Per Med. 2023 Sep 22. doi: 10.2217/pme-2022-0074. Online ahead of print.

NO ABSTRACT

PMID:37736874 | DOI:10.2217/pme-2022-0074

Microbes Infect. 2023 Sep 19:105228. doi: 10.1016/j.micinf.2023.105228. Online ahead of print.

ABSTRACT

It has recently been found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) m6A modifications can affect viral replication and function. However, no studies to date have shown a correlation between SARS-CoV-2 m6A modifications and viral pathogenicity. In this study, we analyzed m6A modification in 2,190,667 SARS-CoV-2 genomic RNAs. m6A modifications of SARS-CoV-2 from different lineages, causing mild or severe COVID-19 and showing breakthrough for different vaccines were analyzed to explore correlations with viral pathogenicity. The results suggested that the presence of more m6A modifications in the SARS-CoV-2 N region (positive strand) correlates with weaker pathogenicity. In addition, we identified three m6A modification sites correlating with weak pathogenicity (924 in ORF1ab, 15659 in ORF1ab, 28288 in N, 28633 in N and 29385 in N, 29707 in 3'UTR) and one with strong pathogenicity (74 in 5'UTR). These results provide new information for understanding the prevalence of SARS-CoV-2 and controlling the virus.

PMID:37734532 | DOI:10.1016/j.micinf.2023.105228

Biomed Pharmacother. 2023 Sep 19;167:115479. doi: 10.1016/j.biopha.2023.115479. Online ahead of print.

ABSTRACT

A wide interindividual variability in therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) palbociclib, ribociclib and abemaciclib, among patients with HR+/HER2- metastatic breast cancer has been reported. This study explored the impact of genetic polymorphisms in ADME genes (responsible for drug absorption, distribution, metabolism, and elimination) on CDKis safety profiles in 230 patients. Selected endpoints include grade 3/4 neutropenia at day 14 of the first treatment cycle, early dose-limiting toxicities (DLTs), and dose reductions within the initial three cycles. Our analysis revealed associations between these endpoints and polymorphisms in CYP3A4, CYP3A5, ABCB1, and ABCG2 genes. Their impact on CDKis plasma concentrations (Ctrough) was also examined. Specifically, ABCB1 c.1236C>T and c.2677C>T polymorphisms correlated significantly with grade 3/4 neutropenia at day 14 (OR 3.94, 95% CI 1.32-11.75; p = 0.014 and OR 3.32, 95% CI 1.12-9.85; p = 0.030). Additionally, ABCB1 c.3435C>T was associated with an elevated risk of early DLTs and dose reductions (OR 3.28, 95% CI 1.22-8.84, p = 0.019; OR 2.60, 95% CI 1.20-5.60, p = 0.015). Carriers of the CYP3A4*22 allele also demonstrated in univariate a higher risk of early DLTs (OR 3.10, 95% CI 1.01-9.56, p = 0.049). Furthermore, individuals with the ABCB1 1236T-3435T-2677T(A) variant haplotype exhibited significant associations with grade 3/4 neutropenia at day 14 (OR 3.36, 95% CI 1.20-9.41; p = 0.021) and early DLTs in univariate (OR 3.08, 95% CI 1.19-7.95; p = 0.020). Homozygous carriers of the ABCB1 T-T-T(A) haplotype tended to have a higher mean ribociclib Ctrough (934.0 ng/mL vs. 752.0 ng/mL and 668.0 ng/mL). Regardless preliminary, these findings offer promising insights into the role of pharmacogenetic markers in CDKis safety profiles, potentially contributing to address the interindividual variability in CDKis responses.

PMID:37734262 | DOI:10.1016/j.biopha.2023.115479

Nat Genet. 2023 Sep 21. doi: 10.1038/s41588-023-01506-8. Online ahead of print.

