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ABSTRACT: BACKGROUND: The relationships between diet, exercise, and prostate cancer (PCa) remain unclear. We have previously reported that a "Western" diet promotes PCa tumor growth in vivo. Presently, we report the effects of sustained aerobic exercise on PCa progression in animals fed a high-fat diet versus a standard diet. METHODS: Athymic mice (n = 43) were inoculated subcutaneously with human PCa (LNCaP) cells, fed ad libitum with either a high-fat or a standard diet, and randomized into forced exercising and non-exercising groups. Body weight, tumor volume, and food consumption were recorded tri-weekly. Terminal serum samples and tumor biopsies were obtained for analysis. RESULTS: Body weight differences were not observed between the groups over time. The high-fat diet with exercise (HF-Ex) group showed significantly increased tumor growth rate compared to all other groups (P < 0.0007). Tumor growth rate of the standard diet with exercise (Std-Ex) group was reduced significantly compared to the high-fat diet without exercise (HF-No Ex) group (P = 0.0008). Significant differences (P ≤ 0.012) were observed in energy consumption (kcal) between the groups over time. Exercising mice consumed significantly more kcal than non-exercising mice, and the HF-Ex group consumed significantly more than each of the other three groups (P < 0.0007). The expression levels of p27 and p21 were increased in exercising animals, while AR expression was elevated in the HF-Ex group versus the Std-Ex and HF-No Ex groups. CONCLUSIONS: Sustained aerobic exercise did not counteract the tumor-promotional effect of increased consumption of a high-fat diet, suggesting that diet is more influential in PCa progression than exercise. Combining exercise with a healthy diet reduced the rate of PCa progression in this model. This study may have implications for PCa risk reduction in humans. Prostate 9999:XX-XX. © 2013 Wiley Periodicals, Inc.
The Prostate 04/2013; · 3.48 Impact Factor
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ABSTRACT: Background/Aim: Shortcomings of current methods of prostate cancer detection call for improved biomarkers. The transmembrane protease, serine 2:ets-related gene (TMPRSS2:ERG) gene fusion leads to the overexpression of ERG, an E-twenty six (ETS) family transcription factor, and is the most prevalent genetic lesion in prostate cancer, but its clinical utility remains unclear.
Two radical prostatectomy samples were analysed by next-generation whole-transcriptome sequencing. The chosen samples differed in fusion gene status, as previously determined by reverse transcription polymerase chain reaction (RT-PCR).
Next-generation sequencing identified the involvement of novel and previously reported prostate cancer-related transcripts, the WNT signalling pathway, evasion of p53-mediated anti-proliferation and several ETS-regulated pathways in the prostate cancer cases examined. Overexpression of Rho GDP-dissociation inhibitor (RhoGDIB), a gene associated with fusion-positive prostate cancer, was found to elicit spindle-shaped morphology, faster cell migration and increased cell proliferation, phenotypic changes suggestive of cancer progression.
The present findings confirm the value of comprehensive sequencing for biomarker development and provide potential avenues of future study.
Anticancer research 09/2012; 32(9):3629-41. · 1.73 Impact Factor
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Rajiv Chopra,
Alexandra Colquhoun,
Mathieu Burtnyk,
William A N'djin,
Ilya Kobelevskiy,
Aaron Boyes,
Kashif Siddiqui,
Harry Foster, Linda Sugar,
Masoom A Haider,
Michael Bronskill,
Laurence Klotz
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ABSTRACT: Purpose: To evaluate the feasibility and safety of magnetic resonance (MR) imaging-controlled transurethral ultrasound therapy for prostate cancer in humans. Materials and Methods: This pilot study was approved by the institutional review board and was performed in eight men (mean age, 60 years; range, 49-70 years) with localized prostate cancer (Gleason score ≤7, prostate-specific antigen level #15 μg/L) immediately before radical prostatectomy. All patients provided written informed consent. This phase 0 feasibility and safety study is the first evaluation in humans. Transurethral ultrasound therapy was performed with the patient under spinal anesthesia by using a clinical 1.5-T MR unit. Patients then underwent radical prostatectomy, and the resected gland was sliced in the plane of treatment to compare the MR imaging measurements with the pattern of thermal damage. The overall procedure time and coagulation rate were measured. In addition, the spatial targeting accuracy was evaluated, as was the thermal history along the thermal damage boundaries in the gland. Results: The average procedure time was 3 hours, with 2 or fewer hours spent in the MR unit. The treatment was well tolerated by all patients, and a temperature uncertainty of less than 2°C was observed in the treatments. The mean temperature and thermal dose measured along the boundary of thermal coagulation were 52.3°C ± 2.1 and 3457 (cumulative equivalent minutes at 43°C) ± 5580, respectively. The mean treatment rate was 0.5 mL/min, and a spatial targeting accuracy of -1.0 mm ± 2.6 was achieved. Conclusion: MR imaging-controlled transurethral ultrasound therapy is feasible, safe, and well tolerated. This technology could be an attractive approach for whole-gland or focal therapy. © RSNA, 2012.
