Impact of Periurethral Inflammation on Continence Status Early After Robot-Assisted Radical Prostatectomy

Abstract

Introduction:

The aim of this study was to investigate the effect of periurethral inflammation on the continence status after robot-assisted radical prostatectomy (RARP).

Methods:

This study included 101 consecutive prostate cancer patients treated with RARP. To evaluate the status of periurethral inflammation, most apical urethral tissues in RARP specimens from these patients were immunohistochemically stained with antibodies for tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Masson trichrome staining (MTS) of these specimens was also performed to determine the degree of periurethral fibrosis. Uni- and multivariate logistic regression analyses were performed to analyze the correlation between several factors and the postoperative continence status.

Results:

Of the 101 patients, urinary continence was achieved in 37 and 62 at 1 and 3 months after RARP, respectively. Immunohistochemical study revealed that 59, 41, and 56 patients were positive for TNF-α, IL-1β, and MTS, respectively, and the findings on MTS were significantly correlated with those on TNF-α and IL-1β expressions. At 1 month after RARP, the proportions of patients positive for TNF-α expression and MTS, but not for IL-1β expression, in the incontinence group were significantly greater than those in the continence group, whereas at 3 months after RARP, a significantly greater proportion of patients in the incontinence group was judged to be positive for TNF-α and IL-1β expressions, but not for MTS, than in the continence group. The following factors were identified as independent predictors of the continence status: preoperatively observed detrusor overactivity and TNF-α expression at 1 month after RARP, and TNF-α expression at 3 months after RARP.

Conclusions:

Periurethral inflammation, particularly that evaluated by TNF-α staining, could be a useful predictive parameter of the continence status early after RARP.

Introduction

Radical prostatectomy (RP) remains the most prevalent curative therapy for patients with localized prostate cancer.¹ Recently, the proportion of patients who are diagnosed with prostate cancer at younger ages and/or in earlier stages has markedly increased because of the introduction of the measurement of prostate-specific antigen (PSA) into routine clinical practice¹; therefore, it is currently regarded as one of the most important issues for patients undergoing RP to manage adverse events, which influence a negative effect on the postoperative quality of life.

Despite improved surgical techniques based on the advance in the field of anatomy around the prostate,² urinary incontinence remains a distressful complication after RP.³ Injury of the external urethral sphincter during RP has been shown to result in the occurrence of urinary incontinence after RP,^4,5 several recent studies showed the involvement of a wide variety of demographic risk factors in the delayed recovery of urinary continence, such as the prostate volume, body mass index, length of the membranous urethra, and bladder dysfunction.^6
–8 Our previous study also showed that detrusor overactivity (DO) diagnosed by urodynamic tests before RP could be used as a reliable predictive factor of incontinence early after RP.⁹

Inflammation is part of the complicated biologic reaction of body tissues induced by harmful stimuli, which is mediated by multiple components, including immunocytes, blood vessels, and several types of molecular mediators.¹⁰ To date, there have been a number of experimental as well as clinical researches showing the association between the inflammatory changes in the urinary tract and bladder dysfunction.^11

–14 For example, Cantiello et al.¹² investigated inflammatory infiltration in the periurethral prostate tissues from 30 patients undergoing RP, and found a positive association between the inflammatory degree and International Prostate Symptom Score among these patients.¹² Furthermore, it has been well documented that inflammation, if chronic, could induce fibrotic degeneration in the tissue architecture,^12

–15 resulting in the functional impairment of various organs, including the urethra.^12,16,17 To the best of our knowledge, however, there has not been any study focusing on the role of inflammatory changes around the urethra as a demographic risk factor for predicting the recovery of urinary continence status in prostate cancer patients after RP.

Taken together, we conducted the retrospective study evaluating the degree of inflammatory changes by the immunohistochemical assessment of two major proinflammatory cytokines, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β),¹⁸ as well as the fibrotic status by Masson trichrome staining (MTS) in periurethral tissues from 101 consecutive prostate cancer patients who received robot-assisted RP (RARP), and examined the effect of the staining outcomes on recovery of the continence status after RARP in these patients.

Materials and Methods

A total of 101 consecutive patients, who were diagnosed with localized prostate cancer and subsequently underwent RARP between January 2013 and August 2014, were included in this study. Informed consent to participate in this study was acquired from all patients, and the Research Ethics Committee at our university approved the execution of this study. In this study, urinary continence was defined as the use of either no or one pad per day as a precaution only, and the postoperative continence status was assessed by hearing surveys before and 1 and 3 months after RARP.

