Landscape of the intratumroal microenvironment in bladder cancer: Implications for prognosis and immunotherapy.

Introduction: This study aims to present the landscape of the intratumoral microenvironment and by which establish a classification system that can be used to predict the prognosis of bladder cancer patients and their response to anti-PD-L1 immunotherapy. Methods: The expression profiles of 1554 bladder cancer cases were downloaded from seven public datasets. Single-sample gene set enrichment analysis (ssGSEA), univariate Cox regression analysis, and meta-analysis were employed to establish the bladder cancer immune prognostic index (BCIPI). Extensive analyses were executed to investigate the association between BCIPI and overall survival, tumor-infiltrated immunocytes, immunotherapeutic response, mutation load, etc. Results: The results obtained from seven independent cohorts and meta-analyses suggested that the BCIPI is an effective classification system for estimating bladder cancer patients' overall survival. Patients in the BCIPI-High subgroup revealed different immunophenotypic outcomes from those in the BCIPI-Low subgroup regarding tumor-infiltrated immunocytes and mutated genes. Subsequent analysis suggested that patients in the BCIPI-High subgroup were more sensitive to anti-PD-L1 immunotherapy than those in the BCIPI-Low subgroup. Conclusions: The newly established BCIPI is a valuable tool for predicting overall survival outcomes and immunotherapeutic responses in patients with bladder cancer.

Radial Extracorporeal Shock Wave Therapy Combined with Resveratrol Derivative Alleviates Chronic Nonbacterial Prostatitis in Rats.

Resveratrol (Res) is a non-flavonoid polyphenol compound with biological pleiotropic properties, but low bioavailability limits its application value. Here, we synthesized a new Res derivative ((E)-5-(dimethylamino)-2-(4-methoxystyryl)phenol), and attempted to determine the function of Res derivative combined with radial extracorporeal shock wave therapy (rESWT) in chronic nonbacterial prostatitis (CNP). CNP model rats were constructed by subcutaneous administration of prostatein suspension (15 mg/ml), followed by rESWT treatment alone or in associated with Res or Res derivatives. In this study, inflammatory cell infiltration and tissue fibrosis in the prostate tissues of CNP rats were significantly deteriorated, which was effectively abolished by rESWT treatment alone or in combination with Res or Res derivative. The expression of interleukin 1ß (IL-1ß), tumor necrosis factor-α (TNF-α), nerve growth factor (NGF), and nuclear factor kappa-B (NF-κB) were increased, while silent information regulator 1 (SIRT1) expression was suppressed in the prostate tissues of CNP rats, which were then rescued by rESWT treatment alone or in associated with Res or Res derivative. Importantly, compared with Res derivative treatment alone or rESWT combined with Res treatment, combination treatment with rESWT and Res derivative was more effective in alleviating inflammation and fibrosis, in reducing IL-1ß, TNF-α, NGF, and SIRT1 expression, and in facilitating SIRT1 expression. Overall, rESWT combined with Res derivative treatment improved CNP in rat by reducing inflammation and fibrosis, which attributed to regulate the expression of SIRT1 and NF-κB. Thus, this work provides a theoretical basis for rESWT combined with Res derivative in the clinical treatment of CNP.

Establishment of a five-enzalutamide-resistance-related-gene-based classifier for recurrence-free survival predicting of prostate cancer.

To identify prostate cancer (PCa) patients with a high risk of recurrence is critical before delivering adjuvant treatment. We developed a classifier based on the Enzalutamide treatment resistance-related genes to assist the currently available staging system in predicting the recurrence-free survival (RFS) prognosis of PCa patients. We overlapped the DEGs from two datasets to obtain a more convincing Enzalutamide-resistance-related-gene (ERRG) cluster. The five-ERRG-based classifier obtained good predictive values in both the training and validation cohorts. The classifier precisely predicted RFS of patients in four cohorts, independent of patient age, pathological tumour stage, Gleason score and PSA levels. The classifier and the clinicopathological factors were combined to construct a nomogram, which had an increased predictive accuracy than that of each variable alone. Besides, we also compared the differences between high- and low-risk subgroups and found their differences were enriched in cancer progression-related pathways. The five-ERRG-based classifier is a practical and reliable predictor, which adds value to the existing staging system for predicting the RFS prognosis of PCa after radical prostatectomy, enabling physicians to make more informed treatment decisions concerning adjuvant therapy.

Dietary habits and lifestyle related to the effectiveness of low-intensity extracorporeal shock wave therapy for chronic prostatitis/chronic pelvic pain syndrome-like symptoms: Initial results.

