Screening for Prostate Cancer
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Raised levels of prostate-specific antigen (PSA) are a common symptom of prostate cancer, however, it can be caused by other conditions too. Routinely screening of all men to check their levels of PSA is a controversial subject across the international medical community, healthcare providers and advocacy groups. This is because there are many risks (including invasive tests, 'false positives', unnecessary treatment and side effects) as well as potential benefits (earlier detection of disease when it is still curable), and the PSA test does not differentiate between slow growing tumours which may never need treatment and more aggressive prostate cancer. Research into better tests is needed.

Current policies vary between different countries. Some advocates recommend all men over 50 have an annual PSA test, many countries recommend against regular mass screening, but increasingly UK and recent US recommendations are for PSA testing to be a individual's decision to make an informed choice. It is complex and best discussed with your doctor.

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Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications
Prostate Cancer
Cancer Screening and Early Detection

Information Patients and the Public (12 links)

Information for Health Professionals / Researchers (4 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Cakmakkaya OS, Kolodzie K, Apfel CC, Pace NL
Anaesthetic techniques for risk of malignant tumour recurrence.
Cochrane Database Syst Rev. 2014; 11:CD008877 [PubMed] Related Publications
BACKGROUND: Surgery remains a mainstay of treatment for malignant tumours; however, surgical manipulation leads to a significant systemic release of tumour cells. Whether these cells lead to metastases is largely dependent on the balance between aggressiveness of the tumour cells and resilience of the body. Surgical stress per se, anaesthetic agents and administration of opioid analgesics perioperatively can compromise immune function and might shift the balance towards progression of minimal residual disease. Regional anaesthesia techniques provide perioperative pain relief; they therefore reduce the quantity of systemic opioids and of anaesthetic agents used. Additionally, regional anaesthesia techniques are known to prevent or attenuate the surgical stress response. In recent years, the potential benefit of regional anaesthesia techniques for tumour recurrence has received major attention and has been discussed many times in the literature. In preparing this review, we aimed to summarize the current evidence systematically and comprehensively.
OBJECTIVES: To establish whether anaesthetic technique (general anaesthesia versus regional anaesthesia or a combination of the two techniques) influences the long-term prognosis for individuals with malignant tumours.
SEARCH METHODS: We searched The Cochrane Library (2013, Issue 12), PubMed (1950 to 15 December 2013), EMBASE (1974 to 15 December 2013), BIOSIS (1926 to 15 December 2013) and Web of Science (1965 to 15 December 2013). We handsearched relevant websites and conference proceedings and reference lists of cited articles. We applied no language restrictions.
SELECTION CRITERIA: We included all randomized controlled trials or controlled clinical trials that investigated the effects of general versus regional anaesthesia on the risk of malignant tumour recurrence in patients undergoing resection of primary malignant tumours. Comparisons of interventions consisted of (1) general anaesthesia alone versus general anaesthesia combined with one or more regional anaesthetic techniques; (2) general anaesthesia combined with one or more regional anaesthetic techniques versus one or more regional anaesthetic techniques; and (3) general anaesthesia alone versus one or more regional anaesthetic techniques. Primary outcomes included (1) overall survival, (2) progression-free survival and (3) time to tumour progression.
DATA COLLECTION AND ANALYSIS: Two review authors independently scanned the titles and abstracts of identified reports and extracted study data.All primary outcome variables are time-to-event data. If the individual trial report provided summary statistics with odds ratios, relative risks or Kaplan-Meier curves, extracted data enabled us to calculate the hazard ratio using the hazard ratio calculating spreadsheet. To assess risk of bias, we used the standard methodological procedures expected by The Cochrane Collaboration.
MAIN RESULTS: We included four studies with a total of 746 participants. All studies included adult patients undergoing surgery for primary tumour resection. Two studies enrolled male and female participants undergoing major abdominal surgery for cancer. One study enrolled male participants undergoing surgery for prostate cancer, and one study male participants undergoing surgery for colon cancer. Follow-up time ranged from nine to 17 years. All four studies compared general anaesthesia alone versus general anaesthesia combined with epidural anaesthesia and analgesia. All four studies are secondary data analyses of previously conducted prospective randomized controlled trials.Of the four included studies, only three contributed to the outcome of overall survival, and two each to the outcomes of progression-free survival and time to tumour progression. In our meta-analysis, we could not find an advantage for either study group for the outcomes of overall survival (hazard ratio (HR) 1.03, 95% confidence interval (CI) 0.86 to 1.24) and progression-free survival (HR 0.88, 95% CI 0.56 to 1.38). For progression-free survival, the level of inconsistency was high. Pooled data for time to tumour progression showed a slightly favourable outcome for the control group (general anaesthesia alone) compared with the intervention group (epidural and general anaesthesia) (HR 1.50, 95% CI 1.00 to 2.25).Quality of evidence was graded low for overall survival and very low for progression-free survival and time to tumour progression. The outcome of overall survival was downgraded for serious imprecision and serious indirectness. The outcomes of progression-free survival and time to tumour progression were also downgraded for serious inconsistency and serious risk of bias, respectively.Reporting of adverse events was sparse, and data could not be analysed.
AUTHORS' CONCLUSIONS: Currently, evidence for the benefit of regional anaesthesia techniques on tumour recurrence is inadequate. An encouraging number of prospective randomized controlled trials are ongoing, and it is hoped that their results, when reported, will add evidence for this topic in the near future.

