The impact of purified protein derivative prior to intravesical bacillus Calmette-Guérin for the treatment of patients with non-muscle invasive bladder cancer.

BACKGROUND: The aim of this study is to investigate the impact of the intradermal injection of purified protein derivative (PPD) and PPD skin test reactions on the oncological outcomes of patients with non-muscle invasive bladder cancer (NMIBC) treated by trans-urethral resection of bladder tumor (TURBT) and adjuvant intravesical BCG. METHODS: The study included 100 consecutive patients with NMIBC prospectively given intradermal PPD 1-2 weeks before starting BCG therapy. Another 100 patients with NMIBC not given intradermal PPD before starting BCG were chosen as a historical control. The control group was chosen to be matching with the study group regarding baseline characteristics. The study group was divided into 2 subgroups with positive and negative reaction to PPD skin test. Oncological outcomes, immunological markers (TNF-α and IL-6) changes and BCG side effects were evaluated. RESULTS: There were no significant differences between patients who received PPD or not regarding the 2-year recurrence free survival (RFS) rates and progression-free survival (PFS) rates and immunological markers changes. The 2-year RFS and PFS rates were significantly higher in patients with positive reactions. Post-induction values of immunological markers increased in all patients with a significant increase in patients with positive reactions. BCG side effects were significantly higher in patients with positive reactions. CONCLUSIONS: The intradermal injection of PPD before intravesical BCG has no impact on oncological outcomes of patients with NMIBC treated with TURBT and intravesical BCG. However, the PPD skin test reactions before BCG therapy can predict the oncological outcomes, BCG side effects and the immunological outcomes of patients.

Association between hepatitis C virus genotype 4 and renal cell carcinoma: Molecular and virological studies.

Hepatitis C virus (HCV) is the most common infection worldwide. The correlation between HCV and renal cell carcinoma (RCC) is still mysterious. Therefore, the relationship between HCV and RCC was investigated. The study included 100 patients with RCC; 32 with HCV infection, and 68 without HCV infection. Expressions of viral proteins (NS3 and NS5A) were tested using an immune electron-microscope (IEM) and immunohistochemistry (IHC). IHC and quantitative real time-PCR investigated the presentation of human proteins TP53 and p21 genes. Transmission electron (TEM) detected viral-like particles in infected RCC tissues. The gene and protein expression of P53 was higher in HCV positive versus HCV negative patients and p21 was lower in HCV positive versus HCV negative in both tumor and normal tissue samples. Viral like particles were observed by TEM in the infected tumor and normal portion of the RCC tissues and the plasma samples. The IEM showed the depositions of NS3 and NS5A in infected renal tissues, while in noninfected samples, were not observed. The study hypothesizes that a correlation between HCV and RCC could exist through successfully detecting HCV-like particles, HCV proteins, and (p53 and p21) in RCC-infected patients.

Predictors of Response Following Neoadjuvant Cisplatin-Based Chemotherapy for Muscle Invasive Urothelial Bladder Cancer Using Molecular Profile: A Prospective Clinical Study.

OBJECTIVES: To predict response of patients with muscle invasive bladder cancer (MIBC) to neoadjuvant chemotherapy (NAC) through analysis of molecular profile assessed clinically (radiologically and by pathological examination of transurethral resection biopsy [TURBT] specimens) and definitively with histopathological examination after radical cystectomy (RC). METHODS: In a prospective study, tumor biopsies were obtained from patients with urothelial MIBC (T2-4a N0-2 M0) during TURBT. Patients were eligible for RC received 4 cycles of cisplatin-based NAC. DNA repair genes (BRACA1, ERCC1) & CTR gene m-RNA expression levels were assessed in resected tissue. The response to chemotherapy was assessed clinically (radiologically & TURBT) following NAC. Response was re-assessed for 64 patients who underwent RC and predictors of cancer-free survival (CFS) were calculated. Receiver operating characteristic (ROC) curve was used to delineate cutoff value copes with the best sensitivity and specificity for prediction of response to NAC. RESULTS: The study included 104 patients, 42 (40.4%) responded well to NAC clinically. Out of 64 patients who underwent RC, 26 (40.6%) showed good response to NAC. CFS at 18 months for patients who underwent RC was 60%. Statistical analysis showed that molecular profile was an independent predictor of good response to NAC both clinically and pathologically and also predicted better CFS. CONCLUSION: Molecular profile could play a decisive role in early detection of patients with MIBC who will get benefit from preoperative NAC.

Hormonal and molecular characterization of calcium oxalate stone formers predicting occurrence and recurrence.

