Biomedical subjects

Christopher J Kane

Publications and source records attributed to Christopher J Kane.

At least 19 recordsLinked to original sources

PubMed2007

Changing nature of high risk patients undergoing radical prostatectomy.

PURPOSE: We examined the outcomes of radical prostatectomy alone in high risk patients with prostate cancer and evaluated changes in high risk prostate cancer outcomes with time. MATERIALS AND METHODS: From 1988 to 2003, 251 men with high risk prostate cancer (prostate specific antigen more than 20 ng/ml and/or biopsy Gleason greater than 7) were identified in a cohort of 1,796 (14%) enrolled in the Shared Equal Access Regional Cancer Hospital Database. Temporal changes in clinicopathological characteristics and prostate specific antigen recurrence rates were examined stratified by 4, 4-year periods. RESULTS: With time significantly more men were considered at high risk due to a high biopsy Gleason score relative to prior years, when the most common reason for being considered at high risk was increased PSA (p <0.001). Only 3% of high risk men from 2000 to 2003 had increased prostate specific antigen and high biopsy Gleason score compared to 23% from 1988 to 1991. With time there were no differences in biochemical recurrence rates (p = 0.147). Men with a high biopsy Gleason score and increased prostate specific antigen had worse outcomes than men with only a high Gleason score or men with only high prostate specific antigen (p = 0.046 and 0.081, respectively). On multivariate analysis that only included preoperative clinical characteristics only prostate specific antigen was an independent predictor of prostate specific antigen failure following radical prostatectomy (p = 0.014). There was a trend, which did not attain statistical significance, for higher biopsy Gleason scores and higher clinical stage to be associated with higher failure rates (p = 0.060 and 0.081, respectively). CONCLUSIONS: Patients are designated as high risk by Gleason grade more commonly now than early in the prostate specific antigen era. Outcomes in high risk patients undergoing radical prostatectomy alone have not significantly improved with time. New treatment strategies, such as multimodality therapy, are needed to improve outcomes in high risk patients with prostate cancer.

Aged↗

PubMed2006

Health-related quality of life for men with prostate cancer and diabetes: a longitudinal analysis from CaPSURE.

OBJECTIVES: To compare diabetic versus nondiabetic men with prostate cancer to understand whether diabetes mellitus (DM) imposes an additional burden on health-related quality of life (HRQOL) before and after radical prostatectomy, adjusting for obesity. METHODS: Data were abstracted from Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a disease registry of 12,005 men with localized prostate cancer. Men were included who had undergone surgical treatment from 1989 to 2003, had body mass index (BMI) information available, and had completed both a pretreatment and at least one posttreatment HRQOL questionnaire within 24 months. A repeated-measures model adjusted for baseline clinical and demographic variables was used to evaluate group differences. RESULTS: The 1248 men were divided into two groups (117 with DM and 1131 without DM) on the basis of a history of DM or the reporting of diabetes medication use. The diabetic men were significantly more likely to be older and nonwhite, have lower education and income, and be less likely to have private insurance. They also had significantly more comorbid conditions (other than DM) and a greater BMI at baseline. Urinary function differed by diabetes status, BMI, and the DM x BMI interaction, with diabetic men who had a greater BMI reporting greater declines in urinary function over time. No other statistically significant differences in HRQOL were observed, although trends by BMI were noted in sexual function and bowel bother. CONCLUSIONS: Although previous studies of men with prostate cancer have found differences in HRQOL by obesity level, our results have indicated that the presence or absence of DM and a high BMI may have a greater impact on HRQOL than obesity alone.

Aged↗

PubMed2006

Multiinstitutional validation of the UCSF cancer of the prostate risk assessment for prediction of recurrence after radical prostatectomy.