Radiology 08/2012; 265(1):303-13. · 5.73 Impact Factor
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ABSTRACT: Estimating the risk of extraprostatic extension and the probability of recurrence with different treatment modalities is common practice in cancer management. A strong predictor of recurrence and organ-confined disease is tumor grade. However, differences exist between genitourinary and non-specialist pathologists in grading prostate cancer. As such, the primary objective of this study was to assess the accuracy of non-specialist prostate cancer biopsies at our institution by analyzing the proportion of cases changing pathologic risk category upon expert review.
Log books from 2003 where our genitourinary pathologists reviewed prostate needle-core biopsies were used to identify cases. A retrospective chart review was completed and descriptive statistics were used to summarize the results for the following synoptic variables: 10 and 20 Gleason Score, number of biopsy sites, overall % involvement, perineural invasion--PNI (present/absent), extracapsular extension--ECE (present/absent).
A total of 151 patients were reviewed. Twenty eight percent of cases (42/151) had a change in risk category after expert review. Of the 98 low risk cases, 33% were upgraded in risk category. Of the 24 intermediate risk cases, 12% were upgraded to high risk and none were downgraded. Of the 29 high risk cases, 24% were downgraded in risk category.
All referred patients should continue to have their pathology centrally reviewed. This practice will help facilitate optimal prostate cancer management and improve quality of care. While these findings are dated given pathologic practice change, such changes do not necessarily equate with disparity elimination or reduction; conclusions can only be drawn with a more recent audit to see if such disparities still exist.
The Canadian Journal of Urology 06/2012; 19(3):6256-60. · 0.64 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) are single-stranded, 18-24 nucleotide long, non-coding RNA molecules. They are involved in virtually every cellular process including development, apoptosis, and cell cycle regulation. MiRNAs are estimated to regulate the expression of 30% to 90% of human genes by binding to their target messenger RNAs (mRNAs). Widespread dysregulation of miRNAs has been reported in various diseases and cancer subtypes. Due to their prevalence and unique structure, these small molecules are likely to be the next generation of biomarkers, therapeutic agents and/or targets. Methods used to investigate miRNA expression include SYBR green I dye-based as well as Taqman-probe based qPCR. If miRNAs are to be effectively used in the clinical setting, it is imperative that their detection in fresh and/or archived clinical samples be accurate, reproducible, and specific. qPCR has been widely used for validating expression of miRNAs in whole genome analyses such as microarray studies. The samples used in this protocol were from patients who underwent radical prostatectomy for clinically localized prostate cancer; however other tissues and cell lines can be substituted in. Prostate specimens were snap-frozen in liquid nitrogen after resection. Clinical variables and follow-up information for each patient were collected for subsequent analysis. Quantification of miRNA levels in prostate tumor samples. The main steps in qPCR analysis of tumors are: Total RNA extraction, cDNA synthesis, and detection of qPCR products using miRNA-specific primers. Total RNA, which includes mRNA, miRNA, and other small RNAs were extracted from specimens using TRIzol reagent. Qiagen's miScript System was used to synthesize cDNA and perform qPCR (Figure 1). Endogenous miRNAs are not polyadenylated, therefore during the reverse transcription process, a poly(A) polymerase polyadenylates the miRNA. The miRNA is used as a template to synthesize cDNA using oligo-dT and Reverse Transcriptase. A universal tag sequence on the 5' end of oligo-dT primers facilitates the amplification of cDNA in the PCR step. PCR product amplification is detected by the level of fluorescence emitted by SYBR Green, a dye which intercalates into double stranded DNA. Specific miRNA primers, along with a Universal Primer that binds to the universal tag sequence will amplify specific miRNA sequences. The miScript Primer Assays are available for over a thousand human-specific miRNAs, and hundreds of murine-specific miRNAs. Relative quantification method was used here to quantify the expression of miRNAs. To correct for variability amongst different samples, expression levels of a target miRNA is normalized to the expression levels of a reference gene. The choice of a gene on which to normalize the expression of targets is critical in relative quantification method of analysis. Examples of reference genes typically used in this capacity are the small RNAs RNU6B, RNU44, and RNU48 as they are considered to be stably expressed across most samples. In this protocol, RNU6B is used as the reference gene.
