Misleading Guidance From Pharmacogenomic Testing.

Am J Psychiatry. 2017 Oct 01;174(10):922-924

Authors: Rahman T, Ash DM, Lauriello J, Rawlani R

PMID: 28965468 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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Impact of SLC22A1 and CYP3A5 genotypes on imatinib response in chronic myeloid leukemia: a systematic review and meta-analysis.

Pharmacol Res. 2018 Feb 07;:

Authors: Cargnin S, Ravegnini G, Soverini S, Angelini S, Terrazzino S

Abstract
Contrasting results have been reported on the role of rs628031 and rs683369 polymorphisms of SLC22A1 and rs776746 of CYP3A5 on imatinib treatment response in patients with chronic myeloid leukemia (CML). In the present study, we conducted a systematic review and meta-analysis of published studies to estimate the impact of the above-mentioned gene variants on major molecular response (MMR) or complete cytogenetic response (CCyR) in imatinib-treated CML patients. We performed a comprehensive search through PubMed, Web of Knowledge, and Cochrane databases up to September 2017. The pooled analyses showed association between carriers of SLC22A1 rs628031A allele (GA + AA vs GG, OR: 0.58, 95% CI: 0.38-0.88, P = 0.011) or rs683369G allele (CG + GG vs CC, OR: 0.64, 95% CI: 0.42-0.96, P = 0.032) and a lower MMR rate. The combined analyses also revealed a correlation between the dominant (GG + AG vs AA, OR: 2.43, 95%CI: 1.12-5.27, P = 0.024) or the allelic model (G vs A, OR: 1.72, 95% CI: 1.09-2.72, P = 0.020) of CYP3A5 rs776746 with higher CCyR rates. The subsequent sensitivity analysis confirmed the statistical significance of CYP3A5 rs776746 among Asian CML patients (dominant model OR: 3.90; 95%CI: 2.47-6.14, P < 0.001; allelic model OR: 2.08; 95% CI: 1.47-2.95, P < 0.001). In conclusion, the present meta-analysis supports the association of SLC22A1 and CYP3A5 genotypes with clinical imatinib response rates of CML patients, nevertheless further large studies, particularly in Caucasians, are still warranted to provide conclusive evidences.

PMID: 29427770 [PubMed - as supplied by publisher]

Statins differentially modulate microRNAs expression in peripheral cells of hyperlipidemic subjects: A pilot study.

Eur J Pharm Sci. 2018 Feb 07;:

Authors: Zambrano T, Hirata RDC, Hirata MH, Cerda Á, Salazar LA

Abstract
AIM: Although statins are considered a cornerstone for the treatment of high cholesterol levels due to their powerful cholesterol-lowering effects, response to drug administration is still one of the main pitfalls of statin treatment. So far, the reasons underlying this undesired outcome are still poorly understood, but recently, various studies have suggested that miRNAs may be involved. Therefore, we aimed at evaluating the effect of short-term low-dose treatment with 2 statins on miRNAs expression in patients with hypercholesterolemia.
METHODS: A total of 40 hypercholesterolemic (HC) subjects following 1 month of atorvastatin (10 mg/day; n = 20) or simvastatin (10 mg/day; n = 20) were included. Multiple available boinformatic algorithms (TargetScan, miRanda, DianaLab, MicroCosm and PicTar) were employed to select miRNAs regulating genes involved in cholesterol metabolism and statin response. Differential miRNAs expression was determined in peripheral cells using the miScript® miRNA PCR Array platform. Pathways involving differentially expressed miRNAs were explored using the Ingenuity Pathway Analysis software.
RESULTS: Atorvastatin repressed miR-29a-3p, miR-29b-3p, miR-300, miR-33a-5p, miR-33b-5p and miR-454-3p in HC subjects. On the contrary, simvastatin did not show any effect on miRNAs expression. Network analysis indicated that atorvastatin-modulated miRNAs regulate key cholesterol genes (ABCA1, HMGCR, INSIG1, LDLR, LPL, SCAP and SREBF1). Further subgroups analyses showed that miR-106b-5p, miR-17-3p and miR-590-5p were repressed in HC subjects within the lower quartile of atorvastatin response (lower LDL-C reduction), while the expression of miR-106b-5p, miR-17-3p and miR-183-5p was higher in the upper quartile of simvastatin response (higher LDL-C reduction) (p < 0.05).
CONCLUSION: We show that a miRNAs-mediated epigenetic mechanism is differentially affected by statins therapy in vivo, which could be implicated in the variable response to these drugs. Further studies are necessary to disclose their particular role in the cholesterol-reduction response to statins.

