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1.  High-Intensity Focused Ultrasound as Salvage Therapy for Patients With Recurrent Prostate Cancer After Radiotherapy 
Korean Journal of Urology  2014;55(2):91-96.
Purpose
To evaluate the oncologic outcomes and postoperative complications of high-intensity focused ultrasound (HIFU) as a salvage therapy after external-beam radiotherapy (EBRT) failure in patients with prostate cancer.
Materials and Methods
Between February 2002 and August 2010, we retrospectively reviewed the medical records of all patients who underwent salvage HIFU for transrectal ultrasound-guided, biopsy-proven locally recurred prostate cancer after EBRT failure (by ASTRO definition: prostate-specific antigen [PSA] failure after three consecutive PSA increases after a nadir, with the date of failure as the point halfway between the nadir date and the first increase or any increase great enough to provoke initiation of therapy). All patients underwent prostate magnetic resonance imaging and bone scintigraphy and had no evidence of distant metastasis. Biochemical recurrence (BCR) was defined according to the Stuttgart definition (PSA nadir plus 1.2 ng/mL).
Results
A total of 13 patients with a median age of 68 years (range, 60-76 years) were included. The median pre-EBRT PSA was 21.12 ng/mL, the pre-HIFU PSA was 4.63 ng/mL, and the period of salvage HIFU after EBRT was 32.7 months. The median follow-up after salvage HIFU was 44.5 months. The overall BCR-free rate was 53.8%. In the univariate analysis, predictive factors for BCR after salvage HIFU were higher pre-EBRT PSA (p=0.037), pre-HIFU PSA (p=0.015), and short time to nadir (p=0.036). In the multivariate analysis, there were no significant predictive factors for BCR. The complication rate requiring intervention was 38.5%.
Conclusions
Salvage HIFU for prostate cancer provides effective oncologic outcomes for local recurrence after EBRT failure. However, salvage HIFU had a relatively high rate of complications.
doi:10.4111/kju.2014.55.2.91
PMCID: PMC3935076  PMID: 24578803
High-intensity focused ultrasound ablation; Prostatic neoplasms; Salvage therapy
2.  Prostatic cancer surveillance following whole-gland high-intensity focused ultrasound: comparison of MRI and prostate-specific antigen for detection of residual or recurrent disease 
The British Journal of Radiology  2012;85(1014):720-728.
Objective
This retrospective study compares dynamic contrast-enhanced (DCE) MRI with the serial prostate-specific antigen (PSA) measurement for detection of residual disease following whole-gland high-intensity focused ultrasound (HIFU) therapy of prostate cancer.
Methods
Patients in whom post-HIFU DCE-MRI was followed within 3 months by ultrasound-guided transrectal biopsy were selected from a local database. 26 patients met the study inclusion criteria. Serial PSA levels following HIFU and post-HIFU follow-up MRI were retrieved for each patient. Three radiologists unaware of other investigative results independently assessed post-HIFU MRI studies for the presence of cancer, scoring on a four-point scale (1, no disease; 2, probably no disease; 3, probably residual disease; and 4, residual disease). Sensitivity, specificity and receiver operating characteristic (ROC) analysis were performed for each reader, post-HIFU PSA nadir and pre-biopsy PSA level thresholds of >0.2 and >0.5 ng ml−1.
Results
The sensitivity of DCE-MRI for detection of residual disease for the three readers ranged between 73% and 87%, and the specificity between 73% and 82%. There was good agreement between readers (κ=0.69–0.77). The sensitivity and specificity of PSA thresholds was 60–87% and 73–100%, respectively. The area under the ROC curve was greatest for pre-biopsy PSA (0.95).
Conclusion
DCE-MRI performed following whole-gland HIFU has similar sensitivity and specificity and ROC performance to serial PSA measurements for detection of residual or recurrent disease.
doi:10.1259/bjr/61380797
PMCID: PMC3474121  PMID: 22253342
3.  Results of low threshold to biopsy following high-intensity focused ultrasound for localized prostate cancer 
Urology Annals  2012;4(2):84-88.
Context:
There are different treatment options for localized prostate cancer. The success of high-intensity focused ultrasound (HIFU) is based largely on biochemical prostate specific antigen (PSA) results.
Aims:
To evaluate the impact of using a low PSA threshold to perform prostate biopsies after HIFU in order to more accurately gauge treatment success.
Settings and Design:
Eleven patients underwent HIFU at Sydney Adventist Hospital in Sydney, 10 as primary and 1 as salvage therapy [post external beam radiation therapy (EBRT)]. The median age was 67 years (49–77 years). This was a prospective case series.
Materials and Methods:
Between 2006 and 2008, the Sonoblate device was used. Prostate biopsies were 12-core biopsies performed under local anesthesia, if PSA was ≥0.5 ng/mL or after two consecutive rises in PSA. The statistical analysis involved prospective data collection of results to calculate median and ranges.
Results:
The median PSA at diagnosis was 6.7 ng/mL (5.7–10.8 ng/mL). The median follow-up was 16 months (7–26 months). Nine men (82%) had post-HIFU biopsy. The median time to post-HIFU biopsy was 11.6 months (5–20 months), and all nine men had biopsy-proven residual disease.
Conclusions:
A low threshold to re-biopsy post-HIFU reveals a high local failure rate of 82%. Oncological efficacy is questioned, and using high threshold to biopsy may therefore be overestimating the effectiveness of HIFU as a primary treatment for localized prostate cancer.
doi:10.4103/0974-7796.95551
PMCID: PMC3355706  PMID: 22629002
High-intensity focused ultrasound; prostate biopsy; prostate cancer
4.  A multi-centre prospective development study evaluating focal therapy using high intensity focused ultrasound for localised prostate cancer: The INDEX study☆☆☆ 
Contemporary Clinical Trials  2013;36(1):68-80.