The purpose of the study is to investigate the role of sex hormones, androgen receptors (ARs) and miRNA/CSF-1 in occurrence and recurrence of calcium oxalate (CaOx) renal urolithiasis. In this prospective study, 74 patients with CaOx stones; stone formers group (SFG) and 40 healthy subjects; control group were compared. SFG includes both de novo and recurrent cases. Steroid sex hormone plasma assay including testosterone, free testosterone, dihydrotestosterone, estradiol, and sex hormone binding globulin was analyzed. ARs, miRNA-185-5p and CSF-1 expression were compared between the groups. SFG showed significant higher ARs and miRNA-185-5p expression (3.7 ± 1.3, 1.8 ± 0.4, respectively) than control group (1 ± 0.08 and 1 ± 0.07, respectively) (p < 0.05). However, CSF-1 expression was significantly lower in stone formers than control group (0.4 ± 0.19 vs 1 ± 0.1, respectively) (p < 0.05). No differences were detected between de novo and recurrent SFG regarding sex hormones, AR, miRNA or CSF-1 expression. Our data suggest the important role of AR, miRNA and CSF-1 signaling in human nephrolithiasis pathogenesis.

Evaluation of molecular signatures in the urinary bladder and upper tract urothelial carcinomas: a prospective controlled clinical study.

BACKGROUND: Urothelial carcinomas (UC) can be either in the upper or in the lower urinary tract or both. Urothelial bladder cancer (UBC) is more common than upper tract urothelial carcinoma (UTUC). This research was designed to study the difference between UBC and UTUC using the molecular pathways including (MAPK/ERK) pathway, cell cycle regulating genes, and oncogenic genes. METHODS: To study the discrepancy between UBC and UTUC, a prospective trial was carried out for 31 radical cystectomy and 19 nephrouretrectomy fresh-frozen specimens of UBC and UTUC patients, respectively. The expression level of mRNA of eight genes namely EGFR, ELK1, c-fos, survivin, TP53, RB1, FGFR3, and hTERT was assessed in normal adjacent tissues, UTUC, and UBC by RT-PCR. RESULTS: Comparison between UTUC and UBC regarding the expression level of mRNA of the EGFR, ELK1, c-fos, survivin, TP53, and FGFR3 had significant difference (p-value < 0.001), while the expression level of RB1 and hTERT level had no significance. Sensitivity/specificity of EGFR, Elk1, c-fos, survivin, TP53, and FGFR3 was 0.78/0.90, 0.84/0.90, 0.84/0.80, 0.84/0.96, 0.94/0.93, and 0.89/0.93, respectively, to differentiate between UTUC and UBC. CONCLUSIONS: Despite the fact that UTUC and UBC share the same origin, there is a clear evidence that there is a molecular difference between them. This molecular difference could be the reason that UTUC is more aggressive than UBC.

Comparison of urinary telomerase, CD44, and NMP22 assays for detection of bladder squamous cell carcinoma.

Background: Squamous cell carcinoma (SCC) of the bladder is common in many regions around the world. Prognosis is very poor, as most cases are diagnosed at an advanced stage due to a lack of affordable and valid screening markers for this type of cancer. The diagnostic accuracy of urinary nuclear matrix protein-22 (NMP22), telomerase activity, and CD44 were evaluated in urine samples of patients with bladder SCC. Materials and methods: We conducted a case-control study comprised of 60 consecutive newly diagnosed bladder SCC patients diagnosed by cystoscopy and histopathological examination, and controls were 60 outpatients with benign urologic conditions and healthy clinic visitors. Urine samples collected from each subject underwent testing for NMP22, telomerase activity, and CD44. Descriptive and correlational statistical analysis of cases and controls were carried out and receiver operating characteristic curve analysis was used to determine optimal cut-off points for the three assays. Results: Area under the curve was calculated at 0.96, 0.93, and 0.62 for NMP22, telomerase, and CD44, respectively. Urine levels of NMP22 and telomerase activity were significantly higher in the SCC group compared to controls (p < 0.001). Urine CD44 levels were not significantly higher in the SCC group compared to controls (p = 0.111). The overall sensitivity of NMP22, telomerase, and CD44 was 96.7%, 87%, and 45%, respectively, while the specificity was 85%, 88.6%, and 86.7%, respectively. Conclusions: Urinary telomerase activity, followed by NMP22 urine levels, showed high diagnostic yield and could hold potential promise as urinary biomarkers for the diagnosis of bladder SCC.

Identification of Epigenetic Interactions between miRNA and Gene Expression as Potential Prognostic Markers in Bladder Cancer.

Purpose: To identify the role of a set of microRNAs and their target genes and protein expression levels in the pathogenesis of bladder cancer with a muscular invasion (T2−T4) and non-muscular invasion (T1). Methods: In 157 patients, bladder specimen was examined for the expression of a set of miRNAs including let-7a-5p, miRNA-449a-5p, miRNA-145-3P, miRNA-124-3P, miRNA-138-5p, and miRNA-23a-5p and their targeted genes; ß-catenin, WNT7A, IRS2, FZD4, SOS1, HDAC1, HDAC2, HIF1α, and PTEN using the qRT-PCR technique. The prognostic effect of miRNAs and their targeted genes on cancer-specific survival (CSS) was evaluated in pT2−pT4 stages. Results: pT1 was found in 40 patients while pT2−4 was found in 117 patients. The expression of let-7a-5P, miR-124-3P, miR-449a-5P, and miR-138-5P significantly decreased in pT2−4 compared with pT1 (p < 0.001), in contrast, miR-23a-5P increased significantly in pT2−pT4 compared with pT1 (p < 0.001). Moreover, the expression of miR-145 did not show a significant change (p = 0.31). Higher expression levels of WNT7A, ß-catenin, IRS2, FZD4, and SOS1 genes were observed in pT2−pT4 compared with pT1, whereas HDAC1, HDAC2, HIF1α, and PTEN genes were downregulated in pT2−pT4 compared with pT1. Lower CSS was significantly associated with lower expression of let-7a-5P, miR-124-3P, miR-449a-5P, and miR-138-5P. Higher expression of ß-catenin, FZD4, IRS2, WNT7a, and SOS1 was significantly associated with worse CSS. In contrast, lower levels of HDAC1, HDAC2, HIF1α, and PTEN were associated with lower CSS. Conclusion: Our results support let-7a-5P, miR-124-3P, miR-138-5P, and their target genes can be developed as accurate biomarkers for prognosis in bladder cancer with a muscular invasion.

Rapamycin Improves Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Renoprotective Effect against Cisplatin-Induced Acute Nephrotoxicity in Rats by Inhibiting the mTOR/AKT Signaling Pathway.

OBJECTIVE: Because the poor survival of transplanted cells in a hostile microenvironment limits stem cell therapy, in the current study, we investigated the effect of rapamycin (Rapa)-preactivated autophagy on the survival and homing of transplanted adipose mesenchymal stem cells (ADMSCs) in a rat model of cisplatin (Cis)-induced nephrotoxicity, as well as the possible role of the mTOR/AKT signaling pathway. MATERIALS AND METHODS: In vitro, ADMSCs isolated from rats were treated with 50 nmol/L rapamycin for 2 h, after which the cytoprotective and autophagy-inducing effects of Rapa were investigated. The cis-induced acute nephrotoxicity rat model was constructed in vivo. ADMSCs and Rapa-ADMSCs were administered into the tail vein before Cis therapy. At 3, 7, and 10 days after Cis injection, all animals were euthanized. The renal functions and morphology as well as autophagy response were assessed. RESULTS: The pretreatment of cultured ADMSCs with Rapa caused a significant increase in autophagic activities and lysosome production of the cells, with a significant increase in the secretion of SDF-1, IL-10 and autophagy promoter LC3 and Beclin from these cells, while mTOR/AKT pathways were inhibited. In addition, the transplantation of Rapa-pretreated ADMSCs restored the kidney functions and morphology dramatically. Renal expression of SDF-1 and HIF1 was upregulated, while expression of IL-6, NF-kB and TGF-ß1 was downregulated. CONCLUSIONS: We concluded that the preactivation of autophagy with Rapa improves the survival and differentiation of the transplanted ADMSCs by inhibiting the mTOR/AKT signaling pathway, which in turn could significantly attenuate the Cis-induced acute renal injury.

Prediction of recurrence of non-muscle invasive bladder cancer: The role of androgen receptor and miRNA-2909.

AIM: The exact role of androgen receptor (AR) and miR-2909 in non-muscle invasive bladder cancer (NMIBC) remains controversial. Our aim is to assess the relationship between NMIBC recurrences with AR expression and miRNA-2909. PATIENTS AND METHODS: This prospective controlled cohort study included 99 male patients with NMIBC (Ta-T1) who were treated by transurethral resection and 50 male patients as healthy control. We quantified blood AR messenger RNA variants 1 and 2 (AR1, AR2) and plasma miRNA-2909 with real-time quantitative polymerase chain reaction and the full length AR (AR-FL) using enzyme-linked immunosorbent assay in serum samples. In addition, AR1 and AR2 expression in tumor as well as normal tissues were analyzed. Kaplan-Meier survival curves and multivariate Cox analysis were used to identify independent predictors of recurrence-free survival. RESULTS: In comparison to control group, blood AR1, AR2, and serum AR-FL expression were significantly lower in the NMIBC group compared to plasma miRNA-2909 expression that was significantly higher in the control group. Blood AR1, AR2, and serum AR-FL were significantly correlated with higher tumor stage (pT1) while plasma miRNA-2909 was not. The median survival time (months) was significantly better for higher blood AR1 (34 vs. 21; P = 0.03), lower plasma miRNA-2909 (29 vs. 8; P <0.001), lower AR2 in normal tissues (32 vs. 22; P = 0.007). On multivariate analysis, serum free testosterone (hazards ratio [HR]: 8.9; 95% CI: 1.8-45.1; P = 0.008), serum AR1 (HR: 0.5; 95% CI: 0.3-0.9; P = 0.02), and plasma miRNA-2909 (HR: 5.8; 95% CI: 2.3-14.7; P = 0.0002), and tissue AR2 (HR: 2.6; 95% CI: 1.4-4.7; P = 0.002) were independent predictor for NMIBC recurrence. CONCLUSIONS: Blood and tissue levels of AR expression have a potential significant effect on NMIBC recurrence. Further studies are recommended to establish its exact role.

