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2014| May-June | Volume 16 | Issue 3
Online since
April 30, 2014
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REVIEW
PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance
Merritt P Edlind, Andrew C Hsieh
May-June 2014, 16(3):378-386
DOI
:10.4103/1008-682X.122876
PMID
:24759575
Prostate cancer (PCa) is the second most common malignancy among men in the world. Castration-resistant prostate cancer (CRPC) is the lethal form of the disease, which develops upon resistance to first line androgen deprivation therapy (ADT). Emerging evidence demonstrates a key role for the PI3K-AKT-mTOR signaling axis in the development and maintenance of CRPC. This pathway, which is deregulated in the majority of advanced PCas, serves as a critical nexus for the integration of growth signals with downstream cellular processes such as protein synthesis, proliferation, survival, metabolism and differentiation, thus providing mechanisms for cancer cells to overcome the stress associated with androgen deprivation. Furthermore, preclinical studies have elucidated a direct connection between the PI3K-AKT-mTOR and androgen receptor (AR) signaling axes, revealing a dynamic interplay between these pathways during the development of ADT resistance. Thus, there is a clear rationale for the continued clinical development of a number of novel inhibitors of the PI3K pathway, which offer the potential of blocking CRPC growth and survival. In this review, we will explore the relevance of the PI3K-AKT-mTOR pathway in PCa progression and castration resistance in order to inform the clinical development of specific pathway inhibitors in advanced PCa. In addition, we will highlight current deficiencies in our clinical knowledge, most notably the need for biomarkers that can accurately predict for response to PI3K pathway inhibitors.
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14,410
1,455
118
ORIGINAL ARTICLES
Neurovascular bundle dissection for Nesbit procedure in congenital penile curvature patients: medial or lateral?
Fatih Akbulut, Tolga Akman, Emre Salabas, Murat Dinçer, Mazhar Ortac, Ates Kadioglu
May-June 2014, 16(3):442-445
DOI
:10.4103/1008-682X.123667
PMID
:24625879
The objective of this study was to compare the outcomes of the modified Nesbit procedure using different techniques for dissecting the neurovascular bundle (NVB) to correct ventral congenital penile curvatures (CPCs). The bundle was mobilized using the medial and lateral dissection technique in 21 (Group 1) and 13 (Group 2) patients, respectively. In the medial technique, Buck's fascia is opened at the dorsal side of the penis, the deep dorsal vein is removed at the most prominent site of the curvature and a diamond-shaped tunica albuginea (TA) is excised from the midline of the penis. In the lateral technique, the bundle is mobilized using a longitudinal lateral incision of the Buck's fascia above the urethra at the 5 and 7 o'clock positions via a bilateral approach. The localization and degree of curvature was evaluated using the combined intracavernous injection stimulation test or from the patients' photographs. The mean patient age and degree of curvature were similar between groups. The mean operation time was longer for Group 2 (
P
= 0.01). In Group 1, nine patients (42.8%) required one diamond excision, 10 (47.6%) required two diamond excisions and two (9.5%) required more than two excisions; in Group 2, six patients (46.2%) required two diamond excisions and seven patients (53.8%) required more than two diamond excisions (
P
= 0.019). The differences in penile shortening, penile straightening and numbness of the glans penis were not statistically significant. Medial dissection of the bundle for the modified Nesbit procedure reduces the number of diamond-shaped removals of TA and thus shortens operation time in comparison with its lateral counterpart.
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11,975
651
3
REVIEW
Lycopene and male infertility
Damayanthi Durairajanayagam, Ashok Agarwal, Chloe Ong, Pallavi Prashast
May-June 2014, 16(3):420-425
DOI
:10.4103/1008-682X.126384
PMID
:24675655
Excessive amounts of reactive oxygen species (ROS) cause a state of oxidative stress, which result in sperm membrane lipid peroxidation, DNA damage and apoptosis, leading to decreased sperm viability and motility. Elevated levels of ROS are a major cause of idiopathic male factor infertility, which is an increasingly common problem today. Lycopene, the most potent singlet oxygen quencher of all carotenoids, is a possible treatment option for male infertility because of its antioxidant properties. By reacting with and neutralizing free radicals, lycopene could reduce the incidence of oxidative stress and thus, lessen the damage that would otherwise be inflicted on spermatozoa. It is postulated that lycopene may have other beneficial effects via nonoxidative mechanisms in the testis, such as gap junction communication, modulation of gene expression, regulation of the cell cycle and immunoenhancement. Various lycopene supplementation studies conducted on both humans and animals have shown promising results in alleviating male infertility-lipid peroxidation and DNA damage were decreased, while sperm count and viability, and general immunity were increased. Improvement of these parameters indicates a reduction in oxidative stress, and thus the spermatozoa is less vulnerable to oxidative damage, which increases the chances of a normal sperm fertilizing the egg. Human trials have reported improvement in sperm parameters and pregnancy rates with supplementation of 4-8 mg of lycopene daily for 3-12 months. However, further detailed and extensive research is still required to determine the dosage and the usefulness of lycopene as a treatment for male infertility.