Introduction
Focal therapy offers the possibility of cancer control, without the side effect profile of radical therapies. Early single centre prospective development studies using high intensity focused ultrasound (HIFU) have demonstrated encouraging genitourinary functional preservation and short-term cancer control. Large multi-centre trials are required to evaluate medium-term cancer control and reproduce functional recovery. We describe the study design of an investigator-led UK multi-centre, single arm trial using HIFU to deliver focal therapy for men with localised prostate cancer.
Methods
One-hundred and forty men with histologically proven localised low or intermediate risk prostate cancer (PSA < 15, Gleason ≤ 7, ≤ T2cN0M0) will undergo precise characterisation of the prostate using a combination of multi-parametric (mp)MRI and transperineal template prostate mapping (TPM) biopsies. Unilateral dominant tumours, the so-called index lesion, will be eligible for treatment provided the contra-lateral side is free of ‘clinically significant’ disease (as defined by Gleason ≥ 7 or maximum cancer core length ≥ 4 mm). Patients will receive focal therapy using HIFU (Sonablate 500®). Treatment effect will be assessed by targeted biopsies of the treated area and TPM biopsies at 36-months.
Results
Primary outcome is the absence of clinically significant disease based on 36-month post-treatment TPM biopsies. Secondary outcomes address a) genitourinary function using validated patient questionnaires (IPSS, IPSS-QoL, IIEF-15, EPIC-Urinary, EPIC-Bowel, FACT-P, EQ-5D), b) the predictive validity of imaging, and c) risk factors for treatment failure.
Conclusions
INDEX will be the first multi-centre, medium term follow-up trial to evaluate the outcomes of a tissue preserving strategy for men with localised prostate cancer using the TPM-ablate-TPM strategy.
doi:10.1016/j.cct.2013.06.005
PMCID: PMC3779353  PMID: 23774040
Focal therapy; High-intensity focused ultrasound; Multi-centre; Prospective study; IDEAL guidelines
5.  Early observed transient prostate-specific antigen elevations on a pilot study of external beam radiation therapy and fractionated MRI guided High Dose Rate brachytherapy boost 
Purpose
To report early observation of transient PSA elevations on this pilot study of external beam radiation therapy and magnetic resonance imaging (MRI) guided high dose rate (HDR) brachytherapy boost.
Materials and methods
Eleven patients with intermediate-risk and high-risk localized prostate cancer received MRI guided HDR brachytherapy (10.5 Gy each fraction) before and after a course of external beam radiotherapy (46 Gy). Two patients continued on hormones during follow-up and were censored for this analysis. Four patients discontinued hormone therapy after RT. Five patients did not receive hormones. PSA bounce is defined as a rise in PSA values with a subsequent fall below the nadir value or to below 20% of the maximum PSA level. Six previously published definitions of biochemical failure to distinguish true failure from were tested: definition 1, rise >0.2 ng/mL; definition 2, rise >0.4 ng/mL; definition 3, rise >35% of previous value; definition 4, ASTRO defined guidelines, definition 5 nadir + 2 ng/ml, and definition 6, nadir + 3 ng/ml.
Results
Median follow-up was 24 months (range 18–36 mo). During follow-up, the incidence of transient PSA elevation was: 55% for definition 1, 44% for definition 2, 55% for definition 3, 33% for definition 4, 11% for definition 5, and 11% for definition 6.
Conclusion
We observed a substantial incidence of transient elevations in PSA following combined external beam radiation and HDR brachytherapy for prostate cancer. Such elevations seem to be self-limited and should not trigger initiation of salvage therapies. No definition of failure was completely predictive.
doi:10.1186/1748-717X-1-28
PMCID: PMC1564026  PMID: 16914054
6.  Preliminary safety and efficacy results with robotic high-intensity focused ultrasound : A single center Indian experience 
Background:
There are no Indian data of high-intensity focused ultrasound (HIFU). Being an alternative, still experimental modality, reporting short-term safety outcome is paramount.
Aims:
This study was aimed at to assess the safety and short-term outcome in patients with prostate cancer treated by HIFU.
Settings and Design:
A retrospective study of case records of 30 patients undergoing HIFU between January 2008 to September 2010 was designed and conducted.
Materials and Methods:
The procedural safety was analyzed at 3 months. Follow-up consisted of 3 monthly prostate-specific antigen (PSA) levels and transrectal biopsy if indicated. All the patients had a minimum follow-up of 6 months.
Results:
A mean prostate volume of 26.9 ± 8.5 cm3 was treated in a mean time of 115 ± 37.4 min. There was no intraoperative complication. The postoperative pain visual analogue score at day 0 was 2.1 ± 1.9 and at day 1 was 0.4 ± 0.8 on a scale of 1-10. Mean duration of perurethral catheter removal was 3.9 days. The complications after treatment were: LUTS in seven patients, stress incontinence in two, stricture in two, and symptomatic urinary tract infection in five. Average follow-up duration was 10.4 months (range, 6-20 months). Mean time to obtain PSA nadir was 6 ± 3 months with a median PSA nadir value of 0.3 ng/ml. Two patients had positive prostatic biopsy in the localized (high risk) group.
Conclusions:
HIFU was safe in carcinoma prostate patients. The short-term results were efficacious in localized disease. The low complication rates and favorable functional outcome support the planning of further larger studies.
doi:10.4103/0970-1591.85431
PMCID: PMC3193732  PMID: 22022055
Carcinoma prostate; high-intensity focused ultrasound; minimally invasive treatment; quality of life
7.  A simple computer program for calculating PSA recurrence in prostate cancer patients 
BMC Urology  2004;4:8.
