曹德宏

勃起功能障碍（阳痿）—男题不难    勃起功能障碍（ED）就是中国人俗称的“阳痿”，是男性最常见的性功能障碍之一，是影响男性健康的一大“男题”。很多患者很苦恼，为什么我身边的人都没问题，而我却得了这病，作为一个纯爷们，真是太丢脸了！其实不然，中国由于历史和文化的原因，关于性的话题大家都很敏感，往往避而不谈。实际勃起功能障碍的发病率非常之高：据流行病学调查显示，成年男性的ED发病率高达26%，平均四个人中就有一个ED患者；而在40岁以上的男性中，这一发病率更高达52%！并且随着经济发展以及生活方式的改变，发病率呈现不断增加的态势。因此，当发现自己“力不从心”的时候不用过于担忧，这是很常见的一种疾病，及时就诊，让专业的医生来帮助你解决问题。勃起功能障碍的致病因素主要有以下五个方面：1.血管源性因素：海绵体动脉供血不足或静脉泄露。临床上可以通过ICI和NPT来进行确诊。2.海绵体内信号传递障碍：阴茎勃起的源头在于男性受到性刺激后产生NO，如果NO合成酶缺损或受体冲突，就会影响细胞内环磷酸鸟甘（cGMP）的含量，从而引起信号传递障碍性ED。3.内分泌因素：雄性激素分泌不足或雌激素过量都会引起ED。4.心理性因素：多发于年轻人，焦虑、压力、精神紊乱、心理障碍等因素导致的ED。5.其他因素：药物的副作用，治疗良性前列腺增生的药物非那雄安、抗焦虑的药物帕罗西汀等都有可能会引起勃起功能障碍。      勃起功能障碍有什么有效的治疗方法呢？1.药物治疗：由于方便、有效、快速、安全等特点，使口服药物治疗成为治疗ED的一线方案。其中根据用药方式的不同，可以分为规律治疗和按需治疗。规律治疗是目前临床上主要的治疗方案，他是利用他达拉非17.5小时长半衰期的特点，通过每天小剂量使用，维持人体内稳定血药浓度，从而达到稳定的治疗效果。规律服用由于单次剂量更小，副作用更小，疗效稳定，并且研究发现长期小剂量使用还可以改善人体的阴茎血管内皮功能。按需治疗主要是帮助解决临时的性需求，代表药物有他达拉非、西地那非（大家熟知的伟哥）、伐地那非。2.真空负压勃起器（VCD）：该种器械套在阴茎上利用手动或电动装置产生负压使得阴茎海绵体充血勃起后在阴茎根部套上伸缩环保持勃起状态即使在血管和神经损伤无法自然勃起的情况下真空勃起器也可以起作用。该方法的缺点在于伴侣不易接受，且无法满足人体的生育需求。3.阴茎假体植入手术：该手术近代的阴茎移植治疗采用的植入假体是合成材料制成的。假体又分为了多种类型可供选择，如完全刚硬型半刚硬型和可充水的伸缩型。    总之，男性勃起功能障碍是一项发病率非常高的疾病，引起这个疾病的因素有很多，目前临床上已经有了非常成熟有效的治疗方案。大家要正确认识自己的问题，到正规的医院寻求医生的帮助，帮助你“重振雄风”！

A comparison among four tract dilation methods of percutaneous nephrolithotomy: a systematic review and meta-analysisCao Dehong • Liu Liangren • Liu Huawei • Wei QiangAbstract The purpose of this study was to evaluate the efficacy and safety of the Amplatz dilation (AD), metal telescopic dilation (MTD), balloon dilation (BD), and oneshot dilation (OSD) methods for tract dilation during percutaneous nephrolithotomy (PCNL). Relevant eligible studies were identified using three electronic databases (Medline, EMBASE, and Cochrane CENTRAL). Database acquisition and quality evaluation were independently performed by two reviewers. Efficacy (stone-free rate, surgical duration, and tract dilatation fluoroscopy time) and safety (transfusion rate and hemoglobin decrease) were evaluated using Review Manager 5.2. Four randomized controlled trials and eight clinical controlled trials involving 6,820 patients met the inclusion criteria. The pooled result from a meta-analysis showed statistically significant differences in tract dilatation fluoroscopy time and hemoglobin decrease between the OSD and MTD groups, which showed comparable stone-free and transfusion rates. Significant differences in transfusion rate were found between the BD and MTD groups. Among patients without previous open renal surgery, those who underwent BD exhibited a lower blood transfusion rate and a shorter surgical duration compared with those who underwent AD. The OSD technique is safer and more efficient than the MTD technique for tract dilation during PCNL, particularly in patients with previous open renal surgery, resulting in a shorter tract dilatation fluoroscopy time and a lesser decrease in hemoglobin. The efficacy and safety of BD are better than AD in patients without previous open renal surgery. The OSD technique should be considered for most patients who undergo PCNL therapy.Keywords  Percutaneous nephrolithotomy ! Tract dilation ! Renal surgery ! Systematic review !Meta-analysis.AbbreviationsPCNL    Percutaneous             nephrolithotomyOSD     One-shot   dilationAD        Amplatz   dilatationMTD     Metal   telescopic dilatationBD        Balloon   dilatation RR         Risk ratioOR        Odds ratioMD       Mean   differenceCI         Confidence   interval.IntroductionPercutaneous nephrolithotomy (PCNL) was first reported more than 35 years ago by Fernstro¨m et al. [1]. In 1976, PCNL was widely used and became a technique for Furthermore, tract dilation is one of the major cost factors in PCNL [3, 4]. Normally, there are three standard tract dilation techniques for PCNL: Amplatz fascial dilation (AD) [5], metal telescopic dilation of the Alken type (MTD) [6], and balloon dilation (BD) [7].However, improvements in tract dilation techniques have led to the introduction of some innovative dilation techniques. One-shot dilation (OSD) was first introduced by Frattini et al. [8]. Among these methods, BD is regarded as the most effective and safe, and it decreases the tract dilatation fluoroscopy time for patients and operators [9, 10]. In contrast, some scholars have reported that OSD is more effective and safer [11–13].As a result, the better method for tract dilation during PCNL is controversial. Most reports relevant to dilation during PCNL come from clinical observational studies [10, 16–20, 27, 28]. Each of the four types of surgical methods has its own advantages and disadvantages and has been selected by different surgeons. Generally, the choice depends on surgeon experience. Therefore, we considered it necessary to perform a systematic review and metaanalysis to compare the efficacy and safety of the four tract dilation methods used during PCNL.Materials and methodsSearch strategy      Medline, EMBASE, and Cochrane central register of controlled trials (CENTRAL) were searched by two cooperators independently (Cao DH and Liu LR). The retrieval deadline was 10th January 2013. The search was performed from the following medical subject heading terms: (Percutaneous Nephrostomy or Nephrostomies, Percutaneous or Percutaneous Nephrostomies or Nephrolithotomy, Percutaneous or Nephrolithotomies, Percutaneous or Percutaneous Nephrolithotomies or Percutaneous Nephrolithotomy) and (tract dilation or tract dilatation or tract creation or nephrostomy tract or nephrostomy access or standard tract or one step or one-stage or one-shot or single increment dilation or Amplatz dilatation or Amplatz dilator or metal telescopic dilation or telescopic technique or balloon dilatation or balloon dilator or fascial dilator). Studies that compared the abovementioned tract dilatation methods among patients who underwent PCNL for the treatment of kidney stones were eligible for inclusion. There were no language restrictions.A database search was performed and the reference lists of the identified articles and other publications were manually searched. All articles were searched independently by two reviewers, and titles and abstracts were screened by Cao DH and Liu LR, respectively. Discrepancies were resolved in consultation with Wei Q.Our main outcomes were the stone-free rate, hemoglobin decrease, tract dilation fluoroscopy time, transfusion rate, and surgical duration. The stone-free rate was defined as all residual fragments of stone with a maximum diameter of \5 mm as evaluated by ultrasonography or kidney–ureter– bladder radiography after the first postoperative visit. Tract dilatation fluoroscopy time was defined as the number of seconds of X-ray exposure that elapsed from the time of insertion of the guidewire until placement of the sheath. Hemoglobin decrease was defined as the change in hemoglobin from before the surgical procedure to 12–24 h after surgery. Stone burden was defined as the maximum diameter of the stone on ultrasonography or plain radiography.   Quality assessmentThe relevant data from the included studies were extracted by two independent reviewers (Cao DH and Liu LR). When the relevant data were missed, we attempted to contact the study authors to obtain more information; otherwise, lost data were calculated by estimation. The quality of the included randomized controlled trials was assessed independently by Cao DH and Liu RL using the Cochrane Collaboration’s tool [14] by recording the assessment of sequence generation, allocation concealment, blinding, incomplete outcome data, free of selective reporting, and other bias. Clinically controlled trials were assessed using a modification of the Newcastle–Ottawa Scale [15]. Review scores ranged from 0 to 9 points for each trial. Scores ranging from 0 to 4 were defined as lowquality scores, while those ranging from 5 to 9 were defined as high-quality scores. Discrepancies were resolved in consultation with Wei Q. AnalysisStatistical analysis was performed using Review Manager (RevMan) software version 5.2 (Cochrane Collaboration, Oxford, UK). The v2 test with N-1 degree of freedom and I2 statistic were used to assess the heterogeneity, with a P value of 0.05 and an a of 0.10 used for the I2 statistic and statistical significance. A P value of\0.05 was considered to be statistically significant. When the I2 value was \60 %, heterogeneity was acceptable. In trials with a lack of heterogeneity, a fixed-effect model was used for the meta-analysis, or a random effects model was used. The odds ratio (OR) or relative risk (RR) was used to evaluate the dichotomous data, and the mean difference (MD) was used to evaluate the continuous data. For comparison of stone-free and transfusion rates between the OSD and MTD groups, the RR with a 95 % confidence interval (CI) was used. For comparison of blood transfusion rates between the BD and AD groups and between the BD and MTD groups, an OR with a 95 % CI was used. For hemoglobin decrease, tract dilatation fluoroscopy time, and surgical duration, the MD was calculated with a 95 % CI. Sensitivity analysis was implemented to explain the existence of significant heterogeneity.ResultsStudy characteristicsAfter a study assessment, four randomized controlled trials [8, 11–13] and eight clinically controlled trials [10, 16–20, 27, 28] involving 6,820 patients met the inclusion criteria from the electronic databases and manual searches. The included literature screening process is summarized in Fig. 1. Three of the included studies [11–13] compared the OSD with MTD methods; four [10, 17–19] compared the BD and AD methods; one [8] compared the MTD, BD, andOSD methods; three [16, 27, 28] compared the MTD and BD methods; and one [20] compared the AD and MTD methods. Basic features and quality assessments of the included studies are summarized in Table 1.EfficacyStone-free rateFour studies [8, 11–13] involving 346 patients compared postoperative stone-free rates after tract dilation during PCNL. The pooled result of the meta-analysis demonstrated no statistically significant differences between the OSD and MTD groups (fixed-effect model; RR = 0.97; 95 % CI = 0.89–1.05; P = 0.44). Statistical heterogeneity was not indicated in the pooled analysis (P = 0.53; I2 = 0 %; Fig. 2a).Surgical durationThreestudies[10,17,18]involving504patientscomparedthe surgical duration between the BD and AD groups. No statistically significant differences were observed between the BD and AD groups (fixed-effect model; MD =-7.10; 95 % CI =-14.86–0.66; P = 0.07). No statistical heterogeneity difference was indicated in the meta-analysis (P = 0.57; I2 = 0 %; Fig. 2b). After deleting the data of Go¨nen et al. [18], the sensitivity analysis demonstrated a statistically significant difference in surgical duration between the BD and AD groups (fixed-effect model; MD =-9.80; 95 % CI = -19.03 to -0.56; P = 0.04; I2 = 0 %). This shows that the meta-analysis was affected by the studies.Tract dilatation fluoroscopy timeFour studies [8, 11–13] involving 346 patients compared the tract dilatation fluoroscopy time between the OSD and MTD groups. A meta-analysis of four studies showed that OSD was associated with a significantly shorter tractBlood transfusion rateFour studies [8, 11–13] involving 346 patients have compared blood transfusion rates between the OSD and MTD groups. Although not statistically significant, the result of the meta-analysis showed that the OSD group was associated with a lower transfusion rate (fixed-effect model; RR = 0.62; 95 % CI = 0.20–1.96; P = 0.42). Statistical heterogeneity was not indicated in the pooled analysis (P = 0.91; I2 = 0 %; Fig. 3a).Three studies [10, 17, 18] involving 504 patients compared blood transfusion rates between the BD and AD groups. Although not statistically significant, the results of the meta-analysis showed that the BD group was associated with a lower transfusion rate (fixed-effect model; OR = 0.61; 95 % CI = 0.35–1.07; P = 0.08). Statistical heterogeneity was not indicated in pooled analysis (P = 0.34; I2 = 8 %; Fig. 3b). After deleting the data of Go¨nen et al. [18], sensitivity analysis showed that there was a statistically significant difference between the BD and AD groups (fixed-effect model; OR = 0.47; 95 % CI = 0.23–0.98; P = 0.04; I2 = 20 %). This indicated that the meta-analysis was influenced by the studies.Four studies [8, 16, 27, 28] involving 5,789 patients compared blood transfusion rates between the BD and MTD groups. The result of meta-analysis showed that BD was associated with a significantly higher transfusion rate (fixed-effect model; OR = 1.51; 95 % CI = 1.21–1.89; P = 0.0003). Statistical heterogeneity was not indicated in the pooled analysis (P = 0.32; I2 = 12 %; Fig. 3c).Hemoglobin decreaseThree studies [8, 11, 13] involving 132 patients compared hemoglobin decrease between the OSD and MTD groups.The result of the meta-analysis showed a lower decrease in the OSD groups than in the MTD groups (fixed-effect model; MD =-0.34; 95 % CI =-0.67 to -0.00;P = 0.05). No heterogeneity was observed in the pooled analysis (P = 0.93; I2 = 0 %; Fig. 3d).Two studies [10, 18] involving 379 patients compared hemoglobin decrease between the BD and AD groups.Although not statistically significant, the result of the metaanalysis showed that BD was associated with a lower decrease in hemoglobin (fixed-effect model; MD =-0.30; 95 % CI =-0.65–0.05; P = 0.10). No statistical heterogeneity was indicated in the pooled analysis (P = 1.00; I2 = 0 %; Fig. 3e).DiscussionTo the best of our knowledge, this is the first systematic review and meta-analysis evaluating the efficacy and safety of four tract dilation methods used during PCNL. In our systematic review and meta-analysis, we included all relevant eligible studies to decrease the confounding variables, decrease bias, and extract data in the most effective manner. After evaluating the studies identified from the databases, four randomized controlled trials [8, 11–13] met the inclusion criteria. We are aware of the many limitations in performing randomized controlled trials of surgical procedures, and common surgical procedures are less likely to be based on this evidence [21, 22]. To enlarge the populations of the included studies, eight assessed clinical controlled trials [10, 16–20, 27, 28] met the inclusion criteria.The main findings of our meta-analysis were that OSD can significantly decrease tract dilatation fluoroscopy time and lower the hemoglobin decrease compared with MTD, particularly in patients with a history of previous open nephrolithotomy. In other words, our results indicate that OSD is effective and safe for patients who have previously undergone open nephrolithotomy. The results clearly showed that there were no significant differences in stonefree and blood transfusion rates between the two groups. The results are consistent with other previous studies [11, 12]. Although rare, conditions for OSD was reportedly unsuited, which can be divided into two main types: kidney.Fig. 3 a Pooled estimate of blood transfusion rate between OSD and MTD using fixed-effect model. b Pooled estimate of blood transfusion rate between BD and AD using fixed-effect model. c Pooled estimate of blood transfusion rate between BD and MTD using fixedeffect model. d Pooled estimate of hemoglobin decrease between OSD and MTD using fixed-effect model. e Pooled estimate of hemoglobin decrease between BD and AD using fixed-effect model hypermobility, which led to avulsion of the entire tissue because of the strength exerted on the vessel pedicle, and heavy resistance of the densely scarred tissue in a previous open renal surgery that prevented the OSD process, necessitating excessive force to dilate the fascia and resulting in kidney bleeding [8]. However, according to our meta-analysis, showed OSD did not lead to more hemorrhages. OSD was clearly proven to be more effective and safer than MTD, even in patients with previous open renal surgery.Some studies reported that BD was associated with a shorter surgical duration, a lower blood transfusion rate, and a lower hemoglobin decrease compared with AD [10, 17, 23]. They considered the following reason for these findings. An inflated balloon supports sustained pressure and tamponades the small vessels that are usually injured during procedures. Significant bleeding may happen frequently during the sequential exchange of AD, but the tamponade effect of the inflated balloon cannot occur with AD [19]. In addition, the tract can be dilated quickly using BD in one step; therefore, BD requires a shorter surgical duration, results in less blood loss, and is less traumatic to the tract [10, 24, 25]. In our meta-analysis, although not statistically significant, the BD groups exhibited a shorter surgical duration, a lower blood transfusion rate, and a lower hemoglobin decrease compared with the AD groups. To our surprise, after deleting the study data of Go¨nen et al. [18], which enrolled patients with a history of previous open nephrolithotomy, a statistically significant difference was found between the BD and AD groups. The BD group was associated with a shorter surgical duration and a lower blood transfusion rate. That is to say, efficacy and safety were decreased in patients with prior open renal surgery who underwent BD during PCNL. The result was confirmed by the study [26]. The reason for this finding is that patients with a previous history of open renal surgery exhibited serious resistance of fascial layers, which prevented BD passage. Therefore, BD was more effective than AD in patients without previous open renal surgery.BD is also reported to be associated with a lower blood transfusion rate compared with MTD [29]. However, the results of the meta-analysis showed that BD was associated with a significantly greater blood transfusion rate compared with MTD. In addition, results of the Global PCNL Study involving5,537patientsalsoshowedagreatertransfusionrate in the BD group than in the MTD group [27, 28]. Differences in results may be influenced by patient heterogeneity, including a history of previous open renal surgery, in addition to the number of staghorn stones, stone burden, and stone location, which are all more frequently associated with BD.By and large, OSD was safe and effective in all the patients. BD was much safer and more effective than AD and MTD in patients without previous open renal surgery. That is, the effectiveness and safety of BD were lower than those of AD and MTD in patients with densely scarred tissue. The advantages of MTD are that it is an effective dilator, and it can dilate even if severe perirenal fibrosis is present after previous surgery. The disadvantages of MTD are that it can cause considerable damage and bleeding. The advantages of AD are that trauma to the renal collecting system is theoretically less likely with this procedure than with MTD; however, the disadvantage is that hemorrhage may occur each time a dilator is withdrawn [30]. Because of the limited number of studies available, differences between AD and MTD were not calculated in this meta- analysis. There was only one study comparing the difference between the two groups [20], and further research is required to clarify these differences.Our review also has some limitations. The evaluation of quality was compromised by the lack of sufficient information in publications or the presence of methodology differences between studies. Several studies did not report the stone-free rate, the blood transfusion rate, etc. These studies did not provide sufficient statistical data and we were unable to obtain relevant data by contacting authors, which may have led to a risk of bias. However, we used sensitivity analysis to explore the influencing factors, which did not significantly change the conclusion. Nonetheless, the statistical heterogeneity and the risk of bias still existed and may have skewed the results. The differences in results may be influenced by patient heterogeneity, including previous open nephrolithotomy, the number of stones treated, stone location, stone burden, rate of staghorn calculi, small sample size, and other factors.Nonetheless, a large number of multicenter randomized controlled trials of high quality are still required to explore the differences among OSD, MTD, BD, and AD.ConclusionsOur meta-analysis showed that OSD was safer and more effective than MTD for tract dilation during PCNL, particularly in patients with previous open renal surgery, resulting in a shorter tract dilatation fluoroscopy time anda lower hemoglobin decrease. The efficacy and safety of BD were better thanADinpatientswithoutpreviousopenrenalsurgery.OSD should be considered for most patients who undergo PCNL therapy. However, multicenter randomized controlled trials are needed to confirm the outcomes of this study.Acknowledgments The authors would like to thank their colleagues and staff in the Chinese Cochrane Centre for their support and help. This research was funded by the National Natural Science Foundation of China (Grant No. 81200551).

