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

Journal Club    2024.03.04 (1402.12.14)

1- Dr. Beiranvand: Influence of unsaturated fatty acids on the antitumor activity of polymeric conjugates grafted with cabazitaxel against prostate cancer

https://doi.org/10.1016/j.biopha.2023.115902

Cabazitaxel (CTX) is a medication used for treating metastatic prostate cancer. However, its effectiveness is majorly limited by its poor water solubility and lack of tumor targeting. In this study, three unsaturated fatty acids, GLA, ALA and DHA, were separately connected with CTX and then covalently attached to bifunctionalized dextran through a linker to produce three dual drug conjugates named dextran-GLA-CTX, dextran-ALA-CTX and dextran-DHA-CTX. The three conjugates displayed enhanced solubility of CTX in water and improved antitumor effects compared to the conventional CTX formulation. The results also confirmed that dextran-GLA-CTX exhibited the strongest antitumor activity, while dextran-DHA-CTX displayed less efficacy, as evaluated through xenografted nude mice bearing PC-3 and DU145 prostate cancer cells. Additionally, dextran-GLA-CTX showed greater inhibition of tumor growth than dextran-CTX. Moreover, the dextran-GLA-CTX conjugate was found to prolong the half-life of CTX in plasma and selectively accumulate in tumors. This study revealed that unsaturated fatty acids can enhance the antitumor activity of dextran-based conjugates grafted with CTX.Journal Club

2- Dr.Najarzadegan: Emerging Roles of Urine-Based Tumor DNA Analysis in Bladder Cancer Management

https://doi.org/10.1200/PO.20.00060

Cancers arising from the urothelium, the specialized epithelial lining of the urinary system, include urothelial carcinoma of the bladder (UCB) and upper tract urothelial carcinoma (UTUC).  In the United States, an estimated 80,000 new UCB cases were diagnosed in 2019, representing the fourth most common cancer diagnosis in men and the sixth most common cancer diagnosis overall.  UTUC is less common, with approximately 4,000 diagnoses in 2019.  Prognosis and management of urothelial carcinoma is largely dictated by the grade (high v low) and stage (degree of invasion) found on cystoscopic/ureteroscopic biopsy or resection.  The vast major-ity of cases are diagnosed when disease remains confined to the urinary tract,  yet even localized disease causes substantial morbidity and bears significant risk for progression to lethal disease. 7 Urine-based biomarkers have long been sought to improve diagnosis, disease monitoring, and treatment stratification.  Although progress has been made, cytologic evaluation of the urine and cystoscopic and ureteroscopic evaluation of the urinary tract remain the gold standard for diagnosis and monitoring. However, not only is this invasive, it is also associated with the highest cost from diagnosis to death among all cancers in the United States. New opportunities for urine-based biomarker analysis have arisen because of better genomic characterization of urothelial carcinoma and technologic improvements for sensitive detection of tumor DNA on the basis of identification of cancer-related mutations and copy number changes.  After initial proof-of-concept studies established the presence of tumor DNA in urine from patients with urothelial carcinoma, more recent studies have evaluated potential clinical applications in better-defined contexts.  Many questions remain to be addressed, but these studies support the exciting possibility that urine-based analysis could decrease the need for invasive evaluations and aid in treatment selection. Here we discuss possible applications and barriers to implementing urinary tumor DNA (utDNA) analysis for patients with UCB and UTUC and translating these findings to improve clinical care.Journal Club

3-Alphil: The fate of clinically insignificant residual fragments following retrograde intrarenal surgery and factors affecting spontaneous passage

