NTRK3 exhibits a pro-oncogenic function in upper tract urothelial carcinomas.

Neurotrophic receptor tyrosine kinase 3 (NTRK3) has pleiotropic functions: it acts not only as an oncogene in breast and gastric cancers but also as a dependence receptor in tumor suppressor genes in colon cancer and neuroblastomas. However, the role of NTRK3 in upper tract urothelial carcinoma (UTUC) is not well documented. This study investigated the association between NTRK3 expression and outcomes in UTUC patients and validated the results in tests on UTUC cell lines. A total of 118 UTUC cancer tissue samples were examined to evaluate the expression of NTRK3. Survival curves were generated using Kaplan-Meier estimates, and Cox regression models were used for investigating survival outcomes. Higher NTRK3 expression was correlated with worse progression-free survival, cancer-specific survival, and overall survival. Moreover, the results of an Ingenuity Pathway Analysis suggested that NTRK3 may interact with the PI3K-AKT-mTOR signaling pathway to promote cancer. NTRK3 downregulation in BFTC909 cells through shRNA reduced cellular migration, invasion, and activity in the AKT-mTOR pathway. Furthermore, the overexpression of NTRK3 in UM-UC-14 cells promoted AKT-mTOR pathway activity, cellular migration, and cell invasion. From these observations, we concluded that NTRK3 may contribute to aggressive behaviors in UTUC by facilitating cell migration and invasion through its interaction with the AKT-mTOR pathway and the expression of NTRK3 is a potential predictor of clinical outcomes in cases of UTUC.

The factors impacting on Gleason score upgrading in prostate cancer with initial low Gleason scores.

BACKGROUND: This study aims to investigate the factors contributing to the discrepancy in between biopsy Gleason score (GS) and radical prostatectomy GS in patients diagnosed with prostate cancer. METHODS: 341 patients who underwent radical prostatectomy from 2011/04 to 2020/12 were identified. 102 Patients with initial GS of six after biopsy were enrolled. Preoperative clinical variables and pathological variables were also obtained and assessed. The optimal cut-off points for significant continuous variables were identified by the area under the receiver operating characteristic curve. RESULTS: Upgrading was observed in 63 patients and non-upgrading in 39 patients. In the multiple variables assessed, smaller prostate volume (PV) (p value = 0.0007), prostate specific antigen density (PSAD) (p value = 0.0055), positive surgical margins (p value = 0.0062) and pathological perineural invasion (p value = 0.0038) were significant predictors of GS upgrading. To further explore preclinical variables, a cut-off value for PV (≤ 38 ml, p value = 0.0017) and PSAD (≥ 0.26 ng/ml2, p value = 0.0013) were identified to be associated with GS upgrading. CONCLUSIONS: Smaller PV and elevated PSAD are associated with increased risk of GS upgrading, whereas lead-time bias is not. A cut-off value of PV < 38 ml and PSAD > 0.26 ng/ml2 were further identified to be associated with pathological GS upgrading.

Lipid Profiles Impact on the Oncologic Outcome of Upper Tract Urothelial Carcinoma.

Background: The prognosis of upper tract urothelial carcinoma (UTUC) varies, with T3/T4 UTUC having less than 50% 5-year survival post-radical nephroureterectomy (RNU). Lipid profiles including cholesterol (CHOL), low-density lipoprotein (LDL), and triglycerides (TGs), and high-density lipoprotein (HDL) have shown correlations with oncologic outcomes in various cancers. We aimed to investigate the prognostic significance of the lipid profiles in UTUC patients who had received RNU. Methods: In this retrospective study, a total of 217 UTUC patients who underwent RNU were analyzed. Prognostic factors for overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) were assessed using Cox proportional hazards regression model and competing risk analysis. Results: The median follow-up duration was 2.36 years. Fifty-one (23.50%) of the patients experienced tumor progression, 16 (7.37%) died from UTUC, and 41 (18.89%) died from all causes during the follow-up period. Multivariate analysis revealed that elevated CHOL, low HDL, and elevated TG were linked to worse OS (P = 0.0188, 0.0002, and 0.0001, respectively). Higher CHOL, LDL, and TG, as well as lower HDL significantly affected PFS (P < 0.001 for all), and elevated CHOL and TG were associated with poorer CSS (P = 0.0033 and 0.0179). A competing risk model indicated that elevated LDL increased the risk of cancer progression (P = 0.407), with CHOL increasing the risk of UTUC-specific mortality (P = 0.0162). Limitations include retrospective design, limited, single-time sampling and relatively small sample size. Conclusions: Lipid profiles were identified as prognostic indicators for UTUC patients post-RNU. It highlights the potential importance of lipid management in improving tumor-related outcomes.