Journal of Visualized Experiments 01/2012;
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Robert K Nam,
William Zhang,
Katherine Siminovitch,
Adam Shlien,
Michael W Kattan,
Laurence H Klotz,
John Trachtenberg,
Yan Lu,
Jinyi Zhang,
Changhong Yu,
Ants Toi,
D Andrew Loblaw,
Vasundara Venkateswaran,
Aleksandra Stanimirovic, Linda Sugar,
David Malkin,
Arun Seth,
Steven A Narod
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ABSTRACT: To identify and examine polymorphisms of genes associated with aggressive and clinical significant forms of prostate cancer among a screening cohort.
We conducted a genome-wide association study among patients with aggressive forms of prostate cancer and biopsy-proven normal controls ascertained from a prostate cancer screening program. We then examined significant associations of specific polymorphisms among a prostate cancer screened cohort to examine their predictive ability in detecting prostate cancer.
We found significant associations between aggressive prostate cancer and five single nucleotide polymorphisms (SNPs) in the 10q26 (rs10788165, rs10749408, and rs10788165, p value for association 1.3 × 10(-10 ) to 3.2 × 10(-11) ) and 15q21 (rs4775302 and rs1994198, p values for association 3.1 × 10(-8 ) to 8.2 × 10(-9)) regions. Results of a replication study done in 3439 patients undergoing a prostate biopsy, revealed certain combinations of these SNPs to be significantly associated not only with prostate cancer but with aggressive forms of prostate cancer using an established classification criterion for prostate cancer progression (odds ratios for intermediate to high-risk disease 1.8-3.0, p value 0.003-0.001). These SNP combinations were also important clinical predictors for prostate cancer detection based on nomogram analysis that assesses prostate cancer risk.
Five SNPs were found to be associated with aggressive forms of prostate cancer. We demonstrated potential clinical applications of these associations.
Cancer biology & therapy 12/2011; 12(11):997-1004. · 2.64 Impact Factor
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Qi Long,
Brent A Johnson,
Adeboye O Osunkoya,
Yu-Heng Lai,
Wei Zhou,
Mark Abramovitz,
Mingjing Xia,
Mark B Bouzyk,
Robert K Nam, Linda Sugar,
Aleksandra Stanimirovic,
Daron J Williams,
Brian R Leyland-Jones,
Arun K Seth,
John A Petros,
Carlos S Moreno
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ABSTRACT: An important challenge in prostate cancer research is to develop effective predictors of tumor recurrence following surgery to determine whether immediate adjuvant therapy is warranted. To identify biomarkers predictive of biochemical recurrence, we isolated the RNA from 70 formalin-fixed, paraffin-embedded radical prostatectomy specimens with known long-term outcomes to perform DASL expression profiling with a custom panel that we designed of 522 prostate cancer-relevant genes. We identified a panel of 10 protein-coding genes and two miRNA genes (RAD23B, FBP1, TNFRSF1A, CCNG2, NOTCH3, ETV1, BID, SIM2, LETMD1, ANXA1, miR-519d, and miR-647) that could be used to separate patients with and without biochemical recurrence (P < 0.001), as well as for the subset of 42 Gleason score 7 patients (P < 0.001). We performed an independent validation analysis on 40 samples and found that the biomarker panel was also significant at prediction of biochemical recurrence for all cases (P = 0.013) and for a subset of 19 Gleason score 7 cases (P = 0.010), both of which were adjusted for relevant clinical information including T-stage, prostate-specific antigen, and Gleason score. Importantly, these biomarkers could significantly predict clinical recurrence for Gleason score 7 patients. These biomarkers may increase the accuracy of prognostication following radical prostatectomy using formalin-fixed specimens.
