Variant histology is associated with more non-urothelial tract recurrence but less intravesical recurrence for upper tract urothelial carcinoma after radical nephroureterectomy.

PURPOSE: To investigate the prognostic impact of variant histology (VH) on oncological outcomes in patients with upper urinary tract urothelial carcinoma (UTUC) who had undergone radical nephroureterectomy (RNU). PATIENTS AND METHODS: A total of 1239 patients with clinically localized UTUC who underwent RNU at a single institution between January 2005 and June 2020 were included. The VH was reviewed by a uro-pathologist at our institution. The Cox regression model was used to perform multivariate analysis, including VH and other established prognostic factors for post-RNU oncological outcomes (intravesical recurrence [IVR], non-urothelial recurrence, and cancer-specific death). RESULTS: Of the 1239 patients with UTUC, 384 patients (31%) were found to have VH. Advanced tumor stage, lymph node metastasis, high tumor grade, lymphovascular invasion, open surgery, and renal pelvis had a significantly larger proportion of UTUC with VH compared to pure UTUC (all p < 0.05). VH was an independent prognostic factor associated with less IVR identified by multivariate analysis, more non-urothelial recurrence, and more cancer-specific mortality. CONCLUSION: Patients with VH account for 31% with UTUC treated with RNU in this cohort. VH was an independent prognostic factor associated with more non-urothelial recurrence and cancer-specific mortality but less IVR.

MicroRNA-145-5p suppresses cell proliferation, migration, and invasion in upper tract urothelial carcinoma by targeting 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase.

Upper tract urothelial carcinoma (UTUC), including renal, pelvic, and ureteral carcinoma, has a high incidence rate in Taiwan, which is different from that in Western countries. Therefore, it is imperative to elucidate the mechanisms underlying UTUC growth and metastasis. To explore the function of miR-145-5p in UTUC, we transfected the BFTC909 cell line with miR-145-5p mimics and analyzed the differences in protein levels by performing two-dimensional polyacrylamide gel electrophoresis. Real-time polymerase chain reaction and Western blot analysis were used to analyze 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inositol monophosphate cyclohydrolase (ATIC) messenger RNA and protein levels. A dual-luciferase assay was performed to identify the target of miR-145-5p in ATIC. The effects of miR-145-5p and ATIC expression by cell transfection on cell proliferation, migration, and invasion were also assessed. miR-145-5p downregulated ATIC protein expression. High ATIC expression is associated with tumor stage, metastasis, recurrence, and a poor prognosis in patients with UTUC. Cell function assays revealed that ATIC knockdown inhibited the proliferation, migration, and invasive abilities of UTUC cells. In contrast, miR-145-5p affected the proliferation, migration, and invasive abilities of UTUC cells by directly targeting the 3'-untranslated regions of ATIC. Furthermore, we used RNA sequencing and Ingenuity Pathway Analysis to identify possible downstream genes regulated by ATIC and found that miR-145-5p regulated the protein levels of fibronectin 1, Slug, cyclin A2, cyclin B1, P57, and interferon-induced transmembrane 1 via ATIC. ATIC may be a valuable predictor of prognosis and a potential therapeutic target for UTUC.

The prognostic significance of histologic variant on survival outcomes in patients with metastatic urothelial carcinoma receiving immune checkpoint inhibitor therapy.

BACKGROUND: While the treatment guidelines have been established for pure urothelial carcinoma (pUC), patients with variant type urothelial carcinoma (vUC) face limited effective treatment options. The effectiveness of immune checkpoint inhibitors (ICI) in patients with vUC remains uncertain and necessitates additional research. METHOD: We conducted a retrospective, multicenter study to explore the effectiveness of ICI in patients with pUC or vUC in Taiwan. We evaluated the overall response rate (ORR) through univariate logistic regression analysis and examined the overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier analysis. Additionally, we employed univariate and multivariate Cox proportional hazards models to analyze the data. RESULT: A total of 142 patients (116 pUC, 26 vUC) were included in our final analysis. The ORR was marginally higher in patients with pUC compared to those with vUC (34.5% vs. 23.1%, p = 0.26). Among all patients, 12.9% with pUC achieved a complete response (CR) after ICI treatment, while no vUC cases achieved CR (p = 0.05). There were no significant differences in PFS (median 3.6 months vs. 4.1 months, p = 0.34) or OS (median 16.3 months vs. 11.0 months, p = 0.24) when comparing patients with pUC or vUC. In the subgroup analysis, patients with pUC who underwent first-line ICI treatment exhibited significantly improved OS compared to those with vUC (24.6 months vs. 9.1 months, p = 0.004). CONCLUSION: The use of ICI as monotherapy is a feasible and effective treatment approach for patients with metastatic vUC.