Background
Prostate cancer is the most common tumor in men. The most commonly used diagnostic and tumor recurrence marker is Prostate Specific Antigen (PSA). After surgical removal or radiation treatment, PSA levels drop (PSA nadir) and subsequent elevated or increased PSA levels are indicative of recurrent disease (PSA recurrence). For clinical follow-up and local care PSA nadir and recurrence is often hand calculated for patients, which can result in the application of heterogeneous criteria. For large datasets of prostate cancer patients used in clinical studies PSA measurements are used as surrogate measures of disease progression. In these datasets a method to measure PSA recurrence is needed for the subsequent analysis of outcomes data and as such need to be applied in a uniform and reproducible manner. This method needs to be simple and reproducible, and based on known aspects of PSA biology.
Methods
We have created a simple Perl-based algorithm for the calculation of post-treatment PSA outcomes results based on the initial PSA and multiple PSA values obtained after treatment. The algorithm tracks the post-surgical PSA nadir and if present, subsequent PSA recurrence. Times to PSA recurrence or recurrence free intervals are supplied in months.
Results
Use of the algorithm is demonstrated with a sample dataset from prostate cancer patients. The results are compared with hand-annotated PSA recurrence analysis. The strengths and limitations are discussed.
Conclusions
The use of this simple PSA algorithm allows for the standardized analysis of PSA recurrence in large datasets of patients who have undergone treatment for prostate cancer. The script is freely available, and easily modifiable for desired user parameters and improvements.
doi:10.1186/1471-2490-4-8
PMCID: PMC441391  PMID: 15207005
8.  Time to PSA nadir independently predicts overall survival in metastatic hormone sensitive prostate cancer patients treated with androgen deprivation therapy 
Cancer  2009;115(5):981-987.
Introduction
The purpose of this study was to evaluate the relationship between the kinetics of PSA decline after androgen deprivation therapy (ADT) initiation and overall survival (OS) in men with metastatic hormone-sensitive prostate cancer (HSPC).
Methods
We identified a cohort of metastatic HSPC patients treated with androgen deprivation therapy (ADT) using our institutional database. Patients were included if they had at least 2 serum PSA determinations before nadir PSA and at least one serum PSA value available within 1 month of ADT initiation. Patient characteristics, PSA at ADT initiation, nadir PSA, time to PSA nadir (TTN) and PSA decline (PSAD) in relation to OS were analyzed.
Results
179 patients were identified, with a median follow-up after ADT initiation of 4.0 years. Median OS after ADT initiation was 7.0 years. Median PSA at ADT initiation and PSA nadir were 47 and 0.28 ng/mL, respectively. On univariate analysis: TTN <6 months, a PSAD >52 ng/mL/year, PSA nadir ≥ 0.2 ng/mL, a PSA≥47.2 ng/mL at ADT initiation and Gleason score >7, were associated with a shorter OS. On multivariate analysis, TTN<6 months, Gleason score >7 and a PSA nadir ≥ 0.2 ng/mL independently predicted a shorter OS.
Discussion
To our knowledge, this is the first report to show that a faster time to reach a PSA nadir post-ADT initiation is associated with shorter survival duration in men with metastatic HSPC. These results need confirmation, but may indicate that a rapid initial response to ADT indicates more aggressive disease.
doi:10.1002/cncr.24064
PMCID: PMC2931827  PMID: 19152438
Prostate cancer; androgen deprivation therapy; hormone-sensitive metastatic prostate cancer; PSA kinetics; Time to PSA nadir
9.  Role of Prostate Volume in the Early Detection of Prostate Cancer in a Cohort with Slowly Increasing Prostate Specific Antigen 
Yonsei Medical Journal  2013;54(5):1202-1206.
Purpose
To investigate the relationship between prostate volume and the increased risk for being diagnosed with prostate cancer (PCa) in men with slowly increasing prostate specific antigen (PSA).
Materials and Methods
A cohort of 1035 men who visited our hospital's health promotion center and were checked for serum PSA levels more than two times between January 2001 and November 2011 were included. Among them, 116 patients had a change in PSA levels from less than 4 ng/mL to more than 4 ng/mL and underwent transrectal ultrasound guided prostate biopsy. Median age was 55.9 years and 26 (22.4%) had PCa. We compared the initial PSA level, the last PSA level, age, prostate volume, PSA density (PSAD), PSA velocity, and follow-up period between men with and without PCa. The mean follow-up period was 83.7 months.
Results
Significant predictive factors for the detection of prostate cancer identified by univariate analysis were prostate volume, follow-up period and PSAD. In the multivariate analysis, prostate volume (p<0.001, odds ratio: 0.890) was the most significant factor for the detection of prostate cancer. In the receiver operator characteristic curve of prostate volume, area under curve was 0.724. At the cut-off value of 28.8 mL for prostate volume, the sensitivity and specificity were 61.1% and 73.1% respectively.
Conclusion
In men with PSA values more than 4 ng/mL during the follow-up period, a small prostate volume was the most important factor in early detection of prostate cancer.
doi:10.3349/ymj.2013.54.5.1202
PMCID: PMC3743199  PMID: 23918570
Prostatic neoplasms; prostate-specific antigen; early diagnosis; organ size
10.  Prostate cancer detection rate in patients with fluctuating prostate-specific antigen levels on the repeat prostate biopsy 
Prostate International  2014;2(1):26-30.
