Breakthroughs of the year 2009

1. Emergence of a Novel Swine-Origin Influenza A (H1N1) Virus in Humans Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team

F. S. Dawood, S. Jain, L. Finelli, M. W. Shaw, S. Lindstrom, R. J. Garten, L. V. Gubareva, X. Y. Xu, C. B. Bridges and T. M. Uyeki

N Engl J Med.2009 Jun;360(25):2605-2615.

Abstract: BACKGROUND On April 15 and April 17, 2009, novel swine-origin influenza A (H1N1) virus (S-OIV) was identified in specimens obtained from two epidemiologically unlinked patients in the United States. The same strain of the virus was identified in Mexico, Canada, and elsewhere. We describe 642 confirmed cases of human S-OIV infection identified from the rapidly evolving U. S. outbreak. METHODS Enhanced surveillance was implemented in the United States for human infection with influenza A viruses that could not be subtyped. Specimens were sent to the Centers for Disease Control and Prevention for real-time reverse-transcriptase-polymerasechain-reaction confirmatory testing for S-OIV. RESULTS From April 15 through May 5, a total of 642 confirmed cases of S-OIV infection were identified in 41 states. The ages of patients ranged from 3 months to 81 years; 60% of patients were 18 years of age or younger. Of patients with available data, 18% had recently traveled to Mexico, and 16% were identified from school outbreaks of S-OIV infection. The most common presenting symptoms were fever (94% of patients), cough (92%), and sore throat (66%); 25% of patients had diarrhea, and 25% had vomiting. Of the 399 patients for whom hospitalization status was known, 36 (9%) required hospitalization. Of 22 hospitalized patients with available data, 12 had characteristics that conferred an increased risk of severe seasonal influenza, 11 had pneumonia, 8 required admission to an intensive care unit, 4 had respiratory failure, and 2 died. The S-OIV was determined to have a unique genome composition that had not been identified previously. CONCLUSIONS A novel swine-origin influenza A virus was identified as the cause of outbreaks of febrile respiratory infection ranging from self-limited to severe illness. It is likely that the number of confirmed cases underestimates the number of cases that have occurred.

Keywords: infection, vaccines, adults

*Times Cited: 1347

PMID: 19423869


2. Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers

P. C. Fong, D. S. Boss, T. A. Yap, A. Tutt, P. J. Wu, M. Mergui-Roelvink, P. Mortimer, H. Swaisland, A. Lau, M. J. O’Connor, A. Ashworth, J. Carmichael, S. B. Kaye, J. H. M. Schellens and J. S. de Bono

N Engl J Med.2009 Jul;361(2):123-134.

Abstract: Background: The inhibition of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects, including those arising in carriers of a BRCA1 or BRCA2 mutation. We conducted a clinical evaluation in humans of olaparib (AZD2281), a novel, potent, orally active PARP inhibitor. Methods: This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib. Selection was aimed at having a study population enriched in carriers of a BRCA1 or BRCA2 mutation. Results: We enrolled and treated 60 patients; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated cancer but declined to undergo mutational testing. The olaparib dose and schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice daily (grade 3 mood alteration and fatigue) and two of five patients receiving 600 mg twice daily (grade 4 thrombocytopenia and grade 3 somnolence). This led us to enroll another cohort, consisting only of carriers of a BRCA1 or BRCA2 mutation, to receive olaparib at a dose of 200 mg twice daily. Other adverse effects included mild gastrointestinal symptoms. There was no obvious increase in adverse effects seen in the mutation carriers. Pharmacokinetic data indicated rapid absorption and elimination; pharmacodynamic studies confirmed PARP inhibition in surrogate samples (of peripheral-blood mononuclear cells and plucked eyebrow-hair follicles) and tumor tissue. Objective antitumor activity was reported only in mutation carriers, all of whom had ovarian, breast, or prostate cancer and had received multiple treatment regimens. Conclusions: Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCA2 mutation. ( number, NCT00516373.) N Engl J Med 2009;361:123-34.

Keywords: dna-repair defect, ovarian-cancer, prostate-cancer, clinical-trials, mutant-cells, solid tumors, guidelines, maintenance, resistance, cisplatin

*Times Cited: 825

PMID: 19553641


3. Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes

D. M. Nathan, J. B. Buse, M. B. Davidson, E. Ferrannini, R. R. Holman, R. Sherwin and B. Zinman

Diabetes Care.2009 Jan;32(1):193-203.