Comparison between thulium laser resection of prostate and transurethral plasmakinetic resection of prostate or transurethral resection of prostateHong DeCao1,*, Jia Wang1,*, Yu Huang1,*, Ren LiangLiu1,*, Hao JunLei1, Liang Gao1, Zhuang Tang1, Chun YingHu2, Xiang Li1, Hong JiuYuan1, Qiang Dong1 & Qiang Wei1   Benign prostatic hyperplasia (BPH) is one of the most common diseases in middle-aged and elderly men. In the present study, we aimed to compare the efficacy and safety of thulium laser resection of the prostate (TMLRP) with either transurethral plasmakinetic resection of the prostate (TUPKP) or transurethral resection of the prostate (TURP). A literature search was performed, eventually, 14 studies involving 1587 patients were included. Forest plots were produced by using Revman 5.2.0 software. Our meta-analysis showed that operation time, decrease in hemoglobin level, length of hospital stay, catheterization time, and development of urethral stricture significantly differed, whereas the transitory urge incontinence rate, urinary tract infection rate, and recatheterization rate did not significantly differ between TMLRP and either TURP or TUPKP. The blood transfusion rate was significantly different between TMLRP and TURP, but not between TMLRP and TUPKP. In addition, the retrograde ejaculation rate between TMLRP and TURP did not significantly differ. At 1, 3, 6, and 12 months of postoperative follow-up, the maximum flow rate, post-void residual, quality of life, and International Prostate Symptom Score did not significantly differ among the procedures. Thus, the findings of this study indicate that TMLRP may be a safe and feasible alternative.    Benign prostatic hyperplasia (BPH) is one of the most common diseases in middle-aged and elderly men, and is one of the most common causes of lower urinary tract symptoms (LUTS)1. LUTS cause discomfort, and often have a significant impact on the quality of life (QoL) of patients. Approximately 50–60% of men aged > 60 years suffer from BPH and the associated LUTS2,3. Surgical removal is an appropriate treatment option for patients with moderate to severe LUTS. Although traditional transurethral resection of the prostate (TURP) has been considered as the standard surgical procedure for patients with BPH for decades4,5, it has been associated with the development of significant complications6,7.     With the development of new scientific and technological methods, more advanced surgical techniques are now being employed in BPH treatment. Transurethral plasmakinetic prostatectomy (TUPKP) is one such procedure; it can be performed with normal saline (NaCl 0.9%) irrigation and overcomes a fundamental disadvantage of TURP, which ensures that surgeons have more time to safely resect larger prostates1,8.    The thulium laser resection of the prostate (TMLRP) technique is also a relatively new approach, and was first reported in 20051. In TMLRP, a wavelength of approximately 2 µ m is emitted in continuous-wavemode, thus enabling the precise incision of tissue by using a wavelength that matches the water absorption peak of 1.92 µ m in tissue. Thus, the procedure ensures more effective resection and vaporization of prostate tissue8. In addition, because TMLRP achieves excellent urine clarity after surgery, patients do not require bladder irrigation. Furthermore, the risk of TUR syndrome is decreased because TMLRP involves the use of physiologic saline as the irrigation fluid8,9.Several clinical trials have proven that the aforementioned techniques are all safe and effective for patients with BPH2–4,8,10. However, no published multinational study or other evidence definitively declares the superiority of the TMLRP technique over the others. Therefore, we performed this systematic review and meta-analysis to assess the TMLRP technique in comparison with either TURP or TUPKP.Results    Literature search. We formulated an exhaustive search strategy—using a combination of electronic database and manual searches—to identify all relevant studies. Our search yielded 614 studies, of which 576 were excluded due to irrelevance, based on their titles and abstracts. After a quality assessment, we finally included 14 studies11–24 in this meta-analysis. Our literature screening process is summarized in Fig. 1.     Characteristics of the included studies. Five studies comparing TMLRP to TUPKP11–15; one study comparing TMLRP, TURP, and TUPKP16; and eight studies comparing TMLRP to TURP17–24 were included. Thus, a total of 1587 patients were included in this study from the fourteen trials. Among these patients, 789 underwent TMLRP, 438 underwent TURP, and 360 underwent TUPKP. Ten studies were randomized controlled trials (RCTs)12–14,17–22,24 and four were clinical controlled trials (CCTs)11,15,16,23. All included studies reported the number of participating patients, their age, follow-up time, maximum flow rate (Qmax), and International Prostate Symptom Score (IPSS). Ten studies reported prostate volume12–15,17–24, three studies failed to report prostate specific antigen (PSA) values16,20,23, one study failed to report post-void residual (PVR)23, and two studies failed to report QoL scores11,17. The basic characteristics and quality assessments of the included studies are summarized in Table 1.     Meta-analysis results. Efficacy. Qmax. No significant difference was noted in Qmax between TMLRP and either TURP or TUPKP during the 1-, 3-, 6-, and 12-month postoperative follow-up (all p >  0.05, Table 2).     PVR. Pooled data revealed that there were no significant differences between TMLRP and either TURP or TMLRP in terms of the PVR during the 1-, 3-, 6-, and 12-month postoperative follow-up (all p ≥  0.05, Table 2).     QoL. TMLRP was associated with a higher QoL score than TURP or TUPKP at the 1-month postoperative follow-up (p <  0.0001 and p =  0.003, respectively), although there were no significant differences during the 3-, 6-, and 12-month postoperative follow-up (p >  0.05, Table 2).    IPSS. TMLRP was associated with an IPSS similar to that of TURP or TUPKP at the 1-, 3-, 6-, and 12-month postoperative follow-up (all p >  0.05, Table 2).    Safety. Operative time (minutes). The operative time was recorded in 13 studies11–17,19–24 that included 1491 patients. Analysis of these studies indicated that the operative time for the TMLRP group was significantly longer than that for the TURP group (mean difference [MD]: 9.93; 95% confidence interval [CI]: 3.71 to 16.16; p =  0.002; I2: 81%; Fig. 2a). Moreover, our meta-analysis showed that the operative time for the TMLRP group was longer than that for the TUPKP group (MD: 19.76; 95% CI: 11.99 to 27.53; p <  0.001; I2: 79%; Fig. 2b). This meta-analysis demonstrated that TMLRP involved a longer operation time than either of the other techniques.    Hemoglobin level decrease (g/dL). We extracted data on the decrease in hemoglobin levels from seven relevant studies11–13,15,17,19–20. The decrease in hemoglobin level was significantly lower for the TMLRP group than for the TURP group (MD: − 0.66; 95% CI: − 0.85 to − 0.47; p <  0.001; I2: 5%; Fig. 2c) or TUPKP group (MD: − 0.56; 95% CI: − 1.04 to − 0.08; p =  0.02; I2: 89%; Fig. 2d).     Length of hospital stay (days). This outcome was reported in 11 relevant studies11–14,16,19–24. The pooled analysis indicated that the TMLRP group had a shorter length of hospital stay than either the TURP group (MD: − 2.02; 95% CI: − 3.12 to − 0.93; p <  0.001; I2: 96%; Fig. 3a) or the TUPKP group (MD: − 1.36; 95% CI: − 1.82 to − 0.91; p <  0.001; I2: 81%; Fig. 3b).     Catheterization time (days). Eleven relevant studies12–14,16,17,19–24 including 1266 patients reported on the catheterization time. The pooled data demonstrated a markedly shorter catheterization time for the TMLRP group as compared to either the TURP group (MD: − 1.97; 95% CI: − 2.89 to − 1.05; p <  0.001; I2: 98%; Fig. 3c) or the TUPKP group (MD: − 1.07; 95% CI: − 1.55 to − 0.60; p <  0.001; I2: 88%; Fig. 3d).    Blood transfusion rate. The blood transfusion rate was recorded in 10 studies11,13,15–17,19–22,24 that included 1155 patients. Our meta-analysis indicated that the TMLRP group had a lower blood transfusion rate than the TURP group (odds ratio [OR]: 0.11; 95% CI: 0.03 to 0.35; p <  0.001), although no statistical heterogeneity was observed in this pooled analysis (I2: 0%; Fig. 4a). However, the pooled estimate showed no significant difference between the TMLRP group and the TUPKP group in terms of the blood transfusion rate (OR: 0.41; 95% CI: 0.08 to 2.10; p =  0.28; I2: 0%; Fig. 4b).    Local complication rate. There was no significant difference between TMLRP and either TURP or TUPKP in the transitory urge incontinence rate (OR: 0.59; 95% CI: 0.32 to 1.08; p =  0.09; I2: 0%; Fig. 4c and OR: 1.03; 95% CI: 0.16 to 6.64; p =  0.98; I2: 67%; Fig. 4d, respectively), urinary tract infection (UTI) rate (OR: 0.60; 95% CI: 0.23 to 1.54; p =  0.29; I2: 0%; Fig. 5a and OR: 0.65; 95% CI: 0.10 to 4.10; p =  0.65; Fig. 5b, respectively), and recatheterization rate (OR: 0.71; 95% CI: 0.35 to 1.43; p =  0.34; I2: 18%; Fig. 5c and OR: 0.62; 95% CI: 0.20 to 1.88; p =  0.40; Fig. 5d, respectively). In addition, there was no significant difference in the retrograde ejaculation rate (OR: 0.79; 95% CI: 0.53 to 1.17; p =  0.23; I2: 0%; Fig. 5e) between the TMLRP and TURP groups. However, the pooled estimates were significantly different between the TMLRP group and either the TURP or TUPKP group in terms of the urethral stricture rate (OR: 0.37; 95% CI: 0.14 to 0.98; p =  0.04; I2: 0%; Fig. 6a and OR: 0.09; 95% CI: 0.02 to 0.32; p <  0.001; I2: 35%; Fig. 6b, respectively). Discussion To our knowledge, the present study is the first meta-analysis to compare the safety and efficacy of the TMLRP technique with either the TURP or TUPKP technique in patients with BPH. TURP is reportedly associated with a significant complication rate of 11.1%2. Moreover, TUPKP is a bipolar electrosurgical procedure that can notably reduce complications such as blood loss and other disadvantages associated with TURP25–27. Various laser treatment options have been developed in recent years. Recently, the thulium laser—a new type of surgical laser—is being increasingly applied in the urology field and overcomes many of the limitations of TURP and TUPKP, with encouraging efficacy and safety28,29. These new laser-based treatments can markedly improve the safety of patients and yield excellent results28.     