At our institution, RARP was performed using a da Vinci^® robotic system (Intuitive Surgical, Inc., Sunnyvale, CA), as previously described.¹⁹ In brief, after isolating and ligating the dorsal venous complex by an anterior approach, bladder neck was dissected and seminal vesicles were mobilized, and the prostate was removed by dissecting the prostatic vascular pedicles. According to the localization of malignant lesions in the prostate based on the findings on the radiologic examinations, the neurovascular bundles were preserved through intra- or interfascial dissection. In all patients, posterior reconstruction of the rhabdomyosphincter was conducted, and vesicourethral anastomosis was performed as previously described.²⁰

Urodynamic studies, consisting of filling cystometry, a pressure flow study, an electromyogram of the external urethral sphincter, and urethral pressure profile, were carried out in these 101 patients a few days before RARP, as previously reported.⁹ In brief, after filling cystometry using saline at a filling rate of 50 mL/min through a two-channel transurethral catheter, a voiding cystometrogram was recorded. Abdominal pressure was evaluated through a transrectal balloon catheter. After voiding cystometry, the transurethral catheter was withdrawn at 0.5 cm/sec, while being perfused at 2 mL/min with saline, to assess the profile of urethral pressure. In this study, the following parameters were examined: first sensation, maximum cystometric capacity (MCC), bladder compliance, DO, maximum flow rate (Q _max), Watt factor maximum (WF_max), maximum urethral closure pressure (MUCP), bladder outlet obstruction index (BOO index), and functional length of the urethra.

To evaluate the status of periurethral inflammation, immunohistochemical staining of the most apical urethral tissues in RARP specimens was carried out as previously reported.²¹ In brief, formaldehyde-fixed tissue sections obtained from a total of 101 RP specimens were deparaffinized. After the block of endogenous peroxidase, sections were boiled in citrate buffer for 10 minutes followed by the incubation with normal blocking serum for 20 minutes. The sections were then reacted with the antihuman antibodies against TNF-α (R&D Systems, Minneapolis, MN) and IL-1β (Cell Signaling, Beverly, MA) for 60 minutes. After incubation with corresponding secondary antibodies (Vector Laboratories, Burlingame, CA) for 30 minutes, the sections were incubated in an avidin–biotin peroxidase complex for 30 minutes, subsequently exposed to diaminobenzidine tetrahydrochloride solution. Counterstaining of these sections was performed with methyl green. In addition, the fibrotic status of periurethral tissues was assessed by MTS of these 101 specimens according to a previous study.²²

All findings on immunohistochemical staining and MTS were independently evaluated by two investigators who were blinded to the clinical findings. When inconsistent estimations were obtained, different outcomes were resolved by a joint assessment and/or consultation with a third physician familiar with immunohistochemical staining. As previously reported,^21,22 TNF-α and IL-1β expressions were scored by the sum of the proportion of positively stained cells (0: 0%–5%, 1: 6%–25%, 2: 25%–75%, or 3: 75%–100%) and the staining intensity (0: no staining, 1: weak staining, 2: medium staining, or 3: strong staining), and a score >3 was regarded as positive expression, whereas the outcomes of MTS were evaluated based on the degree of collagen deposition and classified into none, mild, moderate, or severe, and a specimen judged to be moderate or severe was regarded as positive for fibrosis.

Statview 5.0 software (Abacus Concepts, Inc., Berkeley, CA) was used in all statistical analyses, and p value <0.05 was considered statistically significant. A chi-square test was used to compare differences in values between the two groups. Forward stepwise logistic regression analysis was conducted to examine the correlation between several factors and the continence status after RARP.

