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Thyroid : Official Journal of the... Nov 2019Gene panels are routinely used to assess predisposition to hereditary cancers by simultaneously testing multiple susceptibility genes and/or variants. More recently,...
Gene panels are routinely used to assess predisposition to hereditary cancers by simultaneously testing multiple susceptibility genes and/or variants. More recently, genetic panels have been implemented as part of solid tumor malignancy testing assessing somatic alterations. One example is targeted variant panels for thyroid nodules that are not conclusively malignant or benign upon fine-needle aspiration (FNA). We systematically reviewed published studies from 2009 to 2018 that contained genetic data from preoperative FNA specimens on cytologically indeterminate thyroid nodules (ITNs) that subsequently underwent surgical resection. Pooled prevalence estimates per gene and variant, along with their respective positive predictive values (PPVs) for malignancy, were calculated. Our systematic search identified 540 studies that were supplemented by 18 studies from bibliographies or personal files. Sixty-one studies met all inclusion criteria and included >4600 ITNs. Overall, 26% of nodules contained at least 1 variant or fusion. However, half of them did not include details on the specific gene, variant, and/or complete fusion pair reported for inclusion toward PPV calculations. The PPVs of genomic alterations reported at least 10 times were limited to (98%, 95% confidence interval [CI 96-99%]), (55% [CI 34-78%]), (45% [CI 22-72%]), (42% [CI 19-68%]), and (38% [CI 23-55%]). Excluding , the pooled PPV for all other specified variants and fusions was 47%. Multiple variants within the same nodule were identified in ∼1% of ITN and carried a cumulative PPV of 77%. The chance that a genomic alteration predicts malignancy depends on the individual variant or fusion detected. Only five alterations were reported at least 10 times; had a PPV of 98%, while the remaining four had individual PPVs ranging from 38% to 55%. The small sample size of most variants and fusion pairs found among ITNs, however, limits confidence in their individual PPV point estimates. Better specific reporting of genomic alterations with cytological category, histological subtype, and cancer staging would facilitate better understanding of cancer prediction, and the independent contribution of the genomic profile to prognosis.
Topics: DNA Mutational Analysis; Genetic Variation; Humans; Mutation; Thyroid Nodule
PubMed: 31469053
DOI: 10.1089/thy.2019.0278 -
Thrombosis and Haemostasis Jul 2006The magnitude of the association of factor V Leiden mutation with pregnancy-related venous thrombosis remains unclear. Our objective was to undertake a systematic review... (Meta-Analysis)
Meta-Analysis
The magnitude of the association of factor V Leiden mutation with pregnancy-related venous thrombosis remains unclear. Our objective was to undertake a systematic review and a metaanalysis of the literature to estimate precisely the association of factorV Leiden mutation with the risk of first, or recurrent, pregnancy-related venous thromboembolism. Studies published before October 2005 were identified by Medline((R)). Using both fixed and random effect models, odds ratios (OR) with accompanying 95% confidential intervals (CI) were calculated for the factor V Leiden mutation and the clinical end-point (Yusuf-Peto adaptation of the Mantel-Haenszel, DerSimonian and Laird method). We identified 13 studies including 7 cohorts and 6 casecontrol studies relating to factor V Leiden and pregnancy-related venous thrombosis. The results from the cohorts showed a pooled OR of 4.46 (95% CI, 1.82-10.94; 7,879 pooled women), with no evidence of statistical heterogeneity (p = 0.36), for the risk of a first venous thromboembolism during pregnancy or the postpartum period associated with the factor V Leiden mutation. Case-control studies revealed a higher risk (OR 8.6, 95% CI, 5.85-12.63; 1,433 [corrected] pooled women) with significant heterogeneity (p < 0.005). Because of insufficient data, an analysis for the risk of recurrence could not be performed. Our findings emphasize the fact that limited data are available on this topic. This meta-analysis provides clinicians with an estimate of the average risk of a first thrombosis occurring during pregnancy in women carrying the factor V Leiden to assist the management of such women.
Topics: Adult; Factor V; Female; Humans; Odds Ratio; Point Mutation; Pregnancy; Pregnancy Complications, Hematologic; Risk; Thromboembolism; Venous Thrombosis
PubMed: 16807645
DOI: 10.1160/TH06-02-0086 -
Current Drug Metabolism 2018Natalizumab (NAT), a humanized monoclonal antibody, binding in both α4β1 and α4β7 integrins, is approved for the treatment of Multiple Sclerosis (MS) and Crohn's...