Abstract: The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues Surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.

Keywords: blood-glucose control, dipeptidyl peptidase-4 inhibitor, randomized, controlled-trial, intensive insulin therapy, improved glycemic control, disease risk-factors, cardiovascular-disease, microvascular, complications, exenatide exendin-4, life-style

*Times Cited: 905

PMID: 18945920


4. STRING 8-a global view on proteins and their functional interactions in 630 organisms

L. J. Jensen, M. Kuhn, M. Stark, S. Chaffron, C. Creevey, J. Muller, T. Doerks, P. Julien, A. Roth, M. Simonovic, P. Bork and C. von Mering

Nucleic acids research.2009 Jan;37:D412-D416.

Abstract: Functional partnerships between proteins are at the core of complex cellular phenotypes, and the networks formed by interacting proteins provide researchers with crucial scaffolds for modeling, data reduction and annotation. STRING is a database and web resource dedicated to protein-protein interactions, including both physical and functional interactions. It weights and integrates information from numerous sources, including experimental repositories, computational prediction methods and public text collections, thus acting as a meta-database that maps all interaction evidence onto a common set of genomes and proteins. The most important new developments in STRING 8 over previous releases include a URL-based programming interface, which can be used to query STRING from other resources, improved interaction prediction via genomic neighborhood in prokaryotes, and the inclusion of protein structures. Version 8.0 of STRING covers about 2.5 million proteins from 630 organisms, providing the most comprehensive view on protein-protein interactions currently available. STRING can be reached at

Keywords: interaction networks, interaction database, biological networks, genomic, data, update, prediction, associations, environment, software, resource

*Times Cited: 573

PMID: 18940858


5. A Surgical Safety Checklist to Reduce Morbidity and Mortality in a Global Population

A. B. Haynes, T. G. Weiser, W. R. Berry, S. R. Lipsitz, A. H. S. Breizat, E. P. Dellinger, T. Herbosa, S. Joseph, P. L. Kibatala, M. C. M. Lapitan, A. F. Merry, K. Moorthy, R. K. Reznick, B. Taylor, A. A. Gawande and G. Safe Surgery Saves Lives Study

N Engl J Med.2009 Jan;360(5):491-499.

Abstract: Background: Surgery has become an integral part of global health care, with an estimated 234 million operations performed yearly. Surgical complications are common and often preventable. We hypothesized that a program to implement a 19-item surgical safety checklist designed to improve team communication and consistency of care would reduce complications and deaths associated with surgery. Methods: Between October 2007 and September 2008, eight hospitals in eight cities (Toronto, Canada; New Delhi, India; Amman, Jordan; Auckland, New Zealand; Manila, Philippines; Ifakara, Tanzania; London, England; and Seattle, WA) representing a variety of economic circumstances and diverse populations of patients participated in the World Health Organization’s Safe Surgery Saves Lives program. We prospectively collected data on clinical processes and outcomes from 3733 consecutively enrolled patients 16 years of age or older who were undergoing noncardiac surgery. We subsequently collected data on 3955 consecutively enrolled patients after the introduction of the Surgical Safety Checklist. The primary end point was the rate of complications, including death, during hospitalization within the first 30 days after the operation. Results: The rate of death was 1.5% before the checklist was introduced and declined to 0.8% afterward (P=0.003). Inpatient complications occurred in 11.0% of patients at baseline and in 7.0% after introduction of the checklist (P<0.001). Conclusions: Implementation of the checklist was associated with concomitant reductions in the rates of death and complications among patients at least 16 years of age who were undergoing noncardiac surgery in a diverse group of hospitals. N Engl J Med 2009;360:491-9.

Keywords: antibiotic-prophylaxis, operating-room, surgery, risk, infections, anesthesia, hospitals, australia, teamwork, nurses

*Times Cited: 710

PMID: 19144931


6. Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis

J. M. L. Ebos, C. R. Lee, W. Cruz-Munoz, G. A. Bjarnason, J. G. Christensen and R. S. Kerbel

Cancer Cell.2009 Mar;15(3):232-239.

Abstract: Herein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible “metastatic conditioning” in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments.