Our meta-analysis showed that the TMLRP group exhibited ideal results as compared to the TUPKP and TURP group in terms of Qmax, PVR, IPSS, and QoL. And the QoL was slightly higher in the TMLRP group as compared to the TURP and TUPKP groups at the 1-month follow-up, and a significant difference was noted. All the micturition parameters of the three groups were similar at the subsequent follow-ups. Our study demonstrated that TMLRP was as effective as TURP and TUPKP in improving patient symptoms and urodynamic measurements postoperatively.     Compared with TURP or TUPKP, our meta-analysis demonstrated that TMLRP had a longer operation time. Xia et al.22 showed that TMLRP had a shorter operation time than TURP, although the difference was not significant. There may be three potential explanations for the longer operation time in the TMLRP group. First, the surgeons may have been more experienced in performing TURP or TUPKP techniques. In contrast, TMLRP is a newer technique, and although the procedure is easy to learn, surgeons need time to overcome the learning curve. Second, the resection volume of prostate tissue may be greater in the TMLRP group than in either the TURP or TUPKP group. Third, TMLRP combines the resection and simultaneous vaporization processes, thus resulting in a longer operation time for tissue-cutting15,19,22. Even though TMLRP had a longer operation time, our meta-analysis indicated that this technique was associated with a lower decrease in serum hemoglobin level, a shorter catheterization time and length of hospital stay, and a lower risk of local complications compared with the other two methods. In addition, our meta-analysis also demonstrated that TMLRP was associated with a lower blood transfusion rate than TURP.     The decrease in serum hemoglobin levels and blood transfusion rate was lower in the TMLRP group, as compared with the TURP or TUPKP group. In fact, among the TMLRP patients included in our meta-analysis, only one patient needed blood transfusion in the study by Kim et al.11. This finding may be explained by the excellent coagulation offered by these techniques, considering that the thulium laser wavelength is superior for controlling bleeding during the operation. The central wavelength of the thulium laser used in TMLRP can be adjusted between 1.75 and 2.22 µ m, which enables the matching of this wavelength with the water absorption peak (1.92 µ m) in tissue. The high density of absorbed energy at the tissue surface leads to instant vaporization and limits the penetration depth from 0.5 to 2 mm, thus indicating that the thulium laser may yield a sufficient hemostasis effect with minimal risk of thermal injury to surrounding tissue29. Due to sufficient hemostatic capacity, the thulium laser also provides a surprisingly visual field, along with low blood loss during surgery30. As an added benefit, the patients’ urine becomes clear more quickly after surgery, thus decreasing both the catheterization time and length of hospital stay. Of course, this may also be attributed to the decreased thermal damage and reduced scar formation as well as lower frequency of urethral stricture after the laser incision31.     We also performed a meta-analysis of the local complication rates between TMLRP and either TURP or TUPKP, including complications such as transitory urge incontinence, UTI, and recatheterization. The present meta-analysis indicated that there was a slightly better improvement of the abovementioned adverse events in the TMLRP group as compared with either the TURP or TUPKP group. In addition, the retrograde ejaculation rate was evaluated between the TMLRP and TURP groups, but no significant difference was noted. Although the findings of the present study support the results of previous clinical trials11–24,32, they still require verification in a large study.     Our meta-analysis does have certain limitations. Some of the results (such as Qmax, PVR, QoL, IPSS, operation time, decrease in hemoglobin level, length of hospital stay, and catheterization time) were associated with certain heterogeneities. These heterogeneities may be a result of several factors such as differences in prostate volume, operator skill, and follow-up duration; insufficient or unclear allocation concealment and blinding. In addition, a major limitation of this study may be our consideration of both thulium laser enucleation and thulium laser vaporesection as TMLRP. Another limitation was the limited number of well-constructed prospective trials; only four CCTs were included in our analysis. Furthermore, the difference in the resected weight of the prostate may have an influence on the results, particularly the operation time values. Nevertheless, we applied a sensitivity analysis to explore the reliability of our meta-analysis results. The results of this analysis did not indicate any substantial change in our initial conclusions. Thus, it also strengthened our level of confidence in the meta-analysis findings and credibility of the pooled results.     In conclusion, although our analysis found that TMLRP was associated with a longer operation time than either TURP or TUPKP, patients undergoing TMLRP might yield other benefits such as lower decreases in serum hemoglobin levels, shorter length of hospital stay and catheterization time, and a lower rate of urethral stricture. In addition, our analysis found that TMLRP was also associated with a lower blood transfusion rate than TURP. Moreover, TMLRP demonstrated similar efficacy in terms of Qmax, IPSS, PVR, and QoL at 1, 3, 6, and 12 months of postoperative follow-up and similar safety in terms of local complications such as transitory urge incontinence, UTI, and recatheterization as compared with either TURP or TUPKP. Our data suggest that TMLRP is a promising, minimally invasive technique that is a safe and feasible alternative to TURP or TUPKP for patients with BPH. Of course, more rigorously designed, larger, high-quality RCTs are required for further verification of these findings.   Methods     Search strategy. The Medline, EMBASE, Web of Science, and Google Scholar databases were independently searched by two reviewers in April 2014. This search used the following terms: thulium laser, TMLRP; transurethral plasmakinetic, TUPKP; transurethral resection of prostate, TURP; and benign prostatic hyperplasia, BPH. Our literature search had neither publication status nor language restrictions. In addition, the reviewing of each relevant article was independently performed by 2 reviewers.     Inclusion and exclusion criteria. Relevant studies were included in this systematic review and meta-analysis if they met the following criteria: (1) compared TMLRP with either TUPKP or TURP, (2) clearly documented the indications for resection of the prostate, (3) provided data for at least one of the predefined outcome measurements. In contrast, studies were excluded if (1) the inclusion criteria were not met or (2) data were not provided or were impossible to calculate for TMLRP or TUPKP or TURP. All study titles and abstracts were independently screened by the same reviewers, and the complete texts were reviewed when deemed necessary. Discrepancies were resolved through consultation with another author. Data extraction. The following variables from each study were recorded independently by two reviewers: first author name, publication year, research design type, intervention method, total number of patients enrolled, patient age, prostate volume, PSA level, Qmax, PVR, QoL, IPSS, and follow-up period duration. In addition, the following outcome measures were extracted: operative time, hemoglobin level decrease, length of hospital stay, catheterization time, blood transfusion rate, and rates of local complications, with the latter including transitory urge incontinence, UTI, recatheterization, retrograde ejaculation, and urethral stricture. Discrepancies were resolved by reaching a consensus between all authors contributing to this review.Quality assessment. The quality of the RCTs included in this systematic review was assessed independently by two reviewers by using the Jadad scale score33, which ranges from 0 to 5 points—the higher the score, the better the quality indication. A study with a Jadad score of 3 points or more was considered as a high quality study. The Jadad score evaluates studies based upon their randomization, blinding, and descriptions of participant withdrawals and dropouts. CCTs that were included in the review were assessed through a modification of the Newcastle-Ottawa Scale34. The review scores ranged from 0 to 9 points for each trial; scores between 0 and 4 implied low-quality, while those between 5 and 9 implied high-quality. Discrepancies were resolved by consultation with another author.

