Urology research center journal club: articles presentation 2024.01.15 (1402.10.25)

Journal Club    2024.01.15 (1402.10.25)

1- Dr.GolMohamadi: Docetaxel remodels prostate cancer immune microenvironment and enhances checkpoint inhibitor-based immunotherapy

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9274752/

Prostate cancer is usually considered as immune “cold” tumor with poor immunogenic response and low density of tumor-infiltrating immune cells, highlighting the need to explore clinically actionable strategies to sensitize prostate cancer to immunotherapy. In this study, we investigated whether docetaxel-based chemohormonal therapy induces immunologic changes and potentiates checkpoint blockade immunotherapy in prostate cancer. We performed transcriptome and histopathology analysis to characterize the changes of prostate cancer immune microenvironment before and after docetaxel-based chemohormonal therapy. Furthermore, we investigated the therapeutic benefits and underlying mechanisms of chemohormonal therapy combined with anti-PD1 blockade using cellular experiments and xenograft prostate cancer models. Finally, we performed a retrospective cohort analysis to evaluate the antitumor efficacy of anti-PD1 blockade alone or in combination with docetaxel-based chemotherapy. Histopathology assessments on patient samples confirmed the enrichment of tumor-infiltrating T cells after chemohormonal therapy. Moreover, we found that docetaxel activated the cGAS/STING pathway in prostate cancer, subsequently induced IFN signaling, resulting in lymphocytes infiltration. In a xenograft mouse model, docetaxel-based chemohormonal therapy prompted the intratumoral infiltration of T cells and upregulated the abundance of PD1 and PD-L1, thereby sensitizing mouse tumors to the anti-PD1 blockade. To determine the clinical significance of these results, we retrospectively analyzed a cohort of 30 metastatic castration-resistant prostate cancer patients and found that docetaxel combined with anti-PD1 blockade resulted in better prostate-specific antigen progression-free survival when compared with anti-PD1 blockade alone. Our study demonstrates that docetaxel activates the antitumoral immune response and facilitates T cell infiltration in a cGAS/STING-dependent manner, providing a combination immunotherapy strategy that would improve the clinical benefits of immunotherapy. Journal Club

2- Dr.Najarzadegan: The Long-Term Impact of 5-alpha Reductase Inhibitors on the Development of Bladder Cancer and the Need for Radical Cystectomy: A Nationwide Observational Study

https://doi.org/10.5534/wjmh.230137

To investigate the long-term effects of taking 5-alpha reductase inhibitors (5ARIs) on the development of bladder cancer (BC) and the implementation of radical cystectomy (RC), a standard procedure for advanced BC. From the National Health Insurance Sharing Service database, males aged over 40 years who underwent serum prostate-specific antigen testing from 2006 through 2017 were identified, which is required for the prescription of 5ARIs. The association between the administration duration of 5ARIs and the practice for BC was analyzed. Of the 3,843,968 subjects, 1,514,713 (39.4%) took 5ARIs for an average of 1.53 years, remaining 2,329,255 (60.6%) as non-5ARI counterparts. The incidence of BC was higher in the non-5ARI than in the 5ARI group (1.25% vs. 0.87%, p<0.001), as was the implementation rate of RC (11.1% vs. 10.4%, p=0.037). In a multivariate analysis, the non-5ARI group had a significant risk of BC (hazard ratio [HR]=2.289, 95% confidence interval [CI]=2.241–2.338) and RC (HR=2.199, 95% CI=2.061–2.348) than the 5ARI group. Among the 5ARIs group, though the incidence of BC was maintained (slope=-0.002 per year, p=0.79) after an initial increase for two years, the rate of RC decreased (slope=-1.1, p<0.001) consistently for ten years during the administration. Compared to the untreated group, 5ARIs use was associated with lower rates of BC and RC. In contrast to the increase in BC seen with short-term use of less than two years, long-term use of 5ARIs decreased the rate of RC in a duration-dependent manner for ten years, suggesting a strategy to prevent disease progression. Journal Club