BACKGROUND: The University of California, San Francisco (UCSF) Cancer of the Prostate Risk Assessment (CAPRA) is a novel preoperative index which predicts the risk of biochemical recurrence after radical prostatectomy. The performance of the index is at least as good as the best available instruments based on clinical variables, and the 0 to 10 score is simple to calculate for both clinical and research purposes. This study used a large external dataset to validate CAPRA. METHODS: Data were abstracted from the Shared Equal Access Regional Cancer Hospital (SEARCH) database, a registry of men who underwent radical prostatectomy at 4 Veterans Affairs and 1 active military medical center. Of 2096 men in the database, 1346 (64%) had full data available to calculate the CAPRA score. Performance of the CAPRA score was assessed with proportional hazards regression, survival analysis, and the concordance (c) index. RESULTS: Of the studied patients, 41% were non-Caucasian, and their mean age was 62 years. Twenty-six percent suffered recurrence; median follow-up among patients who did not recur was 34 months. The hazard ratio (HR) for each 1-point increase in CAPRA was 1.39 (95% CI [confidence interval], 1.31-1.46). The 5-year recurrence-free survival rate ranged from 86% for CAPRA 0-1 patients to 21% for CAPRA 7-10 patients. Increasing CAPRA scores were significantly associated with increasing risk of adverse pathologic outcomes. The c-index for CAPRA for the validation set was 0.68, compared with 0.66 for the original development set. CONCLUSIONS: The UCSF-CAPRA accurately predicted both biochemical and pathologic outcomes after radical prostatectomy among a large, diverse, cohort of men. These results validated the effectiveness of this powerful and straightforward instrument.

Adult↗

PubMed2006

Clinical and pathologic outcome after radical prostatectomy for prostate cancer patients with a preoperative Gleason sum of 8 to 10.

BACKGROUND: Men with a biopsy Gleason sum of 8 to 10 are considered high-risk. The current study sought to identify whether there was a subset of men with high biopsy Gleason sums who would have a good pathologic and biochemical outcome with surgical monotherapy. To increase the generalizability of the findings, data were used from patients treated at 2 very different practice settings: a tertiary care referral center (Johns Hopkins Hospital) and multiple equal-access medical centers (Shared Equal Access Regional Cancer Hospital [SEARCH] Database). METHODS: The data were retrospectively reviewed from men with biopsy Gleason sums 8 to 10 treated by radical prostatectomy at the Johns Hopkins Hospital (n = 220, 3.8% of total cohort) and within the SEARCH Database (n = 149, 7.7% of total cohort). The preoperative clinical characteristics predicting unfavorable pathologic disease (nonorgan-confined and/or positive surgical margins) and time to biochemical recurrence were determined using logistic regression and Cox proportional hazards analysis, respectively. RESULTS: Favorable pathologic outcome (organ-confined and negative surgical margins) was observed in 21% of the men in the Johns Hopkins cohort and 41% from the SEARCH cohort. On multivariate analysis, higher serum prostate-specific antigen (PSA) was the only variable that significantly predicted an unfavorable pathologic outcome from both the Johns Hopkins (P = .047) and SEARCH cohorts (P = .002). The 5-year and 10-year estimated biochemical-free survival rates in the Johns Hopkins cohort were 40% (95% confidence interval [CI], 33-48%) and 27% (95% CI, 18-36%), respectively, and 32% (95% CI, 22-42%) and 28% (95% CI, 18-38%) in the SEARCH cohort, respectively. Among men with favorable pathologic findings, the 5- and 10-year estimated biochemical-free survival rates in the Johns Hopkins cohort were 79% (95% CI, 62-89%) and 50% (95% CI, 25-71%), respectively, and 49% (95% CI, 32-65%) and 49% (95% CI, 32-65%) in the SEARCH cohort, respectively. No single preoperative variable significantly predicted the risk of biochemical progression in both the SEARCH or Johns Hopkins cohorts. CONCLUSIONS: The majority of men with a biopsy Gleason sum of >or=8, regardless of where the patient is treated, had unfavorable pathologic disease and experienced a biochemical progression after radical prostatectomy. Even among men with organ-confined disease and negative surgical margins or pathologic Gleason sum <8, at least half of the men experienced a PSA recurrence. Patients with biopsy Gleason sum 8 to 10 cancers are good candidates for multimodal therapy. Whereas multimodal therapy has often meant radiation plus hormonal therapy, newer possibilities for multimodal therapy exist such as surgery with neoadjuvant or adjuvant chemohormonal therapy or surgery with adjuvant radiation.

Aged↗

PubMed2006

Smoking influences aberrant CpG hypermethylation of multiple genes in human prostate carcinoma.