Results

A total of 101 consecutive patients, who were diagnosed with localized prostate cancer and then underwent RARP, were included in this study. The median age, prostate volume, and serum PSA level were 66.4 years, 28.9 cc, and 9.3 ng/mL, respectively. Before RARP, all patients were judged to show urinary continence. Of these 101 patients, 56 (55.4%) received unilateral or bilateral nerve-sparing surgery, whereas the remaining 45 (44.6%) underwent non-nerve-sparing surgery. The findings of preoperatively conducted urodynamic assessments were as follows (each value is expressed as the median value/interquartile range in the 101 patients except for DO): first sensation, 191.2/75.0 mL; MCC, 368.7/171.5 mL; bladder compliance, 47.6/35.7 mL/cmH₂O; DO, positive for 36 patients (36.6%); Q _max, 8.7/5.0 mL/sec; WF_max, 17.3/17.4 μw/m²; MUCP, 87.3/32.6 cmH₂O; BOO index, 31.2/27.5; and functional length of the urethra, 5.7/1.6 cm.

Of the 101 patients included in this study, urinary continence was achieved in 37 (36.6%) and 62 (61.4%) patients at 1 and 3 months after RARP, respectively. Immunohistochemical study revealed that positive expressions of TNF-α and IL-1β were detected in 59 (58.4%) and 41 (40.6%) patients, respectively, and 56 (55.4%) patients were judged to be positive for periurethral fibrosis based on the findings on MTS. Representative outcomes of the immunohistochemical study are presented in Figure 1. As shown in Table 1, the findings on MTS were significantly correlated with those on expressions of TNF-α and IL-1β; that is, the patients with periurethral fibrosis were significantly more likely to be positive for both TNF-α and IL-1β expressions than those without periurethral fibrosis. In addition, at 1 month after RARP, the proportions of patients positive for periurethral TNF-α expressions and fibrosis, but not for periurethral IL-1β expressions, in the incontinence group were significantly greater than those in the continence group, whereas at 3 months after RARP, significantly greater proportions of patients in the incontinence group were judged to be positive for TNF-α and IL-1β expressions, but not for periurethral fibrosis, than those in the continence group (Table 2). However, there were no significant impacts of the expression of TNF-α or IL-1β on any oncologic parameters examined, including PSA level, Gleason score, and risk classification by the D'Amico system (data not shown).

FIG. 1.

Typical findings on immunohistochemical staining of the most apical urethral tissues in robot-assisted radical prostatectomy specimens with antibodies against TNF-α and IL-1β, and those on MTS of these tissues. IL-1β, interleukin-1β; MTS, Masson trichrome staining; TNF-α, tumor necrosis factor-α.

Table 1.

Association of Periurethral Inflammatory Status Evaluated by Tumor Necrosis Factor-α and Interleukin-1β Expression with Fibrotic Change Assessed by Masson Trichrome Staining

	TNF-α expression				IL-1β expression
	Negative (n = 42)	Positive (n = 59)	Measure of concordance	p	Negative (n = 60)	Positive (n = 41)	Measure of concordance	p
MTS			0.42	<0.001			0.42	0.011
Negative (%)	29 (69.0)	16 (27.1)			33 (55.0)	12 (29.3)
Positive (%)	13 (31.0)	43 (72.9)			27 (45.0)	29 (70.7)

IL-1β, interleukin-1β; MTS = Masson trichrome staining; TNF-α = tumor necrosis factor-α.

Table 2.

Postoperative Continence Status According to Periurethral Inflammatory Status Evaluated by Tumor Necrosis Factor-α and Interleukin-1β Expression with Fibrotic Change Assessed by Masson Trichrome Staining

	TNF-α expression				IL-1β expression				MTS
Continence status	Negative (n = 42)	Positive (n = 59)	OR (95% CI)	p	Negative (n = 60)	Positive (n = 41)	OR (95% CI)	p	Negative (n = 45)	Positive (n = 56)	OR (95% CI)	p
1 month after surgery			11.1 (4.3, 28.9)	<0.001			1.7 (0.7, 4.0)	0.20			8.6 (3.4, 21.9)	<0.001
Continence (%)	28 (66.7)	9 (15.3)			25 (41.7)	12 (29.3)			28 (62.2)	9 (16.1)
Incontinence (%)	14 (33.3)	50 (84.7)			35 (58.3)	29 (70.7)			17 (37.8)	47 (83.9)
Sen/Spe/NPV/PPV (%)	78.1/75.6/66.7/84.7				45.3/67.6/41.7/70.7				73.4/75.7/62.2/83.9
Three months after surgery			10.6 (3.5, 29.3)	<0.001			2.5 (1.1, 5.6)	0.032			2.1 (0.9, 4.9)	0.072
Continence (%)	37 (88.1)	25 (42.4)			42 (70.0)	20 (48.8)			32 (71.1)	30 (53.6)
Incontinence (%)	5 (11.9)	34 (57.6)			18 (30.0)	21 (51.2)			13 (28.9)	26 (46.4)
Sen/Spe/NPV/PPV (%)	87.2/59.7/88.1/57.6				53.8/67.7/70.0/51.2				66.7/51.6/71.1/46.4

CI = confidence interval; NPV = negative predictive value; OR = odds ratio; PPV = positive predictive value; Sen = sensitivity; Spe = specificity.