American Journal Of Pathology 07/2011; 179(1):46-54. · 4.89 Impact Factor
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Robert K Nam,
Michael W Kattan,
Joseph L Chin,
John Trachtenberg,
Rajiv Singal,
Ricardo Rendon,
Laurence H Klotz, Linda Sugar,
Christopher Sherman,
Jonathan Izawa,
David Bell,
Aleksandra Stanimirovic,
Vasundara Venkateswaran,
Eleftherios P Diamandis,
Changhong Yu,
D Andrew Loblaw,
Steven A Narod
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ABSTRACT: Prostate cancer risk calculators incorporate many factors to evaluate an individual's risk for prostate cancer. We validated two common North American-based, prostate cancer risk calculators.
We conducted a prospective, multi-institutional study of 2,130 patients who underwent a prostate biopsy for prostate cancer detection from five centers. We evaluated the performance of the Sunnybrook nomogram-based prostate cancer risk calculator (SRC) and the Prostate Cancer Prevention Trial (PCPT) -based risk calculator (PRC) to predict the presence of any cancer and high-grade cancer. We examined discrimination, calibration, and decision curve analysis techniques to evaluate the prediction models.
Of the 2,130 patients, 867 men (40.7%) were found to have cancer, and 1,263 (59.3%) did not have cancer. Of the patients with cancer, 403 (46.5%) had a Gleason score of 7 or more. The area under the [concentration-time] curve (AUC) for the SRC was 0.67 (95% CI, 0.65 to 0.69); the AUC for the PRC was 0.61 (95% CI, 0.59 to 0.64). The AUC was higher for predicting aggressive disease from the SRC (0.72; 95% CI, 0.70 to 0.75) compared with that from the PRC (0.67; 95% CI, 0.64 to 0.70). Decision curve analyses showed that the SRC performed better than the PRC for risk thresholds of more than 30% for any cancer and more than 15% for aggressive cancer.
The SRC performed better than the PRC, but neither one added clinical benefit for risk thresholds of less than 30%. Further research is needed to improve the AUCs of the risk calculators, particularly for higher-grade cancer.
Journal of Clinical Oncology 06/2011; 29(22):2959-64. · 18.37 Impact Factor
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ABSTRACT: This ethics committee-approved pilot study was carried out with informed consent. A protocol was developed to assess the feasibility of in vitro Microfil injection of prostate cancer specimens followed by analysis with micro-computed tomography (microCT) to characterize the functional vascularity of prostatic tissue and evaluate its safety with respect to the preservation of a specimen for pathologic examination. The visible prostatic arteries of two surgically resected prostates frompatients with known prostate cancer (PCa) were injected with MicrofilMV-122 contrast medium immediately after removal. The specimens were scanned using microCT and were qualitatively examined using three-dimensional analysis software (MicroView; GE Healthcare Biosciences). The Microfil perfusion in the two samples was sufficient to view the functional vascularity arising from a major prostatic artery, up to a resolution of 17.626 µm without any indication of adverse effects due to Microfil injection. Malignant prostatic regions showed a greater vascular density on histology but decreased vascular perfusion compared with benign prostatic regions. The use of microCT on Microfil-injected prostates seems to be a feasible and specimen-preserving method for visualizing the three-dimensional vessel patterns present in resected human prostates.
Translational oncology 06/2011; 4(3):173-7. · 3.40 Impact Factor
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ABSTRACT: Expression profiling studies using microarrays and other methods have shown that microRNAs (miRNAs) are dysregulated in a wide variety of human cancers. The up-regulation of miR-221 has been reported in carcinomas of the pancreas, breast, and papillary thyroid, as well as in glioblastoma and chronic lymphocytic leukaemia. In prostate cancer, however, down-regulation of miR-221 has been repeatedly confirmed in miRNA expression studies. Also unique to prostate cancer, and found in more than 50% of patients, is the aberrant expression of a known oncogene, the TMPRSS2:ERG fusion. To date, there has been no published study describing miRNA associations in prostate tumours that overexpress the ERG oncogene from the TMPRSS2:ERG fusion transcript. Herein we report that in a large and diverse cohort of prostate carcinoma samples, miR-221 is down-regulated in patients with tumours bearing TMPRSS2:ERG fusion transcripts, thus providing a link between miRNA and gene fusion expression.