文 / 四川大学华西临床医学院2015级系整A班6组同学指导专家 / 四川大学华西医院泌尿外科王佳教授、曹德宏主治医师、白云金医师【搜狐健康】对于不想喝牛奶或者不想天天喝牛奶这件事，不管是出于过敏、乳糖不耐受、不喜欢味道等等各种原因，在我们医生看来，都是OK的，唯一不能忍的是一些看起来有“道理”，但实质上是鬼扯的谣言——比如，牛奶喝多了要得肾结石。于是，那些坚信的人放弃了牛奶，那些半信半疑的人放弃了高钙牛奶，那些不得好信但怕万一的人放弃了每天一杯牛奶，然后陷入了肾结石和骨质疏松到底哪个先来的迷茫！哎！真嘞是，我们医生又要拿起话筒大声武气地开喊：有肾结石的人都可以照常喝牛奶，你们这些还没有长石头嘞人，慌啥子慌！今天，四川大学华西临床医学院的同学及华西医院泌尿外科的医生一起来给大家讲讲，为啥子喝牛奶不得导致肾结石！肾结石是泌尿系统的常见疾病之一，在30~50岁之间高发。在2017年发表的一项覆盖全国的横断面流行病学研究发现，肾结石在中国成人中的患病率较高，为6.4%，几乎每15人里就有1人患肾结石。而且肾结石又有个特点，就是复发率有点高，得了结石10年的复发率高达50%以上。问：“医生，咋个倒回去几十年感觉没那么多肾结石呢？”答：这确实跟大家这些年生活质量提高，吃得好了有关系，再加上现在体检的普及、检查水平的提高，越来越多的小肾结石就更容易被发现，倒回去几十年，当时的检查仪器还看不到这些的！肾结石是一些晶体物质（如钙、草酸、尿酸、胱氨酸等）和有机基质在肾脏的异常聚积形成草酸钙结石、磷酸钙结石、尿酸结石、磷酸镁胺结石、胱氨酸结石等“石头”。其中，80%的肾结石是含钙类结石。虽然叫含钙类结石，但并不是钙摄入太多引起的，它的发生与年龄（尤其是中老年男性）；高蛋白饮食、大量进食海鲜、肉类等；肥胖、高血脂、高血压、高血糖；慢性肾脏疾病、尿路感染病史；肠道疾病、冠心病等有密切的关系。对于牛奶，大家主要是担心它丰富的蛋白质和钙，天天喝的话身体摄入太多“消化”不到，会引起肾结石。下面，我们就分别从蛋白质和钙这两方面给大家讲一讲，为啥子牛奶跟出现肾结石没有关系！1、牛奶中的蛋白质，并没有多到会引起肾结石问：“医生，你才说了高蛋白饮食和肾结石的发病是有关系的，而牛奶中富含蛋白质，那不是牛奶喝多了就可能导致肾结石的出现？”答：NO！因为喝牛奶≠高蛋白饮食！来看看啥子叫高蛋白饮食，高蛋白饮食是指日常食物中摄入蛋白质含量较多，超过了推荐的蛋白质每日摄入量。这个概念实际上是西方国家提出来的，大家都晓得三，他们可以顿顿是牛排、鸡肉，肉类在他们的饮食中占很大的比例。而相比之下，我们的膳食结构更偏向植物性，比如说吃火锅再咋个都要以一盘土豆冬瓜豆芽收尾，吃羊肉汤如果没有一盆豌豆颠儿那简直不完美，连煮碗面都要丢几根小白菜秧秧看起才舒服。《中国居民膳食指南（2017）》中提到推荐蛋白质的摄入量为1.16-1.27g/（kg·d），这意味着一个体重70kg的成年人，每天推荐摄入75-80g蛋白质。以目前市场上一盒250ml的纯牛奶为例，蛋白质含量约为8g，按照大多数人一天喝一盒250ml牛奶的习惯，我们从牛奶中获得的蛋白质只占每日推荐摄入量的十分之一，只要你不是嘎嘎吃太多，蛋白质不得超标。2、牛奶中的钙，也不会多到吸收成肾结石问：“医生，即使蛋白质不超标，钙超标不是一样会引起肾结石吗？毕竟80%的肾结石是含钙类结石的嘛，毕竟牛奶里面的钙也很啊！”答：看起来这样的逻辑仿佛有点道理，但是，还是错误的哈！首先，我们人体具有强大的调节功能，当摄入了过量钙的时候，你的身体是清醒白醒的，它会在摄入了足够的钙的时候给肠道下达命令，喊它们不要再吸收钙了！所以，不管喝了多少牛奶，可以被人体吸收的钙都是有限的。目前对成年人来说，钙的每日推荐摄入为800mg，一盒250ml的纯牛奶约含有260mg钙，作为补充钙质的优质来源，一盒牛奶补充的钙约为每日推荐摄入量的1/3，所以正常人喝牛奶并不会导致钙摄入量超标。其次，肾结石的形成，实际上是由过多的草酸根离子主导的，而不是钙主导的，意思就是长肾结石要怪这个草酸，而不是怪人家钙。毕竟肠道内不能吸收的钙，在肠道与草酸根结合后会通过粪便排出，而体液里多余的草酸根，就会浓缩在肾脏，通过尿液排出，如果草酸多了，才容易形成肾结石。总结牛奶不仅是一种优质蛋白质和钙的来源，人家还含有一些其它对人体很必要的营养物质和微量元素，所以，只要你对牛奶不过敏、没有乳糖不耐受啊这些，正常人每天喝一盒牛奶是对身体非常有好处的，啥子要得肾结石这些真的不消担心。是的，我们没有豁你，多数的肾结石患者也可以！每！天！喝！牛！奶！问：“医生，这耽怕是有争议哦，我同事遭了肾结石就是医生喊他不要喝牛奶了喃？！”答： 确实有一部分医生会推荐有肾结石的患者不要喝牛奶，认为对于肾结石患者应该限制钙和蛋白的摄入，以免增加肾功能负担。但根据现在的研究看来，肾结石患者对牛奶的限制不应该这么严格。我们华西医生认为，肾结石患者不仅该喝，甚至还要鼓励他们喝牛奶！起码在睡前4小时适量摄入是没有问题的！因为，喝牛奶真的可以帮助控制肾结石患者的病情啊！你想嘛，不被吸收的钙可以在肠道和草酸根离子结合，形成草酸钙从粪便排出，于是草酸根的吸收就相对减少了，这样既不会因为钙被大量吸收形成高钙尿，也有效降低了尿液中的草酸含量，因此，喝牛奶可以同时起到补充钙质和结合尿酸的作用。但是，这里需要敲黑板，有一种肾结石患者，我们的确是不鼓励他们架势喝牛奶的——胱氨酸结石的患者。因为胱氨酸是人体必需氨基酸甲硫氨酸的代谢产物，一部分病人由于基因的问题，导致胱氨酸的排泄量异常增高，容易形成胱氨酸结石，对于成年人来说，这时就需要限制蛋白质的摄入，也就是限制牛奶的摄入。但对于儿童期的这类患者，需要权衡利弊，考虑生长发育的因素，限制可以不那么严格。问：“咋晓得我是不是这种胱氨酸结石呢？”答：一般情况下，肾结石80%都是草酸钙结石，其余20%是其他类型的结石。其中，胱氨酸结石是具有遗传性和高复发性，如果家族中有胱氨酸结石病史的人再加上反复发作的肾结石，那就要怀疑自己的结石有可能就是胱氨酸结石哦！尤其需要碎石、排石的患者，还可以对“石头”做成分分析来确定最终的结石类型。总结所以，多数的肾结石患者可以放心喝牛奶，而家里有胱氨酸结石病史+肾结石反复发作的患者，需要咨询医生意见再来决定是不是该控制喝牛奶的量。【对普通人】还没有出现肾结石的人，预防的方法很简单：多喝水！！尤其多喝白水！另外，啥子菠菜、豆腐吃了要长肾结石啊这些也是没有道理的，还是“多喝水”才是王道。【对有肾结石的人】第一、还是多喝水！肾结石患者应该大量饮水，来稀释尿中形成结石物质的浓度，减少沉积，也利于结石排出。尤其是在夏天, 当每日的尿量低于1200 mL时, 泌尿结石的复发危险性增加, 因此, 需要在一天的各个时间段, 尤其是早晚大量饮水, 避免尿液的浓缩而产生结石。第二，针对结石成分、代谢状态来对应地调节食物构成。草酸盐结石的病人应限制浓茶、菠菜、西红柿、芦笋、花生等摄入。高尿酸病人避免高嘌呤食物如动物内脏。划重点1不管你是哪种类型的肾结石患者，都应该限制钠盐、蛋白质的过量摄入，看到没有，过量！！！增加水果、蔬菜、粗粮、纤维素的摄入。划重点2含糖饮料(包括你们最喜欢的快乐肥宅水)真嘞会增加肾结石风险，同样是不适合肾结石患者的哈。划两根杠的重点慎重补钙！这里说的补钙是吃钙片啊、液体钙的那种补哈，不是指的每天喝牛奶的那种正常摄入。有研究表明，绝经后女性同时补充维生素D和钙，患肾结石的风险会升高18%，因此最好咨询医生后再来看你该不该补、咋个补。参考文献[1]Zeng G, Mai Z, Xia S, Wang Z,Zhang K, Wang L, Long Y,Ma J, Li Y, Wan SP, Wu W, Liu Y, Cui Z, Zhao Z, Qin J, Zeng T, Liu Y,Duan X, Mai X,Yang Z, Kong Z,Zhang T, Cai C, Shao Y, Yue Z,Li S, Ding J, Tang S, Ye Z. Prevalence of kidney stones in China: an ultrasonography based cross-sectional study.[J]. BJU International. 120(1):109-116, 2017 07.[2]Romero V, Akpinar H, Assimos D G. Kidney stones: a global picture of prevalence, incidence, and associated risk factors.[J]. Reviews in Urology, 2010, 12(2-3):e86.[3]Croppi E, Ferraro P M, Taddei L, et al. Prevalence of renal stones in an Italian urban population: a general practice-based study[J]. Urological Research, 2012, 40(5):517-522.[4]何静兵, 孙文斌, 李舟跃, et al. 肾结石发病及危险因素分析[J]. 中国慢性病预防与控制, 2008, 16(6).[5]李婧,杨丽君,陈帆,金伟,杨淑红,刘延友.浅述高蛋白饮食对肾脏产生的影响[J].四川生理科学杂志,2013,35(03):128-132.[6]孙茜.睡前喝牛奶易得肾结石 真的吗?[J].江苏卫生保健,2018(01):46.[7]沈露明. 我国胱氨酸结石患者的临床和基因突变特点[A]. 中国中西医结合学会泌尿外科专业委员会、广东省中西医结合学会泌尿外科专业委员会.中国中西医结合学会泌尿外科专业委员会第十四次全国学术会议暨2016年广东省中西医结合学会泌尿外科专业委员会学术年会论文集[C].中国中西医结合学会泌尿外科专业委员会、广东省中西医结合学会泌尿外科专业委员会:中国中西医结合学会,2016:1.[8]李升华.肾结石患者复发的预防管理对策[J].中医药管理杂志,2018,26(08):198-199.[9] Ferraro PM, Taylor EN, Gambaro G, Curhan GC Soda and other beverages and the risk of kidney stones. Clin J Am Soc Nephrol. 2013 Jul;8(8):1389-95. Epub 2013 May 15.[10] Kahwati LC, Weber RP, Pan H, et al. Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: Evidence Report and Systematic Review for the US Preventive Services Task ForceUSPSTF Evidence Report: Vitamin D and Calcium for Primary Prevention of FracturesUSPSTF Evidence Report: Vitamin D and Calcium for Primary Prevention of Fractures. JAMA. 2018;319(15):1600-1612

        张钰菲，任正举，曹德宏，魏强          （四川大学华西医院泌尿外科、泌尿外科研究所，四川成都，610041） 摘要：炎症可作为致瘤因素，刺激局部组织细胞增生形成肿瘤。“炎-癌转化”在许多癌症如胃癌、肝癌、结肠癌等中均已得到证实。本文首次对前列腺“炎-癌转化”的研究进展进行综述，主要内容包括：组织病理学研究发现慢性前列腺炎和前列腺癌的发生呈正相关；流行病学研究发现前列腺“炎-癌转化”存在种族差异；分子生物学研究发现金属蛋白酶抑制因子 3(Timp3)、核因子 kappaB(NF-κB)、白细胞介素 6（IL-6）、白细胞介素 8（IL-8）、白细胞介素 17（IL-17）、早期生长反应因子 3（EGR-3）等可促进前列腺癌细胞的增殖和侵袭。 关键词：前列腺癌；慢性前列腺炎；炎癌转化；组织病理学；炎症介质中图分类号：R695       文献标志码：R       DOI： 炎症是具有血管系统的活体组织对致炎因子产生的以防御为主的反应。肿瘤是指机体在各种致瘤因子作用下，局部组织细胞增生所形成的新生物。“炎-癌转化”是指炎症转变为癌症，该概念是 19 世纪 60 年代由德国著名病理学家VIRCHOW 首次提出的，他发现肿瘤组织中存在白细胞浸润，认为肿瘤可能起源于慢性炎症部位[1]。而许多研究也证实了慢性炎症与炎症性肠病患者的胃癌、肝癌和结肠癌等癌症有关[2]。炎症可能通过1个或多个潜在的机制促进癌症的发生，包括：①细胞因子和生长因子有利于肿瘤细胞生长；②巨噬细胞和上皮细胞中环氧合酶-2 的诱导；③突变性活性氧和氮的产生[3]。 前列腺炎（prostatitis）是指由多种复杂原因引起的，以尿道刺激症状和慢性盆腔疼痛为主要临床表现的前列腺疾病[4]。1 项回顾性研究发现，前列腺活检、根治性前列腺切除术标本和治疗良性前列腺增生切除的组织中常出现炎症[5]。此外，炎症浸润常出现在以增殖指数增加为特征的萎缩病灶及其周围，这些 收稿日期：2019-4-15     修回日期：2019-5-12 基金项目：国家自然科学基金（No.81770756），四川省科技厅（No.2017KJT0034）通信作者：魏强，教授、博士生导师. E-mail：weiqiang339@126.com 曹德宏，博士、讲师. E-mail：hxcaodehong@163.com. 作者简介：张钰菲，（1998-），女汉族），医师，本科. E-mail：18162271827@163.com；任正举(1989-)，男(土家族)，医师，博士. E-mail：415335464@qq.com，系共同第一作者.网络出版时间：          2019-05-17 10:54:51网络出版地址： http://kns.cnki.net/kcms/detail/61.1374.R.20190517病灶出现增生性炎症性萎缩，可能是早期前列腺癌的前兆，也可能表明前列腺内环境有利于癌症的发展。流行病学研究通过对促炎和抗炎因素的研究间接地验证了慢性炎症在前列腺癌发生中的作用。 我们对综合性传播感染、临床前列腺炎、炎症的遗传和循环标志物以及感染的反应等方面的研究，发现慢性前列腺炎（chronic prostatitis，CPI）与前列腺癌（prostate cancer，PCa）之间存在密切联系。现对前列腺“炎-癌转化”研究的一些新进展进行阐述。 1          慢性前列腺炎与前列腺癌的发生呈正相关 在 1 项关于预防 PCa 的试验中，对病例组（PCa 患者，n=191）和对照组（未患 PCa，n=209）分别进行活检，至少有 1 个炎症活检核心的男性与没有炎症核心的男性相比，前者患 PCa 的几率是后者的 1.78 倍[6]。这提示炎症和癌症的发生之间存在病因联系，并建议通过缓解前列腺内炎症来预防 PCa。 2018年VASAVADA等[7]进行的荟萃分析提示前列腺穿刺活检中出现炎症可能会降低随访诊断PCa的风险。该研究从EMBASE、PubMed和Web of ScienceTM 中检索了从 1990 年 1 月 1 日至 2016 年 10 月 1 日包含关键词 PCa、炎症和活检的摘要，共计 1 030 份摘要。他们对 46 份文献进行了全文回顾，25 份纳入 终分析，共包括 20 585 名受试者和 6 641 名 PCa 患者。在 25 项研究中，任何炎症的存在都与较低的 PCa 风险显著相关当根据炎症类型进行亚分析时，4 项研究中的急性炎症和 15 项研究中的慢性炎症均与较低的 PCa 风险相关。 2          前列腺“炎-癌转化”存在种族差异 流行病学研究发现，白人男性中具有前列腺炎病史的患者临床诊断患 PCa 的风险增加，但组织学研究表明前列腺炎症反而降低了 PCa 的发病风险。 1 项采用嵌套设计的研究，对 574 对（345 对白人，229 对非裔美国人）PCa 和前列腺炎患者[包括临床诊断前列腺炎（NIH I-III 类）和组织学炎症]进行病例对照分析，结果发现在非裔美国人中，临床前列腺炎与 PCa 风险的增加显示出负相关[8]。在白人男性中，仅在无组织学炎症证据时，临床前列腺炎与患 PCa 风险的增加显著相关。前列腺特异性抗原速率（prostate specific antigen velocity， PSAV）和前列腺特异性抗原检测频率可显著降低患 PCa 的风险。这表明前列腺炎症的这些迹象与 PCa 检测之间存在着复杂的相互作用。 3          分子生物学进展 3.1    Timp3 缺失加速 PCa 肿瘤侵袭  蛋白酶的表达和活性改变与炎症和癌症进展有关[9]，蛋白酶活性增高可促进肿瘤的侵袭。组织金属蛋白酶抑制因子 3（tissue inhibitor of metalloproteinase 3, Timp3）是蛋白酶活性的一个重要负调节因子，许多癌症包括晚期 PCa 在内都缺乏 Timp3 的表达，这使得蛋白酶活性不受限制，进而促进肿瘤的侵袭和转移。 ADISSU 等[10]的研究将 Timp3 缺陷小鼠（Timp3-/-）与缺失前列腺特异性肿瘤抑制因子 PTEN（PTEN-/-）的小鼠（一种成熟的 PCa 小鼠模型）杂交，通过组织病理学方法标记肿瘤细胞增殖、侵袭血管的情况，比较 16 周龄的（PTEN-/-、Timp3-/-）和对照（PTEN+/+、Timp3+/+）小鼠的肿瘤生长和进展。结果发现与 PTEN+/+和 Timp3+/+的肿瘤状况相比，PTEN-/-和 Timp3-/-前列腺肿瘤的生长、增殖指数增加，微血管密度和肿瘤浸润性增加，单核细胞趋化蛋白-1、环氧合酶 -2、肿瘤坏死因子α和白细胞介素-1β的表达增加。这些炎症介质导致炎症细胞向缺乏 Timp3 的前列腺肿瘤的浸润明显增加，提示了前列腺炎症是 PCa 进展的一个重要促进因素。 1 项新的研究证实 Timp3 是微小核糖核酸-191（miR-191）的直接靶基因， miR-191 可通过下调 Timp3 的活性来促进 PCa 细胞生长和侵袭能力。该研究采用人 PCa 细胞株 DU145、PC-3、LNCAP、BPH 和人前列腺上皮细胞株 RWPE-1，通过合成的 miR-191 类似物和抑制剂来过度表达或抑制 miR-191 水平，结果发现与正常组相比，PCa 组织样品中的 miR-191 过度表达，PCa 衍生细胞系中的 miR-191 也过表达。在 PC-3 细胞中上调 miR-191 显著促进 PCa 的侵袭，而在DU145 细胞中下调 miR-191 则延缓了癌细胞的增殖和侵袭。Timp3 的敲除可逆转 miR-191 的下调功能[11]。 3.2    CPI可促使肿瘤细胞存活  炎症通过控制肿瘤微环境参与PCa发生过程中细胞事件的调节[12]。多种骨髓源性细胞包括 CD4+淋巴细胞、巨噬细胞和骨髓源性抑制细胞等，是肿瘤微环境的组成成分之一[13]。 NGUYEN 等[14]的研究发现在炎症细胞因子激活后，核因子 kappaB（NuclearFactor-kappaB, NF-κB）复合物能够通过 PCa 的抗凋亡信号促进肿瘤细胞存活，再通过正反馈途径维持 NF-κB 的激活。 WANG 等[15]的研究进一步发现成纤维细胞生长因子（fibroblast growth factor,FGF）可促进 PCa 细胞中的 NF-κB 信号传导，并且这种变化与成纤维细胞生长因子受体 1（fibroblast growth factor receptor 1, FGFR1）的表达有关，FGFR1 激酶活性的中断会使 PCa 细胞中的 FGF 活性和 NF-κB 信号都丧失。在 FGFR1 刺激 NF-κB 信号的过程中，转化生长因子β激酶 1（transforming growth factor-β-activated kinase 1, TAK1）是必需的物质。FGFR1 通过减少 TAK1 的降解来促进 PCa 细胞中的 NF-κB 信号传导，从而使 NF-κB 通路持续激活。 3.3    白细胞介素 6 促进 PCa 细胞增殖  慢性炎症可参与 PCa 发生过程中细胞事件的调节，包括免疫反应的破坏和肿瘤微环境的调节[16]。在 PCa 中，慢性炎症好的代替指标之一是白细胞介素 6（interleukin 6, IL-6）。 研究发现未治疗的转移性或去势抵抗性 PCa（castration resistant prostatecancer, CRPC）患者血清 IL-6 水平升高，与肿瘤生存和化疗反应呈负相关[17]。IL-6 可通过 Janus 酪氨酸家族激酶（JAK）信号转导子和转录激活因子（activator oftranscription 3, STAT）、细胞外信号调节激酶 1 和 2（extracellular signal-regulated kinase 1/2, ERK1/2）、丝裂原激活蛋白激酶（mitogen activated protein kinase, MAPK）和磷酸肌醇 3 激酶（phosphoinositide 3-kinase, PI3-K）等多种信号途径，在体外和体内抑制肿瘤细胞凋亡，促进 PCa 细胞的增殖。 3.4    低表达 CD38 可引发 PCa  LIU 等[18]的研究发现了低表达 CD38（CD38LO）可识别人类前列腺管腔细胞的祖细胞样亚群。CD38LO 管腔细胞在邻近炎性细胞的腺体中富集，并表现出上皮 NF-κB 信号，CD38LO 管腔细胞可以在体内组织再生试验中启动人类 PCa 的癌基因，参与致癌转化。研究还发现 CD38LO 管腔细胞表型和基因特征与 PCa 的疾病进展和不良预后相关，前列腺炎症扩大了易受肿瘤发生影响的祖细胞样靶细胞的数量。 癌细胞代谢需要细胞内存在烟酰胺腺嘌呤二核苷酸（nicotinamide adeninedinucleotide, NAD+），维持 NAD+水解酶活性和 NAD+合成酶活性的平衡。 CHMIELEWSKI 等[19]的研究发现在细胞中表达的 CD38 可降低细胞内 NAD+的水平，导致细胞周期停滞和抑癌基因 p21Cip1（CDKNA1）的表达。同时，CD38 降低糖酵解和线粒体代谢，激活一磷酸腺苷(adenosine monophosphate，AMP）活化蛋白激酶（AMP-activated Protein Kina, AMPK），抑制脂肪酸和脂质合成。新的研究发现与良性前列腺增生相比，PCa 中 CD38 的表达降低[20]，提示肿瘤细胞可能通过减少 CD38 的表达，以增强细胞内 NAD+的聚集，促进癌细胞代谢。 3.5    EGR-3 可促进 IL6 和 IL8 表达  与正常组织相比，早期生长反应因子 3（early growth response 3, EGR-3）在人类前列腺肿瘤中高度表达。BARON 等[21]通过沉淀分析、功能获得实验发现了潜在的 EGR-3 靶基因，EGR-3 调控了约 330 个基因的表达，其中 35%参与免疫反应和炎症过程，15%与 NF-κB 信号通路联系在一起作用于肿瘤细胞的存活。EGR-3 可诱导 50 多种分泌细胞因子、生长因子和基质重塑因子的表达，两个与 PCa 密切相关的白细胞介素 IL6 和 IL8 被进一步验证为 EGR3 靶基因：两个启动子都含有 EGR 共识结合位点。所以 EGR-3 高表达可促进 IL6 和 IL8 的过度产生，导致疾病进展和去势抵抗的发生。 3.6    高胰岛素血症促进 PCa 发展  IL-17 在炎症、自身免疫性疾病和某些癌症中起着重要作用[22]。肥胖患者由于处于慢性炎症状态，血清 IL-17、胰岛素和胰岛素样生长因子 1（insulin-like growth factor 1, IGF1）水平升高[23]，可抑制糖原合成酶激酶 3（glycogen synthase kinase 3, GSK3）和 IL-17 受体 A（interleukin 17 receptor A, IL-17RA）的结合及磷酸化，进而抑制 IL-17RA 的泛素化和蛋白酶体介导的 IL-17RA 降解，从而诱导 IL-17 介导的炎症[24]。 一研究发现，在肥胖小鼠中，高胰岛素血症通过抑制 GSK3 介导的磷酸化和 IL-17RA 的降解，增强 IL-17 诱导下游促炎基因的表达，导致更具侵袭性的 PCa 的发生[25]。与正常细胞相比，增生性 PCa 细胞的 IL-17RA 磷酸化降低，IL-17RA 水平升高。在体外培养的 PCa 细胞系和肥胖小鼠体内模型中显示，胰岛素和 IGF1 通过抑制 GSK3 增强 IL-17 诱导的炎症反应，促进了侵袭性 PCa 的发生。 4          展望 PCa 的组织病理学分析对前列腺“炎-癌转化”的有一定的参考意义，但前列腺炎和 PCa 之间具体的联系仍需要更多的临床研究进行证明。前列腺“炎-癌转化”存在的种族差异还需更多的临床研究来支持，同时应该纳入更多的人种，不同人群之间进行对比，探究不同的基因、环境等对前列腺“炎-癌转化”的影响。目前可确定 Timp3、NF-κB、IL-6、IL-8、IL-17、EGR-3、低水平 CD38 等分子参与了前列腺“炎-癌转化”的过程，虽然具体机制还有待研究，但可作为生物标记物为 PCa 的预防、治疗和预后提供新的方向[26]。 参考文献 [1]     HEIDLAND A, KLASSEN A, RUTKOWSKI P, et al. The contribution of Rudolf Virchow to the concept of inflammation: what is still of importance?[J]. J Nephrol, 2006, 19(Suppl 10) :S102-109.[2]     COUSSENS LM, WERB Z. Inflammation and cancer[J]. Nature, 2002, 420(6917):860-867.[3]     LUCIA MS, TORKKO KC. Inflammation as a target for prostate cancer chemoprevention: pathological and laboratory rationale[J]. J Urol, 2004, 171(2 Pt 2):S30-34; discussion S35.[4]     KHAN FU, IHSAN AU, KHAN HU, et al. Comprehensive overview of prostatitis[J]. Biomed Pharmacother, 2017, 94:1064-1076.[5]     PLATZ EA, De MARZO AM. Epidemiology of inflammation and prostate cancer[J]. J Urol, 2004, 171(2 Pt 2):S36-40.[6]     GUREL B, LUCIA MS, THOMPSON IM Jr, et al. Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial[J]. Cancer Epidemiol Biomarkers Prev, 2014, 23(5):847-856.[7]     VASAVADA SR, DOBBS RW, KAJDACSY-BALLA AA, et al. Inflammation on prostate needle biopsy is associated with lower prostate cancer risk: a Meta-analysis[J]. J Urol, 2018, 199(5):1174-1181.