TGFB1I1 promotes cell proliferation and migration in urothelial carcinoma.

Urothelial carcinoma (UC) is common cancer worldwide with a high prevalence in Taiwan, especially in the upper urinary tract, including the renal pelvis and ureter, also classifying as upper urinary tract urothelial carcinoma. Here, we aim to find a representative prognostic marker that strongly correlates to this type of carcinoma. Transforming growth factor beta-1-induced transcript 1 (TGFB1I1) is a cofactor of cellular TGF-ß1 and interacts with various nuclear receptors. The previous study showed that TGFB1I1 promotes focal adhesion formation, contributing to the epithelial-mesenchymal transition (EMT) with actin cytoskeleton and vimentin through TGFB1I1 regulation. We aim to reveal the role of TGFB1I1 in the tumorigenesis of UC. In silico and clinicopathological data of upper urinary tract urothelial carcinoma (UTUC) and urinary bladder urothelial carcinoma (UBUC) were accessed and analyzed for IHC staining regarding tumor characteristics, including survival outcome. Finally, an in vitro study was performed to demonstrate the biological changes of UC cells. In UTUC, overexpression of TGFB1I1 was significantly correlated with advanced tumor stage, papillary configuration, and frequent mitosis. Meanwhile, overexpression of TGFB1I1 was significantly correlated with advanced tumor stage and histological grade in UBUC. Moreover, the in vitro study shows that TGFB1I1 affects cell proliferation, viability, migration and wound healing. The EMT markers also decreased upon TGFB1I1 knockdown. In this study, we identified that TGFB1I1 regulates UC cell proliferation and viability and induces the EMT to facilitate cell migration in vitro, leading to its essential role in promoting tumor aggressiveness in both UTUC and UBUC.

MicroRNA-299-3p inhibits cell proliferation, motility, invasion and angiogenesis via VEGFA in upper tract urothelial carcinoma.

BACKGROUND: Upper tract urothelial carcinoma (UTUC) is a rare tumor with extraordinarily different features between Eastern and Western countries. Vascular endothelial growth factor-A (VEGFA) was originally identified as a secreted signaling protein and regulator of vascular development and cancer progression. In this study, we aimed to elucidate the molecular mechanisms underlying the regulation of VEGFA by microRNA in UTUC. METHODS: VEGFA expression was evaluated by immunohistochemistry in 140 human UTUC tissue samples. Next, we assessed the regulatory relationship between VEGFA and miR-299-3p by real-time PCR, western blotting, ELISA and dual-luciferase reporter assays using two UTUC cell lines. The role of miR-299-3p/VEGFA in cell proliferation, motility, invasion, and tube formation was analyzed in vitro. RESULTS: High VEGFA expression was significantly associated with tumor stage, grade, distant metastasis and cancer-related death and correlated with poor progression-free and cancer-specific survival. VEGFA knockdown repressed proliferation, migration, invasion and angiogenesis in UTUC cell lines. miR-299-3p significantly reduced VEGFA protein expression and miR-299-3p overexpression inhibited VEGFA mRNA and protein expression by directly targeting its 3'-UTR. Functional studies indicated that VEGFA overexpression reversed the miR-299-3p-mediated suppression of tumor cell proliferation, migration, invasion and angiogenesis. In addition, miR-299-3p/VEGFA suppressed cellular functions in UTUC by modulating the expression of P18 and cyclin E2. CONCLUSIONS: Our findings suggest that miR-299-3p possibly suppresses UTUC cell proliferation, motility, invasion and angiogenesis via VEGFA. VEGFA may act as a prognostic predictor, and both VEGFA and miR-299-3p could be potential therapeutic targets for UTUC.

Downregulation of CRTAC1 in Urothelial Carcinoma Promotes Tumor Aggressiveness and Confers Poor Prognosis.