BACKGROUND: Aberrant CpG methylation profiles of gene promoters and their correlation with advanced pathologic features have been well investigated in prostate carcinoma (PC). Several case-control and prospective studies have revealed a positive association between current smoking and PC. The authors hypothesized that smoking influences both progression and prognosis of PC through CpG hypermethylation of related genes. METHODS: A total of 164 PC patients (52 current, 30 former, and 82 never smokers) and 69 benign prostatic hyperplasia (BPH) patients were examined by methylation-specific PCR (MSP) for 3 genes: adenomatous polyposis coli (APC), glutathione S-transferase pi (GSTP1), and multidrug resistance one (MDR1). The methylation status of representative samples was confirmed by bisulfite DNA sequencing analysis. The newly defined methylation score (M-score) of each sample is the sum of the corresponding log hazard ratio (HR) coefficients derived from multivariate logistic regression analysis for pathology (BPH vs. PC), and was related to clinical and pathologic outcome including smoking status. RESULTS: The M-score was significantly higher in the current smokers than in never smokers (P = 0.008). Spearman rank correlation test demonstrated a significant correlation between pack-years smoked and M-score in PCs (P = 0.039). Significant correlation of the M-score methylation was observed with high pT category (P < 0.001), high Gleason sum (P < 0.001), high preoperative prostate-specific antigen (PSA) (P = 0.041), and advanced pathologic features. In addition, Gleason sum was significantly associated with PSA failure-free probability as a poor outcome (P = 0.020). CONCLUSIONS: This is the first study to demonstrate significant correlation of the methylation status of multigenes with smoking status in PC. Smoking status may influence both progression and prognosis of PC through CpG hypermethylation of related genes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Is biopsy Gleason score independently associated with biochemical progression following radical prostatectomy after adjusting for pathological Gleason score?

PURPOSE: Biopsy Gleason score is known to be associated with prostate specific antigen failure following radical prostatectomy. However, it is unclear whether it remains associated with outcome after surgery when the pathological Gleason score is known. MATERIALS AND METHODS: We determined the association between biopsy Gleason score and biochemical progression after correcting for preoperative and postoperative characteristics, including pathological Gleason score, in 1,931 men treated with radical prostatectomy between 1988 and 2005 in the Shared Equal Access Regional Cancer Hospital Database Study Group database. Gleason score was examined as a categorical variable of 2 to 6, 3 + 4 and 4 + 3 or greater. RESULTS: Higher biopsy Gleason scores were positively associated with extracapsular extension (p <0.001), positive surgical margins (p <0.001), seminal vesicle invasion (p <0.001), positive lymph nodes (p <0.001) and biochemical progression (log rank p <0.001). After adjusting for only preoperative characteristics biopsy Gleason 3 + 4 and 4 + 3 or greater were associated with increased risk of biochemical progression compared to biopsy Gleason 6 or less (p = 0.001 and <0.001, respectively). After further adjusting for multiple pathological characteristics, including pathological Gleason score, the association between higher biopsy Gleason score and progression was little changed, in that men with biopsy Gleason 3 + 4 and 4 + 3 or greater were significantly more likely to experience progression (p = 0.001 and <0.001, respectively). Furthermore, when stratified by pathological Gleason score, higher biopsy Gleason scores were associated with an increased risk of biochemical progression in each pathological Gleason score category (log rank p </=0.007). CONCLUSIONS: Biopsy Gleason score remained strongly associated with progression even when the pathological Gleason score was known and controlled for. If confirmed at other centers, incorporation of biopsy Gleason score into postoperative nomograms designed to estimate the progression risk might improve model precision.

Aged↗

PubMed2006

Prostate biopsy tumor extent but not location predicts recurrence after radical prostatectomy: results from CaPSURE.

PURPOSE: Prostate cancer biopsy information is important for patient risk assessment. Although the number and extent of positive biopsies have been used to predict recurrence, the impact of positive biopsy location and contiguity is less clear. We compared the ability of positive prostate biopsy location and pattern with number and percent positive biopsies to predict recurrence after RP. MATERIALS AND METHODS: From CaPSURE we identified 2,037 men treated with RP from 1992 to 2002 for whom detailed biopsy information and 2 or more followup PSA values were available. Treatment failure was defined as 2 consecutive PSA values of 0.2 ng/ml or higher, or a second treatment delivered more than 6 months after RP. Biopsy tumor volume (number and percent positive sites), location of disease (anatomical site, laterality), and contiguity of positive biopsies were entered into Cox proportional hazards models to predict risk of disease recurrence while controlling for Gleason grade, PSA and T stage. RESULTS: Higher number and percent of positive biopsy cores were associated with prostate cancer recurrence, risk stratification category and Gleason grade, p <0.0001, HR 1.09 (CI 1.02 to 1.16) and 1.01 (CI 1.00 to 1.01), respectively. Number of biopsy cores taken, laterality, contiguity and positive biopsy location were not associated with disease recurrence. CONCLUSIONS: The number and the percentage of biopsies positive for cancer correlated with treatment failure after radical prostatectomy. Contiguity, laterality and location were not associated with recurrence.

