Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR_1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR_1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR_1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR_1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow-up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR_1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.     

Tranexamic acid through intravenous,intramuscular and oral routes: an individual participant data meta‐analysis of pharmacokinetic studies in healthy volunteers

Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post‐partum haemorrhage. One key issue for treatment success is early administration. While usually given intravenously, oral and intramuscular use would be useful in specific circumstances. Therefore, an understanding of TXA pharmacokinetics when given via different routes is valuable. The aim of this study was to perform an individual participant data meta‐analysis of pharmacokinetic studies with TXA given to healthy volunteers via different routes. We searched the following databases: PubMed, Web of Science, Wiley Online Library, Elsevier Science Direct and J‐STAGE. Individual subject data were extracted when available, otherwise arithmetic means were used. A population pharmacokinetic model was developed using nonlinear mixed effect modelling. Seven studies were included in the analysis with data from 10 patients for the IV route, six patients for the IM route and 114 patients for the oral route. The pharmacokinetics was ascribed to a two‐compartment model, and the main covariate was allometrically scaled bodyweight. Oral and IM bioavailabilities were 46 and 105%, respectively. For a 70 kg bodyweight, the population estimates were 7.6 L/h for clearance, 17.9 L for the volume of the central compartment, 2.5 L/h for the diffusional clearance and 16.6 L for the peripheral volume of distribution. Larger well‐designed studies are needed to describe the pharmacokinetics of TXA when given IM or as an oral solution before these can be recommended as alternatives to IV.     

Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. EXPERIMENTAL DESIGN: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. RESULTS: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received > or = 2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 +/- 6.17 ng/mg tissue. CONCLUSION: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.     

Predictive factors of stroke in patients undergoing coronary bypass grafting: statins are protective.

BACKGROUND: Despite major improvement in surgical techniques and intensive care management, stroke remains one of the most devastating complications of coronary artery bypass grafting (CABG). We aimed to determine factors predicting the occurrence of stroke during CABG. A special interest was focused on preoperative therapies. METHODS: We prospectively enrolled 810 consecutive candidates for CABG alone in a specific database, including all pre- and perioperative data (history, clinical, therapeutic, cardiac catheterization, surgical and intensive care data). Univariate tests and then multiple logistic regression analysis were used to determine independent predictive factors. RESULTS: During the first postoperative month, stroke occurred in 11 cases and transient ischemic attack (TIA) in 4 additive cases (cumulative rate: 1.85%). After the multivariate analysis, the following factors remained significant (p<0.05) in the predictive model, with corresponding odds ratios between brackets: redo cardiac surgery (7.45), unstable cardiac status (4.74), past history of cerebrovascular disease (4.14), past history of peripheral arterial disease (3.55), whereas the presence of preoperative statins was protective (0.24, 95% IC: 0.07-0.78). The addition of perioperative data (aortic calcification, postoperative arrhythmia, on/off-pump surgery) did not change the final predictive model. CONCLUSION: To our knowledge, this is the first real-world observational report highlighting the interest of statins for the prevention of stroke in the very special situation of CABG. Even though according to randomized trials coronary patients have a benefit from these drugs, a special level of interest should be directed towards those presenting the above-mentioned risk factors.     

192Ir low dose rate brachytherapy for boosting locally advanced prostate cancers after external beam radiotherapy: a phase II trial.

