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 beneift 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 inlfuencing clinical implementation.

作者： 刊期： 2014年第03期

This study sought to assess the prognostic signiifcance 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 identiifed as statistically signiifcant 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%conifdence 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.

作者： 刊期： 2014年第03期

The speciifcity of prostate-speciifc 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, speciifcities 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.

作者： 刊期： 2014年第03期

作者： 刊期： 2014年第03期

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.

作者： 刊期： 2014年第03期

作者： 刊期： 2014年第03期

Avanaifl, 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 efifcacy 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 avanaifl 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 avanaifl with a placebo. Among the co-primary efifcacy end points indicating that avanaifl 100 mg was more effective than a placebo were successful vaginal penetration (SEP2) (the odds ratio (OR)=5.06, 95%conifdence 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 avanaifl 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). Speciifc AEs with avanaifl included headache and lfushing, which were signiifcantly less likely to occur with placebo. This meta-analysis indicates that avanaifl 100 or 200 mg is an effective and well-tolerated treatment for ED. Compared with avanaifl 100 mg, patients who take avanaifl 200 mg are more likely to experience headaches.

作者： 刊期： 2014年第03期

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 identiifed. 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 ifve of them qualiifed for the meta-analysis. A meta-analysis using a random effects model showed that statins were associated with a signiifcant increase in IIEF-5 scores (mean difference (MD):3.27;95%conifdential interval (CI):1.51 to 5.02;P<0.01) and an overall improvement of lipid proifles 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.

作者： 刊期： 2014年第03期

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-speciifc 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-120 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-10.05). 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.

作者： 刊期： 2014年第03期

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 inlficted on spermatozoa. It is postulated that lycopene may have other beneifcial 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.

作者： 刊期： 2014年第03期

Because of unavoidable complications of vasectomy, this study was undertaken to assess the efifcacy 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 ifxing to the vas deferens (ifxed 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 3rd-6th and 12th 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 signiifcant 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 12th 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.

作者： 刊期： 2014年第03期

作者： 刊期： 2014年第03期

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.

作者： 刊期： 2014年第03期

Several studies have reported that C-reactive protein (CRP), an inlfammation 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 identiifed, and evaluated for quality through multiple search strategies. Data was collected from studies comparing overall and cancer-speciifc 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% conifdence interval (CI) were used to assess the strength of associations. A total of nine studies (n= 1,497) were evaluated in this meta-analysis (ifve for overall survival (OS), four for CSS and two for PFS). For OS and PFS, the pooled HR of CRP was statistically signiifcant 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.

作者： 刊期： 2014年第03期

作者： 刊期： 2014年第03期

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 beneift 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.

作者： 刊期： 2014年第03期

作者： 刊期： 2014年第03期

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 coefifcient (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 mm2 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 ifndings suggest that ADC values of normal testicular tissue increase with advancing age.

作者： 刊期： 2014年第03期

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 iffty-three healthy men (aged 22.8 ± 3.1 years) were enrolled. The individuals were grouped as CAG short (CAGS) if they harbored repeat length of≤20 or as CAG long (CAGL) if their CAG repeat length was>20. Body height/weight, penile length and other parameters were examined and recorded by the speciifed 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 signiifcant 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 (b=-0.024, P= 0.039, 95%conifdence interval (CI):-0.047, 0). Collectively, this study provides the ifrst 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.

作者： 刊期： 2014年第03期

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 ifrst 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 speciifc pathway inhibitors in advanced PCa. In addition, we will highlight current deifciencies in our clinical knowledge, most notably the need for biomarkers that can accurately predict for response to PI3K pathway inhibitors.

作者： 刊期： 2014年第03期