Prevalence and oncologic impact of chronic kidney disease for upper tract urothelial carcinoma in endemic area.

OBJECTIVE: This study aimed to assess the impact of preoperative chronic kidney disease (CKD) on the oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who underwent standard radical nephroureterectomy (RNU). METHODS: A total of 1172 UTUC patients who received RNU at a single center in Taiwan between February 2005 and August 2019 were included. The patients were categorized into two groups based on their preoperative CKD stage: CKD stage ≤3 (811 patients) and CKD stage >3 (361 patients). The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula. The study investigated the oncological outcomes, including intravesical recurrence, non-urothelial recurrence, and cancer-specific mortality, stratified by preoperative CKD status. RESULTS: The main findings indicated that UTUC patients with CKD stage >3 in Taiwan exhibited a higher proportion of females (p < 0.001), a greater history of concurrent bladder cancer (p = 0.003), more multifocal tumor behavior (p < 0.001), a higher incidence of carcinoma in situ (p = 0.008), increased rates of intravesical recurrence (p < 0.001), a lower prevalence of smoking history (p = 0.003), lower utilization of adjuvant chemotherapy (p < 0.001), reduced occurrence of non-urothelial recurrence (p < 0.001), and lower cancer-specific mortality (p = 0.006) compared to patients with CKD stage ≤3. Multivariate Cox regression analysis revealed significant differences in intravesical recurrence (p = 0.014) and non-urothelial recurrence (p = 0.006) between the CKD stage >3 and CKD stage ≤3 groups. The study also demonstrated that patients with concurrent bladder cancer and variant histology had higher rates of intravesical recurrence, non-urothelial recurrence, and cancer-specific mortality. The CKD stage >3 group exhibited lower rates of intravesical recurrence (p = 0.0014), higher rates of non-urothelial recurrence (p < 0.0001), and increased cancer-specific mortality (p = 0.0091) compared to the CKD stage ≤3 group in the 5-year free survival analysis. CONCLUSION: In Taiwan, UTUC patients with CKD stage >3 exhibit distinct characteristics compared to the general population with urothelial carcinoma. They are associated with a non-smoking status, a higher proportion of females, and less aggressive pathological features. Additionally, CKD stage >3 can serve as a clinical indicator for intravesical and non-urothelial recurrence. Further investigation into molecular aspects and treatment modifications for these patients is warranted.

VCAN Hypomethylation and Expression as Predictive Biomarkers of Drug Sensitivity in Upper Urinary Tract Urothelial Carcinoma.

Versican (VCAN), also known as extracellular matrix proteoglycan 2, has been suggested as a potential biomarker in cancers. Previous research has found that VCAN is highly expressed in bladder cancer. However, its role in predicting outcomes for patients with upper urinary tract urothelial cancer (UTUC) is not well understood. In this study, we collected tissues from 10 patients with UTUC, including 6 with and 4 without lymphovascular invasion (LVI), a pathological feature that plays a significant role in determining metastasis. Results from RNA sequencing revealed that the most differentially expressed genes were involved in extracellular matrix organization. Using the TCGA database for clinical correlation, VCAN was identified as a target for study. A chromosome methylation assay showed that VCAN was hypomethylated in tumors with LVI. In our patient samples, VCAN expression was also found to be high in UTUC tumors with LVI. In vitro analysis showed that knocking down VCAN inhibited cell migration but not proliferation. A heatmap analysis also confirmed a significant correlation between VCAN and migration genes. Additionally, silencing VCAN increased the effectiveness of cisplatin, gemcitabine and epirubicin, thus providing potential opportunities for clinical application.

DNA Hypomethylation Is Associated with the Overexpression of INHBA in Upper Tract Urothelial Carcinoma.

