Convection-enhanced delivery of methotrexate-loaded maghemite nanoparticles

Convection-enhanced delivery (CED) is a novel approach for delivering drugs directly into brain tumors by intracranial infusion, enabling the distribution of high drug concentrations over large tissue volumes. This study was designed to present a method for binding methotrexate (MTX) to unique crystalline, highly ordered and superparamagnetic maghemite nanoparticles via human serum albumin (HSA) coating, optimized for CED treatments of gliomas. Naked nanoparticles and HSA- or polyethylene glycol (PEG)-coated nanoparticles with/without MTX were studied. In vitro results showed no toxicity and a similar cell-kill efficacy of the MTX-loaded particles via HSA coating to that of free MTX, while MTX-loaded particles via PEG coating showed low efficacy. In vivo, the PEG-coated nanoparticles provided the largest distributions in normal rat brain and long clearance times, but due to their low efficacy in vitro, were not considered optimal. The naked nanoparticles provided the smallest distributions and shortest clearance times. The HSA-coated nanoparticles (with/without MTX) provided good distributions and long clearance times (nearly 50% of the distribution volume remained in the brain 3 weeks post treatment). No MTX-related toxicity was noted. These results suggest that the formulation in which HSA was bound to our nanoparticles via a unique precipitation method, and MTX was bound covalently to the HSA, could enable efficient and stable drug loading with no apparent toxicity. The cell-kill efficacy of the bound MTX remained similar to that of free MTX, and the nanoparticles presented efficient distribution volumes and slow clearance times in vivo, suggesting that these particles are optimal for CED

Metformin and Prostate Cancer among Diabetic Men

Background: This thesis is composed of three studies. In the first paper, we tested the association of metformin use with prostate cancer incidence. In the second paper, we examined the association of metformin use with all-cause and prostate cancer specific mortality. The final paper explored the benefit of detailed pathology review to predict mortality among diabetic men with prostate cancer. Methods: A total of 5306 incident diabetic men older than 66 who subsequently developed prostate cancer were identified using the Ontario Diabetes Database and the Ontario Cancer Registry between 1994-2008. The association of metformin use and risk of prostate cancer and its grade was tested with a nested case-control design using a conditional logistic regression model. We used a cohort design with a time dependent Cox-proportional hazard model to examine the association of metformin use and mortality. Finally, we employed a c-statistic and Net Reclassification Improvement analysis to study the impact of pathology abstraction on predicting mortality. Results: The data suggest metformin use was not associated with the risk of prostate cancer or its grade at presentation. However, each additional 6 month of metformin use was associated with a 24% decrease in prostate-cancer-specific and 8% decrease in all-cause mortality. Pathology abstraction improved the accuracy in predicting all-cause and prostate-cancer specific mortality. Conclusions: In our study metformin use was not associated with a decreased risk of prostate cancer, but had a significant impact on all-cause and prostate cancer specific mortality. These results may serve as proof of concept in designing an interventional study of metformin to delay progression in prostate cancer.Ph

Data from: Oral contraceptive use is associated with prostate cancer: an ecologic study

INTRODUCTION: Recently there have been several studies suggesting that estrogen exposure may increase the risk of prostate cancer (PCa). In this report we examine associations between PCa incidence and mortality and population-based use of oral contraceptives (OC's). We hypothesized that OC's by-products may cause an environmental contamination leading to an increased low level estrogen exposure and therefore higher PCa incidence and mortality. METHODS: The hypothesis was studied in an ecologic study. We used data from the “international agency for research on cancer” (IACR) to retrieve age-standardized rates of prostate cancer in 2007 and the “United Nations 2007 use of contraceptive report” to retrieve data on contraceptive use. We subsequently used a Pearson correlation and a multivariable linear regression to associate the percentage of women using OC's, intrauterine devices, condoms or vaginal barriers to the age standardized prostate cancer incidence and mortality. We performed these analyses by individual nation and by continent worldwide. RESULTS: OC's use was significantly associated with prostate cancer incidence and mortality in the individual nation world wide (r=0.61 and r=0.53, respectively p<0.05 for all). PCa incidence was also associated with OC's use in Europe (r=0.545 p<0.05) and by continent (r=0.522 p<0.05). All other forms of contraceptives (i.e. intra-uterine devices, condoms or vaginal barriers) were not correlated with prostate cancer incidence or mortality. On multivariable analysis the correlation with OC was independent of nation’s wealth. CONCLUSION: In this hypothesis generating ecologic study we have demonstrated a significant association between OC's and PCa. We hypothesize that oral contraceptive effect may be mediated through environmental estrogen levels; this novel concept is worth further investigation

whole_world_ocp

Excel file containing data on all 160 countries available for analysi