Efficacy of peripheral electrical nerve stimulation on improvements of urodynamics and voiding diary in patients with neurogenic lower urinary tract dysfunction: a systematic review and meta-analysis.

BACKGROUND: Peripheral electrical nerve stimulation is a routinely recommended treatment for non-neurogenic overactive bladder but has not been approved for patients with neurogenic lower urinary tract dysfunction (NLUTD). This systematic review and meta-analysis was to elucidate the efficacy and safety of electrostimulation and thus provide firm evidence for treating NLUTD. MATERIALS AND METHODS: We systematically performed the literature search through PubMed, Web of Science, and Cochrane Library databases in March 2022. The eligible studies were identified across the inclusion criteria and the data on urodynamic outcomes, voiding diary parameters, and safety was collected to quantitatively synthesize the pooled mean differences (MDs) with 95% CIs. Subgroup analyses and sensitivity analyses were subsequently used to investigate the possible heterogeneity. This report was achieved in accordance with the preferred reporting items for systematic reviews and meta-analyses statement. RESULTS: A total of 10 studies involving 464 subjects and 8 studies with 400 patients were included for systematic review and meta-analysis, respectively. The pooled effect estimates indicated that electrostimulation could significantly improve urodynamic outcomes, including maximum cystometric capacity (MD=55.72, 95% CI 15.73, 95.72), maximum flow rate (MD=4.71, 95% CI 1.78, 7.65), maximal detrusor pressure (MD=-10.59, 95% CI -11.45, -9.73), voided volume (MD=58.14, 95% CI 42.97, 73.31), and post-void residual (MD=-32.46, 95% CI -46.63, -18.29); for voiding diary parameters, patients undergoing electrostimulation showed lower MDs of incontinence episodes per 24 h (MD=-2.45, 95% CI -4.69, -0.20) and overactive bladder symptom score (MD=-4.46, 95% CI -6.00, -2.91). In addition to surface redness and swelling, no stimulation-related severe adverse events were reported else. CONCLUSIONS: The current evidence demonstrated that peripheral electrical nerve stimulation might be effective and safe for managing NLUTD, whereas more reliable data from large-scale randomized controlled trials are necessary to strengthen this concept.

Identification of an immune subtype-related prognostic signature of clear cell renal cell carcinoma based on single-cell sequencing analysis.

Background: There is growing evidence that immune cells are strongly associated with the prognosis and treatment of clear cell renal cell carcinoma (ccRCC). Our aim is to construct an immune subtype-related model to predict the prognosis of ccRCC patients and to provide guidance for finding appropriate treatment strategies. Methods: Based on single-cell analysis of the GSE152938 dataset from the GEO database, we defined the immune subtype-related genes in ccRCC. Immediately afterwards, we used Cox regression and Lasso regression to build a prognostic model based on TCGA database. Then, we carried out a series of evaluation analyses around the model. Finally, we proved the role of VMP1 in ccRCC by cellular assays. Result: Initially, based on TCGA ccRCC patient data and GEO ccRCC single-cell data, we successfully constructed a prognostic model consisting of five genes. Survival analysis showed that the higher the risk score, the worse the prognosis. We also found that the model had high predictive accuracy for patient prognosis through ROC analysis. In addition, we found that patients in the high-risk group had stronger immune cell infiltration and higher levels of immune checkpoint gene expression. Finally, cellular experiments demonstrated that when the VMP1 gene was knocked down, 786-O cells showed reduced proliferation, migration, and invasion ability and increased levels of apoptosis. Conclusion: Our study can provide a reference for the diagnosis and treatment of patients with ccRCC.

Neoadjuvant Chemohormonal Therapy in Prostate Cancer Before Radical Prostatectomy: A Systematic Review and Meta-Analysis.