3- Dr.Alphil: Body composition as a predictor of oncological outcome in patients with non-muscle-invasive bladder cancer receiving intravesical instillation after transurethral resection of bladder tumor

https://doi.org/10.3389/fonc.2023.1180888

Body status, categorized as sarcopenia or obesity and assessed using body mass index and body composition, affects the outcome of bladder cancer patients. However, studies comparing disease progression, recurrence, or overall survival in patients with non-muscle-invasive bladder cancer (NMIBC) with different body compositions are lacking. Therefore, we conducted a retrospective study to identify the impact of body composition, sarcopenia, and obesity on the oncological prognosis of patients with NMIBC who underwent transurethral resection of bladder tumor (TURBT) with Bacillus Calmette-Guerin (BCG) intravesical instillation (IVI). Patients with NMIBC who had undergone TURBT with adjuvant IVI with BCG from March 2005 to April 2021 were included. Body composition parameters were evaluated using computed tomography images of the third lumbar vertebrae and further categorized by sarcopenia and obesity. Oncological outcomes including recurrence-free survival (RFS), progression-free survival, and overall survival (OS) after treatment were analyzed. A total of 269 patients were enrolled. Subcutaneous adipose tissue (SAT) density was a significant predictor of RFS, whereas psoas muscle density was a significant predictor of OS in the multivariate analysis. Patients with sarcopenia but without obesity tolerated significantly fewer BCG IVIs than patients without sarcopenia or obesity. Patients with sarcopenia had poorer RFS and OS than those without sarcopenia. In contrast, patients with obesity had better OS than those without obesity. Body composition parameters, including SAT density and psoas muscle density, emerged as significant predictors of OS and RFS, respectively. Hence, our findings indicate that body composition is a helpful measurement to assess the oncological outcomes of patients with NMIBC. Journal Club

4- Dr.Ghiasi: The value of contrast-enhanced ultrasonography in the diagnosis of primary testicular non-neoplastic and neoplastic lesions in adults

https://bmcurol.biomedcentral.com/articles/10.1186/s12894-022-01163-9

Different pathological types of testicular tumors are treated differently. Malignant germ cell tumors require radical orchiectomy, while benign tumors may only need mass enucleation. Contrast-enhanced ultrasonography (CEUS) is more sensitive than conventional ultrasonography in displaying tumor microvessels, which helps distinguish between benign and malignant tumors. This was a retrospective analysis of 35 patients with pathological-confirmed primary testicular non-neoplastic and neoplastic lesions in our hospital from February 2017 to February 2022. Conventional ultrasonography and CEUS imaging findings of included lesions were retrospectively analyzed and their diagnostic values were compared with the pathological results. There were 13 cases of benign testicular lesions (including 1 case of spontaneous hematoma, 2 cases of segmental infarctions, 5 cases of epidermoid cysts, 2 cases of Sertoli cell tumors, and 3 cases of Leydig cell tumors) and 23 cases of malignant testicular lesions (including 10 cases of seminomas, 1 case of embryonal carcinoma, 2 cases of mixed germ cell tumors, 2 cases of spermatocytic tumors, and 8 cases of lymphomas). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy rates of conventional ultrasound in diagnosing benign testicular tumors by “onion skin-like” echo (epidermoid cysts) and peripheral annular blood flow were 30.8%, 100.0%, 100.0%, 71.9% and 75.0%, respectively. All testicular non-neoplastic lesions and epidermoid cysts showed no enhancement by CEUS. All Sertoli-Leydig cell tumors (SLCTs)’ CEUS imaging showed uniform high enhancement (no necrosis area), fast forward, and slow backward. 80.0% (12/15) malignant germ cell tumors showed heterogeneous enhancement and fast forward and fast backward in CEUS. All lymphomas showed fast forward and fast backward, and 87.5% (7/8) of them showed uniform high levels of enhancement in CEUS. According to CEUS without enhancement (non-neoplastic lesions and epidermoid cysts) and uniform high enhancement with fast forward and slow backward (SLCT), the sensitivity, specificity, positive predictive value, negative predictive value and accuracy rates for diagnosing benign testicular tumors were all 100.0%. Compared with conventional ultrasound, the difference was statistically significant (p = 0.004). CEUS could accurately distinguish between benign and malignant testicular tumors, as well as differentiate specific pathological types (testicular focal infarction, epidermoid cysts, spermatocytic tumors, SLTC and lymphoma). Accurate preoperative diagnosis is critical for guiding the selection of appropriate treatment plans for different pathological types of testicular tumors. Journal Club