Adenocarcinoma↗

PubMed2006

Obesity, serum prostate specific antigen and prostate size: implications for prostate cancer detection.

PURPOSE: Obesity has been associated with lower serum testosterone, theoretically resulting in decreased PSA production. Obesity has also been associated with prostatic enlargement, making the detection of existent cancer more difficult. Together these findings would result in an apparent protective effect of obesity on prostate cancer risk due to technical detection issues unrelated to cancer biology. We examined the association between BMI, and PSA and prostate weight in a cohort of men undergoing RP. MATERIALS AND METHODS: We evaluated the association of BMI with prostate weight and PSA using linear regression, adjusting for patient age at RP, year of RP, race, and pathological stage and grade in 1,414 men treated with RP between 1988 and 2004 at the 5 equal access medical centers that comprise the Shared Equal Access Regional Cancer Hospital Database. RESULTS: On multivariate analysis increasing BMI was associated with increasing prostate weight but only in men younger than 63 years and not in men 63 years or older (p-trend <0.001 and 0.44, respectively). In men younger than 63 years mean multivariate adjusted prostate weight +/- SE in those with a BMI of less than 25 vs 30 to 34.9 kg/m was 33.8 +/- 1.4 vs 41.4 +/- 1.6 gm. There was no significant association between BMI and preoperative PSA (p-trend = 0.70). CONCLUSIONS: In a cohort of men undergoing RP obesity was associated with larger prostate size but only in younger men. There was no association between BMI and PSA. Assuming equal PSA, the degree of prostatic enlargement observed in younger obese men in this study would be expected to result in a modest decrease in the odds of detecting prostate cancer in a contemporary series of PSA screened men due to the decreased sensitivity of cancer detection related to larger prostate size. Obesity may appear protective for prostate cancer in younger men due to technical issues unrelated to cancer biology.

Humans↗

PubMed2006

Delay of radical prostatectomy and risk of biochemical progression in men with low risk prostate cancer.

PURPOSE: Men newly diagnosed with prostate cancer are faced with multiple treatment options. Understanding these options and their associated side effects, and making a decision often requires time, resulting in a delay before receiving treatment. This is particularly pertinent in men with low risk disease who may be considered candidates for watchful waiting and, thus, may not experience strong pressure to undergo treatment promptly. Whether delays and especially prolonged delays, eg greater than 180 days, before RP negatively impact the disease outcome is unclear. MATERIALS AND METHODS: We examined the association between time from diagnosis to surgery, and pathological features of the RP specimen and risk of biochemical progression in 895 men with low risk prostate cancer (prostate specific antigen less than 10 ng/ml and biopsy Gleason sum 6 or less) treated with RP between 1988 and 2004 in the Shared-Equal Access Regional Cancer Hospital Database using logistic regression and Cox proportional hazards, respectively. RESULTS: Time from biopsy to surgery was not significantly related to high grade disease in the RP specimen, positive surgical margins or extraprostatic extension (all p-trend >0.05). After adjustment for multiple clinical covariates a longer time from biopsy to surgery was significantly associated with an increased risk of biochemical progression (p-trend = 0.002). However, this increased risk of progression was only apparent in men with delays greater than 180 days (median 263, vs 90 or fewer days RR 2.73, 95% CI 1.51 to 4.94). CONCLUSIONS: Our data suggest that patients with low risk prostate cancer can be reassured that immediate treatment is not necessary. Whether long delays (greater than 180 days) decrease the likelihood of curability in some patients requires further study.

Disease Progression↗

PubMed2006

Laparoscopic versus open cytoreductive nephrectomy in advanced renal-cell carcinoma.