ABSTRACT

Candidate cis-regulatory elements (cCREs) in microglia demonstrate the most substantial enrichment for Alzheimer's disease (AD) heritability compared to other brain cell types. However, whether and how these genome-wide association studies (GWAS) variants contribute to AD remain elusive. Here we prioritize 308 previously unreported AD risk variants at 181 cCREs by integrating genetic information with microglia-specific 3D epigenome annotation. We further establish the link between functional variants and target genes by single-cell CRISPRi screening in microglia. In addition, we show that AD variants exhibit allelic imbalance on target gene expression. In particular, rs7922621 is the effective variant in controlling TSPAN14 expression among other nominated variants in the same cCRE and exerts multiple physiological effects including reduced cell surface ADAM10 and altered soluble TREM2 (sTREM2) shedding. Our work represents a systematic approach to prioritize and characterize AD-associated variants and provides a roadmap for advancing genetic association to experimentally validated cell-type-specific phenotypes and mechanisms.

PMID:37735198 | DOI:10.1038/s41588-023-01506-8

Cas Lek Cesk. 2023 Summer;162(4):148-151.

ABSTRACT

In medicine, there are two main methods of improving the healthcare provided: perfecting (optimizing) the existing ones and seeking new treatment procedures. Despite of tremendous development in the central nervous system research, current treatment of severe mental illnesses, such as schizophrenia and depressive disorder, is suboptimal. Nowadays, optimization of treatment in psychiatry includes therapeutic drug monitoring (TDM) and pharmacogenomic testing, which examines genetic variation involved in medication metabolism and drug action. The TDM enables to determine drug concentrations in blood and adjust the dose accordingly if clinical effects correlate better with drug blood levels than drug doses. The first international guidelines for TDM in neuropsychopharmacology were published in 2004 and regularly updated. The recent update provides therapeutic reference ranges for a majority of commonly prescribed psychiatric medications and gives example of patients regularly treated in clinical practice profiting from TDM (using antipsychotics and changing their smoking habits). TDM in psychiatry is an underused tool, given its ability to optimize treatment, as well as to improve treatment effectiveness.

PMID:37734940

Pharmacol Res Perspect. 2023 Oct;11(5):e01137. doi: 10.1002/prp2.1137.

ABSTRACT

Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have β-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.

PMID:37732835 | DOI:10.1002/prp2.1137

Pharmacogenomics. 2023 Sep 21. doi: 10.2217/pgs-2023-0138. Online ahead of print.

ABSTRACT

The early detection of acute rejection in the allograft is important as it provides an opportunity for timely therapeutic intervention in order to preserve graft function and achieve longer graft survival. Donor-derived cell-free DNA (dd-cfDNA) has emerged as a new biomarker in the field of kidney transplantation. In this review, we used data from various studies to examine the role of dd-cfDNA in comparison to creatinine and donor-specific antibodies in the early detection of transplant rejection. We also reviewed the use of dd-cfDNA in other organ transplants as well as the challenges and potential future direction for dd-cfDNA as a diagnostic tool.

PMID:37732393 | DOI:10.2217/pgs-2023-0138

medRxiv. 2023 Sep 10:2023.09.08.23295248. doi: 10.1101/2023.09.08.23295248. Preprint.

ABSTRACT

RATIONALE: Standardized dosing of anti-tubercular (TB) drugs leads to variable plasma drug levels, which are associated with adverse drug reactions, delayed treatment response, and relapse. Mutations in genes affecting drug metabolism explain considerable interindividual pharmacokinetic variability; however, pharmacogenomic (PGx) assays that predict metabolism of anti-TB drugs have been lacking.

OBJECTIVES: To develop a Nanopore sequencing panel and validate its performance in active TB patients to personalize treatment dosing.

MEASUREMENTS AND MAIN RESULTS: We developed a Nanopore sequencing panel targeting 15 single nucleotide polymorphisms (SNP) in 5 genes affecting the metabolism of isoniazid (INH), rifampin (RIF), linezolid and bedaquiline. For validation, we sequenced DNA samples (n=48) from the 1000 genomes project and compared variant calling accuracy with Illumina genome sequencing. We then sequenced DNA samples from patients with active TB (n=100) from South Africa on a MinION Mk1C and evaluated the relationship between genotypes and pharmacokinetic parameters for INH and RIF.