Kitagawa Y, Sawada K, Urata S, et al.
Impact of PSA levels on second-round screening for the development of prostate cancer in men with low baseline PSA levels (≤2.0 mg/ml).
Anticancer Res. 2014; 34(11):6739-46 [PubMed] Related Publications
BACKGROUND: To investigate the cumulative probability of developing prostate cancer according to prostate-specific antigen (PSA) velocity (PSAV) from first-to second-round PSA-based population screening in men with low baseline serum PSA levels.
PATIENTS AND METHODS: A total of 11,913 men aged between 54 and 69 years with baseline PSA levels of ≤2.0 ng/ml at the first population screening and who underwent population screening at least twice, were enrolled. The cumulative probability of developing prostate cancer according to age, baseline PSA and PSAV was investigated. The clinicopathological features of screen-detected cancer were also investigated.
RESULTS: Out of the 11,913 men, 110 (0.92%) were pathologically diagnosed with prostate cancer during the observation period. The cumulative probability of developing prostate cancer in all participants after 5 and 10 years was 0.64% and 1.79%, respectively. Univariate and multivariate analyses determined that baseline PSA levels and PSAVs were significant predictors of developing cancer and the hazard ratio increased with increasing baseline PSA levels and PSAVs. The optimal PSAV cut-off levels for prostate cancer development were 0.069, 0.106 and 0.285 for the baseline PSA ranges of 0.0-1.0, 1.1-1.5 and 1.6-2.0 ng/ml, respectively. There were no significant differences in baseline PSA levels and PSAVs according to the clinical characteristics of the screen-detected prostate cancer patients.
CONCLUSION: The present study demonstrated that serum PSA levels at second round screening were a strong predictor of cancer development in men with baseline PSA levels≤2.0 ng/ml at the first population screening.

Related: Cancer Screening and Early Detection

Okegawa T, Itaya N, Hara H, et al.
Circulating tumor cells as a biomarker predictive of sensitivity to docetaxel chemotherapy in patients with castration-resistant prostate cancer.
Anticancer Res. 2014; 34(11):6705-10 [PubMed] Related Publications
AIM: We examined whether Circulating Tumor Cells (CTCs) can be used to predict survival in patients with bone-metastatic castration-resistant-prostate cancer (mCRPC) treated with docetaxel chemotherapy.
PATIENTS AND METHODS: All patients with mCRPC who had experienced treatment failure with androgen deprivation therapy and had received docetaxel chemotherapy were eligible for study inclusion. CTCs in whole blood were enumerated with the CellSearch System.
RESULTS: The median CTC count at baseline before starting trial treatment was 7 (range=0-227) CTCs per 7.5 ml blood. Out of the 57 patients, 24 (42.1%) had a CTC count of less than 5, while 27 patients (47.4%) had a CTC count of 5-50 and six patients (10.5%) had a CTC count of more than 50. A threshold of 5 or more CTCs per 7.5 ml blood was used to assess the ability to predict survival. The patient charts were examined to determine the median overall survival time, which ranged from 6 to 37 months (mean=12.8±8.1 months, median=15.3 months). Thirty-three patients (57.9%) had 5 or more CTCs before docetaxel chemotherapy, with a median overall survival of 10.5 months compared to 25.0 months for 24 patients (42.1%) with fewer than 5 CTCs (p<0.001). CTC and alkaline phosphatase (ALP) were independent predictors of overall survival time (p=0.004, and p=0.023, respectively). In addition, poorer overall survival was predicted by a CTC count of 5 or more after three courses of docetaxel chemotherapy.
CONCLUSION: The CTC count may be an independent predictor of overall survival in patients with mCRPC treated with docetaxel chemotherapy. The numbers of CTCs detected was important in assessing response to chemotherapy and predict disease outcome.

Related: Docetaxel

Song G, Hsiao H, Wang JL, et al.
Differential impact of tumor-infiltrating immune cells on basal and luminal cells: implications for tumor invasion and metastasis.
Anticancer Res. 2014; 34(11):6363-80 [PubMed] Related Publications
BACKGROUND/AIM: Regarding the impact of tumor-infiltrating immune cells on tumor cells, many contradictory reports have been published. We have hypothesized that these controversies result from differences in tissue types and tumor stages, in which immune cells are variably distributed and differentially associated with epithelial cells. Our current study compared the pattern and frequency of physical association of tumor-infiltrating immune cells with different parenchymal cells of human breast and prostate tumors harboring normal, hyperplastic, in situ, and invasive components.
MATERIALS AND METHODS: The cytological, biological, and molecular alterations were assessed with double immunohistochemistry, double fluorescent labeling, apoptosis assay, and gene expression profiling.
RESULTS: Our study detected several previously undescribed features: (i) over 95% of infiltrating immune cells were seen within normal, hyperplastic, or in situ cancer structures with focally-disrupted capsules, and fewer than 5% were found within invasive cancer; (ii) over 95% of normal, hyperplastic, and in situ cancerous epithelial cells were physically shielded from immune cells by the surrounding myoepithelial or basal cell layer; (iii) about 90% of myoepithelial or basal cells physically associated with immune cells and such residual cells within focally disrupted layers exhibited distinct degeneration, including apoptosis, necrosis, and reduced expression of tumor suppressor p63; (iv) epithelial cells overlying focally disrupted tumor capsules surrounded by immune cells had substantially higher proliferation than their adjacent counterparts, and some of the proliferating cells were arranged as tongue-like projections invading the stroma; and (v) microdissected cells overlying focally disrupted tumor capsules had more than 5-fold higher expression of stem cell lineage markers KIT and NCOR2.
CONCLUSION: Tumor-infiltrating immune cells are primarily associated with degenerated myoepithelial or basal cells causing focal disruptions of the capsule, which selectively favor proliferation, invasion, and dissemination of the overlying tumor stem cells.

