A simple and fast LC-MS/MS method with a very high sensitivity for the measurement of raltitrexed in human plasma.

Raltitrexed is a thymidylate synthase inhibitor that can be administered safely to patients with cardiovascular disease or dihydropyrimidine dehydrogenase deficiency, as opposed to 5FU. The recommended dose of 3mg/m2 every 3 weeks often leads to toxicity. Interestingly, the 2mg/m2 every 2 weeks dose appears to be less toxic. A pharmacokinetic trial was then performed by our team to investigate such phenomenon. However, there are currently, two main methods for RTX measurement described in the literature: a radioimmunoassay (RIA) and chromatographic-based methods with either UV or mass spectrometry detections. The RIA methods: display a low limit of quantification (below 1µg/L), but also a low extent of linearity for the calibration curve. The chromatographic-based methods: include high level of calibrators, but have poor sensitivity (>2µg/mL). If a high sensitivity is essential to satisfactorily describe the elimination of RTX, high concentrations in the calibration curve are also needed to avoid bias linked to the dilutions of the samples. A new LC-MS/MS method was then developed that allows to simultaneously measure very low (0.1µg/L) and very high (3000µg/L) concentrations in the same run. Moreover, the extraction steps are very simple and fast with mainly a precipitation and a filtration steps. This method was validated following the EMA recommendations. In view of the extent of the calibration curve, the carry-over effect was more deeply investigated. With this method, it was possible to measure RTX in samples taken 3 weeks after the administration. Taken together, this method allows to simply and quickly measure RTX in plasma of patients.

[Quality and outcome assessment in gastrointestinal endoscopy: study of 202 colonoscopies]. / Evaluation de la qualité des soins en endoscopie digestive: étude de 202 coloscopies totales consécutives.

AIM: The aim of this study was to evaluate the quality of the medical care associated with the colonoscopies performed in our gastrointestinal endoscopy unit. This 6-month prospective, comparative study used process and result indicators. Its long-term objective was to improve the quality of care and to select a few pertinent quality indicators for continual monitoring. METHODS: An audit was conducted of all total colonoscopies performed at our general hospital from November 2005 through May 2006. It assessed the principal published process and result indicators for the medical aspects of the procedure as well as patient satisfaction (indication, procedure itself, results, complications, satisfaction). These indicators were also compared between endoscopists. RESULTS: During the 6-month study period, 202 total colonoscopies were performed. Waiting time for the procedure, appropriateness of the indication, proportion of colonoscopies completed, proportion of neoplastic lesions found, adequacy of bowel preparation, frequency of complications, and patient satisfaction were similar to and even above the standard values. However, patient information and the completeness of the legal documents were insufficient. Although the mean values were satisfactory, detailed individual analysis showed statistically significant differences between endoscopists. For example, the proportion of withdrawal times exceeding 6 minutes was 16.3%, 25.0% and 86.4% according to endoscopist. The mean number of polyps each removed per procedure was respectively 1, 2, and 3 (p<0.05). An improvement plan was implemented in view of these results, and appropriate simple indicators were selected for prospective monitoring. CONCLUSION: Despite the overall results, which essentially complied with standard guidelines, our prospective and comparative audit of colonoscopies pointed out significant variations between individual endoscopists and helped us to define improvement actions and indicators.

New Doppler ultrasound signs improve the non-invasive diagnosis of cirrhosis or severe liver fibrosis.

OBJECTIVES: To determine whether ultrasound and, particularly, new Doppler signs increased the diagnostic accuracy of the most accurate, currently available markers for the diagnosis of cirrhosis or severe fibrosis. METHODS: Thirty-two clinical (n = 4), biochemical (n = 11) and Doppler ultrasound (n = 17) variables were recorded in 106 patients with compensated chronic liver disease. Diagnostic accuracy was evaluated by discriminant analysis; first, globally, using all variables then by stepwise analysis. RESULTS: (A) Diagnosis of cirrhosis. Using Doppler ultrasound, diagnostic accuracy was 92% (95% confidence interval 81-98) globally, and 89% (76-95) with three variables (spleen length, hepatic vein spectrum and maximum portal vein velocity). Based upon clinical signs, diagnostic accuracy was 86% (77-92) globally, and 85% (76-91) with one variable (firm liver). Based upon biochemical parameters, diagnostic accuracy was 80% (70-88) globally, and 81% (72-88) with two variables (hyaluronate and platelet count). Based upon all parameters, diagnostic accuracy was 91% (79-96.5) globally, and 91% (79-96.5) with four variables (firm liver, hyaluronate, platelet and hepatic vein spectrum). On an intention to diagnose basis, Doppler ultrasound provided a lower independent contribution due to missing data. (B) In the diagnosis of severe fibrosis, diagnostic accuracy was 83% (69-92) globally, and 77% (62-87) with one variable. CONCLUSIONS: Cirrhosis can be correctly diagnosed in approximately 90% of patients with compensated chronic liver disease using a few Doppler ultrasound signs including a new sign, the hepatic vein spectrum. Doppler ultrasound could be used for the first line diagnosis and biochemical markers, such as hyaluronate, in patients with missing Doppler ultrasound data.

Inter-observer and intra-observer variability in hepatology.

OBJECTIVES: A determination of the inter-observer variability is an important step before determining diagnostic accuracy and requires a specific methodology and statistical tests. The aim of this study was to report the results, characteristics and methodological quality of agreement studies performed in hepatology. METHODS: A search of published studies yielded 42 that could be used in this evaluation: three were clinical studies, 11 were in the field of endoscopy, 12 in histopathology and 16 in radiology. The studies were described with a grid of 28 items and evaluated with a quality score (QUAS; maximum, 35) including 22 items. RESULTS: The following agreement level was noted: intra-observer > inter-observer > inter-centre. The following signs had good agreement. Endoscopy: size and red signs of oesophageal varices; histopathology: cirrhosis, fibrosis and steatosis; Doppler: mean portal vein and superior mesenteric artery velocities, hepatic artery area and perfusion indexes. Frequent methodological weaknesses were noted. The real agreement (such as the kappa index excluding chance), and the prevalence of signs and biases were rarely assessed. Standardized observations (67% of the studies), blind assessment (48%), simultaneous observations (7%), and the recording technique were not frequently used. The mean QUAS was 13 +/- 6 with 17 +/- 4 in histopathology versus 11 +/- 6 in radiology (P < 0.05). Using multiple regression, four variables independently predicted the QUAS with R2 = 0.77: adapted tests, multiple observations, intra-class correlation coefficient and agreement proportion. CONCLUSIONS: Methodology was often insufficient. Agreement is often measured under biased conditions. Some areas were not or were rarely studied, e.g., biology and ultrasound. The agreement and QUAS were often poor, suggesting the need for studies with improved observation and methodological quality of agreement.