Treatment and surveillance for non-muscle-invasive bladder cancer: a clinical practice guideline (2021 edition).

Non-muscle invasive bladder cancer (NMIBC) is a major type of bladder cancer with a high incidence worldwide, resulting in a great disease burden. Treatment and surveillance are the most important part of NIMBC management. In 2018, we issued "Treatment and surveillance for non-muscle-invasive bladder cancer in China: an evidence-based clinical practice guideline". Since then, various studies on the treatment and surveillance of NMIBC have been published. There is a need to incorporate these materials and also to take into account the relatively limited medical resources in primary medical institutions in China. Developing a version of guideline which takes these two issues into account to promote the management of NMIBC is therefore indicated. We formed a working group of clinical experts and methodologists. Through questionnaire investigation of clinicians including primary medical institutions, 24 clinically concerned issues, involving transurethral resection of bladder tumor (TURBT), intravesical chemotherapy and intravesical immunotherapy of NMIBC, and follow-up and surveillance of the NMIBC patients, were determined for this guideline. Researches and recommendations on the management of NMIBC in databases, guideline development professional societies and monographs were referred to, and the European Association of Urology was used to assess the certainty of generated recommendations. Finally, we issued 29 statements, among which 22 were strong recommendations, and 7 were weak recommendations. These recommendations cover the topics of TURBT, postoperative chemotherapy after TURBT, Bacillus Calmette-Guérin (BCG) immunotherapy after TURBT, combination treatment of BCG and chemotherapy after TURBT, treatment of carcinoma in situ, radical cystectomy, treatment of NMIBC recurrence, and follow-up and surveillance. We hope these recommendations can help promote the treatment and surveillance of NMIBC in China, especially for the primary medical institutions.

CRMP4 CpG Hypermethylation Predicts Upgrading to Gleason Score ≥ 8 in Prostate Cancer.

Background: This study determined the predictive value of CRMP4 promoter methylation in prostate tissues collected by core needle biopsies for a postoperative upgrade of Gleason Score (GS) to ≥8 in patients with low-risk PCa. Method: A retrospective analysis of the clinical data was conducted from 631 patients diagnosed with low-risk PCa by core needle biopsy at multiple centers and then underwent Radical Prostatectomy (RP) from 2014-2019. Specimens were collected by core needle biopsy to detect CRMP4 promoter methylation. The pathologic factors correlated with the postoperative GS upgrade to ≥8 were analyzed by logistic regression. The cut-off value for CRMP4 promoter methylation in the prostate tissues collected by core needle biopsy was estimated from the ROC curve in patients with a postoperative GS upgrade to ≥8. Result: Multivariate logistic regression showed that prostate volume, number of positive cores, and CRMP4 promoter methylation were predictive factors for a GS upgrade to ≥8 (OR: 0.94, 95% CI: 0.91-0.98, P=0.003; OR: 3.16, 95% CI: 1.81-5.53, P<0.001; and OR: 1.43, 95% CI: 1.32-1.55, P<0.001, respectively). The positive predictive rate was 85.2%, the negative predictive rate was 99.3%, and the overall predictive rate was 97.9%. When the CRMP4 promoter methylation rate was >18.00%, the low-risk PCa patients were more likely to escalate to high-risk patients. The predictive sensitivity and specificity were 86.9% and 98.8%, respectively. The area under the ROC curve (AUC) was 0.929 (95% CI: 0.883-0.976; P<0.001). The biochemical recurrence (BCR)-free survival, progression-free survival (PFS), and cancer-specific survival (CSS) were worse in patients with CRMP4 methylation >18.0% and postoperative GS upgrade to ≥8 than in patients without an upgrade (P ≤ 0.002). Conclusion: A CRMP4 promoter methylation rate >18.00% in prostate cancer tissues indicated that patients were more likely to escalate from low-to-high risk after undergoing an RP. We recommend determining CRMP4 promoter methylation before RP for low-risk PCa patients.

Clinical practice guideline for transurethral plasmakinetic resection of prostate for benign prostatic hyperplasia (2021 Edition).

