Radiol Oncol. 2021 Sep 17. doi: 10.2478/raon-2021-0036. Online ahead of print.

ABSTRACT

BACKGROUND: The aim of this study was to evaluate changes in prognostic risk profiles of women with endometrial cancer by comparing the clinical risk assessment with the integrated molecular risk assessment profiling.

PATIENTS AND METHODS: This prospective study recruited patients with biopsy proven endometrial cancer treated at the University Medical Centre Maribor between January 2020 to February 2021. Patient clinical data was assessed and categorized according to the currently valid European Society of Gynaecological Oncology, European SocieTy for Radiotherapy and Oncology, and European Society of Pathology (ESGO/ESTRO/ESP) guidelines on endometrial cancer. Molecular tumour characterization included determination of exonuclease domain of DNA polymerase-epsilon (POLE) mutational status by Sanger sequencing and imunohistochemical specimen evaluation on the presence of mismatch repair deficiencies (MMRd) and p53 abnormalities (p53abn).

RESULTS: Fourty-five women were included in the study. Twenty-two tumours were of non-specific mutational profile (NSMP) (56.4%), 13 were classified as MMRd (33.3%), 3 were classified as p53abn (7.7%) and 1 was classified as POLE mutated (2.6%). Six tumours (15.4%) had multiple molecular classifiers, these were studied separately and were not included in the risk assessment. The clinical risk-assessment classified 21 women (53.8%) as low-risk, 5 women (12.8%) as intermediate risk, 2 women as high-intermediate risk (5.1%), 10 women (25.6%) as high risk and 1 patient as advanced metastatic (2.6%). The integrated molecular classification changed risk for 4 women (10.3%).

CONCLUSIONS: Integrated molecular risk improves personalized risk assessment in endometrial cancer and could potentially improve therapeutic precision. Further molecular stratification with biomarkers is especially needed in the NSMP group to improve personalized risk-assessment.

PMID:34529911 | DOI:10.2478/raon-2021-0036

Blood Adv. 2021 Sep 16:bloodadvances.2021004561. doi: 10.1182/bloodadvances.2021004561. Online ahead of print.

ABSTRACT

Sequence variation in the HLA-B gene is critically linked to differential immune responses. A dimorphism at -21 of HLA-B exon 1 gives rise to leader peptides that are markers for risk of acute graft-versus-host disease (GVHD), relapse, and mortality after unrelated donor and cord blood transplantation. To optimize the selection of stem cell transplant sources based on the HLA-B leader, an HLA-B Leader Assessment Tool ("BLEAT") was developed to automate the assignment of leader genotypes, define HLA-B leader match statuses, and rank order candidate stem cell sources according to clinical risk. The base cohort consisted of 9,417,614 registered donors from the Be The Match Registry® with HLA-B typing. Among these donors, the performance of BLEAT was assessed in 1,098,358 donors with sequence data for HLA-B exon 1 (2,196,716 haplotypes). The accuracy of leader assignment was then assessed in a second cohort of 1,259 patients and their unrelated transplant donors. We furthermore established the frequencies of HLA-B leader genotype (MM, MT, TT) representations in broad racial categories in the 9.42 million donors. BLEAT has direct applications for the selection of optimal stem cell sources for transplantation and broad utility in basic and clinical research in pharmacogenomics, vaccine development, and cancer and infectious disease studies of human populations.

PMID:34529780 | DOI:10.1182/bloodadvances.2021004561

Xenobiotica. 2021 Sep 16:1-32. doi: 10.1080/00498254.2021.1982070. Online ahead of print.