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33
ORIGINAL ARTICLES
Disposable circumcision suture device: clinical effect and patient satisfaction
Bo-Dong Lv, Shi-Geng Zhang, Xuan-Wen Zhu, Jie Zhang, Gang Chen, Min-Fu Chen, Hong-Liang Shen, Zai-Jun Pei, Zhao-Dian Chen
May-June 2014, 16(3):453-456
DOI
:10.4103/1008-682X.127816
PMID
:24759586
In our experience patients undergoing circumcision are mostly concerned about pain and penile appearances. We conducted a prospective randomized trial to assess the benefits of a new disposable circumcision suture device (DCSD). A total of 942 patients were equally divided into three groups (conventional circumcision, Shang ring and disposable suture device group). Patients in the DCSD group were anesthetized with compound 5% lidocaine cream, the others with a 2% lidocaine penile block. Operation time, intra-operative blood loss, incision healing time, intra-operative and post-operative pain, the penile appearance and overall satisfaction degree were measured. Operation time and intra-operative blood loss were significantly lower in the Shang ring and suture device groups compared to the conventional group (
P
< 0.001). Intra-operative pain was less in the suture device group compared with the other two groups (
P
< 0.001); whereas post-operative pain was higher in the conventional group compared to the other two groups (
P
< 0.001). Patients in the suture device (80.57%) and Shang ring (73.57%) groups were more satisfied with penile appearances compared with the conventional circumcision group (20.06%,
P
< 0.05). Patients in suture device group also healed markedly faster than the conventional group (
P
< 0.01). The overall satisfaction rate was better in the suture device group (78.66%) compared with the conventional (47.13%) and Shang ring (50.00%) groups (
P
< 0.05). The combination of DCSD and lidocaine cream resulted in shorter operation and incision healing times, reduced intra-operative and post-operative pain and improved patient satisfaction with the cosmetic appearances.
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7,465
650
9
REVIEW
Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer
Mark N Stein, Neal Patel, Alexander Bershadskiy, Alisa Sokoloff, Eric A Singer
May-June 2014, 16(3):387-400
DOI
:10.4103/1008-682X.129133
PMID
:24759590
Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer (CRPC), it is possible to detect persistent activation of the androgen receptor (AR) through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17α-hydroxylase and 17,20-lyase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival (OS) with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17
α
-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone (ACTH), providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-lyase (orteronel, galeterone and VT-464) that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity.
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6,972
981
19
Immunotherapy and therapeutic vaccines in prostate cancer: an update on current strategies and clinical implications
B Harpreet Singh, James L Gulley
May-June 2014, 16(3):364-371
DOI
:10.4103/1008-682X.122585
PMID
:24435055
In recent years, immunotherapy has emerged as a viable and attractive strategy for the treatment of prostate cancer. While there are multiple ways to target the immune system, therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in late-stage clinical trials. The landmark Food and Drug Administration approval of sipuleucel-T for asymptomatic or minimally symptomatic metastatic prostate cancer set the stage for ongoing phase III trials with the cancer vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab. A common feature of these immune-based therapies is the appearance of improved overall survival without short-term changes in disease progression. This class effect appears to be due to modulation of tumor growth rate kinetics, in which the activated immune system exerts constant immunologic pressure that slows net tumor growth. Emerging data suggest that the ideal population for clinical trials of cancer vaccines is patients with lower tumor volume and less aggressive disease. Combination strategies that combine immunotherapy with standard therapies have been shown to augment both immune response and clinical benefit.
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4,998
640
9
RESEARCH HIGHLIGHT
Next generation patient-derived prostate cancer xenograft models
Dong Lin, Hui Xue, Yuwei Wang, Rebecca Wu, Akira Watahiki, Xin Dong, Hongwei Cheng, Alexander W Wyatt, Colin C Collins, Peter W Gout, Yuzhuo Wang
May-June 2014, 16(3):407-412
DOI
:10.4103/1008-682X.125394
PMID
:24589467
There is a critical need for more effective therapeutic approaches for prostate cancer. Research in this area, however, has been seriously hampered by a lack of clinically relevant, experimental
in vivo
models of the disease. This review particularly focuses on the development of prostate cancer xenograft models based on subrenal capsule grafting of patients' tumor tissue into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This technique allows successful development of transplantable, patient-derived cancer tissue xenograft lines not only from aggressive metastatic, but also from localized prostate cancer tissues. The xenografts have been found to retain key biological properties of the original malignancies, including histopathological and molecular characteristics, tumor heterogeneity, response to androgen ablation and metastatic ability. As such, they are highly clinically relevant and provide valuable tools for studies of prostate cancer progression at cellular and molecular levels, drug screening for personalized cancer therapy and preclinical drug efficacy testing; especially when a panel of models is used to cover a broader spectrum of the disease. These xenograft models could therefore be viewed as next-generation models of prostate cancer.