Purpose:
To evaluate whether the risk of prostate cancer was different according to the pattern of fluctuation in prostate-specific antigen (PSA) levels in patients undergoing repeat transrectal ultrasound-guided prostate biopsy (TRUS-Bx).
Methods:
From March 2003 to December 2012, 492 patients underwent repeat TRUS-Bx. The patients were stratified into 3 groups based on the PSA fluctuation pattern: group 1 (continuous elevation of PSA, n=169), group 2 (PSA fluctuation with PSA velocity [PSAV]≥1.0 ng/mL/yr, n=123), and group 3 (PSA fluctuation with PSAV<1.0 ng/mL/yr, n=200).
Results:
Prostate cancer was detected in 112 of 492 patients (22.8%) in the repeat biopsy set. According to the PSA fluctuation pattern, prostate cancer detection rates at repeat TRUS-Bx were 29.6% (50/169) for patients with continuously increasing PSA, 30.1% (37/123) for PSA fluctuation with PSAV ≥1.0 ng/mL/yr, and 12.5% (25/200) for PSA fluctuation with PSAV <1.0 ng/mL/yr. Multivariate analysis showed that PSA fluctuation pattern and high grade prostatic intraepithelial neoplasia at initial TRUS-Bx were the predictive parameters for positive repeat biopsies. Among the 96 patients (85.7%) who underwent radical prostatectomy, no significant differences in pathologic outcomes were found according to the PSA fluctuation pattern.
Conclusions:
The current study shows that the risk of prostate cancer at repeat TRUS-Bx was higher in men with a fluctuating PSA level and PSAV≥1.0 ng/mL/yr than in those with a fluctuating PSA level and PSAV<1.0 ng/mL/yr.
doi:10.12954/PI.13037
PMCID: PMC3970986  PMID: 24693531
Prostate-specific antigen; Prostatic neoplasms; Biopsy; Needles
11.  Associations of serum vitamin A and carotenoid levels with markers of prostate cancer detection among US men 
Cancer causes & control : CCC  2011;22(11):1483-1495.
Associations of serum vitamin A and carotenoid levels with markers of prostate cancer detection were evaluated among 3927 U.S. men, 40–85 years of age, who participated in the 2001–2006 National Health and Nutrition Examination Surveys. Five recommended definitions of prostate cancer detection were adopted using total and free prostate specific antigen (tPSA and fPSA) laboratory measurements. Men were identified as high-risk based on alternative cut-offs, namely, tPSA>10 ng/ml, tPSA>4 ng/ml, tPSA> 2.5 ng/ml, %fPSA<25% and %fPSA<15%. %fPSA was defined as (fPSA÷tPSA)×100%. Serum levels of vitamin A (retinol, retinyl esters) and carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein+zeaxanthin, lycopene) were defined as quartiles and examined as risk/protective factors for PSA biomarkers. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using binary logistic models. After adjustment for known demographic, socioeconomic and lifestyle confounders, high serum levels of retinyl esters (tPSA>10 ng/ml: Q4vs.Q1→OR=0.38, 95% CI: 0.14–1.00) and α-carotene (%fPSA<15%: Q4vs.Q1→OR=0.49, 95% CI: 0.32–0.76) were associated with a lower odds whereas high serum level of lycopene (tPSA>2.5 ng/ml: Q4vs.Q1→OR=1.49, 95% CI: 1.01–2.14) was associated with a greater odds of prostate cancer detection. Apart from the three significant associations observed, no other exposure-outcome association was significant. Monitoring specific antioxidant levels may be helpful in early detection of prostate cancer.
doi:10.1007/s10552-011-9822-8
PMCID: PMC3443554  PMID: 21800039
vitamin A; carotenoids; prostate cancer; prostate-specific antigen
12.  Association of urinary phytoestrogen concentrations with serum concentrations of prostate-specific antigen (PSA) in the National Health and Nutrition Examination Survey (NHANES) 
Nutrition and cancer  2013;65(6):813-819.
Some clinical trials have shown that high phytoestrogen intake may decrease serum concentrations of prostate-specific antigen (PSA), and phytoestrogens may also lower prostate cancer risk. It was the aim of this study to examine the relationship between the serum PSA level and urine phytoestrogen concentration in generally healthy US men. 824 men, 40+ year old without prostate cancer, who participated in the 2001-2004 NHANES surveys, were included in the analysis. The association of total PSA, free PSA, and PSA ratio [free PSA/total PSA * 100] with concentrations of isoflavones and lignans (standardized for urinary creatinine concentration) was examined using multivariable-adjusted linear and logistic regression models. The linear regression analyses showed no clear association between creatinine-standardized urinary phytoestrogen concentrations and serum total or free PSA levels or PSA ratio. However, the odds of having a PSA ratio < 15% rose from quartile 1 to quartile 4 of isoflavone excretion (odds ratio = 2.82, 95 % confidence interval 1.28-6.22 for top versus bottom quartile), but there were no associations with having a PSA ratio < 25%. In generally healthy US men, 40+ years old without a diagnosis of prostate cancer, urinary isoflavone and lignan concentrations were not associated with serum PSA level.
doi:10.1080/01635581.2013.801999
PMCID: PMC4086485  PMID: 23909724
Phytoestrogens; Prostate-specific antigen; Prostate cancer; NHANES
13.  Serum insulin level, disease stage, prostate specific antigen (PSA) and Gleason score in prostate cancer 
British Journal of Cancer  2002;87(7):726-728.
