Hussain M, Tangen CM, Berry DL, et al.
Intermittent versus continuous androgen deprivation in prostate cancer.
N Engl J Med. 2013; 368(14):1314-25 [PubMed]

BACKGROUND: Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence.
METHODS: Men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization.
RESULTS: A total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events.
CONCLUSIONS: Our findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.).

Cante D, Franco P, Sciacero P, et al.
Leptomeningeal metastasis from prostate cancer.
Tumori. 2013 Jan-Feb; 99(1):6e-10e [PubMed]

AIMS AND BACKGROUND: Metastatic prostate carcinoma commonly involves bones and extrapelvic lymph nodes, with occasional visceral deposits. Central nervous system involvement is unusual and particularly the occurrence of leptomeningeal metastasis (LM) is extremely rare, with few cases described in the medical literature. The clinical presentation is characterized by multifocal neurological deficit and the prognosis is generally dismal, with survival ranging between 3 and 6 months. We report on a patient affected by LM due to prostate cancer who was treated with a combined-modality approach consisting of sequential chemotherapy and radiotherapy.
METHODS: A 70-year-old man was referred to our group for cognitive mental disorder, left-sided frontal headache and nausea; the patient had a previous history of metastatic prostate cancer. LM was diagnosed neuroradiologically with brain MRI and evidence of a detectable level of PSA in the cerebrospinal fluid. He was treated with docetaxel and prednisone for 3 cycles followed by external beam radiotherapy (EBRT) to the whole brain to a total dose of 30 Gy in 10 fractions with a simultaneous integrated boost to the macroscopic disease (total dose of 35 Gy in 10 fractions). No acute toxicity was observed.
RESULTS: A substantial clinical response was obtained after EBRT with neurological improvement and radiologically stable disease at post-treatment imaging until 10 weeks after radiation. The patient died of sudden general condition deterioration 3 months after EBRT.
CONCLUSION: Since LM derived from prostate cancer is likely to become a more common clinical event, such patients would need to be included in clinical trials evaluating new therapeutic approaches, considering that the current treatment strategies have been shown to be rather ineffective.

Guarneri A, Botticella A, Filippi AR, et al.
125I brachytherapy for localized prostate cancer: a single institution experience.
Tumori. 2013 Jan-Feb; 99(1):83-7 [PubMed]

AIMS AND BACKGROUND: To evaluate the clinical outcome of a cohort of localized prostate cancer patients treated with 125I permanent brachytherapy at the University of Turin.
METHODS AND STUDY DESIGN: A retrospective analysis was carried out on 167 consecutive patients with early stage prostate adenocarcinoma who underwent 125I brachytherapy between January 2003 and December 2010. A minimum follow-up of ≥ 12 months was mandatory for inclusion. Biochemical disease-free survival (defined on the basis of the ASTRO definition and the ASTRO-Phoenix definition) was chosen as the primary end point. Secondary end points were gastrointestinal and genitourinary toxicity (acute and late, defined according to the RTOG scale).
RESULTS: With a median follow-up of 42 months (range, 13.5-90.7), biochemical disease-free survival at 3 and 5 years was respectively 91.1% and 85.7%, according to the ASTRO definition and 94.5% and 85.1% according to ASTRO-Phoenix definition (for statistical purposes, only the ASTRO definition was used). Hormone treatment and nadir PSA (cutoff of 0.35 ng/ml) were the only factors affecting biochemical disease-free survival both on univariate (P = 0.02 and P = 0.001, respectively) and multivariate analysis (HR 0.024; P = 0.021 and HR 21.6; P = 0.006, respectively). Only 3.6% of patients experienced ≥ grade 3 acute urinary toxicity and 5% ≥ grade 3 late urinary toxicity. Prior transurethral prostate resection was the only independent predictor of grade 3 late urinary toxicity on multivariate analysis (HR 0.13; P = 0.009).
CONCLUSIONS: This mono-institutional series confirmed that brachytherapy is an effective and safe treatment modality for localized prostate cancer, with acceptable short- and long-term morbidity rates.

Ingimarsson JP, Seigne JD
The conundrum of prostatic urethral involvement.
Urol Clin North Am. 2013; 40(2):249-59 [PubMed]

The presence and depth of urothelial cancer involvement in the prostatic urethra can significantly affect the management of a patient with non-muscle invasive bladder cancer. This article presents an overview of the incidence, diagnosis, management, and follow-up of urothelial cancer.

Rashid MM, Alam AK, Habib AK, et al.
Efficacy of lower cut off value of serum prostate specific antigen in diagnosis of prostate cancer.
Bangladesh Med Res Counc Bull. 2012; 38(3):90-3 [PubMed]

Indications of prostate biopsy are high serum prostate specific antigen (PSA) value and or abnormal digital rectal examination (DRE) findings. Although serum PSA value of 4 ng/ml is the most commonly used threshold for recommending prostate biopsy, significant proportion of men harbor prostate cancer even when their serum PSA values are less than 4.0 ng/ml. Therefore present study was designed to determine the performance status of serum PSA in lower cut-off values. This hospital based prospective study was conducted in the Department of Urology of Bangabandhu Sheikh Mujib Medical University (BSMMU) and Comfort Nursing Home Pvt. Ltd, Dhaka from July 2009 to October 2010. Two hundred six male patients aged over 50 years having lower urinary tract symptoms (LUTS) and serum PSA more than 2.5 ng/ml were prepared for prostate biopsy. Trans rectal ultrasound (TRUS) guided biopsy was done. The test statistics used to analyze the data were descriptive statistics, sensitivity, specificity, positive and negative predictive value, ROC curve. For all analytical tests, the level of significance was set at 0.05 and p < 0.05 was considered significant. In 2.5-4 serum PSA range, 28.26% (13 out of 46) of all malignancy were found, which would be missed if we take cut off value 4. At 2.5 PSA cut-off, Sensitivity 91.3%, Specificity 14.37%, PPV 23.46%, NPV 85.18%, Efficacy 31.55%. At 4 PSA cut-off value, Sensitivity 71.73%, Specificity 46.25%, PPV 27.73%, NPV 85.05%, Efficacy 51.94%. So it can be concluded that, for early diagnosis of prostate cancer cut-off value of serum PSA of 2.5 ng/ml can be recommended as an indication for prostate biopsy.

