A hypoxia risk score for prognosis prediction and tumor microenvironment in adrenocortical carcinoma.

Background: Adrenocortical carcinoma (ACC) is a rare malignant endocrine tumor derived from the adrenal cortex. Because of its highly aggressive nature, the prognosis of patients with adrenocortical carcinoma is not impressive. Hypoxia exists in the vast majority of solid tumors and contributes to invasion, metastasis, and drug resistance. This study aimed to reveal the role of hypoxia in Adrenocortical carcinoma and develop a hypoxia risk score (HRS) for Adrenocortical carcinoma prognostic prediction. Methods: Hypoxia-related genes were obtained from the Molecular Signatures Database. The training cohorts of patients with adrenocortical carcinoma were downloaded from The Cancer Genome Atlas, while another three validation cohorts with comprehensive survival data were collected from the Gene Expression Omnibus. In addition, we constructed a hypoxia classifier using a random survival forest model. Moreover, we explored the relationship between the hypoxia risk score and immunophenotype in adrenocortical carcinoma to evaluate the efficacy of immune check inhibitors (ICI) therapy and prognosis of patients. Results: HRS and tumor stage were identified as independent prognostic factors. HRS was negatively correlated with immune cycle activity, immune cell infiltration, and the T cell inflammatory score. Therefore, we considered the low hypoxia risk score group as the inflammatory immunophenotype, whereas the high HRS group was a non-inflammatory immunophenotype. In addition, the HRS was negatively related to the expression of common immune checkpoint molecules such as PD-L1, CD200, CTLA-4, and TIGIT, suggesting that patients with a lower hypoxia risk score respond better to immunotherapy. Conclusion: We developed and validated a novel hypoxia risk score to predict the immunophenotype and response of patients with adrenocortical carcinoma to immune check inhibitors therapy. These findings not only provide fresh prognostic indicators for adrenocortical carcinoma but also offer several promising treatment targets for this disease.

Changes in the Gut Microbiota May Affect the Clinical Efficacy of Oral Anticoagulants.

The mechanism underlying large individual differences in the response to oral anticoagulants has not been fully clarified, and the influence of the intestinal microbiome on exogenous drug metabolism has gradually become an area of increased research interest. However, there has been no research into the influence of the gut microbiota on the pharmacokinetics of oral anticoagulants. Therefore, our study is the first to investigate the effect of the intestinal flora on oral anticoagulant metabolism and the associated mechanism. Antibiotics affected the diversity and abundance of the intestinal flora. Compared with the control group, the bioavailability of warfarin and rivaroxaban were significantly increased in the amoxicillin-treated group, whereas the bioavailability of dabigatran increased and subsequently decreased. Compared with the control group, the expression of P-glycoprotein (P-gp), CYP1A2, CYP2C9, CYP3A4, and nuclear receptor, PXR, were altered in the amoxicillin -treated groups. This trend was consistent with the pharmacokinetic results. Changes in the intestinal flora can affect the expression of liver drug enzymes and P-gp, as well as affect the transport and metabolism of oral anticoagulants (e.g., warfarin, dabigatracin, and rivaroxaban), leading to differences in the efficacy of oral anticoagulants. This study revealed a novel mechanism for influencing individual differences in the treatment efficacy of oral anticoagulants.

Effect of gene polymorphism on bleeding complications in Chinese Han patients taking warfarin.

PURPOSE: The purpose of this study was to analyse the effects of demographic factors, clinical factors, and genetic polymorphisms of related gene loci on warfarin bleeding-related complications in the Han population. METHODS: Retrospective medical record review. The study cases were patients treated at the Fujian Medical University Union Hospital from March 2016 to February 2020, and all received regular warfarin anticoagulation treatment for at least 3 months, and were provided the initial standard dose and stable dose of warfarin. RESULTS: Data were collected from 451 qualifying patients (47% male, 53% female). The average age of patients was 53.8 ± 12.2 years, and the average body surface area was 1.6 ± 0.18 m2. There were nine major bleeding events and 141 minor bleeding events. In the univariate logistic analysis, the p-value of the four factors body weight, body surface area (BSA), amiodarone, and rs429358 was < 0.10. However, the final p-values for amiodarone and rs429358 were < 0.05 in the multifactorial logistic analysis. CONCLUSIONS: The ApoE (rs429358) gene polymorphism influences bleeding complications in Chinese Han patients treated with warfarin. The sample size of this study was relatively small; hence an international study with a larger sample size is needed in the future.

To establish a model for the prediction of initial standard and maintenance doses of warfarin for the Han Chinese population based on gene polymorphism: a multicenter study.

