibits their_ability to metastasize from the mammary_gland to the lung ectopic_expression of twist results in loss of e-cadherin-mediated cell-cell_adhesion activation of mesenchymal_markers and induction of cell_motility suggesting_that twist contributes to metastasis by promoting an epithelial-mesenchymal_transition emt in human breast cancers high level of twist expression is correlated with invasive lobular carcinoma highly infiltrating tumor type associated with loss of e-cadherin expression these_results establish mechanistic_link between twist emt and tumor metastasis

15118073

Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.
Thomas J Lynch, Daphne W Bell, Raffaella Sordella, Sarada Gurubhagavatula, Ross A Okimoto, Brian W Brannigan, Patricia L Harris, Sara M Haserlat, Jeffrey G Supko, Frank G Haluska, David N Louis, David ...
(Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston 02129, USA.)
N. Engl. J. Med.

most patients with non-small-cell_lung cancer have no response to the tyrosine_kinase inhibitor gefitinib which targets the epidermal_growth factor_receptor egfr however about percent of patients have rapid and often dramatic clinical response the molecular_mechanisms underlying sensitivity to gefitinib are unknown we_searched for mutations in the egfr gene in primary tumors from patients with non-small-cell_lung cancer who_had response to gefitinib those_who did_not have response and those_who had not been exposed to gefitinib the functional_consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells somatic_mutations were identified in the tyrosine_kinase domain of the egfr gene in eight of nine patients with gefitinib-responsive lung cancer as compared with none of the seven patients with no response mutations were either small in-frame_deletions or amino_acid substitutions clustered_around the atp-binding pocket of the tyrosine_kinase domain similar mutations were detected in tumors from of patients with primary non-small-cell_lung cancer who_had not been exposed to gefitinib percent all mutations were heterozygous and identical mutations were observed in multiple patients suggesting an additive specific gain of function in vitro egfr_mutants demonstrated enhanced tyrosine_kinase activity in response to epidermal_growth factor and increased sensitivity to inhibition by gefitinib subgroup of patients with non-small-cell_lung cancer have specific mutations in the egfr gene which correlate with clinical responsiveness to the tyrosine_kinase inhibitor gefitinib these mutations lead to increased growth_factor signaling and confer_susceptibility to the inhibitor screening for such mutations in lung cancers may identify patients who will have response to

16014882

Erlotinib in previously treated non-small-cell lung cancer.
Frances A Shepherd, José Rodrigues Pereira, Tudor Ciuleanu, Eng Huat Tan, Vera Hirsh, Sumitra Thongprasert, Daniel Campos, Savitree Maoleekoonpiroj, Michael Smylie, Renato Martins, Maximiliano van Koo ...
(Department of Medical Oncology, University Health Network, Princess Margaret Hospital Site, University of Toronto, Canada.)
N. Engl. J. Med.

we_conducted randomized_placebo-controlled double-blind_trial to determine_whether the epidermal_growth factor_receptor inhibitor erlotinib prolongs_survival in non-small-cell_lung cancer after the failure of first-line or second-line_chemotherapy patients with stage_iiib or iv non-small-cell_lung cancer with performance_status from to were eligible_if they had received one or two prior chemotherapy_regimens the patients were stratified_according to center performance_status response to prior chemotherapy number of prior regimens and prior_platinum-based therapy and were randomly_assigned in ratio to receive oral erlotinib at dose of mg_daily or placebo the median_age of the patients who_underwent randomization was years percent had received two prior chemotherapy_regimens and percent had received platinum-based_chemotherapy the response_rate was percent in the erlotinib group and less_than percent in the placebo_group the median_duration of the response was months and months respectively progression-free_survival was months and months respectively hazard_ratio adjusted for stratification categories overall_survival was months and months respectively hazard_ratio in favor of erlotinib five percent of patients discontinued erlotinib because of toxic_effects erlotinib can_prolong survival in patients with non-small-cell_lung cancer after first-line or second-line_chemotherapy