BACKGROUND
Natalizumab (NAT), a humanized monoclonal antibody, binding in both α4β1 and α4β7 integrins, is approved for the treatment of Multiple Sclerosis (MS) and Crohn's Disease (CD). This review highlights the detailed Pharmacokinetics (PK) and Pharmacodynamics (PD) information of NAT, with the Pharmacogenomics (PG) properties of NAT.
METHODS
We undertake a systemic English-language search of Medline, EMBASE, Cochrane Library electronic databases to identify all potential studies with PK, PD or PG properties of NAT (up to October 2017).
RESULTS
Five papers contain detailed pharmacokinetic parameters are included in this review. Body weight is the most important factor associated with NAT concentration. Greater PK similarity and PD comparability is observed following Subcutaneous (SC) administration than Intramuscular (IM) administration. Initial difference in PK measures was observed between SC and Intravenous (IV) administration. However, trough NAT serum concentrations are similar between SC and IV administration after repeated dosing. Antibodies against NAT result in a low serum NAT concentration and cause a loss of efficacy of NAT. Gln-152, Lys-201, and Lys-256 are the three important point mutation on the α4 residues that NAT binds to. Syndecan-1 gene is a potential candidate gene for personalized approach for NAT use in MS.
CONCLUSION
As MS is a disease that affects young women most and NAT can pass placental barrier before delivery and into breast milk, a proper risk-benefit analysis of NAT therapy in lactating women are still needed. The relationship between Single Nucleotide Polymorphisms (SNPs) and NAT treatment are still not clear.
Topics: Animals; Humans; Immunologic Factors; Integrin alpha4; Natalizumab; Pharmacogenomic Variants
PubMed: 29708072
DOI: 10.2174/1389200219666180427165841 -
Malaria Journal Mar 2019Chloroquine, a previous highly efficacious, easy to use and affordable anti-malarial agent was withdrawn from malaria endemic regions due to high levels of resistance....
BACKGROUND
Chloroquine, a previous highly efficacious, easy to use and affordable anti-malarial agent was withdrawn from malaria endemic regions due to high levels of resistance. This review collated evidence from published-reviewed articles to establish prevalence of Pfcrt 76T and Pfmdr-1 86Y alleles in malaria affected countries following official discontinuation of chloroquine use.
METHODS
A review protocol was developed, registered in PROSPERO (#CRD42018083957) and published in a peer-reviewed journal. Article search was done in PubMed, Scopus, Lilacs/Vhl and Embase databases by two experienced librarians (AK, RS) for the period 1990-to-Febuary 2018. Mesh terms and Boolean operators (AND, OR) were used. Data extraction form was designed in Excel spread sheet 2007. Data extraction was done by three reviewers (NL, BB and MO), discrepancies were resolved by discussion. Random effects analysis was done in Open Meta Analyst software. Heterogeneity was established using I-statistic.
RESULTS
A total of 4721 citations were retrieved from article search (Pubmed = 361, Lilac/vhl = 28, Science Direct = 944, Scopus = 3388). Additional targeted search resulted in three (03) eligible articles. After removal of duplicates (n = 523) and screening, 38 articles were included in the final review. Average genotyping success rate was 63.6% (18,343/28,820) for Pfcrt K76T and 93.5% (16,232/17,365) for Pfmdr-1 86Y mutations. Prevalence of Pfcrt 76T was as follows; East Africa 48.9% (2528/5242), Southern Africa 18.6% (373/2163), West Africa 58.3% (3321/6608), Asia 80.2% (1951/2436). Prevalence of Pfmdr-1 86Y was; East Africa 32.4% (1447/5722), Southern Africa 36.1% (544/1640), West Africa 52.2% (1986/4200), Asia 46.4% (1276/2217). Over half, 52.6% (20/38) of included studies reported continued unofficial chloroquine use following policy change. Studies done in Madagascar and Kenya reported re-emergence of chloroquine sensitive parasites (IC < 30.9 nM). The average time (years) since discontinuation of chloroquine use to data collection was 8.7 ± 7.4. There was high heterogeneity (I > 95%).
CONCLUSION
The prevalence of chloroquine resistance alleles among Plasmodium falciparum parasites have steadily declined since discontinuation of chloroquine use. However, Pfcrt K76T and Pfmdr-1 N86Y mutations still persist at moderate frequencies in most malaria affected countries.
Topics: Africa; Antimalarials; Asia; Chloroquine; Drug Resistance; Endemic Diseases; Gene Frequency; Genetic Markers; Genotype; Malaria, Falciparum; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Point Mutation; Prevalence; Protozoan Proteins; Risk Factors
PubMed: 30871535
DOI: 10.1186/s12936-019-2716-z -
The Journal of Antimicrobial... Feb 2019Reviews assessing the genetic basis of ciprofloxacin resistance in Escherichia coli have mostly been qualitative. However, to predict resistance phenotypes based on...