Urothelial carcinoma includes upper urinary tract cancer (UTUC) and bladder cancer. Although nephroureterectomy is the standard treatment for UTUC, the recurrence rate is approximately half and the tumor is associated with poor prognoses. Metastases are the most devastating and lethal clinical situation in urothelial carcinoma. Despite its clinical importance, few potential diagnostic biomarkers are suitable for early UC detection. We compared high-stage/high-grade urothelial carcinoma tissues to adjacent normal urothelial tissues using methyl-CpG binding domain protein capture for genome-wide DNA methylation analysis. Based on our findings, inhibin ßA (INHBA) might be associated with carcinogenesis and metastasis. Further, clinical UC specimens had significant INHBA hypomethylation based on pyrosequencing. INHBA was detected by real-time PCR and immunohistochemistry staining, and was found to be highly expressed in clinical tissues and cell lines of urothelial carcinoma. Further, INHBA depletion was found to significantly reduce BFTC-909 cell growth and migration by INHBA-specific small interfering RNA. Interestingly, a positive correlation was found between SMAD binding and extracellular structure organization with INHBA using gene set enrichment analysis and gene ontology analysis. Together, these results are the first evidence of INHBA promoter hypomethylation and INHBA overexpression in UTUC. INHBA may affect urothelial carcinoma migration by reorganizing the extracellular matrix through the SMAD pathway.

Prognostic value of PD-L1 combined positive score in patients with upper tract urothelial carcinoma.

PURPOSE: Upper tract urothelial carcinoma (UTUC) is relatively rare in Western countries. The impact of programmed death-ligand 1 (PD-L1) expression on UTUC remains unclear because previous studies have focused on bladder UC. We investigated the association of PD-L1 expression with clinicopathological features and prognosis in patients with UTUC. METHODS: We retrospectively reviewed the patients with UTUC that we treated at our institute from 2013 to 2018. In total, 105 patients with UTUC undergoing radical nephroureterectomy were analyzed to evaluate the PD-L1 expression on representative whole-tissue sections using the Combined Positive Score (CPS; Dako 22C3 pharmDx assay). A PD-L1 CPS ≥ 10 was considered positive. RESULTS: Among the 105 UTUC cases, 17.1% exhibited positive PD-L1 expression. A CPS ≥ 10 was significantly associated with higher tumor stage (≥ T2, p = 0.034) and lymph node invasion at diagnosis (p = 0.021). A multivariable analysis indicated that a CPS ≥ 10 was an independent prognostic predictor of shorter cancer-specific survival (hazard ratio [HR] = 4.59, 95% confidence interval [CI] = 1.66 - 12.7, p = 0.003) and overall survival (HR = 2.51, 95% CI = 1.19 - 5.27, p = 0.015). CONCLUSIONS: A PD-L1 CPS ≥ 10 in UTUC was associated with adverse pathological features and independently predicted worse cancer-specific and overall survival.

Confirming whether KLHL23 deficiency potentiates migration in urothelial carcinoma.

Epithelial-mesenchymal transition (EMT) is associated with malignant tumors. In a previous study, we found that KLHL23 is a tumor suppressor gene that inhibits EMT and cancer dissemination. However, the correlation between its expression and cancer progression in urothelial carcinoma (UC) remains unknown. This study showed that the deficiency of KLHL23 in the invasive leading cancer cells is important for improving cell migration in UC. Currently, little is known about the underlying mechanisms of KLHL23-mediated cytoskeleton remodeling in the metastatic leading cells of tumors. Our findings showed that silencing of KLHL23 promotes cell migration in UC by regulating the translocation of focal adhesion proteins. Lack of KLHL23 causes abnormal formation of lamellipodia and increases the EMT phenotype and migration. Wound healing assay revealed that KLHL23 potentiates the actin bundles and intracellular focal adhesion protein formation in the invasive leading cells. Knockdown of KLHL23 abolishes the formation of actin stress fibers and translocalizes vinculin to the perimembrane, which enhances the mobility of cancer cells. To elucidate the mechanism, we found that during migration, KLHL23 appears in the leading cells in large numbers and binds to the actin stress fibers. A large amount of vinculin accumulated at both ends of the KLHL23/actin fibers, indicating an increase in cell anchorage. Thus, KLHL23 might play a critical role in enhancing actin fibers and promoting focal adhesion complex formation in the invasive leading cells. Analysis of the overall survival revealed that low KLHL23 is associated with poor survival in patients with bladder UC, indicating its clinical significance. We hypothesize that KLHL23 is involved in the formation of actin stress fibers and focal adhesion complexes in the invasive leading cells and may be associated with EMT progression and prognosis in UC patients.