Related: Apoptosis Breast Cancer Basal Cell Carcinoma

McKeown BT, Hurta RA
Magnolol affects expression of IGF-1 and associated binding proteins in human prostate cancer cells in vitro.
Anticancer Res. 2014; 34(11):6333-8 [PubMed] Related Publications
BACKGROUND/AIM: This study investigated the effects of magnolol, a compound from Magnolia officinalis, on the behavior of LNCaP and PC3 human prostate cancer cells in vitro.
MATERIALS AND METHODS: In vitro cell culture approach with biochemical tests and Western blot analyses was used.
RESULTS: Magnolol, (80 μM, 6 hour exposure) was found to affect the expression of insulin-like growth factor-1 (IGF-1) and associated proteins. In both cell lines, protein expression of IGF-1 and insulin-like growth factor binding protein-5 (IGFBP-5) were significantly decreased, while protein expression of IGFBP-3 was significantly increased. Additionally, protein expression of insulin-like growth factor-1 receptor (IGF-1R) was significantly increased and the phosphorylated form of IGF-1 (p-IGF-1R) was significantly decreased in PC3 cells, while IGFBP-4 protein expression was significantly increased in LNCaP cells.
CONCLUSION: This study has demonstrated for the first time that magnolol can alter the expression of IGF-1 and associated proteins in human prostate cancer cells in vitro and suggests that magnolol may have a potential role as a novel anti-prostate cancer agent.

Related: IGF1 IGF1R

Giacinti S, Bassanelli M, Aschelter AM, et al.
Resistance to abiraterone in castration-resistant prostate cancer: a review of the literature.
Anticancer Res. 2014; 34(11):6265-9 [PubMed] Related Publications
Persistent androgen signaling is functionally significant in castration-resistant prostate cancer (CRPC) and it is actually considered a validated therapeutic target. Residual intra-tumoral androgens compensate for the effects of androgen ablation, activating the androgen receptor (AR), AR-mediated gene expression and driving CRPC. The intra-tumoral biosynthesis of androgens takes place in different ways and cytochrome P450 17A1 (CYP17A1) has a crucial role in this context. Abiraterone, a CYP17A1 inhibitor, has shown impressive results in pre- and post-chemotherapy settings, prolonging the survival of patients with CRPC. However, not all patients respond to the treatment and most responders develop resistance, with a widely variable duration of response. Although many hypotheses are emerging, the mechanisms of resistance to abiraterone treatment have not yet been elucidated. The aim of the present review is to describe the main data currently available on resistance to abiraterone.

Chile SA, Ray KB, Shaikh S, et al.
Evaluation of target mRNA cleavage by aurorakinase B specific siRNA in prostate and hepatic cancer cells and its therapeutic potential in mouse models of liver cancer.
Indian J Exp Biol. 2014; 52(10):943-51 [PubMed] Related Publications
The anti proliferative potential of siRNA26, targeted to Aurora kinase B, in prostate cancer cells is known from a previous study from our laboratory. Here we first show that siRNA26 cleaves at the same position of the target mRNA in the prostate cancer and hepatocellular carcinoma cell lines, PC3 and HepG2 respectively. Aurorakinase B specific siRNA, but not a control siRNA, inhibited PC3 and HepG2 cell proliferation and cell migration. These effects correlated to RNA silencing of Aurorakinase B in both the cell lines. Intra-tumoral administration of HiPerfect complexed siRNA26 inhibited the growth of HepG2 xenografts in SCID mice. In an orthotopic setting, intravenous administration of HiPerfect encapsulated siRNA26 appeared to reduce the severity of multifocal lesions.

Duffy MJ
PSA in screening for prostate cancer: more good than harm or more harm than good?
Adv Clin Chem. 2014; 66:1-23 [PubMed] Related Publications
The aim of screening for prostate cancer is to detect malignancy at an early and potentially treatable stage, thereby increasing the chance of cure. Although serum PSA has been used as a screening test for prostate cancer for over 20 years, the practice is controversial. As a screening test for prostate cancer, PSA lacks sensitivity and specificity for early disease. Furthermore, screening may lead to unnecessary biopsies, overdetection, and overtreatment. It is thus unclear whether the benefits of screening outweigh the harms. Although published guidelines differ in their recommendation for PSA screening, almost all state that prior to PSA testing, men should be informed of the risks and benefits of the process. Most guidelines also state that men with a life expectancy of less than 10 years should not be screened. New markers currently undergoing evaluation such as -2proPSA, Prostate Health Index, and PCA3 may complement PSA in the detection of early prostate cancer.

Related: Cancer Screening and Early Detection

Akin M, Öksüz DC, Iktueren B, et al.
Does rectum and bladder dose vary during the course of image-guided radiotherapy in the postprostatectomy setting?
Tumori. 2014 Sep-Oct; 100(5):529-35 [PubMed] Related Publications
AIMS AND BACKGROUND: To assess the variations in actual doses delivered to the rectum and bladder in the course of postprostatectomy radiotherapy using kilovoltage-cone-beam computed tomography datasets acquired during image-guided radiotherapy.
METHODS AND STUDY DESIGN: Twenty consecutive patients treated with intensity-modulated or intensity-modulated arc therapy to the prostate bed were retrospectively evaluated. Both the planning tomography and kilovoltage-cone-beam computed tomography were acquired with an empty rectum and a half-full bladder. Target localization was performed on the basis of soft tissue matching using cone-beam computed tomography scans before each treatment fraction. A total of 16 cone-beam computed tomography scans per patient (acquired at the first 5 fractions and twice weekly thereafter) were used for the assessments. The bladder and rectum were re-contoured offline on each cone-beam computed tomography scan by a single physician, and the delivered doses were recalculated. The variations in certain dose-volume parameters for the rectum and bladder (BD2cc, RD 2cc, V40%, V50%, V60%, V65%) were analyzed using the paired t test.
RESULTS: Most of the dose volume variations for rectum and bladder were significantly higher than predicted (P <0.05) for the 320 kilovoltage-cone-beam computed tomography sets, except for the doses received by 2 cc of the bladder and V50 and V60 of the rectum. The dose-volume parameters of the bladder did not meet our criteria of V65 ≤25% and V40 ≤50% in 10% and 20% of the patients, respectively. None of the dose-volume histograms showed rectal V65 ≥17%; however, the rectal V40 ≤35% dose constraint was not met in 11 patients. For all patients, the ANOVA test revealed no significant difference between the variations.
CONCLUSION: Actual doses delivered during treatment were found to be higher than predicted, but the majority of calculated bladder and rectal doses remained in the limits of our plan acceptance criteria. Interfraction variability of the rectum and bladder is a major concern in the postprostatectomy radiotherapy setting, even when patients are instructed about rectal and bladder preparation before the radiotherapy course. Image guidance with cone-beam computed tomography at each treatment fraction may offer a viable tool to account for interfraction variations of the rectum and bladder throughout the treatment course.