Benign prostatic hyperplasia (BPH) is highly prevalent among older men, impacting on their quality of life, sexual function, and genitourinary health, and has become an important global burden of disease. Transurethral plasmakinetic resection of prostate (TUPKP) is one of the foremost surgical procedures for the treatment of BPH. It has become well established in clinical practice with good efficacy and safety. In 2018, we issued the guideline "2018 Standard Edition". However much new direct evidence has now emerged and this may change some of previous recommendations. The time is ripe to develop new evidence-based guidelines, so we formed a working group of clinical experts and methodologists. The steering group members posed 31 questions relevant to the management of TUPKP for BPH covering the following areas: questions relevant to the perioperative period (preoperative, intraoperative, and postoperative) of TUPKP in the treatment of BPH, postoperative complications and the level of surgeons' surgical skill. We searched the literature for direct evidence on the management of TUPKP for BPH, and assessed its certainty generated recommendations using the grade criteria by the European Association of Urology. Recommendations were either strong or weak, or in the form of an ungraded consensus-based statement. Finally, we issued 36 statements. Among them, 23 carried strong recommendations, and 13 carried weak recommendations for the stated procedure. They covered questions relevant to the aforementioned three areas. The preoperative period for TUPKP in the treatment of BPH included indications and contraindications for TUPKP, precautions for preoperative preparation in patients with renal impairment and urinary tract infection due to urinary retention, and preoperative prophylactic use of antibiotics. Questions relevant to the intraoperative period incorporated surgical operation techniques and prevention and management of bladder explosion. The application to different populations incorporating the efficacy and safety of TUPKP in the treatment of normal volume (< 80 ml) and large-volume (≥ 80 ml) BPH compared with transurethral urethral resection prostate, transurethral plasmakinetic enucleation of prostate and open prostatectomy; the efficacy and safety of TUPKP in high-risk populations and among people taking anticoagulant (antithrombotic) drugs. Questions relevant to the postoperative period incorporated the time and speed of flushing, the time indwelling catheters are needed, principles of postoperative therapeutic use of antibiotics, follow-up time and follow-up content. Questions related to complications incorporated types of complications and their incidence, postoperative leukocyturia, the treatment measures for the perforation and extravasation of the capsule, transurethral resection syndrome, postoperative bleeding, urinary catheter blockage, bladder spasm, overactive bladder, urinary incontinence, urethral stricture, rectal injury during surgery, postoperative erectile dysfunction and retrograde ejaculation. Final questions were related to surgeons' skills when performing TUPKP for the treatment of BPH. We hope these recommendations can help support healthcare workers caring for patients having TUPKP for the treatment of BPH.

[Establishment of a nomogram model to predict systemic inflammatory response syndrome after transrectal ultrasound-guided prostate biopsy].

OBJECTIVE: To access the risk factors of systemic inflammatory response syndrome (SIRS) after transrectal ultrasound-guided biopsy of the prostate (TRUS-Bp) and establish a model and a nomogram for the prediction of SIRS after TRUS-Bp. METHODS: We retrospectively analyzed the clinical data on 752 cases of TRUS-Bp in our hospital from January 2010 to January 2017 and included 570 of the cases in this study. We investigated the independent risk factors for SIRS after TRUS-Bp by univariate and logistic regression analyses, constructed a prediction model and nomogram with the R-Statistics software, evaluated the discrimination of the model with the ROC curve, and measured the conformity by SPSS25.0 Bootstrap sampling. RESULTS: At 1－2 postoperative days, 58 (10.2%) of the 570 patients were diagnosed with SIRS, 22 (3.9%) with bacteremia, and 6 (1.1%) with septic shock, but none died. Logistic regression analysis showed that the independent risk factors for SIRS after TRUS-Bp included old age (>70 yr; OR = 1.1, P = 0.01), high number of biopsy needles (>10; OR = 2.3, P < 0.01), diabetes mellitus (OR = 3.4, P < 0.01), and hypoproteinemia (OR = 2.5, P < 0.01). The area under the ROC curve was 0.947 and internal validation showed a conformity of 92%. CONCLUSIONS: Old age (>70 yr), high number of biopsy needles (>10), diabetes mellitus and hypoproteinemia may increase the risk of SIRS after TRUS-Bp. Evaluation with a model nomogram may help predict the probability of SIRS after TRUS-Bp.

