Selection and Evaluation of a Silver Nanoparticle Imaging Agent for Dual-Energy Mammography

Over the past decade, contrast-enhanced (CE) dual-energy (DE) x-ray breast imaging has emerged as an exciting, new modality to provide high quality anatomic and functional information of the breast. The combination of these data in a single imaging procedure represents a powerful tool for the detection and diagnosis of breast cancer. The most widely used implementation of CEDE imaging is k-edge imaging, whereby two x-ray spectra are placed on either side of the k-edge of the contrast material. Currently, CEDE imaging is performed with iodinated contrast agents. The lower energies used in clinical DE breast imaging systems compared to imaging systems for other organs suggest that an alternative material may be better suited. We developed an analytical model to compare the contrast of various elements in the periodic table. The model predicts that materials with atomic numbers from 42 to 52 should provide the best contrast in DE breast imaging while still providing high-quality anatomical images. Upon consideration, silver was chosen for more detailed study. Through simulation and experimental validation, we determined that not only does silver perform better than iodine when imaged at their respective optimal conditions, but silver is able to provide higher levels of contrast than iodine when imaged with current protocols that are optimal for iodine. Therefore, a silver agent could be translated to the clinic without modification of existing imaging systems or techniques. A prototype silver agent was designed. The agent consists of (i) a silver core for DE contrast, (ii) a silica shell to prevent the release of toxic silver cations, and (iii) a polyethylene glycol layer to improve the biocompatibility of the entire nanostructure. DE imaging with the particles showed a 9-fold increase in contrast when injected into mice, while displaying no acutely toxic effects. The prototype silica-silver nanoparticles represent a first step in developing a biologically stable contrast agent that is specifically suited for DE breast imaging

Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts.

OBJECTIVES: To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. DESIGN: Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. SETTING: Multiple institutions that were members of international PRACTICAL consortium. PARTICIPANTS: All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. MAIN OUTCOME MEASURES: Prediction with hazard score of age of onset of aggressive cancer in validation set. RESULTS: In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. CONCLUSIONS: Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa

Polygenic hazard score to guide screening for aggressive - prostate cancer: development and validation in large scale - cohorts

OBJECTIVESTo develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age.DESIGNAnalysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score >= 7, stage T3-T4, PSA (prostate specific antigen) concentration >= 10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa.SETTINGMultiple institutions that were members of international PRACTICAL consortium.PARTICIPANTSAll consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men.MAIN OUTCOME MEASURESPrediction with hazard score of age of onset of aggressive cancer in validation set.RESULTSIn the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z= 11.2, P98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P= 0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score.CONCLUSIONSPolygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa

A genetic risk score to personalize prostate cancer screening, applied to population data.

Background: A polygenic hazard score (PHS)—the weighted sum of 54 SNP genotypes—was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. Methods: UK population incidence data (Cancer Research UK) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using hazard ratios estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age—when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-years-standard risk)—was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-years-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man’s PHS. Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score >= 7, stage T3-T4, PSA >= 10ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n=71,856), Asian (n=2,382), and African (n=6,253) genetic ancestries (p<10(-180)). Comparing the 80(th)/20(th) PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset. A polygenic hazard score (PHS1) improves prostate cancer screening accuracy in European patients. Here, the authors test the performance of a version compatible with OncoArray genotypes (PHS2) in a multi-ethnic dataset and find that it risk-stratifies men for any, aggressive, and fatal prostate cancer

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset