Drug–drug interactions and pharmacogenomic evaluation in colorectal cancer patients. The new drug-pin® system comprehensive approach

Drug–drug interactions (DDIs) can affect both treatment efficacy and toxicity. We used Drug-PIN® (Personalized Interactions Network) software in colorectal cancer (CRC) patients to evaluate drug–drug–gene interactions (DDGIs), defined as the combination of DDIs and individual genetic polymorphisms. Inclusion criteria were: (i) stage II-IV CRC; (ii) ECOG PS (Performance status sec. Eastern coperative oncology group) ≤2; (iii) ≥5 concomitant drugs; and (iv) adequate renal, hepatic, and bone marrow function. The Drug-PIN® system analyzes interactions between active and/or pro-drug forms by integrating biochemical, demographic, and genomic data from 110 SNPs. We selected DDI, DrugPin1, and DrugPin2 scores, resulting from concomitant medication interactions, concomitant medications, and SNP profiles, and DrugPin1 added to chemotherapy drugs, respectively. Thirty-four patients, taking a median of seven concomitant medications, were included. The median DrugPin1 and DrugPin2 scores were 42.6 and 77.7, respectively. In 13 patients, the DrugPin2 score was two-fold higher than the DrugPin1 score, with 7 (54%) of these patients experiencing severe toxicity that required hospitalization. On chi-squared testing for any toxic-ity, a doubled DrugPin2 score (p = 0.001) was significantly related to G3–G4 toxicity. Drug-PIN® software may prevent severe adverse events, decrease hospitalizations, and improve survival in cancer patients

Oligonucleotide Microarray Analysis of Age-Related Gene Expression Profiles in Miniature Pigs

Miniature pigs are useful model animals for humans because they have similar anatomy and digestive physiology to humans and are easy to breed and handle. In this study, whole blood microarray analyses were conducted to evaluate variations of correlation among individuals and ages using specific pathogen-free (SPF) Clawn miniature pigs. Whole blood RNA is easy to handle compared to isolated white blood cell RNA and can be used for health and disease monitoring and animal control. In addition, whole blood is a heterogeneous mixture of subpopulation cells. Once a great change occurs in composition and expressing condition of subpopulations, their associated change will be reflected on whole blood RNA. From 12 to 30 weeks of age, fractions of lymphocytes, monocytes, neutrophils, eosinophils, and basophils in white blood cells showed insignificant differences with age as a result of ANOVA analysis. This study attempted to identify characteristics of age-related gene expression by taking into account the change in the number of expressed genes by age and similarities of gene expression intensity between individuals. As a result, the number of expressed genes was less in fetal stage and infancy period but increased with age, reaching a steady state of gene expression after 20 weeks of age. Variation in gene expression intensity within the same age was great in fetal stage and infancy period, but converged with age. The variation between 20 and 30 weeks of age was comparable to that among 30 weeks individuals. These results indicate that uniformity of laboratory animals is expected for miniature pigs after 20 weeks of age. Furthermore, a possibility was shown that whole blood RNA analysis is applicable to evaluation of physiological state

Carvedilol and cardiac biomarkers in dialysis patients: Secondary analysis of a randomized controlled trial