Omega-3 polyunsaturated fatty acids: a modified approach for chemo-prevention of bladder cancer in a rat model and molecular studies of antineoplastic mechanisms.

OBJECTIVES: To test the chemo-preventative effects of omega-3 against bladder cancer (BC) induction in a rat model and its potential antineoplastic mechanisms. MATERIAL AND METHODS: Ninety male Fisher rats were divided into three groups during a 22-week protocol: group 1 (control), group 2 (Placebo + N-butyl-N-4- hydroxybutyl nitrosamine (BBN) for induction of BC and group 3 received omega-3 (1200 mg/kg/day) + BBN. At the end, blood samples and bladder tissues were collected and checked for the presence of malignancy, markers of angiogenesis (VEGF relative gene expression), inflammation (IL-6), proliferation (KI-67 expressions), oxidative stress (serum MDA and serum SOD) and epigenetic control (miRNA-145 level). RESULTS: At the end of the study, 60% and 86.6% rats survived in group 2 and 3 with significant weight loss among rats in group 2 when compared with other groups. In group 2, all rats developed visible bladder lesions of which five and 13 developed squamous cell carcinoma (SCC) and transitional cell carcinoma (TCC). In omega3-treated group, only one developed low grade SCC and one developed high grade non- invasive TCC. Bladders from omega-3-treated rats showed lower expression ofKI-67 (p < 0.05), VEGF (p < 0.001) and IL-6 (p < 0.001) and significant higher expression of mi-RNA (p < 0.001). Also, omega-3-treated group showed statistically significant lower MDA level (p < 0.001). CONCLUSION: Omega-3 inhibits bladder tumor growth in the BBN-induced BC rat model, due to anti-inflammatory, antioxidant, anti-proliferative, and anti-angiogenic properties together with epigenetic control.

Identification of Different miRNAs and Their Relevant miRNA Targeted Genes Involved in Sister Chromatid Cohesion and Segregation (SCCS)/chromatin Remodeling Pathway on T1G3 Urothelial Carcinoma (UC) Response to BCG Immunotherapy.

BACKGROUND: Till now, no definite clinical or laboratory marker can predict the recurrence or progression of T1 G3 urothelial carcinoma (UC). Genetic aberrations of the chromatin remodeling genes and sister chromatid cohesion and segregation (SCCS) were identified in UC. Here we investigated the impact of novel miRNAs and their targeted expressed SCCS and chromatin remodeling genes on T1G3 UC response to Bacillus Calmette-Guérin (BCG) therapy. METHODS: One hundred tissue samples were obtained from NMIBC patients. Gene expression and immunohistochemical assay of STAG2, ARID1A, NCOR1and UTX were assessed. MiRNA analysis for their targeting miRNAs (miR-21, miR-31, Let7a and miR-199a) was carried out. Assessed genes were compared between responders and no responders to BCG. Univariate and multivariate analysis of predictors of disease recurrence and progression were performed using cox regression analysis. RESULTS: Thirty-two and 22 patients developed recurrence and progression to MIBC (BCG non-responders). BCG non-responders showed statistically significant higher expression of miR-21 and their targeted STAG2, miR-199a and NCOR1 gene (P < .001), and lower expression of miR-31, Let7a, ARID1A and UTX genes (P < .001). Higher miR-199a (P = .006) and lower miR-31 (P = .01), ARID1A (P = .008) and UTX (P = .03) were independent predictor of higher tumor recurrence. Recurrent disease (P = .003), higher expression of STAG2 (P = .01), NCOR1 (P = .01) and miR-21 (P = .03) genes and lower expression of miR-31 (P = .02), Let7a (P = .04) and ARID1A (P = .04) genes were the independent predictor of disease progression. CONCLUSION: Upregulation of STAG2 and NCOR1 and down regulation of ARID1A and UTX genes and their targeting miRNAs were associated with UC non-response to BCG.