[8]     RYBICKI BA, KRYVENKO ON, WANG Y, et al. Racial differences in the relationship between clinical prostatitis, presence of inflammation in benign prostate and subsequent risk of prostate cancer[J]. Prostate Cancer Prostatic Dis, 2016, 19(2):145-150.[9]     EFTEKHARI R, De LIMA SG, LIU Y, et el. Microenvironment proteinases, proteinase-activated receptor regulation, cancer and inflammation[J]. Biol Chem, 2018, 399(9):1023-1039.[10] ADISSU HA, MCKERLIE C, Di GRAPPA M, et al. Timp3 loss accelerates tumour invasion and increases prostate inflammation in a mouse model of prostate cancer[J]. Prostate, 2015, 75(16):1831-1843.[11] WANG X, SHI Z, LIU X, et al. Upregulation of miR-191 promotes cell growth and invasion via targeting TIMP3 in prostate cancer[J]. J BUON, 2018, 23(2):444-452.[12] GUERON G, De SIERVI A, VAZQUEZ E. Advanced prostate cancer:reinforcing the strings between inflammation and the metastatic behavior[J].Prostate Cancer Prostatic Dis, 2012, 15(3):213-221.[13] STAKHEYEVA M, RIABOV V, MITROFANOVA I, et al. Role of the immune component of tumor microenvironment in the efficiency of cancer treatment:perspectives for the personalized therapy[J]. Curr Pharm Des, 2017, 23(32):4807-4826.[14] NGUYEN, DP, LI J, YADAV SS, et al. Recent insights into NF-κB signalling pathways and the link between inflammation and prostate cancer[J]. BJU Int, 2014, 114(2):168-176.[15] WANG C, KE Y, LIU S. Ectopic fibroblast growth factor receptor 1 promotes inflammation by promoting nuclear factor-κB signaling in prostate cancer cells[J].J Biol Chem, 2018, 293(38):14839-14849.[16] TAVERNA G, PEDRETTI E, Di CARO G, et al. Inflammation and prostate cancer: friends or foe?[J]. Inflamm Res, 2015, 64(5):275-286.[17] NGUYEN DP, LI J, TEWARI AK. Inflammation and prostate cancer: the role of interleukin 6 (IL-6)[J]. BJU Int, 2014, 113(6):986-992.[18] LIU X, GROGAN TR, HIERONYMUS H, et al. Low CD38 identifies progenitor-like inflammation-associated luminal cells that can initiate human prostate cancer and predict poor outcome[J]. Cell Rep, 2016, 17(10):2596-2606.[19] CHMIELEWSKI JP, BOWLBY SC, WHEELER FB, et al. CD38 inhibits prostate cancer metabolism and proliferation by reducing cellular NAD+ pools[J].Mol Cancer Res, 2019, 16(11):1687-1700.[20] MOTTAHEDEH J, HAFFNER MC, GROGAN TR, et al. CD38 is methylated in prostatecancer and regulates extracellular NAD[J]. Cancer Metab, 2018, 6:13.[21] BARON VT, PIO R, JIA Z, et al. Early Growth Response 3 regulates genes of inflammation and directly activates IL6 and IL8 expression in prostate cancer[J].Br J Cancer, 2015, 112(4):755-764.[22] KRYCZEK I, WU K, ZHAO E, et al. IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer[J]. J Immunol, 2011, 186(7):4388-4395.[23] AHMED M, GAFFEN SL. IL-17 in obesity and adipogenesis[J]. Cytokine Growth Factor Rev, 2010, 21(6):449-453.[24] GE D, DAUCHY RT, LIU S, et al. Insulin and IGF1 enhance IL-17-induced chemokine expression through a GSK3B-dependent mechanism: a new target for melatonin's anti-inflammatory action[J]. J Pineal Res, 2013, 55(4):377-387.[25] LIU S, ZHANG Q, CHEN C, et al. Hyperinsulinemia enhances interleukin-17-induced inflammation to promote prostate cancer development in obese mice through inhibiting glycogen synthase kinase 3-mediated phosphorylation and degradation of interleukin-17 receptor[J]. Oncotarget, 2016, 7(12):13651-13666.[26] SCHILLACI O, SCIMECA M, TRIVIGNO D, et al. Prostate cancer and inflammation: A new molecular imaging challenge in the era of personalized medicine[J]. Nucl Med Biol, 2019, 68-69:66-79.

炎症与良性前列腺增生及CD40/CD40L信号通路的研究进展 曹德宏, 柳良仁 综述，魏强，王佳 校审 （四川大学华西医院泌尿外科，四川成都 610041） 摘要：良性前列腺增生（BPH）是引起老年男性排尿障碍中最为常见的一种良性疾病。公认老龄和有功能的睾丸是其发病的两个重要因素，但其确切病因仍不明确。研究证实组织炎症与其关系密切，并且CD40/CD40L 免疫学信号通路可能在前列腺增生疾病中发挥了一定作用。本文就组织炎症与BPH及CD40/CD40L信号通路的研究进展进行综述。 关键词：炎症、良性前列腺增生、CD40、CD40L、信号通路中图分类号：R 392 文献标志码：A 良性前列腺增生症（benign prostatic hyperplasia, BPH）简称前列腺增生，亦名前列腺肥大，是引起老年男性排尿障碍原因中最为常见的一种良性疾病。有关BPH的发病机制研究较多，尽管老龄和有功能的睾丸被公认为是BPH发病的两个重要因素，但确切病因仍不完全清楚，有研究认为组织炎症与 BPH 的发生及进展关系密切。CD40/CD40L 是重要的免疫学信号通路，可通过下游信号通路的激活诱导炎症的发生及组织增生。当前研究也已证实 CD40/CD40L 信号通路蛋白均表达于前列腺组织，且伴有组织炎症的 BPH 组织中其表达量更高。本文将近年来有关炎症与BPH及CD40/CD40L的作用及相关性予以综述。 1 组织炎症与 BPH BPH是发生在老年男性中的常见疾病之一，其组织学诊断是指前列腺移行区平滑肌和上 皮细胞的增殖，主要引起腺体增生并且通常导致下尿路症状(lower urinary tract symptoms, LUTS)[1]。其发生率随着年龄的增长而增加。在60岁以上男性中, 50%被诊断为BPH；70岁以上有75%的男性有一个或多个症状归因于BPH；85岁以上的男性，90%有LUTS的症状；几乎所有的男性在90岁都有因BPH引起的症状[2]。目前认为BPH的危险因素主要有5类：除了年龄外，其它与遗传、性类固醇激素、生活方式和炎症密切相关[3]。 BPH代表着一种被炎性介质、氧化应激等促进前列腺细胞增殖而不受调控的良性疾病。已有大量的临床研究表明组织炎症与BPH的发生和进展密切相关，然而其机制仍不清楚[4]。在BPH病变组织中通常发现伴有炎症浸润，有研究者认为可能这些炎症细胞释放细胞因子和生长因子，进而刺激前列腺基质和上皮细胞增殖[5]。研究已发现BPH与组织炎症的关系紧密相连，炎症的范围和分级与BPH的区域及程度一致[6-9]。在BPH标本中也常常能观察到组织炎症的浸润。NICKEL等[10]对年龄在50~75岁的8 224位男性前列腺穿刺：结果发现77.4% 标本中伴有组织炎症，并且证实患者下尿路症状的程度与炎症分级呈正相关。SONG 等[11]对经过外科治疗的454位BPH患者的前列腺标本进行研究，结果发现95.6%的标本伴有组织炎症，并且炎性细胞浸润BPH组织明显有助于血清PSA水平的升高。BAO等[12]回顾性地分析102 位BPH患者，结果发现伴有组织炎症的BPH组比单纯BPH组患者发生急性尿潴留的发生率高 2.326倍。 ZLOTTA 等[13]对 320 例 30-80 岁亚洲和白种人尸体的前列腺进行研究：结果发现超过 70%的尸体的前列腺组织中伴有慢性炎症，并且伴有慢性炎症组的 BPH 评分比无炎症组的 收稿日期：2015-07-10修回日期：2015-09-01 基金项目：国家自然科学基金（No. 30901484, 81370855，2015SZ0230）通讯作者：魏强，主任医师、教授、博士生导师，E-mail: wqurologist@163.com 王佳，主任医师、教授、博士生导师，E-mail：wangjiaa2002@sina.com 作者简介：曹德宏（1987-），男（汉族），医师，博士在读. 研究方向：微创泌尿、泌尿系疾 病.E-mail:hxcaodehong@163.com 柳良人（1983-），男（汉族），主治医师，博士. 研究方向：前列腺疾病、泌尿系疾 病.E-mail:liuliangren5-17@163.com 系共同第一作者网络出版时间： 2015-10-15 11:22:05 网络出版地址： http://www.cnki.net/kcms/detail/61.1374.R.20151015.1122.002.html 高 6.8 倍。SHAFIEE 等[14]在前列腺疾病动物模型中，纳入了 12 只雄性犬对其前列腺进行研究，结果也表明组织炎症可能是 BPH 进展的重要原因。最近 TORKKO 等[15]对 859 例前列腺活检患者的炎性标志物 CD4、CD8、 CD45 和 CD68 与 BPH 的临床进展风险进行了研究，发现炎症标志物水平与 BPH 的临床进展风险呈正相关。尽管目前仍没有充足的证据表明组织炎症在 BPH 中发病机理和进展的因果关系，但研究数据已表明慢性炎症在老年男性 BPH 组织中是普遍存在的，并且两者关系非常密切。有研究认为炎症反应相关的组织损伤和随后的慢性组织愈合可能是导致 BPH 发展和炎性增殖的原因[5]。炎症浸润在 BPH 患者术后的前列腺组织中十分常见，并且炎症的程度与前列腺的体积和重量有关；炎性损伤有助于前列腺组织通过炎性细胞激发局部生长因子和血管生成因子产生炎性细胞因子。 最近的研究也表明 BPH 是一种免疫炎性疾病，T 细胞的激活及其与之相关的自身免疫反应可能会诱导上皮和基质细胞增殖[16]。通过对 BPH 中组织炎症作用的进一步认识将会拓宽人们对 BPH 病理机制的了解，可以对表现有下尿路症状的 BPH 患者进行危险程度分析，这意味着新的治疗策略可能出现[16]。 2 CD40/CD40L信号通路与炎症 2.1 CD40及CD40L的结构和分布 CD40是一种含有277个氨基酸、分子量为48 kDa大小的细胞表面Ⅰ型跨膜糖蛋白，由跨膜区、胞浆区、胞膜外区和N端信号肽组成; 它被一个仅1.5 Kb大小的信使RNA编码，并且其基因位于人20号染色体的q12-13.2区域[18]。CD40属于肿瘤坏死因子受体家族成员，胞外域为富含半胱氨酸重复序列，包含171个氨基酸，可导致四个亚区和N-氨基末端变形，其中每个亚区又通过二硫键后维持稳定特性。CD40主要表达B细胞、单核细胞/巨噬细胞和树突状细胞的表面,其次也表达于其他细胞如内皮细胞、上皮细胞、平滑肌细胞、角化细胞、成纤维细胞和血小板[19]。CD40的表达能够通过炎性刺激诱导：如IL-1、IL-3、IL-4、TNF-α 和IFN-γ等；通过转录因子如NF-κB和转录激活蛋白激酶调节。除此之外，CD40能够被其配体CD40L激活。 CD40L 又名 CD154、肿瘤坏死因子相关激活蛋白，是 CD40 的配体，分子大小为 39 kD 的肿瘤坏死因子超家族成员[20]。其基因位于X染色体的q26.3-q27.1区域，被认为与CD40 胞外的第二或第三亚区结合、一种能被T淋巴激活后高度表达的细胞表面Ⅱ型跨膜糖蛋白。它含有一个细胞内氨基端和一个外部羧基末端，主要表达于活化的T细胞和血小板，也可表达其他各种细胞：上皮细胞、白细胞、内皮细胞、平滑肌细胞[21]。CD40L 有单聚体、二聚体和三聚体三种类型，除了三聚体的膜结合型外，CD40L 可脱落至血浆，成为可溶性的 sCD40L，研究也表明高水平的sCD40L似乎还是心血管疾病的一个重要征兆[22]。 2.2 CD40/CD40L信号通路的组成及传导 CD40 与 CD40L 结合后启动信号传导，这也是炎症反应中重要的信号转导通路之一，它们的交互作用引起体内产生多种不同的促炎细胞因子，包括 IL-8，单核细胞趋化蛋白-1 （MCP-1）、趋化因子（RANTES）。由于CD40分子胞浆内C-末端缺乏酶活性，CD40和CD40L 在细胞内信号的交互初始是通过肿瘤坏死因子受体相关因子（TRAFs）衔接，随后胞浆激酶和蛋白作用被激活。CD40能够结合TRAF-1，-2，-3，-5和-6，结合不同的TRAF分子取决于细胞的类型和功能，结合后启动不同的信号传导通路，CD40L 能增强 TRAF-1，-2，-3 和 -6的信号表达[23-24]。例如单核/巨噬细胞中，CD40与TRAF6衔接是活化ERK1/2、Src、和IKK、 NF-κB启动促炎反应通路的重要组成，而与TRAF2，3，5衔接则不能启动炎症信号通路[25]。除此之外，CD40信号系统的传导不仅与其结合的TRAF的不同家族成员有关，而且与其受体激活后是否内化有关。受体内化后既可以关闭也可以激活信号传导通路复合体，主要取决于受体募集的胞浆内的复合体。静息状态时，小部分CD40分子位于细胞膜内的脂筏，受到细胞内外刺激后大部分 CD40 转移到脂筏内。对于树突状细胞和 B 细胞，CD40 在脂筏内与 TRAF2/3及下游信号分子相互结合；在内皮细胞膜表面，CD40与CD40L交互后，易位到脂筏与TRAF3结合，通过AKT和NF-κB信号通路诱导促炎细胞因子的产生[26]。而当CD40与sCD40L 交互后，CD40通过Rab5进入胞内与TRAF2和TRAF3衔接，使AKT磷酸化并激活NF-κB，但不能产生促炎细胞因子[27]。 CD40/CD40L信号通路可以发挥多种生物学效应：①、增加细胞因子的表达，如INF-α、 Th1细胞因子、IL-12、IFN-α和NO的产生；②、引起额外的共刺激分子（CD80和CD86）对抗原呈递细胞的上调；③、提高细胞存活，尤其是B细胞和T细胞，树突状细胞和内皮细胞； ④、引起Ig同种型的转换和Ig的超突变[28-30]。NF-κB是CD40/CD40L信号通路的重要信号蛋白，CD40/CD40L 信号通路激活后可导致 NF-κB 易位到细胞核后启动炎性反应[21]。NF-kB 的家族成员包括P50 (P105的处理产物，两者又名为NF-κB1), P52 (p100的处理产物,两者又名为NF-κB2)， P65 (Rel-A)，c-Rel (Rel)， 和Rel-B。NF-κB的每个家族成员都有保守的Rel同源区（RHD），其包含三种类型的基序：核定位的基序，又被称为核定位信号（NLS）；结合特异性DNA序列的基序和二聚化的基序。NF-κB1和NF-κB2 仅包含一个RHD区域，而 Rel-A、Rel、和Rel-B不仅包含一个RHD区外，还包含一个转录活化区域[31]。在静息时，大部分的NF-κB 二聚体通过与细胞质中抑制因子（IκBa、 IκBβ和IκBε）锚蛋白区中的一种结合而以无活性的状态存在于细胞质中。IκB蛋白的主要功能是掩盖NF-κB的NLS信号，阻止其入核后与 DNA 结合，保持 NF-κB 以非活化形式存在于细胞质中。各种信号通过降解 IκBs以活化NF-κB，活化后的NF-κB转位到细胞核内并与其相关的DNA基因序列结合以诱导靶基因的转录。 2.3 CD40/CD40L信号通路与炎症 激活共刺激系统CD40/CD40L和NF-κB通路将促进炎症反应，Wang等[32]进行了一项研究通过同时阻断CD40/CD40L和IκB/NF-κB通路能否保护同种异体移植胰岛，结果发现同时阻断后其 TNF-α, IL-1β和 IFN-γ及炎性细胞浸润明显减少，能够有效的延长鼠同种异体移植胰岛的存活时间。CD40 与 CD40L 的交互作用可促进多种细胞前炎性细胞因子和趋化因子的产生及上调，在炎症发生及进展中起重要作用[33]。QI等[34]对CD40/CD40L在XG1多发性骨髓瘤的共同表达促进IL-6自分泌功能进行了研究，结果发现CD40/CD40L共同表达于XG1多发性骨髓瘤，并且CD40/CD40L对XG1多发性骨髓瘤细胞产生和自分泌IL-6是非常重要的，还发现TNF-α增强了CD40和CD40L的表达，CD40/CD40L信号对于细胞中NF-κB的激活非常重要。 在体液免疫中，CD40/CD40L信号通路对B细胞的活化、增殖及抗体的产生起着重要作用。 CD40与CD40L交互作用可以增加B细胞DNA的合成，引起B细胞的增殖，进而分泌多种粘附分子；此外，还可诱导B细胞进行Ig类别转换和调节B细胞的存活和凋亡[35]。在细胞免疫中，CD40/CD40L交互可通过T细胞和抗原提呈细胞刺激淋巴细胞表达CD40L，进而分泌粘附分子[36]。CD40/CD40L交互还可促进CD4+T细胞自身活化， 提高CD40L和CD25表达水平，促进IL-12的分泌，进而产生及诱导T细胞向Th1细胞因子分化（如IFN-γ）等。 CD40/CD40L交互后可使炎症细胞产生炎性介质，如树突状细胞分泌IL-8、IFN-γ、巨噬细胞炎性蛋白 1α（MIP-1α）。在单核/巨噬细胞中，CD40/C40L 的交互可以上调其细胞表面的CD40、CD54及MHC等的表达，增强抗原提呈作用，促进IL-1β、IL-6、IL-12、MCP-1、 TNF-α、NO、PDGF及基质金属蛋白酶等的分泌，同时能够抑制单核细胞的凋亡，这也许是由于CD40信号直接激活细胞内抗凋亡基因，通过活化抗凋亡蛋白或者抑制凋亡基因的表达所致。在内皮细胞中，CD40/CD40L交互可增进内皮细胞表面CD54及CD106等的表达，并促进内皮细胞粘附分子（如E选择素）表达增加，淋巴细胞迁移至炎症部位，进而加重炎症反应。 在成纤维细胞中，CD40/CD40L 交互可上调 CD54 和 CD106，促进其活化、增殖和产生 IL-6 等炎症因子的释放，并参与组织的修复及重建。 3 通过炎性介质抗BPH的植物药进展 炎症在BPH的发病机制和进展中似乎起着重要作用，抑制炎症的通路有助于降低BPH的风险，因此，炎症也许可作为治疗BPH/LUTS的一个新靶点[37]。当前植物制剂在BPH药物治疗领域越来越引起人们的关注。YANG等[38]研究了披针新月蕨对睾酮诱导BPH时，通过调节其炎症反应、降低氧化应激和抗前列腺细胞增殖来发挥保护作用，研究证实来自披针新月蕨中的总黄酮醇苷和酸解产物能明显降低前列腺组织中炎性细胞因子（环氧酶-2，TNF-α， IL-1β，IL-6，IL-8 和IL-17）的表达水平，下调PI3K/Akt、NF-κB 和Bcl-2 等蛋白的表达，通过抗炎、抗氧化和抗前列腺细胞增殖来抗BPH的发生和进展。 目前研究也发现水飞蓟素能通过抑制炎性介质抗BPH作用。ATAWIA 等[39]在睾酮诱导BPH 的动物模型中，睾酮能明显增加大鼠前列腺的重量、组织炎症、组织增生和胶原沉积，而水飞蓟素的治疗能够明显减轻炎症反应，降低前列腺重量。进一步研究发现水飞蓟素通过降低睾酮引导的NF-κB的表达水平、减弱随后的炎症级联反应及环氧酶-II表达，诱导一氧化氮合成酶上调，并且降低一氧化氮水平和IL-6及IL-8的mRNA表达量，从而抑制前列腺上皮与基质细胞增殖。 最近CHUNG等[40] 对研究了白藜芦醇通过调节炎症及凋亡蛋白在BPH中的作用研究，该团队认为BPH是与炎症、细胞生长和凋亡的不平衡相关的一种疾病，研究发现白藜芦醇能够明显降低大鼠前列腺的重量，抑制细胞增殖，并且能够明显降低BPH相关的iNOS和COX-2 蛋白的表达。除此之外，还可以促进Bax的表达、抑制Bcl-2和Bcl-xL的表达。这表明白藜芦醇通过调节涉及在BPH中炎症与凋亡蛋白的表达水平后，产生了一种抗BPH细胞增殖的作用，从而抑制BPH的发生。 PENG等[41]研究了从樟芝菌丝中提取的名为Antrodan的β-葡聚糖，结果发现其能减少 BPH引起大部分病理生理学临床表现，通过缓解前列腺上皮增生和胶原沉积并且抑制活性氧的产生、上调IL-1、COX-2和CD68的表达。除此之外，它也能有效的抑制血清睾酮和二氢睾酮的水平并且抑制芳香酶、雌激素和雄激素受体的表达。更重要的是，还能抑制 N-钙粘素和波形蛋白及上调E-钙粘素，具有潜在的抑制上皮-基质细胞转换作用。因而，有利于BPH 的治疗。 BERNICHTEIN等[42]研究了伯泌松（蓝棕植物的固醇脂提取物）抗小鼠前列腺增生的作用，使用Ki-67免疫染色作为细胞增殖和Bax/Bcl2mRNA的比值作为凋亡的指标。组织学分析和 CD45免疫染色评估组织炎症和纤维化。使用定量的RT-PCR技术分析促炎细胞因子、趋化因子和趋化因子受体的表达谱。结果发现伯泌松能够明显降低前列腺组织重量和增殖，下调前列腺的促炎细胞因子的表达量，明显降低CCR7，CXCL6，IL-6和IL-17的表达。该研究结论支持伯泌松的角色在治疗BPH的效果是肯定的。 二氢槲皮素具有抗癌和抗菌的作用。BOROVSKAYA等[43]研究了二氢槲皮素在舒必利诱导5 个月威斯塔大鼠BPH中的作用，结果发现二氢槲皮素能够减少大鼠前列腺腺体细胞的增殖活性并且衰减前列腺组织中的炎症反应。 