RESULTS: The PGx panel achieved 100% concordance with Illumina sequencing in variant identification for the samples from the 1000 Genomes Project. In the clinical cohort, coverage was >100x for 1498/1500 (99.8%) amplicons across the 100 samples. One third (33%) of participants were identified as slow, 47% were intermediate and 20% were rapid isoniazid acetylators. Isoniazid clearance was significantly impacted by acetylator status (p<0.0001) with median (IQR) clearances of 11.2 L/h (9.3-13.4), 27.2 L/h (22.0-31.7), and 45.1 L/h (34.1-51.1) in slow, intermediate, and rapid acetylators. Rifampin clearance was 17.3% (2.50-29.9) lower in individuals with homozygous AADAC rs1803155 G>A substitutions (p=0.0015).

CONCLUSION: Targeted sequencing can enable detection of polymorphisms influencing TB drug metabolism on a low-cost, portable instrument to personalize dosing for TB treatment or prevention.

SUMMARY: This manuscript describes the development and validation of Nanopore sequencing panel to detect host pharmacogenomic markers to guide personalized drug dosing for treatment or prevention of tuberculosis. This article has an online data supplement, which is accessible from this issue's table of content online at www.atsjournals.org.

PMID:37732197 | PMC:PMC10508808 | DOI:10.1101/2023.09.08.23295248

MedComm (2020). 2023 Sep 18;4(5):e369. doi: 10.1002/mco2.369. eCollection 2023 Oct.

ABSTRACT

Soft tissue sarcoma (STS) is an uncommon malignancy that often carries a grim prognosis. Trophinin-associated protein (TROAP) is augmented in a variety of tumors and can affect tumor proliferation. Nevertheless, the prognostic value and specific functions of TROAP in STS are still vague. Herein, we display that TROAP exhibits an augmented trend in STS, and its elevation correlates with a poor prognosis of STS. Furthermore, its reduction is related to increased immune cell infiltration, enhanced stroma, and elevation of immune activation. Meanwhile, the TROAP-derived genomic signature is validated to predict patient prognosis, immunotherapy, and drug response reliably. A nomogram constructed based on age, metastatic status, and a TROAP-derived risk score of an STS individual could be used to quantify the survival probability of STS. In addition, in vitro experiments have demonstrated that TROAP is overexpressed in STS, and the downregulation of TROAP could affect the proliferation, migration, metastasis, and cell cycle of STS cells. In summary, the TROAP expression is elevated in STS tissues and cells, which is related to the poor prognosis and malignant biological behaviors of STS. It could act as a potential prognostic biomarker for diagnosis and treatment of STS.

PMID:37731946 | PMC:PMC10507284 | DOI:10.1002/mco2.369

Expert Opin Drug Metab Toxicol. 2023 Sep 20. doi: 10.1080/17425255.2023.2261366. Online ahead of print.

ABSTRACT

INTRODUCTION: Although significant development has been made in high-throughput screening of oral drug absorption and oral bioavailability, in silico prediction continues to play an important role in prediction of oral bioavailability and assisting in the proper selection of potential drug candidates.

AREAS COVERED: This review describes the improvements and latest modeling methods and algorithms available for the prediction of this important parameter. We performed a PubMed database search with a focus on the literature published in the last 15 years.

EXPERT OPINION: A tremendous efforts have been done in the past several years to develop reliable prediction tools that can provide accurate prediction for oral bioavailability. Several studies demonstrated new methodologies and techniques to develop either web-based in silico predictive tools or integrated PBPK models to predict oral bioavailability for new molecules. Improvements in the databases and the computational power will enhance the in silico prediction accuracy and reliability. Finally, introducing artificial intelligence to the drug development process will help improve the prediction tools.

PMID:37728393 | DOI:10.1080/17425255.2023.2261366

Int J Mol Cell Med. 2022;11(4):306-319. doi: 10.22088/IJMCM.BUMS.11.4.306.