ABSTRACT

Acetaminophen is gaining importance as a first-line drug for treating patent ductus arteriosus (PDA) in neonates. Predominant metabolites of acetaminophen in preterm neonates vary from that of adults; and the drug is predominantly metabolized by conjugation and partly by Cytochrome P450 (CYP) enzymes.We carried out the present study to identify the principal urine metabolites of acetaminophen (glucuronide/sulphate) in preterm neonates with hemodynamically significant PDA receiving intravenous acetaminophen, and to evaluate the prevalence of single nucleotide polymorphisms (SNPs) in the key CYP enzymes (CYP1A2*3, CYP1A2*4, CYP1A2*1C, CYP1A2*1K, CYP1A2*6, CYP2D6*10, CYP2E1*2, CYP2E1*5B, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, and CYP3A5*11) and their effect on urinary metabolites and serum acetaminophen concentrations.Nineteen (32.8%) neonates had heterozygous CYP1A2*1C, two (3.3%) with heterozygous CYP1A2*1K, 15 (27.8%) and two (3.7%) had heterozygous and homozygous CYP2D6*10, two (3.7%) had heterozygous CYP2E1*5B, seven (12.3%) and three (5.3%) had heterozygous and homozygous CYP3A4*1B, and three (5.5%) had CYP3A5*7 amongst the study population. Acetaminophen sulphate predominated over glucuronide metabolite at all time points. Postnatal days of life was significantly associated with an increase in the urine acetaminophen metabolites with decreased serum acetaminophen concentrations.A significant prevalence of SNPs in the key CYP enzymes related to acetaminophen metabolism was observed in our neonatal population. Population pharmacokinetic-pharmacodynamic modeling incorporating genetic and metabolite data is urgently needed for implementation of precision medicine in this vulnerable population.

PMID:34529545 | DOI:10.1080/00498254.2021.1982070

Pharmacogenomics. 2021 Sep 16. doi: 10.2217/pgs-2021-0051. Online ahead of print.

ABSTRACT

Genetic polymorphism in olanzapine-metabolizing enzymes, transporters and drug targets is associated with alterations in safety and efficacy. The aim of this systematic review is to describe all clinically relevant pharmacogenetic information on olanzapine and to propose clinically actionable variants. Two hundred and eighty-four studies were screened; 76 complied with the inclusion criteria and presented significant associations. DRD2 Taq1A (rs1800497) *A1, LEP -2548 (rs7799039) G and CYP1A2*1F alleles were related to olanzapine effectiveness and safety variability in several studies, with a high level of evidence. DRD2 -141 (rs1799732) Ins, A-241G (rs1799978) G, DRD3 Ser9Gly (rs6280) Gly, HTR2A rs7997012 A, ABCB1 C3435T (rs1045642) T and G2677T/A (rs2032582) T and UGT1A4*3 alleles were related to safety, effectiveness and/or pharmacokinetic variability with moderated level of evidence.

PMID:34528455 | DOI:10.2217/pgs-2021-0051

Pharmacogenomics. 2021 Sep 16. doi: 10.2217/pgs-2021-0062. Online ahead of print.

ABSTRACT

Aim: Despite the high disease burden of human immunodeficiency virus (HIV) infection and colorectal cancer (CRC) in South Africa (SA), treatment-relevant pharmacogenetic variants are understudied. Materials & methods: Using publicly available genotype and gene expression data, a bioinformatic pipeline was developed to identify liver expression quantitative trait loci (eQTLs). Results: A novel cis-eQTL, rs28967009, was identified for UGT1A1, which is predicted to upregulate UGT1A1 expression thereby potentially affecting the metabolism of dolutegravir and irinotecan, which are extensively prescribed in SA for HIV and colorectal cancer treatment, respectively. Conclusion: As increased UGT1A1 expression could affect the clinical outcome of dolutegravir and irinotecan treatment by increasing drug clearance, patients with the rs28967009A variant may require increased drug doses to reach therapeutic levels or should be prescribed alternative drugs.

PMID:34528449 | DOI:10.2217/pgs-2021-0062

Cancer Epidemiol Biomarkers Prev. 2021 Sep 15:cebp.0353.2021. doi: 10.1158/1055-9965.EPI-21-0353. Online ahead of print.

ABSTRACT

BACKGROUND: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC aetiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNPs) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported.

METHODS: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analysed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using MAGMA software.

RESULTS: In the discovery phase we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P <0.05). In the second phase none of the findings were replicated. In the gene-level analysiswe observed that three genes (TERT, SUGCT and SURF1) involved in the mitochondrial metabolismshowed an association below the Bonferroni-corrected threshold of statistical significance (P=0.05/1588=3.1 x10-5).

CONCLUSIONS: Even though the mitochondrial metabolism might be involved in PDAC aetiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk.

IMPACT: This large case-control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.