3 展望 CD40/CD40L信号通路具有广阔的生物学效应，对炎症及免疫性疾病等具有重要作用。以 CD40/CD40为靶点的药物已用于心血管疾病、自身免疫性疾病的治疗[44]。目前，CD40/CD40L 与BPH的关系尚未完全阐明，仍需进一步研究。相信随着对CD40/CD40L信号通路的进一步研究及组织炎症在BPH中机制的进一步探讨，将会拓宽该通路介导的组织炎症在BPH中调控机制的认识，为通过采用一些方式如抗 CD40/CD40L 单克隆抗体阻断或基因敲除来干预 CD40/CD40L 的异常表达，从而为预防或治疗 BPH 疾病提供新的靶向思路。但是其确切的作用机制及在临床疾病中的应用仍需进一步研究探讨。 参考文献： [1] SUN J, ZHANG X. Pharmacotherapy and herbal treatment of benign prostatic hyperplasia [J]. Front Biosci (Landmark Ed), 2014,19:789-797. [2] PRIEST R, GARZOTTO M, KAUFMAN J. Benign prostatic hyperplasia: a brief overview of pathogenesis, diagnosis, and therapy [J]. Tech Vasc Interv Radiol, 2012, 15(4): 261-264. [3] PARSONS JK. Benign Prostatic Hyperplasia and Male Lower Urinary Tract Symptoms: Epidemiology and Risk Factors [J]. Curr Bladder Dysfunct Rep, 2010, 5(4): 212-218. [4] SOLER R, ANDERSSON, CHANCELLOR MB, et al. Future direction in pharmacotherapy for non-neurogenic male lower urinary tract symptoms [J]. Eur Urol, 2013, 64(4): 610-621. [5] DE NUNZIO C, KRAMER G, MARBERGER M, et al. The controversial relationship between benign prostatic hyperplasia and prostate cancer: the role of inflammation [J]. Eur Urol, 2011, 60(1):106-117. [6] OZDEN C, OZDAL OL, GUZEL O, et al. The correlation between serum prostate specific antigen levels and asymptomatic inflammatory prostatitis [J]. Int Urol Nephrol, 2007, 39(3):859-863. [7] HU J, ZHANG L, ZOU L, et al. Role of inflammation in benign prostatic hyperplasia development among Han Chinese: A population-based and single-institutional analysis [J]. Int J Urol, 2015. [Epub ahead of print] [8] DIKOV D, BACHURSKA S, STAIKOV D, et al. Intraepithelial lymphocytes in relation to NIH category IV prostatitis in autopsy prostate [J]. Prostate, 2015, 75(10):1074-1084. [9] DI SILVERIO F, GENTILE V, DE MATTEIS A, et al. Distribution of inflammation, pre-malignant lesions, incidental carcinoma in histologically confirmed benign prostatic hyperplasia: a retrospective analysis [J]. Eur Urol, 2003, 43(2):164-175. [10] NICKEL JC, ROEHRBORN CG, O'LEARY MP, et al. The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial [J]. Eur Urol, 2008, 54(6):1379-1384. [11] SONG L, ZHU Y, HAN P, et al. A retrospective study: correlation of histologic inflammation in biopsy specimens of Chinese men undergoing surgery for benign prostatic hyperplasia with serum prostate-specific antigen [J]. Urology, 2011, 77(3):688-692. [12] BAO QB, HE GH, LIU GY, et al. Histological changes of the prostate and acute urinary retention in patients with benign prostatic hyperplasia [J]. Zhonghua Nan Ke Xue, 2013, 19(9):811-814. [13] ZLOTTA AR, EGAWA S, PUSHKAR D, et al. Prevalence of inflammation and benign prostatic hyperplasia on autopsy in Asian and Caucasian men [J]. Eur Urol, 2014, 66(4):619-622. [14] SHAFIEE R, SHARIAT A, KHALILI S, et al. Diagnostic investigations of canine prostatitis incidence together with benign prostate hyperplasia, prostate malignancies, and biochemical recurrence in high-risk prostate cancer as a model for human study [J]. Tumour Biol, 2015, 36(4):2437-2445. [15] TORKKO KC, WILSON RS, SMITH EE, et al. Prostate Biopsy Markers of Inflammation are Associated with Risk of Clinical Progression of Benign Prostatic Hyperplasia: Findings from the MTOPS Study [J]. J Urol, 2015, 194(2): 454-461. [16] BOSTANCI Y, KAZZAZI A, MOMTAHEN S, et al. Correlation between benign prostatic hyperplasia and inflammation [J]. Curr Opin Urol, 2013, 23(1):5-10. [17] ST SAUVER JL, JACOBSON DJ, MCGREE ME, et al. Protective association between nonsteroidal antiinflammatory drug use and measures of benign prostatic hyperplasia [J]. Am J Epidemiol, 2006, 164(8):760-768. [18] VAN KOOTEN C, BANCHEREAU J. CD40-CD40 ligand [J]. J Leukoc Biol, 2000, 67(1):2-17. [19] CHEN GH, OSTHOLZERER JJ, CHOE MY, et al. Dual roles of CD40 on microbial containment and the development of immunopathology in response to persistent fungal infection in the lung [J]. Am J Pathol, 2010, 177(5):2459-2471. [20] KORNILUK A, KEMONA H, DYMICKA-PIEKARSKA V. Multifunctional CD40L: pro- and anti-neoplastic activity [J]. Tumour Biol, 2014, 35(10):9447-9457. [21] CHATZIGEORGIOU A, LYBERI M, CHATZILYMPERIS G, et al. CD40/CD40L signaling and its implication in health and disease [J]. Biofactors, 2009, 35(6): 474-483. [22] YUAN M, FU H, REN L, et al. Soluble CD40 Ligand Promotes Macrophage Foam Cell Formation in the Etiology of Atherosclerosis [J]. Cardiology, 2015, 131(1):1-12. [23] MANGINO G, PERCARIO ZA, FIORUCCI G, et al. HIV-1 Nef induces proinflammatory state in macrophages through its acidic cluster domain: involvement of TNF alpha receptor associated factor 2 [J]. PLoS One 2011, 6(8):e22982. [24] PORTILLO JA, SCHWARTZ I, ZARINI S, et al. Proinflammatory responses induced by CD40 in retinal endothelial and Muller cells are inhibited by blocking CD40-Traf2,3 or CD40-Traf6 signaling [J]. Invest Ophthalmol Vis Sci, 2014, 55(12):8590-8597. [25] MUKUNDAN L, BISHOP GA, HEAD KZ, et al. TNF receptor-associated factor 6 is an essential mediator of CD40-activated proinflammatory pathways in monocytes and macrophages [J]. J Immunol, 2005, 174(2):1081-1090. [26] SONG Z, JIN R, YU S, et al. CD40 is essential in the upregulation of TRAF proteins and NF-kappaB-dependent proinflammatory gene expression after arterial injury [J]. PLoS One, 2011, 6(8):e23239. [27] CHEN Y, CHEN J, XIONGY, et al. Internalization of CD40 regulates its signal transduction in vascular endothelial cells [J]. Biochem Biophys Res Commun, 2006, 345(1):106-117. [28] ELGUETA R, BENSON MJ, DE VRIES VC, et al. Molecular mechanism and function of CD40/CD40L engagement in the immune system [J]. Immunol Rev, 2009, 229(1):152-172. [29] MA DY, CLARK EA. The role of CD40 and CD154/CD40L in dendritic cells [J]. Semin Immunol, 2009, 21(5):265-272. [30] SUTTLES J, STOUT RD. Macrophage CD40 signaling: a pivotal regulator of disease protection and pathogenesis [J]. Semin Immunol, 2009, 21(5):257-264. [31] ZHANG J, WANGK, WANG S, et al. Herpes simplex virus 1 E3 ubiquitin ligase ICP0 protein inhibits tumor necrosis factor alpha-induced NF-kappaB activation by interacting with p65/RelA and p50/NF-kappaB1 [J]. J Virol, 2013, 87(23):12935-12948. [32] WANG XH, DING XM, LI Y, et al. Simultaneous blockade of the CD40/CD40L and NF-kappaB pathways prolonged islet allograft survival [J]. Transpl Int, 2012, 25(1):118-126. [33] CHATZIGEORGIOU A, PHIELER J, GEBLER J, et al. CD40L stimulates the crosstalk between adipocytes and inflammatory cells [J]. Horm Metab Res, 2013, 45(10):741-747. [34] QI C, TIAN S, WANG J, et al. Co-expression of CD40/CD40L on XG1 multiple myeloma cells promotes IL-6 autocrine function [J]. Cancer Invest, 2015, 33(1):6-15. [35] KHAN WN, WRIGHT JA, KLEIMAN E, et al. B-lymphocyte tolerance and effector function in immunity and autoimmunity [J]. Immunol Res, 2013, 57(1-3):335-353. [36] HERNANDEZ MG, SHEN L, ROCK KL. CD40-CD40 ligand interaction between dendritic cells and CD8+ T cells is needed to stimulate maximal T cell responses in the absence of CD4+ T cell help [J]. J Immunol, 2007, 178(5):2844-2852. [37] FICARRA V, ROSSANESE M, ZAZZARA M, et al. The role of inflammation in lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) and its potential impact on medical therapy [J]. Curr Urol Rep, 2014,15(12):463. [38] YANG X, YUAN L, XIONG C, et al. Abacopteris penangiana exerts testosterone-induced benign prostatic hyperplasia protective effect through regulating inflammatory responses, reducing oxidative stress and anti-proliferative [J]. J Ethnopharmacol, 2014, 157:105-113. [39] ATAWIA RT, MOSLI HH, TADROS MG, et al. Modulatory effect of silymarin on inflammatory mediators in experimentally induced benign prostatic hyperplasia: emphasis on PTEN, HIF-1alpha, and NF-kappaB [J]. Naunyn Schmiedebergs Arch Pharmacol, 2014, 387(12):1131-1140. [40] CHUNG KS, CHEON SY, AN HJ. Effects of Resveratrol on Benign Prostatic Hyperplasia by the Regulation of Inflammatory and Apoptotic Proteins [J]. J Nat Prod, 2015, 78(4):689-694 [41] PENG CC, LIN YT, CHEN KC, et al. Antrodan, A beta-glucan obtained from Antrodia cinnamomea mycelia, is beneficial to benign prostate hyperplasia [J]. Food Funct, 2015, 6(2):635-645. [42] BERNICHTEIN S, PIGAT N, CAMPARO P, et al. Anti-inflammatory properties of Lipidosterolic extract of Serenoa repens (Permixon(R)) in a mouse model of prostate hyperplasia [J]. Prostate, 2015, 75(7): 706-722. [43] BOROVSKAYA TG, KRIVOVA NA, ZAEVA OB, et al. Dihydroquercetin effects on the morphology and antioxidant/prooxidant balance of the prostate in rats with sulpiride-induced benign hyperplasia [J]. Bull Exp Biol Med, 2015, 158(4):513-516. [44] ZHANG B, WU T, CHEN M. The CD40/CD40L system: a new therapeutic target for disease [J]. Immunol Lett, 2013,153(1-3):58-61.

江湖有云，天下武功，唯快不破。羞羞的时候，你也要以快降伏对手吗？听说国足能90分钟不射，你是否有一丝丝羡慕？早泄，已成为众多英雄好汉的难言之隐。今天，有请到四川大学华西医院男科专家：曹德宏，将带大家正确认识早泄。一．早泄的定义：你是否是快男？如何判断自己是否早泄呢？国际性医学会（International Society for Sexual Medicine，ISSM)从循 征医学的角度上指出 PE（早泄） 的定义应包括以下三点：①射精总是或者几乎总是发生在阴茎插入阴道 1 分钟以内；②不能在阴茎全部或者几乎全部进入阴道后延迟射精；③消极的个人精神心理因素，比如苦脑、忧虑、挫折感或逃避性活动等。 翻译过来就是：时间短，给你1分钟你就能创造奇迹；控制力差，虽然心里一直默念：稳住，我们能赢，但还是不到一分钟，你就开启了贤者模式。这是多么大的心里伤害啊？二．早泄的大致分类： （1）原发性早泄：从首次啪啪啪开始，和任何人几乎每次都会发生，绝大多数不超过60秒，并且在射精即将来临时，根本把持不住自己。 （2）继发性早泄：以前正常，在某个时间段突然或者逐步出现早泄症状，控制能力降低或者消失。并且可能与勃起功能障碍、慢性前列腺炎、甲状腺功能不全等疾病及心理或人际关系问题相关。  （3）自然变异早泄：有时有，有时没有，在早泄发生之前，你都不知道自己是否会早泄，戏称为薛定谔的早泄。 （4）PE 样射精功能障碍：自认为早泄，但是时间正常，伴随有控制能力的低下或者消失。  既然早泄是一种疾病，那么都有什么危害呢？三：早泄的危害：早泄的危害主要分为两大类，心理上的和身理上的。（1）心理上：让男性不自信，回避正常性生活，心理压力巨大从而又会加重早泄造成恶性循环。对家庭关系的影响，还用多说吗？（2）身理上：早泄在临床上常常伴随一些疾病，如慢性前列腺炎/慢性盆腔疼痛综合征、ED（阳痿） 等的发生， 并且在发生、发展过程中可能互为因果，互相影响。治疗早泄，刻不容缓。四：早泄的西医治疗：（1） 心理/行为治疗： 心理治疗对部分早泄患者很重要，特别是由心理社会因素诱发早泄的患者。 心理咨询的目的是帮助患者正确认识性生活，学会控制和延迟射精，增强对性生 活的自信，消除对性生活的紧张和焦虑情绪，增进与性伴侣的沟通和交流。 行为治疗最常用的是“动-停法”（stop-start technique）和“挤压法” （squeeze technique）， 心理/行为治疗的效果目前还存在争议，有的研究认为行为治疗的成功率在 60%~90%，但缺乏长期随访结果。虽然已有证据证实心理/行为治疗对部分早泄 患者有效，但还需要更严谨完善的临床研究来证明。 （2） 局部麻醉药物治疗： 在阴茎表面使用局部麻醉药物，从而延长时间。不足之处是，局部麻醉药物可能导致部分患者因阴 茎麻木不能勃起。在未使用避孕套时，局部麻醉药物可能导致性伴侣出现阴道麻 木感，并失去性生活兴趣。如果患者或其性伴侣对该局部麻醉药物过敏，则绝对 禁用。 （3） SSRI（抗抑郁药物） SSRI 是临床常用的抗抑郁药物，目前发现这类药物对早泄有很好的治疗效果。SSRI 类药物包括二类：1、专用于治疗早泄的达泊西汀；2、以抗抑郁为治 疗目的的西酞普兰、帕罗西汀、舍曲林等。（4） PDE5i（万艾可，伟哥） PDE5i 被广泛应用于治疗勃起功能障碍，单独应用 PDE5i 治疗早泄的效果存 在争议，但有证据显示联合应用西地那非和舍曲林治疗早泄，比单用舍曲林疗效 要好。这可能由于 PDE5i 抑制射精管、输精管、精囊、后尿道平滑肌上的 PDE5 活性，从而使平滑肌舒张，射精潜伏期延长。也可能因为患者阴茎勃起硬度增加 而减少焦虑，达到勃起的性唤起阈值降低，而要达到射精阈值则需较高的性刺激 水平。对于合并有 ED 的早泄患者，可联合采用 PDE5i 治疗，对不伴有 ED 的早泄 患者，不推荐 PDE5i 作为首选治疗药物。  最后，附上使用最广泛的早泄诊断量表（PEDT）得分在8分以上的，请及时到医院就诊，是时候和快男说拜拜了。