PMID: 29427701 [PubMed - as supplied by publisher]

Oxytocin curbs calorie intake via food-specific increases in the activity of brain areas that process reward and establish cognitive control.

Sci Rep. 2018 Feb 09;8(1):2736

Authors: Spetter MS, Feld GB, Thienel M, Preissl H, Hege MA, Hallschmid M

Abstract
The hypothalamic neurohormone oxytocin decreases food intake via largely unexplored mechanisms. We investigated the central nervous mediation of oxytocin's hypophagic effect in comparison to its impact on the processing of generalized rewards. Fifteen fasted normal-weight, young men received intranasal oxytocin (24 IU) or placebo before functional magnetic resonance imaging (fMRI) measurements of brain activity during exposure to food stimuli and a monetary incentive delay task (MID). Subsequently, ad-libitum breakfast intake was assessed. Oxytocin compared to placebo increased activity in the ventromedial prefrontal cortex, supplementary motor area, anterior cingulate, and ventrolateral prefrontal cortices in response to high- vs. low-calorie food images in the fasted state, and reduced calorie intake by 12%. During anticipation of monetary rewards, oxytocin compared to placebo augmented striatal, orbitofrontal and insular activity without altering MID performance. We conclude that during the anticipation of generalized rewards, oxytocin stimulates dopaminergic reward-processing circuits. In contrast, oxytocin restrains food intake by enhancing the activity of brain regions that exert cognitive control, while concomitantly increasing the activity of structures that process food reward value. This pattern points towards a specific role of oxytocin in the regulation of eating behaviour in humans that might be of relevance for potential clinical applications.

PMID: 29426874 [PubMed - in process]

Development of Targeted Therapies Based on Gene Modification.

Methods Mol Biol. 2018;1706:39-51

Authors: Benson TM, Leti F, DiStefano JK

Abstract
With the advent of next-generation sequencing (NGS) and the demand for a personalized healthcare system, the fields of precision medicine and gene therapy are advancing in new directions. There is a push to identify genes that contribute to disease development, either alone or in conjunction with other genes or environmental factors, and then design targeted therapies based on this knowledge, rather than the traditional approach of treating generalized symptoms with pharmaceuticals in a one-size-fits-all manner. Identification of genes that contribute to disease pathogenesis and progression is critical for the maturation of the precision medicine field. Concomitant with a better understanding of disease pathology, precision medicine approaches can be adopted with greater confidence and are expected to lead to a new standard for clinical practice. In this chapter, we provide a brief introduction to precision medicine, discuss the importance of identifying genes and genetic variants that contribute to disease development and progression, offer examples of approaches that can be applied to treat specific diseases, and present some of the current challenges and limitations of precision medicine.

PMID: 29423792 [PubMed - in process]

Clinical Pharmacogenetic Models of Treatment Response to Methotrexate Monotherapy in Slovenian and Serbian Rheumatoid Arthritis Patients: Differences in Patient's Management May Preclude Generalization of the Models.