In the present study, we assessed the relationship of serum insulin levels and three surrogate markers of recurrence, T stage, PSA, and Gleason score, in men with localized prostate cancer. Participants in our study were found through urology and radiation oncology clinics, and all eligible patients were asked to take part. All patients were asymptomatic and had been initially diagnosed on the basis of rising PSA or abnormal physical examination. Histological confirmation of diagnosis was obtained for all subjects. Serum insulin levels were determined by chemoluminescent assay with a standard, commercially available instrument. Patients were divided into three previously defined risk groups: Low risk: PSA ⩽10, stage ⩽T2a, or Gleason grade ⩽6. Medium risk: 10 7, tumour in seminal vesicle biopsy, PSA >15 or stage T2c or T3. One hundred and sixty-three men with prostate cancer were studied. There was a significant increase in serum insulin with risk group (P=0.003, one way anova). Tukey's multiple range test showed that the insulin levels of high risk patients were significantly higher than the insulin levels of medium and low risk patients (P=0.05) but the insulin levels of medium and low risk patients were not significantly different from one another. Multivariate linear regression, with insulin as the dependent variable, Gleason score, PSA, and T stage (T1, T2, T3) as the independent variables, was significant overall (P<0.001, r2=0.120). Increased T stage was independently correlated with increased serum insulin levels (P<0.001). Gleason score was negatively, insignificantly correlated with serum insulin level (P=0.059). The positive correlation of PSA and insulin level was not significant (P=0.097). To assure normal distribution of insulin and PSA values, the regression was repeated with log (insulin) as the dependent variable, log (PSA), T stage (T1, T2, T3), and Gleason score as independent variables. The regression was significant overall (P=0.002, r2 =0.095). Increased T stage was independently correlated with increased log (insulin level) (P=0.026). Gleason score was negatively, insignificantly correlated with log (insulin) level (P=0.728). The positive correlation of log (PSA) and log (insulin) levels was significant (P=0.010). The relationship between increased insulin level and advanced tumour stage in prostate cancer we describe here is biologically quite plausible, since insulin is a growth factor. Further studies may document whether serum insulin levels might be a useful biomarker of prostate cancer stage.
British Journal of Cancer (2002) 87, 726–728. doi:10.1038/sj.bjc.6600526 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600526
PMCID: PMC2364268  PMID: 12232754
prostate cancer progression; insulin; growth factors
14.  PSA Screening: Pro 
Current opinion in urology  2010;20(3):185-188.
Purpose of review
Prostate cancer is the most common noncutaneous malignancy in US men, and is most frequently diagnosed through prostate-specific antigen (PSA)-based screening. Nevertheless, PSA testing has become increasingly controversial. In this review, we will present the evidence supporting the role of PSA in prostate cancer screening.
Recent findings
Numerous studies have shown that the risk of current and future prostate cancer is directly related to the serum PSA level. Moreover, increasing PSA levels predict a greater risk of adverse pathologic features and worse disease-specific survival. Substantial epidemiologic evidence has suggested a reduction in advanced disease and improvements in prostate cancer survival rates since the introduction of PSA-based screening. Recently, evidence from a randomized trial further validated that PSA testing reduces both metastatic disease and prostate cancer-specific mortality.
Summary
PSA is a valid marker for prostate cancer and its aggressiveness. Level 1 evidence is now available that PSA-based screening reduces both the rate of metastatic disease and prostate cancer-specific mortality.
doi:10.1097/MOU.0b013e3283384047
PMCID: PMC3572789  PMID: 20224413
prostate cancer; screening; prostate-specific antigen; detection
15.  How Can Men Destined for Biochemical Failure After Androgen Deprivation and Radiotherapy be Identified Earlier? 
Purpose
The significance of prostate-specific antigen (PSA) increases during the recovery of androgen after androgen deprivation therapy (ADT) and radiotherapy for prostate cancer is not well understood. This study sought to determine whether the initial PSA increase from undetectable after completion of all treatment predicts for eventual biochemical failure (BF).
Methods and Materials
Between July 1992 and March 2004, 163 men with a Gleason score of 8–10 or initial PSA level >20 ng/mL, or Stage T3 prostate cancer were treated with radiotherapy (median dose, 76 Gy) and ADT and achieved an undetectable PSA level. The first detectable PSA level after the cessation of ADT was defined as the PSA sentinel rise (SR). A PSA-SR of >0.25, >0.5, >0.75, and >1.0 ng/mL was studied as predictors of BF (nadir plus 2 ng/mL). Cox proportional hazards models were used for univariate and multivariate analyses for BF adjusting for pretreatment differences in Gleason score, stage, PSA level (continuous), dose (continuous), and ADT duration (<12 vs. ≥12 months).
Results
Of the 163 men, 41 had BF after therapy. The median time to BF was 25 months (range, 4–96). The 5-year BF rate stratified by a PSA-SR of ≤0.25 vs. >0.25 ng/mL was 28% vs. 43% (p = 0.02), ≤0.5 vs. >0.5 ng/mL was 30% vs. 56% (p = 0.0003), ≤0.75 vs. >0.75 ng/mL was 29% vs. 66% (p < 0.0001), and ≤1.0 vs. >1.0 ng/mL was 29% vs. 75% (p < 0.0001). All four PSA-SRs were independently predictive of BF on multivariate analysis.