16199517

Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
Aravind Subramanian, Pablo Tamayo, Vamsi K Mootha, Sayan Mukherjee, Benjamin L Ebert, Michael A Gillette, Amanda Paulovich, Scott L Pomeroy, Todd R Golub, Eric S Lander, Jill P Mesirov
(Broad Institute of Massachusetts Institute of Technology and Harvard, 320 Charles Street, Cambridge, MA 02141, USA.)
Proc. Natl. Acad. Sci. U.S.A.

although genomewide rna expression analysis has_become routine tool in biomedical_research extracting biological insight from such information remains major_challenge here_we describe powerful analytical_method called gene set_enrichment analysis_gsea for interpreting gene expression data the method derives its power by focusing_on gene sets that is groups of genes that share_common biological function chromosomal location or regulation we demonstrate how gsea yields insights_into several cancer-related data_sets including leukemia and lung cancer notably where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer gsea reveals many biological pathways in common the gsea method is embodied in freely_available software_package together with an initial database of biologically defined gene sets

15728811

EGFR mutation and resistance of non-small-cell lung cancer to gefitinib.
Susumu Kobayashi, Titus J Boggon, Tajhal Dayaram, Pasi A Jänne, Olivier Kocher, Matthew Meyerson, Bruce E Johnson, Michael J Eck, Daniel G Tenen, Balázs Halmos
(Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.)
N. Engl. J. Med.

mutations of the epidermal_growth factor_receptor egfr gene have_been identified in specimens from patients with non-small-cell_lung cancer who have response to anilinoquinazoline egfr inhibitors despite the dramatic_responses to such inhibitors most patients ultimately have relapse the mechanism of the drug_resistance is unknown here_we report the case of patient with egfr-mutant gefitinib-responsive advanced_non-small-cell lung cancer who_had relapse after two years of complete_remission during treatment with gefitinib the dna sequence of the egfr gene in his tumor biopsy_specimen at relapse revealed the presence of second point_mutation resulting in threonine-to-methionine amino_acid change at position of egfr structural modeling and biochemical studies showed that this second mutation led to gefitinib resistance

15766527

RAS is regulated by the let-7 microRNA family.
Steven M Johnson, Helge Grosshans, Jaclyn Shingara, Mike Byrom, Rich Jarvis, Angie Cheng, Emmanuel Labourier, Kristy L Reinert, David Brown, Frank J Slack
(Department of Molecular, Cellular and Developmental Biology, Yale University, P.O. Box 208103, New Haven, CT 06520, USA.)
Cell

micrornas_mirnas are regulatory_rnas found in multicellular eukaryotes including humans where_they are implicated in cancer the let-7_mirna times seam cell terminal_differentiation in elegans here_we show_that the let-7_family negatively_regulates let-60/ras loss of let-60/ras suppresses let-7 and the let-60/ras utr contains multiple let-7 complementary sites lcss restricting reporter_gene expression in let-7-dependent manner mir-84 let-7_family member is largely absent in vulval precursor cell p6 at the time that let-60/ras specifies the degrees vulval fate in that cell and mir-84 overexpression suppresses the multivulva phenotype of activating let-60/ras mutations the utrs of the human ras genes contain multiple lcss allowing let-7 to regulate ras expression let-7 expression is lower in lung tumors than in normal lung tissue while ras protein is significantly_higher in

17167137

Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.
Alan Sandler, Robert Gray, Michael C Perry, Julie Brahmer, Joan H Schiller, Afshin Dowlati, Rogerio Lilenbaum, David H Johnson
(Vanderbilt University, Nashville, TN, USA. sandler@vanderbilt.edu)
N. Engl. J. Med.

bevacizumab_monoclonal antibody_against vascular_endothelial growth_factor has_been shown to benefit patients with variety of cancers between_july and april the eastern_cooperative oncology_group ecog conducted randomized study in which patients with recurrent or advanced_non-small-cell lung cancer stage_iiib or iv were assigned to chemotherapy with paclitaxel and carboplatin alone or paclitaxel and carboplatin_plus bevacizumab chemotherapy was administered_every weeks for six_cycles and bevacizumab was administered_every weeks until disease_progression was evident or toxic_effects were intolerable patients with squamous-cell tumors brain_metastases clinically significant hemoptysis or inadequate organ_function or performance_status ecog_performance status were excluded the primary_end point was overall_survival the median_survival was months in the group assigned to chemotherapy plus_bevacizumab as compared with months in the chemotherapy-alone group hazard_ratio for death the median_progression-free survival in the two_groups was and months respectively hazard_ratio for disease_progression with corresponding response_rates of and rates of clinically significant bleeding were and respectively there were treatment-related_deaths in the chemotherapy-plus-bevacizumab group including from pulmonary_hemorrhage the addition of bevacizumab to paclitaxel_plus carboplatin in the treatment of selected patients with non-small-cell_lung cancer has significant survival benefit with the risk of increased treatment-related_deaths clinicaltrials_gov