Salehi P, Koh CJ, Pitukcheewanont P, et al.
Persistent Müllerian duct syndrome: 8 new cases in Southern California and a review of the literature.
Pediatr Endocrinol Rev. 2012 Dec-2013 Jan; 10(2):227-33 [PubMed]

Persistent Müllerian Duct Syndrome (PMDS) is a 46,XY disorder of sex development (DSD) in which Müllerian structures are found in genotypic males with normally virilized external genitalia and unilateral or bilateral cryptorchidism. It is usually diagnosed incidentally during surgical repair of cryptorchidism or inguinal hernia. The majority of cases are due to a mutation of the anti-Müllerian hormone (AMH) gene or the AMH receptor, type II (AMH-RII) gene. Management of patients with PMDS requires a multidisciplinary approach. Long-term prognosis is good although fertility appears to be decreased and there may be a risk of malignancy due to cryptorchidism and retained Müllerian remnants. We describe 8 new cases of PMDS diagnosed in Southern California in the past 10 years and review the literature.

Baena E, Shao Z, Linn DE, et al.
ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients.
Genes Dev. 2013; 27(6):683-98 [PubMed] Free Access to Full Article

Distinguishing aggressive from indolent disease and developing effective therapy for advanced disease are the major challenges in prostate cancer research. Chromosomal rearrangements involving ETS transcription factors, such as ERG and ETV1, occur frequently in prostate cancer. How they contribute to tumorigenesis and whether they play similar or distinct in vivo roles remain elusive. Here we show that in mice with ERG or ETV1 targeted to the endogenous Tmprss2 locus, either factor cooperated with loss of a single copy of Pten, leading to localized cancer, but only ETV1 appeared to support development of invasive adenocarcinoma under the background of full Pten loss. Mechanistic studies demonstrated that ERG and ETV1 control a common transcriptional network but largely in an opposing fashion. In particular, while ERG negatively regulates the androgen receptor (AR) transcriptional program, ETV1 cooperates with AR signaling by favoring activation of the AR transcriptional program. Furthermore, we found that ETV1 expression, but not that of ERG, promotes autonomous testosterone production. Last, we confirmed the association of an ETV1 expression signature with aggressive disease and poorer outcome in patient data. The distinct biology of ETV1-associated prostate cancer suggests that this disease class may require new therapies directed to underlying programs controlled by ETV1.

Jing B, Wang J, Chang WL, et al.
Association of the polymorphism of APE1 gene with the risk of prostate cancer in Chinese Han population.
Clin Lab. 2013; 59(1-2):163-8 [PubMed]

BACKGROUND: DNA damage, caused by numerous carcinogens, contributes to the increased risk of different types of cancer. The base excision repair (BER) pathway including the apurinic/apyrimidic endonuclease (APE1, also known as APEX1) gene plays an important role in preventing the accumulation of DNA damage and maintaining genomic stability. The aim of the present study is to determine whether polymorphisms of APE1 are associated with the risk of prostate cancer (PCa) in the Chinese Han population.
METHODS: This study consisted of 198 patients with PCa and 156 healthy controls. The polymorphisms of APE1, Asp148Glu (rs1130409) and -141T/G (rs1760944) were determined by the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method.
RESULTS: The genotypic distributions of the two polymorphisms in controls were in Hardy-Weinberg equilibrium (p = 0.92 and p = 0.83, respectively). Logistic regression analysis indicated that the -141GG genotype was significantly associated with a decreased risk of PCa compared with the -141TT genotype (p = 0.03; OR 0.49; 95% CI 0.26 - 0.92). The G allele was also significantly associated with a reduced risk of PCa compared with the T allele (p = 0.02; OR 0.71; 95% CI 0.52 - 0.96). However, no association between Asp148Glu polymorphism and the risk of PCa was found.
CONCLUSIONS: The -141GG genotype and G allele of the APE1 gene are associated with a decreased risk of PCa in the Chinese Han population.

Jin G, Su DK, Luo NB, et al.
Meta-analysis of diffusion-weighted magnetic resonance imaging in detecting prostate cancer.
J Comput Assist Tomogr. 2013 Mar-Apr; 37(2):195-202 [PubMed]

PURPOSE: The objective of this study was to determine the diagnostic performance of quantitative diffusion-weighted magnetic resonance imaging in detection of prostate cancer.
METHODS: A comprehensive search was performed for English articles published before May 2012 that fulfilled the following criteria: patients had histopathologically proved prostate cancer; diffusion-weighted imaging (DWI) was performed for the detection of prostate cancer, and data for calculating sensitivity and specificity were included. Methodological quality was assessed by using the quality assessment of diagnostic studies instrument. Publication bias analysis, homogeneity, inconsistency index, and threshold effect were performed by STATA version 12.
RESULTS: Of 119 eligible studies, 12 with 1637 malignant and 4803 benign lesions were included. There was notable heterogeneity beyond threshold effect and publication bias. The sensitivity and specificity with 95% confidence interval (CI) estimates of DWI on a per-lesion basis were 77% (CI, 0.76-0.84) and 84% (CI, 0.78-0.89), respectively, and the area under the curve of summary receiver operating characteristic curve was 0.88 (CI, 0.85-0.90). The overall positive and negative likelihood ratios with 95% CI were 4.93 (3.39-7.17) and 0.278 (0.19-0.39), respectively.
CONCLUSIONS: Quantitative DWI has a relative sensitivity and specificity to distinguish malignant from benign in prostate lesions. However, large-scale randomized control trials are necessary to assess its clinical value because of nonuniformed diffusion gradient b factor, diagnosis threshold, and small number of studies.