Front Pharmacol. 2018;9:20

Authors: Jenko B, Tomšič M, Jekić B, Milić V, Dolžan V, Praprotnik S

Abstract
Objectives: Methotrexate (MTX) is the first line treatment for rheumatoid arthritis (RA), but nevertheless 30% of patients experience MTX inefficacy. Our aim was to develop a clinical pharmacogenetic model to predict which RA patients will not respond to MTX monotherapy. We also assessed whether this model can be generalized to other populations by validating it on a group of Serbian RA patients. Methods: In 110 RA Slovenian patients, data on clinical factors and 34 polymorphisms in MTX pathway were analyzed by Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression to select variables associated with the disease activity as measured by Disease Activity Score (DAS28) score after 6 months of MTX monotherapy. A clinical pharmacogenetic index was constructed from penalized regression coefficients with absolute value above 0.05. This index was cross-validated and also independently validated on 133 Serbian RA patients. Results: A clinical pharmacogenetic index for prediction of DAS28 after 6 months of MTX monotherapy in Slovenian RA patients consisted of DAS28 score at diagnosis, presence of erosions, MTX dose, Solute Carrier Family 19 Member 1 (SLC19A1) rs1051266, Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1) rs2306283, Thymidylate Synthase (TYMS), and Adenosine Monophosphate Deaminase 1 (AMPD1) rs17602729. It correctly classified 69% of Slovenian patients as responders or nonresponders and explained 30% of variability in DAS28 after 6 months of MTX monotherapy. Testing for validity in another population showed that it classified correctly only 22.5% of Serbian RA patients. Conclusions: We developed a clinical pharmacogenetic model for DAS28 after 6 months of MTX monotherapy in Slovenian RA patients by combining clinical and genetic variables. The clinical pharmacogenetic index developed for Slovenian patients did not perform well on Serbian patients, presumably due to the differences in patients' characteristics and clinical management between the two groups.

PMID: 29422864 [PubMed]

Understanding the role of the chromosome 15q25.1 in COPD through epigenetics and transcriptomics.

Eur J Hum Genet. 2018 Feb 08;:

Authors: Nedeljkovic I, Carnero-Montoro E, Lahousse L, van der Plaat DA, de Jong K, Vonk JM, van Diemen CC, Faiz A, van den Berge M, Obeidat M, Bossé Y, Nickle DC, Consortium B, Uitterlinden AG, van Meurs JJB, Stricker BCH, Brusselle GG, Postma DS, Boezen HM, van Duijn CM, Amin N

Abstract
Chronic obstructive pulmonary disease (COPD) is a major health burden in adults and cigarette smoking is considered the most important environmental risk factor of COPD. Chromosome 15q25.1 locus is associated with both COPD and smoking. Our study aims at understanding the mechanism underlying the association of chromosome 15q25.1 with COPD through epigenetic and transcriptional variation in a population-based setting. To assess if COPD-associated variants in 15q25.1 are methylation quantitative trait loci, epigenome-wide association analysis of four genetic variants, previously associated with COPD (P < 5 × 10-8) in the 15q25.1 locus (rs12914385:C>T-CHRNA3, rs8034191:T>C-HYKK, rs13180:C>T-IREB2 and rs8042238:C>T-IREB2), was performed in the Rotterdam study (n = 1489). All four variants were significantly associated (P < 1.4 × 10-6) with blood DNA methylation of IREB2, CHRNA3 and PSMA4, of which two, including IREB2 and PSMA4, were also differentially methylated in COPD cases and controls (P < 0.04). Further additive and multiplicative effects of smoking were evaluated and no significant effect was observed. To evaluate if these four genetic variants are expression quantitative trait loci, transcriptome-wide association analysis was performed in 1087 lung samples. All four variants were also significantly associated with differential expression of the IREB2 3'UTR in lung tissues (P < 5.4 × 10-95). We conclude that regulatory mechanisms affecting the expression of IREB2 gene, such as DNA methylation, may explain the association between genetic variants in chromosome 15q25.1 and COPD, largely independent of smoking.

PMID: 29422661 [PubMed - as supplied by publisher]

Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer.