Published online: December 04, 2017Background/Aims: Cardiac biomarkers are associated with cardiac abnormalities and adverse outcomes in dialysis patients. Our aim was to report the effect of the beta-blocker carvedilol on cardiac biomarkers in adult dialysis patients. Methods: The Beta-Blocker to Lower Cardiovascular Dialysis Events Feasibility Study was a randomized controlled trial comparing carvedilol to placebo. Serum and plasma were collected before the run-in, then 6 and 12 months post-randomization to measure B-type Natriuretic Peptide (BNP), N-terminal BNP (NT-ProBNP), high-sensitivity cardiac troponins I (hs-TnI) and T (hs-TnT), and galectin-3. Left ventricular global longitudinal strain (GLS) was measured by echocardiography at baseline. Results: Seventy-two participants were recruited of whom 49 completed the run-in and were randomized to carvedilol (n=26) or placebo (n=23). Baseline echocardiography demonstrated median (inter-quartile range) GLS of -14.27% (-16.63 to -11.93). NTproBNP and hs-TnT correlated with GLS (Spearman’s rho=0.34 [p=0.018] and rho=0.28 [p=0.049], respectively). Median change scores from baseline to 12 months did not differ significantly between participants with complete biomarker data randomized to carvedilol (n=15) or placebo (n=16) for any biomarkers. Conclusions: NT-proBNP and hs-TnT were associated with GLS. However, changes in levels of the biomarkers from baseline to 12 months were not different between groups randomized to carvedilol and placebo.Matthew A. Roberts, Darsy Darssan, Sunil V. Badve, Robert P. Carroll, Magid A. Fahim, Brian A. Haluska, Carmel M. Hawley, Nicole M. Isbel, Mark R. Marshall, Elaine M. Pascoe, Eugenie Pedagogos, Helen L. Pilmore, Paul Snelling, Tony Stanton, Ken-Soon Tan, Andrew M. Tonkin, Liza A. Vergara, Francesco L. Ierin

Secular trends in cardiovascular mortality rates of patients receiving dialysis compared with the general population

Background: Cardiovascular mortality rates in the general population have decreased over time. We hypothesized that cardiovascular mortality rates in dialysis patients, which are higher than in the general population, have not decreased as much as those in the general population. Study Design: Comparison of registry data with population data. Setting & Participants: Data for prevalent Australian patients for whom dialysis was the first renal replacement therapy were obtained from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry for 1992-2005. Data for a comparable Australian general population were obtained from the Australian Bureau of Statistics. Outcome: Cardiovascular mortality rates per 100 person-years were calculated from ANZDATA Registry data, and age-specific relative risks were calculated relative to cardiovascular mortality rates in the general population. Results: Included in this cohort were 34,741 dialysis patients with 93,112 person-years of follow-up and 7,267 cardiovascular deaths. Cardiovascular mortality rates decreased over time in the general population and in dialysis patients older than 55 years. In patients aged 55-64 years, cardiovascular mortality rates were 9.0 (95% CI, 7.8-10.3) per 100 person-years in 1992-1994 and 6.4 (95% CI, 5.5-7.3) in 2004-2005; corresponding relative risks were 32.4 (95% CI, 28.2-37.2) and 52.0 (95% CI, 45.2-59.9), respectively. The corresponding cardiovascular mortality rates for dialysis patients aged 65-74 years were 11.6 (95% CI, 10.4-13.0) and 8.3 (95% CI, 7.4-9.3); relative risks were 12.9 (95% CI, 11.6-14.5) and 20.8 (95% CI, 18.7-23.2). Using negative binomial regression, the relative risk associated with dialysis compared with the general population increased over time (P for interaction = 0.001). Limitations: Causes of death used to define cardiovascular mortality were not coded using identical systems in the ANZDATA Registry and the Australian population. Conclusions: Despite decreasing cardiovascular mortality rates in some dialysis patients, the excess cardiovascular risk compared with the general population is increasing.Matthew A. Roberts, Kevan R. Polkinghorne, Stephen P. McDonald, Francesco L. Ierin

Perioperative risk assessment for successful kidney transplant in leigh syndrome: a case report