（四川大学华西医院泌尿外科、泌尿外科研究所，四川成都，610041） 摘要：炎症可作为致瘤因素，刺激局部组织细胞增生形成肿瘤。“炎-癌转化”在 许多癌症如胃癌、肝癌、结肠癌等中均已得到证实。本文首次对前列腺“炎-癌转 化”的研究进展进行综述，主要内容包括：组织病理学研究发现慢性前列腺炎和 前列腺癌的发生呈正相关；流行病学研究发现前列腺“炎-癌转化”存在种族差异； 分子生物学研究发现金属蛋白酶抑制因子 3(Timp3)、核因子 kappaB(NF-κB)、白 细胞介素 6（IL-6）、白细胞介素 8（IL-8）、白细胞介素 17（IL-17）、早期生 长反应因子 3（EGR-3）等可促进前列腺癌细胞的增殖和侵袭。 关键词：前列腺癌；慢性前列腺炎；炎癌转化；组织病理学；炎症介质 中图分类号：R695 文献标志码：R DOI： 炎症是具有血管系统的活体组织对致炎因子产生的以防御为主的反应。肿瘤 是指机体在各种致瘤因子作用下，局部组织细胞增生所形成的新生物。“炎-癌转 化”是指炎症转变为癌症，该概念是 19 世纪 60 年代由德国著名病理学家 VIRCHOW 首次提出的，他发现肿瘤组织中存在白细胞浸润，认为肿瘤可能起源 于慢性炎症部位[1]。而许多研究也证实了慢性炎症与炎症性肠病患者的胃癌、肝 癌和结肠癌等癌症有关[2]。炎症可能通过1个或多个潜在的机制促进癌症的发生，包括：①细胞因子和生长因子有利于肿瘤细胞生长；②巨噬细胞和上皮细胞中环 氧合酶-2 的诱导；③突变性活性氧和氮的产生[3]。 前列腺炎（prostatitis）是指由多种复杂原因引起的，以尿道刺激症状和慢性 盆腔疼痛为主要临床表现的前列腺疾病[4]。1 项回顾性研究发现，前列腺活检、 根治性前列腺切除术标本和治疗良性前列腺增生切除的组织中常出现炎症[5]。此 外，炎症浸润常出现在以增殖指数增加为特征的萎缩病灶及其周围，这些病灶出现增生性炎症性萎缩，可能是早期前列腺癌的前兆，也可能表明前列腺内环境有利于癌症的发展。流行病学研究通过对促炎和抗炎因素的研究间接地验证 了慢性炎症在前列腺癌发生中的作用。 我们对综合性传播感染、临床前列腺炎、炎症的遗传和循环标志物以及感染 的反应等方面的研究，发现慢性前列腺炎（chronic prostatitis，CPI）与前列腺癌 （prostate cancer，PCa）之间存在密切联系。现对前列腺“炎-癌转化”研究的一些 新进展进行阐述。 1 慢性前列腺炎与前列腺癌的发生呈正相关 在 1 项关于预防 PCa 的试验中，对病例组（PCa 患者，n=191）和对照组（未 患 PCa，n=209）分别进行活检，至少有 1 个炎症活检核心的男性与没有炎症核 心的男性相比，前者患 PCa 的几率是后者的 1.78 倍[6]。这提示炎症和癌症的发 生之间存在病因联系，并建议通过缓解前列腺内炎症来预防 PCa。 2018年VASAVADA等[7]进行的荟萃分析提示前列腺穿刺活检中出现炎症可 能会降低随访诊断PCa的风险。该研究从EMBASE、PubMed和Web of ScienceTM 中检索了从 1990 年 1 月 1 日至 2016 年 10 月 1 日包含关键词 PCa、炎症和活检 的摘要，共计 1 030 份摘要。他们对 46 份文献进行了全文回顾，25 份纳入终 分析，共包括 20 585 名受试者和 6 641 名 PCa 患者。在 25 项研究中，任何炎症 的存在都与较低的 PCa 风险显著相关当根据炎症类型进行亚分析时， 4 项研究中 的急性炎症和 15 项研究中的慢性炎症均与较低的 PCa 风险相关。 2 前列腺“炎-癌转化”存在种族差异 流行病学研究发现，白人男性中具有前列腺炎病史的患者临床诊断患 PCa 的风险增加，但组织学研究表明前列腺炎症反而降低了 PCa 的发病风险。 1 项采用嵌套设计的研究，对 574 对（345 对白人，229 对非裔美国人）PCa 和前列腺炎患者[包括临床诊断前列腺炎（NIH I-III 类）和组织学炎症]进行病例 对照分析，结果发现在非裔美国人中，临床前列腺炎与 PCa 风险的增加显示出 负相关[8]。在白人男性中，仅在无组织学炎症证据时，临床前列腺炎与患 PCa 风 险的增加显著相关。前列腺特异性抗原速率（prostate specific antigen velocity， PSAV）和前列腺特异性抗原检测频率可显著降低患 PCa 的风险。这表明前列腺 炎症的这些迹象与 PCa 检测之间存在着复杂的相互作用。 3 分子生物学进展 3.1 Timp3 缺失加速 PCa 肿瘤侵袭 蛋白酶的表达和活性改变与炎症和癌症进 展有关[9]，蛋白酶活性增高可促进肿瘤的侵袭。组织金属蛋白酶抑制因子 3（tissue inhibitor of metalloproteinase 3, Timp3）是蛋白酶活性的一个重要负调节因子，许 多癌症包括晚期 PCa 在内都缺乏 Timp3 的表达，这使得蛋白酶活性不受限制， 进而促进肿瘤的侵袭和转移。 ADISSU 等[10]的研究将 Timp3 缺陷小鼠（Timp3-/-）与缺失前列腺特异性肿 瘤抑制因子 PTEN（PTEN-/-）的小鼠（一种成熟的 PCa 小鼠模型）杂交，通过 组织病理学方法标记肿瘤细胞增殖、侵袭血管的情况，比较 16 周龄的（PTEN-/-、 Timp3-/-）和对照（PTEN+/+、Timp3+/+）小鼠的肿瘤生长和进展。结果发现与 PTEN+/+和 Timp3+/+的肿瘤状况相比，PTEN-/-和 Timp3-/-前列腺肿瘤的生长、 增殖指数增加，微血管密度和肿瘤浸润性增加，单核细胞趋化蛋白-1、环氧合酶 -2、肿瘤坏死因子 α 和白细胞介素-1β 的表达增加。这些炎症介质导致炎症细胞 向缺乏 Timp3 的前列腺肿瘤的浸润明显增加，提示了前列腺炎症是 PCa 进展的 一个重要促进因素。 1 项新的研究证实 Timp3 是微小核糖核酸-191（miR-191）的直接靶基因， miR-191 可通过下调 Timp3 的活性来促进 PCa 细胞生长和侵袭能力。该研究采 用人 PCa 细胞株 DU145、PC-3、LNCAP、BPH 和人前列腺上皮细胞株 RWPE-1， 通过合成的 miR-191 类似物和抑制剂来过度表达或抑制 miR-191 水平，结果发 现与正常组相比，PCa 组织样品中的 miR-191 过度表达，PCa 衍生细胞系中的 miR-191 也过表达。在 PC-3 细胞中上调 miR-191 显著促进 PCa 的侵袭，而在 DU145 细胞中下调 miR-191 则延缓了癌细胞的增殖和侵袭。Timp3 的敲除可逆 转 miR-191 的下调功能[11]。 3.2 CPI可促使肿瘤细胞存活 炎症通过控制肿瘤微环境参与PCa发生过程中细 胞事件的调节[12]。多种骨髓源性细胞包括 CD4+淋巴细胞、巨噬细胞和骨髓源性 抑制细胞等，是肿瘤微环境的组成成分之一[13]。 NGUYEN 等[14]的研究发现在炎症细胞因子激活后，核因子 kappaB（Nuclear Factor-kappaB, NF-κB）复合物能够通过 PCa 的抗凋亡信号促进肿瘤细胞存活， 再通过正反馈途径维持 NF-κB 的激活。 WANG 等[15]的研究进一步发现成纤维细胞生长因子（fibroblast growth factor, FGF）可促进 PCa 细胞中的 NF-κB 信号传导，并且这种变化与成纤维细胞生长 因子受体 1（fibroblast growth factor receptor 1, FGFR1）的表达有关，FGFR1 激 酶活性的中断会使 PCa 细胞中的 FGF 活性和 NF-κB 信号都丧失。在 FGFR1 刺 激 NF-κB 信号的过程中，转化生长因子 β 激酶 1（transforming growth factor-β-activated kinase 1, TAK1）是必需的物质。FGFR1 通过减少 TAK1 的降解 来促进 PCa 细胞中的 NF-κB 信号传导，从而使 NF-κB 通路持续激活。 3.3 白细胞介素 6 促进 PCa 细胞增殖 慢性炎症可参与 PCa 发生过程中细胞事 件的调节，包括免疫反应的破坏和肿瘤微环境的调节[16]。在 PCa 中，慢性炎症 好的代替指标之一是白细胞介素 6（interleukin 6, IL-6）。 研究发现未治疗的转移性或去势抵抗性 PCa（castration resistant prostate cancer, CRPC）患者血清 IL-6 水平升高，与肿瘤生存和化疗反应呈负相关[17]。IL-6 可通过 Janus 酪氨酸家族激酶（JAK）信号转导子和转录激活因子（activator of transcription 3, STAT）、细胞外信号调节激酶 1 和 2（extracellular signal-regulated kinase 1/2, ERK1/2）、丝裂原激活蛋白激酶（mitogen activated protein kinase, MAPK）和磷酸肌醇 3 激酶（phosphoinositide 3-kinase, PI3-K）等多种信号途径， 在体外和体内抑制肿瘤细胞凋亡，促进 PCa 细胞的增殖。 3.4 低表达 CD38 可引发 PCa LIU 等[18]的研究发现了低表达 CD38（CD38LO） 可识别人类前列腺管腔细胞的祖细胞样亚群。CD38LO 管腔细胞在邻近炎性细胞 的腺体中富集，并表现出上皮 NF-κB 信号，CD38LO 管腔细胞可以在体内组织 再生试验中启动人类 PCa 的癌基因，参与致癌转化。研究还发现 CD38LO 管腔 细胞表型和基因特征与 PCa 的疾病进展和不良预后相关，前列腺炎症扩大了易 受肿瘤发生影响的祖细胞样靶细胞的数量。 癌细胞代谢需要细胞内存在烟酰胺腺嘌呤二核苷酸（nicotinamide adenine dinucleotide, NAD+），维持 NAD+水解酶活性和 NAD+合成酶活性的平衡。 CHMIELEWSKI 等[19]的研究发现在细胞中表达的 CD38 可降低细胞内 NAD+的 水平，导致细胞周期停滞和抑癌基因 p21Cip1（CDKNA1）的表达。同时，CD38 降低糖酵解和线粒体代谢，激活一磷酸腺苷(adenosine monophosphate，AMP）活 化蛋白激酶（AMP-activated Protein Kina, AMPK），抑制脂肪酸和脂质合成。 新的研究发现与良性前列腺增生相比，PCa 中 CD38 的表达降低[20]，提示肿 瘤细胞可能通过减少 CD38 的表达，以增强细胞内 NAD+的聚集，促进癌细胞代谢。 3.5 EGR-3可促进IL6和IL8表达 与正常组织相比，早期生长反应因子3（early growth response 3, EGR-3）在人类前列腺肿瘤中高度表达。BARON 等[21]通过沉 淀分析、功能获得实验发现了潜在的 EGR-3 靶基因，EGR-3 调控了约 330 个基 因的表达，其中 35%参与免疫反应和炎症过程，15%与 NF-κB 信号通路联系在 一起作用于肿瘤细胞的存活。EGR-3 可诱导 50 多种分泌细胞因子、生长因子和 基质重塑因子的表达，两个与 PCa 密切相关的白细胞介素 IL6 和 IL8 被进一步验 证为 EGR3 靶基因：两个启动子都含有 EGR 共识结合位点。所以 EGR-3 高表达 可促进 IL6 和 IL8 的过度产生，导致疾病进展和去势抵抗的发生。 3.6 高胰岛素血症促进 PCa 发展 IL-17 在炎症、自身免疫性疾病和某些癌症中 起着重要作用[22]。肥胖患者由于处于慢性炎症状态，血清 IL-17、胰岛素和胰岛 素样生长因子 1（insulin-like growth factor 1, IGF1）水平升高[23]，可抑制糖原合 成酶激酶 3（glycogen synthase kinase 3, GSK3）和 IL-17 受体 A（interleukin 17 receptor A, IL-17RA）的结合及磷酸化，进而抑制 IL-17RA 的泛素化和蛋白酶体 介导的 IL-17RA 降解，从而诱导 IL-17 介导的炎症[24]。 一研究发现，在肥胖小鼠中，高胰岛素血症通过抑制 GSK3 介导的磷酸化和 IL-17RA 的降解，增强 IL-17 诱导下游促炎基因的表达，导致更具侵袭性的 PCa 的发生[25]。与正常细胞相比，增生性 PCa 细胞的 IL-17RA 磷酸化降低，IL-17RA 水平升高。在体外培养的 PCa 细胞系和肥胖小鼠体内模型中显示，胰岛素和 IGF1 通过抑制 GSK3 增强 IL-17 诱导的炎症反应，促进了侵袭性 PCa 的发生。 4 展望 PCa 的组织病理学分析对前列腺“炎-癌转化”的有一定的参考意义，但前列 腺炎和 PCa 之间具体的联系仍需要更多的临床研究进行证明。前列腺“炎-癌转 化”存在的种族差异还需更多的临床研究来支持，同时应该纳入更多的人种，不 同人群之间进行对比，探究不同的基因、环境等对前列腺“炎-癌转化”的影响。 目前可确定 Timp3、NF-κB、IL-6、IL-8、IL-17、EGR-3、低水平 CD38 等分子参与了前列腺“炎-癌转化”的过程，虽然具体机制还有待研究，但可作为生物标 记物为 PCa 的预防、治疗和预后提供新的方向[26]。 参考文献 [1] HEIDLAND A, KLASSEN A, RUTKOWSKI P, et al. The contribution of Rudolf Virchow to the concept of inflammation: what is still of importance?[J]. J Nephrol, 2006, 19(Suppl 10) :S102-109. [2] COUSSENS LM, WERB Z. Inflammation and cancer[J]. Nature, 2002, 420(6917):860-867. [3] LUCIA MS, TORKKO KC. Inflammation as a target for prostate cancer chemoprevention: pathological and laboratory rationale[J]. J Urol, 2004, 171(2 Pt 2):S30-34; discussion S35. [4] KHAN FU, IHSAN AU, KHAN HU, et al. Comprehensive overview of prostatitis[J]. Biomed Pharmacother, 2017, 94:1064-1076. [5] PLATZ EA, De MARZO AM. Epidemiology of inflammation and prostate cancer[J]. J Urol, 2004, 171(2 Pt 2):S36-40. [6] GUREL B, LUCIA MS, THOMPSON IM Jr, et al. Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial[J]. Cancer Epidemiol Biomarkers Prev, 2014, 23(5):847-856. [7] VASAVADA SR, DOBBS RW, KAJDACSY-BALLA AA, et al. Inflammation on prostate needle biopsy is associated with lower prostate cancer risk: a Meta-analysis[J]. J Urol, 2018, 199(5):1174-1181. [8] RYBICKI BA, KRYVENKO ON, WANG Y, et al. Racial differences in the relationship between clinical prostatitis, presence of inflammation in benign prostate and subsequent risk of prostate cancer[J]. Prostate Cancer Prostatic Dis, 2016, 19(2):145-150. [9] EFTEKHARI R, De LIMA SG, LIU Y, et el. Microenvironment proteinases, proteinase-activated receptor regulation, cancer and inflammation[J]. Biol Chem, 2018, 399(9):1023-1039. [10] ADISSU HA, MCKERLIE C, Di GRAPPA M, et al. Timp3 loss accelerates tumour invasion and increases prostate inflammation in a mouse model of prostate cancer[J]. Prostate, 2015, 75(16):1831-1843. [11] WANG X, SHI Z, LIU X, et al. Upregulation of miR-191 promotes cell growth and invasion via targeting TIMP3 in prostate cancer[J]. J BUON, 2018, 23(2):444-452. [12] GUERON G, De SIERVI A, VAZQUEZ E. Advanced prostate cancer: reinforcing the strings between inflammation and the metastatic behavior[J]. Prostate Cancer Prostatic Dis, 2012, 15(3):213-221. [13] STAKHEYEVA M, RIABOV V, MITROFANOVA I, et al. Role of the immune component of tumor microenvironment in the efficiency of cancer treatment: perspectives for the personalized therapy[J]. Curr Pharm Des, 2017, 23(32):4807-4826. [14] NGUYEN, DP, LI J, YADAV SS, et al. Recent insights into NF-κB signalling pathways and the link between inflammation and prostate cancer[J]. BJU Int, 2014, 114(2):168-176. [15] WANG C, KE Y, LIU S. Ectopic fibroblast growth factor receptor 1 promotes inflammation by promoting nuclear factor-κB signaling in prostate cancer cells[J]. J Biol Chem, 2018, 293(38):14839-14849. [16] TAVERNA G, PEDRETTI E, Di CARO G, et al. Inflammation and prostate cancer: friends or foe?[J]. Inflamm Res, 2015, 64(5):275-286. [17] NGUYEN DP, LI J, TEWARI AK. Inflammation and prostate cancer: the role of interleukin 6 (IL-6)[J]. BJU Int, 2014, 113(6):986-992. [18] LIU X, GROGAN TR, HIERONYMUS H, et al. Low CD38 identifies progenitor-like inflammation-associated luminal cells that can initiate human prostate cancer and predict poor outcome[J]. Cell Rep, 2016, 17(10):2596-2606. [19] CHMIELEWSKI JP, BOWLBY SC, WHEELER FB, et al. CD38 inhibits prostate cancer metabolism and proliferation by reducing cellular NAD+ pools[J]. Mol Cancer Res, 2019, 16(11):1687-1700. [20] MOTTAHEDEH J, HAFFNER MC, GROGAN TR, et al. CD38 is methylated in prostatecancer and regulates extracellular NAD[J]. Cancer Metab, 2018, 6:13. [21] BARON VT, PIO R, JIA Z, et al. Early Growth Response 3 regulates genes of inflammation and directly activates IL6 and IL8 expression in prostate cancer[J]. Br J Cancer, 2015, 112(4):755-764. [22] KRYCZEK I, WU K, ZHAO E, et al. IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer[J]. J Immunol, 2011, 186(7):4388-4395. [23] AHMED M, GAFFEN SL. IL-17 in obesity and adipogenesis[J]. Cytokine Growth Factor Rev, 2010, 21(6):449-453. [24] GE D, DAUCHY RT, LIU S, et al. Insulin and IGF1 enhance IL-17-induced chemokine expression through a GSK3B-dependent mechanism: a new target for melatonin's anti-inflammatory action[J]. J Pineal Res, 2013, 55(4):377-387. [25] LIU S, ZHANG Q, CHEN C, et al. Hyperinsulinemia enhances interleukin-17-induced inflammation to promote prostate cancer development in obese mice through inhibiting glycogen synthase kinase 3-mediated phosphorylation and degradation of interleukin-17 receptor[J]. Oncotarget, 2016, 7(12):13651-13666. [26] SCHILLACI O, SCIMECA M, TRIVIGNO D, et al. Prostate cancer and inflammation: A new molecular imaging challenge in the era of personalized medicine[J]. Nucl Med Biol, 2019, 68-69:66-79. 收稿日期：2019-4-15 修回日期：2019-5-12 基金项目：国家自然科学基金（No.81770756），四川省科技厅（No.2017KJT0034）通信作者：魏强，教授、博士生导师. E-mail：weiqiang339@126.com 曹德宏，博士、讲师. E-mail：hxcaodehong@163.com. 作者简介：张钰菲， （1998-），女汉族），医师，本科. E-mail：18162271827@163.com；任正举(1989-)，男(土家族)，医师，博士. E-mail：415335464@qq.com， 系共同第一作者.