Trans-retro-peritoneal laparoscopic partial nephrectomy for posterior hilar tumor: technical feasibility and preliminary results.

Background: Urologists still encounter challenges when it comes to the surgical management of tumors located on the posterior lip and posterior renal hilar region. We propose a trans-retro-peritoneal (TRP) technique to address the difficulties associated with posterior hilar tumors during retroperitoneal laparoscopic partial nephrectomy (LPN). Its efficacy was evaluated in a retrospective case-control study. Methods: The patients with posterior hilar tumors (≤7 cm) that underwent retroperitoneal LPN were included. The TRP technique allowed the posterior hilar tumor completely visible by incising the ventral peritoneum and rotating kidney ventrally during retroperitoneal LPN, which was applied in 36 cases, while the conventional retroperitoneal LPN was performed in 22 cases. Perioperative data were analyzed to evaluate the efficacy of TRP-LPN. Results: In TRP-LPN group, the TRP technique was successfully performed in all the patients without converting to open surgery or radical nephrectomy. The warm ischemia time was significantly shorter in TRP-LPN group than conventional LPN group (20.3 vs. 28.5 min, P<0.001). Furthermore, the mean estimated blood loss in TRR-LPN group was significantly less than that in conventional LPN group (86.5 vs. 90.9 mL, P<0.05). The mean operation time and recovery time of gastrointestinal function were similar between two groups. No severe complications occurred, and no positive surgical margin was found. The rate of Trifecta achievement was 50.0% (18/36) and 31.8% (7/22) respectively for TRP-LPN and conventional LPN (P=0.175). After mean follow-up of 21 months, no recurrence or metastasis occurred in all cases. Conclusions: Our findings, as demonstrated by the Trifecta outcomes, support the feasibility and efficacy of TRP-LPN in managing posterior renal hilar tumors. This approach may be considered as an efficient option for surgical management of such tumors.

Intravesical Therapy for Upper Urinary Tract Urothelial Carcinoma: A Comprehensive Review.

Upper tract urothelial carcinoma (UTUC) poses unique challenges in diagnosis and treatment. This comprehensive review focuses on prophylactic intravesical therapy for UTUC, summarizing key aspects of intravesical therapy in various clinical scenarios, including concurrent with or following radical nephroureterectomy, kidney-sparing surgery, ureteroscopy-guided biopsy. The incidence of intravesical recurrence in UTUC after surgical treatment is significant, necessitating effective preventive measures. Intravesical therapy plays a vital role in reducing the risk of bladder recurrence following UTUC surgery. Tailoring timing, drug selection, dosage, and frequency is vital in optimizing treatment outcomes and reducing intravesical recurrence risk in UTUC. This review provides a comprehensive summary of the history, clinical trials, guideline recommendations, and clinical applications of intravesical therapy for UTUC. It also discusses the future directions based on current clinical needs and ongoing trials. Future directions entail optimizing dosage, treatment duration, and drug selection, as well as exploring novel agents and combination therapies. Intravesical therapy holds tremendous potential in improving outcomes for UTUC patients and reducing the risk of bladder recurrence. Although advancements have been made in UTUC treatment research, further refinements are necessary to enhance efficacy and safety.

Integrative transcriptome and proteome analyses of clear cell renal cell carcinoma develop a prognostic classifier associated with thrombus.