Pepe P, Garufi A, Priolo G, et al.
Prostate cancer detection at repeat biopsy: can pelvic phased-array multiparametric MRI replace saturation biopsy?
Anticancer Res. 2013; 33(3):1195-9 [PubMed]

AIM: Magnetic resonance imaging (MRI) accuracy in prostate cancer (PCa) diagnosis in men submitted to saturation prostate biopsy (SPBx) was evaluated.
MATERIALS AND METHODS: From June 2011 to December 2012, 78 patients (median 63 years) underwent repeat SPBx (median 28 cores). Multiparametric MRI using a 3 Tesla pelvic phased-array coil was performed before SPBx and lesions suspicious for PCa were submitted to additional targeted biopsies.
RESULTS: A T1c PCa was found in 32 (41%) cases. SPBx vs. MRI-suspicious targeted biopsy diagnosed 28 (87.5%) vs. 26 (81.2%) PCa missing four (12.5%) and six (18.8%) cancers localized in the anterior zone and in the lateral margin of the prostate, respectively; moreover, MRI diameter lesions correlated with PCa diagnosis and Gleason score (p<0.05).
CONCLUSION: Multiparametric MRI improved SPBx accuracy in diagnosing PCa of the anterior zone; moreover, suspicious areas >10 mm resulted as highly predictive of cancer (about 70% of the cases).

Kadono Y, Yaegashi H, Izumi K, et al.
Efficacy of androgen deprivation therapy for localized prostate cancer: analysis of pT0 evaluated by radical prostatectomy specimen.
Anticancer Res. 2013; 33(3):1147-51 [PubMed]

AIM: In order to investigate which types of localized prostate cancer can be treated most effectively by androgen deprivation therapy (ADT), cases of no residual cancer in radical prostatectomy specimens (pT0) after neoadjuvant ADT were analyzed.
PATIENTS AND METHODS: Patients with localized prostate cancer who underwent radical prostatectomy after neoadjuvant ADT were investigated retrospectively.
RESULTS: Thirty-two patients (24.2%) were diagnosed with pT0 disease by pathological evaluation. The positive-core proportion of prostate biopsy was lower, the duration of neoadjuvant ADT was longer, and prostate-specific antigen (PSA) nadir before radical prostatectomy was lower in pT0 cases compared to non-pT0 cases, and these differences were statistically significant. The percentage of pT0 cases with PSA nadir <0.2 ng/ml and <0.008 ng/ml before radical prostatectomy were 29.2% (21 out of 72 cases) and 83.3% (5 out of 6 cases), respectively. The positive-core proportion of prostate biopsy and PSA nadir before radical prostatectomy had a significant impact on pT0 status after neoadjuvant ADT.
CONCLUSION: ADT for localized prostate cancer is thought to be highly effective in cases with low cancer volume. ADT is effective in cases of localized prostate cancer with PSA below the levels of detection by supersensitive PSA assay, and such cases show no cancer recurrence. Treatment options in such cases include intermittent or discontinuation of ADT.

Sugie S, Tsukino H, Yamauchi T, et al.
Functional polymorphism in the CAV1 T29107A gene and its association with prostate cancer risk among Japanese men.
Anticancer Res. 2013; 33(3):1023-7 [PubMed]

AIM: To evaluate the relationship between the Caveolin-1 (CAV1) T29107A (rs7804372) polymorphism and the risk of prostate cancer among Japanese populations, and the associations between CAV1 polymorphisms and clinicopathological characteristics, including Gleason grade and prostate-specific antigen (PSA) grade.
MATERIALS AND METHODS: We recruited 134 patients with prostate cancer and 86 healthy controls matched for age and smoking status. The CAV1 T29107A polymorphism status was determined by polymerase chain reaction and restriction fragment-length polymorphism analysis.
RESULTS: Genotype distributions (p=0.0045) and allelic frequencies (p=0.0018) differed between prostate cancer and control groups in terms of the CAV1 T29107A polymorphism (Pearson's χ(2) test). Logistic regression analysis of case and control outcomes showed an odds ratio of 0.35 (95% Condifence interval=0.13-0.91, p=0.033) between the TT and AA polymorphisms, indicating a reduced risk of prostate cancer to be associated with the AA polymorphism. Subset analysis revealed no significant associations between this polymorphism and clinicopathological characteristics of prostate cancer.
CONCLUSION: The results of this study demonstrated a relationship between the CAV1 T29107A variant and risk of prostate cancer. This polymorphism thus, merits further investigation as a potential genomic marker for the early detection of prostate cancer. Our results support the hypothesis that the CAV1 T29107A (rs7804372) polymorphism may influence susceptibility to prostate cancer; however, prostate cancer progression was not associated with this polymorphism in a Japanese population.