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4,734
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15
ORIGINAL ARTICLES
The role of statins in erectile dysfunction: a systematic review and meta-analysis
Xiang Cai, Ye Tian, Tao Wu, Chen-Xi Cao, Si-Yuan Bu, Kun-Jie Wang
May-June 2014, 16(3):461-466
DOI
:10.4103/1008-682X.123678
PMID
:24556747
To evaluate the effect of statins for erectile dysfunction (ED), a systematic review of the literature was conducted in the Cochrane Library, Embase and PubMed from the inception of each database to June 2013. Only randomized controlled trials (RCTs) comparing treatment for ED with statins were identified. Placebo RCTs with the International Index of Erectile Function (IIEF) as the outcome measure were eligible for meta-analysis. A total of seven RCTs including two statins with a total of 586 patients strictly met our criteria for systematic review and five of them qualified for the meta-analysis. A meta-analysis using a random effects model showed that statins were associated with a significant increase in IIEF-5 scores (mean difference (MD): 3.27; 95% confidential interval (CI):1.51 to 5.02;
P
< 0.01) and an overall improvement of lipid profiles including total cholesterol (MD: −1.08; 95% CI: −1.68 to −0.48;
P
< 0.01), low-density lipoprotein (LDL) cholesterol (MD: −1.43; 95% CI: −2.07 to −0.79;
P
< 0.01), high-density lipoprotein (HDL) cholesterol (MD: 0.24; 95% CI: 0.13 to 0.35;
P
< 0.01) and triglycerides (TGs) (MD: −0.55; 95% CI: −0.61 to −0.48;
P
< 0.01). In summary, our study revealed positive consequences of these lipid-lowering drugs on erectile function, especially for nonresponders to phosphodiesterase type 5 inhibitors (PDE5Is). However, it has been reported that statin therapy may reduce levels of testosterone and aggravate symptoms of ED. Therefore, larger, well-designed RCTs are needed to investigate the double-edged role of statins in the treatment of ED.
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4,667
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25
Association between
FOXO3A
gene polymorphisms and human longevity: a meta-analysis
Ji-Ming Bao, Xian-Lu Song, Ying-Qia Hong, Hai-Li Zhu, Cui Li, Tao Zhang, Wei Chen, Shan-Chao Zhao, Qing Chen
May-June 2014, 16(3):446-452
DOI
:10.4103/1008-682X.123673
PMID
:24589462
Numerous studies have shown associations between the
FOXO3A
gene, encoding the forkhead box O3 transcription factor, and human or specifically male longevity. However, the associations of specific
FOXO3A
polymorphisms with longevity remain inconclusive. We performed a meta-analysis of existing studies to clarify these potential associations. A comprehensive search was conducted to identify studies of
FOXO3A
gene polymorphisms and longevity. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by comparing the minor and major alleles. A total of seven articles reporting associations of
FOXO3A
polymorphisms with longevity were identified and included in this meta-analysis. These comprised 11 independent studies with 5241 cases and 5724 controls from different ethnic groups. rs2802292, rs2764264, rs13217795, rs1935949 and rs2802288 polymorphisms were associated with human longevity (OR = 1.36, 95% CI = 1.10-1.69,
P
= 0.005; OR = 1.20, 95% CI = 1.04-1.37,
P
= 0.01; OR = 1.27, 95% CI = 1.10-1.46,
P
= 0.001; OR = 1.14, 95% CI = 1.01-1.27 and OR = 1.24, 95% CI = 1.07-1.43,
P
= 0.003, respectively). Analysis stratified by gender indicated significant associations between rs2802292, rs2764264 and rs13217795 and male longevity (OR = 1.54, 95% CI = 1.33-1.79,
P
< 0.001; OR = 1.38, 95% CI = 1.15-1.66,
P
= 0.001; and OR = 1.39, 95% CI = 1.15-1.67,
P
= 0.001), but rs2802292, rs2764264 and rs1935949 were not linked to female longevity. Moreover, our study showed no association between rs2153960, rs7762395 or rs13220810 polymorphisms and longevity. In conclusion, this meta-analysis indicates a significant association of five
FOXO3A
gene polymorphisms with longevity, with the effects of rs2802292 and rs2764264 being male-specific. Further investigations are required to confirm these findings.
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30
REVIEW
Treatment sequencing in metastatic castrate-resistant prostate cancer
Oliver Sartor, Silke Gillessen
May-June 2014, 16(3):426-431
DOI
:10.4103/1008-682X.126378
PMID
:24675654
Six different treatments have demonstrated improved survival in phase III trials targeted to patients with metastatic castration-resistant prostate cancer (mCRPC). Front-line therapeutic options for mCRPC include docetaxel, sipuleucel-T, abiraterone and radium-223. Post-docetaxel options include cabazitaxel, abiraterone, enzalutamide and radium-223. Despite much progress in recent years, much is yet unknown and debates occur over optimal treatment choices and sequences. None of the new agents have been compared to one another, thus physicians in practice today must make choices based on non-randomized comparisons, toxicity considerations and various assumptions. Abiraterone is now moving into the front line mCRPC space given recent regulatory approvals and enzalutamide will follow soon. Both of the hormonal agents have less toxicity when compared to chemotherapeutic options and both of these hormonal agents are expected to be used in a considerable number of mCRPC patients in the years ahead. Little data are available for the post-abiraterone or post-enzalutamide setting. In this review the currently available sequencing data are summarized and interpreted. It is now clear that cross resistance is a potential issue between various treatments, especially those agents that target the androgen axis. This review highlights the need for additional studies to optimize the current treatments for these patients.
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4,263
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22
Radium-223 in metastatic castration resistant prostate cancer
Winston Vuong, Oliver Sartor, Sumanta K Pal
May-June 2014, 16(3):348-353
DOI
:10.4103/1008-682X.127812
PMID
:24713838
In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival benefit in phase III studies. These agents include sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and (most recently) radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer (e.g. samarium-153 and strontium-89), radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors influencing clinical implementation.