Mirabegron for treatment of erectile dysfunction concomitant with lower urinary tract symptoms in patients with benign prostatic obstruction: A randomized controlled trial.

OBJECTIVE: To assess the efficacy of mirabegron in the treatment of erectile dysfunction concomitant with lower urinary tract symptoms in benign prostatic obstruction patients. METHODS: In this randomized controlled trial, 55 sexually active lower urinary tract symptoms/benign prostatic obstruction patients with concomitant erectile dysfunction were randomly allocated in two groups: the first received mirabegron 50 mg plus doxazosin 2 mg once daily (mirabegron group) and the second received tolterodine 4 mg plus doxazosin 2 mg (tolterodine group) for 12 weeks. The evaluation was based on the International Index of Erectile Function questionnaire, Erection Hardness Score questionnaire, International Prostate Symptom Score, quality of life, uroflowmetry and post-voiding residual. The therapeutic outcomes were assessed at 4 and 12 weeks compared with the baseline. RESULTS: Only the mirabegron group achieved significant improvement in sexual functions after 4 and 12 weeks. By using ≥5 points difference from the baseline as a cut-off point of change, there was a significant difference in change of direction of the International Index of Erectile Function-15 total score in favor of the mirabegron group; after 12 weeks, the International Index of Erectile Function-15 total score decreased in 0%, was unchanged in 8.3% and improved in 91.7% in the mirabegron group compared with 8.7%, 65.2% and 26.1%, respectively, in the tolterodine group (P < 0.001). Regarding the urinary characteristics, both groups showed significant improvement in the International Prostate Symptom Score, quality of life, and post-voiding residual after 4 and 12 weeks, with no significant difference among them. CONCLUSION: Mirabegron improves urinary characteristics and the associated sexual dysfunction in patients with lower urinary tract symptoms/benign prostatic obstruction.

Zinc oxide nanoparticles attenuate prepubertal exposure to cisplatin- induced testicular toxicity and spermatogenesis impairment in rats.

Cisplatin exposure represents a significant fertility problem for childhood cancer. In this study we examined the possible therapeutic role of Zinc oxide nanoparticles (ZnO-NPs) on Cisplatin (Cis) induced impairment in the spermatogenesis initiation during puberty. Seventy-two male rats aged 30 days were distributed into four equal groups: Control group; ZnO-NPs group (intraperitoneal i.p. injected with 5 mg/kg ZnO-NPs once a week for eight weeks); Cis group (i.p. injected with a single dose of 5 mg/kg); ZnO-NPs + Cis group (ZnO-NPs injection 2 hrs before Cis). Each group was subdivided into three groups and was sacrificed 7, 30 and, 60 days after cisplatin induction, which considered prepubertal at 37-day-old, productive at 60-day-old, and completely adult at 90-day-old. Biochemical, molecular, immunohistochemical, and ultrastructural examinations were studied on the testicular tissues and sperm samples. Group treated with Cis showed a decrease in the antioxidant activity and an increase in the reactive oxygen species (ROS), which in turn caused disruption in blood-testis barrier (BTB) proteins in the three different rat ages, and sperm DNA damage in the adult rats compared to control group (p < 0.05). Moreover, alterations in the structural and the ultrastructural morphology of the testis were observed compared with the control at 37, 60 and 90 days old rats. ZnO-NPs administration to Cis group manifested a significant decrease in the ROS that restored the BTB proteins, enhanced the architecture of the testis in the three different rat ages, and increased sperm DNA integrity in the adult rats. Zinc oxide nanoparticles could restore the male reproductive capacity in the adult rats after induction of Cis in the prepubertal period by promoting spermatogenesis.

Prognostic influence of microsatellite alterations of muscle-invasive bladder cancer treated with radical cystectomy.

OBJECTIVE: To examine the prognostic effect of microsatellite instability (MSI) and loss of heterozygosity (LOH) on cancer-specific survival (CSS) in patients with muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: The liquid nitrogen-preserved specimens of 220 patients between March 2009 and December 2012 were analyzed for the presence of MSI and LOH in 12 loci (ACTBP2, D16S310, D16S476, D18S51, D4S243, D9S162, D9S171, D9S747, FGA, INF-α, MBP, MJD) using polymerase chain reaction. MSI was defined as MSI-stable, MSI-Low, or MSI-High if instability was detected in 0, 1, or 2 or more of the examined markers, respectively. The association between MSI-High and LOH and CSS was analyzed using uni- and multivariate analyses and the degree of agreement between tumor and urine samples were determined. RESULTS: MSI were found in 1030 (39%) and 1148 (43.5%) in tumor and urine specimens, respectively (Kappa = 0.77). On the other hand, LOH was found in 163 (6.2%) of tumor tissues and 44 (1.7%) in urine specimens (Kappa = 0.34). Microsatellite alterations were significantly associated with worse CSS at 1- and 5-year in tumor tissue (95% and 83.7% vs. 65.8% and 3.5%, respectively; P < 0.001) and in urine sample (90% and 64% vs. 46.5% and 9.3%, respectively; P < 0.001). MSI and/or LOH was an independent predictor of CSS (HR: 9.8; 95%CI: 5.1-18.9; P < 0.001). CONCLUSIONS: Microsatellite alterations were potentially an independent predictor of CSS in patients with MIBC. The agreement was good between tumor and urine MSI but weak for LOH.

