A protocol for systematic review and meta-analysis

h Abstract Background: Increasing studies were performed to explore the prognostic value of E-cadherin in prostatic carcinoma, however, with inconsistent results. Hence, this systematic review is aimed to evaluate the prognostic role of E-cadherin in patients with prostatic carcinoma (PCa). Methods:A comprehensive literature search in all available databases will be conducted to identify eligible studies. We will employ hazard ratios (HRs) and 95% confidence intervals (95% CIs) to estimate the correlations between E-cadherin expression and overall survival (OS), disease-free survival (DFS), relapse-free survival (RFS), progression-free survival (PFS) and clinicopathological features. Meta-analysis will be performed using Review Manager (Revman) 5.3.5 software (Cochrane Community, London, United Kingdom) and STATA 14 software (version 14.0; Stata Corp, College Station, TX). Results: This study will provide a high-quality synthesis of current evidence of the correlations between snail expression and OS, DFS/RFS, PFS and clinicopathological features. Conclusion: The study will provide updated evidence to assess whether the expression of E-cadherin is in association with poor prognosis in patients with PCa. Ethics anddissemination: It is not necessary for ethical approval because individuals cannot be identified. The protocol will be disseminated in a peer-reviewed journal or presented at a relevant conference. Prospero registration number: This systematic review protocol has been registered in the PROSPERO network (No. CRD42019128353).


Introduction
Benign prostatic hyperplasia (BPH) is ubiquitous in the aging male with prevalence increasing with age [1] and affecting 50% of those older than 50 and 80% of those older than 80. [2] Elderly males are frequently complaining of lower urinary tract symptoms (LUTS) which are due to bladder outflow obstruction secondary to BPH. [3] There are many long-term complications due to untreated bladder outflow obstruction, such as detrusor failure, renal failure, recurrent urinary tract infections (UTIs), urinary retention, bladder diverticula, and bladder stones. [4]If prostate tissue was removed in men with suspected BPH, symptoms and obstruction are reduced and resolved substantially.
Transurethral resection of the prostate (TURP) has been considered the gold standard surgical option for patients with moderate to severe LUTS secondary to BPH, especially for small/ medium prostates. [5,6]Substantial improvements on outcomes, including maximum urinary flow rate (Qmax), quality of life (QoL), international prostate symptom score (IPSS), and postvoiding residual urine volume (PRV) have added to its success.However, despite several technical and procedural improvements, TURP is still a potentially dangerous procedure, particularly in patients with larger prostates, indwelling catheters, bleeding disorders, or in patients undergoing anticoagulation therapy.Therefore, many endoscopic procedures and surgical skills using different energy sources, such as plasmakinetic TURP, plasmakinetic transurethral enucleation of the prostate, holmium laser enucleation of the prostate (HoLEP), and green light laser vaporization or enucleation of the prostate (green laser enucleation of the prostate), have been proposed to replace TURP as the new operative standard.These procedures have a satisfactory evidence base showing an advantage over TURP and a rise in use.Regardless of which kind of energy source is used, each approach of the transurethral procedure can be subdivided into three principles: resection, vaporization, and enucleation. [7]o far, numerous studies have summarized the growing evidence supporting the use of these new techniques.In the present study, our aim was to perform a systematic review and meta-analysis using data from previously published studies to review the contemporary status of endoscopic enucleation (EEP) and the endoscopic vaporization procedures (EVP) techniques for the treatment of BPH.Moreover, we compared the safety and efficacy of the techniques that take advantage of the laser as energy sources, including laser enucleation procedures (L-EEP) and laser vaporization procedures (L-EVP).

