The combination of immune checkpoint inhibitors and antibody-drug conjugates in the treatment of urogenital tumors: a review insights from phase 2 and 3 studies.

With the high incidence of urogenital tumors worldwide, urinary system tumors are among the top 10 most common tumors in men, with prostate cancer ranking first and bladder cancer fourth. Patients with resistant urogenital tumors often have poor prognosis. In recent years, researchers have discovered numerous specific cancer antigens, which has led to the development of several new anti-cancer drugs. Using protein analysis techniques, researchers developed immune checkpoint inhibitors (ICIs) and antibody-conjugated drugs (ADCs) for the treatment of advanced urogenital tumors. However, tumor resistance often leads to the failure of monotherapy. Therefore, clinical trials of the combination of ICIs and ADCs have been carried out in numerous centers around the world. This article reviewed phase 2 and 3 clinical studies of ICIs, ADCs, and their combination in the treatment of urogenital tumors to highlight safe and effective methods for selecting individualized therapeutic strategies for patients. ICIs activate the immune system, whereas ADCs link monoclonal antibodies to toxins, which can achieve a synergistic effect when the two drugs are combined. This synergistic effect provides multiple advantages for the treatment of urogenital tumors.

Expression of Tight Junction Proteins Is Altered in Bladder Cancer.

Bladder cancer (BC) is one of the tumors which occur most frequently in urological system, but less is known about the expression of tight junction proteins and its clinical significance in BC. In this study, expression of claudin-4, zonula occludens-1 (ZO-1) and zonula occludens-1 nucleic acid-binding protein (ZONAB), in BC tissues, adjacent nontumor tissue (ANTT), and BC cell lines was examined by Western blotting, semiquantitative RT-PCR, and immunohistochemistry, and then, the clinical significance of these proteins was investigated. The mRNA and protein expression of ZONAB were significantly upregulated, while those of ZO-1 was significantly downregulated in some BC cell lines and tissues in comparison with nontumor urothelial cell lines and ANTT. High expression rate of ZO-1 and ZONAB had negative correlation in BC tissues and was also correlated with muscle-invasive lesions in BC tissues. In conclusion, the expression of tight junction proteins is significantly altered in BC and ZO-1, and ZONAB interaction might be involved in BC development.

Biological Support to Obesity Paradox in Renal Cell Carcinoma: A Review.

Obesity is a proven risk factor and a debated prognostic factor in renal cell carcinoma (RCC). Termed as an "obesity paradox," the topic has churned controversies, with a few arguing of no true biological association. Suggesting otherwise, a few studies revealed adiposity-induced altered molecular and transcriptomic signatures, at both the systemic and local (tumor and peritumoral adipose tissue) levels, in RCC patients, favoring the paradox. Summarizing such studies suggests of a considerable biological support to adiposity as a promising prognostic factor in RCC patients, although much needs to be clarified before adopting it as a valuable addition to the existing prognostic model.

Lentinan Inhibits Tumor Progression by Immunomodulation in a Mouse Model of Bladder Cancer.

Background: Lentinan (LNT), an isolated traditional Chinese herbal component, has antitumor potential. In the current study, the intrinsic mechanism of LNT-induced immunity against bladder cancer was explored in a mouse model. Methods: In the mouse model of bladder cancer, we used flow cytometry to detect the LNT caused population changes of T cells, macrophages, MDSC cells, and Treg cells. ELISA was used to evaluate cytokines expression in the supernatant of splenocytes. Results: We found that the administration of LNT increased the proportions of CD3+CD4+ and CD3+CD8+ T cell subsets as well as CD11b+F480+ macrophages, whereas it diminished the subpopulations of CD4+CD25+Foxp3+ regulatory T cells (Tregs) and Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs). LNT also upregulated the expression of interferon (IFN)-γ and interleukin (IL)-12, accompanied by a significant reduction in IL-10 and tumor growth factor (TGF)-ß (P < .05). Our research further confirmed the synergy between LNT and gemcitabine (GEM) to activate immunity and inhibit the growth of bladder tumors in mouse model. Conclusions: LNT induced macrophage activation, followed by the enhanced proliferation of CD4+ and CD8+ T cells, and the upregulated expression of IFN-γ and IL-2. Meanwhile, the proportions of MDSCs and Tregs were downregulated, leading to a reduced expression of the anti-inflammatory cytokines IL-10 and TGF-ß. The synergy between LNT and GEM provides additional evidence supporting the application of this traditional Chinese herbal component for bladder cancer therapy.

Laparoscopic and Robotic-Assisted Partial Nephrectomy: An Overview of Hot Issues.