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4,056
658
8
Heat shock and other apoptosis-related proteins as therapeutic targets in prostate cancer
Costantine Albany, Noah M Hahn
May-June 2014, 16(3):359-363
DOI
:10.4103/1008-682X.126400
PMID
:24713836
Defects within apoptotic pathways have been implicated in prostate cancer (PCa) tumorigenesis, metastatic progression and treatment resistance. A hallmark of cancers is the ability to derail apoptosis by inhibiting the apoptotic signal, reducing the expression of apoptotic proteins and/or amplifying survival signals through increased production of antiapoptotic molecule. This review describes associations between heat shock proteins (HSPs) and the human androgen receptor (AR), the role of HSPs and other stress-induced proteins in PCa development and emerging strategies in targeting these protective proteins to treat PCa.
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3,979
710
12
ORIGINAL ARTICLES
Avanafil for male erectile dysfunction: a systematic review and meta-analysis
Yuan-Shan Cui, Nan Li, Huan-Tao Zong, Hui-Lei Yan, Yong Zhang
May-June 2014, 16(3):472-477
DOI
:10.4103/1008-682X.123670
PMID
:24589460
Avanafil, a potent new selective phosphodiesterase type 5 (PDE5) inhibitor, has been developed for the treatment of erectile dysfunction (ED). We carried out a systematic review and meta-analysis to assess the efficacy and safety of this drug for the treatment of ED. A literature review was performed to identify all published randomized, double-blind, placebo-controlled trials of avanafil for the treatment of ED. The search included the following databases: MEDLINE, EMBASE and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. Four publications, involving a total of 1381 patients, were used in the analysis, including four randomized controlled trials (RCTs) that compared avanafil with a placebo. Among the co-primary efficacy end points indicating that avanafil 100 mg was more effective than a placebo were successful vaginal penetration (SEP2) (the odds ratio (OR) =5.06, 95% confidence interval (CI) =3.29-7.78,
P
< 0.00001) and successful intercourse (SEP3) (OR = 3.99, 95% CI = 2.80-5.67,
P
< 0.00001). Men randomized to receive avanafil were less likely than those receiving the placebo to drop out due to an adverse event (AE) (OR = 1.48, 95% CI = 0.54-4.08,
P
= 0.44). Specific AEs with avanafil included headache and flushing, which were significantly less likely to occur with placebo. This meta-analysis indicates that avanafil 100 or 200 mg is an effective and well-tolerated treatment for ED. Compared with avanafil 100 mg, patients who take avanafil 200 mg are more likely to experience headaches.
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3,930
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4
REVIEW
Glucocorticoids and prostate cancer treatment: friend or foe?
Bruce Montgomery, Heather H Cheng, James Drechsler, Elahe A Mostaghel
May-June 2014, 16(3):354-358
DOI
:10.4103/1008-682X.125392
PMID
:24625881
Glucocorticoids have been used in the treatment of prostate cancer to slow disease progression, improve pain control and offset side effects of chemo- and hormonal therapy. However, they may also have the potential to drive prostate cancer growth via mutated androgen receptors or glucocorticoid receptors (GRs). In this review we examine historical and contemporary use of glucocorticoids in the treatment of prostate cancer, review potential mechanisms by which they may inhibit or drive prostate cancer growth, and describe potential means of defining their contribution to the biology of prostate cancer.
[ABSTRACT]
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3,789
691
21
ORIGINAL ARTICLES
Apparent diffusion coefficient values of normal testis and variations with age
Athina C Tsili, Dimitrios Giannakis, Anastasios Sylakos, Alexandra Ntorkou, Loukas G Astrakas, Nikolaos Sofikitis, Maria I Argyropoulou
May-June 2014, 16(3):493-497
DOI
:10.4103/1008-682X.122865
PMID
:24556745
The usefulness of diffusion-weighted magnetic resonance imaging (DWI) in the evaluation of scrotal pathology has recently been reported. A standard reference of normal testicular apparent diffusion coefficient (ADC) values and their variations with age is necessary when interpreting normal testicular anatomy and pathology. We evaluated 147 normal testes using DWI, including 71 testes from 53 men aged 20-39 years (group 1), 67 testes from 42 men aged 40-69 years (group 2) and nine testes from six men older than 70 years (group 3). DWI was performed along the axial plane, using a single shot, multislice spin-echo planar diffusion pulse sequence and b-values of 0 and 900 s mm
−2
. The mean and standard deviation of the ADC values of normal testicular parenchyma were calculated for each age group separately. Analysis of variance (ANOVA) followed by post hoc analysis (Dunnett T3) was used for statistical purposes. The ADC values (× 10
−3
mm
2
s
−1
) of normal testicular tissue were different among age groups (group 1: 1.08 ± 0.13; group 2: 1.15 ± 0.15 and group 3: 1.31 ± 0.22). ANOVA revealed differences in mean ADC among age groups (
F
= 11.391,
P
< 0.001). Post hoc analysis showed differences between groups 1 and 2 (
P
= 0.008) and between groups 1 and 3 (
P
= 0.043), but not between groups 2 and 3 (
P
= 0.197). Our findings suggest that ADC values of normal testicular tissue increase with advancing age.