Fowler JF, Toma-Dasu I, Dasu A
Is the α/β ratio for prostate tumours really low and does it vary with the level of risk at diagnosis?
Anticancer Res. 2013; 33(3):1009-11 [PubMed]

AIM: To answer the questions: Is the α/β ratio (radiosensitivity to size of dose-per-fraction) really low enough to justify using a few large dose fractions instead of the traditional many small doses? Does this parameter vary with prognostic risk factors?
METHODS AND MATERIALS: Three large statistical overviews are critiqued, with results for 5,000, 6,000 and 14,000 patients with prostate carcinoma, respectively.
RESULTS: These major analyses agree in finding the average α/β ratio to be less than 2 Gy: 1.55, (95% confidence interval=0.46-4.52), 1.4 (0.9-2.2), and the third analysis 1.7 (1.4-2.2) by the ASTRO and 1.6 (1.2-2.2) by Phoenix criteria. All agree that α/β values do not vary significantly with the low, intermediate, high and "all-included" risk factors.
CONCLUSION: The high sensitivity to dose-per-fraction is an intrinsic property of prostate carcinomas and this supports the use of hypo-fractionation to increase the therapeutic gain for these tumours with dose-volume modelling to reduce the risk of late complications in rectum and bladder.

Yang ES, Huh YJ, Park JW
RNA interference targeting sensitive-to-apoptosis gene potentiates doxorubicin- and staurosporine-induced apoptosis of PC3 cells.
Anticancer Res. 2013; 33(3):847-55 [PubMed]

Several anticancer agents exert their cancer cell killing effects by generating reactive oxygen species (ROS). Thus, a combination of ROS-producing agents and the inhibition of ROS elimination promotes the death of cancer cells. The sensitive to apoptosis gene (SAG) protein, a redox-inducible protein and potential ROS scavenger, protects mammalian cells from redox agent-induced apoptosis. In the present study, we found that silencing of SAG expression in human prostate cancer PC3 cells by transfection with SAG small-interfering RNA (siRNA) markedly enhanced susceptibility to doxorubicin- and to staurosporine-induced apoptotic cell death. Furthermore, pre-treatment with the thiol antioxidant N-acetylcysteine suppressed increases in ROS and apoptosis. This study suggests that knockdown of SAG augments the apoptosis of PC3 cells exposed to doxorubicin or staurosporine presumably by increasing intracellular ROS levels.

Argellati F, Nuzzo PV, Ricci F, et al.
Dihydrotestosterone and bicalutamide do not affect Periostin expression in androgen-dependent LNCaP prostate cancer cell lines.
Anticancer Res. 2013; 33(3):815-20 [PubMed]

BACKGROUND/AIM: To investigate periostin (POSTN) expression in the LNCaP cell line.
MATERIALS AND METHODS: Our LNCaP strain did not constitutively express the POSTN gene. Through cell transfection with a cloning vector, we developed an LNCaP cell line that stably expressed POSTN. LNCaP wild-type and transfected cells were incubated with dihydrotestosterone (DHT) in the presence/or absence of bicalutamide (BIC). POSTN mRNA was detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) and growth was measured with the MTT assay.
RESULTS: POSTN transfection stimulated LNCaP cell growth. While POSTN transfection did not interfere with the stimulatory effect of DHT, BIC had an inhibitory effect on cell proliferation. However, exposure to either DHT and/or BIC was not able to interfere with POSTN expression per se.
CONCLUSION: We confirmed the role of POSTN in promoting cancer cell growth. Although POSTN transcription is not likely to be androgen-dependent, the fact that increased cell proliferation POSTN-mediated was impaired by BIC suggests an androgen modulation of POSTN interaction proteins.

Etzioni R, Gulati R
Response: Reading between the lines of cancer screening trials: using modeling to understand the evidence.
Med Care. 2013; 51(4):304-6 [PubMed]

In our article about limitations of basing screening policy on screening trials, we offered several examples of ways in which modeling, using data from large screening trials and population trends, provided insights that differed somewhat from those based only on empirical trial results. In this editorial, we take a step back and consider the general question of whether randomized screening trials provide the strongest evidence for clinical guidelines concerning population screening programs. We argue that randomized trials provide a process that is designed to protect against certain biases but that this process does not guarantee that inferences based on empirical results from screening trials will be unbiased. Appropriate quantitative methods are key to obtaining unbiased inferences from screening trials. We highlight several studies in the statistical literature demonstrating that conventional survival analyses of screening trials can be misleading and list a number of key questions concerning screening harms and benefits that cannot be answered without modeling. Although we acknowledge the centrality of screening trials in the policy process, we maintain that modeling constitutes a powerful tool for screening trial interpretation and screening policy development.

Melnikow J, LeFevre M, Wilt TJ, Moyer VA
Counterpoint: Randomized trials provide the strongest evidence for clinical guidelines: The US Preventive Services Task Force and Prostate Cancer Screening.
Med Care. 2013; 51(4):301-3 [PubMed]

BACKGROUND: The US Preventive Services Task Force recommended against prostate-specific antigen (PSA) screening for prostate cancer based primarily on 2 large long-term randomized-controlled trials (RCTs) and a systematic review of harms resulting from screening.
OBJECTIVE: To support use of large, long-term randomized trials as the evidence base for clinical guidelines on screening and to draw attention to limitations of modeling studies used for this purpose.
METHODS: We respond to critiques of use of RCTs as the primary evidence base, considering the results of the Prostate, Lung, Colorectal and Ovarian (PLCO) and European Randomized Study of Screening for Prostate Cancer (ERSPC) trials, documented harms resulting from PSA screening, and methodological concerns with modeling studies.
RESULTS: The PLCO and ERSPC provided 11-13 years of follow-up on over 250,000 subjects. The PLCO, despite limitations, is most representative of US populations, screening and treatment practices, and showed no mortality benefit resulting from annual PSA testing after 13 years of follow-up. The confidence interval was narrow and precluded more than a 13% relative mortality reduction. Competing causes of mortality in older men make it progressively less likely that longer follow-up will demonstrate a large absolute reduction in disease-specific mortality. With continued screening, the increasing prevalence of asymptomatic cancers in older men will increase the rate of overdiagnosis. Potential harms from screening and treatment are significant.
CONCLUSIONS: Projections from models are subject to mistaken assumptions and investigator biases, and should not be accorded the same weight as evidence from RCTs. Current empiric evidence is sufficient to support the US Preventive Services Task Force guideline that clinicians should recommend against PSA screening for prostate cancer.