Predictive value of immunological markers after bacille Calmette-Guérin induction in bladder cancer.

OBJECTIVES: To investigate the predictive value of different immunological markers on treatment outcomes after bacille Calmette-Guérin (BCG) induction in high-risk non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Patients who underwent transurethral resection of bladder tumour for NMIBC were assessed for study eligibility. Urine and blood samples were taken from patients at baseline (immediately before first dose of induction) and after induction (4 h after last [sixth] dose). Urine samples were evaluated for interleukin (IL)-2 and IL-10 by solid-phase enzyme-linked immunosorbent assay. Blood samples were evaluated for tumour necrosis factor α (TNF-α), cytotoxic T-lymphocyte antigen 4 (CTLA-4) and transcription factors (TFs) (GATA-binding protein 3 [GATA3], T-box expressed in T cells [T-bet], and forkhead box protein 3 [FoxP3]) using quantitative reverse transcriptase-polymerase chain reaction analysis. Change pattern and fold change of each evaluable marker was assessed in relation to different treatment outcomes (initial complete response [ICR]/recurrence/progression). RESULTS: Between July 2013 and May 2019, 204 patients were included. Among evaluable markers, urinary IL-2 and serum TNF-α increased in all patients, serum CTLA-4 and FoxP3+ showed a predominant decreased pattern in 188 (92.2%) and 192 (94.1%) patients, respectively. An ICR was achieved in 186 (91.2%) patients. Serum TNF-α fold change and urinary IL-10 change pattern were significantly associated with an ICR (P = 0.001 and P = 0.03, respectively). At a median (range) follow-up of 37 (20-88) months, 104 (56%) patients developed recurrence. Urinary IL-10, serum CTLA-4, T-bet+ , FoxP3+ change patterns and GATA3+ /T-bet+ ratio were significantly associated with tumour recurrence (P = 0.001, P = 0.001, P = 0.02, P = 0.009 and P = 0.001, respectively). Tumour progression occurred in 34 (18.3%) patients. Urinary IL-10, serum CTLA-4, serum T-bet+ change patterns and GATA3+ /T-bet+ ratio were independent predictors of tumour progression (P = 0.001, P = 0.001, P = 0.02 and P = 0.001, respectively). CONCLUSIONS: Urinary IL-10 and serum TNF-α can significantly predict ICR. Moreover, change pattern of urinary IL-10, serum CTLA-4, TFs (GATA3, T-bet and FoxP3) and GATA3+ /T-bet+ ratio after BCG induction can independently predict further BCG response. These markers could be implemented in clinical practice when management options are discussed or in systems with severe BCG shortage.

Egyptian clinical practice guideline for kidney transplantation.