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3,702
442
13
REVIEW
Poly (ADP-ribose) polymerase inhibitor: an evolving paradigm in the treatment of prostate cancer
Jingsong Zhang
May-June 2014, 16(3):401-406
DOI
:10.4103/1008-682X.123684
PMID
:24589464
Recent phase I studies have reported single-agent activities of poly (ADP-ribose) polymerase (PARP) inhibitor in sporadic and in BRCA-mutant prostate cancers. Two of the most common genetic alterations in prostate cancer, ETS gene rearrangement and loss of PTEN, have been linked to increased sensitivity to PARP inhibitor in preclinical models. Emerging evidence also suggests that PARP1 plays an important role in mediating the transcriptional activities of androgen receptor (AR) and ETS gene rearrangement. In this article, the preclinical work and early-phase clinical trials in developing PARP inhibitor-based therapy as a new treatment paradigm for metastatic prostate cancer are reviewed.
[ABSTRACT]
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[PubMed]
3,376
748
10
ORIGINAL ARTICLES
Prognostic role of C-reactive protein in prostate cancer: a systematic review and meta-analysis
Zhu-Qing Liu, Li Chu, Jue-Min Fang, Xi Zhang, Hua-Xin Zhao, Yi-Jing Chen, Qing Xu
May-June 2014, 16(3):467-471
DOI
:10.4103/1008-682X.123686
PMID
:24589465
Several studies have reported that C-reactive protein (CRP), an inflammation biomarker, may be associated with the prognosis of prostate cancer (PCa). The objective of this systematic review is to summarize the predictive role of CRP for survival in PCa as reported in previous studies. Related studies were identified, and evaluated for quality through multiple search strategies. Data was collected from studies comparing overall and cancer-specific survival (CSS) in patients with elevated CRP levels and those having lower levels. However, for progression-free survival (PFS), data were collected according to the log of CRP. The hazard ratio (HR) and its 95% confidence interval (CI) were used to assess the strength of associations. A total of nine studies (
n
= 1,497) were evaluated in this meta-analysis (five for overall survival (OS), four for CSS and two for PFS). For OS and PFS, the pooled HR of CRP was statistically significant at 1.51 (95% CI, 1.28-1.79) and 1.50 (95% CI, 1.25-1.81), respectively. For CSS, the pooled HR was 1.91 (95% CI, 1.36-2.69) with higher CRP expression in PCa, which strongly indicates poorer survival in PCa. This study demonstrates that CRP may have a critical prognostic value in patients with prostatic cancer.
[ABSTRACT]
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[PubMed]
3,553
568
30
REVIEW
Chemotherapy and its evolving role in the management of advanced prostate cancer
Michael T Schweizer, Emmanuel S Antonarakis
May-June 2014, 16(3):334-340
DOI
:10.4103/1008-682X.122593
PMID
:24435058
Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer (CRPC). Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing 'level-1 evidence' that docetaxel-based chemotherapy led to prolongation in overall survival (OS). This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents (e.g. abiraterone and enzalutamide) have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include: how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.
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3,461
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6
ORIGINAL ARTICLES
The
PCA3
test for guiding repeat biopsy of prostate cancer and its cut-off score: a systematic review and meta-analysis
Yong Luo, Xin Gou, Peng Huang, Chan Mou
May-June 2014, 16(3):487-492
DOI
:10.4103/1008-682X.125390
PMID
:24713827
The specificity of prostate-specific antigen (PSA) for early intervention in repeat biopsy is unsatisfactory. Prostate cancer antigen 3 (
PCA3
) may be more accurate in outcome prediction than other methods for the early detection of prostate cancer (PCa). However, the results were inconsistent in repeated biopsies. Therefore, we performed a systematic review and meta-analysis to evaluate the role of
PCA3
in outcome prediction. A systematic bibliographic search was conducted for articles published before April 2013, using PubMed, Medline, Web of Science, Embase and other databases from health technology assessment agencies. The quality of the studies was assessed on the basis of QUADAS criteria. Eleven studies of diagnostic tests with moderate to high quality were selected. A meta-analysis was carried out to synthesize the results. The results of the meta-analyses were heterogeneous among studies. We performed a subgroup analysis (with or without inclusion of high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP)). Using a
PCA3
cutoff of 20 or 35, in the two sub-groups, the global sensitivity values were 0.93 or 0.80 and 0.79 or 0.75, specificities were 0.65 or 0.44 and 0.78 or 0.70, positive likelihood ratios were 1.86 or 1.58 and 2.49 or 1.78, negative likelihood ratios were 0.81 or 0.43 and 0.91 or 0.82 and diagnostic odd ratios (ORs) were 5.73 or 3.45 and 7.13 or 4.11, respectively. The areas under the curve (AUCs) of the summary receiver operating characteristic curve were 0.85 or 0.72 and 0.81 or 0.69, respectively.
PCA3
can be used for repeat biopsy of the prostate to improve accuracy of PCa detection. Unnecessary biopsies can be avoided by using a PCa cutoff score of 20.