PURPOSE: The purpose of this paper is to study the correlation between demographic and clinical factors and warfarin dose of patients in Chinese Han population taking warfarin and study gene polymorphisms impact of related gene loci (CYP2C9*3, VKORC1-1639G > A) on warfarin doses, to establish a model to predict initial standard dose and maintenance dose based on CYP2C9*3, VKORC1-1639G > A genotype. METHODS: The study collects the data of patients in our hospital and other subcenters which incorporates 2160 patients to establish the initial dose model and 1698 patients for the stable dose model, and sequences 26 multigene sites in 451 patients. Based on the patient's dosage, clinical data, and demographic characteristics, the genetic and non-genetic effects on the initial dose and stable dose of warfarin are calculated by using statistical methods, and the prediction model of initial standard dose and maintenance dose can be established via multiple linear regression. RESULTS: The initial dose of warfarin (mg/day) was calculated as (1.346 + 0.350 × (VKORC1-1639G > A) - 0.273 × (CYP2C9*3) + 0.245 × (body surface area) - 0.003 × (age) - 0.036 × (amine-iodine) + 0.021 × (sex))2. This model incorporated seven factors and explained 55.3% of the individualization differences of the warfarin drug dose. The maintenance dose of warfarin (mg/day) was calculated as (1.336 + 0.299 × (VKORC1-1639G > A) + 0.480 × (body surface area) - 0.214 × (CYP2C9*3) - 0.074 × (amine-iodine) - 0.003 × (age) - 0.077 × (statins) - 0.002 × (height))2. This model incorporated six factors and explained 42.4% of the individualization differences in the warfarin drug dose. CONCLUSION: The genetic and non-genetic factors affecting warfarin dose in Chinese Han population were studied systematically in this study. The pharmacogenomic dose prediction model constructed in this study can predict anticoagulant efficacy of warfarin and has potential application value in clinical practice.

Comprehensive Analysis of Aquaporin Superfamily in Lung Adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is the most predomintnt lung cancer subtype with increasing morbidity and mortality. Previous studies have shown that aquaporin (AQP) family genes were correlated with tumor progression and metastasis in several kinds of malignancies. However, their biological behaviors and prognostic values in LUAD have not been comprehensively elucidated. Methods: RNA sequencing and real-time reverse transcription PCR (RT-PCR) were used to assess AQP1/3/4/5 gene expressions in LUAD patients using GEPIA and UALCAN databases. And then Kaplan-Meier analysis, cBioPortal, Metascape, GeneMANIA, TISIDB, and TIMER were utilized to determine the prognostic value, mutation frequency, and immune cell infiltration of AQP family members in LUAD. Results: We found that AQP3 expression was significantly elevated and AQP1 expression was markedly reduced in LUAD patients, whereas the expression levels of AQP4 and AQP5 exhibited no significant changes. The Kaplan-Meier survival analysis indicated that the higher expressions of AQP1/4/5 were related to longer overall survival (OS). Of interest, AQP3 was significantly correlated with the clinical tumor stage and lower AQP3 expression showed favorable prognosis in stage I LUAD patients, which indicated that AQP3 may be a potential prognostic biomarker for patients. Through functional enrichment analysis, the functions of these four AQPs genes were mainly involved in the passive transport by aquaporins, water homeostasis, and protein tetramerization. Moreover, AQP1/3/4/5 expression was strongly associated with tumor-infiltrating lymphocytes (TILs) in LUAD. Conclusion: AQP3 can be used as a prognosis and survival biomarker for stage I LUAD. These findings may provide novel insights into developing molecular targeted therapies in LUAD.

Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.

RATIONALE: Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation. PATIENT CONCERNS: A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission. DIAGNOSES: The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. INTERVENTIONS: All drugs used prior to admission were discontinued and the patient was given antiallergic drugs. OUTCOMES: After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown. LESSONS: This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.

Comparison of clinical performance of four gastrointestinal bleeding risk scores in Chinese patients with atrial fibrillation receiving oral anticoagulants.

Gastrointestinal bleeding is the most common bleeding complication during anticoagulant therapy. A reliable bleeding risk score can help the clinician assess risk of bleeding in individual patients and select the anticoagulant regimen. This study retrospectively analyzed the data of patients with atrial fibrillation who received anticoagulant therapy from July 2015 to December 2018 at two centers-the Fujian Medical University Union Hospital and Fuzhou Second Hospital Affiliated to Xiamen University. Demographic data, clinical findings, and laboratory results were collected from the hospital records. Patients were followed up for 6 months. The performance of four bleeding risk scores (New Score, RIETE Score, Cuschieri et al. Score, de Groot et al. Score) for prediction of gastrointestinal bleeding was assessed using the area under the curve. A total of 3462 patients (mean age, 66.3 ± 11.5 years; 59.6% males; 1055 direct oral anticoagulants users and 2407 warfarin users) were followed up for 6 months. While 99/3462 (2.9%) patients had gastrointestinal bleeding. The area under the curves for the New, RIETE, Cuschieri et al., de Groot et al. scores were 0.652 (95% CI 0.576-0.728), 0.862 (95% CI 0.809-0.914), 0.606 (95% CI 0.527-0.685), and 0.873 (95% CI 0.816-0.929), respectively. Among the four BRSs evaluated, the RIETE score and the de Groot et al. score appear to have the good predictive value, while the NEW score and the Cuschieri et al. score did not sufficiently predict gastrointestinal bleeding risk within the study Chinese population.