Ghazi A, Erturk E, Joseph JV
Modifications to facilitate extraperitoneal robot-assisted radical prostatectomy post kidney transplant.
JSLS. 2012 Apr-Jun; 16(2):314-9 [PubMed] Free Access to Full Article

INTRODUCTION: Renal transplantation is the treatment of choice for patients with end-stage renal failure. With advances in immunosuppression, the short-term and long-term outcome has improved significantly. Subsequently, urologists are encountering more transplant recipients with genitourinary malignancies, and therefore urologists are becoming increasingly compelled to offer curative treatment options.
MATERIALS AND METHODS: We present modifications to facilitate E-RARP in these patients that include modified trocar arrangement, delayed bladder neck transection, utilizing the robotic Hem-o-lok applier, and posterior reconstruction of the anastomosis using a barbed V-loc suture. A 68-year-old male with a history of polycystic kidney disease, end-stage renal failure, and an allograft renal transplantation in the right iliac fossa, presented with T1c, Gleason 3+4 prostate cancer. He had a preoperative PSA of 6.93ng/mL, ASA score of 3, and a BMI of 26kg/m2. Follow-up for metastasis (MRI and bone scan) was negative. E-RARP was performed via the extraperitoneal approach using a 5-port 2-arm approach at an insufflation pressure of 10 mm Hg.
RESULTS: The radical prostatectomy was successfully performed. Ureterovesical anastomosis was completed, and total console time was 130 minutes, with an estimated blood loss of 125mL. Final pathology was T2bNx, Gleason 3+4 with negative surgical margins. The patient was discharged with no change in serum creatinine or GFR. The catheter was removed on POD 10 with no intraoperative or immediate postoperative complications.
CONCLUSION: E-RARP in the carefully selected renal allograft recipient is feasible and accomplished safely with technical modifications to avoid injuring the renal allograft, transplanted ureter, and ureteroneocystostomy.

Lim SD, Kim WS, Kwon GY
ROR2 and Wnt5a expression in stage 1 pure testicular seminomas.
Anal Quant Cytol Histol. 2013; 35(1):41-51 [PubMed]

OBJECTIVE: To elucidate the prognostic utility of several biomarkers including ROR2/Wnt5a in stage 1 pure seminoma, which is a highly curable tumor in need of prognostic markers to avoid unnecessary treatment.
STUDY DESIGN: A total of 47 patients of stage 1 seminoma who underwent radical orchiectomy were included in the study. Tissue microarray-based immunohistochemical analysis of placental alkaline phosphatase, D2-40, c-Kit, Oct-3/4, ROR2, Wnt5a, beta-catenin, CD30, vimentin, pancytokeratin, beta-hCG and p53 was conducted, and relevant clinicopathologic features were assessed.
RESULTS: ROR2 protein revealed strong diffuse membranous immunoreactivity (IR) in 12.8% and partial weak IR in 40.4%, respectively. Cytoplasimc Wnt5a IR was observed in 27.7%. ROR2 IR was correlated with Wnt5a IR (p = 0.029) and Oct3/4 IR (p = 0.035). c-Kit IR was correlated with Wnt5a IR (p = 0.034). No significant differences were found between ROR2/Wnt5a protein expression and the prognostically relevant features such as lymphatic invasion or pathologic T stage. Pathologic T stage was not correlated with rete invasion (p= 0.23). The expression or loss of other aforementioned antibodies was not associated with the prognostic clinicopathologic characteristics.
CONCLUSION: Our results do not support the relevance of ROR2/Wnt5a as biomarkers in stage 1 pure seminomas. The utility of the explored biomarkers as prognostic or differentiation indicators remains to be clarified.

Tsivian M, Abern MR, Polascik TJ
Evolution of the concept of focal therapy for prostate cancer.
Oncology (Williston Park). 2013; 27(1):64-8, 70; discussion 70 [PubMed]

The landscape of prostate cancer has been rapidly evolving, and technological advances in imaging and biopsy tools offer novel approaches to focal therapy. In this dynamic environment, the role of focal therapy for prostate cancer is being shaped both by advances in technology and by reconsidering the epidemiological and outcomes data for available treatments. Here we focus on the evolution of the concept of focal therapy and its potential roles in the management of prostate cancer.

Arora A, Sharma S, Seth A
Unusual retrovesical cystic mass in a male patient.
Urology. 2013; 81(3):e23-4 [PubMed]

Primary tumors of the seminal vesicles are very rare, with most reported cases being malignant. Benign tumors of the seminal vesicles are even rarer. A spectrum of tumors is derived from both epithelium and stroma and constitutes a distinct subset termed "epithelial-stromal tumors." We present the classic imaging findings of a cystadenoma of the seminal vesicles in a 23-year-old man, who presented with lower abdominal pain and obstructive urinary symptoms.

