The effect of CYP3A5 and ABCB1 single nucleotide polymorphisms on tacrolimus dose requirements in Caucasian liver transplant patients

Background: Tacrolimus is a substrate of cytochrome P-450 (CYP) 3A enzyme and of the drug transporter ABCBl. We have investigated the effects of possible relevant CYP3A5 and ABCBl single nucleotide polymorphisms (SNPs) present in both donors and recipients on tacrolimus blood levels achieved in a population of 32 Caucasian liver transplant patients. Material/Methods: At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C0) were determined. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for gen-otyping CYP3A5*3 [6986A>G] as well as ABCBl at exons 21 [2677G>T] and 26 [3435C>T]. Results:87.5% of the population showed a CYP3A5*3/*3 genotype. For the ABCBl SNPs, in the case of 3435C>T the total frequency observed for the allelic variant was 50%. For the 2677G>T, the total frequency of the allelic variant was 12.5%, lower than in other Caucasian populations and without any significant linkage with 3435C>T. At 3 and 6 months after transplantation, tacrolimus dose requirements were significantly higher in patients receiving a liver with one copy of the *1 al-lele compared to those homozygous for the *3 allele (0.111±0.057 vs. 0.057±0.030 [P<0.05] at 3 month and 0.086±0.051 vs. 0.044±0.025 [P<0.05] at 6 month). For the recipients' genotypes, the presence of at least one *1 copy tended, though not statistically significantly, to increase tacrolimus doses. With regard to the ABCBl SNPs, they did not show any influence on tacrolimus dosing requirements. Conclusions: Pharmacogenetic analysis of CYP3A5 in the donor could contribute to determine the appropriate initial dosage of tacrolimus in liver transplant patient

The role of basiliximab induction therapy in adult-to-adult living-related transplantation and deceased donor liver transplantation: a comparative retrospective analysis of a single-center series

Basiliximab in association with tacrolimus and steroids is effective in reducing episodes of acute cellular rejection (ACR) and increasing ACR-free survival after ALRLT and DDLT. No difference in patient and graft survival was found between group 1 and 2, nor was there any difference in the incidence of ACR between the 2 groups. However, less risk of HCV recurrence was present in the LRLT group

Genetically-Engineered Pig-to-Baboon Liver Xenotransplantation: Histopathology of Xenografts and Native Organs

Orthotopic liver transplantation was carried out in baboons using wild-type (WT, n = 1) or genetically-engineered pigs (α1,3-galactosyltransferase gene-knockout, GTKO), n = 1; GTKO pigs transgenic for human CD46, n = 7) and a clinically-acceptable immunosuppressive regimen. Biopsies were obtained from the WT pig liver pre-Tx and at 30 min, 1, 2, 3, 4 and 5 h post-transplantation. Biopsies of genetically-engineered livers were obtained pre-Tx, 2 h after reperfusion and at necropsy (4–7 days after transplantation). Tissues were examined by light, confocal, and electron microscopy. All major native organs were also examined. The WT pig liver underwent hyperacute rejection. After genetically-engineered pig liver transplantation, hyperacute rejection did not occur. Survival was limited to 4–7 days due to repeated spontaneous bleeding in the liver and native organs (as a result of profound thrombocytopenia) which necessitated euthanasia. At 2 h, graft histology was largely normal. At necropsy, genetically-engineered pig livers showed hemorrhagic necrosis, platelet aggregation, platelet-fibrin thrombi, monocyte/macrophage margination mainly in liver sinusoids, and vascular endothelial cell hypertrophy, confirmed by confocal and electron microscopy. Immunohistochemistry showed minimal deposition of IgM, and almost absence of IgG, C3, C4d, C5b-9, and of a cellular infiltrate, suggesting that neither antibody- nor cell-mediated rejection played a major role

Treatment of non-small-cell lung cancer: a perspective on the recent advances and the experience with gefitinib

Worldwide, non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related mortality and, until screening detects early disease, treatment for the majority of patients will consist of radiation therapy, chemotherapy or combinations thereof. Modern mono and doublet chemotherapy regimens have translated into modest increases in life expectancy and improved quality of life, but at the expense of systemic and pulmonary adverse events (AEs). There is a great unmet need to provide effective therapy for advanced NSCLC that does not have the toxicity burden of conventional chemotherapy and radiotherapy. Novel drugs that inhibit a range of growth factor receptors, such as the epidermal growth factor receptor tyrosine kinase inhibitors gefitinib (‘Iressa’) and erlotinib (‘Tarceva’) or the monoclonal antibody cetuximab (‘Erbitux’), have recently been evaluated. Having demonstrated antitumour activity and rapid symptom improvement in pretreated patients with advanced NSCLC, gefitinib was approved in the USA, Japan and other countries. Gefitinib is well tolerated with a low incidence of grade 3/4 AEs. Interstitial lung disease has been reported in a small number of patients receiving gefitinib, although this may be attributed to other treatments and conditions. Nevertheless, although the use of novel treatments requires vigilance for unexpected AEs such as pulmonary toxicity, in this area of high unmet clinical need, the benefits outweigh the risks in patients for whom no other proven effective treatment exists

Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer

This randomised multicentre trial was conducted to establish the optimal duration of palliative chemotherapy in advanced non-small-cell lung cancer (NSCLC). We compared a policy of three vs six courses of new-generation platinum-based combination chemotherapy with regard to effects on quality of life (QoL) and survival. Patients with stage IIIB or IV NSCLC and WHO performance status (PS) 0–2 were randomised to receive three (C3) or six (C6) courses of carboplatin (area under the curve (AUC) 4, Chatelut's formula, equivalent to Calvert's AUC 5) on day 1 and vinorelbine 25 mg m−2 on days 1 and 8 of a 3-week cycle. Key end points were QoL at 18 weeks, measured with EORTC Quality of Life Questionnaire (QLQ)-C30 and QLQ-LC13, and overall survival. Secondary end points were progression-free survival and need of palliative radiotherapy. Two hundred and ninety-seven patients were randomised (C3 150, C6 147). Their median age was 65 years, 30% had PS 2 and 76% stage IV disease. Seventy-eight and 54% of C3 and C6 patients, respectively, completed all scheduled chemotherapy courses. Compliance with QoL questionnaires was 88%. There were no significant group differences in global QoL, pain or fatigue up to 26 weeks. The dyspnoea palliation rate was lower in the C3 arm at 18 and 26 weeks (P<0.05), but this finding was inconsistent across different methods of analysis. Median survival in the C3 group was 28 vs 32 weeks in the C6 group (P=0.75, HR 1.04, 95% CI 0.82–1.31). One- and 2-year survival rates were 25 and 9% vs 25 and 5% in the C3 and C6 arm, respectively. Median progression-free survival was 16 and 21 weeks in the C3 and C6 groups, respectively (P=0.21, HR 0.86, 95% CI 0.68–1.08). In conclusion, palliative chemotherapy with carboplatin and vinorelbine beyond three courses conveys no survival or consistent QoL benefits in advanced NSCLC

Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study.

Background. The addition of cyclo-oxygenase-2 (COX-2) inhibitors and prolonged constant infusion (PCI) of gemcitabine to treatment for advanced non-small-cell lung cancer (NSCLC) might improve treatment efficacy. We aimed to assess whether the addition of rofecoxib or PCI gemcitabine could improve overall survival compared with first-line treatment with cisplatin plus gemcitabine given by standard infusion. Methods. Patients with stage IV or IIIb (with supraclavicular nodes or pleural effusion) NSCLC who were under 70 years of age and who had performance status 0 or 1 were eligible for this multicentre, prospective, open-label, randomised phase III trial with 2×2 factorial design. Patients were randomly assigned to one of four treatment groups: group A,gemcitabine 1200 mg/m2 in a 30-min intravenous infusion on days 1 and 8 and intravenous cisplatin 80 mg/m2 on day 1, every 21 days for six cycles; group B, the same treatments as group A plus oral rofecoxib 50 mg/day until disease progression; group C, intravenous PCI gemcitabine 1200 mg/m2 in a 120-min infusion on days 1 and 8 and intravenous cisplatin 80 mg/m2 on day 1, every 21 days for six cycles; group D, the same drugs as group C plus oral rofecoxib 50 mg/day until disease progression. The primary endpoint was overall survival; secondary endpoints were progression free survival, response rate, quality of life, and toxicity. Analyses were intention-to-treat. This trial is registered on the clinical trials site of the US National Institutes of Health website http://clinicaltrials.gov/ct/show/NCT00385606. Findings. Between Jan 30, 2003, and May 3, 2005, 400 patients were enrolled. Median age was 60 years (range 29–71). PCI gemcitabine did not improve overall survival (median 47 weeks [95% CI 40–55] vs 44 [36–52], with standard gemcitabine infusion, hazard ratio (HR) of death 0·93 [0·74–1·17], p=0·41), progression-free survival, nor any other secondary endpoint. Vomiting and fatigue were significantly worse with PCI gemcitabine. The two rofecoxib groups were closed early (on Oct 1, 2004) due to withdrawal of the drug because of safety issues. With intention-to-treat statistical analyses limited to 240 patients (ie, those randomised before July 1, 2004) who had at least 3 months of treatment, rofecoxib did not prolong overall survival (median 44 weeks [CI 36–55] vs 44 [40–54] without rofecoxib, and HR of death 1·00 [0·75–1·34], p=0·85), or progression-free survival, but did improve response rate (41% vs 26%, p=0·02), global quality of life, physical, emotional and role functioning, fatigue, and sleeping. Rofecoxib significantly increased the incidence of diarrhoea and decreased constipation, fatigue, fever, weight loss, and pain, and analgesic consumption. Severe cardiac ischaemia was more frequent with rofecoxib than without; however, the diff erence was not statistically signifi cant in the primary analysis (p=0·06) and became significant when patients who were randomised between July 1, 2004, and Sept 30, 2004, were included in the analysis (p=0·03). Interpretation. Neither PCI gemcitabine nor rofecoxib prolonged survival in the patients in this study. Rofecoxib improved response rate and several quality-of-life items, including pain-related items and global quality of life. Further studies with less cardiotoxic COX-2 inhibitors are needed in NSCLC