5- Dr.Chivaei: Predictive value of SIRI and SII for metastases in RCC: a prospective clinical study

https://bmcurol.biomedcentral.com/articles/10.1186/s12894-024-01401-2

In this prospective cross-sectional clinical study, we aimed to determine the efficiency of preoperative hematological markers namely SIRI (systemic inflammatory response index) and SII (systemic inflammatory index) for renal cell cancer to predict the possibility of postoperative metastases. Istanbul Education and Research Hospital, Clinic of Urology and Medical Oncology in the clinic between the dates of June 2022 to 2023 February, a diagnosis of renal cell cancer by surgical or medical oncology units imported into the treatment planning of 72 patients were included in the study. All cases with diagnoses of renal cell carcinoma were searched from hospital records. Patients with secondary malignancy, hematological or rheumatological disorders or ones with recent blood product transfusion or diagnoses of infection within the 1-month-time of diagnoses were excluded for data analyses. The data within complete blood counts (CBC) analyzed just before the time of renal biopsy or surgery were studied for SIRI and SII calculations. Twenty-two metastatic and 50 non-metastatic RCC patients were included. SIRI and SII values were compared among groups to seek change of values in case of metastasis and in non-metastatic patients a cut-off value were sought to indicate malignancy before pathological diagnosis. Mean age of non-metastatic RCC patients were 60.12+/-11.55 years and metastatic RCC patients were 60.25+/-11.72. Histological sub-types of the RCC specimens were clear cell (72%), chromophobe cell (17%), papillary cell (7%) and others (4%). Median SIRI values for non-metastatic and metastatic groups were 1.26 and 2.1 (mean+/-S.D. 1.76 +/-1.9 and 3.12+/-4.22 respectively (p < 0.05). Median SII values for non-metastatic and metastatic groups were 566 and 1434 (mean+/-S.D. 870 +/-1019 and 1537+/-917) respectively (p < 0.001). AUC for detection of metastasis were 0.809 for SII and 0.737 for SIRI. SIRI and SII indexes seem to show a moderate efficiency to show metastases in RCC. Journal Club

6-Dr.Beiranvand: Therapeutic potential of urine exosomes derived from rats with diabetic kidney disease

https://doi.org/10.3389/fendo.2023.1157194

Kidney disease is prevalent in diabetes. Urinary exosomes (uE) from animal models and patients with Diabetic nephropathy (DN) showed increased levels of miRs with reno-protective potential. We examined whether urinary loss of such miRs is associated with their reduced renal levels in DN patients. We also tested whether injecting uE can leverage kidney disease in rats. In this study (study-1) we performed microarray profiling of miRNA in uE and renal tissues in DN patients and subjects with diabetes without DN (controls). In study-2, diabetes was induced in Wistar rats by Streptozotocin (i.p. 50 mg/kg of body weight). Urinary exosomes were collected at 6th, 7th and 8th weeks, and injected back into the rats (100ug/biweekly, uE-treated n=7) via tail vein on weeks 9 and 10. Equal volume of vehicle was injected in controls (vehicle, n=7). uE from the human and rat showed the presence of exosome-specific proteins by immunoblotting. Microarray profiling revealed a set of 15 miRs having high levels in the uE, while lower in renal biopsies, from DN, compared to controls (n=5-9/group). Bioinformatic analysis also confirmed the Renoprotective potential of these miRs. Taqman qPCR confirmed the opposite regulation of miR-200c-3p and miR-24-3p in paired uE and renal biopsy samples from DN patients (n=15), relative to non-DN controls. A rise in 28 miRs levels, including miR-200c-3p, miR-24-3p, miR-30a-3p and miR-23a-3p were observed in the uE of DN rats, collected between 6th-8th weeks, relative to baseline (before diabetes induction). uE- treated DN rats had significantly reduced urine albumin-to-creatinine ratio, attenuated renal pathology, and lower miR-24-3p target fibrotic/inflammatory genes (TGF-beta, and Collagen IV), relative to vehicle treated DN rats. In uE treated rats, the renal expression of miR-24-3p, miR-30a-3p, let-7a-5p and miR-23a-3p was increased, relative to vehicle control. Patients with diabetic nephropathy had reduced renal levels, while higher uE abundance of miRs with reno-protective potential. Reverting the urinary loss of miRs by injecting uE attenuated renal pathology in diabetic rats. Journal Club

