Simulation-based systematic review of imatinib population pharmacokinetics and PK-PD relationships in chronic myeloid leukemia (CML) patients

Objectives: Several population pharmacokinetic (PPK) and pharmacokinetic-pharmacodynamic (PK-PD) analyses have been performed with the anticancer drug imatinib. Inspired by the approach of meta-analysis, we aimed to compare and combine results from published studies in a useful way - in particular for improving the clinical interpretation of imatinib concentration measurements in the scope of therapeutic drug monitoring (TDM). Methods: Original PPK analyses and PK-PD studies (PK surrogate: trough concentration Cmin; PD outcomes: optimal early response and specific adverse events) were searched systematically on MEDLINE. From each identified PPK model, a predicted concentration distribution under standard dosage was derived through 1000 simulations (NONMEM), after standardizing model parameters to common covariates. A "reference range" was calculated from pooled simulated concentrations in a semi-quantitative approach (without specific weighting) over the whole dosing interval. Meta-regression summarized relationships between Cmin and optimal/suboptimal early treatment response. Results: 9 PPK models and 6 relevant PK-PD reports in CML patients were identified. Model-based predicted median Cmin ranged from 555 to 1388 ng/ml (grand median: 870 ng/ml and inter-quartile range: 520-1390 ng/ml). The probability to achieve optimal early response was predicted to increase from 60 to 85% from 520 to 1390 ng/ml across PK-PD studies (odds ratio for doubling Cmin: 2.7). Reporting of specific adverse events was too heterogeneous to perform a regression analysis. The general frequency of anemia, rash and fluid retention increased however consistently with Cmin, but less than response probability. Conclusions: Predicted drug exposure may differ substantially between various PPK analyses. In this review, heterogeneity was mainly attributed to 2 "outlying" models. The established reference range seems to cover the range where both good efficacy and acceptable tolerance are expected for most patients. TDM guided dose adjustment appears therefore justified for imatinib in CML patients. Its usefulness remains now to be prospectively validated in a randomized trial.

Gambling among youths in Switzerland and its association with other addictive behaviours: a population-based study.

OBJECTIVE: To assess the prevalence of problem gambling in a population of youths in Switzerland and to determine its association with other potentially addictive behaviours. METHODS: Cross-sectional survey including 1,102 participants in the first and second year of post-compulsory education, reporting gambling, socio-demographics, internet use and substance use. For three categories of gambling (nongambler; nonproblem gambler and at-risk/problem gambler). socio-demographic and addiction data were compared using a bivariate analysis. All significant variables were included in a multinominal logistic regression using nongamblers as the reference category. RESULTS: The prevalence of gamblers was 37.48% (n = 413), with nonproblem gamblers being 31.94% (n = 352) and at-risk/problem gamblers 5.54% (n = 61). At the bivariate level, severity of gambling increased among adults (over 18 years) and among males, vocational students, participants not living with both parents and youths having a low socio-economic status. Gambling was also associated to the four addictive behaviours studied. At the multivariate level, risk of nonproblem gambling was increased in males, older youths, vocational students, participants of Swiss origin and alcohol misusers. Risk of at-risk/problem gambling was higher for males, older youths, alcohol misusers, participants not living with both parents and problem internet users. CONCLUSIONS: One-third of youths in our sample had gambled in the previous year and gambling is associated with other addictive behaviours. Clinicians should screen their adolescent patients for gambling habits, especially if other addictive behaviours are present. Additionally, gambling should be included in prevention campaigns together with other addictive behaviours.

Is the diagnostic yield of upper GI endoscopy improved by the use of explicit panel-based appropriateness criteria?

