Personalized medicine最新文献

Background: The application of personalized medication management for Voriconazole(VCZ), such as therapeutic drug monitoring (TDM), is the gold standard for attaining therapeutic goals in invasive fungal infections. Infectious disease (ID) pharmacists are the best for ensuring the recommendations are properly implemented.

Aim: To assess the adherence of healthcare teams to VCZ dose individualization and the impact of the ID pharmacy team.

Method: This study included pediatric oncology patients who received VCZ in the inpatient department and had VCZ TDM level measurements for 3 months (from January to March 2019) and after implementing the (ID) pharmacy service during the same months in two different years (2020, 2021).

Results: This study included 989 patients who received VCZ; only 588/989 patients (59.5%) had VCZ TDM levels. Dose individualization was required for 62.6% (849/1357) levels, while 37.4% (508/1357) levels were in the therapeutic range. The overall compliance rate with the TDM recommendations was 92.9% (789/849). Additionally, there was a significant increase in VCZ dose individualization adherence after ID pharmacy implementation (88.6% (210/237) vs. 94.6% (579/612), p = 0.002). The rate of doctor acceptance of the ID pharmacist intervention was 94.7%.

Conclusion: ID pharmacists' contributions are crucial and can increase clinicians' adherence to individualized dose recommendations.

Background: Essential hypertension (EH) is influenced by genetic and environmental factors. The CYP11B2 gene, encoding aldosterone synthase, plays a major role in blood pressure regulation. This study investigated the association of the CYP11B2 -344C/T (rs1799998) variant with EH in Jordanians and evaluated its influence on response to amlodipine and valsartan.

Methods: A case-control study was conducted involving 309 Jordanian participants (154 hypertensive patients and 155 normotensive controls). Genotyping was performed using PCR-RFLP. Blood pressure (BP) was recorded before and after 1 month of treatment with either 80 mg valsartan or 10 mg amlodipine.

Results: Genotype frequencies (TT: 32.0%, TC: 50.5%, CC: 17.5%) and T allele frequency (57.28%) did not differ significantly between hypertensive and control groups (p > 0.05). No association was found between rs1799998 and EH. Both valsartan and amlodipine significantly reduced BP (p < 0.001). While no CYP11B2 -344C/T genotype-dependent response was seen with valsartan, amlodipine was more effective in TT genotype carriers (SBP: 37 ± 2.0 mmHg, DBP: 20 ± 0.2 mmHg) compared to TC and CC (p = 0.028).

Conclusion: The CYP11B2 -344C/T variant was not associated with EH in Jordanians, but it was associated with amlodipine response. Further studies with larger sample size are needed to validate these findings.

Introduction: Ototoxicity is a dose-limiting toxicity of cisplatin. Several DNA repair gene polymorphisms have been investigated for their association with cisplatin-induced ototoxicity (CIO), but their predictive value remains controversial. This systematic review evaluated genetic predisposition to CIO via DNA repair gene polymorphisms.

Method: PubMed, SCOPUS, Web of Science, trial registries, and gray literature sources were searched, and reference lists of included studies were screened. Study quality was assessed using the Q-Genie tool, and reporting followed PRISMA guidelines. The protocol was registered on PROSPERO (ID: CRD420251112849).

Results: Eight studies with 672 subjects were deemed eligible, investigating nine DNA repair genes (XPA, XPC, ERCC1, ERCC2, XRCC1, EX01, ERCC4, and ERCC5), covering 96 single-nucleotide polymorphisms (SNPs), 54 of which were in DNA repair pathways. AC+CC genotypes of XPC rs2228001 were associated with decreased risk of CIO (OR: 0.20, 95% CI: 0.06-0.70, p = 0.01). Conversely, combining XPC rs2228001 with SNPs in GSTP1, FASL, or MSH3 showed the highest risks (ORs of 32.22, 22.29, and 17.09).

Conclusion: Although several DNA repair gene polymorphisms have been explored, findings remain inconsistent and limited by populations and SNPs studied. Larger, well-designed studies with standardized methodologies are needed to confirm these associations and identify genetic markers for predicting high-risk patients for CIO.

Introduction: The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene has been linked to antidepressant treatment response in patients with major depressive disorder (MDD), yet findings remain inconclusive. This updated meta-analysis aimed to clarify this association and explore subgroup effects based on antidepressant class and treatment duration.

Methods: A systematic search of PubMed, Web of Science, and Google Scholar was conducted through 27 December 2024. Studies were included if they assessed BDNF rs6265 genotypes and antidepressant response in MDD. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using Review Manager 5.4 under four genotypic models. Study quality was assessed using the Clark-Baudouin scale, and sensitivity and subgroup analyses were performed.

Results: Fourteen studies with 19 datasets were included in the meta-analysis. The overall outcomes indicated no association between the polymorphism and treatment response to antidepressants. Upon removal of outlier studies and studies that deviated from the Hardy-Weinberg equilibrium, significant and homogenous associations were noted with a strong relationship among East Asians treated with selective serotonin reuptake inhibitors (SSRIs).

Conclusion: The Met allele may predict favorable antidepressant response in SSRI-treated East Asian patients. Limitations include small sample sizes, moderate study quality, and limited ethnic diversity.

Melanoma is a malignant tumour arising from melanocytes and is the most aggressive type of skin cancer. In advanced disease standard treatments are largely ineffective. About 40% of cutaneous melanomas carry BRAF mutations-more common in younger patients-and these are linked to more aggressive behaviour and a higher risk of brain metastasis. Over the past decade, targeted therapies (TT) using BRAF and MEK inhibitors (BRAFi, MEKi), along with immune checkpoint inhibitors (ICI), have significantly improved response rates and survival in metastatic melanoma.