BACKGROUND AND PURPOSE: There is growing evidence of the benefit of cytoreductive nephrectomy prior to immunotherapy in patients with advanced renal-cell carcinoma (RCC). We compared the outcomes of patients with metastatic RCC undergoing laparoscopic and open cytoreductive nephrectomy prior to systemic therapy. PATIENTS AND METHODS: We retrospectively analyzed 27 patients undergoing cytoreductive nephrectomy for metastatic RCC between 2000 and 2004, 16 laparoscopically and 11 by an open approach. Patients with inferior vena-caval tumor thrombus were excluded from analysis. The two groups were comparable with regard to tumor size, clinical stage, and performance status. Surgical, pathologic, and perioperative characteristics and outcomes were compared. RESULTS: The laparoscopic technique was associated with reduced blood loss (149 v 1135 mL; P = 0.03), transfusion rate and quantity (13% v 55%; P = 0.03; 0.13 v 2.0 units of packed red blood cells; P = 0.007), shorter time to oral intake (1.2 v 2.7 days; P < 0.001), and shorter hospitalization (3.6 v 6.8 days; P < 0.001) compared with open nephrectomy. No significant differences were observed with respect to pathologic stage, operative time, complications, fraction receiving subsequent systemic therapy, time to systemic therapy, or survival. CONCLUSIONS: Laparoscopic cytoreductive nephrectomy is associated with reduced morbidity and hospital stay compared with open surgery. There was no increase in complications, and the ability to proceed with subsequent systemic therapy was maintained in the majority of patients. The laparoscopic approach can be considered in patients with metastatic RCC as part of a cytoreductive and systemic-therapy regimen.

Carcinoma, Renal Cell↗

PubMed2005

Racial differences in prognostic value of adult height for biochemical progression following radical prostatectomy.

PURPOSE: Adult height, as a surrogate of childhood and adolescent hormone activity and diet, has been associated with the risk for development and death from prostate cancer in predominantly White populations. However, hormonal activity and diets vary between races. We examined whether height was significantly associated with biochemical progression following radical prostatectomy and whether there was an interaction between height and race. EXPERIMENTAL DESIGN: Multivariate Cox proportional hazards analysis was used to determine if height significantly predicted biochemical progression among 1,503 men (450 Black and 1,053 White) treated with radical prostatectomy between 1988 and 2003. We examined for possible interactions between height and race. RESULTS: Taller men (>175.3 cm) were significantly younger (P = 0.001), treated in more recent years (P = 0.02), had more clinical stage T(1) disease (P = 0.001), and were less likely to have extraprostatic extension (P = 0.02) than shorter men (< or =175.3 cm). Height was not significantly related to race, preoperative serum prostate-specific antigen concentrations, biopsy or pathologic Gleason sum, positive surgical margins, seminal vesicle invasion, or lymph node metastasis. Height was significantly associated with progression among Black men [relative risk (RR), 1.67; 95% confidence interval (95% CI), 1.00-2.79] but not among White men (RR, 1.03; 95% CI, 0.77-1.38). The interaction between race and height for predicting biochemical progression was statistically significant (P(interaction) = 0.05). CONCLUSIONS: There was an interaction between height and race in that height predicted progression for Black men but not for White men. The explanation for these findings is unclear, although lower insulin-like growth factor-binding protein-3 concentrations among Black men may be involved.

Aged↗

PubMed2005

Prostate size and risk of high-grade, advanced prostate cancer and biochemical progression after radical prostatectomy: a search database study.

PURPOSE: Prostate growth and differentiation are under androgenic control, and prior studies suggested that tumors that develop in hypogonadal men are more aggressive. We examined whether prostate weight was associated with tumor grade, advanced disease, or risk of biochemical progression after radical prostatectomy (RP). PATIENTS AND METHODS: We evaluated the association of prostate weight with pathologic tumor grade, positive surgical margins, extracapsular disease, and seminal vesicle invasion using logistic regression and with biochemical progression using Cox proportional hazards regression among 1,602 men treated with RP between 1988 and 2003 at five equal-access medical centers, which composed the Shared Equal Access Regional Cancer Hospital (SEARCH) Database. RESULTS: In outcome prediction models including multiple predictor variables, it was found that the predictor variable of prostate weight was significantly inversely associated with the outcomes of high-grade disease, positive surgical margins, extracapsular extension (all P < or = .004), and biochemical progression (comparing prostate weight < 20 v > or = 100 g: relative risk = 8.43; 95% CI, 2.9 to 24.0; P < .001). Similar associations were seen between preoperative transrectal ultrasound-measured prostate volume and high-grade disease, positive surgical margins, extracapsular extension (all P < or = .005), seminal vesicle invasion (P = .07), and biochemical progression (P = .06). CONCLUSION: Men with smaller prostates had more high-grade cancers and more advanced disease and were at greater risk of progression after RP. These results suggest that prostate size may be an important prognostic variable that should be evaluated for use pre- and postoperatively to predict biochemical progression.