BACKGROUND: Increasing the appropriateness of use of upper gastrointestinal (GI) endoscopy is important to improve quality of care while at the same time containing costs. This study explored whether detailed explicit appropriateness criteria significantly improve the diagnostic yield of upper GI endoscopy. METHODS: Consecutive patients referred for upper GI endoscopy at 6 centers (1 university hospital, 2 district hospitals, 3 gastroenterology practices) were prospectively included over a 6-month period. After controlling for disease presentation and patient characteristics, the relationship between the appropriateness of upper GI endoscopy, as assessed by explicit Swiss criteria developed by the RAND/UCLA panel method, and the presence of relevant endoscopic lesions was analyzed. RESULTS: A total of 2088 patients (60% outpatients, 57% men) were included. Analysis was restricted to the 1681 patients referred for diagnostic upper GI endoscopy. Forty-six percent of upper GI endoscopies were judged to be appropriate, 15% uncertain, and 39% inappropriate by the explicit criteria. No cancer was found in upper GI endoscopies judged to be inappropriate. Upper GI endoscopies judged appropriate or uncertain yielded significantly more relevant lesions (60%) than did those judged to be inappropriate (37%; odds ratio 2.6: 95% CI [2.2, 3.2]). In multivariate analyses, the diagnostic yield of upper GI endoscopy was significantly influenced by appropriateness, patient gender and age, treatment setting, and symptoms. CONCLUSIONS: Upper GI endoscopies performed for appropriate indications resulted in detecting significantly more clinically relevant lesions than did those performed for inappropriate indications. In addition, no upper GI endoscopy that resulted in a diagnosis of cancer was judged to be inappropriate. The use of such criteria improves patient selection for upper GI endoscopy and can thus contribute to efforts aimed at enhancing the quality and efficiency of care. (Gastrointest Endosc 2000;52:333-41).

Effect of school based physical activity programme (KISS) on fitness and adiposity in primary schoolchildren: cluster randomised controlled trial.

To assess the effectiveness of a school based physical activity programme during one school year on physical and psychological health in young schoolchildren. Cluster randomised controlled trial. 28 classes from 15 elementary schools in Switzerland randomly selected and assigned in a 4:3 ratio to an intervention (n=16) or control arm (n=12) after stratification for grade (first and fifth grade), from August 2005 to June 2006. 540 children, of whom 502 consented and presented at baseline. Children in the intervention arm (n=297) received a multi-component physical activity programme that included structuring the three existing physical education lessons each week and adding two additional lessons a week, daily short activity breaks, and physical activity homework. Children (n=205) and parents in the control group were not informed of an intervention group. For most outcome measures, the assessors were blinded. Primary outcome measures included body fat (sum of four skinfolds), aerobic fitness (shuttle run test), physical activity (accelerometry), and quality of life (questionnaires). Secondary outcome measures included body mass index and cardiovascular risk score (average z score of waist circumference, mean blood pressure, blood glucose, inverted high density lipoprotein cholesterol, and triglycerides). 498 children completed the baseline and follow-up assessments (mean age 6.9 (SD 0.3) years for first grade, 11.1 (0.5) years for fifth grade). After adjustment for grade, sex, baseline values, and clustering within classes, children in the intervention arm compared with controls showed more negative changes in the z score of the sum of four skinfolds (-0.12, 95 % confidence interval -0.21 to -0.03; P=0.009). Likewise, their z scores for aerobic fitness increased more favourably (0.17, 0.01 to 0.32; P=0.04), as did those for moderate-vigorous physical activity in school (1.19, 0.78 to 1.60; P<0.001), all day moderate-vigorous physical activity (0.44, 0.05 to 0.82; P=0.03), and total physical activity in school (0.92, 0.35 to 1.50; P=0.003). Z scores for overall daily physical activity (0.21, -0.21 to 0.63) and physical quality of life (0.42, -1.23 to 2.06) as well as psychological quality of life (0.59, -0.85 to 2.03) did not change significantly. A school based multi-component physical activity intervention including compulsory elements improved physical activity and fitness and reduced adiposity in children. Trial registration Current Controlled Trials ISRCTN15360785.

Eligibility for statin therapy in primary prevention: discrepancies using different guidelines in a population-based study in Switzerland