BACKGROUND: Cartilage acidic protein 1 (CRTAC1) is a glycosylated calcium-binding extracellular matrix protein. The oncological functions of CRTAC1 in urothelial carcinoma (UC) of the urinary bladder (UB) and upper urinary tract (UT) have not yet been elucidated. Based on the published UBUC transcriptome data, we re-evaluated the differential expression profile of calcium ion binding-related genes (GO:0005509), and we found that CRTAC1 was the most significantly downregulated gene in UBUC progression. Therefore, we analyzed the prognostic value and biological significance of CRTAC1 expression in UC. METHODS: We used immunohistochemistry to determine the CRTAC1 expression levels in 340 patients with UTUC and 295 patients with UBUC. The CRTAC1 expression was compared with the clinicopathological characteristics, and the prognostic impact of CRTAC1 on metastasis-free survival (MFS) and disease-specific survival (DSS) was evaluated. To study the biological functions of CRTAC1, the proliferation, migration, invasion, and tube formation abilities of UC-derived cells were evaluated. RESULTS: A low CRTAC1 expression significantly correlated with high tumor stage, high histological grade, perineural invasion, vascular invasion, nodal metastasis, and high mitotic rate (all p < 0.01). Moreover, the CRTAC1 immunoexpression status was an independent prognostic factor for MFS and DSS in UBUC and UTUC patients (all p < 0.001) in the multivariate analysis. The exogenous expression of CRTAC1 suppressed the cell proliferation, invasion, and angiogenesis, and downregulated the matrix metallopeptidase 2 (MMP2) level in BFTC909 and T24 cells. CONCLUSIONS: CRTAC1 may participate in progression of UC and serve as a prognostic marker for metastasis. Low CRTAC1 expression was significantly associated with aggressive UC characteristics and worse clinical outcomes. The inclusion of CRTAC1 immunoexpression in the standard pathological variables may optimize the risk stratification of patients.

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.

Cumulative sum analysis of the learning curve of laparoendoscopic single-site robot-assisted radical prostatectomy.

BACKGROUND: Radical prostatectomy has become the gold standard for treating localized prostate cancer. Improvement in the single-site technique and surgeon's skill reduces not only the hospital duration but also the number of wounds. Realizing the learning curve for a new procedure can prevent unnecessary mistakes. OBJECTIVE: To analyze the learning curve of extraperitoneal laparoendoscopic single-site robot-assisted radical prostatectomy (LESS-RaRP). METHODS: We retrospectively evaluated 160 patients diagnosed with prostate cancer during June 2016 to December 2020 who underwent extraperitoneal LESS-RaRP. Calculated cumulative sum analysis (CUSUM) was used to evaluate the learning curves for the extraperitoneal setting time, robotic console time, total operation time, and blood loss. The operative and functional outcomes were also assessed. RESULTS: The learning curve of the total operation time was observed in 79 cases. For the extraperitoneal setting and robotic console times, the learning curve was observed in 87 and 76 cases, respectively. The learning curve for blood loss was observed in 36 cases. No in-hospital mortality or respiratory failure was observed. CONCLUSION: Extraperitoneal LESS-RaRP using the da Vinci Si system is safe and feasible. Approximately 80 patients are required to achieve a stable and consistent operative time. A learning curve for blood loss was observed after 36 cases.

High MRE11 Expression Level Predicts Poor Survival in Upper Tract Urothelial Carcinomas.

Upper tract urothelial carcinoma (UTUC) is an aggressive malignancy with characteristics of high metastasis and poor prognosis. There are some particularly different features of UTUC between the Asian and Western countries. Double-strand break repair protein MRE11 is a component of the MRN complex that is involved in the DNA repair pathway. Emerging studies have focused on the role of MRE11 in human malignancies with conflicting results. We aimed to establish the relationship between MRE11 expression and the oncological outcome of UTUC. This study retrospectively reviewed 150 patients who underwent radical nephroureterectomy with pathologically confirmed UTUC. Pathologic slides were reviewed, and clinical parameters were collected. An immunohistochemical study was performed, and the cytoplasmic and nuclear-staining results of UTUC were recorded. The expression of MRE11 was analyzed to identify correlations with various clinicopathological parameters, metastasis-free survival, and cancer-specific survival (CSS). MRE11 expression was significantly correlated with patients with a high pathologic stage ( P =0.001), perineural invasion ( P =0.015), and tumor necrosis ( P =0.034). Upon univariate analysis, a high MRE11 expression was associated with poor metastasis-free survival ( P =0.014, 95% CI 1.18, 4.38) and poor CSS ( P =0.001, 95% CI 2.45, 27.75). Upon multivariable analysis, a high MRE11 expression was associated with poor CSS ( P =0.019, 95% CI 1.28, 15.65). In summary, MRE11 expression could serve as a potential predictor of prognosis in patients with UTUC.