Laparoscopic partial nephrectomy and robot-assisted partial nephrectomy are attracting increased attention from urologists. They can achieve the same effect of oncology control as radical nephrectomy; moreover, they can offer better preservation of renal function, thus obtaining long-term living benefits. The indications are also expanding, making it possible for larger and more difficult tumors. Laparoscopic partial nephrectomy and robot-assisted partial nephrectomy can be performed by transperitoneal and retroperitoneal approaches, with their individual advantages and limitations. In addition, the renal tumor scoring systems have been widely used and studied in laparoscopic partial nephrectomy and robot-assisted partial nephrectomy. In -order to better preserve renal function, the zero-ischemia technique is widely used. The application of intraoperative imaging technology provides convenience and greater benefits. Besides, whether minimal invasive partial nephrectomy can be performed without stop antiplatelet treatment is still disputed. Clinicians perform substantial exploration and practice to achieve the "trifecta" of surgery: complete resection of the tumor, maximum protection of renal function, and no complications.

Development and Validation of a Model for Predicting Intravesical Recurrence in Organ-confined Upper Urinary Tract Urothelial Carcinoma Patients after Radical Nephroureterectomy: a Retrospective Study in One Center with Long-term Follow-up.

Although radical nephroureterectomy is the standard treatment method for upper urinary tract urothelial carcinoma, it is associated with a high risk of intravesical recurrence. There are no models for predicting IVR after RNU in patients with organ-confined UTUC. Therefore, we developed and validated a model for postoperative prediction of IVR after RNU. The development cohort consisted of 416 patients who underwent RNU with bladder cuff excision at our center between 1 January 2007 and 31 December 2015. Patient clinicopathologic data were recorded. Multivariate Cox proportional hazard ratio regression was used to build a predictive model with regression coefficients, backward step-wise selection was applied, and the likelihood ratio test with Akaike's information criterion was used as the stopping rule. An independent cohort consisting of 152 consecutive patients from 1 January 2016 and 31 December 2017 was used for validation. The performance of this predictive model was assessed with respect to discrimination, calibration, and clinical usefulness. The predictors in this model included tumor stage, tumor diameter, tumor location, and tumor grade. In the validation cohort, the model showed good discrimination, with a concordance index of 0.689 (95% CI, 0.629 to 0.748) and good calibration. Decision curve analysis demonstrated that the model was also clinically useful. This study presents a good model that may facilitate individualized postoperative prediction of IVR after RNU in patients with organ-confined UTUC, and thus, may help improve postoperative strategies and facilitate treatment outcomes.

Development and validation of a predictive model for predicting cardiovascular morbidity in patients after pheochromocytoma surgery.

OBJECTIVE: Although surgical resection is the primary treatment method for pheochromocytoma, it carries a high risk of morbidity, especially cardiovascular-related morbidity. There are no models for predicting cardiovascular morbidity after pheochromocytoma surgery. Thus, we developed and validated a model for the preoperative prediction of cardiovascular morbidity after pheochromocytoma surgery. DESIGN: The development cohort consisted of 262 patients who underwent unilateral laparoscopic or open pheochromocytoma surgery at our centre between 1 January 2007 and 31 December 2016. Patient's clinicopathologic data were recorded. The LASSO regression was used for data dimension reduction and feature selection; then, multivariable logistic regression analysis was used to develop the prediction model. An independent cohort consisting of 112 consecutive patients from 1 January 2017 and 31 December 2018 was used for validation. The performance of this prediction model was assessed with respect to discrimination, calibration and clinical usefulness. RESULTS: The predictors in this prediction model included body mass index, history of coronary heart disease, tumour size, intraoperative hemodynamic instability and use of crystal/colloid fluids preoperatively. In the validation cohort, the model showed good discrimination with an AUROC of 0.869 (95% CI, 0.797, 0.940) and good calibration (unreliability test, P = .852). Decision curve analysis demonstrated that the model was also clinically useful. CONCLUSION: This study presented a good nomogram that could facilitate the preoperative individualized prediction of cardiovascular morbidity after pheochromocytoma surgery, which may help improve perioperative strategy and good treatment outcomes.

Circular RNA CEP128 promotes bladder cancer progression by regulating Mir-145-5p/Myd88 via MAPK signaling pathway.