Clinical analysis of the effects of azole antifungal agents on the anticoagulant activity of warfarin.

To investigate the frequency and degree of azole antifungal agents that influence the anticoagulant activity of warfarin to reduce the potential bleeding risk and provide a reference for rational administration of warfarin in clinics.Patients with an abnormal international normalized ratio (INR; INR ≥ 4.5) and treated with warfarin plus azole antifungal agents were screened from February 2011 to July 2016, and their data were extracted.Thirty-two patients treated with warfarin plus azole antifungal agents were included. The INR of all the included patients increased by more than 20% of the INR of warfarin alone, and the warfarin sensitivity index showed an upward trend. The INRs of 21 patients treated with fluconazole (FLCZ) and warfarin was closely monitored for 1 week after the combination treatment, and the interaction between warfarin and the azole antifungal agents peaked on the seventh day. The INRs when warfarin was coadministered with azoles (Y) correlated significantly with those in the absence of azoles (X): FLCZ: Y = 1.2515X + 2.1538, R = 0.8128; and voriconazole Y = 2.4144 X + 2.6216, R2 = 0.7828.The combination of FLCZ and voriconazole will enhance the anticoagulant effect of warfarin. Therefore, it is recommended to detect the genotype of CYP2C9 in patients and evaluate the interaction between the 2 drugs to adjust the warfarin dose. It is also recommended to closely monitor INR within 1 week of the addition of azole antifungal agents.

Left atrial appendage thrombus formation in a patient with atrial fibrillation on dabigatran therapy associated with CES1 and ABCB1 genetic polymorphisms: A case report.

RATIONALE: Dabigatran is a direct thrombin inhibitor that is widely used to prevent the formation of thrombus formation. Amiodarone can increase the plasma concentration of dabigatran. CES1 (carboxylesterase 1) and ABCB1 (ATP-binding cassette subfamily B member 1) genetic polymorphisms associate with the pharmacokinetics of dabigatran. PATIENT CONCERNS: A 62-year-old woman was admitted to the hospital due to chest tightness, fatigue, and discomfort despite long-term anticoagulation with dabigatran 110 mg twice daily for 6 months, with concomitant use of amiodarone. DIAGNOSES: Left atrial appendage thrombus formation with a history of atrial fibrillation. INTERVENTIONS: The clinician changed dabigatran to warfarin. To explore the causes of insufficient anticoagulation using dabigatran in this patient, we examined the ABCB1 and CES1 genes. Results showed that she carried ABCB1 variant alleles with 3 heterozygote single nucleotide polymorphisms (SNPs: rs4148738, rs1045642, rs2032582) and CES1 variant alleles with 2 heterozygote SNPs (rs2244613, rs4580160). OUTCOMES: The left atrial appendage thrombus disappeared. LESSONS: Multiple mutations in the ABCB1 and CES1 genes may influence the pharmacokinetics of dabigatran and could have contributed to the thrombus formation in the left atrial appendage.

The effect of anti-Xa monitoring on the safety and efficacy of low-molecular-weight heparin anticoagulation therapy: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Low-molecular-weight heparin (LMWH) is widely used in the prevention and treatment of venous thromboembolism (VTE), and anti-Xa assay is the gold standard for monitoring LMWH. However, it is still controversial whether monitoring is necessary for patients receiving LMWH therapy. Therefore, we conducted a meta-analysis to explore the effect of anti-Xa monitoring on the safety and efficacy of LMWH anticoagulant therapy. METHODS: PubMed, EMBASE, Web of Science and The Cochrane Library were searched on 27 May 2019 for eligible studies published in English. Odds ratio (OR) and 95% confidence intervals (CI) were estimated (Mantel-Haenszel method) using Review Manager version 5.3 software. The systematic review and meta-analysis was performed according to the recommendations of the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS AND DISCUSSION: Six studies involving 1617 patients were eligible for our meta-analysis, with 724 patients in the anti-Xa monitoring group and 893 patients in the control group. There was no significant difference in the incidence of bleeding events between the two groups, while the anti-Xa monitoring group had a lower incidence of venous thromboembolism events (OR 0.44, 95% CI 0.29-0.68, P = .0002). Subgroup analysis showed that the incidence of venous thromboembolism events in the anti-Xa monitoring group was lower than that in the control group when the trough level was monitored (OR 0.40, 95% CI 0.25-0.63, P < .0001), while there was no significant difference between the two groups when the peak level was monitored. WHAT IS NEW AND CONCLUSION: Patients receiving LMWH anticoagulant therapy to prevent VTE can benefit from anti-Xa monitoring, for which the trough level may be the more appropriate time status to monitor.