Chen J, Yan WG, Li HZ, et al.
Long-term outcome of high-risk prostate cancer treated with brachytherapy combined with external-beam radiation therapy and androgen deprivation therapy.
Tumori. 2014 Sep-Oct; 100(5):524-8 [PubMed] Related Publications
AIMS AND BACKGROUND: To evaluate long-term outcome and biochemical progression-free survival (bPFS) in high-risk prostate cancer patients treated with brachytherapy combined with external-beam radiation therapy (EBRT) and androgen deprivation therapy (ADT).
METHODS AND STUDY DESIGN: We retrospectively analyzed 97 high-risk prostate cancer patients treated with brachytherapy combined with EBRT and ADT. During follow-up, the post-operation prostate-specific antigen (PSA) level was monitored regularly and biochemical relapse, progression to castration-resistant prostate cancer or metastases, and causes of death were documented. We evaluated bPFS, cause-specific survival (CSS) and overall survival (OS).
RESULTS: The bPFS, CSS and OS of the patients were 81.4%, 88.7% and 81.4%, respectively. The bPFS of the subcategories of patients stratified based on the presence or absence of a Gleason pattern 5 were 55.6% and 87.7%, respectively.
CONCLUSION: Brachytherapy combined with EBRT and ADT can effectively control PSA level and delay biochemical relapse in localized high-risk prostate cancer. However, patients presenting with a Gleason pattern 5 should be managed with further treatment intensification.

Related: Brachytherapy

Vanasek J, Odrazka K, Dolezel M, et al.
Searching for an appropriate image-guided radiotherapy method in prostate cancer--implications for safety margin.
Tumori. 2014 Sep-Oct; 100(5):518-23 [PubMed] Related Publications
AIMS AND BACKGROUND: The aim of the study was to compare the safety margin width using skin marks, pelvic skeleton-based targeting and adaptive protocol combining cone-beam computed tomography and kilovoltage image matching.
METHODS: A total of 434 consecutive patients were treated by image-guided radiotherapy from November 2008 to April 2012. An adaptive protocol combining cone-beam computed tomography and kilovoltage image matching with individualized safety margin calculation according to the Van Herk method was used in a total of 201 patients. The remaining 233 patients had their setup corrected using cone-beam computed tomography daily.
RESULTS: Analysis of the 3,137 cone-beam computed tomography images (201 patients) revealed that the margins between the clinical target volume and planning target volume with skin marks registration should be 1.24 cm in the anteroposterior, 0.98 cm in the craniocaudal, and 1.03 cm in the laterolateral direction. Considering pelvic skeleton-based setup, values of the clinical target volume and planning target volume margins in the anteroposterior, craniocaudal and laterolateral axis were 0.79 cm, 0.41 cm, and 0.19 cm, respectively. In a group of 8,872 cone-beam computed tomography images (233 patients) using CBCT assessment, the calculated margins between clinical target volume and planning target volume with skin marks were 1.15 cm in anteroposterior, 1.06 in craniocaudal, and 1.19 in laterolateral directions. Considering the pelvic skeleton-based setup, the corresponding values were 0.74 cm, 0.51 cm, and 0.25 cm. With the adaptive technique, the margins of most patients in the anteroposterior, craniocaudal, and laterolateral axes were 6 mm, 6 mm, and 6 mm or 8 mm, 6 mm, and 6 mm, respectively.
CONCLUSIONS: The adaptive protocol combining cone-beam computed tomography and kilovoltage image matching or daily cone-beam computed tomography allowed us to substantially reduce the safety margins compared with skin marks targeting.

Dell'Atti L
Correlation between prolonged use of aspirin and prognostic risk in prostate cancer.
Tumori. 2014 Sep-Oct; 100(5):486-90 [PubMed] Related Publications
AIMS AND BACKGROUND: In recent years the role of inflammation in cancer etiology has gained attention and several studies have suggested that acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs may have chemopreventive activity and reduce the risk of prostate cancer. We investigated whether there is a correlation between prolonged use of aspirin and prognostic risk in prostate cancer.
METHODS AND STUDY DESIGN: From January 2002 to December 2007 we performed 385 radical prostatectomies for localized prostate cancer. Patients were divided into 2 groups: group A (GA) comprised 174 patients who took aspirin 100 mg once daily for 2 years or more; group B (GB) consisted of 211 patients who did not take NSAIDs, or only occasionally. To evaluate the correlation between aspirin use and prognostic risk in prostate cancer we examined the following factors: biochemical recurrence, percentage of positive surgical margins, pathological stage, pathological Gleason score, percentage of positive lymph nodes, and preoperative PSA level.
RESULTS: There was no statistical difference in preoperative PSA levels (6.5 and 6.9 ng/mL; P = 0.045) between the 2 groups. The incidence of positive surgical margins was 18.9% in GA and 28.9% in GB (P <0.002). The percentage of positive lymph nodes in patients with positive surgical margins in GB (47.5%) was statistically higher than that in GA (27.2%). With an average follow-up period of 4.6 years, 22.7% of patients in GA and 32.7% in GB developed biochemical recurrence. In the stratified analysis we observed significant differences in the association between prediagnostic aspirin use and prognostic risk for patients with Gleason score 7 and T2 stage of disease. The daily use of aspirin was significantly associated with a lower risk of disease progression, with a hazard ratio of 0.92 (95% CI 0.85-0.99).
CONCLUSIONS: These results provide further evidence that aspirin may have chemopreventive activity against prostate cancer and highlight the need for additional research. Additional studies with more detailed exposure measurement are warranted to evaluate questions about dose, the best age to begin treatment, and the duration of therapy.