Introduction: Recommendations for statin use for primary prevention of coronary heart disease (CHD) are based on estimation of the 10-year CHD risk. We compared the 10-year CHD risk assessments and eligibility percentages for statin therapy using three scoring algorithms currently used in Switzerland. Methods: We studied 5683 women and men, aged 35-75, without overt cardiovascular disease (CVD), in a population-based study in Lausanne, Switzerland. We compared the 10-year CHD risk using three scoring schemes, i.e., the Framingham risk score (FRS) from the U.S. National Cholesterol Education Program's Adult Treatment Panel III (ATP III), the PROCAM scoring scheme from the International Atherosclerosis Society (IAS), and the European risk SCORE for low-risk countries, without and with extrapolation to 60 years as recommended by the European Society of Cardiology guidelines (ESC). With FRS and PROCAM, high-risk was defined as a 10-year risk of fatal or non-fatal CHD >20% and a 10-year risk of fatal CVD >= 5% with SCORE. We compared the proportions of high-risk participants and eligibility for statin use according to these three schemes. For each guideline, we estimated the impact of increased statin use from current partial compliance to full compliance on potential CHD deaths averted over 10 years, using a success proportion of 27% for statins. Results: Participants classified at high-risk (both genders) were 5.8% according to FRS and 3.0% to the PROCAM, whereas the European risk SCORE classified 12.5% at high-risk (15.4% with extrapolation to 60 years). For the primary prevention of CHD, 18.5% of participants were eligible for statin therapy using ATP III, 16.6% using IAS, and 10.3% using ESC (13.0% with extrapolation) because ESC guidelines recommend statin therapy only in high-risk subjects. In comparison with IAS, agreement to identify eligible adults for statins was good with ATP III, but moderate with ESC (Figure). Using a population perspective, a full compliance with ATP III guidelines would reduce up to 17.9% of the 24'310 CHD deaths expected over 10 years in Switzerland, 17.3% with IAS and 10.8% with ESC (11.5% with extrapolation). Conclusion: Full compliance with guidelines for statin therapy would result in substantial health benefits, but proportions of high-risk adults and eligible adults for statin use varied substantially depending on the scoring systems and corresponding guidelines used for estimating CHD risk in Switzerland.

Externalizing disorders and substance use: empirically derived subtypes in a population-based sample of adults.

PURPOSE: Attention-deficit/hyperactivity disorder (ADHD), conduct disorder (CD), and oppositional defiant disorder (ODD) are common externalizing disorders of childhood. The common effects of these disorders on substance abuse need further investigation. The current study investigated the joint clusters of childhood/adolescence ADHD, CD, and ODD, and their influence on substance abuse/dependence in a population-based sample of adults. METHODS: The data were drawn from the PsyCoLaus study (n = 3,720) conducted in Lausanne, Switzerland. The population-based sample included 238 subjects meeting criteria for ADHD/ODD/CD diagnoses before the age of 15. Latent class analyses (LCA) were performed to derive comorbidity subtypes, which were subsequently characterized with respect to psychosocial correlates and substance use. RESULTS: The best fit in LCAs was achieved with three latent classes: an ADHD subtype (35.7 %); an externalizing multimorbid subtype (33.6 %) involving ODD, ADHD, and CD; and a third subtype with CD (30.7 %). The CD subtype showed the highest association with substance use. Apart from this, the externalizing multimorbid subtype was also significantly linked to substance use. The ADHD subtype had only elevated frequencies for alcohol dependence in comparison with subjects that had no history of ADHD, ODD, and CD during childhood or adolescence. Finally, important interactions between subtypes and sex were observed with regard to substance use. CONCLUSIONS: This study provides evidence showing that subtyping the externalizing disorders, ADHD, ODD and CD, along their comorbidity patterns leads to important differences regarding substance use. This could have implications for the etiology, prevention, and treatment of substance use disorders.

Synthesis and characterization of a new class of anti-angiogenic agents based on ruthenium clusters.

New triruthenium-carbonyl clusters derivatized with glucose-modified bicyclophosphite ligands have been synthesized. These compounds were found to have cytostatic and cytotoxic activity and depending on the number of bicyclophosphite ligands, and could be tuned for either anti-cancer or specific anti-angiogenic activity. While some compounds had a broad cellular toxicity profile in several cell types others showed endothelial cell specific dose-dependent anti-proliferative and anti-migratory efficacy. A profound inhibition of angiogenesis was also observed in the in vivo chicken chorioallantoic membrane (CAM) model, and consequently, these new compounds have considerable potential in drug design, e.g. for the treatment of cancer.

Ultimate test bench for pediatric biventricular assist device based on artificial muscles.