PMID:34526302 | DOI:10.1158/1055-9965.EPI-21-0353

BMC Cancer. 2021 Sep 16;21(1):1030. doi: 10.1186/s12885-021-08745-0.

ABSTRACT

BACKGROUND: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3-4 toxicity.

METHODS: Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms.

RESULTS: Reported grade ≤ 2 and 3-4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70-10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19-1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity.

CONCLUSION: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.

PMID:34525956 | DOI:10.1186/s12885-021-08745-0

Curr Drug Metab. 2021 Aug 25. doi: 10.2174/1389200222666210825160021. Online ahead of print.

ABSTRACT

BACKGROUND: Although the pharmacokinetic variability of Tacrolimus (Tac) metabolism is primarily influenced by CYP3A5 genotypes, the potential effect according to CYP3A5 polymorphisms in Tac extended-release (Tac-ER) and immediate-release (Tac-IR) and between these formulations' conversion needs further investigation. The purpose of this study was to clarify the association of CYP3A5 genotypes and pharmacokinetics of different Tac formulations in renal transplant recipients.

METHODS: PubMed, EMBASE, and Cochrane Library databases were searched for eligible studies (protocol registration No. CRD 42019133790 in PROSPERO network). The summary weighted mean difference with 95% confidence intervals was calculated for pharmacokinetic parameters using the random-effects model according to post-transplantation periods, genotypes and formulations. Sensitivity analysis, publication bias, and subgroup analyses were conducted.

RESULTS: A total of 27 studies involving 2,713 renal transplant recipients were adopted. Whether patients treated with Tac-ER or Tac-IR, CYP3A5 non-expressors (*3/*3) had a decreased daily dose and CL/F, an increased Ctrough, Ctrough/D, AUC0-24h/D and Cmax/D than expressors (*1/*1 or *1/*3) at most post-transplantation periods. Furthermore, when 1:1 dose conversion from Tac-IR to Tac-ER (all at ≥12 months post-transplantation), Ctrough and Cmax were decreased in both CYP3A5 non-expressors and expressors, while daily dose was only decreased in CYP3A5 non-expressors and AUC0-24h was only decreased in CYP3A5 expressors. Finally, subgroup analyses indicated that ethnicity, mean age, and male percentage influenced daily dose and Ctrough of Tac, especially for Tac-IR.

CONCLUSION: The results indicated that CYP3A5 genotypes affect the pharmacokinetics of Tac in renal transplant recipients in both formulations and between formulations' conversion. Future studies should be exploring more other associations of CYP3A5 genotypes and the pharmacodynamics of Tac.

PMID:34525930 | DOI:10.2174/1389200222666210825160021

Pharmacogenomics. 2021 Sep 16. doi: 10.2217/pgs-2021-0048. Online ahead of print.

ABSTRACT

Although gene fusions occur rarely in non-small-cell lung cancer (NSCLC) patients, they represent a relevant target in treatment decision algorithms. To date, immunohistochemistry and fluorescence in situ hybridization are the two principal methods used in clinical trials. However, using these methods in routine clinical practice is often impractical and time consuming because they can only analyze single genes and the quantity of tissue material is often insufficient. Thus, novel technologies, able to test multiple genes in a single run with minimal sample input, are being under investigation. Here, we discuss the utility of next-generation sequencing and nCounter technologies in detecting simultaneous gene fusions in NSCLC patients.

PMID:34525844 | DOI:10.2217/pgs-2021-0048

Cell Stem Cell. 2021 Sep 14:S1934-5909(21)00343-X. doi: 10.1016/j.stem.2021.08.006. Online ahead of print.

ABSTRACT

Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but its use is limited by dose-dependent cardiotoxicity. A recent genome-wide association study identified a SNP (rs2229774) in retinoic acid receptor-γ (RARG) as statistically associated with increased risk of anthracycline-induced cardiotoxicity. Here, we show that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with rs2229774 and who suffered doxorubicin-induced cardiotoxicity (DIC) are more sensitive to doxorubicin. We determine that the mechanism of this RARG variant effect is mediated via suppression of topoisomerase 2β (TOP2B) expression and activation of the cardioprotective extracellular regulated kinase (ERK) pathway. We use patient-specific hiPSC-CMs as a drug discovery platform, determining that the RARG agonist CD1530 attenuates DIC, and we confirm this cardioprotective effect in an established in vivo mouse model of DIC. This study provides a rationale for clinical prechemotherapy genetic screening for rs2229774 and a foundation for the clinical use of RARG agonist treatment to protect cancer patients from DIC.