Hypomethylated RRBP1 Potentiates Tumor Malignancy and Chemoresistance in Upper Tract Urothelial Carcinoma.

Ribosome-binding protein 1 (RRBP1) is a potential oncogene in several cancer types. However, the correlation between RRBP1 expression and the prognosis of patients with upper tract urothelial carcinoma (UTUC) remains unclear. In this study, we identified that RRBP1 is associated with carcinogenesis and metastasis in UTUC using a methylation profiling microarray. High correlations between RRBP1 and cancer stages, nodal metastasis status, molecular subtypes, and prognosis in bladder urothelial cancer (BLCA) were found. Aberrant DNA methylation in the gene body region of RRBP1 was determined in UTUC tissues by methylation-specific PCR. RRBP1 expression was significantly increased in UTUC tissues and cell lines, as determined by real-time PCR and immunohistochemistry. RRBP1 depletion significantly reduced BFTC909 cell growth induced by specific shRNA. On the other hand, molecular subtype analysis showed that the expression of RRBP1 was associated with genes related to cell proliferation, epithelial-mesenchymal transition, and basal markers. A patient-derived organoid model was established to analyze patients' responses to different drugs. The expression of RRBP1 was related to chemoresistance. Taken together, these results provide the first evidence that RRBP1 gene body hypomethylation predicts RRBP1 high expression in UTUC. The data highlight the importance of RRBP1 in UTUC malignancy and chemotherapeutic tolerance.

Comparative Study of the Safety and Efficacy of First-Line Cisplatin and Carboplatin Chemotherapy in Elderly Patients with Metastatic Urothelial Carcinoma.

OBJECTIVES: Platinum-based chemotherapy is the standard treatment for metastatic urothelial carcinoma (mUC). However, considering elderly patients often experience comorbidities and frailty, the utility of cisplatin-based chemotherapy for elderly patients is still debatable. We conducted this study to compare the safety and efficacy of carboplatin and cisplatin in elderly patients with mUC. METHODS: This retrospective study enrolled elderly patients with mUC (defined as aged ≥70 years) who underwent first-line platinum-based chemotherapy between September 2001 and October 2018. The primary endpoints were chemotherapy-related adverse events (AEs), including treatment-related hospitalization or death. The secondary outcomes were overall survival (OS) and progression-free survival calculated by Kaplan-Meier analysis. RESULTS: In total, 108 elderly patients with mUC were enrolled and allocated into the cisplatin or carboplatin group. Patients treated with carboplatin-based chemotherapy had a significantly higher incidence of all grade ≥3 AEs (78.8 vs. 50.0%, p = 0.008) than those on cisplatin. AE-related hospitalization (47.5 vs. 19.1%, p = 0.002) and treatment-related death (17.5 vs. 4.4%, p = 0.02) were significantly increased in the carboplatin group. In the univariate analysis, the median OS in the cisplatin group was significantly increased compared with the carboplatin group (13.6 vs. 7.2 months, p = 0.045). The Cox multivariate regression model indicated that leukocytosis (HR 3.17, 95% CI 1.84-5.46, p < 0.001) and anemia (HR 2.02, 95% CI 1.11-3.65, p = 0.02) were independent prognostic factors. CONCLUSION: Elderly patients with mUC treated with cisplatin-based chemotherapy had better survival and safety profiles than those treated with carboplatin. Age itself was not a crucial factor in determining cisplatin eligibility.

Unusual presentation of upper urinary tract urothelial carcinoma in Taiwan: Direct comparison from Taiwan-Japan UTUC Collaboration Cohort.