Nat Commun. 2018 Feb 08;9(1):556

Authors: Klein AP, Wolpin BM, Risch HA, Stolzenberg-Solomon RZ, Mocci E, Zhang M, Canzian F, Childs EJ, Hoskins JW, Jermusyk A, Zhong J, Chen F, Albanes D, Andreotti G, Arslan AA, Babic A, Bamlet WR, Beane-Freeman L, Berndt SI, Blackford A, Borges M, Borgida A, Bracci PM, Brais L, Brennan P, Brenner H, Bueno-de-Mesquita B, Buring J, Campa D, Capurso G, Cavestro GM, Chaffee KG, Chung CC, Cleary S, Cotterchio M, Dijk F, Duell EJ, Foretova L, Fuchs C, Funel N, Gallinger S, M Gaziano JM, Gazouli M, Giles GG, Giovannucci E, Goggins M, Goodman GE, Goodman PJ, Hackert T, Haiman C, Hartge P, Hasan M, Hegyi P, Helzlsouer KJ, Herman J, Holcatova I, Holly EA, Hoover R, Hung RJ, Jacobs EJ, Jamroziak K, Janout V, Kaaks R, Khaw KT, Klein EA, Kogevinas M, Kooperberg C, Kulke MH, Kupcinskas J, Kurtz RJ, Laheru D, Landi S, Lawlor RT, Lee IM, LeMarchand L, Lu L, Malats N, Mambrini A, Mannisto S, Milne RL, Mohelníková-Duchoňová B, Neale RE, Neoptolemos JP, Oberg AL, Olson SH, Orlow I, Pasquali C, Patel AV, Peters U, Pezzilli R, Porta M, Real FX, Rothman N, Scelo G, Sesso HD, Severi G, Shu XO, Silverman D, Smith JP, Soucek P, Sund M, Talar-Wojnarowska R, Tavano F, Thornquist MD, Tobias GS, Van Den Eeden SK, Vashist Y, Visvanathan K, Vodicka P, Wactawski-Wende J, Wang Z, Wentzensen N, White E, Yu H, Yu K, Zeleniuch-Jacquotte A, Zheng W, Kraft P, Li D, Chanock S, Obazee O, Petersen GM, Amundadottir LT

Abstract
In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

PMID: 29422604 [PubMed - in process]

Visit-to-visit lipid variability: Clinical significance, effects of lipid-lowering treatment, and (pharmaco)genetics.

J Clin Lipidol. 2018 Jan 11;:

Authors: Smit RAJ, Jukema JW, Postmus I, Ford I, Slagboom PE, Heijmans BT, Le Cessie S, Trompet S

Abstract
In recent years, visit-to-visit variability of serum lipids has been linked to both clinical outcomes and surrogate markers for vascular disease. In this article, we present an overview of the current evidence connecting this intraindividual variability to these outcome measures, discuss its interplay with lipid-lowering treatment, and describe the literature regarding genetic factors of possible interest. In addition, we undertook an explorative genome-wide association analysis on visit-to-visit variability of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, examining additive effects in 2530 participants from the placebo arm of the PROspective Study of Pravastatin in the Elderly at Risk trial. While we identified suggestive associations (P < 1 × 10-6) at 3 different loci (KIAA0391, amiloride-sensitive cation channel 1 neuronal [ACCN1], and Dickkopf WNT signaling pathway inhibitor 3 [DKK3]), previously published data from the genome-wide association study literature did not suggest plausible mechanistic pathways. Given the large degree of both clinical and methodological heterogeneity in the literature, additional research is needed to harmonize visit-to-visit variability parameters across studies and to definitively assess the possible role of (pharmaco)genetic factors.

PMID: 29422286 [PubMed - as supplied by publisher]

A Stepwise Integrated Approach to Personalized Risk Predictions in Stage III Colorectal Cancer.