Al-Rikabi AC, Alkhalidi H
Interobserver variations in reporting of prostatic adenocarcinoma using core biopsy specimens: a retrospective study from a tertiary referral hospital in Saudi Arabia.
East Mediterr Health J. 2014; 20(9):578-81 [PubMed] Related Publications
In recent years, greater numbers of prostate biopsy cores are being submitted for histopathological assessment, with a concomitant increase in workload for the pathologist. This retrospective study aimed to assess the concordance and interobserver variation between histopathologists in reporting prostatic adenocarcinoma using material obtained from prostatic core biopsy specimens. A total of 810 prostatic needle core biopsy specimens obtained from 100 patients with suspected prostatic adenocarcinoma were retrieved from the archival material at King Khalid University Hospital, Riyadh, and classified independently by 3 experienced histopathologists who were blinded to the original diagnosis. There was considerable interobserver agreement between the pathologists, with unweighted kappa scores ranging from 0.69-0.85. We would encourage other hospital pathologists to review periodically the uniformity of diagnoses in an attempt to improve their practices in prostate gland pathology.

Chun YJ
Knockdown of clusterin expression increases the in vitro sensitivity of human prostate cancer cells to paclitaxel.
J Toxicol Environ Health A. 2014; 77(22-24):1443-50 [PubMed] Related Publications
Clusterin/apolipoprotein J is a secreted heterodimeric glycoprotein that is implicated in several pathophysiological processes, including tissue remodeling, reproduction, lipid transport, and apoptosis. Although previous studies demonstrated that clusterin is able to protect against apoptosis, the role of the clusterin in cellular proliferation remains elusive. To determine whether clusterin plays an important role in cellular proliferation, the function of clusterin was examined using a small interfering RNA (siRNA) in PC3 human prostate cancer cells. Transient transfection with clusterin siRNA resulted in significant suppression of clusterin mRNA and protein expression. Clusterin knockdown resulted in a decrease in protein expression of phospho-Akt and an increase in expression of proteins phosphatase type 2AC (PP2AC) and phosphorylation of p38. However, treatment with PP2AC siRNA exerted minimal effects on clusterin expression. Interestingly, clusterin mRNA expression was reduced in paclitaxel-treated cells, and the cytotoxic effect of paclitaxel was more potent when cells were incubated with clusterin siRNA. In addition, co-treatment with paclitaxel and clusterin siRNA significantly enhanced PP2AC levels. Taken together, these results indicate that clusterin plays a crucial role in PC3 cell proliferation and that clusterin depletion may contribute to enhanced sensitivity of PC3 cells to anticancer agents such as paclitaxel.

Related: Apoptosis CLU Paclitaxel

Chu G, Lo P, Ramakrishna B, et al.
Bone tumor segmentation on bone scans using context information and random forests.
Med Image Comput Comput Assist Interv. 2014; 17(Pt 1):601-8 [PubMed] Related Publications
Bone tumor segmentation on bone scans has recently been adopted as a basis for objective tumor assessment in several phase II and III clinical drug trials. Interpretation can be difficult due to the highly sensitive but non-specific nature of bone tumor appearance on bone scans. In this paper we present a machine learning approach to segmenting tumors on bone scans, using intensity and context features aimed at addressing areas prone to false positives. We computed the context features using landmark points, identified by a modified active shape model. We trained a random forest classifier on 100 and evaluated on 73 prostate cancer subjects from a multi-center clinical trial. A reference segmentation was provided by a board certified radiologist. We evaluated our learning based method using the Jaccard index and compared against the state of the art, rule based method. Results showed an improvement from 0.50 +/- 0.31 to 0.57 +/- 0.27. We found that the context features played a significant role in the random forest classifier, helping to correctly classify regions prone to false positives.

Scott R, Khan FM, Zeineh J, et al.
Gland ring morphometry for prostate cancer prognosis in multispectral immunofluorescence images.
Med Image Comput Comput Assist Interv. 2014; 17(Pt 1):585-92 [PubMed] Related Publications
Morphometric features characterizing the fusion and fragmentation of the glandular architecture of advanced prostate cancer have not previously been based upon the automated segmentation of discrete gland rings, due in part to the difficulty of extracting these structures from the H&E stained tissues. We present a novel approach for segmenting gland rings in multi-spectral immunofluorescence (IF) images and demonstrate the utility of the resultant features in predicting cancer recurrence in a cohort of 1956 images of prostate biopsies and prostatectomies from 679 patients. The proposed approach is evaluated for prediction of actual clinical outcomes of interest to physicians in comparison with previously published gland-unit features, yielding a concordance index (CI) of 0.67. This compares favorably to the CI of 0.66 obtained using a semi-automated segmentation of the corresponding H&E images from the same patients. This work presents the first algorithms for segmentation of gland rings lacking a central lumen, and for separation of touching epithelial units, and introduces new gland adjacency features for predicting prostate cancer clinical progression across both biopsy and prostatectomy images.