Clear cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) is associated with poor prognosis. Our integrative analyses of transcriptome and proteome reveal distinctive molecular features of ccRCC with VTT, and yield the development of a prognostic classifier to facilitate ccRCC molecular subtyping and treatment. The RNA sequencing and mass spectrometry were performed in normal-tumor-thrombus tissue triples of five ccRCC patients. Statistical analysis, GO and KEGG enrichment analysis, and protein-protein interaction network construction were used to interpret the transcriptomic and proteomic data. A six-gene-based classifier was developed to predict patients' survival using Cox regression, which was validated in an independent cohort. Transcriptomic analysis identified 1131 tumorigenesis-associated differentially expressed genes (DEGs) and 856 invasion-associated DEGs. Overexpression of transcription factor EGR2 in VTT indicated its important role in tumor invasion. Furthermore, proteomic analysis showed 597 tumorigenesis-associated differentially expressed proteins (DEPs) and 452 invasion-associated DEPs. The invasion-associated DEPs showed unique enrichment in DNA replication, lysine degradation, and PPAR signaling pathway. Integration of transcriptome and proteome reveals 142 tumorigenesis-associated proteins and 84 invasion-associated proteins displaying changes consistent with corresponding genes in transcriptomic profiling. Based on their different expression patterns among normal-tumor-thrombus triples, RAB25 and GGT5 were supposed to play a consistent role in both tumorigenesis and invasion processes, while SHMT2 and CADM4 might play the opposite roles in tumorigenesis and thrombus invasion. A prognostic classifier consisting of six DEGs (DEPTOR, DPEP1, NAT8, PLOD2, SLC7A5, SUSD2) performed satisfactorily in predicting survival of ccRCC patients (HR = 4.41, P < 0.001), which was further validated in an independent cohort of 40 cases (HR = 5.52, P = 0.026). Our study revealed the transcriptomic and proteomic profiles of ccRCC patients with VTT, and identified the distinctive molecular features associated with VTT. The six-gene-based prognostic classifier developed by integrative analyses may facilitate ccRCC molecular subtyping and treatment.

Adjuvant radiotherapy in patients with node-positive prostate cancer after radical prostatectomy.

PURPOSE: Our study was to determine whether immediate androgen deprivation therapy (ADT) plus radiotherapy (RT) extends survival in men with node-positive prostate cancer (PCa) after radical prostatectomy (RP) compared with those who received ADT alone. METHODS: A total of 99 consecutive patients with pathological positive lymph nodes (pN1) PCa were included in this study to receive immediate ADT plus RT (n = 70) or to receive immediate ADT alone (n = 29). The primary endpoint was castration-resistant prostate cancer (CRPC) free survival; the secondary endpoints were distant metastasis-free survival. Cox regression was used to assess the independent risk factors for CRPC. RESULTS: The median follow-up time was 34.0 (24.8, 47.8) months and 34.25 (23.0, 49.0) months, respectively, in the ADT + RT group and ADT-alone group. The 5-year CRPC-free survival rate was 79.5% and 58.3%, respectively, in the ADT + RT group and ADT-alone group (p = 0.308). The 5-year distant metastasis-free survival rate was 71.4% and 38.8, respectively, in the ADT + RT group and ADT-alone group (p = 0.478). Compared with ADT-alone group, we saw a modest, but no significant improvement in CRPC-free survival and distant metastasis-free survival in ADT + RT group. The results of Cox regression showed that positive lymph nodes ≥ 4 was an independent risk factor for CRPC (p = 0.041). CONCLUSIONS: We found that immediate ADT plus RT compared to ADT alone did not improve CRPC-free and metastasis-free survival. Multivariate Cox regression analyses also indicated that patients with positive lymph nodes < 4 may benefits from ADT plus RT.

Clinicopathological and immunological profiles of prostate adenocarcinoma and neuroendocrine prostate cancer.