Ventricular assist devices (VADs) are used in treatment for terminal heart failure or as a bridge to transplantation. We created biVAD using the artificial muscles (AMs) that supports both ventricles at the same time. We developed the test bench (TB) as the in vitro evaluating system to enable the measurement of performance. The biVAD exerts different pressure between left and right ventricle like the heart physiologically does. The heart model based on child's heart was constructed in silicone. This model was fitted with the biVAD. Two pipettes containing water with an ultrasonic sensor placed on top of each and attached to ventricles reproduced the preload and the after load of each ventricle by the real-time measurement of the fluid height variation proportionally to the exerted pressure. The LabVIEW software extrapolated the displaced volume and the pressure generated by each side of our biVAD. The development of a standardized protocol permitted the validation of the TB for in vitro evaluation, measurement of the performances of the AM biVAD herein, and reproducibility of data.

Schistosomiasis control based on repeated chemotherapy in a rural village of the sugar-cane zone in Northeast Brazil

A schedule of repeated chemotherapy with oxamniquine, consisting of biannual treatment of school-aged (7-13 years) children and annual treatment of all other age groups, was used in a representative rural village from a highly endemic area of schistosomiasis in Pernambuco. Significant reductions in infection were obtained only after two cycles of treatment, as the overall prevalence decreased from 72.6% to 41.7% and the geometric mean egg counts per gram of faeces among positives fell from 188.4 to 76. In a school-aged cohort (n=29) three treatments at six-month intervals were necessary to significantly reduce the proportion of positives (from 75.9% to 51.7%). In a cohort of children under 7 years of age (n=20) the proportion of positives actually increased (from 30% to 45%) despite two annual treatments. Water contact was intense and host snail density was relatively high. As there is no short-term perspective of improved sanitation, auxiliary measures such as focal mollusciciding are needed for an adequate control of schistosomiasis in this and alike areas.

Syndrome de Sjögren: enfin une nouvelle approche de traitement [Sjögren's syndrome: a new approach to treatment].

Södgren's syndrome treatment has essentially been based on symptomatic approach and has been of limited efficacy. Novel biological therapies targeting B cells, a key player in the pathophysiology of the syndrome, have recently been tested in controlled clinical trials and raise the hope of improving glandular and extraglandular manifestations of Söigren's syndrome.

Treatment of extraintestinal manifestations in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a systemic disease associated with a large number of extraintestinal manifestations (EIM). EIM are present in 15-20% of patients with ulcerative colitis and in 20-40% of patients with Crohn's disease. The management of EIM is best provided by a multidisciplinary team, which includes specialists in the affected organ systems with training in the treatment of IBD. Therapeutic strategy is often empirical. This is explained by the paucity of randomized-controlled studies for the specific treatment of EIM in IBD and by the fact that treatment models are based on extrapolation from patients with similar conditions but without IBD. For most EIM, the mainstay of therapy is the treatment of the underlying active IBD. However, some EIM such as axial arthritis, pyoderma gangrenosum, uveitis and primary sclerosing cholangitis run a clinical course independent of IBD activity and need specific therapy (e.g. TNF antagonists in ankylosing spondylitis and skin manifestations). This review summarizes the conventional and novel (e.g. anti-TNF) treatment modalities, and the therapeutic implications for the management of extraintestinal symptoms in IBD, in order to assist clinicians in optimizing treatment strategies for IBD patients with EIM.

Predictors of nonresponse in a questionnaire-based outcome study of vocational rehabilitation patients.

OBJECTIVE: To identify predictors of nonresponse to a self-report study of patients with orthopedic trauma hospitalized for vocational rehabilitation between November 15, 2003, and December 31, 2005. The role of biopsychosocial complexity, assessed using the INTERMED, was of particular interest. DESIGN: Cohort study. Questionnaires with quality of life, sociodemographic, and job-related questions were given to patients at hospitalization and 1 year after discharge. Sociodemographic data, biopsychosocial complexity, and presence of comorbidity were available at hospitalization (baseline) for all eligible patients. Logistic regression models were used to test a number of baseline variables as potential predictors of nonresponse to the questionnaires at each of the 2 time points. SETTING: Rehabilitation clinic. PARTICIPANTS: Patients (N=990) hospitalized for vocational rehabilitation over a period of 2 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Nonresponse to the questionnaires was the binary dependent variable. RESULTS: Patients with high biopsychosocial complexity, foreign native language, or low educational level were less likely to respond at both time points. Younger patients were less likely to respond at 1 year. Those living in a stable partnership were less likely than singles to respond at hospitalization. Sex, psychiatric, and somatic comorbidity and alcoholism were never associated with nonresponse. CONCLUSIONS: We stress the importance of assessing biopsychosocial complexity to predict nonresponse. Furthermore, the factors we found to be predictive of nonresponse are also known to influence treatment outcome and vocational rehabilitation. Therefore, it is important to increase the response rate of the groups of concern in order to reduce selection bias in epidemiologic investigations.