Mohareri O, Ruszkowski A, Lobo J, et al.
Multi-parametric 3D quantitative ultrasound vibro-elastography imaging for detecting palpable prostate tumors.
Med Image Comput Comput Assist Interv. 2014; 17(Pt 1):561-8 [PubMed] Related Publications
In this article, we describe a system for detecting dominant prostate tumors, based on a combination of features extracted from a novel multi-parametric quantitative ultrasound elastography technique. The performance of the system was validated on a data-set acquired from n = 10 patients undergoing radical prostatectomy. Multi-frequency steady-state mechanical excitations were applied to each patient's prostate through the perineum and prostate tissue displacements were captured by a transrectal ultrasound system. 3D volumetric data including absolute value of tissue elasticity, strain and frequency-response were computed for each patient. Based on the combination of all extracted features, a random forest classification algorithm was used to separate cancerous regions from normal tissue, and to compute a measure of cancer probability. Registered whole mount histopathology images of the excised prostate gland were used as a ground truth of cancer distribution for classifier training. An area under receiver operating characteristic curve of 0.82 +/- 0.01 was achieved in a leave-one-patient-out cross validation. Our results show the potential of multi-parametric quantitative elastography for prostate cancer detection for the first time in a clinical setting, and justify further studies to establish whether the approach can have clinical use.

Wang H, Singanamalli A, Ginsburg S, Madabhushi A
Selecting features with group-sparse nonnegative supervised canonical correlation analysis: multimodal prostate cancer prognosis.
Med Image Comput Comput Assist Interv. 2014; 17(Pt 3):385-92 [PubMed] Related Publications
This paper presents Group-sparse Nonnegative supervised Canonical Correlation Analysis (GNCCA), a novel methodology for identifying discriminative features from multiple feature views. Existing correlation-based methods do not guarantee positive correlations of the selected features and often need a pre-feature selection step to reduce redundant features on each feature view. The new GNCCA approach attempts to overcome these issues by incorporating (1) a nonnegativity constraint that guarantees positive correlations in the reduced representation and (2) a group-sparsity constraint that allows for simultaneous between- and within- view feature selection. In particular, GNCCA is designed to emphasize correlations between feature views and class labels such that the selected features guarantee better class separability. In this work, GNCCA was evaluated on three prostate cancer (CaP) prognosis tasks: (i) identifying 40 CaP patients with and without 5-year biochemical recurrence following radical prostatectomy by fusing quantitative features extracted from digitized pathology and proteomics, (ii) predicting in vivo prostate cancer grade for 16 CaP patients by fusing T2w and DCE MRI, and (iii) localizing CaP/benign regions on MR spectroscopy and MRI for 36 patients. For the three tasks, GNCCA identifies a feature subset comprising 2%, 1% and 22%, respectively, of the original extracted features. These selected features achieve improved or comparable results compared to using all features with the same Support Vector Machine (SVM) classifier. In addition, GNCCA consistently outperforms 5 state-of-the-art feature selection methods across all three datasets.

Safi R, Nelson ER, Chitneni SK, et al.
Copper signaling axis as a target for prostate cancer therapeutics.
Cancer Res. 2014; 74(20):5819-31 [PubMed] Article available free on PMC after 15/10/2015 Related Publications
Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies.

Related: Apoptosis Signal Transduction

Gandaglia G, Trinh QD
Models of assessment of comparative outcomes of robot-assisted surgery: best evidence regarding the superiority or inferiority of robot-assisted radical prostatectomy.
Urol Clin North Am. 2014; 41(4):597-606 [PubMed] Related Publications
The widespread dissemination of robot-assisted radical prostatectomy (RARP) occurred despite the absence of high-level evidence supporting its safety and efficacy in patients with clinically localized prostate cancer. This study aims at systematically evaluating the models adopted in scientific reports assessing the comparative effectiveness of RARP versus open radical prostatectomy (ORP). Although several retrospective observational studies have assessed the comparative effectiveness of RARP and ORP, currently no published randomized data are available to comprehensively evaluate this issue. Furthermore, well-designed prospective investigations are needed to ultimately assess the benefits of RARP compared with other treatment modalities in patients with clinically localized prostate cancer.

Eifler JB, Cookson MS
Best evidence regarding the superiority or inferiority of robot-assisted radical prostatectomy.
Urol Clin North Am. 2014; 41(4):493-502 [PubMed] Related Publications
Robotic-assisted laparoscopic radical prostatectomy (RALP) has enjoyed rapid adoption over the past decade without rigorous clinical studies demonstrating superior clinical outcomes over radical retropubic prostatectomy (RRP). This article reviews the literature comparing RALP and RRP with regard to oncologic, perioperative, and functional outcomes, summarizing evidence for and against the superiority of RALP.

Sood A, Jeong W, Peabody JO, et al.
Robot-assisted radical prostatectomy: inching toward gold standard.
Urol Clin North Am. 2014; 41(4):473-84 [PubMed] Related Publications
Robot-assisted radical prostatectomy (RARP) offers excellent and lasting oncologic control. Technical refinements in apical dissection, such as the retroapical approach of synchronous urethral transection, and adoption of real-time frozen section analysis of the excised prostate during RARP have substantially reduced positive surgical margin rates, particularly in high-risk disease patients. Furthermore, precision offered by the robotic platform and technical evolution of radical prostatectomy, including enhanced nerve sparing (veil), have led to improved potency and continence outcomes as well as better safety profile in patients undergoing surgical therapy for prostate cancer.