The significance of several factors for predicting the postoperative continence was then assessed using uni- and multivariate analyses. As shown in Table 3, univariate analyses identified the following significant predictors of the continence: prostate volume, preoperatively observed DO, periurethral expressions of TNF-α, and periurethral fibrosis at 1 month after RARP, and age, prostate volume, and periurethral expression of TNF-α at 3 months after RARP. Moreover, multivariate analyses of these significant factors revealed independent impacts of the following factors on the association with the postoperative continence: preoperatively observed DO and periurethral expression of TNF-α at 1 month after RARP, and periurethral expression of TNF-α at 3 months after RARP.

Table 3.

Uni- and Multivariate Analyses of Several Factors Predicting Postoperative Urinary Continence Recovery

	One month after surgery				Three months after surgery
	Univariate analysis		Multivariate analysis		Univariate analysis		Multivariate analysis
Variables	OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p
Age (years)^a (<66 vs ≥66)	0.56 (0.14, 2.25)	0.41	—	—	0.22 (0.067, 0.74)	0.013	0.57 (0.13, 2.51)	0.46
Prostate volume (cc)^a (<29 vs ≥9)	0.22 (0.066, 0.75)	0.015	0.27 (0.052, 1.44)	0.13	0.36 (0.14, 0.92)	0.032	0.43 (0.14, 1.34)	0.15
Prostate-specific antigen (ng/mL)^a (<9 vs ≥9)	0.84 (0.26, 2.73)	0.77	—	—	0.87 (0.31, 2.45)	0.79	—	—
Nerve-sparing procedure (no vs yes)	1.89 (0.67, 5.31)	0.22	—	—	1.08 (0.43, 2.77)	0.86	—	—
First sensation (mL)^a (<191 vs ≥191)	1.41 (0.46, 4.17)	0.55	—	—	1.03 (0.39, 2.70)	0.95	—	—
Maximum cystometric capacity (mL)^a (<369 vs ≥369)	0.81 (0.29, 2.27)	0.69	—	—	0.59 (0.22, 1.59)	0.29	—	—
Bladder compliance^a (mL/cmH₂O) (<48 vs ≥48)	1.92 (0.64, 5.88)	0.24	—	—	0.92 (0.36, 2.33)	0.85	—	—
Detrusor overactivity (negative vs positive)	0.11 (0.023, 0.51)	0.0049	0.059 (0.0061, 0.59)	0.016	0.39 (0.15, 1.00)	0.051	—	—
Maximum flow rate (mL/sec)^a (<9 vs ≥ 9)	1.18 (0.35, 4.35)	0.16	—	—	1.52 (0.51, 3.99)	0.53	—	—
Watt factor maximum (μw/m²) ^a (<17 vs ≥ 17)	1.49 (0.49, 4.55)	0.48	—	—	0.63 (0.24, 1.69)	0.35	—	—
Maximum urethral closure pressure (cmH₂O)^a (<87 vs ≥87)	1.25 (0.37, 4.00)	0.70	—	—	1.96 (0.64, 5.26)	0.27	—	—
Functional length of urethra (cm)^a (<6 vs ≥6)	1.37 (0.45, 4.17)	0.57	—	—	1.23 (0.48, 3.23)	0.67	—	—
Bladder outlet obstruction index^a (<31 vs ≥31)	0.68 (0.23, 1.97)	0.48	—	—	0.94 (0.36, 2.47)	0.90	—	—
TNF-α expression (negative vs positive)	0.17 (0.049, 0.55)	0.0031	0.19 (0.044, 0.85)	0.029	0.16 (0.044, 0.54)	0.0029	0.17 (0.46, 0.62)	0.0072
IL-1β expression (negative vs positive)	0.36 (0.11, 1.19)	0.093	—	—	0.42 (0.15, 1.20)	0.11	—	—
MTS (negative vs positive)	0.24 (0.082, 0.70)	0.0092	0.31 (0.073, 1.35)	0.12	0.46 (0.18, 1.18)	0.11	—	—

Cut-off level of each variable was determined based on its median value in 101 patients included in this study.