BACKGROUND: Biomarkers of DNA damage repair deficiency provide opportunities for personalized treatment with immunotherapy. However, there is limited research on the immune microenvironment of adeno-neuroendocrine prostate cancer (NEPC). In this study, we aimed to assess and describe the comprehensive clinicopathological manifestations of NEPC to improve diagnosis and predict prognosis. METHODS: A retrospective medical record review of 66 patients with prostate cancer (PCa) was performed. PCa samples from the 66 patients were analyzed using immunohistochemical staining for the detection of chromogranin, neural cell adhesion molecule 1, and synaptophysin. For tumor-associated immune microenvironment analysis, PD-L1, CD3, and CD8 were labeled in tissue slides. The effect of clinicopathological factors on the survival of patients with Adeno-NEPC was analyzed. RESULTS: Twenty patients presented with adeno-NEPC, whereas 46 presented with adeno-PCa. The median age of patients at PCa diagnosis was 67.86 ± 7.05 years (68.65 ± 7.23 years, adeno-NEPC; 67.52 ± 7.02 years, adeno-PCa). Eleven patients with adeno-NEPC underwent prostatectomy, whereas nine received primary androgen deprivation therapy (ADT). Additionally, 30 patients with adeno-PCa underwent prostatectomy, whereas 16 (34.8%) received primary ADT. There was a significant difference in overall survival between patients with adeno-NEPC and those with adeno-PCa (46.0 months vs. 65.0 months). There was also a significant difference in time from prostatectomy to biochemical recurrence between the groups of patients who underwent prostatectomy. Prostatectomy and normal lactate dehydrogenase levels were clinical factors that were significantly associated with better outcomes in patients with adeno-NEPC. Metastatic adeno-NEPC was associated with a higher programmed death ligand 1 (PD-L1) score (2-4) than localized PCa. The data showed that PD-L1 expression in adeno-NEPC may be negatively associated with that in CD8+ T cells. CONCLUSIONS: Our study revealed clinicopathological manifestations of adeno-NEPC and some possible predictive factors significantly associated with better outcomes in patients with adeno-NEPC. These findings might be beneficial in the development of diagnostic strategies and customized treatment plans.

Single-cell transcriptional regulation and genetic evolution of neuroendocrine prostate cancer.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer, with a 10% five-year survival rate. However, little is known about its origin and the mechanisms governing its emergence. Our study characterized ADPC and NEPC in prostate tumors from 7 patients using scRNA-seq. First, we identified two NEPC gene expression signatures representing different phases of trans-differentiation. New marker genes we identified may be used for clinical diagnosis. Second, integrative analyses combining expression and subclonal architecture revealed different paths by which NEPC diverges from the original ADPC, either directly from treatment-naïve tumor cells or from specific intermediate states of treatment-resistance. Third, we inferred a hierarchical transcription factor (TF) network underlying the progression, which involves constitutive regulation by ASCL1, FOXA2, and selective regulation by NKX2-2, POU3F2, and SOX2. Together, these results defined the complex expression profiles and advanced our understanding of the genetic and transcriptomic mechanisms leading to NEPC differentiation.

Intratumor heterogeneity and clonal evolution revealed in castration-resistant prostate cancer by longitudinal genomic analysis.

Intratumor heterogeneity is a key driver for local relapse and treatment failure. Thus, using multifocal prostate cancer as a model to investigate tumor inter-clonal relationships and tumor evolution could aid in our understanding of drug resistance. Previous studies discovered genomic alterations by comparing hormone-sensitive prostate cancer (HSPC) with castration-resistant prostate cancer (CRPC) in large cohorts. However, most studies did not sequentially sample tumors from the same patient. In our study, we performed whole-exome sequencing (WES) on 14 specimens from five locally relapsed patients before and after androgen-deprivation therapy. We described the landscape of genomic alterations before and after treatment and identified critical driver events that could have contributed to the evolution of CRPC. In addition to confirming known cancer genes such as TP53 and CDK12, we also identified new candidate genes that may play a role in the progression of prostate cancer, including MYO15A, CHD6 and LZTR1. At copy number alteration (CNA) level, gain of 8q24.13-8q24.3 was observed in 60% of patients and was the most commonly altered locus in both HSPC and CRPC tumors. Finally, utilizing phylogenetic reconstruction, we explored the clonal progression pattern from HSPC to CRPC in each patient. Our findings highlight the complex and heterogeneous mechanisms underlying the development of drug resistance, and underscore the potential value of monitoring tumor clonal architectures during disease progression in a clinical setting.

A morphology-based nephrometry score to predict pathological upstaging to T3 renal cell carcinoma.