Conclusion
The PSA-SR predicts for BF. A PSA-SR of >0.5 ng/mL can be used for early identification of men at greater risk of BF.
doi:10.1016/j.ijrobp.2007.08.057
PMCID: PMC2763093  PMID: 18164854
Prostate cancer; Radiotherapy; Androgen deprivation therapy; Prostate-specific antigen; Biochemical failure
16.  Capsaicin may slow PSA doubling time: case report and literature review 
Capsaicin is the main pungent component of chili peppers. This is the first case, to our knowledge, that describes prostate-specific antigen (PSA) stabilization in a patient with prostate cancer, who had biochemical failure after radiation therapy. A 66-year-old male underwent radiotherapy treatment for a T2b, Gleason 7 (3+4) adenocarcinoma of the prostate, with a PSA level of 13.3 ng/mL in April 2001. He had 3-dimensional conformal radiotherapy of 46 Gy in 23 fractions to the prostate and pelvis, and a prostate boost of 30 Gy in 15 fractions. Radiotherapy was completed in May 2001 and PSA nadired in January 2002 (0.57). Due to the continued PSA rise, the patient was started on bicalutamide (50 mg orally, daily) and leuprolide acetate (1 dose of 22.5 mg intramuscularly) in July 2005 when PSA was 38.5 ng/mL. Due to poor tolerance of androgen ablation therapy, the patient discontinued treatment and started taking 2.5 mL of habaneros chili sauce, containing capsaicin, 1 to 2 times a week in April 2006. Prostate-specific antigen doubling time (PSAdt) increased from 4 weeks before capsaicin to 7.3 months by October 2006. From October 2006 until November 2007, the patient remained on capsaicin (2.5 to 15 mL daily) and his PSA was stable (between 11 to 14 ng/mL). By January 2008, his PSA rose to 22.3 and he has maintained a PSAdt between 4 and 5 months, where it presently remains. Due to the patient’s continued PSA rise, he was restarted on bicalutamide (12.5 mg daily). Apart from PSA relapse, the patient remains free of signs or symptoms of recurrence.
PMCID: PMC2825034  PMID: 20174488
17.  Contribution of allelic variability in prostate specific antigen (PSA) & androgen receptor (AR) genes to serum PSA levels in men with prostate cancer 
Background & objectives:
Wide variability in serum prostate specific antigen (PSA) levels exists in malignant conditions of the prostate. PSA is expressed in normal range in 20 to 25 per cent of prostate cancer cases even in presence of high grade Gleason score. This study was aimed to assess the influence of genetic variants exhibited by PSA and androgen receptor (AR) genes towards the variable expression of PSA in prostate cancer.
Methods:
Pre-treatment serum PSA levels from 101 prostate cancer cases were retrieved from medical record. PSA genotype analysis in promoter region and AR gene microsatellite Cytosine/Adenine/Guanine (CAG) repeat analysis in exon 1 region was performed using DNA sequencing and fragment analysis techniques.
Results:
A total of seven single nucleotide polymorphisms (SNPs) in the PSA promoter region were noted. Only two SNPs viz., 158G/A (P<0.001) in the proximal promoter region and -3845G/A (P<0.001) in enhancer region showed significant association with serum PSA levels. The carriers of homozygous GG genotype (P<0.001) at both of these polymorphic sites showed higher expression of PSA whereas homozygous AA genotype (P<0.001) carriers demonstrated lower PSA levels. The combination effect of PSA genotypes along with stratified AR CAG repeats lengths (long, intermediate and short) was also studied. The homozygous GG genotype along with AR long CAG repeats and homozygous AA genotype along with AR short CAG repeats at position -3845 and -158 showed strong interaction and thus influenced serum PSA levels.
Interpretation & conclusions:
The genetic variants exhibited by PSA gene at positions -3845G/A and -158G/A may be accountable towards wide variability of serum PSA levels in prostate cancer. Also the preferential binding of G and A alleles at these polymorphic sites along with AR long and short CAG repeats may contribute towards PSA expression.
PMCID: PMC4069730  PMID: 24820830
Androgen receptor; polymorphism; prostate cancer; prostate specific antigen; SNP
18.  Histological changes in the human prostate after radiotherapy and salvage high intensity focused ultrasound 
The histological changes (both macroscopic and microscopic) in the prostate following the combination of external beam radiotherapy and salvage high intensity focused ultrasound (HIFU) have not been previously described. This article describes the case of a 65-year-old male who presented with recurrent localized prostate cancer after undergoing external beam radiotherapy for low-risk prostate cancer. He was treated with salvage HIFU, and 4 weeks later presented with symptoms and signs consistent with a prostatorectal fistula. During a period of conservative management, his serum prostate-specific antigen levels started rising after having reached a nadir. A radical cystoprostatectomy and repair of fistula were performed after conservative management failed. Histological changes of dense fibrosis were noted in the region where the prostate should have been located. A literature review of the histological findings in the prostate after HIFU is discussed in this article, as well as the available evidence for the management of patients with local failure after the combination of external beam radiotherapy and salvage HIFU.
PMCID: PMC2911989  PMID: 20694085
19.  Detection of Life-Threatening Prostate Cancer With Prostate-Specific Antigen Velocity During a Window of Curability 
Background
Prostate-specific antigen (PSA) level is typically used as a dichotomous test for prostate cancer, resulting in overdiagnosis for a substantial number of men. The rate at which serum PSA levels change (PSA velocity) may be an important indicator of the presence of life-threatening disease.
Methods
PSA velocity was determined in 980 men (856 without prostate cancer, 104 with prostate cancer who were alive or died of another cause, and 20 who died of prostate cancer) who were participants in the Baltimore Longitudinal Study of Aging for up to 39 years. The relative risks (RRs) of prostate cancer death and prostate cancer–specific survival stratified by PSA velocity were evaluated in the three groups of men by Cox regression and Kaplan–Meier analyses. Statistical tests were two-sided.