Related: Watchful Waiting - Prostate Cancer

Hathout L, Folkert MR, Kollmeier MA, et al.
Dose to the bladder neck is the most important predictor for acute and late toxicity after low-dose-rate prostate brachytherapy: implications for establishing new dose constraints for treatment planning.
Int J Radiat Oncol Biol Phys. 2014; 90(2):312-9 [PubMed] Related Publications
PURPOSE: To identify an anatomic structure predictive for acute (AUT) and late (LUT) urinary toxicity in patients with prostate cancer treated with low-dose-rate brachytherapy (LDR) with or without external beam radiation therapy (EBRT).
METHODS AND MATERIALS: From July 2002 to January 2013, 927 patients with prostate cancer (median age, 66 years) underwent LDR brachytherapy with Iodine 125 (n=753) or Palladium 103 (n=174) as definitive treatment (n=478) and as a boost (n=449) followed by supplemental EBRT (median dose, 50.4 Gy). Structures contoured on the computed tomographic (CT) scan on day 0 after implantation included prostate, urethra, bladder, and the bladder neck, defined as 5 mm around the urethra between the catheter balloon and the prostatic urethra. AUT and LUT were assessed with the Common Terminology Criteria for Adverse Events, version4. Clinical and dosimetric factors associated with AUT and LUT were analyzed with Cox regression and receiver operating characteristic analysis to calculate area under the receiver operator curve (ROC) (AUC).
RESULTS: Grade ≥2 AUT and grade ≥2 LUT occurred in 520 patients (56%) and 154 patients (20%), respectively. No grade 4 toxicities were observed. Bladder neck D2cc retained a significant association with AUT (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.03-1.04; P<.0001) and LUT (HR, 1.01; 95% CI, 1.00-1.03; P=.014) on multivariable analysis. In a comparison of bladder neck with the standard dosimetric variables by use of ROC analysis (prostate V100 >90%, D90 >100%, V150 >60%, urethra D20 >130%), bladder neck D2cc >50% was shown to have the strongest prognostic power for AUT (AUC, 0.697; P<.0001) and LUT (AUC, 0.620; P<.001).
CONCLUSIONS: Bladder neck D2cc >50% was the strongest predictor for grade ≥2 AUT and LUT in patients treated with LDR brachytherapy. These data support inclusion of bladder neck constraints into brachytherapy planning to decrease urinary toxicity.

Related: Brachytherapy

Nascimento M, Aguilar-Nascimento JE, Caporossi C, et al.
Efficacy of synbiotics to reduce acute radiation proctitis symptoms and improve quality of life: a randomized, double-blind, placebo-controlled pilot trial.
Int J Radiat Oncol Biol Phys. 2014; 90(2):289-95 [PubMed] Related Publications
PURPOSE: To evaluate whether the daily intake of synbiotics interferes in radiation-induced acute proctitis symptoms and in quality of life in patients with prostate cancer.
METHODS AND MATERIALS: Twenty patients who underwent 3-dimensional conformal radiation therapy for prostate cancer were randomized to intake either a synbiotic powder containing Lactobacillus reuteri 10(8) colony-forming units and 4.3 g of soluble fiber (Nestlé) or placebo. The questionnaire EORTC QLQ-PRT23 was applied before the beginning of radiation therapy and in every week for the first 4 weeks of treatment. The sum of both the complete (proctitis symptoms plus quality of life) and partial (proctitis symptoms) scores of the EORTC QLQ-PRT23 (European Organization for Research and Treatment of Cancer Quality of Life Module for Proctitis-23 items) questionnaire were the main endpoints.
RESULTS: This pilot study showed that the complete questionnaire score (median [range]) was higher in the second (23 [21-30] vs 26.5 [22-34], P<.05) and third (23 [21-32] vs 27.5 [24-33], P<.01) weeks in the placebo group. Proctitis symptoms were highest scored in the placebo group in both the second (19.5 [16-25]) and third (19 [17-24]) weeks than in the synbiotic group (week 2: 16.5 [15-20], P<.05; week 3: 17 [15-23], P<.01). In both scores the placebo group had a significantly higher result (P<.01) than the synbiotic group (repeated-measures analysis of variance).
CONCLUSIONS: Synbiotics reduce proctitis symptoms and improve quality of life in radiation-induced acute proctitis during radiation therapy for prostate cancer.

Mok G, Benz E, Vallee JP, et al.
Optimization of radiation therapy techniques for prostate cancer with prostate-rectum spacers: a systematic review.
Int J Radiat Oncol Biol Phys. 2014; 90(2):278-88 [PubMed] Related Publications
Dose-escalated radiation therapy for localized prostate cancer improves disease control but is also associated with worse rectal toxicity. A spacer placed between the prostate and rectum can be used to displace the anterior rectal wall outside of the high-dose radiation regions and potentially minimize radiation-induced rectal toxicity. This systematic review focuses on the published data regarding the different types of commercially available prostate-rectum spacers. Dosimetric results and preliminary clinical data using prostate-rectum spacers in patients with localized prostate cancer treated by curative radiation therapy are compared and discussed.

Doctor SM, Tsao CK, Godbold JH, et al.
Is prostate cancer changing?: evolving patterns of metastatic castration-resistant prostate cancer.
Cancer. 2014; 120(6):833-9 [PubMed] Related Publications
BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) most commonly metastasizes to the bone, and less commonly to nonosseous sites (eg, lymph nodes, liver, lung). With new therapies extending survival in mCRPC, it was hypothesized that the pattern of metastases is changing over time. The pattern of metastatic disease was evaluated in men with mCRPC, as reported in baseline characteristics of prospective clinical trials over 2 decades.
METHODS: This study identified all phase 2 and 3 therapeutic studies in men with mCRPC in PubMed and American Society of Clinical Oncology abstracts from 1990 to 2012. Studies were excluded if they did not report demographic data and sites of metastasis, or excluded patients with a specific site of metastatic disease (except brain). For each type of metastasis, weighted least squares linear regression models were used to evaluate temporal trends.
RESULTS: A total of 290 eligible studies (270 phase 2 studies and 20 phase 3 studies) involving 19,110 patients were identified. Between 1990 and 2012, the rate of nonosseous metastasis increased significantly at 1.6% per year (P < .0001), whereas the rate of osseous metastasis decreased at 0.5% per year (P < .0001). The rate of lymph node metastasis increased at 1.4% per year (P < .0001), but the rate of liver and lung metastasis remained relatively stable.
CONCLUSIONS: A notable change was found in the pattern of metastasis in patients with mCRPC. Because these evolving patterns may have important implications in treatment selection and prognosis, it is crucial that future clinical trials of patients with mCRPC define patients with a uniform reporting of nonosseous metastasis.