Objective: To present the first Egyptian clinical practice guideline for kidney transplantation (KT). Methods: A panel of multidisciplinary subspecialties related to KT prepared this document. The sources of information included updates of six international guidelines, and review of several relevant international and Egyptian publications. All statements were graded according to the strength of clinical practice recommendation and the level of evidence. All recommendations were discussed by the panel members who represented most of the licensed Egyptian centres practicing KT. Results: Recommendations were given on preparation, surgical techniques and surgical complications of both donors and recipients. A special emphasis was made on the recipient's journey with immunosuppression. It starts with setting the scene by covering the donor and recipient evaluations, medicolegal requirements, recipient's protective vaccines, and risk assessment. It spans desensitisation and induction strategies to surgical approach and potential complications, options of maintenance immunosuppression, updated treatment of acute rejection and chemoprophylactic protocols. It ends with monitoring for potential complications of the recipient's suppressed immunity and the short- and long-term complications of immunosuppressive drugs. It highlights the importance of individualisation of immunosuppression strategies consistent with pre-KT risk assessment. It emphasises the all-important role of anti-human leucocyte antigen antibodies, particularly the donor-specific antibodies (DSAs), in acute and chronic rejection, and eventual graft and patient survival. It addresses the place of DSAs across the recipient's journey with his/her gift of life. Conclusion: This guideline introduces the first proposed standard of good clinical practice in the field of KT in Egypt. Abbreviations: Ab: antibody; ABMR: Ab-mediated rejection; ABO: ABO blood groups; BKV: BK polyomavirus; BMI: body mass index; BTS: British Transplantation Society; CAN: chronic allograft nephropathy; CDC: complement-dependent cytotoxicity; CKD: chronic kidney disease; CMV: cytomegalovirus; CNI: calcineurin inhibitor; CPRA: Calculated Panel Reactive Antibodies; (dn)DSA: (de novo) donor-specific antibodies; ECG: electrocardiogram; ESWL: extracorporeal shockwave lithotripsy; FCM: flow cytometry; GBM: glomerular basement membrane; GN: glomerulonephritis; HIV: human immunodeficiency virus; HLA: human leucocyte antigen; HPV: human papilloma virus; IL2-RA: interleukin-2 receptor antagonist; IVIg: intravenous immunoglobulin; KT(C)(R): kidney transplantation/transplant (candidate) (recipient); (L)(O)LDN: (laparoscopic) (open) live-donor nephrectomy; MBD: metabolic bone disease; MCS: Mean channel shift (in FCM-XM); MFI: mean fluorescence intensity; MMF: mycophenolate mofetil; mTOR(i): mammalian target of rapamycin (inhibitor); NG: 'not graded'; PAP: Papanicolaou smear; PCN: percutaneous nephrostomy; PCNL: percutaneous nephrolithotomy; PKTU: post-KT urolithiasis; PLEX: plasma exchange; PRA: panel reactive antibodies; PSI: proliferation signal inhibitor; PTA: percutaneous transluminal angioplasty; RAS: renal artery stenosis; RAT: renal artery thrombosis;:rATG: rabbit anti-thymocyte globulin; RCT: randomised controlled trial; RIS: Relative MFI Score; RVT: renal vein thrombosis; TB: tuberculosis; TCMR: T-cell-mediated rejection; URS: ureterorenoscopy; (CD)US: (colour Doppler) ultrasonography; VCUG: voiding cystourethrogram; XM: cross match; ZN: Ziehl-Neelsen stain.

Possible mechanisms for the renoprotective action of adipose-derived mesenchymal stem cells with CD44-targeted hyaluronic acid against renal ischemia.

The present study aimed to investigate the invitro preconditioning of adipose-derived mesenchymal stem cells (ADMSCs) with CD44-targeted hyalournic acid (HA) on ischemic kidney injury in rats. Ninety male Sprague Dawley rats were randomly allocated into the following groups; i) sham group, ii) control group: rats exposed to 45 min left renal ischemia with saline treatment, iii) HA group as control group but rats treated with HA, iv) ADMSCs group as control but rats treated with ADMSCs v) HA + ADMSCs group as ADMSCs but rats treated with ADMSCs preconditioned with CD44-tageted HA for 14 days. We found that treattment with either ADMSCs or HA + ADMSCs caused significant decrease in the elevated serum creatinine and BUN and malondialdehyde (MDA) concentrations and expression of TGF-ß1, fibronectin, collagen type I, inducible nitric oxide synthease (iNOS) and microRNAs (miR-21, miR-17-5p, miR-10a) in kidney and significant increase in creatinine clearance, superoxide dismutase (SOD), reduced glutathione (GSH) and the expression of Bcl2, vascular endothelial growth factor (VEGF), Wnt/ß-catenin pathway genes in kidney compared to control group (p < 0.05). Moreover, HA + ADMSCs group caused more significant improvement in these parameters than ADMSCs group (p < 0.05), while HA group did not cause any significant improvement in these parameters compared to control group. These results suggest that preconditioning of ADMSCs preconditioned with CD44-targted HA enhanced their cytoprotective effect against ischemic kidney injury. This renoprotective effect might be due to activation of angiogenesis, Wnt/ß-catenin pathway proteins, and suppression of oxidative stress, apoptosis, inflammation and fibrosis.

Trigonal-sparing versus trigonal-involved Botox injection for treatment of idiopathic overactive bladder: A randomized clinical trial.

OBJECTIVE: To evaluate safety and efficacy of trigone-involved Botox injections in comparison with trigone-sparing injections in refractory idiopathic overactive bladder (OAB). MATERIALS AND METHODS: One hundred and three patients randomly received a 100-IU intradetrusal injection of Botox either sparing the trigone (52 patients) or involving the trigone (51 patients). Patients were prospectively evaluated at 1, 3, and 6 months. Efficacy was evaluated by 3-day voiding diaries, OAB symptom score (OABSS), and pressure flow study. Any complications were recorded. An ascending cystogram was done at 3 months for detection of vesicoureteral reflux. Urinary tract infection (UTI) was estimated on urine culture basis. Primary outcome was the difference of total OABSS at 3 months. RESULTS: The mean age ± SD was 34.3 ± 10 years (range 18-59 years). There was a reduction of episodes of all components of OAB in both groups in comparison with baseline by the end of the study but without significant difference between both groups. The trigonal-sparing group had less score of frequency compared with the trigonal-involved group throughout the study period (P < .05). There was no difference in OABSS at 3 months (1.5 ± 0.4 vs 1.6 ± 0.3, P .875). Two patients in the trigonal-involved group out of 51 (3.9%) were in need of clean intermittent catheterization because of voiding difficulty and a postvoid residual > 200 mL. There was a higher rate of UTI in the trigonal-involved group ranging from 5.6% up to 11.7% at each follow-up visit. No patient had reflux. CONCLUSION: Trigone injections are not superior to trigone-sparing injections. On the contrary, the incidence of UTI and voiding difficulty were higher. The concept of reflux induced by trigonal injection has not been proven.