Anticancer research 02/2011; 31(2):403-10. · 1.73 Impact Factor
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ABSTRACT: To confirm the correlation between planning and thermal injury of the prostate as determined by magnetic resonance imaging (MRI) and histology in canine and humans treated with transurethral ultrasound.
Canine studies: 2 sets of in vivo studies were performed under general anesthesia in 1.5 T clinical MRI. Nine dogs were treated using single transducer; 8 dogs were treated using urethral applicator with multiple transducers. Rectal cooling was maintained. After initial imaging, a target boundary was selected and high-intensity ultrasound energy delivered. The spatial temperature distribution was measured continuously every 5 seconds with MR thermometry using the proton-resonant frequency shift method. The goal was to achieve 55 °C at the target boundary. After treatment, the prostate was harvested and fixed with adjoining tissue, including rectum. Temperature maps, anatomical images, and histologic sections were registered to each other and compared. Human studies: To date, 5 patients with localized prostate cancer have been treated immediately before radical prostatectomy. Approximately 30% of the gland volume was targeted.
A continuous pattern of thermal coagulation was successfully achieved within the target region, with an average spatial precision of 1-2 mm. Radical prostatectomy was routine, with an uncomplicated postoperative course in all patients. The correlation between anatomical, thermal, and histologic images was ≤3 mm. Treatment time was <30 minutes. No thermal damage to rectal tissue was observed.
Thermal ablation within the prescribed target of the prostate has been successfully demonstrated in canine studies. The treatment is also feasible in humans.
Urology 12/2010; 76(6):1506-11. · 2.43 Impact Factor
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ABSTRACT: A high carbohydrate-high fat (HC-HF) diet-associated with hyperinsulinemia has been previously reported to induce accelerated growth of prostate cancer in a xenograft model. High energy supply and insulin/insulin growth factor-1 axis are two of the mechanisms proposed. We hypothesize that metformin may have a protective effect against prostate cancer progression by affecting metabolisms associated with high energy intake. In the present study, animals were randomized into five groups, receiving a HC-HF diet with 50, 100, or 250mg/kg body weight (mg/kg) metformin in drinking water, a standard diet or HC-HF diet alone. Animals on the HC-HF diet developed obesity and insulin resistance. They had significantly higher body weight, fasting blood glucose at an upper level of normal range, higher insulin secretion and utilization, and fatty degeneration of the liver. Metformin at the doses employed significantly reduced food and water consumption; however, only a dose of 250mg/kg showed a significant reduction in body weight gain and suppression of gluconeogenesis as well remarkably reduced insulin secretion. There was no observed metformin-related hepato-toxicity in any of the groups. In summary, metformin at various doses exhibits protective effects on the metabolic disorder caused by the HC-HF diet with the most effective protection at a dose of 250mg/kg. These effects may explain its translational role relating to its anti-neoplastic potential.
Biochemical and Biophysical Research Communications 07/2010; 397(3):537-42. · 2.48 Impact Factor
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ABSTRACT: Abstract
Background
Longstanding evidence implicates an inadequate diet as a key factor in the onset and progression of prostate cancer. The purpose herein was to discover, validate and characterize functional biomarkers of dietary supplementation capable of suppressing the course of prostate cancer in vivo .
Methods
The Lady transgenic mouse model that spontaneously develops prostate cancer received a diet supplemented with a micronutrient cocktail of vitamin E, selenium and lycopene ad libitum. A proteomic analysis was conducted to screen for serum biomarkers of this dietary supplementation. Candidate peptides were validated and identified by sequencing and analyzed for their presence within the prostates of all mice by immunohistochemistry.