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3,410
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25
REVIEW
Bone targeted therapies for the prevention of skeletal morbidity in men with prostate cancer
Philip J Saylor
May-June 2014, 16(3):341-347
DOI
:10.4103/1008-682X.122591
PMID
:24435057
Men with prostate cancer suffer substantially from bone-related complications. Androgen deprivation therapy itself is a cause of loss of bone mineral density and is associated with an increased incidence of osteoporotic fractures. In advanced disease, bone is by far the most common site of metastasis. Complications of bone metastases prominently include pain and the potential for skeletal events such as spinal cord compression and pathologic fractures. Elevated osteoclast activity is an important aspect of the pathophysiology of both treatment-related osteoporosis and skeletal complications due to metastases. The osteoclast is therefore a therapeutic target. Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor-
κ
-B ligand that was designed to potently inhibit osteoclast activity and is the central focus of this review. Bisphosphonates, radiopharmaceuticals and systemically-active hormonal agents such as abiraterone acetate and enzalutamide have each been shown to improve skeletal morbidity in specific clinical situations. Denosumab is the only agent that has been shown to prevent osteoporotic fractures in men receiving androgen deprivation therapy and at elevated risk for fracture. It has also demonstrated superiority to the potent bisphosphonate zoledronic acid for the prevention of skeletal-related events in men with castration-resistant prostate cancer metastatic to bone. Efficacy and toxicity data will be discussed.
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3,313
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5
Anti-angiogenesis in prostate cancer: knocked down but not out
Marijo Bilusic, Yu-Ning Wong
May-June 2014, 16(3):372-377
DOI
:10.4103/1008-682X.125903
PMID
:24759579
Angiogenesis is a very complex physiological process, which involves multiple pathways that are dependent on the homeostatic balance between the growth factors (stimulators and inhibitors). This tightly controlled process is stimulated by angiogenic factors, which are present within the tumor and surrounding tumor-associated stromal cells. The dependence of tumor propagation, invasion and metastasis on angiogenesis makes the inhibitors of new blood vessel formation attractive drugs for treating the malignancies. Angiogenesis can be disrupted by several distinct mechanisms: by inhibiting endothelial cells, by interrupting the signaling pathways or by inhibiting other activators of angiogenesis. This strategy has shown therapeutic benefit in several types of solid tumors, leading to Food and Drug Administration (FDA) approval of anti-angiogenic agents in the treatment of kidney, non-small cell lung, colon and brain cancers. Although no angiogenesis inhibitors have been approved for patients with metastatic prostate cancer, therapies that target new blood vessel formation are still an emerging and promising area of prostate cancer research.
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3,322
640
10
ORIGINAL ARTICLES
Relationships among androgen receptor CAG repeat polymorphism, sex hormones and penile length in Han adult men from China: a cross-sectional study
Yan-Min Ma, Kai-Jie Wu, Liang Ning, Jin Zeng, Bo Kou, Hong-Jun Xie, Zhen-Kun Ma, Xin-Yang Wang, Yong-Guang Gong, Da-Lin He
May-June 2014, 16(3):478-481
DOI
:10.4103/1008-682X.124560
PMID
:24589466
This study aimed to investigate the correlations among androgen receptor (AR) CAG repeat polymorphism, sex hormones and penile length in healthy Chinese young adult men. Two hundred and fifty-three healthy men (aged 22.8 ± 3.1 years) were enrolled. The individuals were grouped as CAG short (CAG
S
) if they harbored repeat length of ≤20 or as CAG long (CAG
L
) if their CAG repeat length was >20. Body height/weight, penile length and other parameters were examined and recorded by the specified physicians; CAG repeat polymorphism was determined by the polymerase chain reaction (PCR) method; and the serum levels of the sex hormones were detected by radioimmunoassay. Student's
t
-test or linear regression analysis was used to assess the associations among AR CAG repeat polymorphism, sex hormones and penile length. This investigation showed that the serum total testosterone (T) level was positively associated with the AR CAG repeat length (
P
= 0.01); whereas, no significant correlation of T or AR CAG repeat polymorphism with the penile length was found (
P
= 0.593). Interestingly, an inverse association was observed between serum prolactin (PRL) levels and penile length by linear regression analyses (β= −0.024,
P
= 0.039, 95% confidence interval (CI): −0.047, 0). Collectively, this study provides the first evidence that serum PRL, but not T or AR CAG repeat polymorphism, is correlated with penile length in the Han adult population from northwestern China.
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3,346
471
3
RESEARCH HIGHLIGHT
Long noncoding RNA-mediated activation of androgen receptor in prostate cancer
Gyorgy Petrovics, Shiv Srivastava
May-June 2014, 16(3):418-419
DOI
:10.4103/1008-682X.126398
PMID
:24713835
Remarkable progress has been made in molecular characterization of prostate cancer (PCa) with continued innovations in high throughput technologies evaluating human cancer.
[1],[2],[3]
Since the completion of the Human Genome Project it has been estimated that only about 1.5%-2% of our genome codes for proteins. Various genome-wide approaches, e.g. the ENCODE project, revealed that a much larger percent of the genome is transcribed as non-protein coding (nc) RNA, including long noncoding (lnc) RNA (over 200 bps long). Although the biological roles of lncRNA (the 'dark matter of the genome') are not nearly as well-understood as the protein coding mRNAs, it is increasingly clear that they play important roles in almost every aspects of biology, including cancer biology.
[4],[5]
This is exemplified by recent genome-wide association studies revealing that over 80% of cancer-associated single nucleotide polymorphisms (SNPs) are in noncoding regions of the genome.
[ABSTRACT]
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3,098
489
1
ORIGINAL ARTICLES
A randomized, controlled, multicenter contraceptive efficacy clinical trial of the intravas device, a nonocclusive surgical male sterilization
Wen-Hong Lu, Xiao-Wei Liang, Yi-Qun Gu, Wei-Xiong Wu, Li-Wei Bo, Tian-Gui Zheng, Zhen-Wen Chen
May-June 2014, 16(3):432-436
DOI
:10.4103/1008-682X.122860
PMID
:24589454
Because of unavoidable complications of vasectomy, this study was undertaken to assess the efficacy and safety of male sterilization with a nonobstructive intravas device (IVD) implanted into the vas lumen by a mini-surgical method compared with no-scalpel vasectomy (NSV). IVDs were categorized into two types: IVD-B has a tail used for fixing to the vas deferens (fixed wing) whereas IVD-A does not. A multicenter prospective randomized controlled clinical trial was conducted in China. The study was comprised of 1459 male volunteers seeking vasectomy who were randomly assigned to the IVD-A (
n
= 487), IVD-B (
n
= 485) or NSV (
n
= 487) groups and underwent operation. Follow-up included visits at the 3
rd
-6
th
and 12
th
postoperative months. The assessments of the subjects involved regular physical examinations (including general and andrological examinations) and semen analysis. The subjects' partners also underwent monitoring for pregnancy by monthly interviews regarding menstruation and if necessary, urine tests. There were no significant differences in pregnancy rates (0.65% for IVD-A, 0 for IVD-B and 0.21% for NSV) among the three groups (
P
> 0.05). The cumulative rates of complications at the 12
th
postoperative month were zero, 0.9% and 1.7% in the three groups, respectively. In conclusion, IVD male sterilization exhibits a low risk of long-term adverse events and was found to be effective as a male sterilization method, similar to the NSV technique. IVD male sterilization is expected to be a novel contraceptive method.
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2,926
473
2
INVITED EDITORIAL
The metastatic castration-resistant prostate cancer treatment paradigm: more choices, more questions
Evan Y Yu, William K Oh
May-June 2014, 16(3):331-333
DOI
:10.4103/1008-682X.127813
PMID
:24759585
[FULL TEXT]
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2,532
615
-
ORIGINAL ARTICLES
Prognostic significance of the degree of extranodal extension in patients with penile carcinoma
Jin-You Wang, Yao Zhu, Shao-Xian Tang, Hai-Liang Zhang, Xiao-Jian Qin, Shi-Lin Zhang, Bo Dai, Ding-Wei Ye
May-June 2014, 16(3):437-441
DOI
:10.4103/1008-682X.122862
PMID
:24480925
This study sought to assess the prognostic significance of the degree of extranodal extension (ENE) and several other risk factors in pathological ENE penile carcinoma. We analyzed prospectively collected data on a consecutive series of 31 chemotherapy-naive patients with proven ENE who underwent therapeutic regional lymphadenectomy. Postoperative external radiotherapy was then performed. We studied the extent of ENE utilizing a novel grading system and correlated patient grades with their outcome measures. ENE was graded as 1 - if the capsule of the lymph node (LN) was ruptured less than one-third of its circumference or 2 - if the capsule was disrupted more than one-third of its circumference or the entire LN was disrupted. We estimated overall survival (OS) using the Kaplan-Meier method. Multivariate analysis was performed according to the Cox proportional hazards model using factors that were identified as statistically significant in univariate analysis. The incidence rate of ENE was 51.8% in patients with pathological node-positive carcinoma of the penis. The median OS and 5-year survival were 18 months (95% confidence interval (CI), 14.4-21.6) and 23%, respectively. Prognostic variables on univariate analysis were ENE grade 2, ≥3 LNs with ENE, maximal LN ≥ 35 mm, ≥5 positive LNs and pelvic LN involvement. On multivariate analysis, only ENE grade 2 remained associated with decreased OS (hazard ratio (HR): 6.50). In conclusion, patients with ENE have a poor outcome, and ENE grade 2 is an independent predictive factor of poor OS in patients with pathological ENE penile carcinoma.
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2,627
371
5
Time-dependent effects of castration on the bladder function and histological changes in the bladder and blood vessels
Tomohiro Magari, Yasuhiro Shibata, Seiji Arai, Bunzo Kashiwagi, Keiji Suzuki, Kazuhiro Suzuki
May-June 2014, 16(3):457-460
DOI
:10.4103/1008-682X.123676
PMID
:24556746
We examined the effect of androgens on bladder blood flow (BBF), bladder function and histological changes in castrated male rats. Male Wistar rats were classified into unoperated group (control group), groups castrated at the age of 8 weeks (group 8wPC) and groups castrated at the age of 4 weeks (group 4wPC). Each rat was used at the age of 20 weeks. BBF was measured using fluorescent microspheres. Bladder cystometry was performed without anesthesia or restraint; the bladder was first irrigated with saline and then with 0.25% acetic acid (AA) solution. Maximum voiding pressure and voiding interval were measured. The bladder and iliac artery were histologically examined for differences in smooth muscle and quantity of collagen fiber to analyze the effect of castration on the smooth muscle content. No differences were noted in BBF following castration. The voiding intervals for all groups were shortened (
P
< 0.001) following AA irrigation. No significant difference was noted in the maximum voiding pressure. Histological changes were observed in bladder and iliac artery. Smooth muscle/collagen ratio at the bladder was lower in groups 8wPC and 4wPC compared to the control group (
P
< 0.01), while that at the iliac artery was decreased in group 4wPC compared to the control group (
P
< 0.001). In conclusion, our findings indicate that castration does not alter BBF, but leads to histological changes in the bladder as well as its associated blood vessels.