Long-term Outcome of Yang-Monti Ileal Replacement of the Ureter: A Technique Suitable for Mild, Moderate Loss of Kidney Function and Solitary Kidney.

OBJECTIVE: To present long-term outcome of Yang-Monti ileal ureter, with a focus on patients with mild/moderate loss of kidney function and solitary kidney. PATIENTS AND METHODS: Between March 2001 and December 2019, Yang-Monti ileal ureter was performed on 36 patients with ureteric defects and median age 46.5 years. Of these, 4, 14, 15 and 3 patients had stage 1, stage 2, stage 3a and stage 4a chronic kidney disease, respectively; 6 had solitary kidney. Patients were regularly followed for complications, morphological, and functional outcome. RESULTS: Ureteric stricture etiology was iatrogenic (16), Bilharzial (7), tuberculous (4), retroperitoneal fibrosis (5), malignancy (3), and gunshot injury (1). The median (range) ureteric defect length was 11 (8-16) cm. Four grade 1/2 postoperative Clavien-Dindo complications were noted. Median follow-up was 68 months (range 12-215). Intestinal obstruction developed in 1 patient and urinary tract infection in 10. At last follow-up, serum creatinine, split renographic clearance, and estimated glomerular filtration rate showed significant improvement compared to preoperative values, in the whole series, in cases with chronic kidney disease (stages 2, 3a and 3b) and solitary kidney. Four cases with chronic kidney disease (stage 3) showed deterioration of the kidney function parameters. Magnetic resonance urography showed improvement of hydronephrosis in most patients. No metabolic complications were noted. CONCLUSION: Yang-Monti Ileal ureter is durable and effective in improving kidney function with few complications. It can be safely used in cases of mild/moderate kidney function loss and solitary kidney. A threshold eGFR <40 mL/min/1.73 m2 is considered relative contraindication.

Effect of low-energy shock wave therapy on intravesical epirubicin delivery in a rat model of bladder cancer.

OBJECTIVES: To study the efficacy of low-energy shock wave therapy (LESW) on enhancing intravesical epirubicin (EPI) delivery in a rat model of bladder cancer (BCa). MATERIALS AND METHODS: A total of 100 female Fischer rats were randomly allocated into five groups: control; BCa; LESW; EPI; and EPI plus LESW. After BCa induction by N-butyl-N-(4-hydroxybutyl)nitrosamine, EPI (0.6 mg/0.3 mL of EPI diluted in 0.3 mL saline) or saline (0.6 mL) was administered and retained in the bladders for 1 h with or without LESW treatment (300 pulses at 0.12 mJ/mm2 ). This was repeated weekly for 6 weeks. Survival was then calculated, rats were weighed and their bladders were harvested for bladder/body ratio estimation, histopathological examination, p53 immunostaining, miR-210, hypoxia-inducible factor (HIF)-1α, tumour necrosis factor (TNF)-α and interleukin (IL)-6 relative gene expression and fluorescence spectrophotometric drug quantification. Heart and blood samples were also collected for assessment of the safety profile and toxicity. RESULTS: The EPI plus LESW group had significantly lower mortality rates, loss of body weight and bladder/body ratio. Histopathological results in terms of grossly visible bladder lesions, mucosal thickness, dysplasia formation and tumour invasion were significantly better in the combined treatment group. The EPI plus LESW group also had statistically significant lower expression levels of p53 , miR-210, HIF-1α, TNF-α and IL-6. LESW increased urothelial concentration of EPI by 5.7-fold (P < 0.001). No laboratory variable exceeded the reference ranges in any of the groups. There was an improvement of the indicators of EPI-induced cardiomyopathy in terms of congestion, hyalinization and microvesicular steatosis of cardiomyocytes (P = 0.068, 0.003 and 0.046, respectively) in the EPI plus LESW group. CONCLUSIONS: The combined use of intravesical EPI and LESW results in less BCa invasion and less dysplasia formation, as LESW increases urothelial permeability of EPI and enhances its delivery into tumour tissues, without subsequent toxicity.