To identify factors that could influence the treatment outcomes of low-intensity extracorporeal shock wave therapy (Li-ESWT) on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)-like symptoms and establish a predictive model based on these factors to precisely screen individuals who might be more suitable for Li-ESWT. This study enrolled 84 patients with CP/CPPS-like symptoms who received Li-ESWT. Patients were divided into an effective group and an ineffective group based on the reduction of their National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI). A nomogram was established based on logistic regression analyses. Then, receiver operating characteristic (ROC) curves, calibration curves and decision curve analysis (DCA) were used to evaluate the nomogram. Univariate and multivariate logistic regression analysis showed that a higher NIH-CPSI score, a habit of holding urine, alcohol consumption, and urination soon after intercourse were independent predictors of Li-ESWT efficacy (p < 0.05). The nomogram constructed based on these four indicators and the added age effectively predicted the probability of Li-ESWT effectiveness for CP/CPPS-like symptoms (0.809 [95% CI: 0.717-0.901]; Hosmer-Lemeshow: p = 0.936). This study established a predictive model for the efficacy of Li-ESWT in treating CP/CPPS-like symptoms patients and help improve the management of CP/CPPS-like symptoms.

Establishment and Validation of Coagulation Factor-Based Nomogram for Predicting the Recurrence-Free Survival of Prostate Cancer.

INTRODUCTION: We aimed to establish and validate a coagulation feature-based nomogram to predict recurrence-free survival in prostate cancer patients. METHODS: The study included 168 prostate cancer patients who had received radical prostatectomy between 2012 and 2018. Kaplan-Meier plot and log-rank analysis were used to screen recurrence-free survival-related features. The nomogram was established by combining the significant coagulation features with clinicopathological characteristics by using Cox regression analysis. The accuracy and clinical significance of the nomogram model were assessed by the receiver operating characteristic curve, Kaplan-Meier plot, and calibration plot. We explored the correlation between coagulation pathway activity and patient prognosis in public datasets by using gene set variation analysis (GSVA). RESULTS: The results suggested that patients classified by the nomogram into the high-risk subgroup showed unfavorable prognoses compared with those in the low-risk subgroup in both the training (log-rank p < 0.0001) and validation (log-rank p = 0.0004) cohorts. The nomogram model exhibited high discriminative accuracy in the training cohort (1-year area under the curve [AUC] of 0.74 and 3-year AUC of 0.69), which was confirmed in the internal validation cohort (C-index = 0.651). The calibration plots confirmed good concordance for the prediction of recurrence-free survival at 1 and 3 years. Subgroup analyses confirmed the utility of this model in different clinicopathological subgroups. Finally, GSVA suggested that patients with higher coagulation pathway scores mostly had unfavorable prognoses compared to those with lower scores, a result consistent with the findings above. CONCLUSIONS: We developed a practical nomogram model for predicting recurrence-free survival in prostate cancer patients. This model may offer clinicians prognostic assessments and facilitate personalized treatment.

Efficacy and safety evaluation of low-intensity extracorporeal shock wave therapy on prostatitis-like symptoms: An open-label, single-arm trial.

The present work aims to evaluate the clinical efficacy and safety of low-intensity extracorporeal shock wave therapy (Li-ESWT) on patients with prostatitis-like symptoms (PLS). Patients with PLS were recruited and received four-week Li-ESWT (once per week), which was conducted at a frequency of 3 Hz with a preferred energy flow density of 0.25 mJ/mm2 . The scores of the National Institute of Health Chronic Prostatitis Symptoms Index (NIH-CPSI), International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF-5), and Visual Analogue Scale (VAS) were recorded to assess the remission of disease in the 0, 1st, 2nd, 3rd, 4th, 5th, 8th and 16th weeks. A decrease of the NIH-CPSI score ≥6 was regarded as the effectiveness standard of Li-ESWT. Among 91 enrolled patients, the scores of all validated questionnaires presented significant improvements in the 4th week (p < .05) compared with that in baseline, except for IIEF-5. The treatment effective rates in the 1st, 2nd, 3rd, 4th, 5th, 8th and 16th weeks were 28.57%, 38.46%, 47.25%, 51.65%, 57.30%, 68.18% and 69.44%, respectively. No pronounced undesirable side effect has occurred. Li-ESWT is effective and safe in treating PLS. The efficacy can be maintained within three months.