BACKGROUND AND PURPOSE: To evaluate on 201 locally advanced prostatic cancers prospectively treated in a phase II trial, the efficacy of a combination of external beam radiotherapy (39.6 Gy) and (192)Ir low dose rate brachytherapy (Bt) (40-45 Gy). PATIENTS AND METHODS: Sixty-four patients were included in the intermediate prognosis group with only one of the following adverse factors (PSA > 10 ng/ml, Gleason score > or = 7 or clinical stage > or =T2b) and 137 in the unfavourable group when at least two of these factors were present. RESULTS: The actuarial 4 years biochemical no evidence of disease is 82.8% for the entire population. It is, respectively, 97 and 76% in the intermediate and unfavourable prognosis groups (P < 0.0001). Grade > or =3 late urinary complications occurred in 13 patients (6.5%). Eight patients (4%) presented late grade 2 rectal complications but no grades 3-5 was observed. CONCLUSIONS: Even if an alpha/beta of 1.5-3 Gy theoretically favours the use of a high dose rate mode of irradiation, the early results presented here are as good as those reported for similar groups of patients with high dose rate treatments. Late toxicity is identical but our urinary toxicity is within the less favourable and rectal toxicity within the most favourable results. We can postulate that while inducing very high hyperdosage regions (V150) mainly focused on the peripheral zone, most of the Bt techniques consist of a more ablative treatment. Many of the radiobiological studies on Bt did not in fact take into account the heterogeneity of irradiation inside the CTV. This study highlights the need to explore pulsed dose rate therapies, permanent implant and new available radioisotopes such as (169)Ytterbium that will offer the safety of low and lower dose rates. The actual late toxicity of the different Bt techniques is not yet inexistent indeed.     

Serum monitoring of antipsychotic drug levels during concomitant administration of sertraline and antipsychotic medication.

OBJECTIVE: To assess whether pharmacokinetic drug interactions occur when sertraline is added to antipsychotic medications. METHOD: Forty-eight patients with remitted DSM-IV schizophrenia and comorbid major depression were randomized to placebo for 6 weeks or sertraline 50 mg for 4 weeks followed by sertraline 50 mg to 100 mg for 2 weeks for nonresponders. Treatment with the patients' usual antipsychotic continued. Weekly clinical outcome assessments occurred for 6 weeks, and serum samples for drug monitoring were collected at Weeks 1, 5, and 6. Serum concentrations of sertraline and antipsychotics were measured with standard assays. RESULTS: In both placebo- and sertraline-treated groups, most patients displayed minor fluctuations in antipsychotic serum levels over 6 weeks. There was no clinical evidence of drug interactions in the sertraline-treated group. CONCLUSIONS: Clinically significant adverse effects did not occur despite variable antipsychotic serum levels with or without sertraline. Concern about pharmacokinetic interactions should not deter the use of sertraline for depression in individuals with schizophrenia.     

Educating African American men about the prostate cancer screening dilemma: a randomized intervention.

BACKGROUND: Until there is a definitive demonstration that early diagnosis and treatment of prostate cancer reduces disease-related mortality, it is imperative to promote informed screening decisions by providing balanced information about the potential benefits and risks of prostate cancer screening. Within a community/academic collaboration, we conducted a randomized trial of a printed booklet and a videotape that were designed for African American (AA) men. The purpose of the trial was to determine the effect of the interventions on knowledge, decisional conflict, satisfaction with the screening decision, and self-reported screening. METHODS: Participants were 238 AA men, ages 40 to 70 years, who were members of the Prince Hall Masons in Washington, DC. Men were randomly assigned to the (a) video-based information study arm, (b) print-based information study arm, or (c) wait list control study arm. Intervention materials were mailed to men at home. Assessments were conducted at baseline, 1 month, and 12 months postintervention. Multivariate analyses, including ANCOVA and logistic regression, were used to analyze group differences. RESULTS: The booklet and video resulted in a significant improvement in knowledge and a reduction in decisional conflict about prostate cancer screening, relative to the wait list control. Satisfaction with the screening decision was not affected by the interventions. Self-reported screening rates increased between the baseline and the 1-year assessment, although screening was not differentially associated with either of the interventions. In exploratory analyses, prostate-specific antigen testing at 1 year was more likely among previously screened men and was associated with having low baseline decisional conflict. CONCLUSIONS: This study represents one of the first randomized intervention trials specifically designed to address AA men's informed decision making about prostate cancer screening. We have developed and evaluated culturally sensitive, balanced, and disseminable materials that improved knowledge and reduced decisional conflict about prostate cancer screening among AA men. Due to the high incidence and mortality rates among AA men, there is a need for targeted educational materials, particularly materials that are balanced in terms of the benefits and risks of screening.