BACKGROUND: Leigh syndrome (LS) is a rare neurodegenerative mitochondrial disorder which typically presents in childhood but has a varied clinical course. Renal involvement such as proximal tubulopathy in patients with mitochondrial disorders has been described. However, end stage renal disease (ESRD) is uncommon and literature regarding patients undergoing kidney transplantation is limited. Successful deceased donor renal transplant has not been previously described in a patient with Leigh Syndrome. CASE PRESENTATION: We report a 21-year-old Han Chinese man who presented with limb weakness and unsteady gait, which progressed rapidly over a period of months until he was wheelchair-bound. He subsequently developed ESRD and was commenced on hemodialysis. Investigations revealed a m.13513G > A mutation with clinical and radiological features consistent with LS. His mitochondrial disease stabilised and he underwent a multidisciplinary assessment for deceased donor kidney transplantation to identify and minimise the LS-associated perioperative risks and potential negative effects of immunosuppressants on his LS. Successful kidney transplantation followed with excellent graft function three and a half years post-transplant and improvement in the patient's physical function. CONCLUSION: This case highlights the importance of careful pre-transplant perioperative risk assessment and post-transplant care in a rare and heterogeneous neurological disease to achieve an ultimately excellent clinical outcome. To our knowledge, this is the first report of successful deceased donor kidney transplant in a patient with known LS

Taking the challenge: A protocolized approach to optimize Pneumocystis pneumonia prophylaxis in renal transplant recipients

While trimethoprim‐sulfamethoxazole is considered first‐line therapy for Pneumocystis pneumonia prevention in renal transplant recipients, reported adverse drug reactions may limit use and increase reliance on costly and less effective alternatives, often aerosolized pentamidine. We report our experience implementing a protocolized approach to trimethoprim‐sulfamethoxazole adverse drug reaction assessment and rechallenge to optimize prophylaxis in this patient cohort. We retrospectively reviewed 119 patients receiving Pneumocystis pneumonia prophylaxis prior to and after protocol implementation. Forty‐two patients (35%) had 48 trimethoprim‐sulfamethoxazole adverse drug reactions documented either at baseline or during the prophylaxis period, of which 83% were non‐immune‐mediated and 17% were immune‐mediated. Significantly more patients underwent trimethoprim‐sulfamethoxazole rechallenge after protocol implementation (4/22 vs 23/27; P = .0001), with no recurrence of adverse drug reactions in 74%. In those who experienced a new or recurrent reaction (26%), all were mild and self‐limiting with only 1 recurrence of an immune‐mediated reaction. After protocol implementation, aerosolized pentamidine‐associated costs were reduced. The introduction of a standard approach to trimethoprim‐sulfamethoxazole rechallenge in the context of both prior immune and non‐immune‐mediated reactions was safe and successful in improving the uptake of first‐line Pneumocystis pneumonia prophylaxis in renal transplant recipients

Clinical Outcomes and Risk Factors for Tunneled Hemodialysis Catheter-Related Bloodstream Infections

Diabetes and left internal jugular vein insertion site were significantly associated with increased risk of a catheter-related bloodstream infection from a tunneled hemodialysis catheter. Ex-smoker status was significantly associated with reduced risk

Approaching the promise of operational tolerance in clinical transplantation

Long-term acceptance of transplanted organs without requirement for indefinite immunosuppression remains the ultimate goal of transplant clinicians and scientists. This clinical state of allograft acceptance termed "operational tolerance" has been elusive in routine practice. However, there are published reports of recipients where immunosuppression has been discontinued, by intention or patient noncompliance, in which the outcome is a nondestructive immune response and normal function. The question now arises how clinical operational tolerance might be achieved in the majority of recipients. This review provides an overview of current approaches to achieve operational tolerance, including the use of donor bone marrow and depletion of recipient T cells and the resistance of liver transplants to rejection. It also describes the key role of clinical immune monitoring and future approaches to tolerance induction including inhibition of T-cell signaling, manipulation of costimulatory pathways, and expansion of regulatory T cells. The principles of these experimental approaches may ultimately be extended to provide safe and effective control of transplant rejection and induction of clinical operational tolerance.G. Alex Bishop, Francesco L. Ierino, Alexandra F. Sharland, Bruce M. Hall, Stephen I. Alexander, Mauro S. Sandrin, P. Toby Coates, Geoffrey W. McCaugha