Study criteria and search strategy
In our present systematic review and meta-analysis, we included the publications focus on patients treated surgically for symptomatic LUTS utilizing EEP and EVP.Studies using any kind of instrument for EEP and EVP were included, for example, holmium laser, green light laser, bipolar plasma, thulium laser, and transurethral vaporization in saline.When comparing L-EEP and L-EVP, only the holmium laser, greenlight laser, and thulium laser were included.The language was restricted to English.Studies were selected by searching PubMed, EMBASE, and the Cochrane Library up to December 2019.The search keywords included, but were not limited to, holmium laser enucleation of the prostate, HoLEP, transurethral enucleation, EEP, PVP, photoselective vaporization of the prostate, transurethral vaporization, endoscopic vaporization, GreenLight, transurethral prostatectomy, minimally invasive prostatectomy.We modified the search strategy as required for each electronic database.The bibliographies of included studies and recent reviews were hand-searched.

Selection of studies, data extraction, and methodological quality assessment
Studies that meet the prespecified inclusion criteria were selected.Abstracts of the identified articles were subjected to independent review by 2 authors.The full-text articles were retrieved for those studies that appeared to meet the inclusion criteria.Two reviewers independently extracted the data.To obtain missing data, the authors of the study were contacted.The methodological quality of randomized controlled trials (RCTs) was assessed according to the Jadad scale and not a RCT according to the Newcastle-Ottawa Scale (NOS) scale.

Outcome measures
The outcomes assessed included perioperative outcomes, complications, and efficacy of the surgery.The perioperative outcomes were assessed for a decrease in sodium, a drop in hemoglobin (HB) levels, irrigation length, hospital stay, conversion of surgical techniques, the total energy used, operative time, and catheterization time.Complications included capsular perforation, haematuria, clot retention, urge incontinence, stress incontinence, retreatment for residual adenoma, UTI, bladder neck contracture (BNC), urethral stricture, transient incontinence, blood transfusions, and urinary incontinence (including urge incontinence, stress incontinence, transient incontinence, and other incontinence not classified).For the efficacy of surgery, the following outcomes were used: maximum flow rates (Qmax), IPSS, QoL, and postvoid residual volume (PRV) at 1, 3, 6, 12, 24, and 36 months postsurgery.

Statistical analysis
RevMan5.3 was used to perform statistical analysis.Meta-analysis was conducted to generate summary statistics where possible.The weighted mean difference or standardized mean difference were calculated for continuous outcomes along with the 95% confidence interval (CI) and P value.Summary odds ratios (OR) and its 95% CI were calculated for binary outcomes.Statistical significance was defined as P < .05.For articles offering continuous data as median and interquartile range, we calculated the mean and standard deviation using the procedure described by Luo et al [8] and Wan et al. [9] The pooled results were calculated by the fixedeffect model [I 2 (inconsistency) 50% and P ≥ .1].Otherwise, the random effect model was used.Moreover, the effects of pooled results were determined by the z test, and P < .05 was considered statistically significant.Due to inconsistent data reporting, the meta-analysis was not feasible for all studies.

Perioperative outcomes in L-EEP vs L-EVP
Similar to the results of perioperative outcomes in EEP vs EVP, the total energy used was the only statistically different pooled data in our analysis, L-EEP procedures using less energy in operation (108.67 minutes 95% CI, [À166.29,À51.05]; P = .0002)(Fig. 5A).However, no statistical differences were observed between L-EEP and L-EVP in terms of HB level drop, hospital stay, conversion of surgical techniques, operative time, and catheterization time in the pooled data.There were insufficient data to analyze the decrease in sodium, or irrigation length during perioperative periods.(see Supplementary information, http://links.lww.com/MD/F233).