https://link.springer.com/article/10.1007/s00240-024-01544-9

The remaining stone fragments after retrograde intrarenal surgery (RIRS) can lead to stone recurrence/regrowth, or stone-related events (SRE). We aimed to delineate the clinical circumstances that are decisive for spontaneous passage of clinical insignificant residual fragments (CIRF) (primary outcome) and define risk factors for stone recurrence/regrowth and their clinical manifestation (secondary outcome). A total of 115 patients who had CIRF following RIRS were included in this study. Demographic, clinical data, stone, and anatomic characteristics including infundibulopelvic angle (IPA), infundibular length (IL) and follow-up data of patients were analyzed. The mean follow-up time was 27.5 ± 6.9 months. 31 (26.9%) patients passed the CIRF spontaneously. Patients were divided into two groups as spontaneous fragment passage group and fragment remaining group and compared with respect to demographic, clinical, stone-related, and anatomic characteristics. 61.2% of patients had lower pole CIRF in fragment remaining group and 83.3% of patients in spontaneous fragment passage group (p = 0.031). In addition, IPA was wider in spontaneous fragment passage group (60.7° vs 51.4°, p = 0.001). A subanalysis was performed for fragment remaining group. In 84 patients, 44 (52.4%) patients were stable for their CIRF at their follow-up and included in stable group. 40 (47.6%) patients experienced stone re-growth (27 patients) or SRE (13 patients) at their follow up. Patients in re-growth/SRE group were older (49.1 vs 39.4 years, p = 0.047), had higher body mass index (28.2 vs 27 kg/m2, p = 0.03) and larger CIRF (2.8 vs 2.1 mm). CIRFs may be not expelled spontaneously and they may lead to additional morbidity and lithotripsy interventions.Journal Club

4- Dr.Ghiasi: The Visualized Urethral Mobility Profile in Stress Urinary Incontinence Described by Four-Dimensional Transperineal Ultrasound

https://doi.org/10.1002/jum.15828

To describe the urethral mobility during urine leaking in stress urinary incontinence (SUI) by transperineal ultrasound (TPUS) with urethral mobility profile (UMP) analysis. This was a prospective study of 380 women who had a cough stress test (CST) with TPUS. UMP software automatically placed six equidistant points from the bladder neck (Point 1) to the external urethral meatus (Point 6) and determined their x and y coordinates relative to the symphysis pubis. Urethral mobility vector of Points 1–6 (Vectors 1–6) and the distance between the six points and the symphysis (Dist. 1–6) were calculated and compared between the two groups. The visualized UMP was created by reproducing the positions of the six points at rest and on Valsalva. Valid data of 188 women with SUI and 174 continent women were analyzed. The mean age of all 362 women was 49.3 years. Mean body mass index in the SUI group was significantly increased (23.8 vs 22.2 kg/m2, P < .001). During CST, Vectors 1–6 and Dist. 2–6 were significantly increased (all P < .005) in the SUI group. The UMP showed the mid-urethral rotated down around the symphysis pubis. The upper urethral profile in the two groups was similar. But the gap between the mid-urethra and the symphysis was wider in the SUI group. The visualized UMP illustrated the mid-urethral hypermobility in SUI by showing a wider gap due to the unstable connection between the mid-urethra and the symphysis pubis.Journal Club

5-Dr.Chivaei: Prevention of Postoperative Urethral Strictures by Irrigation with 5-Fluorouracil via a Modified Urinary Catheter

https://doi.org/10.3390/medicina60010102

Urethral strictures are the most common complications after surgical treatments of benign prostatic hyperplasia (BPH). Despite various preventive measures, the search for medications with antiproliferative activity and the development of surgical procedures to prevent the development of urethral strictures are still relevant. We evaluated the preventive efficacy of 5-fluorouracil against urethral strictures in patients undergoing surgery for BPH. Materials and Methods: A non-randomized clinical trial including 246 male patients with an average age of 70.0 ± 8.0 years was conducted. The main study group included 124 patients who, in addition to the standard treatment, received lavage with a 5-fluorouracil solution (1000 mg/20 mL per 500 mL of 0.9% isotonic saline) using a modified three-way urethral catheter. The monitoring of clinical, laboratory, and instrumental parameters was carried out 10 days, 3 months, and 6 months after surgery. Results: The evaluation of severity for dysuria symptoms in patients using the IPSS scale throughout the entire follow-up period showed a statistically significant decrease in ischuria and stranguria, prolongation of the interval between urinations, a decrease in intermittent urination, urinary incontinence, and straining before urination in the main group in comparison with the control patients. The patients of both study groups noted an improvement in the quality of life. It was found statistically significant decrease in the maximum urinary flow rate in the main group (p < 0.001). In the control group, after three months, four cases of urethral strictures and stenosis were recorded; after six months, this rate reached nine cases (7.3%), while in the main group, only one patient with infravesical obstruction was found (0.8%) (χ2 = 3.855, p < 0.05). Conclusions: The results of our study could indicate the effectiveness of the antiproliferative drug 5-fluorouracil in combination with use of a modified catheter in relation to the development of postoperative urethral strictures.Journal Club