Genetic Polymorphisms of IFNG, IFNGR1, and Androgen Receptor and Chronic Prostatitis/Chronic Pelvic Pain Syndrome in a Chinese Han Population.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) refers to a common disorder with unclear etiology and unsatisfactory treatment, which reduces the male's quality of life. OBJECTIVE: To examine the effects of genetic polymorphisms of IFNG, IFNGR1, and androgen receptor (AR) on CP/CPPS. METHODS: The single nucleotide polymorphisms (SNPs) of IFNG, IFNGR1, and AR were genotyped with the improved multiplex ligation detection reaction. The GTEx, RegulomeDB, HaploReg, and 3DSNP databases were adopted to predict the regulatory functions of the genotyped SNPs. The correlation between SNPs and CP/CPPS was analyzed with the χ 2 test, logistic regression, and two genetic models (codominant and log-additive models). The nomogram was built to predict the risk of CP/CPPS occurrence. RESULTS: On the whole, 130 CP/CPPS patients and 125 healthy controls were recruited in the study, and 18 SNPs of IFNG, IFNGR1, and AR were genotyped. The results of functional annotation indicated that the 18 genotyped SNPs might have regulatory effects in the whole blood. The rs144488434 was correlated with the elevated CP/CPPS risk (odds ratio (OR): 2.40, 95% confidence interval (CI): 1.12-5.13, χ 2 = 5.37, and P = 0.021) by the χ 2 test. In the built genetic models, rs10457655 was correlated with the elevated National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) scores (codominant model: GA/GG: crude mean difference (MD) = 0.98, 95% CI: -1.71-3.67 and AA/GG: crude MD = 9.10, 95% CI: 0.58-17.62, P = 0.10). In subgroup analysis, rs2069718 was correlated with the elevated CP/CPPS risk (log-additive model: crude OR = 2.18, 95% CI: 1.03-4.64, and P = 0.034) in patients ≥ 35 years. The nomogram integrating age, rs2069718, rs10457655, and rs144488434 showed good performance to predict the risk of CP/CPPS. CONCLUSIONS: Genetic polymorphisms of IFNG, IFNGR1, and AR might act as the genetic factors for CP/CPPS susceptibility, which deserved further explorations.

Immunological alterations in patients with chronic prostatitis/chronic pelvic pain syndrome and experimental autoimmune prostatitis model: A systematic review and meta-analysis.

BACKGROUND: As one of the most common conditions in urological outpatients, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) puzzles many individuals because of its unclear etiology and lack of effective treatment. Recently, immunological alterations underpinning CP/CPPS have been extensively investigated. METHODS: The PubMed, Web of Science, Cochrane library, and EMBASE databases were used to search original articles on immune mediators in patients with CP/CPPS and in experimental autoimmune prostatitis (EAP) models through April 10, 2020. Standardized mean differences (SMD) were calculated to summarize the differences in immune mediator levels between groups. Funnel plot, Begg's funnel plot, Egger's regression test, and the sensitivity analysis were applied to determine and visualize the stability of our findings. RESULTS: A total of 34 original studies were included in the meta-analysis, including 24 studies on patients with CP/CPPS and 10 studies on EAP models. We found that TNF-α, IL-1ß, IL-6, and IL-8 were the four immune mediators that elevated in most of the samples derived from patients with CP/CPPS and the EAP models. The adjusted publication bias analysis indicated that publication bias was not existed, and the sensitivity analyses showed that the results were stable. CONCLUSIONS: Immune responses play significant roles during the pathogenesis of CP/CPPS by promoting intraprostatic inflammation. Our findings provide potential diagnostic and therapeutic targets for CP/CPPS patients.

Fifteen-MiRNA-Based Signature Is a Reliable Prognosis-Predicting Tool for Prostate Cancer Patients.

Recurrence is a major problem for prostate cancer patients, thus, identifying prognosis-related markers to evaluate clinical outcomes is essential. Here, we established a fifteen-miRNA-based recurrence-free survival (RFS) predicting signature based on the miRNA expression profile extracted from The Cancer Genome Atlas (TCGA) database by the LASSO Cox regression analysis. The median risk score generated by the signature in both the TCGA training and the external Memorial Sloan-Kettering Cancer Center (MSKCC) validation cohorts was employed and the patients were subclassified into low- and high-risk subgroups. The Kaplan-Meier plot and log-rank analyses showed significant survival differences between low- and high-risk subgroups of patients (TCGA, log-rank P < 0.001 & MSKCC, log-rank P = 0.045). In addition, the receiver operating characteristic curves of both the training and external validation cohorts indicated the good performance of our model. After predicting the downstream genes of these miRNAs, the miRNA-mRNA network was visualized by Cytoscape software. In addition, pathway analyses found that the differences between two groups were mainly enriched on tumor progression and drug resistance-related pathways. Multivariate analyses revealed that the miRNA signature is an independent indicator of RFS prognosis for prostate cancer patients with or without clinicopathological features. In summary, our novel fifteen-miRNA-based prediction signature is a reliable method to evaluate the prognosis of prostate cancer patients.

