Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large interpatient variability, partly due to genetic variations in the gene encoding cytochrome P450 (CYP)2C9 ...(CYP2C9). Furthermore, the variant allele HLA‐B*15:02, encoding human leukocyte antigen, is associated with an increased risk of Stevens–Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA‐B genotype (also available on PharmGKB: http://www.pharmgkb.org). The purpose of this guideline is to provide information for the interpretation of HLA‐B and/or CYP2C9 genotype tests so that the results can guide dosing and/or use of phenytoin. Detailed guidelines for the use of phenytoin as well as analyses of cost‐effectiveness are out of scope. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are periodically updated at http://www.pharmgkb.org.
Clinical Pharmacology & Therapeutics (2014); 96 5, 542–548. doi:10.1038/clpt.2014.159
Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the ...cytochrome P450–2C9 (CYP2C9) and vitamin K–epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2–3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer–reviewed gene–drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field.1
Clinical Pharmacology & Therapeutics (2011) 90 4, 625–629. doi:10.1038/clpt.2011.185
This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature ...is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype‐guided warfarin dosing to achieve a target international normalized ratio of 2–3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.
Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic ...information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base.
Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators.
In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring < or = 21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring > or = 49 mg per week).
The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.
If strong electron-electron interactions between neighboring Fe atoms mediate the Cooper pairing in iron-pnictide superconductors, then specific and distinct anisotropic superconducting energy gaps Δ ...j (K⃗) should appear on the different electronic bands i. Here, we introduce intraband Bogoliubov quasiparticle scattering interference (QPI) techniques for determination of Δ j (K⃗) in such materials, focusing on lithium iron arsenide (LiFeAs). We identify the three hole-like bands assigned previously as γ, α₂ and αⁱ, and we determine the anisotropy, magnitude, and relative orientations of their Δ j (K⃗). These measurements will advance quantitative theoretical analysis of the mechanism of Cooper pairing in iron-based superconductivity.
The effect of anthropogenic aerosols on cloud droplet concentrations and radiative properties is the source of one of the largest uncertainties in the radiative forcing of climate over the industrial ...period. This uncertainty affects our ability to estimate how sensitive the climate is to greenhouse gas emissions. Here we perform a sensitivity analysis on a global model to quantify the uncertainty in cloud radiative forcing over the industrial period caused by uncertainties in aerosol emissions and processes. Our results show that 45 per cent of the variance of aerosol forcing since about 1750 arises from uncertainties in natural emissions of volcanic sulphur dioxide, marine dimethylsulphide, biogenic volatile organic carbon, biomass burning and sea spray. Only 34 per cent of the variance is associated with anthropogenic emissions. The results point to the importance of understanding pristine pre-industrial-like environments, with natural aerosols only, and suggest that improved measurements and evaluation of simulated aerosols in polluted present-day conditions will not necessarily result in commensurate reductions in the uncertainty of forcing estimates.
Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment.
We ...selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample.
Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing.
Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).
Background
Use of polysomnography (PSG) is the gold standard of diagnosis and measurement of treatment effectiveness for paediatric obstructive sleep apnoea (OSA). Although adenotonsillectomy (T&A) ...is effective in diminishing the apnoea–hypopnoea index (AHI), a meta‐analysis of postoperative changes for all other PSG parameters and outcome comparisons between obese and non‐obese children following T&A have never been conducted.
Objective of review
To comprehensively review polysomnographic findings after surgery for obese and non‐obese children with OSA.
Search strategy
Study protocol was registered on PROSPERO (CRD42013004737). Two authors independently searched databases including PubMed, MEDLINE, EMBASE and Cochrane Review from January 1997 to July 2014. The keywords used included the following: sleep apnea, OSA, sleep apnea syndromes, tonsillectomy, adenoidectomy, infant, child, adolescent, and Humans.
Evaluation method
A comprehensive systematic review and meta‐analysis for literature for OSA children treated by T&A with polysomnography data. Random‐effects model was applied to determine postoperative sleep parameter changes and the surgical success rate between obese and non‐obese groups. The quality of studies was assessed using the Newcastle–Ottawa Scale.
Results
In total, 51 studies with 3413 subjects were enrolled. After surgery, sleep architecture was altered by a significant decrease in sleep stage 1, and an increase in slow‐wave sleep and the rapid eye movement stage, and enhanced sleep efficiency. The mean difference between pre‐ and postoperative was a significant reduction of 12.4 event/h in AHI, along with a reduction of obstructive index, hypopnoea index, central index and arousal index. Mean and minimum oxygen saturation increased significantly after surgery. The overall success rate was 51% for postoperative AHI <1 (obese versus non‐obese versus combined, 34% versus 49% versus 56%), and 81% for AHI <5 (obese versus non‐obese versus combined, 61% versus 87% versus 84%). Meta‐regression analyses demonstrate that postoperative AHI was positively correlated with AHI and body mass index z score before surgery.
Conclusions
Meta‐analysis of current literature shows T&A offers prominent improvement in a variety of sleep parameters. Improvements in non‐obese children exceeded those for obese children. Postoperative residual OSA remained in roughly half of the children, especially those with severe disease and obesity, making additional treatment strategies and/or long‐term follow‐up highly desirable.
We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC).
The ...PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected toin vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling.
The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations ofFGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib.
FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.
Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%–4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug ...target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC.
Eligible patients ≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2 with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats.
Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4–33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8–11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%).
MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479).
•This study provides first evidence of clinically meaningful antitumor activity of capmatinib in MET-dysregulated NSCLC.•Accurate biomarker selection of the patients is needed to identify the patients expected to respond better to capmatinib.•MET amplification GCN ≥6 and/or METex14 skipping are strong predictive biomarkers for response to capmatinib.•Overexpression alone cannot be considered as a reliable biomarker to predict the efficacy of capmatinib.•Capmatinib is well tolerated with the majority of the AEs grade 1 and 2.
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