Results
Dietary supplementation with the combined micronutrients significantly induced the expression of the megakaryocyte-specific inhibitor of angiogenesis, platelet factor-4 (P = 0.0025). This observation was made predominantly in mice lacking tumors and any manifestations associated with progressive disease beyond 37 weeks of life, at which time no survivors remained in the control group (P < 0.0001). While prostates of mice receiving standard chow were enlarged and burdened with poorly differentiated carcinoma, those of mice on the supplemented diet appeared normal. Immunohistochemical analysis revealed marked amplifications of both platelet binding and platelet factor-4 within the blood vessels of prostates from mice receiving micronutrients only.
Conclusion
We present unprecedented data whereby these combined micronutrients effectively promotes tumor dormancy in early prostate cancer, following initiation mutations that may drive the angiogenesis-dependent response of the tumor, by inducing platelet factor-4 expression and concentrating it at the tumor endothelium through enhanced platelet binding.
BMC Cancer. 01/2010;
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ABSTRACT: A new MRI-guided therapy is being developed as a minimally invasive treatment for localized prostate cancer utilizing high-intensity ultrasound energy to generate a precise region of thermal coagulation within the prostate gland. The purpose of this study was to evaluate in vivo the capability to produce a spatial heating pattern in the prostate that accurately matched the shape of a target region using transurethral ultrasound heating and active MR temperature feedback. Experiments were performed in a canine model (n = 9) in a 1.5 T MR imager using a prototype device comprising a single planar transducer operated under rotational control. The spatial temperature distribution, measured every 5 s with MR thermometry, was used to adjust the acoustic power and rotation rate in order to achieve a temperature of 55 degrees C along the outer boundary of the target region. The results demonstrated the capability to produce accurate spatial heating patterns within the prostate gland. An average temperature of 56.2 +/- 0.6 degrees C was measured along the outer boundary of the target region across all experiments in this study. The average spatial error between the target boundary and the 55 degrees C isotherm was 0.8 +/- 0.7 mm (-0.2 to 3.2 mm), and the overall treatment time was < or =20 min for all experiments. Excellent spatial agreement was observed between the temperature information acquired with MRI and the pattern of thermal damage measured on H&E-stained tissue sections. This study demonstrates the benefit of adaptive energy delivery using active MR temperature feedback, and an excellent capability to treat precise regions within the prostate gland with this technology.
Physics in Medicine and Biology 04/2009; 54(9):2615-33. · 2.83 Impact Factor
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Robert K Nam,
William W Zhang,
John Trachtenberg,
Arun Seth,
Laurence H Klotz,
Aleksandra Stanimirovic,
Sanoj Punnen,
Vasundara Venkateswaran,
Ants Toi,
D Andrew Loblaw, Linda Sugar,
Katherine A Siminovitch,
Steven A Narod
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ABSTRACT: Several single nucleotide polymorphisms (SNP) have been associated with the risk of prostate cancer. The clinical utility of using SNPs in the early detection of prostate cancer has not been evaluated.
We examined a panel of 25 SNPs from candidate genes and chromosomal regions in 3,004 unselected men who were screened for prostate cancer using serum prostate-specific antigen (PSA) and digital rectal examination. All underwent a prostate biopsy. We evaluated the ability of these SNPs to help predict the presence of prostate cancer at biopsy.
Of the 3,004 patients, 1,389 (46.2%) were found to have prostate cancer. Fifteen of the 25 SNPs studied were significantly associated with prostate cancer (P=0.02-7x10(-8)). We selected a combination of 4 SNPs with the best predictive value for further study. After adjusting for other predictive factors, the odds ratio for patients with all four of the variant genotypes compared with men with no variant genotype was 5.1 (95% confidence interval, 1.6-16.5; P=0.006). When incorporated into a nomogram, genotype status contributed more significantly than PSA, family history, ethnicity, urinary symptoms, and digital rectal examination (area under the curve=0.74). The positive predictive value of the PSA test ranged from 42% to 94% depending on the number of variant genotypes carried (P=1x10(-15)).
SNP genotyping can be used in a clinical setting for the early detection of prostate cancer in a nomogram approach and by improving the positive predictive value of the PSA test.
Clinical Cancer Research 03/2009; 15(5):1787-93. · 7.74 Impact Factor
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ABSTRACT: Preclinical experiments were performed in an acute canine model to analyze the spatial pattern of thermal damage generated in the prostate gland following treatment with a prototype magnetic resonance imaging guided transurethral ultrasound heating system. In particular the boundary of tissue coagulation was analyzed to quantify the treatment margin resulting from this technology.