Humans↗

PubMed2005

Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer.

Heparanase plays a critical role in the degradation of extracellular matrix and cell membrane and is frequently upregulated in malignant tumors. Transcription factor, early growth response 1 (EGR1), is closely associated with inducible transcription of the heparanase gene. We hypothesized that promoter CpG hypomethylation with increased EGR1 expression could determine heparanase expression during the pathogenesis of bladder cancer. Bladder cancer cell lines (J82, T24 and transitional cell carcinoma) significantly restored heparanase expression after 5-Aza-dC treatment. Transfection of EGR1 siRNA with T24 bladder cancer cell line significantly downregulated heparanase expression compared to the control siRNA transfection. In 54 bladder cancer and paired normal bladder samples, heparanase expression was significantly higher in bladder cancer than in normal bladder (P<0.01). We performed methylation-specific PCR targeting the CpG sites within the core-binding consensus motifs of EGR1 (GGCG) and Sp1 (GGGCGG). Methylation prevalence was significantly higher in normal bladder than in bladder cancer (P<0.05) and inversely correlated with heparanase expression (P=0.055). In the total series of bladder cancer and normal bladder samples, the combination of promoter CpG methylation and EGR1 expression regulated heparanase expression in a stepwise manner, where heparanase expression was the lowest in methylation-positive and EGR1-negative samples and the highest in methylation-negative and EGR1-positive samples. To our knowledge, this is the first study demonstrating that increased heparanase expression during the pathogenesis of bladder cancer is due to promoter hypomethylation and transcription factor EGR1.

Base Sequence↗

PubMed2005

Multigene methylation analysis for detection and staging of prostate cancer.

PURPOSE: Aberrant gene promoter methylation profiles have been well-studied in human prostate cancer. Therefore, we rationalize that multigene methylation analysis could be useful as a diagnostic biomarker. We hypothesize that a new method of multigene methylation analysis could be a good diagnostic and staging biomarker for prostate cancer. EXPERIMENTAL DESIGN: To test our hypothesis, prostate cancer samples (170) and benign prostatic hyperplasia samples (69) were examined by methylation-specific PCR for three genes: adenomatous polyposis coli (APC), glutathione S-transferase pi (GSTP1), and multidrug resistance 1 (MDR1). The methylation status of representative samples was confirmed by bisulfite DNA sequencing analysis. We further investigated whether methylation score (M score) can be used as a diagnostic and staging biomarker for prostate cancer. The M score of each sample was calculated as the sum of the corresponding log hazard ratio coefficients derived from multivariate logistic regression analysis of methylation status of various genes for benign prostatic hyperplasia and prostate cancer. The optimal sensitivity and specificity of the M score for diagnosis and for staging of prostate cancer was determined by receiver-operator characteristic (ROC) curve analysis. A pairwise comparison was employed to test for significance using the area under the ROC curve analysis. For each clinicopathologic finding, the association with prostate-specific antigen (PSA) failure-free probability was determined using Kaplan-Meier curves and a log-rank test was used to determine significance. The relationship between M score and clinicopathologic findings was analyzed by either the Mann-Whitney U test, Kruskal-Wallis test, or the Spearman rank correlation test. RESULTS: The frequency of positive methylation-specific PCR bands for APC, GSTP1, and MDR1 genes in prostate cancer samples was 64.1%, 54.0%, and 55.3%, respectively. In benign prostatic hyperplasia samples, it was 8.7%, 5.8%, and 11.6%, respectively. There was a significant correlation of M score with high pT category (P < 0.001), high Gleason sum (P < 0.001), high preoperative PSA (P = 0.027), and advanced pathologic features. For all patients, the M score had a sensitivity of 75.9% and a specificity of 84.1% as a diagnostic biomarker using a cutoff value of 1.0. In patients with low or borderline PSA levels (<10.0 ng/mL), the M score was significantly higher in prostate cancers than in benign prostatic hyperplasias (2.635 +/- 0.200 and 0.357 +/- 0.121, respectively). ROC curve analysis revealed that the M score had a sensitivity of 65.4% and a specificity of 94.2% when 1.0 was used as a cutoff value. For all patients, M score can distinguish organ-confined (< or =pT(2)) from locally advanced cancer (> or =pT(3)) with a sensitivity of 72.1% and a specificity of 67.8%. Moreover, considering patients with PSA levels of <10 ng/mL, the M score has a sensitivity of 67.1% and a specificity of 85.7%. The ROC curve analysis showed a significant difference between M score and PSA (P = 0.010). CONCLUSIONS: This is the first report demonstrating that M score is a new method for multigene methylation analysis that can serve as a good diagnostic and staging biomarker for prostate cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Ethnic group-related differences in CpG hypermethylation of the GSTP1 gene promoter among African-American, Caucasian and Asian patients with prostate cancer.