BACKGROUND
Reviews assessing the genetic basis of ciprofloxacin resistance in Escherichia coli have mostly been qualitative. However, to predict resistance phenotypes based on genotypic characteristics, it is essential to quantify the contribution of genotypic determinants to resistance.
OBJECTIVES
We performed a systematic review to assess the relative contribution of known genomic resistance determinants to the MIC of ciprofloxacin in E. coli.
METHODS
PubMed and Web of Science were searched for English language studies that assessed ciprofloxacin MIC and presence or introduction of genetic determinants of ciprofloxacin resistance in E. coli. We included experimental and observational studies without time restrictions. Medians and ranges of MIC fold changes were calculated for individual resistance determinants and combinations thereof.
RESULTS
We included 66 studies, describing 604 E. coli isolates that carried at least one genetic ciprofloxacin resistance determinant. Mutations in gyrA and parC, genes encoding targets of ciprofloxacin, contribute to the largest fold changes in ciprofloxacin resistance in E. coli compared with the WT. Efflux and physical blocking or enzymatic modifications confer smaller increases in ciprofloxacin MIC than mutations in gyrA and parC. However, the presence of these other resistance mechanisms in addition to target alteration mutations further increases ciprofloxacin MIC, thus resulting in ciprofloxacin MIC increases ranging from 250- to 4000-fold.
CONCLUSIONS
This quantitative review of genomic determinants of ciprofloxacin resistance in E. coli demonstrates the complexity of resistance phenotype prediction from genomic data and serves as a reference point for studies aiming to predict ciprofloxacin MIC from E. coli genomes.
Topics: Anti-Bacterial Agents; Ciprofloxacin; Drug Resistance, Bacterial; Escherichia coli; Genes, Bacterial; Microbial Sensitivity Tests; Mutation; Observational Studies as Topic; Phenotype
PubMed: 30357339
DOI: 10.1093/jac/dky417 -
Neuro-oncology Nov 2018Noninvasive and accurate modality to predict isocitrate dehydrogenase (IDH) mutant glioma may have great potential in routine clinical practice. We aimed to investigate... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Noninvasive and accurate modality to predict isocitrate dehydrogenase (IDH) mutant glioma may have great potential in routine clinical practice. We aimed to investigate the diagnostic performance of 2-hydroxyglutarate (2HG) magnetic resonance spectroscopy (MRS) for prediction of IDH mutant glioma and provide an optimal cutoff value for 2HG.
METHODS
A systematic literature search of Ovid-MEDLINE and EMBASE was performed to identify original articles investigating the diagnostic performance of 2HG MRS up to March 20, 2018. Pooled sensitivity and specificity were calculated using a bivariate random-effects model. Subgroup analysis and meta-regression were performed to explain heterogeneity effects. An optimal cutoff value for 2HG was calculated from studies providing individual patient data.
RESULTS
Fourteen original articles with 460 patients were included. The pooled sensitivity and specificity for the diagnostic performance of 2HG MRS for prediction of IDH mutant glioma were 95% (95% CI, 85-98%) and 91% (95% CI, 83-96%), respectively. The Higgins I2 statistic demonstrated that heterogeneity was present in the sensitivity (I2 = 50.69%), but not in the specificity (I2 = 30.37%). In the meta-regression, echo time (TE) was associated with study heterogeneity. Among the studies using point-resolved spectroscopy (PRESS), a long TE (97 ms) resulted in higher sensitivity (92%) and specificity (97%) than a short TE (30-35 ms; sensitivity of 90%, specificity of 88%; P < 0.01). The optimal 2HG cutoff value of 2HG using individual patient data was 1.76 mM.
CONCLUSION
2HG MRS demonstrated excellent specificity for prediction of IDH mutant glioma, with TE being associated with heterogeneity in the sensitivity.
KEY POINTS
1. HG MRS has excellent diagnostic performance in the prediction of IDH mutant glioma. 2. The pooled sensitivity was 95% and the pooled specificity was 91%. 3. Echo time was associated with study heterogeneity in the meta-regression.
Topics: Brain Neoplasms; Glioma; Glutarates; Humans; Isocitrate Dehydrogenase; Magnetic Resonance Spectroscopy; Mutation; Prognosis
PubMed: 30020513
DOI: 10.1093/neuonc/noy113