Background: Patients with clinical T1-2 renal cell carcinoma (RCC) upstaging to pathological T3 showed worse survival prognosis than those without upstaging. We aimed to develop and validate a morphology-based nephrometry scoring system for predicting pathological upstaging to T3 of RCC. Methods: We retrospectively reviewed 200 patients with clinical T1-2 RCC who underwent surgical treatment. The nephrometry scores were measured through preoperative computed tomography images. The risk factors of pathological upstaging were identified by logistic regression models. The predictive accuracy of a novel morphology-based nephrometry scoring system (M-Index), was compared with R.E.N.A.L (radius, exophytic/endophytic, nearness, anterior/posterior, location), PADUA (preoperative aspects and dimensions used for an anatomic classification), DAP (diameter, axial, polar) and C-Index scores. Results: The upstaging rate of the population was 17% (34 out of 200 patients). The upstaging and non-upstaging groups were comparable in terms of age, gender ratio, body mass index, tumor laterality, and pathological type, while the upstaging group tended to have large tumor diameter, irregular tumor morphology, inner tumor location, and short polar and axial distance. Large tumor diameter refers to larger than 5 cm, while irregular tumor morphology refers to not regular shapes such as round, oval, or lobular. Univariate and multivariate logistic regression analyses showed that tumor morphology [odds ratio (OR) 3.26, 95% confidence interval (CI): 1.79-5.97] and tumor rim location (OR 2.95, 95% CI: 1.16-7.46) were independent risk factors for pathological upstaging. The receiver operating characteristic curve and decision curve analysis (DCA) demonstrated the novel M-Index based on tumor morphology and rim location outperformed R.E.N.A.L, PADUA, DAP, and C-Index in the prediction of pathological upstaging (area under curve 0.756 vs. 0.728 vs. 0.641 vs. 0.661 vs. 0.743). Conclusions: Consisting of fewer non-complex parameters, the M-Index is an intuitive and practical tool with satisfactory predictive power for pathological upstaging to T3 in RCC patients undergoing surgery.

Identification of Long Noncoding RNA APOC1P1 as an Oncogene in Clear Cell Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is one of the most common genitourinary cancers worldwide. Previous evidence shows that long noncoding RNA (LncRNA) APOC1P1 plays an important role in cancer development. However, the role of LncRNA APOC1P1 in ccRCC remains to be explored. LncRNA APOC1P1 expression in 283 ccRCC tissues and 30 normal kidney tissues was detected by quantitative real-time PCR, and its prognostic association with ccRCC was assessed by the Kaplan-Meier method and Cox proportional hazard model. Cell proliferation, apoptosis, migration, and invasion were determined in RCC cells with downregulation of LncRNA APOC1P1 expression. LncRNA APOC1P1 expression was increased in ccRCC tissues compared with normal kidney tissues (P < 0.001). Its expression was higher in the Fuhrman grade III and IV group than in the Fuhrman grade I and II group (P < 0.05) and significantly upregulated in the advanced stage group (P < 0.05). Kaplan-Meier analyses revealed that elevated LncRNA APOC1P1 expression was significantly associated with poor overall survival (P < 0.05) but may not be an independent prognostic factor. Knockdown of LncRNA APOC1P1 inhibited cell proliferation, induced apoptosis, and arrested cells at the G1/S phase (P < 0.05). Silencing of LncRNA APOC1P1 also led to decreased cell migration and invasion (P < 0.05). LncRNA APOC1P1 acts as an oncogene, plays an important role in ccRCC development, and can be considered a prognostic biomarker and therapeutic target in ccRCC patients.

Profiling and bioinformatics analyses of differential circular RNA expression in prostate cancer cells.

AIM: There is little knowledge about the expression profile and function of circular RNAs (circRNAs) in prostate cancer (PCa). METHODS: The expression profiles of circRNAs in RWPE-1, 22RV1 and PC3 cells were explored via high-throughput circRNAs sequencing and validated by real-time qPCR. The roles of differentially expressed circRNAs were evaluated by bioinformatics analyses. RESULTS: Altogether 9545 circRNAs were identified and hundreds of differentially expressed circRNAs were recognized. CircRNA-miRNA networks analysis showed that many circRNAs, including circSLC7A6, circGUCY1A2 and circZFP57 could cross-talk with tumor-related miRNAs such as miR-21, miR-143 and miR-200 family. CONCLUSION: The results of our bioinformatics analyses suggested that circRNAs should play critical roles in the development and progression of PCa.