OBJECTIVES: To carry out a comparison of upper urinary tract urothelial carcinoma characteristics and behavior between patients in Taiwan and Japan. METHODS: A Taiwan urinary tract urothelial carcinoma cohort was obtained from Kaohsiung Chang Gung Memorial Hospital, and a Japan urinary tract urothelial carcinoma cohort from Hirosaki University Hospital. The inclusion criteria were urinary tract urothelial carcinoma patients who underwent radical nephroureterectomy. Those who received perioperative chemotherapy were excluded. Finally, 765 patients in the Taiwan cohort and 325 in the Japan cohort were analyzed. The end-point of this study was to study the natural course of urinary tract urothelial carcinoma within 5 years between these two groups. RESULTS: The main finding was that urinary tract urothelial carcinoma patients in Taiwan were younger (P < 0.001), more were women (P < 0.001), with low-stage disease (P < 0.001), with more chronic kidney disease (P < 0.001), with less smoking history (P < 0.001), with more bladder cancer history (P = 0.002), with more multifocal (P < 0.001) and less high-grade disease (P = 0.015), as well as less lymphovascular invasion (P < 0.001) and more squamous differentiation (P < 0.001). However, the multivariate Cox regression analysis showed no racial difference in oncologic outcome, such as intravesical recurrence, systemic recurrence or cancer-specific death in primary and propensity-matched cohorts. Bladder cancer history was found to be the most important factor predicting intravesical recurrences, whereas stage was strongly associated with systemic recurrence and cancer specific mortality. CONCLUSIONS: The clinical characteristics of urinary tract urothelial carcinoma in Taiwan are significantly different from those of urinary tract urothelial carcinoma in Japan. However, there is no racial difference in stage-specific oncologic outcome after standard nephroureterectomy.

Does preoperative percutaneous nephrostomy insertion worsen upper-tract urothelial cancer oncological outcome? A retrospective single center study.

BACKGROUND: Physicians doubt percutaneous nephrostomy (PCN) insertion on cancer related hydronephrosis patients causes tumor seeding and worse cancer control. In this article, we attempted to determine if preoperative PCN alters cancer control in upper tract urothelial cancer (UTUC) patients. METHODS: Retrospective analysis of UTUC patients in a single center from 2005 to 2015. Exclusion criteria included lymph node metastasis, and patients underwent perioperative adjuvant chemotherapy or radiotherapy. There were 664 patients in this analysis, with clinico-pathological data being collected retrospectively for Cox-regression statistical analysis. Outcomes were measured by local recurrence, distant metastasis and cancer-specific death with Kaplan-Meier curves. RESULTS: There were respectively 25 and 639 UTUC cancers in the preoperative PCN and non-PCN insertion groups with mean follow-up duration of 37.9 and 48.6 months, respectively. The preoperative PCN group consisted of 17 patients (68%) with tumor located in the ureter, while the PCN-negative group included 236 patients (36%) with tumor located in the ureter being statistically significant. These two groups were comparable in gender, age, follow-up duration, tumor stage, and pathological features of the UTUC. As for the cancer control in the PCN group, 4(16%), 1(4%) and 1(4%) had local recurrence, distant metastasis and cancer-specific death respectively; in the non-PCN group, 101(15.8%), 96(15%) and 72(11.2%) exhibited local recurrence, distant metastasis and cancer-specific death respectively. Statistical analysis showed no difference in oncologic outcomes between these two groups.(p = 0.804, 0.201 and 0.254). CONCLUSIONS: Preoperative percutaneous nephrostomy on upper-tract urothelial cancer poses little risk on tumor seeding and could be considered as part of treatment strategy if renal function preservation is needed.

Proteomics Analysis of Tangeretin-Induced Apoptosis through Mitochondrial Dysfunction in Bladder Cancer Cells.

Tangeretin is one of the most abundant compounds in citrus peel, and studies have shown that it possesses anti-oxidant and anti-cancer properties. However, no study has been conducted on bladder cancer cells. Bladder cancer has the second highest mortality rate among urological cancers and is the fifth most common malignancy in the world. Currently, combination chemotherapy is the most common approach by which to treat patients with bladder cancer, and thus identifying more effective chemotherapeutic agents that can be safely administered to patients is a very important research issue. Therefore, this study investigated whether tangeretin can induce apoptosis and identified the signaling pathways of tangeretin-induced apoptosis in human bladder cancer cells using two-dimensional gel electrophoresis (2DGE). The results of the study demonstrated that 60 µM tangeretin reduced the cell survival of a BFTC-905 bladder carcinoma cell line by 42%, and induced early and late apoptosis in the cells. In this study 2DGE proteomics technology identified 41 proteins that were differentially-expressed in tangeretin-treated cells, and subsequently LC⁻MS/MS analysis was performed to identify the proteins. Based on the functions of the differentially-expressed proteins, the results suggested that tangeretin caused mitochondrial dysfunction and further induced apoptosis in bladder cancer cells. Moreover, western blotting analysis demonstrated that tangeretin treatment disturbed calcium homeostasis in the mitochondria, triggered cytochrome C release, and activated caspase-3 and caspase-9, which led to apoptosis. In conclusion, our results showed that tangeretin-induced apoptosis in human bladder cancer cells is mediated by mitochondrial inactivation, suggesting that tangeretin has the potential to be developed as a new drug for the treatment of bladder cancer.

