Aims The aim of the study was to investigate the combined impact of genetic polymorphisms in key pharmacokinetic genes on plasma concentrations and clinical outcomes of cyclophosphamide (CPA) in Chinese patients with systemic lupus erythematosus (SLE). Methods One hundred and eighty nine Chinese SLE patients treated with CPA induction therapy (200 mg, every other day) were recruited and adverse reactions were recorded. After 4 weeks induction therapy, 128 lupus nephritis (LN) patients continued to CPA maintenance therapy (200–600 mg week–1) for 6 months, and their clinical outcomes were recorded. Blood samples were collected for CYP2C19, CYP2B6, GST and PXR polymorphism analysis, as well as CPA and its active metabolite (4‐hydroxycyclophosphamide (4‐OH‐CPA)) plasma concentration determination. Results Multiple linear regression analysis revealed that CYP2B6 ‐750 T > C (P < 0.001), −2320 T > C (P < 0.001), 15582C > T (P = 0.017), CYP2C19*2 (P < 0.001) and PXR 66034 T > C (P = 0.028) accounted for 47% of the variation in 4‐OH‐CPA plasma concentration. Among these variants, CYP2B6 ‐750 T > C and CYP2C19*2 were selected as the combination genetic marker because these two SNPs contributed the most to the inter‐individual variability in 4‐OH‐CPA concentration, accounting for 23.6% and 21.5% of the variation, respectively. Extensive metabolizers (EMs) (CYP2B6 ‐750TT, CYP2C19*1*1) had significantly higher median 4‐OH‐CPA plasma concentrations (34.8, 11.0 and 6.6 ng ml‐1 for EMs, intermediate metabolizers (IMs) and poor metabolizers (PMs), P < 0.0001), higher risks of leukocytopenia (OR = 7.538, 95% CI 2.951, 19.256, P < 0.0001) and gastrointestinal toxicity (OR = 7.579, 95% CI 2.934, 19.578, P < 0.0001), as well as shorter median time to achieve complete remission (13.2, 18.3 and 23.3 weeks for EMs, IMs and PMs, respectively, P = 0.026) in LN patients than PMs (CYP2B6 ‐750CC, CYP2C19*2*2) and IMs. Conclusions Our findings have indicated that genetic markers of drug metabolizing enzymes could predict the 4‐hydroxylation, adverse reactions and clinical efficacy of CPA. This is a necessary first step towards building clinical tools that will help assess clinical benefit and risk before undergoing CPA treatment in Chinese SLE patients.

Aim: Cyclosporine requires close therapeutic drug monitoring because of its narrow therapeutic index and marked inter-individual pharmacokinetic variation. In this study, we investigated the associations of CYP3A4, CYP3A5, ABCB1, NFKB1, and NR1I2 polymorphisms with cyclosporine concentrations in Chinese renal transplant recipients in the early period after renal transplantation. Methods: A total of 101 renal transplant recipients receiving cyclosporine were genotyped for CYP3A4*1G, CYP3A5*3, ABCB1 C1236T, G2677T/A, C3435T, NFKB1 -94 ins/del ATTG, and NR1I2 polymorphisms. Cyclosporine whole blood levels were measured by a fluorescence polarization immunoassay. Trough concentrations of cyclosporine were determined for days 7-18 following transplantation. Conclusion: These results illustrate that the ABCB1 and NFKB1 genotypes are closely correlated with cyclosporine trough concentrations, suggesting that these SNPs are useful for determining the appropriate dose of cyclosporine.