Results
PSA velocity measured 10–15 years before diagnosis (when most men had PSA levels below 4.0 ng/mL) was associated with cancer-specific survival 25 years later; survival was 92% (95% confidence interval [CI] = 84% to 96%) among men with PSA velocity of 0.35 ng/mL per year or less and 54% (95% CI = 15% to 82%) among men with PSA velocity above 0.35 ng/mL per year (P<.001). Furthermore, men with PSA velocity above 0.35 ng/mL per year had a higher relative risk of prostate cancer death than men with PSA velocity of 0.35 ng/mL per year or less (RR = 4.7, 95% CI = 1.3 to 16.5; P = .02); the rates per 100 000 person-years were 1240 for men with a PSA velocity above 0.35 ng/mL per year and 140 for men with a PSA velocity of 0.35 ng/mL per year or less.
Conclusions
PSA velocity may help identify men with life-threatening prostate cancer during a period when their PSA levels are associated with the presence of curable disease.
doi:10.1093/jnci/djj410
PMCID: PMC2645644  PMID: 17077354
20.  Black Men Have Lower Rates Than White Men of Biochemical Failure with Primary Androgen-Deprivation Therapy 
The Permanente Journal  2011;15(3):4-8.
Introduction: Black men have a higher incidence of advanced stage at diagnosis and mortality from prostate cancer than do men in other racial groups. Given that androgen-deprivation therapy (ADT) is one of the mainstays of treatment for advanced prostate cancer, we investigated the development of biochemical failure, or recurrence of elevated prostate-specific antigen (PSA) levels, among different races in men receiving ADT.
Methods: Patients with prostate cancer who received ADT in the Kaiser Permanente Southern California Cancer Registry between January 2003 and December 2006 were eligible for inclusion in our study. Patients who had prior treatment for their cancer with surgery or radiation were excluded. Treatment failure was defined as an increase in PSA of >2 ng/mL from PSA nadir, with no subsequent decrease in PSA. We compared the biochemical failure rate in white patients to those in black, Hispanic, and Asian/other patients. The Cox proportional hazards regression model was used to estimate hazards ratios.
Results: Our study population consisted of 681 patients: 416 (61%) were white; 107 (16%) were black; 107 (16%) were Hispanic; and 51 (7%) were Asian or another race. After we controlled for all demographic variables and for variables related to prostate cancer, blacks were the only group with a lower risk of treatment failure compared with whites. The hazard ratios for treatment failure were as follows: black versus white, 0.66 (p = 0.03); Hispanic versus white, 1.00 (p = 0.8); Asian/other race versus white, 1.5 (p = 0.1). In this multivariate analysis, pretreatment PSA level and cancer stage were the only other variables associated with a higher risk of treatment failure.
Conclusion: Among patients receiving ADT as primary monotherapy for prostate cancer, blacks may have a lower rate of biochemical failure compared with whites. Although the etiology of this finding is unclear, it suggests the possibility that prostate cancer in black men may be more androgen sensitive than it is in white men.
PMCID: PMC3200099  PMID: 22058663
21.  Evaluation of prostate cancer prevalence in Iranian male population with increased PSA level, a one center experience 
Purpose:
This study was conducted to evaluate the incidence of prostate cancer (PCa) in Iranian male patients with increased prostate-specific antigen (PSA), and normal or abnormal digital rectal examination (DRE) that underwent prostate biopsy.
Materials and methods:
From March 2006 to April 2009, a total of 346 consecutive males suspected of having PCa due to increased PSA levels underwent transrectal ultrasonography (TRUS)-guided sextant biopsy of the prostate. The total PSA (tPSA), demographic data, incidence of PCa, benign prostate hyperplasia (BPH), and prostatitis were assessed.
Results:
The patients were divided into two groups according to their PSA values (group A serum tPSA level, 4–10 ng/mL; group B serum tPSA level, 10.1–20.0 ng/mL). Of the 346 biopsied cases, 193 cases (56%) had PCa, 80 cases (23%) had BPH, and 73 cases (21%) had prostatitis. The mean PSA and the age of the carcinoma group were significantly higher than those of the benign group (P < 0.01). The biopsy results were grouped as PCa, BPH, and prostatitis. Incidence of PCa for group A and group B cases were 115 cases (51%), and 78 cases (65%), respectively. In the case of PCa, BPH, and prostatitis, the mean PSAs were 10.02 ng/mL, 8.76 ng/mL, and 8.41 ng/mL, respectively (P < 0.40).
Conclusion:
TRUS-guided prostate biopsy and interpretation by a skilled team is highly recommended for early detection of PCa or its ruling-out. It seems that a PSA cutoff value of 4 ng/mL may be applied to the Iranian population. Although the chance of PCa is high in the PSA levels of 4–10 ng/mL, the combination of some data, like age and prostate volume, can decrease the rate of unnecessary prostate biopsies. We recommend prostate biopsy when PSA and/or DRE is elevated in symptomatic patients with obstructive and/or irritative lower urinary tract symptoms (LUTS) such as dysuria, frequency, or nocturia. Due to the very high incidence of PCa in the patients with PSA greater than 10 ng/mL, TRUS-guided biopsy is indicated, whatever the findings on DRE and/or LUTS, since the PCa detection rate is high.
doi:10.2147/CMR.S18147
PMCID: PMC3139483  PMID: 21792331
prostate-specific antigen; benign prostate hyperplasia; BPH; prostate biopsy; prostate carcinoma; PCa; digital rectal examination; DRE; lower urinary tract symptoms; LUTS
22.  Postoperative prostate-specific antigen nadir improves accuracy for predicting biochemical recurrence after radical prostatectomy: Results from the Shared Equal Access Regional Cancer Hospital (SEARCH) and Duke Prostate Center databases 
Objectives
We previously showed that prostate-specific antigen (PSA) nadir after radical prostatectomy (RP) significantly predicts biochemical recurrence (BCR). Herein, we sought to explore the effect of including PSA nadir into commonly used models on their accuracy to predict BCR after RP.