PMID:34525346 | DOI:10.1016/j.stem.2021.08.006

Biomed Pharmacother. 2021 Sep 12;142:112060. doi: 10.1016/j.biopha.2021.112060. Online ahead of print.

ABSTRACT

BACKGROUND: Adequate opioid prescribing is critical for therapeutic success of pain management. Despite the widespread use of opioids, optimized opioid therapy remains unresolved with risk of accidental lethal overdosing. With the emergence of accumulating evidence linking genetic variation to opioid response, pharmacogenetic based treatment recommendations have been proposed.

OBJECTIVE: The aim of this review is to evaluate pharmacogenetic evidence and provide an overview on genes involved in the pharmacokinetics and pharmacodynamics of opioids.

METHODS: For this review, a systematic literature search of published articles was used in PubMed®, with no language restriction and between the time period of January 2000 to December 2020. We reviewed randomized clinical studies, study cohorts and case reports that investigated the influence of genetic variants on selected opioid pharmacokinetics and pharmacodynamics. In addition, we reviewed current CPIC clinical recommendations for pharmacogenetic testing.

RESULTS: Results of this review indicate consistent evidence supporting the association between selected genetic variants of CYP2D6 for opioid metabolism. CPIC guidelines include recommendations that indicate the avoidance of tramadol use, in addition to codeine, in CYP2D6 poor metabolizers and ultrarapid metabolizers, and to monitor intermediate metabolizers for less-than-optimal response. While there is consistent evidence for OPRM1 suggesting increased postoperative morphine dosing requirements in A118G G-allele carriers, the clinical relevance remains limited.

CONCLUSION: There is emerging evidence of clinical relevance of CYP2D6 and, to a lesser extent, OPRM1 polymorphism in personalized opioid drug dosing. As a result, first clinics have started to implement pharmacogenetic guidelines for CYP2D6 and codeine.

PMID:34523422 | DOI:10.1016/j.biopha.2021.112060

Pharmacogenomics. 2021 Sep 15. doi: 10.2217/pgs-2021-0083. Online ahead of print.

ABSTRACT

Aim: Sirolimus (SIR) is an immunosuppressant with limitations, including a narrow treatment window, multiple adverse reactions and large differences within and among individuals. Objective: We analyzed the correlation between numerous SNPs and SIR in terms of trough concentration in the early stage after kidney transplantation. Materials & method: A retrospective cohort study involving 69 kidney transplantation recipients was designed. Blood samples were collected to extract total DNAs, and trough SIR concentrations were measured. Logistic regression was used to analyze the association between SNPs and SIR trough concentrations. Result: At 7 days, 1 month and 3 months, the mean SIR trough concentration of patients in the CYP3A5 rs4646453-CC group was significantly higher than that in the CYP3A5 rs4646453-AA and CYP3A5 rs4646453-CA groups (p < 0.001) and CYP3A5 rs15524-AA group was significantly higher than that in the CYP3A5 rs15524-AG and CYP3A5 rs15524-GG groups (p < 0.001). Conclusion: Our study indicated that both CYP3A5 rs4646453 and CYP3A5 rs15524 had a certain influence on SIR trough concentration at 7 days, 1 month and 3 months.

PMID:34523354 | DOI:10.2217/pgs-2021-0083

Curr Pharm Teach Learn. 2021 Oct;13(10):1370-1375. doi: 10.1016/j.cptl.2021.07.017. Epub 2021 Jul 24.

ABSTRACT

BACKGROUND: An interprofessional (IP) experience was created that demonstrated the roles and responsibilities of pharmacists and physicians in clinical implementation of pharmacogenomics (PGx). The IP experience focused on PGx-themed patient cases and application of genotyping results to drug therapy management.