7- Dr.Zemanati: External validation of the T.O.HO. score as predictor of success after retrograde intrarenal surgery

https://bmcurol.biomedcentral.com/articles/10.1186/s12894-022-01018-3

To assess the effectiveness of T.O.HO. (Tallness, Occupied lesion, Houndsfield unit evaluation) score in predicting the retrograde intrarenal surgery (RIRS) success and to validate this scoring system. The age, sex, previous stone surgery, hospitalization, surgery duration, postoperative complication, stone length, stone location, stone density, stone number, lateralization, presence of hydronephrosis, and presence of preoperative stent datas of 611 patients who underwent RIRS in our clinic between January 2013 and January 2021 were retrospectively assessed. The patients were divided into two groups as successful and unsuccessful. The T.O.HO scores of all patients were calculated. The success rate was 72.5%. Compared to the unsuccessful group, stone length and stone density were lower, surgery duration was shorter and there were less lower pole stones in the successful group (p < 0.001). No significant difference was found between the two groups in terms of the other parameters. The T.O.HO. score was significantly lower in the successful group compared to the unsuccessful group (p < 0.001). According to the multivariate logistic regression analysis, stone length (OR: 0.905; 95% Cl: 0.866–0.946; p < 0.001), lower pole location (OR: 0.546; 95% Cl: 0.013–0.296; p < 0.001), stone density (OR: 0.999; 95% Cl: 0.998–1; p = 0.044) and the T.O.HO. score (OR: 0.684; 95%Cl: 0.554–0.844; p < 0.001) were found as the independent risk factors for RIRS success. ROC curve analysis showed that the T.O.HO. score could predict the RIRS success with 7.5 cut-off point (AUC: 0.799, CI: 0.76–0.839; p < 0.001). The T.O.HO. score can predict RIRS success with a high rate of accuracy.Journal Club

8-Dr.Karimian: Super-stiff guidewire or loach guidewire during percutaneous nephrolithotomy?

https://doi.org/10.1002/bco2.219

The objectives of this work are to compare the outcomes between loach guidewire and super-stiff guidewire during percutaneous nephrolithotomy (PCNL) and find potential indications of different guidewires. We retrospectively reviewed our institutional PCNL database from 2017 to 2021. Patients who underwent PCNL guided by loach guidewire were assigned to group A (489 patients); patients who received super-stiff guidewire were assigned to group B (269 patients). Preoperative demographic data, intraoperative parameters, and postoperative complications were compared. The conditions and reasons of failed placement of guidewire needed readjustment were evaluated as well. Preoperative demographic data and most intraoperative parameters were not statistically different between the groups. Postoperative Clavien–Dindo complications were also comparable, with low rate of complications. However, failed placement of guidewire more occurred in group A (8.2% vs. 4.0%, respectively, p = 0.03). Compared with the super-stiff guidewire, the loach guidewire was easier pass/slip into any place either it be perinephric or blood vessels. In most failed group A cases and all failed group B cases, the guidewire was placed in the perirenal fat. Six patients (15%) in group A, the guidewires entered into vessels. Our results support that the faulty placement of loach guidewire is significantly more common compared with super-stiff guidewire. Double confirmation is needed to prevent a major complication out of wrong dilatation whenever there is doubt about the wrong location of the guidewire. Journal Club