ABSTRACT

Alternative pathways frequently operate as the origins of resistance to drugs that block the vascular endothelial growth factor (VEGF) pathway. To find possible therapeutic targets and indicators, this study explored the VEGF pathway and how miRNAs control it in recurrent glioblastoma multiforme (rGBM). Differentially expressed miRNAs (DEmiRNAs) were identified by using GBM GSE profiles (GSE32466). To find pathways containing DEmiRNAs, VEGF pathway genes, and their related genes, DIANA-miRPath v3.0 and the ToppGene database were utilized. miRNAs linked to VEGF signaling pathway genes, interactional genes, and DEmiRNAs were discovered by extracting common pathways. The ability of these miRNAs to distinguish rGBM patients from those with primary GBM was assessed using ROC analysis. The study revealed that in rGBM, 30 miRNAs were significantly up-regulated and 49 miRNAs were considerably down-regulated. Among them, the VEGF pathway was connected to 22 up-regulated miRNAs and 29 down-regulated miRNAs. The MAPK pathway shared the most genes with the VEGF pathway, accounting for 1,014 of the interacting genes, which were discovered to have interactions with VEGF signaling pathway genes. Furthermore, 14 miRNAs were identified as having a great deal of potential as molecular biomarkers and therapeutic targets for rGBM. The results indicate that the VEGF pathway in rGBM is regulated by a number of interrelated pathways. The discovered miRNAs hold promise as rGBM biomarkers and therapeutic targets, offering possibilities for novel therapy strategies and aiding rGBM diagnosis and prognosis.

PMID:37727644 | PMC:PMC10506677 | DOI:10.22088/IJMCM.BUMS.11.4.306

Ther Drug Monit. 2023 Jul 13. doi: 10.1097/FTD.0000000000001113. Online ahead of print.

ABSTRACT

BACKGROUND: Cisplatin is commonly used to treat solid tumors; however, its use can be complicated by drug-induced hearing loss (ie, ototoxicity). The presence of certain genetic variants has been associated with the development/occurrence of cisplatin-induced ototoxicity, suggesting that genetic factors may be able to predict patients who are more likely to develop ototoxicity. The authors aimed to review genetic associations with cisplatin-induced ototoxicity and discuss their clinical relevance.

METHODS: An updated systematic review was conducted on behalf of the Canadian Pharmacogenomics Network for Drug Safety, based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 statement. Pharmacogenomic studies that reported associations between genetic variation and cisplatin-induced ototoxicity were included. The evidence on genetic associations was summarized and evaluated, and knowledge gaps that can be used to inform future pharmacogenomic studies identified.

RESULTS: Overall, 40 evaluated reports, considering 47 independent patient populations, captured associations involving 24 genes. Considering GRADE criteria, genetic variants in 2 genes were strongly (ie, odds ratios ≥3) and consistently (ie, replication in ≥3 independent populations) predictive of cisplatin-induced ototoxicity. Specifically, an ACYP2 variant has been associated with ototoxicity in both children and adults, whereas TPMT variants are relevant in children. Encouraging evidence for associations involving several other genes also exists; however, further research is necessary to determine potential clinical relevance.

CONCLUSIONS: Genetic variation in ACYP2 and TPMT may be helpful in predicting patients at the highest risk of developing cisplatin-induced ototoxicity. Further research (including replication studies considering diverse pediatric and adult patient populations) is required to determine whether genetic variation in additional genes may help further identify patients most at risk.

PMID:37726872 | DOI:10.1097/FTD.0000000000001113

Pharmacogenomics J. 2023 Sep 19. doi: 10.1038/s41397-023-00316-9. Online ahead of print.