Keywords: endothelial progenitor cells, sunitinib malate, kinase inhibitor, cancer, therapy, models, cyclophosphamide, selectivity, progression, disease

*Times Cited: 586

PMID: 19249681


7. Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis

M. Paez-Ribes, E. Allen, J. Hudock, T. Takeda, H. Okuyama, F. Vinals, M. Inoue, G. Bergers, D. Hanahan and O. Casanovas

Cancer Cell.2009 Mar;15(3):220-231.

Abstract: Multiple angiogenesis inhibitors have been therapeutically validated in preclinical cancer models, and several in clinical trials. Here we report that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis. Increased invasiveness is also seen by genetic ablation of the Vegf-A gene in both models, substantiating the results of the pharmacological inhibitors. The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies.

Keywords: endothelial growth-factor, central-nervous-system, carcinoma-cell, invasion, high-grade glioma, breast-cancer, mouse model, in-vivo, angiogenesis, vegf, tumorigenesis

*Times Cited: 703

PMID: 19249680


8. Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer

E. Van Cutsem, C. H. Kohne, E. Hitre, J. Zaluski, C. R. C. Chien, A. Makhson, G. D’Haens, T. Pinter, R. Lim, G. Bodoky, J. K. Roh, G. Folprecht, P. Ruff, C. Stroh, S. Tejpar, M. Schlichting, J. Nippgen and P. Rougier

N Engl J Med.2009 Apr;360(14):1408-1417.

Abstract: Background We investigated the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer and sought associations between the mutation status of the KRAS gene in tumors and clinical response to cetuximab. Methods We randomly assigned patients with epidermal growth factor receptor-positive colorectal cancer with unresectable metastases to receive FOLFIRI either alone or in combination with cetuximab. The primary end point was progression-free survival. Results A total of 599 patients received cetuximab plus FOLFIRI, and 599 received FOLFIRI alone. The hazard ratio for progression-free survival in the cetuximab-FOLFIRI group as compared with the FOLFIRI group was 0.85 (95% confidence interval [CI], 0.72 to 0.99; P = 0.048). There was no significant difference in the overall survival between the two treatment groups (hazard ratio, 0.93; 95% CI, 0.81 to 1.07; P = 0.31). There was a significant interaction between treatment group and KRAS mutation status for tumor response (P = 0.03) but not for progression-free survival (P = 0.07) or overall survival (P = 0.44). The hazard ratio for progression-free survival among patients with wild-type-KRAS tumors was 0.68 (95% CI, 0.50 to 0.94), in favor of the cetuximab-FOLFIRI group. The following grade 3 or 4 adverse events were more frequent with cetuximab plus FOLFIRI than with FOLFIRI alone: skin reactions (which were grade 3 only) (in 19.7% vs. 0.2% of patients, P<0.001), infusion-related reactions (in 2.5% vs. 0%, P<0.001), and diarrhea (in 15.7% vs. 10.5%, P = 0.008). Conclusions First-line treatment with cetuximab plus FOLFIRI, as compared with FOLFIRI alone, reduced the risk of progression of metastatic colorectal cancer. The benefit of cetuximab was limited to patients with KRAS wild-type tumors. ( number, NCT00154102.)

Keywords: k-ras mutations, 1st-line treatment, plus irinotecan, phase-iii, fluorouracil, oxaliplatin, leucovorin, kras, combination, trial

*Times Cited: 811

PMID: 19339720


9. Cytochrome P-450 Polymorphisms and Response to Clopidogrel

J. L. Mega, S. L. Close, S. D. Wiviott, L. Shen, R. D. Hockett, J. T. Brandt, J. R. Walker, E. M. Antman, W. Macias, E. Braunwald and M. S. Sabatine

N Engl J Med.2009 Jan;360(4):354-362.

Abstract: Background: Clopidogrel requires transformation into an active metabolite by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function. Methods: We tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. We then examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1477 subjects with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38. Results: In healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers (P<0.001). Carriers also had an absolute reduction in maximal platelet aggregation in response to clopidogrel that was 9 percentage points less than that seen in noncarriers (P<0.001). Among clopidogrel-treated subjects in TRITON-TIMI 38, carriers had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs. 8.0%; hazard ratio for carriers, 1.53; 95% confidence interval [CI], 1.07 to 2.19; P=0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs. 0.8%; hazard ratio, 3.09; 95% CI, 1.19 to 8.00; P=0.02). Conclusions: Among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers. N Engl J Med 2009;360:354-62.