MicroRNA-145-5p modulates Krüppel-like factor 5 and inhibits cell proliferation, migration, and invasion in nasopharyngeal carcinoma.

BACKGROUND: In several human cancers, Krüppel-like factor 5 (KLF5), a zinc finger transcription factor, can contribute to both tumor progression or suppression; however, the precise role of KLF5 in nasopharyngeal carcinoma (NPC) remains poorly understood. In this study, the association between KLF5 and microRNA-145-5p (miR-145-5p) in NPC cells was elucidated. RESULTS: Our results showed that KLF5 expression was up-regulated in NPC group compared to normal group. We found that KLF5 exhibited an oncogenic role in NPC cells. The upregulation of miR-145-5p inhibited the proliferation, migration, and invasion of NPC cells. It was observed that miR-145-5p could down-regulate the mRNA and protein expression of KLF5 in NPC cell lines. Additionally, the activity of focal adhesion kinase (FAK), a migration marker, was regulated by miR-145-5p and KLF5 in NPC cells. CONCLUSIONS: The results of this study indicated that miR-145-5p could repress the proliferation, migration, and invasion of NPC cells via KLF5/FAK regulation, and could be a potential therapeutic target for patients with NPC.

High MT2A Expression Predicts Worse Prognosis in Patients with Urothelial Carcinoma.

Introduction: Dysregulation of metal ion homeostasis is associated with urothelial carcinogenesis. From a published urinary bladder urothelial carcinoma (UBUC) transcriptome, we identified metallothionein 2A (MT2A) as the most significantly upregulated gene implicated in cancer progression among metal ion binding-related genes. Therefore, we analyzed the association between MT2A expression and clinical significance in our well-characterized cohort of patients with upper tract urothelial carcinoma (UTUC) and UBUC. Methods: We retrospectively reviewed the clinicopathological characteristics of 295 and 340 patients with UBUC and UTUC, respectively. MT2A expression was assessed using real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry. We further correlated MT2A expression with clinicopathological factors, disease-specific survival (DSS) and metastasis-free survival (MFS) using the Pearson's χ2 test, Kaplan-Meier analysis, and multivariate Cox proportional hazards model. Results: High MT2A expression was significantly associated with aggressive pathological features including high tumor stage, lymph node metastasis, high tumor grade, vascular invasion, and perineural invasion. In the Kaplan-Meier analysis, high MT2A expression was significantly correlated with poor DSS (p < 0.0001) and MFS (p < 0.0001); in the multivariate analysis, it was an independent predictor of CSS (p < 0.001) and MFS (p = 0.001). Gene coexpression analysis demonstrated that MT2A overexpression promotes UC progression through complement activation. Conclusion: High MT2A expression correlated with aggressive UC features and was an independent predictor of cancer metastasis and patient survival, suggesting its role in risk stratification and decision-making in patients with UTUC and UBUC.

Whole-exome sequencing identified mutational profiles of urothelial carcinoma post kidney transplantation.

Kidney transplantation is a lifesaving option for patients with end-stage kidney disease. In Taiwan, urothelial carcinoma (UC) is the most common de novo cancer after kidney transplantation (KT). UC has a greater degree of molecular heterogeneity than do other solid tumors. Few studies have explored genomic alterations in UC after KT. We performed whole-exome sequencing to compare the genetic alterations in UC developed after kidney transplantation (UCKT) and in UC in patients on hemodialysis (UCHD). After mapping and variant calling, 18,733 and 11,093 variants were identified in patients with UCKT and UCHD, respectively. We excluded known single-nucleotide polymorphisms (SNPs) and retained genes that were annotated in the Catalogue of Somatic Mutations in Cancer (COSMIC), in the Integrative Onco Genomic cancer mutations browser (IntOGen), and in the Cancer Genome Atlas (TCGA) database of genes associated with bladder cancer. A total of 14 UCKT-specific genes with SNPs identified in more than two patients were included in further analyses. The single-base substitution (SBS) profile and signatures showed a relative high T > A pattern compared to COMSIC UC mutations. Ingenuity pathway analysis was used to explore the connections among these genes. GNAQ, IKZF1, and NTRK3 were identified as potentially involved in the signaling network of UCKT. The genetic analysis of posttransplant malignancies may elucidate a fundamental aspect of the molecular pathogenesis of UCKT.

Is Lymph Node Dissection Necessary During Radical Nephroureterectomy for Clinically Node-Negative Upper Tract Urothelial Carcinoma? A Multi-Institutional Study.