Objective: This meta-analysis was to investigate the effects of neoadjuvant chemohormonal therapy (NCHT) on patients with prostate cancer (PCa) before radical prostatectomy (RP) and attempt to provide meaningful evidence. Methods: A systematic search was performed using the PubMed, Web of Science, and Cochrane Library databases in February 2022 based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The relevant studies were critically screened and we extracted the data of demography, postoperative pathology, and survival to calculate the pooled effect sizes. Subgroup analyses and sensitivity analyses were used to explore the source of heterogeneity. Results: Six identified studies involving 1717 subjects were included according to the selection criteria. There was no significant difference between NCHT plus RP and RP alone groups regarding lymph node involvement (risk ratio [RR]=1.03, 95% confidence interval [CI]: 0.57-1.87, P=0.92). However, NCHT prior to RP significantly decreased the rates of positive surgical margin (PSM, RR=0.35, 95% CI: 0.22-0.55, P<0.0001) and seminal vesicle invasion (SVI, RR=0.78, 95% CI: 0.65-0.95, P=0.01), and increase pathological downstaging (RR=1.64, 95% CI: 1.17-2.29, P=0.004). Additionally, biochemical recurrence-free survival (BRFS) and overall survival (OS) were significantly prolonged under the administration of NCHT (HR=0.54, 95% CI: 0.34-0.85, P=0.008 and HR=0.67, 95% CI: 0.48-0.94, P=0.02, respectively). Conclusions: Compared to the RP alone group, patients with NCHT plus RP showed significant improvements in PSM, SVI, pathological downstaging, BRFS, and OS, whereas further multicenter randomized controlled trials are needed to consolidate this concept.

Combined Signature of the Urinary Microbiome and Metabolome in Patients With Interstitial Cystitis.

Interstitial cystitis (IC) is a clinical syndrome characterized by frequency, urgency, and bladder pain or pelvic pain; however, the underlying pathophysiological mechanisms and diagnostic markers are unknown. In this study, microbiome and metabolome analysis were used to explain the urine signatures of IC patients. Urine samples from 20 IC patients and 22 control groups were analyzed by using 16S rRNA sequence and liquid chromatography coupled with mass spectrometry. Four opportunistic pathogen genera, including Serratia, Brevibacterium, Porphyromonas, and Citrobacter, were significantly upregulated in IC group. The altered metabolite signatures of the metabolome may be related to sphingosine metabolism, amino acid metabolism, and fatty acid biosynthesis. Meanwhile, the associations were observed between different metabolites and microbiomes of IC. The present study suggests that the combined signatures of IC in urine microbiome and metabolome may become its prospective diagnostic markers.

Management and Follow-Up Practices of Women With Recurrent Stress Urinary Incontinence Following Transobturator Mid-urethral Synthetic Sling Procedure: A 6-Year Retrospective Monocentric University-Based Study.

Purpose: The purpose of this study is to evaluate the efficacy of management and follow-up practices in repeat retropubic mid-urethral synthetic sling (MUS) procedure after transobturator tape/tension-free vaginal tape-obturator (TOT/TVT-O) failure, and to clarify the possible etiology of recurrent stress urinary incontinence. Methods: The charts of all women patients who underwent tension-free vaginal tape (TVT) slings after previous failed transobturator MUS procedures between February 2012 and November 2018 at a single center were reviewed retrospectively. The transperineal ultrasound was performed to assess the pre-operative or post-operative urethral mobility and location of the slings. Furthermore, some essential evaluations were also made, mainly including medical history, physical examination, 1 h pad test, and urodynamic study. Finally, primary outcomes were evaluated according to the above items at 3, 6, and 12 months after the second operation, respectively. Results: Thirty-five patients were included in the primary transobturator MUS sling procedure. At the 6 months follow-up, 32 (91.42%) patients were socially continent and negative in 1 h pad test. The transperineal ultrasound measurement results revealed that the bladder neck descent (BND) values were significantly decreased after the repeat sling operation, and better urinary continence function was observed according to the post-operative urodynamic study. Multifactorial etiologies resulted in recurrent stress urinary incontinence (SUI), including poor surgical technique, inadequate sling tension when treating ISD, and inappropriate sling position. Then the detail of the surgical procedure varied with the results of pre-operative evaluations, affecting the validity of the second sling. Conclusion: Recurrent SUI has resulted from multi factors, pre-operative urodynamic study and transperineal ultrasound might be valuable tools to guide repeat sling operation and predict post-operative outcomes. A repeat TVT procedure may be regarded as a remedial measure for a failed transobturator MUS operation.

Nrf2 Pathway Ameliorates Bladder Dysfunction in Cyclophosphamide-Induced Cystitis via Suppression of Oxidative Stress.