ABSTRACT

Personalized medicine is a novel frontier in health care that is based on each person's unique genetic makeup. It represents an exciting opportunity to improve the future of individualized health care for all individuals. Pharmacogenomics, as the main part of personalized medicine, aims to optimize and create a more targeted treatment approach based on genetic variations in drug response. It is predicted that future treatments will be algorithm-based instead of evidence-based that will consider a patient's genetic, transcriptomic, proteomic, epigenetic, and lifestyle factors resulting in individualized medication. A generative pretrained transformer (GPT) is an artificial intelligence (AI) tool that generates language resembling human-like writing enabling users to engage in a manner that is practically identical to speaking with a human being. GPT's predictive algorithms can respond to questions that have never been addressed. Chat Generative Pretrained Transformer (ChatGPT) is an AI chatbot's advanced with conversational capabilities. In the present study, questions were asked from ChatGPT about the future of personalized medicine and pharmacogenomics. ChatGPT predicted both to be a promising approach with a bright future that holds great promises in improving patient outcomes and transforming the field of medicine. But it still has several limitations that need to be solved.

PMID:37726551 | DOI:10.1038/s41397-023-00316-9

Pharm Res. 2023 Sep 19. doi: 10.1007/s11095-023-03603-z. Online ahead of print.

ABSTRACT

AIMS: Dasatinib, a second-generation tyrosine kinase inhibitor of BCR-ABL 1, used for first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML), exhibits high pharmacokinetic (PK) variability. However, its PK data in Chinese patients with CML remains rarely reported to date. Thus, we developed a population pharmacokinetic (PPK) model of dasatinib in Chinese patients and identified the covariate that could explain the individual variability of PK for optimal individual administration.

METHODS: PPK modeling for dasatinib was performed based on 754 plasma concentrations obtained from 140 CML patients and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was evaluated using internal and external validation. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages.

RESULTS: The PK of dasatinib were well described by a two-compartment with a log-additive residual error model. Patients in the current study had a relatively low estimate of CL/F (126 L/h). A significant association was found between the covariate of age and CL/F of dasatinib, which was incorporated into the final model. None of the genetic factors was confirmed as a significant covariate for dasatinib. The results of external validation with 140 samples from 36 patients were acceptable. Simulation results showed significantly higher exposures in elderly patients.

CONCLUSIONS: This study's findings suggested that low-dose dasatinib would be better suited for Chinese patients, and the dosage can be appropriately reduced according to the increase of age, especially for the elderly.

PMID:37726405 | DOI:10.1007/s11095-023-03603-z

JMIRx Med. 2022 May 3;3(2):e32902. doi: 10.2196/32902.

ABSTRACT

BACKGROUND: The availability of pharmacogenomic (PGx) methods to determine the right drug and dosage for individualized patient treatment has increased over the past decade. Adoption of the resulting PGx reports in a clinical setting and monitoring of clinical outcomes is a challenging and long-term commitment.

OBJECTIVE: This study summarizes an extended PGx deep sequencing panel intended for medication dosing and prescription guidance newly adopted in a pain management clinic. The primary outcome of this retrospective study reports the number of cases and types of drugs covered, for which PGx data appears to have assisted in optimal drug prescription and dosing.

METHODS: A PGx panel is described, encompassing 23 genes and 141 single-nucleotide polymorphisms or indels, combined with PGx dosing guidance and drug-gene interaction (DGI) and drug-drug interaction (DDI) reporting to prevent adverse drug reactions (ADRs). During a 2-year period, patients (N=171) were monitored in a pain management clinic. Urine toxicology, PGx reports, and progress notes were studied retrospectively for changes in prescription regimens before and after the PGx report was made available to the provider. An additional algorithm provided DGIs and DDIs to prevent ADRs.

RESULTS: Among patient PGx reports with medication lists provided (n=146), 57.5% (n=84) showed one or more moderate and 5.5% (n=8) at least one serious PGx interaction. A total of 96 (65.8%) patients showed at least one moderate and 15.1% (n=22) one or more serious DGIs or DDIs. A significant number of active changes in prescriptions based on the 102 PGx/DGI/DDI report results provided was observed for 85 (83.3%) patients for which a specific drug was either discontinued or switched within the defined drug classes of the report, or a new drug was added.

CONCLUSIONS: Preventative action was observed for all serious interactions, and only moderate interactions were tolerated for the lack of other alternatives. This study demonstrates the application of an extended PGx panel combined with a customized informational report to prevent ADRs and improve patient care.