A heating device incorporating a planar 20 x 3.5 mm transducer operated at 9.1 MHz was used to deliver ultrasound energy to targeted regions in the prostate gland in 7 animals monitored with magnetic resonance imaging thermometry during heating. The animals were sacrificed approximately 45 minutes after treatment. The thermal damage pattern was evaluated using contrast enhanced magnetic resonance imaging, vital tissue staining, and whole mount hematoxylin and eosin stained histological sections. An image warping technique enabled quantitative comparison of these data.
Regions of thermal fixation, coagulative necrosis and hemorrhage were observed in the treated prostate glands. The extent of the necrotic region was relatively insensitive to vessel cooling effects. Metabolic enzyme functionality coincided with tissue outside of the treatment area. At the edge of the thermal damage pattern the transition from coagulative necrosis to no visible damage occurred within 3 mm or less.
The narrow extent of the thermal margin suggests that tissue sparing outside of the prostate could be an advantage of this treatment. Histological measurements showed a high level of spatial accuracy, useful for developing accurate control techniques for directional transurethral ultrasound thermal therapy in the treatment of prostate diseases.
The Journal of Urology 10/2007; 178(3 Pt 1):1080-5. · 3.75 Impact Factor
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ABSTRACT: To construct a clinical nomogram instrument to estimate individual risk for having prostate cancer (PC) for patients undergoing prostate specific antigen (PSA) screening, using all risk factors known for PC.
We conducted a cross-sectional study of 3,108 men who underwent a prostate biopsy, including a subset of 408 volunteers with normal PSA levels. Factors including age, family history of PC (FHPC), ethnicity, urinary symptoms, PSA, free:total PSA ratio, and digital rectal examination (DRE) were incorporated in the model. A nomogram was constructed to assess risk for any and high-grade PC (Gleason score >or= 7).
Of the 3,108 men, 1,304 (42.0%) were found to have PC. Among the 408 men with a normal PSA (< 4.0 ng/mL), 99 (24.3%) had PC. All risk factors were important predictors for PC by multivariate analysis (P, .01 to .0001). The area under the curve (AUC) for the nomogram in predicting cancer, which included age, ethnicity, FHPC, urinary symptoms, free:total PSA ratio, PSA, and DRE, was 0.74 (95% CI, 0.71 to 0.81) and 0.77 (95% CI, 0.74 to 0.81) for high-grade cancer. This was significantly greater than the AUC that considered using the conventional screening method of PSA and DRE only (0.62; 95% CI, 0.58 to 0.66 for any cancer; 0.69; 95% CI, 0.65 to 0.73 for high-grade cancer). From receiver operating characteristic analysis, risk factors including age, ethnicity, FHPC, symptoms, and free:total PSA ratio contributed significantly more predictive information than PSA and DRE.
In a PC screening program, it is important to consider age, family history of PC, ethnicity, urinary voiding symptoms, and free:total PSA ratio, in addition to PSA and DRE.
Journal of Clinical Oncology 08/2007; 25(24):3582-8. · 18.37 Impact Factor
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ABSTRACT: The prostate-specific gene, TMPRSS2, is fused with the transcription factor gene, ERG in a high proportion of prostate cancers. However, the clinical significance of TMPRSS2:ERG gene fusion among prostate cancer patients is unknown. We assayed for the presence of the TMPRSS2:ERG gene fusion product among 26 patients who underwent surgery for clinically localized prostate cancer using RT-PCR and direct DNA sequencing, and evaluated its prognostic significance. All 26 patients had cancers of the same histologic grade (Gleason score 7). The fusion protein was present within prostate cancer tumor cells in eleven patients (42.3%). Nine patients experienced biochemical disease relapse (elevated PSA) after a mean follow-up of 12 months (range 1 to 48 months). Patients with the fusion protein had a significantly higher rate of recurrence (5-year recurrence rate 79.5%) compared to patients who lacked the fusion protein (five-year recurrence rate 37.5%, p = 0.009). The adjusted hazard ratio for disease relapse for patients with the fusion protein was 7.1 (95% C.I.: 1.1-45, p = 0.03) compared to patients without the fusion protein. In multivariate analysis, the presence of gene fusion was the single most important prognostic factor. Our study indicates that the expression of TMPRSS2:ERG fusion gene among prostate cancer patients treated with surgery is a strong prognostic factor for disease relapse, and may have important clinical implications.