Discussion
For many years, TURP is still considered gold standard for the small/medium prostates and open prostatectomy [26] was the most appropriate choice for men with large gland volumes.However, TURP is still accompanied by some life-threatening risks, such as a 2% to 4.8% rate of hemorrhage requiring blood transfusion, [27] and elevated morbidity occurred in open prostatectomy. [28]Therefore, diverse transurethral techniques have been adopted in recent years which possess excellent functional outcomes and lower complication rates.[31] Some superb meta-analyses have been published comparing diverse endoscopic procedures [31] and head-to-head compared specific technologies, such as HoLEP vs bipolar transurethral resection of the prostate, [32] thulium laser enucleation of the prostate vs TURP. [33]Although EEP is a widely used surgical procedure, it has never been investigated as a whole and compared with EVP techniques.It is difficult but important to select the best surgical treatment for BPH.Hence, it is worth comparing different surgical procedures, whether it is through direct or indirect studies.As far as we know, our meta-analysis represents the first study to indirectly compare EEP with EVP in terms of the efficacy and safety for the treatment of BPH.Moreover, since laser surgery is a popular procedure today but was rarely used in the last century, [34] we further analyzed the differences between L-EEP and L-EVP.
During the entire postoperative follow-up, greater Qmax values were obtained with enucleation methods, including bipolar plasma enucleation of the prostate, plasmakinetic transurethral enucleation, HoLEP, thulium enucleation of the prostate, and green laser enucleation of the prostate.even after 24 to 36 months.Enucleation methods were also associated with better PRV, IPSS, and QoL compared with vaporization methods when the postoperative follow-up period exceeded 12 months.However, when laser techniques were considered, better functional outcomes of Qmax only became apparent 6 months postsurgery.However, the lower PRV seemed to persist throughout the follow-up duration (except 3 months after operation) and the differences with IPSS and QoL could be observed over 12 months following surgical treatment.
EEP methods imitate open prostatectomy and remove more tissues using fibreoptic lasers or bipolar loops. [35]Therefore, it is not surprising that enucleation methods yielded the greatest Qmax values compared with resection and vaporization methods, since more tissues were removed using enucleation methods than vaporization methods. [36]In a systematic review and network meta-analysis performed by Huang et al, [37] EEP procedures have been shown to improve Qmax by about 1.71 to 1.98 mL/s and 4.12 to 4.82 mL/s at 6 to 12 and 24 to 36 months postsurgery, respectively, compared with EVP procedures which have been considered clinically significant.In this study, EEP was observed to improve Qmax by 2.78 and 1.85 mL/s than vaporization methods at 1 month and 3 months, and by 3.14, 3.23, 15.2, and 11.9 mL/s more at 6, 12, 24, and 36 months following surgery, respectively.Accordingly, it was clinically significant for the difference of Qmax between EEP and EVP procedures.
As we compared the perioperative data of EEP and EVP, both showed effective outcomes.On the other hand, based on our meta-analysis, EVP favored significant differences with respect to catheterization time, while there was no significant difference between the L-EEP and L-EVP groups.Our analysis also showed that EVP and L-EVP methods seemed to generate higher total energy used during surgery compared with EEP and L-EEP.EEP is widely believed to increase the risk of urinary incontinence and capsular perforation. [38]Nevertheless, our study did not observe any differences in the rate of implications between groups.A lower rate of retreatment for residual adenoma in EEP and L-EEP was observed.This could be explained by the fact that EEP methods remove whole hyperplastic adenoma of the prostate as open prostatectomy, while EVP methods remove less apical prostate tissue to prevent sphincter injury. [39]Therefore, in order to overcome the shortcomings of vaporization, some surgeons resect the apex of the prostate after vaporization. [40] published network meta-analysis of 88 randomly controlled trials with 15 procedures found that HoLEP was the first choice for PRV values, although diode laser vaporization of prostate gave better results in terms of IPSS and Qmax. [34]nother network meta-analysis comparing different lasers for surgical treatment of BPH, comprising 36 randomized studies involving 3831 patients found that HoLEP was the most advantageous operative procedure for improving PRV. [41]Our results indicated that enucleation technology is more effective than vaporization, regardless of the laser energy that was utilized.
Huang et al [37] reported superior functional outcomes and parallel safety when comparing enucleation methods to vaporization methods.Such results were confirmed by our metaanalysis again.Regarding laser energy, the results were similar when comparing L-EEP and L-EVP.However, Zhang et al [41] comparing different lasers for the treatment of BPH found that dysuria was the most frequent short-term complication in patients treated with green laser vapo-enucleation of the prostate and HoLEP, but was rarely seen in Nd:YAG laser with vaporization.When long-term complications-related outcomes were considered, BNC or stenosis was oftentimes found in KTP/ Nd:YAG with vaporization and HoLEP comparing with green laser vaporization of the prostate and diode laser with vaporization.
Our study included only 2 RCTs.Hence, we must interpret the results within the context of some limitations.22]24,25] Consequently, we lacked the data to evaluate the differences in long-term efficacy and safety between EEP and EVP.Second, as a result of rare complications and zero events reported by some studies, the pooled ORs were less precise.Third, there existed high heterogeneity in most analyses, which could be interpreted as the difference in each trial studied, such as the initial volume of prostate, the degree of urodynamic obstruction, and the level of experience of the surgeons.Fourth, because of a lack of standardized definition and techniques, we did not distinguish vapo-enucleation from enucleation.Hence, further investigations are required to evaluate the differences in outcomes between vapo-enucleation and enucleation or vaporization methods.Nevertheless, this review still enjoys several advantages.To our knowledge, this study is the first comprehensive systematic review and meta-analysis that focuses on comparing EEP and EVP methods for treatment of BPH, and that offers an evaluation of their efficacy and safety, with a view of providing valuable insights and recommendations for clinician surgeons.