Clin Cancer Res. 2017 Mar 01;23(5):1200-1212

Authors: Salvucci M, Würstle ML, Morgan C, Curry S, Cremona M, Lindner AU, Bacon O, Resler AJ, Murphy ÁC, O'Byrne R, Flanagan L, Dasgupta S, Rice N, Pilati C, Zink E, Schöller LM, Toomey S, Lawler M, Johnston PG, Wilson R, Camilleri-Broët S, Salto-Tellez M, McNamara DA, Kay EW, Laurent-Puig P, Van Schaeybroeck S, Hennessy BT, Longley DB, Rehm M, Prehn JH

Abstract
Purpose: Apoptosis is essential for chemotherapy responses. In this discovery and validation study, we evaluated the suitability of a mathematical model of apoptosis execution (APOPTO-CELL) as a stand-alone signature and as a constituent of further refined prognostic stratification tools.Experimental Design: Apoptosis competency of primary tumor samples from patients with stage III colorectal cancer (n = 120) was calculated by APOPTO-CELL from measured protein concentrations of Procaspase-3, Procaspase-9, SMAC, and XIAP. An enriched APOPTO-CELL signature (APOPTO-CELL-PC3) was synthesized to capture apoptosome-independent effects of Caspase-3. Furthermore, a machine learning Random Forest approach was applied to APOPTO-CELL-PC3 and available molecular and clinicopathologic data to identify a further enhanced signature. Association of the signature with prognosis was evaluated in an independent colon adenocarcinoma cohort (TCGA COAD, n = 136).Results: We identified 3 prognostic biomarkers (P = 0.04, P = 0.006, and P = 0.0004 for APOPTO-CELL, APOPTO-CELL-PC3, and Random Forest signatures, respectively) with increasing stratification accuracy for patients with stage III colorectal cancer.The APOPTO-CELL-PC3 signature ranked highest among all features. The prognostic value of the signatures was independently validated in stage III TCGA COAD patients (P = 0.01, P = 0.04, and P = 0.02 for APOPTO-CELL, APOPTO-CELL-PC3, and Random Forest signatures, respectively). The signatures provided further stratification for patients with CMS1-3 molecular subtype.Conclusions: The integration of a systems-biology-based biomarker for apoptosis competency with machine learning approaches is an appealing and innovative strategy toward refined patient stratification. The prognostic value of apoptosis competency is independent of other available clinicopathologic and molecular factors, with tangible potential of being introduced in the clinical management of patients with stage III colorectal cancer. Clin Cancer Res; 23(5); 1200-12. ©2016 AACR.

PMID: 27649552 [PubMed - indexed for MEDLINE]

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.

Oncotarget. 2016 Oct 11;7(41):66328-66343

Authors: Zhang M, Wang Z, Obazee O, Jia J, Childs EJ, Hoskins J, Figlioli G, Mocci E, Collins I, Chung CC, Hautman C, Arslan AA, Beane-Freeman L, Bracci PM, Buring J, Duell EJ, Gallinger S, Giles GG, Goodman GE, Goodman PJ, Kamineni A, Kolonel LN, Kulke MH, Malats N, Olson SH, Sesso HD, Visvanathan K, White E, Zheng W, Abnet CC, Albanes D, Andreotti G, Brais L, Bueno-de-Mesquita HB, Basso D, Berndt SI, Boutron-Ruault MC, Bijlsma MF, Brenner H, Burdette L, Campa D, Caporaso NE, Capurso G, Cavestro GM, Cotterchio M, Costello E, Elena J, Boggi U, Gaziano JM, Gazouli M, Giovannucci EL, Goggins M, Gross M, Haiman CA, Hassan M, Helzlsouer KJ, Hu N, Hunter DJ, Iskierka-Jazdzewska E, Jenab M, Kaaks R, Key TJ, Khaw KT, Klein EA, Kogevinas M, Krogh V, Kupcinskas J, Kurtz RC, Landi MT, Landi S, Le Marchand L, Mambrini A, Mannisto S, Milne RL, Neale RE, Oberg AL, Panico S, Patel AV, Peeters PH, Peters U, Pezzilli R, Porta M, Purdue M, Quiros JR, Riboli E, Rothman N, Scarpa A, Scelo G, Shu XO, Silverman DT, Soucek P, Strobel O, Sund M, Małecka-Panas E, Taylor PR, Tavano F, Travis RC, Thornquist M, Tjønneland A, Tobias GS, Trichopoulos D, Vashist Y, Vodicka P, Wactawski-Wende J, Wentzensen N, Yu H, Yu K, Zeleniuch-Jacquotte A, Kooperberg C, Risch HA, Jacobs EJ, Li D, Fuchs C, Hoover R, Hartge P, Chanock SJ, Petersen GM, Stolzenberg-Solomon RS, Wolpin BM, Kraft P, Klein AP, Canzian F, Amundadottir LT