Prospective Study of CRMP4 Promoter Methylation in Prostate Biopsies as a Predictor For Lymph Node Metastases.

Background: For patients with prostate cancer (PCa), the presence of pelvic lymph node metastasis (LNM) is a strong predictor of poor outcome. However, the approaches with promising sensitivity and specificity to detect LNM are still lacking. We investigated the value of collapsin response mediator protein 4 (CRMP4) promoter methylation in biopsies as a predictor for LNM. Methods: CRMP4 promoter methylation at two previously identified CpG sites was determined in 80 case-matched biopsy samples (the training set) using bisulfite pyrosequencing. The predictive cutoff value was independently validated using cohort I of 339 PCa patients (Southern China) and cohort II of 328 case patients (Germany, across China). Mann-Whitney U test, the receiver operating characteristic curve, McNemar's test, and logistic regression were used to assess data. All statistical tests were two-sided. Results: In the training set, CRMP4 promoter methylation (≥15.0% methylated) was statistically significantly associated with LNM (P < 001). Successful validations were achieved in both cohorts I and II (sensitivity = 92.3%, 95% confidence interval [CI] = 79.3 to 97.9, and sensitivity = 92.2%, 95% CI = 81.1 to 97.8, respectively; specificity = 92.7%, 95% CI = 80.2 to 99.1, and specificity = 91.3%, 95% CI = 87.4 to 94.4, respectively). The sensitivity of CRMP4 promoter methylation is superior to conventional MRI (cohort I: 92.3% vs 26.2%, P < 001; cohort II: 92.2% vs 33.3%, P < 001). CRMP4 promoter methylation is an independent predictor of LNM (cohort I: hazard ratio [HR] = 8.35, 95% CI = 5.64 to 12.35, P < 001; cohort II: HR = 12.46, 95% CI = 5.82 to 26.70, P < 001) in a multivariable analysis model. Conclusion: CRMP4 promoter methylation in diagnostic biopsies could be a robust biomarker for LNM in PCa.

[Comparison of laparoscopic pyelolithotomy and percutaneous nephrolithotomy for renal pelvic stones larger than 2.5 cm].

OBJECTIVE: To compare the safety, efficacy and complications of laparoscopic pyelolithotomy (LPL) and percutaneous nephrolithotomy (PCNL) for treatment of renal pelvic stones larger than 2.5 cm. METHODS: From 2011 to 2016, 32 patients underwent LPL and another 32 patients received PCNL for renal pelvic stones larger than 2.5 cm. The baseline characteristics of the patients, stone size, mean operative time, estimated blood loss, postoperative hospital stay, stone-free rate, postoperative analgesia, blood transfusion, and the intraoperative, early postoperative and long-term complications were compared between the two groups. RESULTS: The baseline characteristics and stone size were comparable between the two groups. The mean operative time of LPL and PCNL was 117∓23.12 and 118.16∓25.45 min, respectively (P>0.05). The two groups showed significant differences in the mean estimated blood loss (63∓11.25 vs 122∓27.78 mL, P<0.01) and blood transfusion rate (0 vs 6.2%, P<0.01) but not in postoperative hospital stay (4.5∓1.34 vs 4.8∓2.2 days, P>0.05), stone-free rate (93.1% vs 87.5%, P>0.05) or the postoperative analgesia time (1.7∓0.5 and 1.9∓0.6 days, P>0.05). The incidence of intraoperative complications were significant lower in LPL group than in PCNL group (6.2% vs 25.0%, P<0.01), but the incidences of early postoperative complications (25.0% vs 34.4%, P>0.05) and long-term postoperative complications (9.4% vs 12.5%, P>0.05) were similar between them. CONCLUSION: PCNL is the standard treatment for pelvic stones larger than 2.5 cm, but for urologists experienced with laparoscopic technique, LPL provides a feasible and safe option for management of such cases.