17625570

Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
Manabu Soda, Young Lim Choi, Munehiro Enomoto, Shuji Takada, Yoshihiro Yamashita, Shunpei Ishikawa, Shin-ichiro Fujiwara, Hideki Watanabe, Kentaro Kurashina, Hisashi Hatanaka, Masashi Bando, Shoji Ohn ...
(Division of Functional Genomics, Jichi Medical University, Tochigi 329-0498, Japan.)
Nature

improvement in the clinical_outcome of lung cancer is likely to be achieved by identification of the molecular_events that underlie its pathogenesis here_we show_that small inversion within chromosome_2p results in the formation of fusion_gene comprising portions of the echinoderm_microtubule-associated protein-like_eml4 gene and the anaplastic_lymphoma kinase_alk gene in non-small-cell_lung cancer nsclc cells mouse 3t3_fibroblasts forced to express this human fusion tyrosine_kinase generated transformed foci in culture and subcutaneous tumours in nude_mice the eml4-alk_fusion transcript was detected in out of of nsclc patients examined these individuals were distinct from those harbouring mutations in the epidermal_growth factor_receptor gene our_data demonstrate_that subset of nsclc patients may express transforming fusion kinase that is promising_candidate for therapeutic_target as_well as for diagnostic molecular marker in nsclc

17463250

MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.
Jeffrey A Engelman, Kreshnik Zejnullahu, Tetsuya Mitsudomi, Youngchul Song, Courtney Hyland, Joon Oh Park, Neal Lindeman, Christopher-Michael Gale, Xiaojun Zhao, James Christensen, Takayuki Kosaka, Al ...
(Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.)
Science

the epidermal_growth factor_receptor egfr kinase_inhibitors gefitinib and erlotinib are effective treatments for lung cancers with egfr activating_mutations but these tumors invariably_develop drug_resistance here_we describe gefitinib-sensitive lung cancer cell_line that developed resistance to gefitinib as result of focal_amplification of the met_proto-oncogene inhibition of met signaling in these cells restored their sensitivity to gefitinib met_amplification was detected in of lung cancer specimens that had developed resistance to gefitinib or erlotinib we find that amplification of met causes gefitinib resistance by driving erbb3 her3 dependent activation of pi3k_pathway thought to be specific to egfr/erbb family receptors thus we_propose that met_amplification may promote drug_resistance in other erbb-driven

19692680

Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.
Tony S Mok, Yi-Long Wu, Sumitra Thongprasert, Chih-Hsin Yang, Da-Tong Chu, Nagahiro Saijo, Patrapim Sunpaweravong, Baohui Han, Benjamin Margono, Yukito Ichinose, Yutaka Nishiwaki, Yuichiro Ohe, Jin-Ji ...
(State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong. tony@clo.cuhk.edu.hk)
N. Engl. J. Med.