The study of energy metabolism in bladder cancer cells in co-culture conditions using a microfluidic chip.

OBJECTIVES: This study aimed to systematically analyze changes in mitochondrial-related protein expression in bladder cancer cells and tumor-associated fibroblasts and to investigate the characteristics of bladder cancer cell energy metabolism. METHODS: In this study, we utilized the following techniques to achieve the objectives: (1) a co-culture system of bladder tumor cells and fibroblasts was built using a microfluidic chip as a three-dimensional culture system; (2) the concentration of lactic acid in the medium from the different groups was determined using an automatic micro-plate reader; (3) a qualitative analysis of mitochondria-related protein expression was performed by immunofluorescent staining; and (4) a quantitative analysis of mitochondrial-associated protein expression was conducted via Western blot. SPSS software was utilized to analyze the data. RESULTS: (1) Determination of lactic acid concentration: The lactic acid concentration was determined to be highest in the experimental group, followed by the T24 cell control group and then the fibroblast control group. (2) Qualitative results: In the control group, the mitochondrial-related protein fluorescence intensity was higher in the fibroblasts compared with the cancer cells, and the fluorescence intensity of the fibroblasts was reduced compared with the experimental group. The mitochondrial-related protein fluorescence intensity of the cancer cells was higher in the experimental group compared with the control group, and the opposite results were obtained with the fibroblasts. (3) Quantitative results: The expression of mitochondria-related proteins was higher in fibroblasts compared with cancer cells in the control group, and the opposite results were obtained in the experimental group (P<0.05). The expression of mitochondria-related proteins was increased in cancer cells in the experimental group compared with the control group; the opposite results were observed for the fibroblasts (P<0.05). CONCLUSIONS: The energy metabolism of bladder tumor cells does not parallel the "Warburg effect" because even under sufficient oxygen conditions, cancer cells still undergo glycolysis. Bladder cancer cells also have an efficient oxidative phosphorylation process wherein cancer cells promote glycolysis in adjacent interstitial cells, thereby causing increased formation of nutritional precursors. These high-energy metabolites are transferred to adjacent tumor cells in a specified direction and enter the Krebs Cycle. Ultimately, oxidative phosphorylation increases, and sufficient ATP is produced.

A bladder cancer microenvironment simulation system based on a microfluidic co-culture model.

A tumor microenvironment may promote tumor metastasis and progression through the dynamic interplay between neoplastic cells and stromal cells. In this work, the most representative and significant stromal cells, fibroblasts, endothelial cells, and macrophages were used as vital component elements and combined with bladder cancer cells to construct a bladder cancer microenvironment simulation system. This is the first report to explore bladder cancer microenvironments based on 4 types of cells co-cultured simultaneously. This simulation system comprises perfusion equipment, matrigel channel units, a medium channel and four indirect contact culture chambers, allowing four types of cells to simultaneously interact through soluble biological factors and metabolites. With this system, bladder cancer cells (T24) with a tendency to form a 'reticular' structure under 3 dimensional culture conditions were observed in real time. The microenvironment characteristics of paracrine interactions and cell motility were successfully simulated in this system. The phenotype change process in stromal cells was successfully reproduced in this system by testing the macrophage effector molecule Arg-1. Arg-1 was highly expressed in the simulated tumor microenvironment group. To develop "precision medicine" in bladder cancer therapy, bladder cancer cells were treated with different clinical 'neo-adjuvant' chemotherapy schemes in this system, and their sensitivity differences were fully reflected. This work provides a preliminary foundation for neo-adjuvant chemotherapy in bladder cancer, a theoretical foundation for tumor microenvironment simulation and promotes individual therapy in bladder cancer patients.