OBJECTIVE: To investigate the protective effect and molecular mechanism of nuclear factor E2-related factor 2 (Nrf2) pathway in interstitial cystitis (IC). METHODS: We established a mouse model of IC by cyclophosphamide (CYP) in wild-type mice and Nrf2 gene knockout mice. We examined the histological and functional alterations, the changes of oxidative stress markers, and the expression of the antioxidant genes downstream of Nrf2 pathway. RESULTS: After CYP administration, the mice showed urinary frequency and urgency, pain sensitization, decreased contractility, bladder edema, and oxidative stress disorder. Notably, the Nrf2-/- CYP mice had more severe symptoms. The mRNA and protein levels of antioxidant genes downstream of Nrf2 pathway were significantly upregulated in the Nrf2+/+ CYP mice, while there were no significant changes in the Nrf2-/- CYP mice. CONCLUSION: Nrf2 pathway protects bladder injury and ameliorates bladder dysfunction in IC, possibly by upregulating antioxidant genes and inhibiting oxidative stress.

Primary bladder mucosa-associated lymphoid tissue lymphoma: A case report and literature review.

INTRODUCTION: Primary bladder mucosa-associated lymphoid tissue (MALT) lymphoma is a rare tumor. To date, the PubMed database contains only 39 English articles covering 63 cases of primary bladder MALT lymphoma. Herein, we report a case of this disease and review the current literature. PATIENT CONCERNS: A 77-year-old woman presented with frequent urination, urinary urgency, and dysuria for 3 years. In the past 3 years, the patient's symptoms recurred and progressively worsened, and she was admitted to the hospital. DIAGNOSIS: A histopathological examination revealed the bladder mass as a tumor with high proliferation of atypical B-lymphocytes. Immunohistochemistry showed positive results for CD20, PAX-5, Ki-67, BCL-2, and CD21 and negative results for CD10, MUM1, TDT, and cyclin D1. These data supported the diagnosis of primary bladder MALT lymphoma. INTERVENTIONS: A transurethral resection of bladder tumor was performed to treat the disease. OUTCOMES: The patient was alive and healthy at the 15-month follow-up. CONCLUSION: Primary bladder MALT lymphoma is a rare disease and can be easily missed or misdiagnosed before achieving a histological confirmation. Surgery may be the best choice for both diagnosis and treatment.

Author Correction: Down-regulated GATA-1 up-regulates interferon regulatory factor 3 in lung adenocarcinoma.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Preclinical trial of the multi-targeted lenvatinib in combination with cellular immunotherapy for treatment of renal cell carcinoma.

Lenvatinib is an oral, multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor ß, RET and KIT. Cellular immunotherapy has the potential to be a highly targeted treatment, with low toxicity to normal tissues and a high capacity to eradicate tumor tissue. The present study assessed the safety, maximum tolerated dose (MTD) and preliminary antitumor activity of lenvatinib and cellular immunotherapy in a murine model of renal cell carcinoma (RCC). The present study used a therapeutic dose of 0.12 mg lenvatinib and/or 104 rat uterine cancer adenocarcinoma (RuCa)-sensitized lymphocytes administered once daily continuously in 7-day cycles. Tumor regression was observed in mice with RCC following treatment with lenvatinib and 104 RuCa-sensitized lymphocytes. MTD was established as once daily administration of 0.18 mg lenvatinib and 106 RuCa-sensitized lymphocytes. The most common treatment-related adverse effects observed were fatigue (40%), mucosal inflammation (30%), proteinuria, diarrhea, vomiting, hypertension and nausea (all 40%). Combination therapy using lenvatinib and cellular immunotherapy enhanced the antitumor effect induced by single treatments and prolonged the survival of mice with RCC compared with either of the single treatments. Treatment with lenvatinib (0.12 mg) combined with 104 RuCa-sensitized lymphocytes was associated with manageable toxicity consistent with individual agents. Further evaluation of this combination therapy in mice with advanced RCC is required. In conclusion, cellular immunotherapy and oncolytic therapy for cancer may be improved by the synergistic effects of lenvatinib and sensitized lymphocytes. In the present study, the inherent antineoplastic and immune stimulatory properties of the two agents were enhanced when used in combination, which may provide a basis for clinical treatment of patients with RCC.

Down-regulated GATA-1 up-regulates interferon regulatory factor 3 in lung adenocarcinoma.