The incidence and mortality of prostate cancer (PC) is approximately 2-fold higher among African-Americans as compared to Caucasians and very low in Asian. We hypothesize that inactivation of GSTP1 genes through CpG methylation plays a role in the pathogenesis of PC, and its ability to serve as a diagnostic marker that differs among ethnic groups. GSTP1 promoter hypermethylation and its correlation with clinico-pathological findings were evaluated in 291 PC (Asian = 170; African-American = 44; Caucasian = 77) and 172 benign prostate hypertrophy samples (BPH) (Asian = 96; African-American = 38; Caucasian = 38) using methylation-specific PCR. In PC cells, 5-aza-dC treatment increased expression of GSTP1 mRNA transcripts. The methylation of all CpG sites was found in 191 of 291 PC (65.6%), but only in 34 of 139 BPH (24.5%). The GSTP1 hypermethylation was significantly higher in PC as compared to BPH in each ethnic group (p < 0.0001). Logistic regression analysis (PC vs. BPH) showed that African-Americans had a higher hazard ratio (HR) (13.361) compared to Caucasians (3.829) and Asian (8.603). Chi-square analysis showed correlation of GSTP1 hypermethylation with pathological findings (pT categories and higher Gleason sum) in Asian PC (p < 0.0001) but not in African-Americans and Caucasian PC. Our results suggest that GSTP1 hypermethylation is a sensitive biomarker in African-Americans as compared to that in Caucasians or Asian, and that it strongly influences tumor progression in Asian PC. Ours is the first study investigating GSTP1 methylation differences in PC among African-American, Caucasian and Asian.

Adult↗

PubMed2005

CpG methylation at promoter site -140 inactivates TGFbeta2 receptor gene in prostate cancer.

BACKGROUND: The action of transforming growth factor beta (TGF-beta) is mediated through type 1 (TbetaRI) and type 2 (TbetaRII) receptors. Prostate cancer cells are often resistant to TGF-beta signaling due to loss of TbetaRII expression. The authors of the current study hypothesized that CpG methylation of the TbetaRII promoter at the Sp1 binding site -140 mediates this loss of TbetaRII expression in prostate cancer. METHODS: Sixty-seven prostate cancer (PC) samples, 8 benign prostatic hyperplasia (BPH) samples, and 4 prostate cancer cell lines (DUPro, LNCaP, ND-1 and PC-3) were analyzed for 1) TbetaRII mRNA expression by semiquantitative RT-PCR, 2) TbetaRII protein expression by immunohistochemistry, and 3) TGFbetaRII promoter methylation at CpG site -140 by methylation specific PCR and bisulfite DNA sequencing. Prostate cancer cell lines were treated with the demethylating agent 5aza2'deoxycytidine to determine if TbetaRII gene expression could be increased by blocking promoter methylation. RESULTS: mRNA and protein expression of TbetaRII was lower in the PC samples than in the BPH samples. CpG methylation at site -140 was higher in PC than in BPH (P < 0.01). Promoter methylation was inversely correlated with TbetaRII mRNA expression in the PC and BPH samples (P < 0.0001). PC3, ND1, and DUPro TbetaRII mRNA expression increased following treatment of cells with 5-aza-2'-deoxycytidine. CONCLUSION: CpG methylation of the TbetaRII promoter at CPG site -140 leads to functional loss of the TbetaRII gene in prostate cancer. Treatment with 5-aza-2' deoxycytidine can restore gene expression. The current study results report the first association between prostate cancer and loss of the TGF- beta signaling pathway by TbetaRII DNA promoter methylation.