Keywords: acute coronary syndromes, st-segment elevation, platelet inhibition, individual responsiveness, atherothrombotic events, myocardial-infarction, stent thrombosis, healthy-subjects, increased, risk, prasugrel

*Times Cited: 784

PMID: 19106084


10. Dabigatran versus Warfarin in Patients with Atrial Fibrillation

S. J. Connolly, M. D. Ezekowitz, S. Yusuf, J. Eikelboom, J. Oldgren, A. Parekh, J. Pogue, P. A. Reilly, E. Themeles, J. Varrone, S. Wang, M. Alings, D. Xavier, J. Zhu, R. Diaz, B. S. Lewis, H. Darius, H. C. Diener, C. D. Joyner, L. Wallentin, R.-L. S. Comm and Investigator

N Engl J Med.2009 Sep;361(12):1139-1151.

Abstract: Background: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. Methods: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran — 110 mg or 150 mg twice daily — or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. Results: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). Conclusions: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. ( number, NCT00262600.) N Engl J Med 2009;361:1139-51.

Keywords: non-inferiority trial, antithrombotic therapy, anticoagulant-therapy, oral anticoagulant, prevent stroke, aspirin, thromboembolism, metaanalysis, clopidogrel, etexilate

*Times Cited: 1312

PMID: 19717844


11. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial

R. Stupp, M. E. Hegi, W. P. Mason, M. J. van den Bent, M. J. B. Taphoorn, R. C. Janzer, S. K. Ludwin, A. Allgeier, B. Fisher, K. Belanger, P. Hau, A. A. Brandes, J. Gijtenbeek, C. Marosi, C. J. Vecht, K. Mokhtari, P. Wesseling, S. Villa, E. Eisenhauer, T. Gorlia, M. Weller, D. Lacombe, J. G. Cairncross, R. O. Mirimanoff, R. European Org, Treatment, G. Canc Brain Tumour, G. Radiat Oncol and T. Natl Canc Inst Canada Clin

Lancet Oncology.2009 May;10(5):459-466.

Abstract: Background In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. Methods Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with, number NCT00006353. Findings Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. Interpretation Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide.

Keywords: newly-diagnosed glioblastoma, recursive partitioning analysis, mgmt, promoter methylation, controlled clinical-trial, aspartic acid peptide, malignant glioma, prognostic-factors, accelerated radiotherapy, oncology-group, multiforme

*Times Cited: 703

PMID: 19269895


12. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial

A. L. Cheng, Y. K. Kang, Z. D. Chen, C. J. Tsao, S. K. Qin, J. S. Kim, R. C. Luo, J. F. Feng, S. L. Ye, T. S. Yang, J. M. Xu, Y. Sun, H. J. Liang, J. W. Liu, J. J. Wang, W. Y. Tak, H. M. Pan, K. Burock, J. Zou, D. Voliotis and Z. Z. Guan

Lancet Oncology.2009 Jan;10(1):25-34.

Abstract: Background Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase 111, randomised, double-blind, placebo. controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. Methods Between Sept 20, 2005, and Jan 31, 2007, patients with hepatorcellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with, number NCT00492752. Findings 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6.5 months (95% Cl 5.56-7.56) in patients treated with sorafenib, compared with 4.2 months (3.75-5.46) in those who received placebo (hazard ratio [HR] 0.68 [95% CI 0.50-0.93]; p=0.014). Median TTP was 2.8 months (2.63-3.58) in the sorafenib group compared with 1.4 months (1.35-1.55) in the placebo group (HR 0.57 [0.42-0.791; p=0.0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10.7%]), diarrhoea (nine patients [6.0%]), and fatigue (five patients [3.4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11.4%]) and diarrhoea (11 patients [7.4%]); these adverse events rarely led to discontinuation. Interpretation Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma.

Keywords: over-expression, natural-history, cancer, epidemiology, guidelines, therapies, prognosis, cirrhosis, tumors, japan

*Times Cited: 653

PMID: 19095497


13. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse

P. O. McGowan, A. Sasaki, A. C. D’Alessio, S. Dymov, B. Labonte, M. Szyf, G. Turecki and M. J. Meaney

Nat Neurosci.2009 Mar;12(3):342-348.

Abstract: Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls. We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1(F) splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A-inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression.