Inhibition of LDHA suppresses tumor progression in prostate cancer.

A key hallmark of cancer cells is their altered metabolism, known as Warburg effect. Lactate dehydrogenase A (LDHA) executes the final step of aerobic glycolysis and has been reported to be involved in the tumor progression. However, the function of LDHA in prostate cancer has not been studied. In current study, we observed overexpression of LDHA in the clinical prostate cancer samples compared with benign prostate hyperplasia tissues as demonstrated by immunohistochemistry and real-time qPCR. Attenuated expression of LDHA by siRNA or inhibition of LDHA activities by FX11 inhibited cell proliferation, migration, invasion, and promoted cell apoptosis of PC-3 and DU145 cells. Mechanistically, decreased Warburg effect as demonstrated by reduced glucose consumption and lactate secretion and reduced expression of MMP-9, PLAU, and cathepsin B were found after LDHA knockdown or FX11 treatment in PC-3 and DU145 cells. Taken together, our study revealed the oncogenic role of LDHA in prostate cancer and suggested that LDHA might be a potential therapeutic target.

Effects of insulin-like growth factor-1 on the relaxation responses of the cavernous smooth muscle from aged rats.

OBJECTIVE: The aim of this study was determine whether intracavernosal injection (ICI) of insulin-like growth factor-1 (IGF-1) protein can improve corpus cavernosal smooth muscle relaxation in aging rats. MATERIALS AND METHODS: Ten young (4-month-old) and 30 old (24-month-old) Sprague-Dawley male rats were enrolled in the study. The old rats were divided into three groups: vehicle-only (n = 10), IGF-1 1 µg/kg (n = 10) and IGF-1 10 µg/kg treatment groups (n = 10). After 4 weeks of single IGF-1 injection treatment, strips of corporal tissue were precontracted with phenylephrine, and dose-response curves were generated to evaluate endothelial-dependent [acetylcholine (ACh)], endothelial-independent [sodium nitroprusside (SNP)] and electrical field stimulation (EFS) vasoreactivity. The changes in percentage of cavernosal smooth muscle and the concentration of nitric oxide (NO) in penile tissue were also evaluated. RESULTS: After IGF-1 treatment, the vasoreactivity was significantly improved in both the 1 µg/kg and the 10 µg/kg treatment groups compared with the vehicle-only group at 4 weeks in response to ACh, SNP and EFS (all p < 0.05). The percentage of cavernosal smooth muscle was increased in the IGF-1 treatment groups. The NO concentrations were increased after IGF-1 treatment. CONCLUSIONS: These data demonstrate that ICI of IGF-1 can improve vasoreactivity via endothelium-dependent and endothelial-independent mechanisms in the corpus cavernosum of the aging rat.

[Influences of three surgical approaches to urethral stricture on the erectile function of the patients].

OBJECTIVE: To evaluate the impacts of three different surgical approaches to urethral stricture on the erectile function of the patients. METHODS: This study included 126 male patients with urethral stricture, 35 treated by substitution urethroplasty (group A), 52 by anastomotic urethroplasty (group B), and 39 by internal urethroplasty (group C). We evaluated the pre- and postoperative erectile function of the patients using IIEF-5 scores by telephone calls and interviews. We also monitored their nocturnal penile tumescence (NPT). RESULTS: The IIEF-5 scores in groups A, B and C were 13.5 +/- 4.5, 11.1 +/- 4.8 and 14.5 +/- 4.41 respectively after surgery, all significantly decreased as compared with 17.1 +/- 2.6, 17.1 +/- 3.0 and 17.6 +/- 2.2 preoperatively (P < 0.05). CONCLUSION: All the three surgical approaches can reduce IIEF-5 scores in patients with urethral stricture, but anastomotic urethroplasty may induce a higher incidence of erectile dysfunction than the other two approaches.

shRNA constructs targeting IGFBP-3 alleviate age related erectile dysfunction in the rat.