Discussion

It has been widely accepted that RP is a standard therapeutic option for patients with clinically localized prostate cancer¹; however, despite the excellent oncologic outcomes, RP negatively affects the urinary function, including the recovery of postoperative urinary incontinence, particularly early after surgery.² Furthermore, despite the introduction of RARP, which makes it possible to perform precise and exact movements that contribute to preserve important anatomic structures to achieve superior postoperative functional results, there is still debate concerning the superiority of RARP over other surgical procedures with respect to postoperative urinary continence recovery.²³ To date, multiple factors have been shown to be associated with the recovery of the urinary continence status early after RP,^4,5 and in particular, special attention has recently been paid to the significance of several demographic factors as predictive factors of the urinary continence status after RP.^6

–9 To the best of our knowledge, however, there has not been any investigation evaluating the effect of urethral inflammation in the recovery of urinary continence in patients who underwent RARP; therefore, we immunohistochemically assessed the degree of the periurethral inflammatory status in 101 consecutive patients with localized prostate cancer treated with RARP, and the association between these outcomes and the continence status early after RARP was analyzed.

The inflammatory cascade has been demonstrated to be driven by a wide variety of molecular events, including proinflammatory cytokine formation. Of these cytokines, TNF-α and IL-1β have been demonstrated to play significant roles in the development of inflammatory changes and as molecular markers reflecting the degree of this change in multiple organs.^18,24 In the prostate as well, there have been numerous studies describing the important roles of TNF-α and IL-1β in a wide variety of pathophysiologic events, including the inflammation.^25,26 For example, Adissu and coworkers.²⁶ reported the involvement of these cytokines in both the acceleration of tumor cell invasion and the enhancement of inflammation in the prostate using a murine model of prostate cancer. In this study, therefore, immunohistochemical stainings of the most apical urethral tissues in RARP specimens with antibodies against TNF-α and IL-1β were carried out to evaluate the periurethral inflammatory status, and positive expressions of TNF-α and IL-1β were detected in 58.4% and 40.6% of the included patients, respectively. This proportion of patients with periurethral fibrosis was comparable to those in previous studies, showing ∼60% of patients positive for ≥grade 2 inflammation.^12,13 In addition, we identified 55.4% of the patients as positive for periurethral fibrosis, and the significant correlation of the periurethral fibrotic status with both TNF-α and IL-1β expressions, suggesting the possible involvement of the inflammatory change in the induction of urethral fibrosis. In a previous study as well, patients with urethral inflammation were shown to have a greater amount of collagen in the urethra.¹² However, it is absolutely necessary to perform the histologic evaluation of periurethral inflammation by evaluating the degree of inflammatory infiltrate to achieve the conclusive findings on the significance of TNF-α and IL-1β expressions in the urethra.

In this series, 36.6% and 61.4% of the included patients were judged to achieve continence at 1 and 3 months after RARP, respectively. We then assessed the impact of TNF-α and IL-1β expressions around the urethra on the continence status early after RARP, and showed that the periurethral expression of TNF-α, but not IL-1β, was significantly associated with the continence status at 1 month after RARP, whereas both TNF-α and IL-1β expressions had significantly affected the continence status at 3 months after RARP. To our knowledge, this might be the initial study clearly showing the correlation between the recovery of continence after RARP and the periurethral inflammation, assessed by the expression of proinflammatory cytokines. Furthermore, inconsistent with our previous study revealing the significant effect of urethral fibrosis examined by magnetic resonance imaging on the recovery of the postoperative continence status in patients receiving RARP,²⁷ fibrotic changes documented by MTS also appeared to have a significant effect on the postoperative urinary continence status. Collectively, these findings suggest that an unfavorable continence status in patients with periurethral inflammatory change may theoretically be explained by the functional damage of periurethral tissues characterized by inflammation-induced fibrotic destruction.