Overexpression of monocarboxylate anion transporter 1 and 4 in T24-induced cancer-associated fibroblasts regulates the progression of bladder cancer cells in a 3D microfluidic device.

Stromal fibroblasts are essential for tumor proliferation and invasion. Here we presented a 3-dimensional (3D) microfluidic co-culture device to reconstruct an in vivo-like tumor microenvironment for investigation of the interactions of cancer-associated fibroblasts (CAFs) and bladder cancer cells. With this device, we verified that the cytokines secreted by bladder cancer cells T24 effectively transform the fibroblasts into CAFs. Compared to fibroblasts, the CAFs, which undergo the aerobic glycolysis, showed higher ability to produce lactate and provide energy for bladder cancer cell proliferation and invasion. We also demonstrated that this kind of tumor-promoting effect was associated with the upregulation of monocarboxylate anion transporter 1 (MCT1) and MCT4 expression in CAFs. We concluded that MCT1 and MCT4 are involved in bladder cancer cell proliferation and invasiveness. Moreover, this 3D microfluidic co-culture device allows for the assay to characterize various cellular events in a single device sequentially, facilitating a better understanding of the interactions among heterotypic cells in a sophisticated microenvironment.

Perioperative Blood Transfusion Promotes Worse Outcomes of Bladder Cancer after Radical Cystectomy: A Systematic Review and Meta-Analysis.

BACKGROUND: Multiple studies have investigated the effect of perioperative blood transfusion (PBT) for patients with radical cystectomy (RC), but the results have been inconsistent. We conducted a systematic review and meta-analysis to investigate the relationship between PBT and the clinical outcomes of RC patients. METHODS: We searched MEDLINE, EMBASE, the Cochrane library and BIOSIS previews to identify relevant literature for studies that focused on the relationship of PBT and outcomes of patients undergoing RC. A fixed or random effects model was used in this meta-analysis to calculate the pooled hazard ratio (HR) with 95% confidence intervals (CIs). RESULTS: A total of 7080 patients in 6 studies matched the selection criteria. Aggregation of the data suggested that PBT in patients who underwent RC correlated with increased all-cause mortality, cancer-specific mortality and cancer recurrence. The combined HRs were 1.19 (n = 6 studies, 95% CI: 1.11-1.27, Z = 4.71, P<0.00001), 1.17 (n = 4 studies, 95% CI: 1.06-1.30, Z = 3.06, P = 0.002), 1.14 (n = 3 studies, 95% CI: 1.03-1.27, Z = 2.50, P = 0.01), respectively. The all-cause mortality associated with PBT did not vary by the characteristics of the study, including number of study participants, follow-up period and the median blood transfusion ratio of the study. CONCLUSION: Our data showed that PBT significantly increased the risks of all-cause mortality, cancer-specific mortality and cancer recurrence in patients undergoing RC for bladder cancer.

The status, limitation and improvement of adoptive cellular immunotherapy in advanced urologic malignancies.

In recent years, immunotherapy has been gradually established as the fourth frequently adopted antitumor therapy, following surgery, chemotherapy and radiotherapy, for advanced urologic malignancies with an improved understanding of theoretical basis, such as molecular biology and immunology. Thereinto, adoptive cellular immunotherapy (ACI) has become one of the hotspots, which comprises a variety of treatment approaches, such as TIL, CIK cell, γδ T cell, CAR-engineered T cell and Allogeneic stem cell transplantation (alloSCT). Although preclinical efficacy has been demonstrated remarkably, clinical trials could not consistently show the benefit due to multi-factors in complex immunosuppressive microenvironment in vivo compared to that of in vitro. Here we review some timely aspects of ACI for advanced urologic malignancies, and describe the current status and limitation of immunotherapy from the cellular level. It's our expectation to provide prompting consideration of novel combinatorial ACI strategies and a resurgence of interest in ACI for advanced urologic malignancies.