Keywords: major depression, maternal-care, stress responses, genetic-analysis, mood disorders, messenger-rna, young-adults, schizophrenia, methylation, suicide

*Times Cited: 583

PMID: 19234457


14. Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma

T. S. Mok, Y. L. Wu, S. Thongprasert, C. H. Yang, D. T. Chu, N. Saijo, P. Sunpaweravong, B. H. Han, B. Margono, Y. Ichinose, Y. Nishiwaki, Y. Ohe, J. J. Yang, B. Chewaskulyong, H. Y. Jiang, E. L. Duffield, C. L. Watkins, A. A. Armour and M. Fukuoka

N Engl J Med.2009 Sep;361(10):947-957.

Abstract: Background: Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer. Methods: In this phase 3, 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 (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. Results: The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% 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, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 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, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 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, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group. Conclusions: 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 a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. ( number, NCT00322452.) N Engl J Med 2009;361:947-57.

Keywords: cell lung-cancer, receptor gene-mutations, prospective phase-ii, egfr, mutations, functional assessment, 1st-line gefitinib, treated patients, never-smokers, therapy, erlotinib

*Times Cited: 1293

PMID: 19692680


15. Genetic Determinants of Response to Clopidogrel and Cardiovascular Events

T. Simon, C. Verstuyft, M. Mary-Krause, L. Quteineh, E. Drouet, N. Meneveau, P. G. Steg, J. Ferrieres, N. Danchin, L. Becquemont and S. T. E. French Registry Acute

N Engl J Med.2009 Jan;360(4):363-375.

Abstract: Background: Pharmacogenetic determinants of the response of patients to clopidogrel contribute to variability in the biologic antiplatelet activity of the drug. The effect of these determinants on clinical outcomes after an acute myocardial infarction is unknown. Methods: We consecutively enrolled 2208 patients presenting with an acute myocardial infarction in a nationwide French registry and receiving clopidogrel therapy. We then assessed the relation of allelic variants of genes modulating clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19), and biologic activity (P2RY12 and ITGB3) to the risk of death from any cause, nonfatal stroke, or myocardial infarction during 1 year of follow-up. Results: Death occurred in 225 patients, and nonfatal myocardial infarction or stroke in 94 patients, during the follow-up period. None of the selected single-nucleotide polymorphisms (SNPs) in CYP3A5, P2RY12, or ITGB3 were associated with a risk of an adverse outcome. Patients with two variant alleles of ABCB1 (TT at nucleotide 3435) had a higher rate of cardiovascular events at 1 year than those with the ABCB1 wild-type genotype (CC at nucleotide 3435) (15.5% vs. 10.7%; adjusted hazard ratio, 1.72; 95% confidence interval [CI], 1.20 to 2.47). Patients carrying any two CYP2C19 loss-of-function alleles (*2, *3, *4, or *5), had a higher event rate than patients with none (21.5% vs. 13.3%; adjusted hazard ratio, 1.98; 95% CI, 1.10 to 3.58). Among the 1535 patients who underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among patients with two CYP2C19 loss-of-function alleles was 3.58 times the rate among those with none (95% CI, 1.71 to 7.51). Conclusions: Among patients with an acute myocardial infarction who were receiving clopidogrel, those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not. This effect was particularly marked among the patients undergoing percutaneous coronary intervention. ( number, NCT00673036.) N Engl J Med 2009;360:363-75.

Keywords: st-segment elevation, percutaneous coronary intervention, healthy, japanese subjects, of-function polymorphism, sequence variations, myocardial-infarction, p-glycoprotein, duodenal enterocytes, controlled, trial, drug response

*Times Cited: 603

PMID: 19106083


16. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C

Y. Tanaka, N. Nishida, M. Sugiyama, M. Kurosaki, K. Matsuura, N. Sakamoto, M. Nakagawa, M. Korenaga, K. Hino, S. Hige, Y. Ito, E. Mita, E. Tanaka, S. Mochida, Y. Murawaki, M. Honda, A. Sakai, Y. Hiasa, S. Nishiguchi, A. Koike, I. Sakaida, M. Imamura, K. Ito, K. Yano, N. Masaki, F. Sugauchi, N. Izumi, K. Tokunaga and M. Mizokami

Nature Genetics.2009 Oct;41(10):1105-U1181.