Abstract
Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

PMID: 27579533 [PubMed - indexed for MEDLINE]

Limits and potential of targeted sequencing analysis of liquid biopsy in patients with lung and colon carcinoma.

Oncotarget. 2016 10 11;7(41):66595-66605

Authors: Rachiglio AM, Esposito Abate R, Sacco A, Pasquale R, Fenizia F, Lambiase M, Morabito A, Montanino A, Rocco G, Romano C, Nappi A, Iaffaioli RV, Tatangelo F, Botti G, Ciardiello F, Maiello MR, De Luca A, Normanno N

Abstract
The circulating free tumor DNA (ctDNA) represents an alternative, minimally invasive source of tumor DNA for molecular profiling. Targeted sequencing with next generation sequencing (NGS) can assess hundred mutations starting from a low DNA input. We performed NGS analysis of ctDNA from 44 patients with metastatic non-small-cell lung carcinoma (NSCLC) and 35 patients with metastatic colorectal carcinoma (CRC). NGS detected EGFR mutations in 17/22 plasma samples from EGFR-mutant NSCLC patients (sensitivity 77.3%). The concordance rate between tissue and plasma in NSCLC was much lower for other mutations such as KRAS that, based on the allelic frequency and the fraction of neoplastic cells, were likely to be sub-clonal. NGS also identified EGFR mutations in plasma samples from two patients with EGFR wild type tumor tissue. Both mutations were confirmed by droplet digital PCR (ddPCR) in both plasma and tissue samples. In CRC, the sensitivity of the NGS plasma analysis for RAS mutations was 100% (6/6) in patients that had not resection of the primary tumor before blood drawing, and 46.2% (6/13) in patients with primary tumor resected before enrollment. Our study showed that NGS is a suitable method for plasma testing. However, its clinical sensitivity is significantly affected by the presence of the primary tumor and by the heterogeneity of driver mutations.

PMID: 27448974 [PubMed - indexed for MEDLINE]

Relevance of BRAF and NRAS mutations in the primary tumor and metastases of papillary thyroid carcinomas.

Head Neck. 2016 Dec;38(12):1772-1779

Authors: Cañadas-Garre M, Becerra-Massare P, Moreno Casares A, Calleja-Hernández MÁ, Llamas-Elvira JM

Abstract
BACKGROUND: Multifocality of papillary thyroid carcinoma (PTC) is common. BRAF and NRAS mutations are the most frequent genetic alterations in PTC. The purpose of this study was to determine the distribution and relevance of BRAFT1799A and NRAS mutations in PTC.
METHODS: BRAFT1799A and NRAS mutations were evaluated in 195 intrathyroid or metastatic foci from 29 patients with multifocal PTC.
RESULTS: BRAFT1799A mutation was positive in 46.7% of the 59 intrathyroid and 136 metastatic foci (91/195 foci). Heterogeneous BRAF pattern was observed in 51.7% patients (15/29 patients). Irrespective of BRAF status at diagnosis (thyroid or nodes), all patients with recurrent PTC presented BRAF-mutated metastases during follow-up. All foci were negative for NRAS mutations.
CONCLUSION: BRAF but not NRAS mutations were heterogeneously distributed among primary tumor, nodal sites, and recurrent disease. The BRAF status of metastases generated during the follow-up can differ from the status of foci at diagnosis. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1772-1779, 2016.

PMID: 27299298 [PubMed - indexed for MEDLINE]

Prevalence and management of intrathecal morphine-induced pruritus in New Zealand Māori healthcare recipients.