Azacitidine↗

PubMed2005

Methylation of the gamma-catenin gene is associated with poor prognosis of renal cell carcinoma.

PURPOSE: Gamma-catenin is a cell adhesion protein, and its functional loss is associated with tumor invasion and metastasis. We hypothesize that (1) promoter CpG methylation regulates the expression and function of the gamma-catenin gene in renal cell carcinoma (RCC) and (2) methylation of the gamma-catenin gene is associated with poor prognosis of RCC. To test these hypotheses, we analyzed the CpG methylation status of the gamma-catenin gene and its correlation with clinical outcome in RCC. EXPERIMENTAL DESIGN: Genomic DNA and total RNA were extracted from three renal cancer cell lines (A498, Caki-1, and Caki-2) and 54 RCC tissue samples with their corresponding normal kidney tissue samples. Expression of gamma-catenin gene was analyzed by reverse transcription-PCR and immunostaining. Promoter methylation was analyzed by two different methylation-specific PCR (MSP-A and MSP-B), and the results were verified by DNA sequencing. RESULTS: The demethylating agent (5-aza-2'-deoxycytidine) increased levels of mRNA transcript of the gamma-catenin gene in three renal cancer cell lines. Gamma-catenin mRNA and protein expression were significantly reduced in RCC samples compared with normal kidney samples, respectively (P < 0.05). MSP-A and MSP-B bands were detected in 45 of 54 (83.3%) and 49 of 54 (90.7%) RCC samples, respectively. In normal kidney, weak products of MSP-A and MSP-B were detected in 5 of 54 (9.3%) and 6 of 54 (11.1%) samples, respectively. Likewise, both MSP-A and MSP-B ratios were significantly higher in RCC samples compared with normal kidney samples, respectively (P < 0.01). Multivariate analysis revealed that the MSP-B ratio was a powerful and independent predictor superior to nuclear grade and Robson stage with respect to survival and disease progression (P = 0.029 and 0.0071, respectively). No mutations in the NH(2)-terminal region of gamma-catenin were found in this study. CONCLUSION: Expression of gamma-catenin is regulated by promoter CpG methylation, and the balance between methylated and unmethylated RCC cell populations could determine its functional role. Because the conventional nuclear grade and/or staging system have some limitations to predict precise clinical outcome, this is the first report demonstrating that promoter CpG methylation of gamma-catenin can be an independent and superior predictor for survival and disease progression.

Adult↗

PubMed2005

Impact of obesity on prostate cancer recurrence after radical prostatectomy: data from CaPSURE.

OBJECTIVES: To determine the association between obesity and prostate cancer recurrence after primary treatment with radical prostatectomy. METHODS: Data were abstracted from CaPSURE, a disease registry of 10,018 men with prostate cancer. We included 2131 men who had undergone radical prostatectomy between 1989 and 2003 and had body mass index (BMI) information available. Recurrence was defined as two consecutive prostate-specific antigen (PSA) levels of 0.2 ng/mL or greater or any second treatment. Patients were risk stratified using the PSA level, Gleason grade, and clinical T stage. RESULTS: Patients were followed up for a median of 23 months. Of the 2131 patients, 251 (12%) developed recurrence at a median of 13 months (range 1 to 107); 183 (9%) of these men had PSA failure and 68 (3%) received a second treatment. After adjusting for risk group, ethnicity, age, and comorbidities, a significant association was found between an increasing BMI and disease recurrence (P = 0.028). Very obese patients (BMI 35 kg/m2 or more) were 1.69 times more likely to have recurrence relative to men of normal weight (BMI less than 25.0 kg/m2; 95% confidence interval [CI] 1.01 to 2.84). An increasing PSA level (P <0.0001) and Gleason grade (P <0.0001) were also associated with recurrence. Ethnicity was not significantly associated with either BMI or PSA recurrence (P = 0.685 and P = 0.068, respectively). CONCLUSIONS: The results of our study have shown that obesity is an independent predictor of prostate cancer recurrence. Because of the increased comorbidities and greater rates of recurrence, obese individuals undergoing radical prostatectomy need vigilant follow-up care.

Adult↗