Methylation of SPARCL1 Is Associated with Oncologic Outcome of Advanced Upper Urinary Tract Urothelial Carcinoma.

Advanced upper urinary tract urothelial carcinoma (UTUC) is often associated with poor oncologic outcomes. The secreted protein acidic and rich in cysteine-like 1 (SPARCL1) protein, belongs to the SPARC-related family of matricellular proteins. Much literature has been published describing the role of SPARCL1 in the prognosis many cancers. In this study, methylated promoter regions in high-grade and high-stage upper urinary urothelial tumours compared with normal urothelium were analyzed and revealed that SPARCL1 was the most significantly hypermethylated gene in UTUC tissues. Then we prospectively collected UTUC samples and adjacent normal urothelium for pyrosequencing validation, identifying significant CpG site methylation in UTUC tissues. In addition, SPARCL1 RNA levels were significantly lower in UTUC samples. Multivariate Cox regression analysis from 78 patients with solitary renal pelvic or ureteral pT3N0M0 urothelial carcinomas revealed that only negative SPARCL1 expression and nonpapillary tumour architecture were independently associated with systemic recurrence (p = 0.011 and 0.008, respectively). In vitro studies revealed that the behaviour of BFTC-909 cells was less aggressive and more sensitive to radiation or chemotherapy after SPARCL1 overexpression. Thus, SPARCL1 could be considered as a prognostic marker and help decision-making in clinical practice.

Aristolochic Acid Affects Upper Tract Urothelial Cancer Behavior through the MAPK Pathway.

The prevalence of upper tract urothelial carcinoma (UTUC) in Taiwan is relatively higher than thatin Western countries. Aristolochic acid (AA), which is widely used in traditional Chinese herbology, is now recognized to be one of the carcinogens for UTUC. Numerous UTUC patients have chronic kidney diseases or end-stage renal diseases; however, little literature hasreported on theoncogenic pathway of AA-related UTUC. The aim of our study was to identify the potential target treatment for AA-related UTUC. Here, we established an AA pre-exposure followed bya 3-methylcholanthrene (MCA) stimulus tumorigenic cell model. We not only demonstrated that AA pre-exposure MCA stimulus tumorigenic cells have more behaviors of cell migration and invasion by enhancing the metalloproteinases (MMP) activity, which is compatible with clinical findings of AA-related UTUC, but we also validated that AA pre-exposure MCA stimulus tumorigeniccells could be activated through the mitogen-activated protein kinases (MAPK) pathway. We further dissected the route of the MAPK pathway and found that the p38 and extracellular signal regulated kinases (ERK) sub-pathways might play essential roles in AA pre-exposure urothelial cancer cell lines. This consequence was also corroborated with a tissue study in AA-exposed patients.

MiR-30a-5p Inhibits Epithelial-to-Mesenchymal Transition and Upregulates Expression of Tight Junction Protein Claudin-5 in Human Upper Tract Urothelial Carcinoma Cells.

The involvement of microRNAs (miRNAs) in cancer development and their potential as prognostic biomarkers are becoming increasingly known. However, the signature of miRNAs and their regulatory roles in tumorigenesis of upper tract urothelial carcinoma (UTUC) remain to be elucidated. This study aimed to profile the miRNA expression pattern in UTUC tumor tissues and identify candidate miRNAs with prognostic and/or therapeutic functions. METHODS AND RESULTS: We collected 22 UTUC tissue and adjacent normal tissues samples from patients who underwent nephroureterectomy. The miRNAs signatures of three selected UTUC samples using next-generation sequencing showed that miR-30a-5p was significantly downregulated in UTUC tumors compared to adjacent normal tissues. The differentially-expressed miRNAs were specifically validated by quantitative real-time polymerase chain reaction. In addition, the miRNA expression signatures were analyzed with the transcriptome profile characterized by microarray. Further in vitro studies indicated that overexpression of miR-30a-5p significantly suppressed proliferation, migration, and epithelial-to-mesenchymal transition (EMT) in cultured BFTC-909 UTUC cells. As a potential target gene of miR-30a-5p in the tight junction pathway suggested by the pathway enrichment analysis, the reduced expression of tight junction protein claudin-5 in UTUC cells was demonstrated to be upregulated by miR-30a-5p genetic delivery. CONCLUSIONS: Taken together, our findings demonstrated that miR-30a-5p inhibits proliferation, metastasis, and EMT, and upregulates the expression of tight junction claudin-5 in UTUC cells. Thus, miR-30a-5p may provide a promising therapeutic strategy for UTUC treatment.