Br J Pain. 2018 Feb;12(1):20-25

Authors: Woods JM, Lim AG

Abstract
Aims and objectives: The aim of this article was to determine whether the incidence of intrathecal morphine-induced pruritus (ITMI) was influenced by ethnicity, age or gender in relation to orthopaedic versus caesarean surgeries.
Background: The use of intrathecal morphine for patients undergoing total hip and knee joint replacements and for lower segment caesarean sections (LSCS) has gained popularity worldwide since its introduction over 30 years ago. Several international studies show that morphine delivered via the intrathecal route is an effective and safe method of pain relief. However, while the beneficial effects of intrathecal morphine have been clearly documented in many studies, so also have the adverse effects, predominantly being nausea and vomiting, pruritus and respiratory depression. Pruritus is described as one of the most common adverse effects, with a reported incidence of 30-100%.
Design: A retrospective study was conducted using data collected over a 21-month period on post-operative patients who had received intrathecal morphine as their post-operative pain management.
Methods: A two-phased approach was undertaken. The study was conducted to determine the incidence of ITMI pruritus among two patient groups, New Zealand Māori and New Zealand European, 96 subjects in total, and if treatment was received.
Results: The findings revealed significant ethnic disparities whereas New Zealand Māori had a significantly higher rate of ITMI pruritus than New Zealand European, New Zealand Māori experienced the pruritus with more intensity and are less likely to be treated for it.
Conclusion: Increased international knowledge and awareness for health professionals around the diversities of ethnicity and associated pharmacogenetics playing a significant role in patient response to opioid therapy can lead to improved overall care and patient satisfaction.

PMID: 29416861 [PubMed]

Clinical efficacy and safety of afatinib in the treatment of non-small-cell lung cancer in Chinese patients.

Onco Targets Ther. 2018;11:529-538

Authors: Wang LY, Cui JJ, Guo AX, Yin JY

Abstract
Compared with various malignant tumors, lung cancer has high incidence and the highest mortality worldwide. Non-small-cell lung cancer (NSCLC), the most common kind of lung cancer, is still a great threat to the world, including China. Surgery, platinum-based chemotherapy, and radiotherapy are still the primary treatments for NSCLC patients in the clinic, whereas immunotherapy and targeted therapy are gradually playing more important roles. A next-generation tyrosine kinase inhibitor (TKI), afatinib, was developed as a targeted reagent for epidermal growth factor receptor (EGFR). This targeted drug was effective in a series of trials. The US Food and Drug Administration then approved afatinib as a new first-line treatment for EGFR L858R and exon 19 deletion mutant patients in 2013. This review focused on current clinical studies of afatinib. Although this TKI was not widely available in China until recently, we aim to provide a reference for its future use in China.

PMID: 29416353 [PubMed]

Accurate determination of the CYP2D6 (*1/*4)xN genotype by quantitative PCR.

Drug Metab Pers Ther. 2018 Feb 08;:

Authors: Pondman KM, van Schaik RHN, van der Weide J

Abstract
BACKGROUND: CYP2D6 is responsible for the metabolism of approximately 25% of all drugs. The expression of cytochrome P450 2D6 (CYP2D6) is influenced by a combination of factors including polymorphisms in the CYP2D6 gene. Analysis of the CYP2D6 genotype is used to personalize the medication to a patient's metabolism. Although many genotypes can be determined using standard genotype analysis, in some cases, an incomplete analysis is performed. The CYP2D6 genotype *1/*4 often occurs in combination with a multiplication of the CYP2D6 gene, and is reported as (*1/*4)xN. Accurate determination of the multiplied gene is essential to provide a phenotype prediction for these patients. Duplication of the *1 gene leads to an extensive metabolizer genotype whereas multiplication of the *4 gene would not lead to extra functional enzyme and therefore provides an intermediate metabolizer phenotype.
METHODS: Here, a technique is described in which the copy numbers of both the *4 and *1 genes are determined using quantitative PCR techniques.
RESULTS AND CONCLUSIONS: This technique provides a method to predict the patient's CYP2D6 phenotype, and is therefore an important step toward personalized medicine.