PMID:37725552 | DOI:10.2196/32902

Pharmgenomics Pers Med. 2023 Sep 13;16:847-857. doi: 10.2147/PGPM.S422495. eCollection 2023.

ABSTRACT

BACKGROUND: N-acetyltransferase 2 (NAT2) enzyme is a Phase II drug-metabolizing enzyme that metabolizes different compounds. Genetic variations in NAT2 can influence the enzyme's activity and potentially lead to the development of certain diseases.

AIM: This study aimed to investigate the association of NAT2 variants with the risk of Type II diabetes mellitus (T2DM) and the lipid profile among Jordanian patients.

METHODS: We sequenced the whole protein-coding region in NAT2 using Sanger's method among a sample of 45 Jordanian T2DM patients and 50 control subjects. Moreover, we analyzed the lipid profiles of the patients and examined any potential associations with NAT2 variants.

RESULTS: This study revealed that the heterozygous NAT2*13 C/T genotype is significantly (P = 0.03) more common among T2DM (44%) than non-T2DM subjects (23.5%). Furthermore, the frequency of homozygous NAT2*13 T/T genotype was found to be significantly higher (P = 0.03) among T2DM patients (26.7%) compared to that of non-T2DM subjects (11%). The heterozygous NAT2*7 G/A genotype was exclusively observed in T2DM patients (11.1%) and absent in the control non-T2DM group. Moreover, among T2DM patients, those with a homozygous NAT2*11 T/T genotype exhibited significantly higher levels of triglycerides (381.50 ± 9.19 ng/dL) with a P value of 0.01 compared to those with heterozygous NAT2*11 C/T (136.23 ± 51.12 ng/dL) or wild-type NAT2*11 C/C (193.65 ± 109.89 ng/dL) genotypes. T2DM patients with homozygous NAT2*12 G/G genotype had a significantly (P = 0.04) higher triglyceride levels (275.67 ± 183.42 ng/dL) than the heterozygous NAT2*12 A/G (140.02 ± 49.53 ng/dL) and the wild NAT2*12 A/A (193.65 ± 109.89 ng/dL).

CONCLUSION: The finding in this study suggests that the NAT2 gene is a potential biomarker for the development of T2DM and changes in triglyceride levels among Jordanians. However, it is important to note that our sample size was limited; therefore, further clinical studies with a larger cohort are necessary to validate these findings.

PMID:37724295 | PMC:PMC10505377 | DOI:10.2147/PGPM.S422495

Cureus. 2023 Aug 18;15(8):e43697. doi: 10.7759/cureus.43697. eCollection 2023 Aug.

ABSTRACT

Diabetes mellitus poses a substantial global health challenge, necessitating innovative approaches to improve patient outcomes. Conventional one-size-fits-all treatment strategies have shown limitations in addressing the diverse nature of the disease. In recent years, personalized medicine has emerged as a transformative solution, tailoring treatment plans based on individual genetic makeup, lifestyle factors, and health characteristics. This review highlights the role of genetic screening in predicting diabetes susceptibility and response to treatment, as well as the potential of pharmacogenomics in optimizing medication choices. Moreover, it discusses the incorporation of lifestyle modifications and behavioral interventions to empower patients in their health journey. Telemedicine and remote patient monitoring are also examined for their role in enhancing accessibility and adherence. Ethical considerations and challenges in implementing personalized medicine are addressed. The review envisions a future where personalized medicine becomes a cornerstone in diabetes management, ensuring improved patient outcomes and fostering more effective and patient-centric care on a global scale.

PMID:37724233 | PMC:PMC10505357 | DOI:10.7759/cureus.43697

JCO Oncol Pract. 2023 Sep 18:OP2300034. doi: 10.1200/OP.23.00034. Online ahead of print.

ABSTRACT

PURPOSE: There is a paucity of real-world data on opioid screening and urine toxicology testing in outpatient oncology palliative medicine.