Purpose: This study aimed to compare the oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) without clinical lymph node metastasis (cN0) undergoing lymph node dissection (LND) during radical nephroureterectomy (NU). Methods: From the updated data of the Taiwan UTUC Collaboration Group, a total of 2726 UTUC patients were identified. We only include patients with ≥ pT2 stage and enrolled 658 patients. The Kaplan-Meier estimator and Cox proportional hazards model were used to analyze overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and bladder recurrence-free survival (BRFS) in LND (+) and LND (-) groups. Results: A total of 658 patients were included and 463 patients without receiving LND and 195 patients receiving LND. From both univariate and multivariate survival analysis, there are no significant difference between LND (+) and LND (-) group in survival rate. In LND (+) group, 18.5% patients have pathological LN metastasis. After analyzing pN+ subgroup, it revealed worse CSS (p = 0.010) and DFS (p < 0.001) compared with pN0 patients. Conclusions: We found no significant survival benefit related to LND in cN0 stage, ≥ pT2 stage UTUC, irrespective of the number of LNs removed, although pN+ affected cancer prognosis. However, from the result of pN (+) subgroup of LND (+) cohort analysis, it may be reasonable to not perform LND in patients with cT2N0 stage due to low positive predictive value of pN (+). In addition, performing LND may be considered for ureter cancer, which tends to cause lymphatic and hematogenous tumor spreading. Further large prospective studies are needed to validate our findings.

Impact of Adjuvant Chemotherapy on Variant Histology of Upper Tract Urothelial Carcinoma: A Propensity Score-Matched Cohort Analysis.

Background: The advantage of adjuvant chemotherapy for upper urinary tract urothelial cancer (UTUC) has been reported, whereas its impact on upper tract cancer with variant histology remains unclear. We aimed to answer the abovementioned question with our real-world data. Design Setting and Participants: Patients who underwent radical nephroureterectomy (RNU) and were confirmed to have variant UTUC were retrospectively evaluated for eligibility of analysis. In the Taiwan UTUC Collaboration database, we identified 245 patients with variant UTUC among 3,109 patients with UTUC who underwent RNU after excluding patients with missing clinicopathological information. Intervention: Those patients with variant UTUC were grouped based on their history of receiving adjuvant chemotherapy or not. Outcome Measurements and Statistical Analysis: Propensity score matching was used to reduce the treatment assignment bias. Multivariable Cox regression model was used for the analysis of overall, cancer-specific, and disease-free survival. Results and Limitations: For the patients with variant UTUC who underwent adjuvant chemotherapy compared with those without chemotherapy, survival benefit was identified in overall survival in univariate analysis (hazard ratio (HR), 0.527; 95% confidence interval (CI), 0.285-0.973; p = 0.041). In addition, in multivariate analysis, patients with adjuvant chemotherapy demonstrated significant survival benefits in cancer-specific survival (OS; HR, 0.454; CI, 0.208-0.988; p = 0.047), and disease-free survival (DFS; HR, 0.324; 95% CI, 0.155-0.677; (p = 0.003). The main limitations of the current study were its retrospective design and limited case number. Conclusions: Adjuvant chemotherapy following RNU significantly improved cancer-related survivals in patients with UTUC with variant histology.

High Ubiquitin-Specific Protease 2a Expression Level Predicts Poor Prognosis in Upper Tract Urothelial Carcinoma.

BACKGROUND: Ubiquitin-mediated protein degradation has been reported to be involved in regulating the activity of oncoproteins and tumor suppressors. Dysfunction or dysregulation of the ubiquitin-proteasome system may induce tumorigenesis. Deubiquitinase ubiquitin-specific protease 2a (USP2a) has been reported to regulate cell growth or death and is involved in the pathogenesis of various diseases, including cancers. However, the role of USP2a in upper tract urothelial carcinoma (UTUC) has not been investigated yet. The goal of this study was to evaluate the clinical significance of USP2a expression in UTUC. MATERIALS AND METHODS: A total of 110 UTUC cases were included in this study. USP2a expression level was evaluated through immunohistochemistry staining, and the correlation of USP2a expression level with both clinical and pathologic variables was analyzed. RESULTS: High USP2a expression level was observed in 48 (43.6%) cancer specimens. USP2a expression level was significantly correlated with tumor stage (P=0.001), grade (P=0.033), and tumor recurrence (P=0.008). High USP2a expression level was correlated with poor disease-free survival (P=0.005) and cancer-specific survival (P<0.001). In addition, high USP2a expression level was an independent predictor of poor disease-free survival (hazard ratio=2.31; P=0.007) and cancer-specific survival (hazard ratio=5.49; P=0.009). CONCLUSIONS: This study indicated that USP2a protein expression level may be a potential biomarker for predicting UTUC patient survival. Further prospective studies are needed to investigate the role of USP2a in UTUC progression.