Nakabayashi M, Xie W, Buckle G, et al.
Long-term follow-up of a phase II trial of chemotherapy plus hormone therapy for biochemical relapse after definitive local therapy for prostate cancer.
Urology. 2013; 81(3):611-6 [PubMed]

OBJECTIVE: To evaluate long-term follow-up of a phase II trial of chemohormonal therapy in 62 men with prostate cancer biochemical relapse (BR).
METHODS: Treatment was 4 cycles of docetaxel (70 mg/m(2)) every 3 weeks and estramustine 280 mg three times a day (days 1-5) followed by 15 months of goserelin acetate/bicalutamide. The primary endpoint was the proportion with prostate-specific antigen (PSA) <0.1 with recovered testosterone 5 years after completion of therapy. Secondary endpoints included time to progression (TTP), time to reinitiate androgen deprivation therapy (ADT), the proportion with castration-resistant prostate cancer (CRPC), and overall survival (OS).
RESULTS: Median follow-up was 8.6 years (range 1.3-11.1 years). At 5 year follow-up, 7 patients (11%) had PSA <0.1 (5 undetectable); 8 (13%) had PSA >0.1 but without reinitiation of ADT (median PSA 0.37). Of the 15 (24%) men without reinitiation of ADT, and 14 have recovered testosterone to normal range. Median TTP for the complete cohort was 35.0 months (95% confidence interval [CI] 31.7-39.2). Baseline PSA <3.0 ng/dL, no prior ADT, and prostatectomy (vs radiation) were associated with longer TTP (P = .0001, P = .0055, and P = .0398, respectively). At the time of analysis, 42 men (68%) had restarted ADT, 23 men had CRPC (37%), and 11 (18%) had chemotherapy. Median time to reinitiation of ADT was 32.6 months (range 0-107.6 months). Median OS has not been reached; there were 15 deaths.
CONCLUSION: Chemotherapy plus ADT for BR resulted in durable (>5 years) complete responses (<0.1 ng/mL) in 7 men (11%). Twenty-four percent of men have not re-initiated ADT 5 years from completion of protocol therapy.

Lalong-Muh J, Colm T, Steggall M
Erectile dysfunction following retropubic prostatectomy.
Br J Nurs. 2013 Feb 28-Mar 13; 22(4):S4, S7-9 [PubMed]

Prostate cancer is the most common cancer to affect men in the UK. Treatment options depend on the grade of tumour, the patient's co-existing diseases and choice of treatment. One potentially curative option is surgery, specifically a radical retropubic prostatectomy or variation thereof. As a consequence of the surgery, men commonly experience two side-effects: urinary incontinence and erectile dysfunction (ED). This paper outlines the clinical management of ED following surgery and aims to provide an overview of how to assess a man who has developed ED and discuss the various treatment options available, along with the efficacy in terms of recovery of erections.

First-line treatment of metastatic prostate cancer. Androgen suppression for symptomatic disease.
Prescrire Int. 2013; 22(135):48-51 [PubMed]

Prostate cancer sometimes metastasizes, especially to bone, which may cause pain, fractures and spinal cord compression. What are the best first-line treatment options for patients with metastatic prostate cancer? To answer this question, we conducted a review of the literature, using the standard Prescrire methodology. Suppressing androgen secretion by surgically removing the testicles (orchiectomy) or by administering a gonadorelin agonist relieves the pain associated with bone metastases in about 80% of patients. This treatment has a clear impact on symptoms, despite the lack of clinical trials versus placebo or no treatment. Its impact on overall survival is uncertain. In terms of survival, goserelin therapy appears to have similar efficacy to orchiectomy. The efficacy of other gonadorelin agonists is less well documented. Degarelix, a gonadorelin antagonist, does not appear to provide a therapeutic advantage over gonadorelin agonist. In 2012, oestrogen should not be used in the treatment of metastatic prostate cancer, because of its cardiovascular adverse effects. Antiandrogen monotherapy, preferably with flutamide, appears to be less beneficial than orchiectomy in terms of survival. Overall, adverse effects are more frequent with nonsteroidal antiandrogens than with gonadorelin agonists, but sexual dysfunction is less frequent. Cyproterone, a steroidal antiandrogen, seems to have fewer adverse effects leading to treatment discontinuation than nonsteroidal antiandrogens. There is no firm evidence that starting hormonal therapy before metastases become symptomatic is beneficial. When symptoms have disappeared and the PSA level is low, one option is to temporarily interrupt gonadorelin agonist therapy if it is poorly tolerated, even though this may shorten survival by a few months. The addition of a nonsteroidal antiandrogen to androgen suppression therapy slightly improves 5-year survival, preventing about 3 deaths per 100 patients, but at a cost of additional adverse effects. First-line hormonal treatments are initially very effective in relieving symptoms of metastatic prostate cancer. Our analysis of the available data suggests that the best treatment option is androgen suppression with goserelin. Flutamide monotherapy is an alternative for some patients.

Langsenlehner T, Döller C, Winkler P, et al.
Impact of inter- and intrafraction deviations and residual set-up errors on PTV margins. Different alignment techniques in 3D conformal prostate cancer radiotherapy.
Strahlenther Onkol. 2013; 189(4):321-8 [PubMed]

PURPOSE: The aim of this work was to analyze interfraction and intrafraction deviations and residual set-up errors (RSE) after online repositioning to determine PTV margins for 3 different alignment techniques in prostate cancer radiotherapy.
METHODS: The present prospective study included 44 prostate cancer patients with implanted fiducials treated with three-dimensional (3D) conformal radiotherapy. Daily localization was based on skin marks followed by marker detection using kilovoltage (kV) imaging and subsequent patient repositioning. Additionally, in-treatment megavoltage (MV) images were obtained for each treatment field. In an off-line analysis of 7,273 images, interfraction prostate motion, RSE after marker-based prostate localization, prostate position during each treatment session, and the effect of treatment time on intrafraction deviations were analyzed to evaluate PTV margins.
RESULTS: Margins accounting for interfraction deviation, RSE and intrafraction motion were 14.1, 12.9, and 15.1 mm in anterior-posterior (AP), superior-inferior (SI), and left-right (LR) direction for skin mark alignment and 9.6, 8.7, and 2.6 mm for bony structure alignment, respectively. Alignment to implanted markers required margins of 4.6, 2.8, and 2.5 mm. As margins to account for intrafraction motion increased with treatment prolongation PTV margins could be reduced to 3.9, 2.6, and 2.4 mm if treatment time was ≤ 4 min.
CONCLUSION: With daily online correction and repositioning based on implanted fiducials, a significant reduction of PTV margins can be achieved. The use of an optimized workflow with faster treatment techniques such as volumetric modulated arc techniques (VMAT) could allow for a further decrease.