previous uncontrolled studies have suggested_that first-line_treatment with gefitinib would_be efficacious in selected patients with non-small-cell_lung cancer in this phase open-label study we randomly_assigned previously_untreated patients in east_asia who_had advanced pulmonary adenocarcinoma and who were nonsmokers or former light_smokers to receive gefitinib_mg per_day patients or carboplatin at dose calculated to produce an area_under the curve of or mg_per milliliter per_minute plus_paclitaxel mg_per square_meter of body-surface_area patients the primary_end point was progression-free_survival the 12-month rates of progression-free_survival were with gefitinib and with carboplatin-paclitaxel the study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority as compared with carboplatin-paclitaxel with respect to progression-free_survival in the intention-to-treat_population hazard_ratio for progression or death confidence_interval ci to in the subgroup of patients who were positive for the epidermal_growth factor_receptor gene egfr_mutation progression-free_survival was significantly_longer among those_who received gefitinib than among those_who received carboplatin-paclitaxel hazard_ratio for progression or death ci to whereas in the subgroup of patients who were negative for the mutation progression-free_survival was significantly_longer among those_who received carboplatin-paclitaxel hazard_ratio for progression or death with gefitinib ci to the most_common adverse_events were rash or acne in of patients and diarrhea in the gefitinib group and neurotoxic effects neutropenia and alopecia in the carboplatin-paclitaxel group gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among_nonsmokers or former light_smokers in east_asia the presence in the tumor of mutation of the egfr gene is strong_predictor of better outcome with gefitinib clinicaltrials_gov

20573926

Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.
Makoto Maemondo, Akira Inoue, Kunihiko Kobayashi, Shunichi Sugawara, Satoshi Oizumi, Hiroshi Isobe, Akihiko Gemma, Masao Harada, Hirohisa Yoshizawa, Ichiro Kinoshita, Yuka Fujita, Shoji Okinaga, Harut ...
(Miyagi Cancer Center, Miyagi, Japan.)
N. Engl. J. Med.

non-small-cell_lung cancer with sensitive mutations of the epidermal_growth factor_receptor egfr is highly_responsive to egfr_tyrosine kinase_inhibitors such_as gefitinib but little is known_about how its efficacy and safety_profile compares with that of standard chemotherapy we randomly_assigned patients with metastatic non-small-cell_lung cancer and egfr_mutations who_had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel the primary_end point was progression-free_survival secondary_end points_included overall_survival response_rate and toxic_effects in the planned_interim analysis of data for the first patients progression-free_survival was significantly_longer in the gefitinib group than in the standard-chemotherapy group hazard_ratio for death or disease_progression with gefitinib resulting in early_termination of the study the gefitinib group had significantly_longer median_progression-free survival months vs months in the chemotherapy group hazard_ratio confidence_interval to as_well as higher response_rate vs the median overall_survival was months in the gefitinib group and months in the chemotherapy group the most_common adverse_events in the gefitinib group were rash and elevated aminotransferase levels and in the chemotherapy group neutropenia_anemia appetite_loss and sensory_neuropathy one_patient receiving gefitinib died from interstitial lung disease first-line gefitinib for patients with advanced_non-small-cell lung cancer who were selected on the basis of egfr_mutations improved progression-free_survival with acceptable_toxicity as compared with standard chemotherapy umin-ctr

20979469

Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
Eunice L Kwak, Yung-Jue Bang, D Ross Camidge, Alice T Shaw, Benjamin Solomon, Robert G Maki, Sai-Hong I Ou, Bruce J Dezube, Pasi A Jänne, Daniel B Costa, Marileila Varella-Garcia, Woo-Ho Kim, Thomas J ...
(Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. ekwak@partners.org)
N. Engl. J. Med.

oncogenic fusion_genes consisting of eml4 and anaplastic_lymphoma kinase_alk are present in subgroup of non-small-cell_lung cancers representing to of such tumors we explored the therapeutic_efficacy of inhibiting alk in such tumors in an early-phase_clinical trial of crizotinib_pf-02341066 an orally_available small-molecule_inhibitor of the alk tyrosine_kinase after screening tumor samples from approximately patients with non-small-cell_lung cancer for the presence of alk_rearrangements we identified patients with advanced_alk-positive disease who were eligible for the clinical_trial most of the patients had received previous treatment these patients were enrolled in an expanded cohort study instituted after phase dose_escalation had established recommended crizotinib dose of mg_twice daily in 28-day_cycles patients were assessed for adverse_events and response to therapy patients with alk_rearrangements tended to be younger_than those without the rearrangements and most of the patients had little or no exposure to tobacco and had adenocarcinomas at mean treatment duration of months the overall response_rate was of patients with confirmed partial_responses and confirmed complete_response patients had_stable disease total of of patients were continuing to receive crizotinib at the time of data cutoff and the estimated probability of 6-month_progression-free survival was with no median for the study reached the drug resulted in grade or mild gastrointestinal side_effects the inhibition of alk in lung tumors with the alk_rearrangement resulted in tumor_shrinkage or stable_disease in most patients funded_by pfizer and others_clinicaltrials gov_number