Extracorporeal shock wave therapy decreases the number of total and degranulated mast cells and alleviates pelvic pain in a rat model of prostatitis.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common male urological disease characterized by chronic pelvic pain. Extracorporeal shock wave therapy (ESWT) has been used to treat patients with CP/CPPS, but the parameters used by ESWT are not uniformly determined. Herein, this study aims to assess the effects of ESWT with different energy flux densities on pelvic pain in CP/CPPS rats and to explore the mechanisms. A rat model of CP/CPPS was induced by intraprostatic injection of 1% carrageenan. ESWT with different energy flux densities (0.09, 0.20, 0.30, 0.40 mJ/mm2) was applied in the pelvic region of CP/CPPS rats once a week for 4 weeks. The results showed that compared with the other energy flux densities (0.09, 0.30, and 0.40 mJ/mm2), ESWT with 0.20 mJ/mm2 exhibited a more powerful effect in alleviating pelvic pain and prostate damage. The therapeutic effect is associated with the reduction of the number of total and degranulated mast cells. Collectively, ESWT with 0.20 mJ/mm2 achieved the optimal therapeutic effect in alleviating pelvic pain in CP/CPPS rats.

Immune response drives outcomes in prostate cancer: implications for immunotherapy.

The heterogeneity of the immune microenvironment leads to different responses in immune checkpoint blockade therapy. We aimed to propose a robust molecular classification system to investigate the relevance of the immune microenvironment subtype and prognosis of prostate cancer patients, as well as the therapeutic response to immune checkpoint blockade therapy. A total of 1,557 prostate cancer patients were enrolled, including 69 real-world samples from our institute (titled the AHMU-PC cohort). The non-negative matrix factorization algorithm was employed to virtually microdissect patients. The immune enrichment was characterized by a high enrichment of T cell-, B cell-, NK cell-, and macrophage-associated signatures, by which patients were subclassified into nonimmune and immune classes. Subsequently, the immune class was dichotomized into immune-activated and immune-suppressed subtypes based on the stromal signature, represented by the activation of WNT/TGF-ß, TGF-ß1, and C-ECM signatures. Approximately 14.9% to 24.3% of patients belonged to the immune-activated subtype, which was associated with favorable recurrence-free survival outcomes. In addition, patients in the immune-activated subtype were predicted to benefit more from anti-PD-1/PD-L1 therapy. In conclusion, our study identifies a novel immune molecular classifier that is closely related to clinical prognosis and provides novel insights into immunotherapeutic strategies for prostate cancer patients.

Prognostic Role of Prothrombin Time Activity, Prothrombin Time, Albumin/Globulin Ratio, Platelets, Sex, and Fibrinogen in Predicting Recurrence-Free Survival Time of Renal Cancer.

BACKGROUND: To help with the clinical practice of renal cancer patients, prognostic models are urgently warranted. We hunted and identified prognostic variables associated with recurrence-free survival (RFS) for renal cancer patients. PATIENTS AND METHODS: In this retrospective study, 187 renal cancer patients who had received curative radical/partial nephrectomy between November 2011 and January 2017 were enrolled in the current study. These patients were randomly split into the training (n = 95) and validation sets (n = 92) by the ratio of 1:1. Univariate and multivariable Cox regression analyses were used to establish the nomogram, which was then evaluated by receiver operating characteristic (ROC) and Kaplan-Meier (K-M) analyses. RESULTS: Patient characteristics and outcomes were well balanced between the training and validation sets; the median RFS values were 54.1 months and 58.9 months for the training and validation cohorts, respectively. The final nomogram included six independent prognostic variables (prothrombin time (%), prothrombin time (second), albumin/globulin ratio, platelets, sex and fibrinogen). The mean values of RFS for the low- and high-risk groups defined by a prognostic formula were 56.22 ± 18.50 months and 49.54 ± 23.57 months, respectively, in the training cohort and were 59.00 ± 19.50 months and 53.32 ± 19.95 months, respectively, in the validation cohort. The significance and stability of the model were tested by the time-dependent K-M model and ROC curves, respectively. CONCLUSION: Our validated prognostic model incorporates variables routinely collected from renal cancer patients, identifying subsets of patients with different survival outcomes, which provides useful information for patient care and clinical trial design.