Breast cancer (BC) is the world's most prevalent cancer and can affect almost any post-pubertal woman. Early detection is associated with improved survival, and most high-income countries have adopted population-based screening programs to enhance early detection and survival although significant differences in screening age, methodology, and frequency exist. BC is known to be a heritable disease, with a small percentage of women having pathogenic variants in moderate or high-risk genes. However, Polygenic Risk Scores (PRS) incorporate many low penetrance single nucleotide polymorphisms (SNPs) and are the most powerful tool to help stratify women based on their personalized BC risk. PRS are particularly useful if incorporated into established risk prediction models (RPM). Risk stratification using PRS-containing RPMs can guide eligibility for enhanced screening and prevention programmes. This review discusses the role PRS plays in personalized risk prediction screening and prevention approaches as some of the challenges to their use.

Introduction: Tacrolimus is the cornerstone of immunosuppressive therapy in kidney transplantation. However, it exhibits significant pharmacokinetic (PK) variability among patients. Therefore, Population Pharmacokinetic (PopPK) modeling is crucial for personalized tacrolimus treatment. While PopPK models have been extensively developed for transplant patients in Asian and Caucasian populations, it is true that limited data are available for Arab/North-African populations. Thus, our objective was to develop a PopPK model for the Tunisian population to optimize tacrolimus treatment after kidney transplantation.

Methods: Data on tacrolimus exposure and other patient factors were collected for the first 3 months after kidney transplantation. Genotyping for 6-SNPs was performed. The PK analysis was performed using nonlinear mixed-effects modeling.

Results: A total of 1901 whole-blood pre-dose tacrolimus concentrations (C0) of 196 Tunisian kidney transplant recipients were collected and described using a two-compartment model. CYP3A5*1 carriers had a 1.28-fold higher tacrolimus clearance (CL/F) compared to non-carriers. Higher body mass index (BMI) and lower hematocrit resulted in increased tacrolimus CL/F.

Conclusion: In the first 3 months post-transplant, tacrolimus CL/F was significantly influenced by CYP3A5 genotype, BMI, hematocrit, and time after transplantation. The model supports individualized dose adjustment; prospective external validation and a simple dose-adjustment algorithm are warranted to facilitate clinical implementation.

Background: Vancomycin is a widely used nephrotoxic drug in pediatric oncology. Our aim was to assess the initial vancomycin dosing protocols required for achieving the target therapeutic concentrations of vancomycin between 10 and 20 mcg/ml.

Methods: We analyzed 4134 vancomycin trough levels from 1678 pediatric oncology patients treated at CCHE 57357 (2017-2023).

Results: Higher initial Vancomycin doses (80 and 100 mg/kg/day) yielded better target levels (45.5%, 51.4%) compared to 60 mg/kg/day (38.1%). Younger patients (<10 years) showed higher sub-therapeutic levels than older ones (53.4% vs. 24.8%, p < 0.0001). Co-administration of nephrotoxic medications increased vancomycin toxicity risk (13.3% vs. 8.9%, p < 0.0001). Weight-based dosing of vancomycin resulted in higher therapeutic levels compared to capping doses at 500 mg.

Conclusion: Higher initial vancomycin doses (80-100 mg/kg/day) may be necessary to achieve therapeutic levels in pediatric oncology. Kg dosing beats capping for reaching targets without raising toxicity.

Aims: Clinical case reports in oncology are an untapped resource of patient data that include relationships between molecular alterations, tumor types, and response to targeted therapy. A current challenge to widespread utilization of case reports in clinical practice is the lack of systematic organization of clinical evidence across disease types, patient outcomes, therapies, and associated molecular features. To address this challenge, we sought to demonstrate the utility of Cancer Knowledgebase (CKB) (https://ckb.genomenon.com/) in interpreting oncology case report data for health care providers.

Methods: We analyzed data from 5527 manually curated case reports in CKB to gain insights related to treatment options and patient response associated with specific molecular alterations.

Results: Each case report in CKB is represented as a unique efficacy evidence annotation and is associated with a specific molecular profile, therapy, indication, and response to therapy. Efficacy evidence from case reports spans over 500 genes, 2800 molecular profiles, and 300 tumor types, including several rare cancers and pediatric tumor types.

Conclusion: CKB is a powerful resource for leveraging case reports to identify treatment options for patients with rare cancers and oncogenic variants, patients for whom multiple therapies exist, and patients experiencing resistance to first-line therapy.

Aim: This study aims to validate the relevance of IL-17A rs8193036 polymorphisms in susceptibility to Alzheimer's disease.

Materials and methods: A total of 210 healthy volunteers and 260 Alzheimer's disease patients were recruited. The genotype distribution of IL-17A rs8193036 was detected using the TaqMan-qPCR. The RT-qPCR was used to detect the expression of IL-17A in serum. The subjects of each genotype subgroup were statistically compared in terms of IL-17A expression and MMSE score. Logistic regression was used to analyze the independent risk factors for Alzheimer's disease.

Results: The CC genotypes of IL-17A rs8193036 showed a high distribution in Alzheimer's disease patients (χ² = 8.115, OR = 1.879, 95% CI = 1.213-2.910, p = 0.004). The expression of IL-17A was higher, and the ROC curves showed the favorable diagnostic significance of IL-17A in Alzheimer's disease. The serum level of IL-17A was higher in Alzheimer's disease patients with the CC genotype than the TT and CT genotypes. MMSE score of the CC genotype patients was lower than TT and CT genotypes. Gender, Education, MMSE score, IL-17A expression, and rs8193036 CC genotypes were risk factors for Alzheimer's disease.

Conclusion: The expression level of IL-17A is higher in Alzheimer's disease patients. The CC genotype of IL-17A rs8193036 is the causative genotype of Alzheimer's disease.