Abstract: The recommended treatment for patients with chronic hepatitis C, pegylated interferon-alpha (PEG-IFN-alpha) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in all patients. We report a genome-wide association study (GWAS) to null virological response (NVR) in the treatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We found two SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P = 1.93 x 10(-13), and rs8099917, 3.11 x 10(-15)). We replicated these associations in an independent cohort (combined P values, 2.84 x 10(-27) (OR = 17.7; 95% CI = 10.0-31.3) and 2.68 x 10(-32) (OR = 27.1; 95% CI = 14.6-50.3), respectively). Compared to NVR, these SNPs were also associated with SVR (rs12980275, P = 3.99 x 10(-24), and rs8099917, P = 1.11 x 10(-27)). In further fine mapping of the region, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668) located in the IL28B region showed the most significant associations (P = 5.52 x 10(-28)-2.68 x 10(-32); OR = 22.3-27.1). Real-time quantitative PCR assays in peripheral blood mononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P = 0.015).

Keywords: plus ribavirin, combination therapy, virological response, host factors, virus, genotype-1, trial, 1b

*Times Cited: 731

PMID: 19749757


17. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes

W. Duckworth, C. Abraira, T. Moritz, D. Reda, N. Emanuele, P. D. Reaven, F. J. Zieve, J. Marks, S. N. Davis, R. Hayward, S. R. Warren, S. Goldman, M. McCarren, M. E. Vitek, W. G. Henderson, G. D. Huang and V. Investigators

N Engl J Med.2009 Jan;360(2):129-U162.

Abstract: Background The effects of intensive glucose control on cardiovascular events in patients with long-standing type 2 diabetes mellitus remain uncertain. Methods We randomly assigned 1791 military veterans ( mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or standard glucose control. Other cardiovascular risk factors were treated uniformly. The mean number of years since the diagnosis of diabetes was 11.5, and 40% of the patients had already had a cardiovascular event. The goal in the intensive- therapy group was an absolute reduction of 1.5 percentage points in the glycated hemoglobin level, as compared with the standard- therapy group. The primary outcome was the time from randomization to the first occurrence of a major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene. Results The median follow- up was 5.6 years. Median glycated hemoglobin levels were 8.4% in the standard- therapy group and 6.9% in the intensive- therapy group. The primary outcome occurred in 264 patients in the standard- therapy group and 235 patients in the intensive- therapy group (hazard ratio in the intensive- therapy group, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P = 0.14). There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause ( hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P = 0.62). No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard- therapy group and 24.1% in the intensive- therapy group. Conclusions Intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications. (ClinicalTrials. gov number, NCT00032487.).

Keywords: microvascular complications, macrovascular disease, glycemic control, mellitus, trial, association, progression, retinopathy, risk

*Times Cited: 929

PMID: 19092145


18. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy

V. Suppiah, M. Moldovan, G. Ahlenstiel, T. Berg, M. Weltman, M. L. Abate, M. Bassendine, U. Spengler, G. J. Dore, E. Powell, S. Riordan, D. Sheridan, A. Smedile, V. Fragomeli, T. Muller, M. Bahlo, G. J. Stewart, D. R. Booth, J. George and C. S. Hepatitis

Nature Genetics.2009 Oct;41(10):1100-U1174.

Abstract: Hepatitis C virus (HCV) infects 3% of the world’s population. Treatment of chronic HCV consists of a combination of PEGylated interferon-alpha (PEG-IFN-alpha) and ribavirin (RBV). To identify genetic variants associated with HCV treatment response, we conducted a genome-wide association study of sustained virological response (SVR) to PEG-IFN-alpha/RBV combination therapy in 293 Australian individuals with genotype 1 chronic hepatitis C, with validation in an independent replication cohort consisting of 555 individuals. We report an association to SVR within the gene region encoding interleukin 28B (IL28B, also called IFN lambda 3; rs8099917 combined P = 9.25 x 10(-9), OR = 1.98, 95% CI = 1.57-2.52). IL28B contributes to viral resistance and is known to be upregulated by interferons and by RNA virus infection. These data suggest that host genetics may be useful for the prediction of drug response, and they also support the investigation of the role of IL28B in the treatment of HCV and in other diseases treated with IFN-alpha.

Keywords: genome-wide association, gene-expression, antiviral activity, virus-replication, randomized-trial, plus ribavirin, ifn-lambda, iii, ifn, infection, opinion

*Times Cited: 667

PMID: 19749758


*Updated on 03/26/2013

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