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2,517
400
5
RESEARCH HIGHLIGHT
Morbidity and psychological impact of prostate biopsy: the future calls for a change
Andrea Minervini, Gianni Vittori, Giampaolo Siena, Marco Carini
May-June 2014, 16(3):415-417
DOI
:10.4103/1008-682X.126388
PMID
:24713833
Currently transrectal ultrasound-guided prostate biopsy (TRUS-Bx) is one of the most common urological procedures, with more than 1 million performed per year in Europe and the United States.
[1]
Among patients undergoing TRUS-Bx, approximately one-third will receive a diagnosis of prostate cancer (PCa), while two-thirds receive a negative result on initial biopsy. Negative biopsy patients maintain an estimated risk of repeated biopsy of 12% at 1 year and 38% at 5 years.
[2]
Standard TRUS-Bx is likely to systematically miss significant tumors, particularly in the anterior and apical parts of the gland.
[3]
A crucial aim of urologists in the next decade is to increase the accuracy of the procedure and avoid the use of inappropriate biopsies.
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2,530
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2
ORIGINAL ARTICLES
The influence of prostate volume on cancer detection in the Chinese population
Yi-Shuo Wu, Rong Na, Jian-Feng Xu, Pei-De Bai, Hao-Wen Jiang, Qiang Ding
May-June 2014, 16(3):482-486
DOI
:10.4103/1008-682X.125905
PMID
:24625884
In western populations, prostate volume (PV) has been proven to be one of the strongest predictors of detecting prostate cancer (PCa) in biopsies. We performed this study in a biopsy cohort, to evaluate associations among the prostate volume, prostate-specific antigen (PSA) and PCa detection in the Chinese population. Between the years, 2007-13, 1486 men underwent prostate biopsy at Huashan Hospital, Fudan University, Shanghai, China. The study population was divided into two groups for analysis according to total PSA (tPSA) range (4 ng ml
−1
< tPSA ≤20 ng ml
−1
and tPSA > 20 ng ml
−1
). PV, age, tPSA, digital rectal examination (DRE) and transrectal ultrasound (TRUS) results were also included in the analysis. Although the positive biopsy rates decreased in both tPSA range groups, the downtrend was more pronounced in the 4 ng ml
−1
< tPSA ≤20 ng ml
−1
group; therefore, we focused on 853 men in this group with increasing PV. In multivariate logistic regression analysis, only DRE was found to be associated with PCa in four PV groups (
P
< 0.05) and tPSA did not show a good predictive ability when PV exceeded 50 ml (
P
> 0.05). Further, it may suggest that with increasing PV, the cancer detection rate decreased in men with different tPSA, DRE and TRUS nodule statuses (all
P
values for trends were <0.001). Our study indicates that in tPSA ranging from 4 to 20 ng ml
−1
, the use of PV ranges of 0-35 ml, 35-50 ml and > 50 ml might be taken into consideration for the biopsy decision-making in the Chinese population.
[ABSTRACT]
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2,262
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6
RESEARCH HIGHLIGHT
Long-term survival of participants in the prostate cancer prevention trial
Jonathan L Silberstein, Oliver Sartor
May-June 2014, 16(3):413-414
DOI
:10.4103/1008-682X.122868
PMID
:24625877
The Prostate Cancer Prevention Trial (PCPT) is a seminal study in the field of urology. More than 10 years after its initial publication, updated data from this trial continue to shape our understanding of prostate cancer. Among the major findings from the PCPT has been the demonstration that prostate cancer is common in men with prostate-specific antigen (PSA) once thought to be in the normal range,
[1]
finasteride prevents the development of benign prostatic hypertrophy,
[2]
it increases the sensitivity of PSA
[3]
and digital rectal examination.
[4]
Furthermore the PCPT helped to establish the link between erectile dysfunction and cardiovascular disease,
[5]
and perhaps most importantly finasteride demonstrated a 25% relative risk reduction in the diagnosis of prostate cancer compared with placebo.
[6]
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2,235
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1
COMMENTARY
Lycopene and male infertility: do we know enough?
Tarita Pakrashi, Sergio Oehninger
May-June 2014, 16(3):500-500
DOI
:10.4103/1008-682X.127818
PMID
:24713839
[FULL TEXT]
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[PubMed]
2,242
391
-
Digit ratio links prenatal hormone exposure with adult lung function
Denise Brooks McQuade
May-June 2014, 16(3):499-499
DOI
:10.4103/1008-682X.123682
PMID
:24556748
[FULL TEXT]
[PDF]
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[PubMed]
2,032
299
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RESEARCH HIGHLIGHT
Re: Long-term survival of participants in the Prostate Cancer Prevention Trial
Ian M Thompson, Catherine M Tangen, Phyllis J Goodman
May-June 2014, 16(3):414-414
DOI
:10.4103/1008-682X.125714
[FULL TEXT]
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1,798
318
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COMMENTARY
Optimal treatment for castration-resistant prostate cancer
Kouji Izumi, Mikio Namiki
May-June 2014, 16(3):498-498
DOI
:10.4103/1008-682X.126380
PMID
:24759581
[FULL TEXT]
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1,617
322
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in association with Editorial office, Asian Journal of Andrology
Online since 1999, New website online since 10 September, 2013