6- Dr.Beiranvand: Role of heat shock protein 70 in silibinin-induced apoptosis in bladder cancer

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751677/

Hsp70 (heat shock protein 70) plays critical roles in cancer cell proliferation and apoptosis. Recently, accumulating evidences have demonstrated the cancer promoting effects of Hsp70 in bladder cancer. The development of novel therapeutic approaches targeting Hsp70 thus received great attention from researchers. In this study, we demonstrated that silibinin, a natural polyphenolic flavonoid isolated from the milk thistle, targeted Hsp70 by inhibiting its transcription in bladder cancer cells. We also demonstrated that knockdown of endogenous Hsp70 enhanced silibinin-induced apoptosis, while overexpression of exogenous Hsp70 could partially reverse the effects of silibinin-induced cell apoptosis. Furthermore, we found that silibinin could activate HSF1/Hsp70-regulated mitochondrial apoptotic pathway. Mechanically, silibinin inhibited the interaction between Apaf-1 and Hsp70, thus increasing the recruitment of pro caspase-9. Results from in vivo study demonstrated that silibinin suppressed the growth of bladder cancer xenografts, which was accompanied with the activation of caspase-3 and downregulation of HSF1 and Hsp70. Taken together, our data indicates that silibinin induces mitochondrial apoptosis via inhibiting HSF1/Hsp70 pathway and also suggests the therapeutic potential of silibinin in the treatment of bladder cancer.

7-Zemanati: Cystine Stones: Developments in Minimally Invasive Surgery and Their Impact on Morbidity and Stone Clearance

https://www.tandfonline.com/doi/full/10.2147/RRU.S381190

Cystinuria is a rare genetic condition that is responsible for cystine stones. Besides stone recurrence, patients with cystine stones have reduced health-related quality of life, increased rates of chronic kidney disease and hypertension. Although lifestyle measures, medical therapy and close follow up are essential to reduce and monitor cystine stone recurrences, surgical intervention is frequently needed for most cystinuria patients. Shock wave lithotripsy, ureteroscopy, percutaneous nephrolithotomy and active surveillance all have a role, and technological advances in endourology are vital in achieving a stone-free status and to prevent recurrences. The complexity of managing cystine stones necessitates a multidisciplinary team discussion, patient involvement and an individualised approach in a specialist centre for optimum management. Thulium fibre laser and virtual reality may have an increasing role in the future of cystine stone management.Journal Club

8- Dr.Karimian: Engineered tumor cell-derived vaccines against cancer: The art of combating poison with poison

https://doi.org/10.1016/j.bioactmat.2022.10.016

Tumor vaccination is a promising approach for tumor immunotherapy because it presents high specificity and few side effects. However, tumor vaccines that contain only a single tumor antigen can allow immune system evasion by tumor variants. Tumor antigens are complex and heterogeneous, and identifying a single antigen that is uniformly expressed by tumor cells is challenging. Whole tumor cells can produce comprehensive antigens that trigger extensive tumor-specific immune responses. Therefore, tumor cells are an ideal source of antigens for tumor vaccines. A better understanding of tumor cell-derived vaccines and their characteristics, along with the development of new technologies for antigen delivery, can help improve vaccine design. In this review, we summarize the recent advances in tumor cell-derived vaccines in cancer immunotherapy and highlight the different types of engineered approaches, mechanisms, administration methods, and future perspectives. We discuss tumor cell-derived vaccines, including whole tumor cell components, extracellular vesicles, and cell membrane-encapsulated nanoparticles. Tumor cell-derived vaccines contain multiple tumor antigens and can induce extensive and potent tumor immune responses. However, they should be engineered to overcome limitations such as insufficient immunogenicity and weak targeting. The genetic and chemical engineering of tumor cell-derived vaccines can greatly enhance their targeting, intelligence, and functionality, thereby realizing stronger tumor immunotherapy effects. Further advances in materials science, biomedicine, and oncology can facilitate the clinical translation of tumor cell-derived vaccines.Journal Club