INTERPROFESSIONAL EDUCATION ACTIVITY: In 2016 and 2017, third-year pharmacy students and first-year medical students were placed on interprofessional teams with two to three students each. The teams resolved PGx patient cases, medical students wrote prescriptions for altered drug therapy based on the PGx profiles of the patients, and pharmacy students assessed and provided feedback to medical students about the prescriptions. Student could also volunteer to be genotyped for CYP2C19*2, and the results were compared.

DISCUSSION: The IP experience significantly enhanced PGx knowledge and increased the confidence of using PGx in patient cases for the majority of participants. The experience did not increase the recognition of each discipline's role in precision medicine in a statistically significant manner. Accurate prescription writing was challenging for the first-year medical students (44.3% prescriptions written correctly). The genotyping results did not deviate from a Hardy Weinberg equilibrium for this population.

IMPLICATIONS: IP experiences focused on PGx present an ideal opportunity to educate and initiate collaborations between pharmacists and physicians and to promote utilization of PGx in precision medicine. The roles and responsibilities for each discipline can be easily recreated in an IP experience to provide robust training to the students.

PMID:34521534 | DOI:10.1016/j.cptl.2021.07.017

Trials. 2021 Sep 14;22(1):616. doi: 10.1186/s13063-021-05456-6.

ABSTRACT

BACKGROUND: Internationally, older patients (≥65 years) account for more than 40% of acute admissions. Older patients admitted to the emergency department (ED) are frequently malnourished and exposed to inappropriate medication prescribing, due in part to the inaccuracy of creatinine-based equations for estimated glomerular filtration rate (eGFR). The overall aims of this trial are to investigate: (1) the efficacy of a medication review (MED intervention) independent of nutritional status, (2) the accuracy of eGFR equations based on various biomarkers compared to measured GFR (mGFR) based on 99mTechnetium-diethylenetriaminepentaacetic acid plasma clearance, and (3) the efficacy of an individualized multimodal and transitional nutritional intervention (MULTI-NUT-MED intervention) in older patients with or at risk of malnutrition in the ED.

METHODS: The trial is a single-center block randomized, controlled, observer-blinded, superiority and explorative trial with two parallel groups. The population consists of 200 older patients admitted to the ED: 70 patients without malnutrition or risk of malnutrition and 130 patients with or at risk of malnutrition defined as a Mini Nutritional Assessment-Short Form score ≤11. All patients without the risk of malnutrition receive the MED intervention, which consists of a medication review by a pharmacist and geriatrician in the ED. Patients with or at risk of malnutrition receive the MULTI-NUT-MED intervention, which consists of the MED intervention in addition to, dietary counseling and individualized interventions based on the results of screening tests for dysphagia, problems with activities of daily living, low muscle strength in the lower extremities, depression, and problems with oral health. Baseline data are collected upon study inclusion, and follow-up data are collected at 8 and 16 weeks after discharge. The primary outcomes are (1) change in medication appropriateness index (MAI) score from baseline to 8 weeks after discharge, (2) accuracy of different eGFR equations compared to mGFR, and (3) change in health-related quality of life (measured with EuroQol-5D-5L) from baseline to 16 weeks after discharge.

DISCUSSION: The trial will provide new information on strategies to optimize the treatment of malnutrition and inappropriate medication prescribing among older patients admitted to the ED.

TRAIL REGISTRATION: ClinicalTrials.gov NTC03741283 . Retrospectively registered on 14 November 2018.

PMID:34521465 | DOI:10.1186/s13063-021-05456-6

Pharmacogenomics. 2021 Sep 15. doi: 10.2217/pgs-2021-0064. Online ahead of print.

ABSTRACT

Aim: To identify novel genetic variants predisposing to elevation of Alanine aminotransferase (ALT) in rheumatoid arthritis (RA) patients after initiation of methotrexate (MTX) treatment. Patients & methods: We performed genome-wide association studies in 198 RA patients starting MTX. Outcomes were maximum level of ALT and ALT >1.5-times the upper level of normal within the first 6 months of treatment. Results: RAVER2 (rs72675408) was significantly associated with maximum level of ALT (p = 4.36 × 10-8). This variant is in linkage disequilibrium with rs72675451, which is associated with differential expression of JAK1 and RAVER2. Conclusion: We found an association between ALT elevation and genetic variants that may regulate the expression of JAK1 and RAVER2. JAK1 encodes a janus kinase involved in the pathogenesis of RA.