McCree-Hale R, Hale TM, Rutley KR, et al.
Evaluating a theory-based health education intervention to improve awareness of prostate cancer among men in Western Jamaica.
West Indian Med J. 2012; 61(6):580-6 [PubMed]

OBJECTIVE: To evaluate the impact of a theory-based health education intervention on awareness of prostate cancer and intention to screen among men in Western Jamaica.
METHODS: One hundred and eighty-eight men attending outpatient clinics in a hospital in Western Jamaica completed an interviewer-administered pretest survey. Following the pretest, participants received a health education intervention related to prostate cancer and an immediate post-test survey
RESULTS: There were statistically significant increases in the percentage of correct responses between the pretest and post-test (p < 0.05). The greatest improvement was among items measuring knowledge of prostate cancer screening tests. Participants moved across the Stages of Change theoretical constructs indicating intention to screen.
CONCLUSION: The sample was receptive to information about prostate cancer and the use of a theory-based educational intervention positively influenced knowledge of prostate cancer risk factors, symptoms, and types of screenings. Practice implications: This theory-based patient education programme can be replicated to promote awareness of prostate cancer and informed screening methods including potential risk associated with screening behaviours.

Ilic D, Neuberger MM, Djulbegovic M, Dahm P
Screening for prostate cancer.
Cochrane Database Syst Rev. 2013; 1:CD004720 [PubMed]

BACKGROUND: Any form of screening aims to reduce disease-specific and overall mortality, and to improve a person's future quality of life. Screening for prostate cancer has generated considerable debate within the medical and broader community, as demonstrated by the varying recommendations made by medical organizations and governed by national policies. To better inform individual patient decision-making and health policy decisions, we need to consider the entire body of data from randomised controlled trials (RCTs) on prostate cancer screening summarised in a systematic review. In 2006, our Cochrane review identified insufficient evidence to either support or refute the use of routine mass, selective, or opportunistic screening for prostate cancer. An update of the review in 2010 included three additional trials. Meta-analysis of the five studies included in the 2010 review concluded that screening did not significantly reduce prostate cancer-specific mortality. In the past two years, several updates to studies included in the 2010 review have been published thereby providing the rationale for this update of the 2010 systematic review.
OBJECTIVES: To determine whether screening for prostate cancer reduces prostate cancer-specific mortality or all-cause mortality and to assess its impact on quality of life and adverse events.
SEARCH METHODS: An updated search of electronic databases (PROSTATE register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CANCERLIT, and the NHS EED) was performed, in addition to handsearching of specific journals and bibliographies, in an effort to identify both published and unpublished trials.
SELECTION CRITERIA: All RCTs of screening versus no screening for prostate cancer were eligible for inclusion in this review.
DATA COLLECTION AND ANALYSIS: The original search (2006) identified 99 potentially relevant articles that were selected for full-text review. From these citations, two RCTs were identified as meeting the inclusion criteria. The search for the 2010 version of the review identified a further 106 potentially relevant articles, from which three new RCTs were included in the review. A total of 31 articles were retrieved for full-text examination based on the updated search in 2012. Updated data on three studies were included in this review. Data from the trials were independently extracted by two authors.
MAIN RESULTS: Five RCTs with a total of 341,342 participants were included in this review. All involved prostate-specific antigen (PSA) testing, with or without digital rectal examination (DRE), though the interval and threshold for further evaluation varied across trials. The age of participants ranged from 45 to 80 years and duration of follow-up from 7 to 20 years. Our meta-analysis of the five included studies indicated no statistically significant difference in prostate cancer-specific mortality between men randomised to the screening and control groups (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.86 to 1.17). The methodological quality of three of the studies was assessed as posing a high risk of bias. The European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial were assessed as posing a low risk of bias, but provided contradicting results. The ERSPC study reported a significant reduction in prostate cancer-specific mortality (RR 0.84, 95% CI 0.73 to 0.95), whilst the PLCO study concluded no significant benefit (RR 1.15, 95% CI 0.86 to 1.54). The ERSPC was the only study of the five included in this review that reported a significant reduction in prostate cancer-specific mortality, in a pre-specified subgroup of men aged 55 to 69 years of age. Sensitivity analysis for overall risk of bias indicated no significant difference in prostate cancer-specific mortality when referring to the meta analysis of only the ERSPC and PLCO trial data (RR 0.96, 95% CI 0.70 to 1.30). Subgroup analyses indicated that prostate cancer-specific mortality was not affected by the age at which participants were screened. Meta-analysis of four studies investigating all-cause mortality did not determine any significant differences between men randomised to screening or control (RR 1.00, 95% CI 0.96 to 1.03). A diagnosis of prostate cancer was significantly greater in men randomised to screening compared to those randomised to control (RR 1.30, 95% CI 1.02 to 1.65). Localised prostate cancer was more commonly diagnosed in men randomised to screening (RR 1.79, 95% CI 1.19 to 2.70), whilst the proportion of men diagnosed with advanced prostate cancer was significantly lower in the screening group compared to the men serving as controls (RR 0.80, 95% CI 0.73 to 0.87). Screening resulted in a range of harms that can be considered minor to major in severity and duration. Common minor harms from screening include bleeding, bruising and short-term anxiety. Common major harms include overdiagnosis and overtreatment, including infection, blood loss requiring transfusion, pneumonia, erectile dysfunction, and incontinence. Harms of screening included false-positive results for the PSA test and overdiagnosis (up to 50% in the ERSPC study). Adverse events associated with transrectal ultrasound (TRUS)-guided biopsies included infection, bleeding and pain. No deaths were attributed to any biopsy procedure. None of the studies provided detailed assessment of the effect of screening on quality of life or provided a comprehensive assessment of resource utilization associated with screening (although preliminary analyses were reported).
AUTHORS' CONCLUSIONS: Prostate cancer screening did not significantly decrease prostate cancer-specific mortality in a combined meta-analysis of five RCTs. Only one study (ERSPC) reported a 21% significant reduction of prostate cancer-specific mortality in a pre-specified subgroup of men aged 55 to 69 years. Pooled data currently demonstrates no significant reduction in prostate cancer-specific and overall mortality. Harms associated with PSA-based screening and subsequent diagnostic evaluations are frequent, and moderate in severity. Overdiagnosis and overtreatment are common and are associated with treatment-related harms. Men should be informed of this and the demonstrated adverse effects when they are deciding whether or not to undertake screening for prostate cancer. Any reduction in prostate cancer-specific mortality may take up to 10 years to accrue; therefore, men who have a life expectancy less than 10 to 15 years should be informed that screening for prostate cancer is unlikely to be beneficial. No studies examined the independent role of screening by DRE.