Interferon regulatory factor 3 (IRF-3) is widely known for its prompt response against viral infection by activating the interferon system. We previously reported that E2F1, Sp1 and Sp3 regulated transcriptional activity of IRF-3. Recently, different expression patterns of IRF-3 were found in lung cancer, leading to the alternation of the immunomodulatory function in tumorigenesis. However, the mechanism of transcriptional regulation of IRF-3 in lung cancer has not been extensively studied. Here, we investigated the characterization of IRF-3 promoter and found that GATA-1 bound to a specific domain of IRF-3 promoter in vitro and in vivo. We found elevated IRF-3 and decreased GATA-1 gene expression in lung adenocarcinoma in Oncomine database. Additionally, higher IRF-3 gene expression was observed in human lung adenocarcinoma, accompanied by aberrant GATA-1 protein expression. We further analyzed the relationship of GATA-1 and IRF-3 expression in lung adenocarcinoma cell lines and found that inhibition of GATA-1 by siRNA increased the promoter activity, mRNA and protein levels of IRF-3, while over-expression of GATA-1 down-regulated IRF-3 gene expression. Taken together, we conclude that reduced GATA-1 could be responsible for the upregulation of IRF-3 in lung adenocarcinoma cells through binding with a specific domain of IRF-3 promoter.

Integrin-Linked Kinase Improves Functional Recovery of Diabetic Cystopathy and Mesenchymal Stem Cell Survival and Engraftment in Rats.

OBJECTIVES: Diabetic cystopathy (DCP), characterized by peripheral neuropathy-associated bladder dysfunction, is a common urinary complication in patients with diabetes (~80%). Bone marrow mesenchymal stem cell (BMMSC) transplantation, a new and emerging regenerative therapy, provides a curative option for DCP. However, the application of this therapy is limited by the low survival rate and engraftment of transplanted stem cells. This study was undertaken to determine whether integrin-linked kinase (ILK) overexpression would improve stem cell survival and engraftment after BMMSC transplantation. METHODS: Diabetes was induced in rats by injection of streptozotocin. ILK expression was detected by qRT-PCR and Western blot. Bladder function was measured by urodynamic analyses. Smooth-muscle regeneration and vascularization were evaluated by immunohistochemistry staining. RESULTS: ILK overexpression by adenovirus promotes proliferation of BMMSCs in vitro. ILK overexpression enhanced the ability of BMMSCs to decrease the volume threshold for micturition and residual urine in the rats with diabetes. The contractile response of bladder strips, tissue structure of bladder and smooth-muscle regeneration/vascularization were also improved in the rats receiving ILK-modified BMMSCs. CONCLUSIONS: Our data highlight the clinical potential of transplantation of gene-modified BMMSCs in the treatment of DCP, thereby serving as a rapid and effective first-line strategy to cure the bladder dysfunction resulting from long-term diabetes.

RETRACTED: Sulforaphane restores oxidative stress induced by di-N-butylphthalate in testicular Leydig cells with low basal reactive oxygen species levels.

OBJECTIVE: To investigate the role and therapeutic potential of Nuclear factor erythroid-related factor 2 (Nrf2) in oxidative stress induced by di-N-butylphthalate (DBP) in testicular Leydig cells. MATERIALS AND METHODS: Levels of reactive oxygen species (ROS) and Nrf2 in testicles from offspring of mice fed with DBP were studied. Basal ROS and Nrf2 level in mouse TM3 testicular Leydig cells were studied. Cells were treated with silencing or overexpression of Nrf2 in the presence and absence of DBP. Oxidative profiles were examined. Expressions of antioxidant genes downstream of Nrf2 were studied. Therapeutic effect of Nrf2 inducer sulforaphane (SFN) was evaluated. RESULTS: Leydig cells with low basal Nrf2 and ROS are more vulnerable to DBP. DBP-induced intracellular oxidative stress to a similar extent with Nrf2 knockdown. Nrf2 level was increased together with its target genes, hemeoxygenase 1, quinone 1, and peroxiredoxin 6, after DBP stimulation. Endogenous Nrf2 of Leydig cells was upregulated to battle against ROS. Upregulation of Nrf2 by SFN not only restored the intracellular oxidative toxicity but also cell proliferation and testosterone secretion in response to DBP. CONCLUSION: SFN restores oxidative stress induced by DBP in testicular Leydig cells with low basal ROS.