PMID:34521259 | DOI:10.2217/pgs-2021-0064

Pharmacogenomics. 2021 Sep 15. doi: 10.2217/pgs-2021-0044. Online ahead of print.

ABSTRACT

Opioid misuse and mismanagement has been a public health crisis for several years. Pharmacogenomics (PGx) has been proposed as another tool to enhance opioid selection and optimization, with recent studies demonstrating successful implementation and outcomes. However, broad engagement with PGx for opioid management is presently limited. The purpose of this Perspective is to highlight a series of barriers to PGx implementation within the specific context of opioid management. Areas of advancement needed for more robust pharmacogenomic engagement with opioids will be discussed, including clinical and economic research needs, education and training needs, policy and public health considerations, as well as legal and ethical issues. Continuing efforts to address these issues may help to further operationalize PGx toward improving opioid use.

PMID:34521258 | DOI:10.2217/pgs-2021-0044

J Mol Neurosci. 2021 Sep 14. doi: 10.1007/s12031-021-01892-w. Online ahead of print.

ABSTRACT

Cluster headache (CH) is a severe primary headache disorder with a genetic component, as indicated by family and twin studies. Diurnal and seasonal rhythmicity are key features of the disease and might be related to vitamin D, as low vitamin D levels have been observed in patients with cluster headache. In addition, the vitamin D receptor (VDR) occurs in brain areas and particularly in the hypothalamus. The aim of the present case-control study was to investigate the association of cluster headache susceptibility and clinical phenotypes with the VDR gene polymorphisms FokI, BsmI and TaqI in a Southeastern European Caucasian population. DNA was extracted from 131 unrelated CH patients and 282 non-headache controls and genotyped using real-time PCR (melting curve analysis). Linkage disequilibrium (LD) analysis confirmed that BsmI and TaqI, both located in the 3'UTR of the VDR gene, are in strong LD. Genotype and allele frequency distribution analysis of the VDR FokI, BsmI, and TaqI polymorphisms showed no statistically significant difference between cases and controls, whereas haplotype analysis indicated that the TAC haplotype might be associated with decreased cluster headache susceptibility. Intra-patient analysis according to diverse clinical phenotypes showed an association of the BsmI GG and TaqI TT genotypes with more frequent occurrence of CH attacks in this cohort. Therefore, a possible association was observed between VDR gene polymorphisms BsmI and TaqI or a linked locus and susceptibility for cluster headache development and altered clinical phenotypes in the Southeastern European Caucasian study population. Further large-scale replication studies are needed to validate these findings.

PMID:34519950 | DOI:10.1007/s12031-021-01892-w

Pharmacogenomics. 2021 Sep 14. doi: 10.2217/pgs-2021-0061. Online ahead of print.

ABSTRACT

Aim: To compare the cost-effectiveness of olaparib versus control treatment in metastatic castration-resistant prostate cancer patients with at least one gene mutation in BRCA1, BRCA2 or ATM from the US payer perspective. Methods: A Markov model was constructed to assess the quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios. Sensitivity analyses and scenario analyses were conducted to explore the impact of uncertainties. Results: The base-case result indicated that, for patients with specific gene mutations, olaparib gained 1.26 QALYs and USD$ 157,732 total cost. Compared with control treatment, the incremental cost-effectiveness ratio of olaparib was USD$ 248,248/QALY. The price of olaparib was the most influential parameter. Conclusion: Olaparib is not cost-effective in comparison with control treatment in metastatic castration-resistant prostate cancer patients with specific gene mutations.

PMID:34517749 | DOI:10.2217/pgs-2021-0061

Sci Adv. 2021 Sep 3;7(36):eabg9241. doi: 10.1126/sciadv.abg9241. Epub 2021 Sep 1.

ABSTRACT

[Figure: see text].

PMID:34516906 | DOI:10.1126/sciadv.abg9241

JMIR Mhealth Uhealth. 2021 Sep 13;9(9):e33223. doi: 10.2196/33223.

ABSTRACT

[This corrects the article DOI: 10.2196/24555.].

PMID:34516388 | DOI:10.2196/33223