PMID: 29420304 [PubMed - as supplied by publisher]

Concise Review: Chronic Myeloid Leukemia: Stem Cell Niche and Response to Pharmacologic Treatment.

Stem Cells Transl Med. 2018 Feb 08;:

Authors: Arrigoni E, Del Re M, Galimberti S, Restante G, Rofi E, Crucitta S, Baratè C, Petrini M, Danesi R, Di Paolo A

Abstract
Nowadays, more than 90% of patients affected by chronic myeloid leukemia (CML) survive with a good quality of life, thanks to the clinical efficacy of tyrosine kinase inhibitors (TKIs). Nevertheless, point mutations of the ABL1 pocket occurring during treatment may reduce binding of TKIs, being responsible of about 20% of cases of resistance among CML patients. In addition, the presence of leukemic stem cells (LSCs) represents the most important event in leukemia progression related to TKI resistance. LSCs express stem cell markers, including active efflux pumps and genetic and epigenetic alterations together with deregulated cell signaling pathways involved in self-renewal, such as Wnt/β-catenin, Notch, and Hedgehog. Moreover, the interaction with the bone marrow microenvironment, also known as hematopoietic niche, may influence the phenotype of surrounding cells, which evade mechanisms controlling cell proliferation and are less sensitive or frankly resistant to TKIs. This Review focuses on the role of LSCs and stem cell niche in relation to response to pharmacological treatments. A literature search from PubMed database was performed until April 30, 2017, and it has been analyzed according to keywords such as chronic myeloid leukemia, stem cell, leukemic stem cells, hematopoietic niche, tyrosine kinase inhibitors, and drug resistance. Stem Cells Translational Medicine 2018.

PMID: 29418079 [PubMed - as supplied by publisher]

Breaking Down Barriers to Effective Patient Care.

Clin Pharmacol Ther. 2018 Mar;103(3):360-364

Authors: O'Donnell PH, Reynolds KS

Abstract
The theme for the 2018 ASCPT Annual Meeting is "Breaking Down Barriers to Effective Patient Care." This theme refers to the essential contributions of clinical pharmacology to the development of today's discovery into tomorrow's medicine. The various subdisciplines within clinical pharmacology serve to move molecules through the various stages of drug development and also refine or expand use of the drug postapproval. The wide range of topics covered by the 2018 Annual Meeting scientific program demonstrates the breadth of clinical pharmacology's impact. Because of new methods being developed to identify drug targets, medicines are being developed for patients with rare diseases. Biomarkers and diagnostic tools are advancing the development of drugs for neurodegenerative disorders, cancer, and many other diseases. Preclinical data are playing a key role in informing the quantitative clinical pharmacology of drugs, especially antimicrobials, and animal efficacy data are pivotal for drugs that are developed and approved under the animal rule. The use of pharmacogenomics, model-based drug development, informatics, and identification and evaluation of subgroups are key topics. With our focus on the patient, the Annual Meeting, and this issue of Clinical Pharmacology & Therapeutics, will highlight the many innovative ways that current clinical pharmacology investigations are attempting to dissolve barriers to effective patient care.

PMID: 29417567 [PubMed - in process]

Education and Knowledge in Pharmacogenomics: Still a Challenge?

Clin Pharmacol Ther. 2018 Feb 08;:

Authors: Giri J, Curry TB, Formea CM, Nicholson WT, Rohrer Vitek CR

Abstract
A number of barriers exist for adoption of pharmacogenomics into practice. Physicians, pharmacists, and nurses report limited knowledge about pharmacogenomics and its use in patient care. Lack of pharmacogenomics education curricula as part of professional schools or postgraduate training programs has been reported as a potential cause. Understanding pharmacogenomics is further complicated by a complex and nonstandard lexicon, limited medication guidelines, rapidly changing evidence, and insufficient awareness of test availability and utility.

PMID: 29417560 [PubMed - as supplied by publisher]