Sorafenib for the treatment of metastatic thyroid cancer patients.

Segons resultats de fases II amb inhibidors tirosina quinasa i el coneixement de les alteracions moleculars de la carcinogènesis tiroïdal, es va dissenyar un estudi retrospectiu de pacients amb càncer de tiroide metastàtic tractats amb sorafenib. S’analitzaren la taxa de respostes, toxicitat, supervivència i la correlació amb els marcadors tumorals de 34 pacients. Segons subtipus histològic, la taxa de respostes va ser 47% en medul•lars, 19% en diferenciats i 33% en anaplàsics. La mitjana de supervivència-lliure-de-progressió va ser 13.5, 10.5 i 4.4 mesos, respectivament. Es va observar correlació significativa entre la reducció dels nivells de marcador tumoral i la resposta. El perfil de toxicitat va ser favorable.

Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research.

PURPOSE: This randomized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate (ORR) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil (ECF) as first-line advanced gastric cancer therapy. PATIENTS AND METHODS: Chemotherapy-naïve patients with measurable unresectable and/or metastatic gastric carcinoma, a performance status <or= 1, and adequate hematologic, hepatic, and renal function randomly received <or= eight 3-weekly cycles of ECF (epirubicin 50 mg/m(2) on day 1, cisplatin 60 mg/m(2) on day 1, and fluorouracil [FU] 200 mg/m(2)/d on days 1 to 21), TC (docetaxel initially 85 mg/m(2) on day 1 [later reduced to 75 mg/m(2) as a result of toxicity] and cisplatin 75 mg/m(2) on day 1), or TCF (TC plus FU 300 mg/m(2)/d on days 1 to 14). Study objectives included response (primary), survival, toxicity, and quality of life (QOL). RESULTS: ORR was 25.0% (95% CI, 13% to 41%) for ECF, 18.5% (95% CI, 9% to 34%) for TC, and 36.6% (95% CI, 23% to 53%) for TCF (n = 119). Median overall survival times were 8.3, 11.0, and 10.4 months for ECF, TC, and TCF, respectively. Toxicity was acceptable, with one toxic death (TC arm). Grade 3 or 4 neutropenia occurred in more treatment cycles with docetaxel (TC, 49%; TCF, 57%; ECF, 34%). Global health status/QOL substantially improved with ECF and remained similar to baseline with both docetaxel regimens. CONCLUSION: Time to response and ORR favor TCF over TC for further evaluation, particularly in the neoadjuvant setting. A trend towards increased myelosuppression and infectious complications with TCF versus TC or ECF was observed.

Quantification of dose nonuniformities by voxel-based dosimetry in patients receiving 90Y-ibritumomab-tiuxetan.

OBJECTIVE: To assess the impact of nonuniform dose distribution within lesions and tumor-involved organs of patients receiving Zevalin, and to discuss possible implications of equivalent uniform biological effective doses (EU-BED) on treatment efficacy and toxicity. MATLAB? -based software for voxel-based dosimetry was adopted for this purpose. METHODS: Eleven lesions from seven patients with either indolent or aggressive non-Hodgkin lymphoma were analyzed, along with four organs with disease. Absorbed doses were estimated by a direct integration of single-voxel kinetic data from serial tomographic images. After proper corrections, differential BED distributions and surviving cell fractions were estimated, allowing for the calculation of EU-BED. To quantify dose uniformity in each target area, a heterogeneity index was defined. RESULTS: Average doses were below those prescribed by conventional radiotherapy to eradicate lymphoma lesions. Dose heterogeneity and effect on tumor control varied among lesions, with no apparent relation to tumor mass. Although radiation doses to involved organs were safe, unexpected liver toxicity occurred in one patient who presented with a pattern of diffuse infiltration. CONCLUSION: Voxel-based dosimetry and radiobiologic modeling can be successfully applied to lesions and tumor-involved organs, representing a methodological advance over estimation of mean absorbed doses. However, effects on tumor control and organ toxicity still cannot be easily predicted.