Conclusion
Our study showed that EEP and EVP provide efficacy and safety for the treatment of BPH.Most perioperative data existed no significant difference between both groups, but EEP favors total energy used and retreatment for residual adenoma and reduces catheterization time.EEP shows better functional outcomes than EVP.Compared with L-EVP, L-EEP provides greater total energy used and retreatment for residual adenoma with the same complications and better functional profiles.However, the clinical significance of these findings remains unclear.Therefore, more long-term, larger-scale, and well-designed head-to-head RCTs are needed to provide a clear direction as to which techniques to select in clinical conditions.

Figure 2 .
Figure 2. A-B, The forest plot of pooled estimates of perioperative outcomes in EEP vs EVP.C, The forest plot of pooled estimates of postoperative complications in EEP vs EVP.EEP = endoscopic enucleation, EVP = endoscopic vaporization procedures.

Figure 3 .
Figure 3. A, The forest plot of pooled estimates of the efficacy of operation at 1 month of postoperation in EEP vs EVP.B, The forest plot of pooled estimates of the efficacy of operation at 3 months of postoperation in EEP vs EVP.C, The forest plot of pooled estimates of the efficacy of operation at 6 months of postoperation in EEP vs EVP.D-F, The forest plot of pooled estimates of efficacy of operation at 12 months of postoperation in EEP vs EVP.EEP = endoscopic enucleation, EVP = endoscopic vaporization procedures

Figure 4 .
Figure 4. A-F, The forest plot of pooled estimates of the efficacy of operation at 24 and 36 months of postoperation in endoscopic enucleation vs endoscopic vaporization procedures.

Figure 5 .
Figure 5. A, The forest plot of pooled estimates of the efficacy of perioperative outcomes in L-EEP vs L-EVP.B, The forest plot of pooled estimates of postoperative complications in L-EEP vs L-EVP.L-EEP = laser enucleation procedures, L-EVP = laser vaporization procedures.

Figure 6 .
Figure 6.A, The forest plot of pooled estimates of the efficacy of operation at 1 month of postoperation in L-EEP vs L-EVP.B-C, The forest plot of pooled estimates of the efficacy of operation at 6 months of postoperation in L-EEP vs L-EVP.D-F The forest plot of pooled estimates of efficacy of operation at 12 months of postoperation in L-EEP vs L-EVP.L-EEP = laser enucleation procedures, L-EVP = laser vaporization procedures.

Figure 7 .
Figure 7. A-F The forest plot of pooled estimates of the efficacy of operation at 24 and 36 months of postoperation in laser enucleation procedures vs laser vaporization procedures.

Table 1 A
summary of comparative studies.

Table 2
Baseline demographic and clinical characteristics.