The present experiment was designed for exploring the regulatory mechanism of circ-CEP128/miR-145-5p/MYD88 axis in bladder cancer. MiRNAs and circRNAs expression data were derived from Gene Expression Omnibus database with bladder tumor tissues and paracarcinoma tissue samples. Differentially expressed genes in tumor were analyzed via R software. Interaction network of differently expressed miRNAs and differently expressed mRNA was established by means of Cytoscape software. CircCEP128 and miR-145-5p expression levels were determined using qRT-PCR. The expression of MAPK signaling-related proteins MYD88, p38, ERK and JNK was examined by western blot. The relationship between circCEP128 and miR-145-5p was validated using RNA immunoprecipitation. The level of cell propagation and migration was determined by CCK8 and wound healing assay, 5-bromo-2'-deoxyuridine assay and migration assay. Cell apoptosis rate and cell cycle were detected via flow cytometry. Tumor xenograft assay was implemented to investigate the function of circCEP128 in vivo. CircCEP128 and MYD88 were overexpressed in bladder cancer based on microarray analysis and miR-145-5p was a potential targeting factor in bladder cancer. CircCEP128 targeted miR-145-5p and miR-145-5p targeted MYD88. Expression of miR-145-5p was decreased in cancer samples. Knockdown of circCEP128 induced the inhibition of cell viability and mobility and cell cycle arrest. Overexpression of miR-145-5p or knockdown of circCEP128 promoted MAKP signaling pathway and related proteins expression. In addition, knockdown of circCEP128 suppressed the growth of bladder cancer tumor tissues in vivo. Overexpression of circCEP128 promoted bladder cancer progression through modulating miR-145-5p and MYD88 via MAKP signaling pathway.

Circ_0058063 regulates CDK6 to promote bladder cancer progression by sponging miR-145-5p.

BACKGROUND: The study was aimed to investigate the influence of circ_0058063 on tumorigenesis as well as the regulatory mechanism of circ_0058063/miR-145-5p/ CDK6 pathway in bladder cancer (BC). METHODS: Bioinformatics analysis was used to screen highly expressed circle RNA (circRNA) and search its downstream microRNA (miRNA) and protein. The expression level of circRNA, miRNA, and CDK6 in BC cell lines T24 and J82 were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Small interfering RNA was used to downregulate circ_0058063 expression. Cell proliferation, cell cycle, cell apoptosis, and cell migration of T24 cells and J82 cells were detected through MTT assay, flow cytometry, and wound-healing assay, respectively. The relationships among miR-145-5p, circ_0058063, and CDK6 were confirmed through dual luciferase reporter assay. In vivo experiment was also performed to explore the impact of circ_0058063/miR-145-5p/ CDK6 pathway on tumorigenesis in BALB/c nude mice. RESULTS: Circ_0058063 was significantly overexpressed in BC tissues. The downregulation of circ_0058063 impaired BC cell proliferation and migration ability but improved cell apoptosis ability. Circ_0058063 repressed miR-145-5p, which inhibited the expression of CDK6. Downregulation of circ_0058063 or miR-145-5p transfection contributed to more cells arresting in G0/G1 stage. MiR-145-5p suppressed cell growth and migration ability in BC, whereas CDK6 exerted the opposite influence on these cellular events. In vivo experiment also indicated that tumor development in BALB/c nude mice was repressed remarkably when circ_0058063 was downregulated. CONCLUSION: Circ_0058063 acted as a sponge of miR-145-5p to promote BC progression by regulating CDK6 expression, which provided some potential targets for BC treatment.

Long non-coding RNAs in renal cell carcinoma: A systematic review and clinical implications.

Renal cell carcinoma is one of the most common malignancy in adults, its prognosis is poor in an advanced stage and early detection is difficult due to the lack of molecular biomarkers. The identification of novel biomarkers for RCC is an urgent and meaningful project. Long non-coding RNA (lncRNA) is transcribed from genomic regions with a minimum length of 200 bases and limited protein-coding potential. Recently, lncRNAs have been greatly studied in a variety of cancer types. They participate in a wide variety of biological processes including cancer biology. In this review, we provide a new insight of the profiling of lncRNAs in RCC and their roles in renal carcinogenesis, with an emphasize on their potential in diagnosis, prognosis and potential roles in RCC therapy.

MicroRNAs in renal cell carcinoma: a systematic review of clinical implications (Review).

Despite recent advances in the understanding of the biology of renal cell carcinoma (RCC), successful surgical treatment and implementation of novel­targeted therapies, the prognosis for RCC patients remains poor. Late presentation, tumor heterogeneity and in particular the lack of molecular biomarkers for early detection, classification and the surveillance of RCC treatments are major obstacles. The increasing knowledge regarding the functional role of microRNAs (miRNAs) in pathophysiological processes may provide an important link to the identification of suitable therapeutic targets and diagnostic/prognostic biomarkers for RCC. The aim of this review was to provide new insight into the function of miRNAs in the pathogenesis of RCC and to emphasize their potential as diagnostic and prognostic markers, as well as therapeutic targets.

