Male sex and prolonged laparoscopic surgery are independent risk factors for BDI during LC. Frequent use of IOC does not seem to reduce BDI or the number of injuries missed during surgery.

BACKGROUND: This analysis was initiated to define the predictive value of the area under the curve of high-dose methotrexate (AUC HD-MTX ) in patients with primary central nervous system lymphoma (PCNSL). PATIENTS AND METHODS: We included 55 patients with PCNSL and available pharmacokinetic (PK) data from the International Extranodal Lymphoma Study Group (IELSG) no. 20 trial, randomised to HD-MTX (n ¼ 30) or HD-MTX and high-dose cytarabine (HD-AraC) (n ¼ 25). Individual AUC HD-MTX from population PK analysis was tested on drug toxicity and clinical outcome using multivariate logistic regression analysis and Cox hazards modelling. RESULTS: AUC HD-MTX , the IELSG score and treatment group were significant predictors for treatment response (complete or partial) in the adjusted model. The AUC HD-MTX did not predict toxicity, with the exception of liver toxicity and neutropaenia. A high AUC HD-MTX was associated with better event-free survival (EFS) (P ¼ 0.01) and overall survival (OAS) (P ¼ 0.02). Both the AUC HD-MTX and the IELSG score were significant predictors of EFS and OAS in the adjusted model, with a hazard ratio of 0.82 and 0.73, respectively, per 100 mmol l À1 h À1 increase in AUC HD-MTX .

Gender-specific elimination of 5FU is supported by the present data and may partly explain the gender-specific association between DPYD risk variants and 5FU-specific toxicity.

Mitochondrial metabolism was studied in liver mitochondria isolated from rats with secondary biliary cirrhosis induced by bile duct ligation for 5 wk. State 3 oxidation rates were decreased in mitochondrial preparations from bile duct-ligated rats as compared with sham-operated control rats by 63% and 42% using beta-hydroxybutyrate and succinate as substrates, respectively. In contrast, when the substrate was ascorbate/N,N,N',N'-tetramethyl-p-phenylenediamine state 3 oxidation rates were not affected by bile duct ligation. Oxidation rates after uncoupling with dinitrophenol were decreased for both beta-hydroxybutyrate and succinate as substrates in mitochondria from bile duct-ligated rats. The phosphate potential was reduced in mitochondria from bile duct-ligated rats (12.5 +/- 0.5 vs. 13.6 +/- 0.2 kcal in control and bile duct-ligated rats, respectively; p less than 0.05). The inner mitochondrial membrane of liver mitochondria from rats with secondary biliary cirrhosis contained three times more cholesterol as compared with control rats, whereas the phospholipid composition was essentially unchanged. Mitochondrial protein content expressed per liver (calculated on the basis of activities of mitochondrial enzymes determined in liver homogenate and in isolated mitochondria) was increased by 50% in bile duct-ligated rats as compared with control rats. In conclusion, the function of the electron transport chain in liver mitochondria isolated from rats with secondary biliary cirrhosis is impaired. This decrease could be related to altered lipid composition of the inner mitochondrial membrane.

In the present study, a non-covalent (biotin-streptavidin) coupling procedure for the preparation of pegylated immunoliposomes is presented, which simplifies the attachment of targeting vectors to sterically stabilized liposomes. A biotinylated poly(ethylene glycol) (PEG)-phospholipid [bio-PEG-distearoylphosphatidylethanolamine (DSPE)] was used as a linker between a streptavidin-conjugated monoclonal antibody (mAb) (i.e. the OX26 mAb raised against the rat transferrin receptor) and 150 nm liposomes. OX26-streptavidin had a biotin binding capacity of two to three biotin molecules per OX26-streptavidin conjugate. Immunostaining experiments with the OX26 mAb followed by fluorescent confocal microscopy revealed immunofluorescence labelling of the transferrin receptor on skeletal muscle, as well as in L6 cells, a continuous cell line derived from rat skeletal muscle. Uptake experiments with L6 cells using the OX26 mAb, fluorescence-labelled OX26-streptavidin or fluorescent OX26-immunoliposomes demonstrated cellular uptake and accumulation within an intracellular compartment of the OX26 mAb and its conjugates. Cellular uptake of OX26 conjugates was sensitive to competition with free OX26 antibody. In summary, these studies describe the design of biotinylated immunoliposomes as a universal drug transport vector and their potential for targeting of the transferrin receptor of skeletal muscle.