METHODS: This was a retrospective analysis of adult patients with cancer completing ≥ one outpatient palliative medicine visit and the Edmonton Symptom Assessment Scale (ESAS). Patient demographics, the Screener and Opioid Assessment for Patients with Pain-Short Form (SOAPP-SF), ESAS, medications, and urine toxicology screens (UTSs) were collected at baseline and follow-up visits. The primary end point was the frequency and type(s) of noncompliant UTSs (ie, presence of a nonprescribed substance or absence of a prescribed substance). Secondarily, risk factors for noncompliant UTSs were evaluated using univariate and multivariable logistic regression.

RESULTS: Of 189 evaluable patients (632 clinic visits), 113 underwent ≥one UTSs, 125 SOAPP-SF, and 75 had both. The median age was 56 (range, 26-80) years, 56% were female, 58% were White, 40% were Black, 48% had stage IV disease, the median baseline pain score was 7, and the median SOAPP-SF was 3. Oxycodone was the most prescribed drug (n = 125). Of 113 patients who underwent UTSs, 54% (n = 61) had ≥one noncompliant result. Thirty-nine percent (n = 44) had a total of 128 noncompliant results for the presence of a nonprescribed substance; 29% (n = 33) had a total of 53 noncompliant results for the absence of a prescribed substance. SOAPP-SF Q4 (use of illegal drugs) (odds ratio [OR], 3.61; 95% CI, 1.81 to 7.19; P < .001) and prescription with nonopioid adjuvant medications (OR, 2.83; 95% CI, 1.12 to 7.19; P = .029) were associated with increased odds of a noncompliant UTS.

CONCLUSION: More than half of the tested population had noncompliant UTS. Screening and evaluating risk factors for nonmedical opioid use is critical in oncology palliative medicine.

PMID:37722086 | DOI:10.1200/OP.23.00034

JAMA Netw Open. 2023 Sep 5;6(9):e2333533. doi: 10.1001/jamanetworkopen.2023.33533.

ABSTRACT

IMPORTANCE: The optimal maintenance strategy after induction chemotherapy with anti-epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated.

OBJECTIVE: To evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy.

DESIGN, SETTING, AND PARTICIPANTS: The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]-UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022.

INTERVENTIONS: After first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen.

MAIN OUTCOMES AND MEASURES: The primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile.

RESULTS: Of 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]).

CONCLUSION AND RELEVANCE: The randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02404935.

PMID:37721754 | DOI:10.1001/jamanetworkopen.2023.33533

Clin Transl Sci. 2023 Sep 18. doi: 10.1111/cts.13637. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) implementation into clinical care is rapidly increasing in China. However, the extent to which the public understands PGx testing and important knowledge domains requiring patient education or counseling remains unclear. To address this, we created and validated the Chinese version of the Minnesota Assessment of Pharmacogenomic Literacy (MAPL-C). The MAPL-C was developed by translating English MAPL to Chinese following cross-cultural translation guidelines. An online survey validated the MAPL-C and assessed Chinese individuals' PGx literacy. Validation analyses and associations with participants' characteristics were quantified. Of 959 high-quality responses, the majority of respondents were Han Chinese (96.3%), male (54.5%), aged 18-29 years (70.9%), residing in China (97.3%), and had received college or higher education (95.0%). Out of 15 starting items developed to query specific predefined knowledge domains, two uninformative items were excluded, resulting in a 13-item MAPL-C. Chinese participants' MAPL-C performance was best explained by a three-factor model, encompassing PGx concepts and function, testing limitations, and privacy. Higher MAPL-C performance was associated with younger age, higher education, and previous genetic testing experience. Correct response rates for questions related to testing limitations were lower than other domains. The creation and validation of the MAPL-C fills a gap in determining PGx knowledge among Chinese speakers, quantifying PGx literacy within a Chinese cohort and identifying response patterns and knowledge gaps. The MAPL-C can be useful in clinical practice to guide patient counseling, assess PGx education interventions, and quantify PGx knowledge in relation to outcomes in research studies involving Chinese participants.

PMID:37721333 | DOI:10.1111/cts.13637