PURPOSE: We investigated whether injecting shRNA constructs targeting IGFBP-3 in the penis of old rats would improve erectile function. MATERIALS AND METHODS: The most validated IGFBP-3 shRNA plasmid vector (pGPU6/GFP/Neo-shIGFBP-3) was prepared and injected in penile corpus cavernosum tissue. A total of 30 old (age 24 months) male Sprague Dawley® rats were randomly divided into 3 groups, including 10 each that received phosphate buffered saline only (100 µl), pGPU6/GFP/Neo-shNC (100 µg) and the most validated plasmid constructs pGPU6/GFP/Neo-shIGFBP-3 (100 µg). At 4 weeks the erectile response was measured as intracavernous pressure. The percent of smooth muscle in corpus cavernosum tissue was evaluated. Nitric oxide synthase activity and the cGMP concentration in penile tissue were also analyzed. IGFBP-3 was estimated in penile tissue by Western blot, real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry. RESULTS: pGPU6/GFP/Neo-shIGFBP-3 corrected the impaired erectile response in aged rats compared with the response in those injected with phosphate buffered saline and pGPU6/GFP/Neo-shNC (each p <0.01). The percent of cavernous smooth muscle was increased in the pGPU6/GFP/Neo-shIGFBP-3 group. Nitric oxide synthase activity and the cGMP concentration were also significantly increased in rats treated with pGPU6/GFP/Neo-shIGFBP-3. IGFBP-3 shRNA effectively reduced IGFBP-3 mRNA and protein expression in penile corpus cavernosum tissue. CONCLUSIONS: Decreasing IGFBP-3 expression by plasmid expressed shRNA improved erectile function in aged rats. The therapy may modulate smooth muscle integrity and increase the cGMP concentration. This may be a new direction for treating erectile dysfunction in clinical practice.

[Impact of aging on the secretion of insulin-like growth factor-1 in the corpus cavernosum smooth muscle cells of rats in vitro].

OBJECTIVE: To observe the secretion of insulin-like growth factor-1 (IGF-1) in corpus cavernosum smooth muscle cells (CCSMCs) in rats of different ages and explore the possible relationship of IGF-1 with aging-related erectile dysfunction (ED). METHODS: We primarily cultured CCSMCs of rats aged 4, 12 and 24 months, and identified them by immunohistochemistry. We quantitatively cultured the CCSMCs in 6-well culture plates, determined the levels of IGF-1 secreted from the CCSMCs by enzyme immunoassay (EIA) and analyzed the effect of age on the IGF-1 level. RESULTS: CCSMCs were successfully cultured in vitro. The level of IGF-1 secreted from the CCSMCs was decreased with the increase of age, with 7.1 ng/10(5) cells in the 4-month-old group, 2.2 ng/10(5) cells in the 12-month group, and 1.9 ng/10(5) cells in the 24-month group, with statistically significant differences among the three groups (P < 0.01). CONCLUSION: The secretion of IGF-1 is reduced with the increase of age, and the decreased expression of IGF-1 might be associated with aging-related ED.

[Insulin-like growth factor-1 gene therapy improves the levels of mRNA and protein of endothelial nitric oxide synthase in aging related erectile dysfunction in rats].

OBJECTIVE: To explore the effects of gene transfer of insulin like growth factor-1 (IGF-1) on the penis of senile rats and the altered levels of mRNA and protein of endothelial nitric oxide synthase (eNOS). METHODS: Ten young (4 months) and 20 senile (24 months) Sprague-Dawley male rats were selected. The senile rats were divided into 2 groups: phosphate buffer solution (PBS)-only (n = 10) and 100 µg IGF-1 plasmid treatment group (n = 10). After a 4-week injection of IGF-1, the responses of intracavernous pressure (ICP) with electrical stimulation to the cavernous nerve and systemic mean arterial pressure (MAP) were evaluated. In the control and transfected senile rats, the levels of eNOS mRNA and protein were examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot respectively. RESULTS: The ICP/MAP and total ICP were significantly higher in the young control group versus the PBS-only group at Week 4 (P < 0.05). The ICP/MAP and total ICP were significantly higher in the young control group and the 100 µg IGF-1 treatment group versus the PBS-only group at Week 4 (P < 0.05). The levels of mRNA and protein of eNOS were higher in the 100 µg IGF-1 treatment group versus the PBS-only group at Week 4 (0.62 ± 0.16 vs 0.25 ± 0.08, 0.71 ± 0.19 vs 0.27 ± 0.09, both P < 0.05, respectively). CONCLUSION: The gene therapy of IGF-1 can ameliorate erectile functions and improve the levels of mRNA and protein of eNOS in senile rats.