22658128

Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
Julie R Brahmer, Scott S Tykodi, Laura Q M Chow, Wen-Jen Hwu, Suzanne L Topalian, Patrick Hwu, Charles G Drake, Luis H Camacho, John Kauh, Kunle Odunsi, Henry C Pitot, Omid Hamid, Shailender Bhatia, R ...
(Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA.)
N. Engl. J. Med.

programmed death pd-1 protein t-cell coinhibitory receptor and one of its ligands pd-l1 play_pivotal role in the ability of tumor cells to evade the host_immune system blockade of interactions_between pd-1 and pd-l1 enhances immune_function in vitro and mediates antitumor_activity in preclinical_models in this multicenter_phase trial we administered intravenous anti-pd-l1 antibody at escalating_doses ranging_from to mg_per kilogram of body_weight to patients with selected advanced cancers anti-pd-l1 antibody was administered_every days in 6-week_cycles for up to cycles or until the patient had complete_response or confirmed disease_progression as of february total of patients--75 with non-small-cell_lung cancer with melanoma with colorectal cancer with renal-cell cancer with ovarian cancer with pancreatic cancer with gastric cancer and with breast cancer--had received anti-pd-l1 antibody the median_duration of therapy was weeks range to grade or toxic_effects that investigators considered to be related to treatment occurred in of patients among patients with response that could_be evaluated an objective_response complete or partial_response was observed in of patients with melanoma of with renal-cell cancer of with non-small-cell_lung cancer and of with ovarian cancer responses lasted for year or more in of patients with at_least year of follow-up antibody-mediated blockade of pd-l1 induced durable tumor regression objective_response rate of to and prolonged stabilization of disease rates of to at weeks in patients with advanced cancers including non-small-cell_lung cancer melanoma and renal-cell cancer funded_by

22658127

Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Suzanne L Topalian, F Stephen Hodi, Julie R Brahmer, Scott N Gettinger, David C Smith, David F McDermott, John D Powderly, Richard D Carvajal, Jeffrey A Sosman, Michael B Atkins, Philip D Leming, Davi ...
(Department of Surgery, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA. stopali1@jhmi.edu)
N. Engl. J. Med.

blockade of programmed death pd-1 an inhibitory receptor expressed by cells can overcome immune resistance we assessed the antitumor_activity and safety of bms-936558 an antibody that specifically blocks pd-1 we enrolled patients with advanced melanoma non-small-cell_lung cancer castration-resistant_prostate cancer or renal-cell or colorectal cancer to receive anti-pd-1 antibody at dose of to mg_per kilogram of body_weight every_weeks response was assessed after each 8-week treatment cycle patients received up to cycles until disease_progression or complete_response occurred total of patients received treatment through february grade or drug-related_adverse events_occurred in of patients there were three deaths from pulmonary toxicity no maximum_tolerated dose was defined adverse_events consistent with immune-related causes were observed among patients in whom response could_be evaluated objective_responses complete or partial_responses were observed in those with non-small-cell_lung cancer melanoma or renal-cell cancer cumulative response_rates all doses were among patients with non-small-cell_lung cancer of patients among patients with melanoma of patients and among patients with renal-cell cancer of patients responses were durable of responses lasted year or more in patients with year or more of follow-up to assess the role of intratumoral pd-1 ligand_pd-l1 expression in the modulation of the pd-1-pd-l1 pathway immunohistochemical_analysis was performed on pretreatment tumor specimens_obtained from patients of patients with pd-l1-negative tumors none had an objective_response of patients with pd-l1-positive tumors had an objective_response anti-pd-1 antibody produced objective_responses in approximately one in four to one in five patients with non-small-cell_lung cancer melanoma or renal-cell cancer the adverse-event profile does_not appear to preclude its use preliminary_data suggest relationship_between pd-l1_expression on tumor cells and