Cancer biology & therapy 02/2007; 6(1):40-5. · 2.64 Impact Factor
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Robert K Nam,
William W Zhang,
Laurence H Klotz,
John Trachtenberg,
Michael A S Jewett,
Joan Sweet,
Ants Toi,
Seamus Teahan,
Vasundara Venkateswaran, Linda Sugar,
Andrew Loblaw,
Kathy Siminovitch,
Steven A Narod
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ABSTRACT: Increased levels of serum human kallikrein-2 (hK2) and an hK2 gene (KLK2) variant are positively associated for prostate cancer, but the relationships between them remain unclear. We examined five variants of the KLK2 gene to further define its relevance to prostate cancer susceptibility and hK2 levels.
We genotyped 645 men with biopsy-proven prostate cancer (cases) and 606 males with biopsies negative for prostate cancer (controls) for five additional single nucleotide polymorphisms (SNP) across the KLK2 gene and also tested for serum hK2 levels. These SNPs were identified from sequencing the KLK2 gene among 20 patients with aggressive prostate cancer. Odds ratios (OR) for prostate cancer detection and haplotype analysis were done.
Among the SNPs studied, the A allele of the KLK2-SNP1 (G>A, rs2664155) and the T allele of the KLK2-SNP5 (C>T, rs198977) polymorphisms showed positive associations with prostate cancer, adjusted ORs for KLK2-SNP1 AG and AA genotypes being 1.4 [95% confidence interval (95% CI), 1.2-1.8; P=0.002] and for KLK2-SNP5 TT or CT genotypes being 1.3 (95% CI, 1.1-1.6; P=0.05). Haplotype analyses also revealed a significant association between prostate cancer and the haplotype containing both risk alleles (ACCTT), OR being 5.1 (95% CI, 1.6-6.5; P=0.005). Analysis of serum hK2 revealed hK2 levels to be significantly increased in association with KLK2-SNP1 AA and AG risk genotypes compared with the GG genotype (P=0.001) and also in association with the ACCTT risk haplotype compared with the most common non-risk haplotype (P=0.05).
These findings suggest a role for the KLK2 gene in prostate cancer susceptibility and imply that this role may be realized at least in part by the induction of increases in hK2 production.
Clinical Cancer Research 12/2006; 12(21):6452-8. · 7.74 Impact Factor
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Robert K Nam,
Ants Toi,
Laurence H Klotz,
John Trachtenberg,
Michael A S Jewett,
Andrew Loblaw,
Greg R Pond,
Marjan Emami, Linda Sugar,
Joan Sweet,
Steven A Narod
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ABSTRACT: There is a large amount of confusion in interpreting prostate specific antigen (PSA) values for prostate cancer. More precise risk assessments for prostate cancer detection are needed for men faced with an abnormal PSA.
We studied a sample of 2,637 men who underwent a prostate biopsy for an abnormal digital rectal exam (DRE) or PSA. Using factors including age, ethnicity, family history of prostate cancer, previous negative biopsy, presence of voiding symptoms, prostate volume, DRE and PSA, we constructed nomograms to predict the probability of prostate cancer at biopsy.
Of the 2,637 men, 1,282 men (48.6%) had prostate cancer detected. Age, ethnicity, family history of prostate cancer, a previous negative biopsy, prostate volume, DRE and PSA were all significant predictors of prostate cancer. Nomograms were constructed based on these factors to predict the risk of prostate cancer and of aggressive prostate cancer (defined as a Gleason Score 7 or more). The positive predictive value varied from 5% to 95% based on the nomograms. The nomograms were validated using bootstrapping methods and the expected and observed proportions were found to be highly concordant.
For men with an abnormal PSA or DRE, the risk for prostate cancer can be accurately estimated using a nomogram based on age, ethnicity, family history of prostate cancer, previous negative biopsy, presence of voiding symptoms, prostate volume, DRE and PSA. This tool will aid physicians and patients in determining the need for prostate biopsy.
The Canadian Journal of Urology 05/2006; 13 Suppl 2:2-10. · 0.64 Impact Factor