Extracellular matrix metalloproteinase inducer: a novel poor prognostic marker for human seminomas.

OBJECTIVE: Extracellular matrix metalloproteinase inducer (EMMPRIN) is a glycosylated member of the immunoglobulin superfamily whose function in human seminomas is unknown. We have recently determined that EMMPRIN possesses the ability to stimulate fibroblast and endothelial cell matrix metalloproteinase production, and that its expression was frequently up-regulated in several tumours of the urinary system. Thus, EMMPRIN expression might be associated with the progression of human seminomas. The aim of this study was to investigate whether the presence of EMMPRIN in seminoma tissues might help to predict the patients' prognosis. METHODS: Paraffin-embedded tissues from 65 patients with seminomas and 20 normal testes were processed for immunohistochemical staining using a mouse monoclonal antibody generated against human EMMPRIN, as primary antibody, and a biotinylated goat-anti-mouse IgG, as secondary antibody. In addition, the correlation of EMMPRIN expression with clinicopathologic characteristics and patients' prognosis was also analysed. RESULTS: EMMPRIN was detected in cancerous tissues of 53 patients with seminoma, but not normal testes. Thirty- five patients showed weakly to moderately positive and 18 patients intensely positive expression. Moreover, positive EMMPRIN staining correlated significantly with various clinicopathological factors (increased TNM stage and higher histological differentiation type) as well as decreased tumour-specific survival (log-rank, p=0.02). In particular, EMMPRIN expression was an independent prognosticator as shown by Cox regression analysis (p<0.001). CONCLUSION: EMMPRIN expression in a primary tumour predicts an unfavourable prognosis in human seminoma, suggesting its crucial role in the progression of this tumour.

Over-expression of extracellular matrix metalloproteinase inducer in prostate cancer is associated with high risk of prostate-specific antigen relapse after radical prostatectomy.

PURPOSE: The prognostic efficiency of clinical grading and staging in patients with confined or moderately differentiated prostate cancer (PCa) has been markedly improved, which underscores the importance of new prognostic markers. Extracellular matrix metalloproteinase inducer (EMMPRIN) has been demonstrated to be involved in cancerangiogenesis, metastasis and invasion. EMMPRIN expression was evaluated by measuring mRNA and protein levels in a large cohort of patients with PCa following prostatectomy and the findings were compared with clinico-pathological parameters, including prostate-specific antigen (PSA) relapse time. METHODS: EMMPRIN mRNA levels in 20 pairs of normal and cancerous prostate tissues were determined by quantitative real-time PCR. Protein expression in paraffin-embedded specimens of prostates gathered from 300 patients with PCa was detected by immunohistochemistry using a monoclonal antibody against EMMPRIN. The associations of EMMPRIN protein expression with the clinico-pathological parameters and PSA relapse-free time after radical prostatectomy were subsequently assessed. RESULTS: Both EMMPRIN mRNA and protein levels were higher in PCa tissue, compared with adjacent normal tissue. In addition, the positive expression rates of EMMPRIN in PCa tissues were significantly associated with preoperative PSA levels (p=0.008), AJCC stage (p=0.006) and Gleason Score (p < 0.001), Risk classification (p < 0.001), lymph node status post-surgery (p < 0.001) and surgical margin status (p < 0.001) were also determined. Multivariate analysis, using the Cox proportional hazards model, revealed that positive EMMPRIN expression was an independent prognostic factor for an increased risk of PSA relapse. CONCLUSION: Over-expression of EMMPRIN correlated with the aggressiveness of PCa, and the PSA relapse-free time, and may be a novel and useful biomarker for follow-up and treatment decisions for PCa.