Aberrant DNA methyltransferase 1 expression in clear cell renal cell carcinoma development and progression.

OBJECTIVE: To better understand the contribution of dysregulated DNA methyltransferase 1 (DNMT1) expression to the progression and biology of clear cell renal cell carcinoma (ccRCC). METHODS: We examined the differences in the expression of DNMT1 in 89 ccRCC and 22 normal tissue samples by immunohistochemistry. In addition, changes in cell viability, apoptosis, colony formation and invading ability of ccRCC cell lines (786-0 and Caki-1) were assessed after transfection with DNMT1 siRNA. RESULTS: We found DNMT1 protein was significantly higher expressed in ccRCC than that of in no-tumor tissues (56.2% and 27.3%, respectively, P=0.018). The expression of DNMT1 was strongly associated with ccRCC tumor size, tumor pathology stage, histological grading, lymph node metastasis, vascular invasion, recurrence and prognosis. Moreover, knockdown of DNMT1 expression significantly inhibited ccRCC cell viability, induced apoptosis, decreased colony formation and invading ability. CONCLUSIONS: Expression of DNMT1 protein is increased in ccRCC tissues, and DNMT1 expression is associated with poor prognosis of patients. Experiments in vitro further showed DNMT1 played an essential role in proliferation and invasion of renal cancer cells. Moreover, targeting this enzyme could be a promising strategy for treating ccRCC, as evidenced by inhibited cell viability, increased apoptosis, decreased colony formation and invading ability.

Expression profiling and clinicopathological significance of DNA methyltransferase 1, 3A and 3B in sporadic human renal cell carcinoma.

PURPOSE: This study aimed to evaluate the expression of DNA methyltransferase (DNMT) family proteins in renal cell carcinoma (RCC) and to assess the clinical significance and prognostic value of their expression patterns. METHODS: A total of 97 renal cell carcinoma and 52 no-tumor tissues were recruited for immunohistochemical analysis of their expression. RESULTS: DNMT1, DNMT3A and DNMT3B proteins were highly expressed in clear cell RCC, papillary RCC and chromophobe RCC tissues than that of no-tumor tissues (all P < 0.05). DNMT1, DNMT3A and DNMT3B expression was significantly associated with tumor size (P=0.003, 0.001 and 0.003, respectively), tumor pathology stage (P=0.039, 0.034 and 0.037, respectively), histopathological grading (P=0.042, 0.026 and 0.031, respectively), lymph node metastasis (P=0.022, 0.030 and 0.020, respectively) and vascular invasion (P=0.042, 0.031 and 0.044, respectively). The Kaplan-Meier survival analysis demonstrated that expression of DNMTs protein in RCC was significantly associated with shorter over all survival and disease-free survival (all P < 0.05). Furthermore, multivariate analysis showed that the expression of DNMT1 was an independent prognostic factor for overall survival (OS) (P=0.036), and the expression of DNMT3A or DNMT3B was an independent prognostic factor for disease-free survival (DFS) in the patients (P=0.031 and P=0.023, respectively). CONCLUSIONS: DNMTs were higher expressed in RCC than no-tumor tissues, and the expression of DNMTs were strongly associated with RCC tumor size, tumor pathology stage, histological grading, lymph node metastasis, vascular invasion, recurrence, and prognosis. DNMTs may thus serve as prognostic markers and novel therapeutic targets for RCC patients.

Methylation and aberrant expression of the Wnt antagonist secreted Frizzled-related protein 1 in bladder cancer.

The aims of this study were to determine the methylation and expression status of secreted Frizzled-related protein 1 (SFRP1) in bladder cancer, to explore the mechanisms involved and to study the role of SFRP1 in the pathogenesis of bladder cancer. SFRP1 mRNA was detected by reverse transcription PCR (RT-PCR). The DNA methylation status was determined by methylation-specific PCR and protein was detected using western blotting. The results of the present study demonstrated that SFRP1 was methylated in the bladder cancer cell lines T24 and 5637, but not in SCaBER cells. After treating T24 and 5637 cells with a demethylating agent, the cells expressed SFRP1 mRNA and protein. Among the 45 patients with bladder cancer, methylation of SFRP1 was detected in 28 patients (62.2%). Of the matched cancer-adjacent tissues, 6 (13.3%) were found to have methylated SFRP1. The result is statistically significant (P<0.01). In conclusion, SFRP1 is downregulated in certain bladder cancer patients as a consequence of methylation. SFRP1 methylation may be involved in the pathogenesis of bladder cancer via excessive activation of the Wnt signaling pathway.