Gwak M, Choi YJ, Yoo NJ, Lee S
Expression of DNA cytosine deaminase APOBEC3 proteins, a potential source for producing mutations, in gastric, colorectal and prostate cancers.
Tumori. 2014 Jul-Aug; 100(4):112e-7e [PubMed] Related Publications
AIMS AND BACKGROUND: APOBEC3B is a deaminase that possesses DNA C-to-T editing activity. A recent report showed that APOBEC3B mRNA was overexpressed in breast cancer and that its expression was responsible for the high C-to-T mutation spectrum in breast cancer, suggesting that APOBEC3B could serve as a source for producing mutations. To see whether APOBEC3B is overexpressed in other common cancers at the protein level, we investigated APOBEC3 protein expression in 100 gastric, 103 colorectal and 107 prostate cancer tissues as well as in 10 breast cancers by immunohistochemistry using antibody that could detect APOBEC3B, APOBEC3F and APOBEC3D proteins.
RESULTS: In the cancers, APOBEC3 expression was detected in 100% of breast cancers, 67% of gastric, 84% of colorectal and 67% of prostate cancer. Also, it was expressed in 100% of normal breast, 90% of normal stomach, 82% of normal colon and 93% of normal prostate tissues. In contrast to earlier data that showed an increased APOBEC3B expression in breast cancer cells compared to normal breast cells, APOBEC3 expression in cancers was lower than in normal tissues (gastric and prostate cancer) or was not different from normal tissues (colorectal and breast cancer). There was no significant association of APOBEC3 expression with clinocopathological parameters, including histology, metastasis and stage.
CONCLUSIONS: Our data indicate that APOBEC3 overexpression might not be restricted to specific cancer types. Also, APOBEC3 expression in many normal epithelial cells suggests that there might be a mutation unrelated function of APOBEC3 in the normal cells.

Related: Colorectal (Bowel) Cancer Stomach Cancer Gastric Cancer

Theurillat JP, Udeshi ND, Errington WJ, et al.
Prostate cancer. Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer.
Science. 2014; 346(6205):85-9 [PubMed] Article available free on PMC after 15/10/2015 Related Publications
Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. We highlight DEK as a SPOP substrate that exhibited decreases in ubiquitylation and proteasomal degradation resulting from heteromeric complexes of wild-type and mutant SPOP protein. DEK stabilization promoted prostate epithelial cell invasion, which implicated DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation.

Related: DEK gene

Grasso AA, Cozzi G, Palumbo C, et al.
Concordance between biopsy and radical prostatectomy specimen Gleason score in internal and external pathology facilities.
Anticancer Res. 2014; 34(10):5585-8 [PubMed] Related Publications
BACKGROUND: Biopsy Gleason score (bGS) is an important tool for staging and decision making in patients with prostate cancer. Therefore, the data from biopsy should be both reproducible across different pathologists and predictive of the true underlying tumour. We evaluated the agreement between bGS with prostatectomy Gleason score (pGS) comparing patients who underwent prostate biopsy at our hospital with those who did it at an outside facility.
MATERIALS AND METHODS: We retrospectively analyzed patients who underwent robot-assisted radical prostatectomy at our Hospital in 2011 and 2012. Patients were divided depending on the site of prostate biopsy. We calculated a weighted κ statistic to evaluate the concordance from bGS and pGS in the two groups and to evaluate the Gleason score (GS) concordance comparing the proportion of positive cores at biopsy.
RESULTS: A total of 124 patients with completed data were identified (70 patients performed biopsy at our institution and 54 at an outside facility). The weighted κ score for GS agreement was 0.40 for our Institution and 0.27 for other facilities. The weighted κ score stratified by biopsy hospital for patients with at least 30% of positive cores was 0.46 for our hospital and 0.42 for other facilities.
CONCLUSION: Internal prostate biopsy predicted better pGS than outside facility biopsy reports. When the percentage of biopsy-positive cores increases, the agreement between bGS and pGS is similar between the two groups. For certain cases in which an outside laboratory biopsy results in equivocal clinical decision, biopsy re-evaluation by internal pathologists can help reveal the true underlying tumor architecture and extension.

Kadono Y, Ueno S, Makino T, et al.
Intrapelvic fat makes robot-assisted radical prostatectomy difficult.
Anticancer Res. 2014; 34(10):5523-8 [PubMed] Related Publications
AIM: We investigated the relationship between a new index considering the estimated working space and difficulty of robot-assisted radical prostatectomy (RARP) using our database.
PATIENTS AND METHODS: Working height was calculated by the obstetric conjugate diameter minus the bladder and rectal wall thicknesses minus the thickness of postvesical fat minus the rectal fat thicknesses measured using preoperative magnetic resonance imaging (MRI). The proportion of working height was calculated by dividing the working height by the obstetric conjugate diameter.
RESULTS: A total of 112 RARP cases were enrolled. The mean obstetric conjugate was 105 mm and the mean proportion of working height was 72.5%. Multivariate linear regression analysis indicated that the proportion of working height was an independent predictive factor for both console time and estimated blood loss.
CONCLUSION: The difficulty of RARP can be predicted by measuring the fat thicknesses around the rectum and bladder by MRI before surgery.

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