Genomic alterations as independent prognostic factors to predict the type of lung cancer recurrence.

INTRODUCTION: 33-70% of lung cancer (LC) patients develop recurrence after radical treatment. Previous studies have shown the importance of clinical-pathological characteristics for the risk of recurrence. The role of molecular mechanisms remains unclear. The aim was analyzing genomic features in LC patients with local (LR) versus distant recurrence (DR) to predict the risk and type of recurrence. MATERIALS AND METHODS: Patients previously curatively treated with LC recurrences from 2015 to 2017 were retrospectively enrolled. Histological specimens collected at the time of LC diagnosis were sent for whole exome sequencing (WES). Genomic data was analyzed for single nucleotide polymorphisms (SNPs) and insertion-deletion mutations (INDELs). RESULTS: 191 patients were included. 33% of patients had LR and 67% DR, with median recurrence-free survival (RFS) 15.4 versus 11.2 months (p = 0.20) and overall survival (OS) after recurrence 12.9 versus 8.5 months (p = 0.007), respectively. Of various laboratory parameters studied, lymphocytes were significantly decreased at recurrence (p < 0.0001) in the DR group. In genetic analysis, significantly enriched INDEL mutations were found in 38 and 98 genes and SNP mutations in 63 and 179 genes in DR and LR groups, respectively. DMXL2 and ABCC9 gene mutations caused by INDELs appeared exclusively in the DR group. Enrichment analysis detected genes, like KNTC1, CLASP1, CLASP2 and CENPE, responsible of microtubule disturbance in the DR group. Furthermore, genes related to cytosolic Ca2+ such as STIM1, ITPR3 and RYR3, were significantly enriched in DR group whereas in LR group enrichment of pathways related to endoplasmic/sarcoplasmic reticulum Ca2+ was observed. CONCLUSION: Our findings indicate distinct genomic signatures in the LR and DR cohorts, with microtubule disturbance and calcium regulation playing a crucial role in invasiveness in DR of LC. Understanding molecular mechanisms of LC recurrence may lead to the discovery of novel drug targets that could potentially stop spread of cancer cells.

Pharmacokinetics and pharmacodynamics of piperacillin/tazobactam during high volume haemodiafiltration in patients with septic shock.

BACKGROUND: The purpose of the study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of piperacillin and tazobactam during high-volume haemodiafiltration (HVHDF). METHODS: A single dose of piperacillin/tazobactam (4/0.5 g) was administered as 30 minute infusion during HVHDF to 10 patients with acute kidney injury due to septic shock. Arterial blood samples were collected before and at 30 or 60 min intervals over 8 h (12 samples) after study drug administration. Concentrations of piperacillin and tazobactam were determined by HPLC-MS/MS. R software was used for population PK analysis and Monte Carlo Simulation of probability of PK/PD target attainment (PTA) in 1000 subjects. RESULTS: A total of 101 samples were collected during HVHDF. The median (IQR) estimated glomerular filtration rate of the patients was 16 (11.25-27.5) ml/min/1.73 m(2) and HVHDF effluent rate was 208 (146.3-298.3) ml/kg/h. A final two-compartment population PK model predicted mean (%SE) total piperacillin clearance on HVHDF was 6.9 (6.4) l/h, volume of distribution of central compartment 9.0 (10.1) l and of peripheral compartment 11.2 (12.2) l. The PTA of 50% fT>MIC for piperacillin 4 g/tazobactam 0.5 g dosed every 8 h as 0.5-h and 4-h infusion was 84.3% and 100% for MIC of 16 mg/l respectively. Aiming 100% fT>MIC of 16 mg/l, the PTA values were 88.6% and 61.0%, for piperacillin 4 g/tazobactam 0.5 g 4-h infusion every 6 and 8 h respectively. CONCLUSIONS: For bactericidal PK/PD target attainment piperacillin/tazobactam doses of 4/0.5 g every 8 h appear appropriate in septic shock patients with minimal residual renal function during HVHDF.

Pharmacokinetics of meropenem determined by microdialysis in the peritoneal fluid of patients with severe peritonitis associated with septic shock.

Our objective was to describe the pharmacokinetics of meropenem in the peritoneal fluid (PF) of six patients with severe peritonitis and septic shock and to relate measured concentrations to the minimum inhibitory concentration of bacteria. Microdialysis catheters were placed into the peritoneal space during surgery. Meropenem concentrations in plasma and in PF were analyzed using compartmental modeling. Meropenem areas under the concentration-time curve were lower in PF than in plasma (average ratio, 73.8+/-15%) because of degradation confirmed ex vivo. Compartment modeling with elimination from a peripheral compartment described the data adequately, and was used to simulate steady-state concentration profiles in plasma and PF during various dosing regimens. At the currently recommended dosing regimen of 1 g infused over 20 min every 8 h, PF concentrations of meropenem in patients with severe peritonitis associated with septic shock reach values sufficient for antibacterial effects against susceptible, but not always against intermediately susceptible, bacteria.

Quantitative determination of MDR1 mRNA expression in peripheral blood lymphocytes: a possible role of genetic polymorphisms in the MDR1 gene.

BACKGROUND: P-glycoprotein is a transmembrane efflux pump that extrudes a wide variety of drugs, thereby reducing their intracellular access. In humans, P-glycoprotein is encoded by the MDR1 gene. Recently, several single nucleotide polymorphisms in the MDR1 gene were identified. Moreover, it was postulated that, in addition to the full-length P-glycoprotein, a 'mini' P-glycoprotein was also present in lymphocytes. MATERIALS AND METHODS: We investigated the effect of the genetic polymorphisms G2677T and C3435T in the MDR1 gene on MDR1 mRNA expression in FACS-sorted peripheral blood CD4+, CD8+, CD19+, and CD56+ cells. MDR1 mRNA expression was determined in 45 healthy individuals using a real-time quantitative RT-PCR. RESULTS: We detected the highest expression of MDR1 mRNA in CD56+ cells, followed by CD8+ > CD4+ > CD19+ cells. However, genetic polymorphisms of the MDR1 gene failed to affect (P > 0.05) MDR1 mRNA levels in the peripheral blood lymphocytes. Furthermore, the transcript levels for the MDR1 N-terminal half were almost two-fold lower than that of the MDR1 C-terminal half in all cell populations investigated (P < 0.0001). CONCLUSIONS: An almost two-fold difference in MDR1 C- and N-terminal half expressions supports the presence of mini-P-glycoprotein, an alternatively spliced form of the full-length molecule, in peripheral blood lymphocytes.

Digoxin: use pattern in Estonia and bioavailability of the local market leader.

BACKGROUND: In comparison with neighbouring Scandinavian countries, the use of digoxin in Estonia is high. The present study was carried out to determine the use pattern of digoxin in Estonia and bioavailability of the local market leader preparation in comparison with Lanoxin. METHOD: Drug use data were evaluated from the annual reports of wholesale companies. For the bioequivalence study, a single-blind cross-over randomised two-way single-dose comparative bioavailability study was performed using 14 healthy volunteers. Digoxin concentrations in serum samples and urine were measured by chemiluminescent competitive immunoassay. RESULTS: The use of digoxin in Estonia has increased by 35% during the period 1994-97. The steady market leader was the local generic drug. No statistically significant differences were found in any pharmacokinetic parameter between the generic preparation and Lanoxin. All parameters showed considerable variability. The total amount of drug excreted was the parameter with lowest inter- individual variation. CONCLUSION: The present study indicates that the generic digoxin preparation studied is bioequivalent to Lanoxin. The increasing use of digoxin in Estonia is not caused by low bioavailability of the local market leader but by therapeutic traditions.