Methods
This was a retrospective analysis of 943 and 1792 subjects from the Shared Equal Access Regional Cancer Hospital (SEARCH) and Duke Prostate Cancer (DPC) databases, respectively. The discrimination accuracy for BCR of seven previously published models was assessed using concordance index and compared with and without adding PSA nadir level in SEARCH. Using data from SEARCH, we developed a new nomogram incorporating PSA nadir to other known predictors (preoperative PSA, pathological Gleason score, PSA nadir level, surgical findings, prostate weight, body mass index and race) of BCR and externally validated it in the DPC.
Results
In SEARCH, the mean concordance index across all seven nomograms was 0.687. After the inclusion of PSA nadir, the concordance index increased by nearly 7% (mean = 0.753). The concordance index of the new nomogram in SEARCH was 0.779 (bias-corrected = 0.767), which was 5% better than the next best model. In DPC, the new nomogram yielded a concordance index of 0.778.
Conclusion
The addition of postoperative PSA nadir to commonly used nomograms increased their accuracies by nearly 7%. Based upon this, we developed and externally validated a new nomogram, which was well calibrated and highly accurate, and is a potentially valuable tool for patients and physicians to predict BCR after RP.
doi:10.1111/j.1442-2042.2010.02631.x
PMCID: PMC3188446  PMID: 20880361
disease-free survival; nomograms; prostate cancer; prostate-specific antigen; prostatectomy; validation studies
23.  Prostate-specific antigen in serum of women with breast cancer. 
British Journal of Cancer  1995;72(3):728-731.
Prostate-specific antigen (PSA) was recently found in 30% of female breast tumours. In this study we have examined if PSA circulates in the blood of breast cancer patients and if serum PSA has any clinical application. We have compared serum PSA levels between women with and without breast cancer, between women with PSA-positive and PSA-negative breast cancer and between women with breast cancer before and after surgical removal of the tumour. We found that for women > or = 50 years, there is no difference in serum PSA between normal or breast cancer patients. We also could not find any difference in presurgical or post-surgical serum PSA between women who have PSA-positive or PSA-negative breast cancer. We found no correlation between PSA concentrations in matched presurgical and post-surgical sera, between presurgical sera and tumour cytosols and between post-surgical sera and tumour cytosols. High-performance liquid chromatography has shown that PSA in normal male serum consists mostly of PSA bound to alpha 1-antichymotrypsin (molecular weight approximately 100,000), and PSA in breast tumours and presurgical and post-surgical serum consists mostly of free PSA (molecular weight approximately 33,000). These data suggest that female serum PSA is not associated with tumour PSA levels. We speculate that most of the circulating PSA in women originates from the normal breast. It appears that serum PSA in women does not have potential for breast cancer diagnosis or monitoring, but our previous data are consistent with the view that tumour PSA concentration is a favourable prognostic indicator in women with breast cancer.
PMCID: PMC2033864  PMID: 7545417
24.  Magnetic resonance image-guided versus ultrasound-guided high-intensity focused ultrasound in the treatment of breast cancer 
Chinese Journal of Cancer  2013;32(8):441-452.
Image-guided high-intensity focused ultrasound (HIFU) has been used for more than ten years, primarily in the treatment of liver and prostate cancers. HIFU has the advantages of precise cancer ablation and excellent protection of healthy tissue. Breast cancer is a common cancer in women. HIFU therapy, in combination with other therapies, has the potential to improve both oncologic and cosmetic outcomes for breast cancer patients by providing a curative therapy that conserves mammary shape. Currently, HIFU therapy is not commonly used in breast cancer treatment, and efforts to promote the application of HIFU is expected. In this article, we compare different image-guided models for HIFU and reviewed the status, drawbacks, and potential of HIFU therapy for breast cancer.
doi:10.5732/cjc.012.10104
PMCID: PMC3845578  PMID: 23237221
High-intensity focused ultrasound; breast cancer; magnetic resonance imaging; ultrasound; ablation
25.  Nomogram for Prediction of Prostate Cancer with Serum Prostate Specific Antigen Less than 10 ng/mL 
Journal of Korean Medical Science  2014;29(3):338-342.
Although prostate-specific antigen (PSA) is a very useful screening tool, prostate biopsy is still necessary to confirm prostate cancer (PCA). However, it is reported that PSA is associated with a high false-positive rate and prostate biopsy also has various procedure-related complications. Therefore, the authors have devised a nomogram, which can be used to estimate the risk of PCA, using available clinical data for men with a serum PSA less than 10 ng/mL. Prostate biopsies were obtained from 2,139 patients from January 1998 to March 2011. Of them, 1,171 patients with a serum PSA less than 10 ng/mL were only included in this study. Patient age, PSA, free PSA, prostate volume, PSA density and percent free PSA ratio were analyzed. Among 1,171 patients, 255 patients (21.8%) were diagnosed as PCA. Multivariate analyses showed that patient age, prostate volume, PSA and percent free PSA had statistically significant relationships with PCA (P < 0.05) and were used as nomogram predictor variables. The area under the (ROC) curve for all factors in a model predicting PCA was 0.759 (95% CI, 0.716-0.803).
Graphical Abstract
doi:10.3346/jkms.2014.29.3.338
PMCID: PMC3945127  PMID: 24616581
Biopsy; Nomograms; Prostate; Prostatic Neoplasms

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