It is of interest to analyze the significance of the periurethral inflammatory status in the prediction of continence recovery in patients undergoing RARP compared with other conventional parameters. Accordingly, the variables of multiple factors, including the periurethral inflammatory status, as predictors of postoperative continence recovery assessed by uni- and multivariate analyses, and we identified the following independent predictors of the continence status: preoperatively observed DO and TNF-α expression at 1 month after RARP, and TNF-α expression at 3 months after RARP. To date, there have been several researches demonstrating the negative effect of preoperatively detectable DO on the recovery of urinary continence after RP.^9,28 Considering these findings, we suggest that the presence of inflammation around the urethra may induce some degree of fibrotic change and cause lower urinary tract symptoms (LUTS) through decreased flexibility of the urethra and the compromised urethral ability to enlarge urinary flow, resulting in BOO as well as its functional damage. This may, at least in part, be supported by several previous studies showing an association between periurethral inflammation and an impaired bladder function.^11,17 In fact, Ma et al.¹⁷ reported that periurethral tissues from men diagnosed with LUTS were stiffer with a significantly greater content of the collagen than those from men without LUTS. However, when interpreting the findings of this study, the urodynamic characteristics of the current cohort should be carefully considered. For example, the Q _max of this study population is atypically low, whereas despite being previously shown to be associated with periurethral fibrosis,¹⁷ BOO index lacked a significant impact on postoperative continence status in this series.

Here, several limitations of this study should be mentioned. This was conducted as a retrospective study, and a sample size of a total of 101 patients for such a common malignancy like prostate cancer is not large enough to draw valid conclusions. Second, the definition of postoperative urinary continence has remained variable in studies. Third, we assessed the effects of periurethral inflammation on the continence status early after surgery alone; thus, it may be difficult to apply the current findings to the prediction of long-term incontinence, which is the most concerning postoperative morbidity. Fourth, if possible, it would be desirable to analyze the urethral fibrosis with a more longitudinal extension rather than the most apical urethral tissues in RARP specimens, to achieve more reliable findings. Fifth, some of inflammatory changes in the urethra in the cohort of this study could be an artifact induced by the prostate biopsy and/or RARP. Finally, this study subjectively selected only TNF-α and IL-1β from numerous proinflammatory cytokines; thus, there may be some other molecules showing more close association with the postoperative continence status.

Conclusions

We immunohistochemically evaluated the expressions of two major proinflammatory cytokines, TNF-α and IL-1β, in the most apical urethral tissues in RARP specimens from prostate cancer patients to evaluate the degree of periurethral inflammation. The positive expressions of TNF-α and IL-1β in the urethra were shown to be closely correlated with the urethral fibrotic change assessed by MTS. Furthermore, the periurethral expressions of these two cytokines appeared to have significant impacts on the delayed recovery of the postoperative continence status in patients undergoing RARP, and, in particular, TNF-α expression in the urethra was independently associated with the continent status early after RARP. Collectively, these findings indicate that it might be useful to immunohistochemically assess the periurethral expressions of proinflammatory cytokines, such as TNF-α and IL-1β, to help predict postoperative continence recovery in prostate cancer patients treated with RARP.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Abbreviations Used

References

Heidenreich

, Bastian

, Bellmunt

, et al. EAU guidelines on prostate cancer. Part 1: Screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol, 2014; 65:124–137.

Vora

, Dajani

, Lynch

, et al. Anatomic and technical considerations for optimizing recovery of urinary function during robotic-assisted radical prostatectomy. Curr Opin Urol, 2013; 23:78–87.

Bauer

, Gozzi

, Hübner

, et al. Contemporary management of postprostatectomy incontinence. Eur Urol, 2011; 59:985–996.

Kleinhans

, Gerharz

, Melekos

, et al. Changes of urodynamic findings after radical retropubic prostatectomy. Eur Urol, 1999; 35:217–221.

Winters

, Appell

, Rackley

. Urodynamic findings in postprostatectomy incontinence. Neurourol Urodyn, 1998; 17:493–498.

Porena

, Mearini

, et al. Voiding dysfunction after radical retropubic prostatectomy: More than external urethral sphincter deficiency. Eur Urol, 2007; 52:38–45.

Sandhu

, Eastham

. Factors predicting early return of continence after radical prostatectomy. Curr Urol Rep, 2010; 11:191–197.

Wolin

, Luly

, Sutcliffe

, et al. Risk of urinary incontinence following prostatectomy: The role of physical activity and obesity. J Urol, 2010; 183:629–633.