To investigate the impact of cytochrome P450 (CYP) genetic polymorphisms CYP2B6, CYP2C19, and CYP3A5 on mRNA expression, cyclophosphamide/4-hydroxycyclophosphamide pharmacokinetics, and treatment outcomes of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in Chinese patients with non-Hodgkin's lymphoma, 567 cases were investigated. Plasma concentrations of cyclophosphamide/4-hydroxycyclophosphamide were determined using liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters calculated. The frequencies of CYP2B6*1/*29 and CYP2B6*1/*30 were 18 (3.2%) and 30 (5.3%), respectively. Liver samples with CYP2B6*29/*30, CYP2C19*2, CYP2B6*6, or CYP3A5*3 had significantly lower target mRNA expression. Samples with CYP2B6*6 and/or CYP2C19*2 had lower exposure to 4-hydroxycyclophosphamide, whereas those with CYP2B6*1G/*1H had higher exposure. Multivariate model showed that samples with CYP2C19*2 or CYP2B6 785A>raG had worse treatment response than samples with CYP3A5*3. CYP2C19*2, CYP2B6*6, CYP2B6*29, and CYP2B6*30 were protective factors for toxicity in the multivariate model. The best model for gene-gene interactions for treatment response contained CYP2C19*2, CYP2B6 785A>G, and CYP3A5*3 (cross-validation consistency [CVC], 8/10; P = .0035). The best prediction model for grade 2-4 toxicities had CYP2C19*2, CYP2B6 785A>G, and 516 G>T (CVC, 10/10; P < .0001). In previous reports, we were the first to report that the frequency of copy-number variations in CYP2B6 is higher among Chinese than among other ethnic populations. Genetic variations in CYP2B6, CYP2C19, and CYP3A5 dramatically affected the mRNA expression of proteins, the pharmacokinetics of 4-hydroxycyclophosphamide, and the R-CHOP treatment response in Chinese subjects. Patients carrying CYP3A5*3 were more likely to have a better treatment response, whereas patients with CYP2C19*2 or CYP2B6 516G>T, or CYP2B6 785A>G had higher tolerance to treatment.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Important cytogenetic and genetic risk factors for the development of UM include chromosome 3 monosomy, mutations in the guanine nucleotide-binding proteins GNAQ/GNA11, and loss of the BRACA1-associated protein 1 (BAP 1). Most primary UMs are treated conservatively with radiotherapy, but enucleation is necessary for large tumours. Despite the effectiveness of local control, up to 50% of UM patients develop metastasis for which there are no effective therapies.Attempts to utilize the targeted therapies that have been developed for the treatment of other cancers, including a range of signal transduction pathway inhibitors, have rarely produced significant outcomes in UM. Similarly, the application of immunotherapies that are effective in cutaneous melanoma to treat UM have also been disappointing. Other approaches that have been initiated involve proteasomal inhibitors and histone deacetylase inhibitors that are approved for the treatment of other cancers. Nevertheless, there have been occasional positive outcomes from these treatments in UM. Moreover, combination approaches in UM have also yielded some positive developments. It would be valuable to identify how to apply such therapies efficiently in UM, potentially via individualized tumour profiling. It would also be important to characterize UM tumours to differentiate the potential drivers of progression from those in other types of cancers.The recent identification of novel kinases and metastatic genes in UM tumours makes the development of new UM-specific treatments feasible. Accepted ArticleThis article is protected by copyright. All rights reserved A) Uveal Melanoma: Background and risk factors Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and represents ~5 % of melanoma diagnoses in the US annually [1-3]. UM originates from ocular melanocytes with 85% of cases arising from the choroid region and the remainder from the ciliary body and iris [4]. The prognosis in UM is poor, in particular because around 50% of patients develop metastatic disease. Hepatic metastases occur in up to 90% of individuals, followed by metastases in lung and bones, and after establishment of metastatic disease the median survival time is only 4-5 months [5]. At the time of diagnosis, systemic metastases are reported in only 3%of patients, but it is likely that micro-metastases have already developed in many cases [6,7].Currently there are no effective systemic drug therapies for primary or metastatic UM [8,9].The median age at diagnosis is 62 years and the incidence of UM in males and females, and whether there is right or left eye involvement, is similar [10]. Underlying risk factors for UM include melanocytosis, melanocytoma, neurofibromatosis and the presence of atypical nevi [11][12][13][14]. Race is also a significant risk factor with a 150-fold greater incidence in fair-skinned over dark-skinned populations [15]. The incidence of UM in European countries varies wi...