Gene-based anticoagulation regimens for an infant after mitral-valve replacement: A case report.

RATIONALE: Heart-valve replacement is one of the main surgical methods for various heart-valve diseases. Warfarin is the only oral anticoagulant used for thrombosis prevention after heart-valve replacement. However, warfarin has a narrow therapeutic window, large differences in efficacy between individuals, and can be affected by drugs, food and disease status. PATIENT CONCERNS: We used the Hamberg model to develop an anticoagulation regimen for a 10-month-old Chinese male after mitral-valve replacement. DIAGNOSES: Echocardiography revealed mitral malformation with severe regurgitation, patent foramen ovale, thickening of the left ventricular wall, enlargement of the left atrium, and the overall systolic function of the left ventricle was lower than normal. INTERVENTIONS: First, the patient was treated with Mitral valvuloplasty plus temporary implantation of a pacing wire. Since this was inadequate, he underwent mitral-valve replacement. Then, we used the Hamberg model to develop an anticoagulation regimen. OUTCOMES: After discharge from hospital, the pharmacist provided anticoagulation management for this pediatric patient using an "Online Anticoagulation Clinic" (OAC). Point-of-care testing could be employed by the boy's mother at home to obtain the International Normalized Ratio. His time to response was 89.6% during the 6 months after hospital discharge, and adverse reactions such as bleeding or thrombosis did not occur. LESSONS: This is the first time the Hamberg model has been employed to design anticoagulation therapy for an Asian infant. His anticoagulation therapy may be managed using the OAC.

Comparison of the outcomes of warfarin therapy and economics by online and offline anticoagulation management models: protocol for a randomised controlled trial.

INTRODUCTION: Warfarin is widely used in the world as oral anticoagulant, but it is difficult to manage patients after medication due to its narrow treatment window and individualised differences. Therefore, every region uses network means to carry out online anticoagulant therapy services. The purpose of this paper is to compare monitoring results and randomised controlled studies of the complications of warfarin treated by offline or online management in a Chinese population. METHODS AND ANALYSIS: This is a randomised controlled, multicentre clinical trial. Taking the Union Hospital Affiliated to Fujian Medical University as the main centre, a randomised controlled study of several subcentres around China produced a nationally representative sample. 496 participants who took warfarin will be recruited and then randomly divided into two groups at a ratio of 1:1. We will collect data on patient characteristics, diagnosis, treatment, hospitalisation results and later complications. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of the Union Hospital Affiliated to Fujian Medical University. All cooperative hospitals have been approved by the Central Ethics Committee. The results of the survey will be disseminated in future peer review documents and will provide the basis for a management model for patients in China taking warfarin. TRIAL REGISTRATION NUMBER: ChiCTR1900021920.

Effect of Gene-Based Warfarin Dosing on Anticoagulation Control and Clinical Events in a Real-World Setting.

The cytochrome P450 2C9 and vitamin K epoxide reductase complex subunit 1 genotypes are associated with anticoagulation control and the clinical events in warfarin therapy. However, the clinical utility of gene-based warfarin dosing (GBWD) is controversial. We compared the anticoagulation control and clinical events related to warfarin with GBWD to those with clinically fixed dosing (CFD). A retrospective cohort study was conducted in a real-world setting. Of the 915 patients who were reviewed, 844 patients met the study-entry criteria; 413 cases were guided by GBWD using the International Warfarin Pharmacogenetic Consortium algorithm; 431 cases were guided by CFD (2.5 mg/day). The primary outcomes were the time needed to achieve the therapeutic International Normalized Ratio (INR) and the time in the therapeutic range (TTR) during a 3-month timeframe. The time needed to achieve the therapeutic INR (in days) for patients in the GBWD group was shorter than that for patients in the CFD group (10.21 ± 4.68 vs. 14.31 ± 8.26, P < 0.001). The overall TTR (Day 4-90) was significantly different between the GBWD group and CFD group (56.86 ± 10.72 vs. 52.87 ± 13.92, P = 0.007).In subgroup analysis, the TTR was also significantly different between the GBWD group and CFD group during the first month of treatment (Day 4-14: 54.28 ± 21.90 vs. 47.01 ± 26.25, P = 0.012; Day 15-28: 59.60 ± 20.12 vs. 51.71 ± 18.96, P = 0.001). However, no significant difference in the TTR was observed after 29 days of treatment. These data suggest that GBWD provided clinical benefits.