Yanagiuchi

, Miyake

, Tanaka

, et al. Significance of preoperatively observed detrusor overactivity as a predictor of continence status early after robot-assisted radical prostatectomy. Asian J Androl, 2014; 16:869–872.

10.

Ferrero-Miliani

, Nielsen

, Andersen

, et al. Chronic inflammation: Importance of NOD2 and NALP3 in interleukin-1beta generation. Clin Exp Immunol, 2007; 147:227–235.

11.

Nickel

, Roehrborn

, O'Leary

, et al. The relationship between prostate inflammation and lower urinary tract symptoms: Examination of baseline data from the REDUCE trial. Eur Urol, 2008; 54:1379–1384.

12.

Cantiello

, Cicione

, Salonia

, et al. Periurethral fibrosis secondary to prostatic inflammation causing lower urinary tract symptoms: A prospective cohort study. Urology, 2013; 81:1018–1023.

13.

Cantiello

, Cicione

, Salonia

, et al. Metabolic syndrome correlates with peri-urethral fibrosis secondary to chronic prostate inflammation: Evidence of a link in a cohort of patients undergoing radical prostatectomy. Int J Urol, 2014; 21:264–269.

14.

Metcalfe

, Wang

, Jiao

, et al. Bladder outlet obstruction: Progression from inflammation to fibrosis. BJU Int, 2010; 106:1686–1694.

15.

Wynn

, Ramalingam

. Mechanisms of fibrosis: Therapeutic translation for fibrotic disease. Nat Med, 2012; 18:1028–1040.

16.

Novo

, di Bonzo

, Cannito

, et al. Hepatic myofibroblasts: A heterogeneous population of multifunctional cells in liver fibrogenesis. Int J Biochem Cell Biol, 2009; 41:2089–2093.

17.

, Gharaee-Kermani

, Kunju

, et al. Prostatic fibrosis is associated with lower urinary tract symptoms. J Urol, 2012; 188:1375–1381.

18.

Kasama

, Miwa

, Isozaki

, et al. Neutrophil-derived cytokines: Potential therapeutic targets in inflammation. Curr Drug Targets Inflamm Allergy, 2005; 4:273–279.

19.

Patel

, Thaly

, Shah

. Robotic radical prostatectomy: Outcomes of 500 cases. BJU Int, 2007; 99:1109–1112.

20.

van Velthoven

, Ahlering

, Peltier

, et al. Technique for laparoscopic running urethrovesical for laparoscopic running urethrovesical anastomosis: The single knot method. Urology, 2003; 61:699–702.

21.

Harada

, Miyake

, Kusuda

, et al. Expression of epithelial-mesenchymal transition markers in renal cell carcinoma: Impact on prognostic outcomes in patients undergoing radical nephrectomy. BJU Int, 2012; 110:E1131–E1137.

22.

Eguchi

, Kim

, Kang

, et al. Ischemia-reperfusion injury leads to distinct temporal cardiac remodeling in normal versus diabetic mice. PLoS One, 2012; 7:e30450.

23.

Ficarra

, Novara

, Rosen

, et al. Systematic review and meta-analysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. Eur Urol, 2012; 62:405–417.

24.

Kato

, Kitagawa

. Regulation of neutrophil functions by proinflammatory cytokines. Int J Hematol, 2006; 84:205–209.

25.

Rodríguez-Berriguete

, Sánchez-Espiridión

, Cansino

, et al. Clinical significance of both tumor and stromal expression of components of the IL-1 and TNF-α signaling pathways in prostate cancer. Cytokine, 2013; 64:555–563.

26.

Adissu

, McKerlie

, Di Grappa

, et al. Timp3 loss accelerates tumour invasion and increases prostate inflammation in a mouse model of prostate cancer. Prostate, 2015; 75:1831–1843.

27.

Momozono

, Miyake

, Miyazaki

, et al. Significance of urethral fibrosis evaluated by preoperative magnetic resonance imaging as a predictor of continence status after robot-assisted radical prostatectomy. Int J Med Robot, 2016; 12:496–501.

28.

Dubbelman

, Groen

, Wildhagen

, et al. Quantification of changes in detrusor function and pressure-flow parameters after radical prostatectomy: Relation to postoperative continence status and the impact of intensity of pelvic floor muscle exercises. Neurourol Urodyn, 2012; 31:637–641.