Double-barreled colon conduit and colostomy for simultaneous urinary and fecal diversions: long-term follow-up.

BACKGROUND: Best strategies for simultaneous urinary and stool diversion remain indeterminate. Here we present what is to our knowledge the longest outcome data on double-barreled colon conduit and colostomy (DBCCC) in a cohort of patients needing simultaneous urinary and fecal diversion. METHODS: We identified 9 patients who underwent DBCCC between March 2002 and March 2013. Nine patients who underwent separate urinary and fecal diversion (colostomy plus percutaneous nephrostomy or ureterocutaneostomy) served as the control group. We compared demographics, comorbidities, follow-up morbidities, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-item questionnaire in the two groups. RESULTS: The preservation of renal function was better in the DBCCC group. There were significant improvements in global state of health, fatigue, insomnia, appetite, bowel habit, and social function in the DBCCC group. In comparison with the separate urinary and fecal diversion group, the patients in the DBCCC group had statically significant improvement in global health status, functional scales, and symptom scales. CONCLUSIONS: Compared with the separate urinary and fecal diversion technique, DBCCC provides preservation of renal function, easy stoma bag care, better quality of life, and improved body image for patients who need simultaneous urinary and fecal diversion.

Subclassification of upper urinary tract urothelial carcinoma by the neutrophil-to-lymphocyte ratio (NLR) improves prediction of oncological outcome.

OBJECTIVE: To examine the potential role of the neutrophil-to-lymphocyte ratio (NLR) for subclassification of localised upper urinary tract urothelial carcinoma (UUT-UC). PATIENTS AND METHODS: From 2004 to 2010, 234 patients with localised UUT-UC underwent radical nephroureterectomy (RNU). NLRs were only obtained under afebrile conditions before RNU. Patients that underwent neoadjuvant or adjuvant chemotherapy were excluded. The prognostic impact of the NLR was assessed using the log-rank test and multivariate analyses. RESULTS: Only advanced pathological stage (>T2) and a NLR of >3 were independently associated with metastasis (P < 0.001 and P = 0.02, respectively) and cancer-specific mortality (P = 0.002 and P = 0.006, respectively). The use of a NLR of >3 further identified a poor prognostic group, especially in patients with T3 UUT-UC for metastasis-free survival and cancer-specific survival (log-rank test, both P < 0.001). CONCLUSIONS: For localised UUT-UC, pathological stage and preoperative NLR independently predict systemic recurrence and cancer-specific death after RNU. Using the NLR for subclassification of T3 UUT-UC seems to further identify a poor prognostic group and may help with clinical decisions about treatment intervention in clinical practice.

Oncological impact of endoscopic bladder cuff management during nephroureterectomy varies according to upper urinary tract tumor location.

OBJECTIVES: To compare the oncological outcome between extravesical excision and transurethral excision for bladder cuff management in patients undergoing nephroureterectomy with upper urinary tract urothelial cancer. METHODS: From January 2005 to December 2010, 396 patients were enrolled in the present retrospective study. Nephroureterectomy was carried out either by endoscopic or extravesical bladder cuff excision. The oncological outcome between these two procedures was analyzed in patients with different tumor locations. RESULTS: The average age of the patients was 66.41 ± 10.52 years, and the median follow-up duration was 40.65 ± 23.84 months. For upper urinary tract urothelial cancer management, extravesical bladder cuff excision was carried out in 240 patients, whereas the endoscopic method was carried out in 156 patients. Previous bladder cancer is still the most independent predictor for bladder recurrence (P < 0.001). In addition, endoscopic bladder cuff management for low ureteral tumor was also independently associated with more bladder tumor recurrence (P = 0.017). Non-organ confined pathological stage still independently predicted metastasis (P < 0.001) and cancer-specific death (P < 0.001). CONCLUSIONS: There are similar oncological outcomes after nephroureterectomy combined with extravesical or endoscopic bladder cuff management for patients with upper urinary tract urothelial cancer above the low ureter. However, there is a higher incidence of bladder tumor recurrence for the low ureteral tumor after nephroureterectomy with endoscopic bladder cuff excision.