Tsili AC, Argyropoulou MI, Astrakas LG, et al.
Dynamic contrast-enhanced subtraction MRI for characterizing intratesticular mass lesions.
AJR Am J Roentgenol. 2013; 200(3):578-85 [PubMed]

OBJECTIVE: The objective of our study was to analyze the enhancement patterns of various intratesticular mass lesions at dynamic contrast-enhanced subtraction MRI and assess the value of the technique in distinguishing between benign and malignant lesions.
MATERIALS AND METHODS: We retrospectively evaluated the records and images of 44 consecutive men (11 benign and 16 malignant intratesticular lesions) who presented to the department of urology with a variety of clinical symptoms and were referred for imaging. Dynamic contrast-enhanced subtraction MRI was performed using a 3D fast-field echo sequence after the administration of paramagnetic contrast medium. Patients were divided into three groups according to the final diagnosis: benign intratesticular lesions, malignant intratesticular lesions, and normal testes. The patterns of contrast enhancement of both the normal testes and the intratesticular lesions were evaluated. Time-signal intensity plots were created and classified according to shape: Type I presented a linear increase of contrast enhancement throughout the examination, type II showed an initial upstroke followed by either a plateau or a gradual increase in the late contrast-enhanced phase, and type III presented an initial upstroke followed by gradual washout of the contrast medium. The relative percentages of peak height, maximum time, and mean slope were also calculated.
RESULTS: Normal testes enhanced homogeneously with a type I curve. Most benign intratesticular lesions showed inhomogeneous or homogeneous contrast enhancement and a type II curve. Testicular carcinomas showed heterogeneous contrast enhancement with a type III curve. The relative percentages of maximum time to peak proved the most important discriminating factor in differentiating malignant from benign intratesticular masses (p < 0.001).
CONCLUSION: Dynamic contrast-enhanced MRI may be used to distinguish between benign and malignant intratesticular mass lesions.

Wang ZA, Mitrofanova A, Bergren SK, et al.
Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity.
Nat Cell Biol. 2013; 15(3):274-83 [PubMed]

A key issue in cancer biology is whether oncogenic transformation of different cell types of origin within an adult tissue gives rise to distinct tumour subtypes that differ in their prognosis and/or treatment response. We now show that initiation of prostate tumours in basal or luminal epithelial cells in mouse models results in tumours with distinct molecular signatures that are predictive of human patient outcomes. Furthermore, our analysis of untransformed basal cells reveals an unexpected assay dependence of their stem cell properties in sphere formation and transplantation assays versus genetic lineage tracing during prostate regeneration and adult tissue homeostasis. Although oncogenic transformation of basal cells gives rise to tumours with luminal phenotypes, cross-species bioinformatic analyses indicate that tumours of luminal origin are more aggressive than tumours of basal origin, and identify a molecular signature associated with patient outcome. Our results reveal the inherent plasticity of basal cells, and support a model in which different cells of origin generate distinct molecular subtypes of prostate cancer.

Patel R, Gao M, Ahmad I, et al.
Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression.
J Clin Invest. 2013; 123(3):1157-75 [PubMed] Free Access to Full Article

Concurrent activation of RAS/ERK and PI3K/AKT pathways is implicated in prostate cancer progression. The negative regulators of these pathways, including sprouty2 (SPRY2), protein phosphatase 2A (PP2A), and phosphatase and tensin homolog (PTEN), are commonly inactivated in prostate cancer. The molecular basis of cooperation between these genetic alterations is unknown. Here, we show that SPRY2 deficiency alone triggers activation of AKT and ERK, but this is insufficient to drive tumorigenesis. In addition to AKT and ERK activation, SPRY2 loss also activates a PP2A-dependent tumor suppressor checkpoint. Mechanistically, the PP2A-mediated growth arrest depends on GSK3β and is ultimately mediated by nuclear PTEN. In murine prostate cancer models, Pten haploinsufficiency synergized with Spry2 deficiency to drive tumorigenesis, including metastasis. Together, these results show that loss of Pten cooperates with Spry2 deficiency by bypassing a novel tumor suppressor checkpoint. Furthermore, loss of SPRY2 expression correlates strongly with loss of PTEN and/or PP2A subunits in human prostate cancer. This underlines the cooperation between SPRY2 deficiency and PTEN or PP2A inactivation in promoting tumorigenesis. Overall, we propose SPRY2, PTEN, and PP2A status as an important determinant of prostate cancer progression. Characterization of this trio may facilitate patient stratification for targeted therapies and chemopreventive interventions.