Prognostic Value of Comorbidity for Patients with Upper Tract Urothelial Carcinoma after Radical Nephroureterectomy.

Patients with upper tract urothelial carcinoma (UTUC) have a high prevalence of comorbidities. However, the prognostic impact of comorbidities in these patients is not well studied. We aimed to outline the comorbidity burden in UTUC patients and investigate its relationship with overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS). We retrospectively reviewed the clinicopathological data of 409 non-metastatic UTUC patients who received radical nephroureterectomy between 2000 and 2015. The comorbidity burden was evaluated using the Adult Comorbidity Evaluation-27 (ACE-27). Kaplan-Meier survival analysis showed that high ACE-27 grade was significantly associated with worse PFS, CSS, and OS. In multivariate Cox regression and competing risk analyses, we found that ACE-27 grade, tumor stage, and tumor grade were independent prognosticators of OS, CSS, and PFS. We combined these three significant factors to construct a prognostic model for predicting clinical outcomes. A receiver operating characteristic curve revealed that our prognostic model had high predictive performance. The Harrel's concordance indices of this model for predicting OS, CSS, and PFS were 0.81, 0.85, and 0.85, respectively. The results suggest that the UTUC patient comorbidity burden (ACE-27) provides information on the risk for meaningful clinical outcomes of OS, CSS, and PFS.

MicroRNA-375-3p Suppresses Upper Tract Urothelial Carcinoma Cell Migration and Invasion via Targeting Derlin-1.

Little is known regarding the molecular characterization of upper tract urothelial carcinoma (UTUC). Novel therapeutic targets and prognostic predictors are imminent. In the present study, we aim to examine the oncogenic function and molecular mechanism of Derlin-1 in UTUC. Derlin-1 overexpression is significantly associated with poor prognosis in patients with UTUC. In vitro, knockdown or over-expression of Derlin-1 markedly regulated UTUC cell invasion and migration. We further discovered miR-375-3p suppresses cell invasion and migration by inversely regulating Derlin-1 and blocking EMT in UTUC cells. Taking this together, miR-375-3p functions as a tumor suppressive microRNA by directly targeting Derlin-1 and blocking epithelial-mesenchymal transition (EMT) in UTUC.

Perineural Invasion is a Powerful Prognostic Factor for Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy.

BACKGROUND: Taiwan has the highest incidence of upper tract urothelial carcinoma (UTUC) worldwide. Although many pathological factors can predict the prognosis of UTUC, previous studies have rarely discussed perineural invasion (PNI). Therefore, we aimed to investigate the effect of PNI on a well-established cohort of patients with UTUC. METHODS: This retrospective study included 803 patients with non-metastatic UTUC who underwent radical nephroureterectomy between June 2000 and August 2019. Demographic and clinicopathological parameters, including PNI, were collected for analysis. Using the Kaplan-Meier method and Cox proportional hazards model, we evaluated the significance of PNI with respect to progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: The median follow-up was 30.9 months, and there were 83 cases of PNI (10.3%). PNI-positive patients had unfavorable pathological features, including high pT stage, positive lymph node involvement, high tumor grade, and more lymphovascular invasion (all p < 0.001). Kaplan-Meier analysis showed that PNI was significantly associated with PFS, CSS, and OS (all p < 0.00001), and when combined with lymphovascular invasion, patients could be divided into groups with distinct survival rates (all p < 0.00001). In multivariate analysis, PNI was an independent factor leading to worse PFS (hazard ratio [HR] 1.72, 95% confidence interval [CI] 1.19-2.50; p = 0.004), CSS (HR 2.54, 95% CI 1.58-4.10; p = 0.0001), and OS (HR 1.78, 95% CI 1.19-2.65; p = 0.005). CONCLUSIONS: We demonstrated an association between PNI and the prognosis of UTUC. Routine assessment of PNI in UTUC with standardized protocols may help achieve better risk stratification and subject selection for perioperative treatment.

Comparison of oncological outcomes for hand-assisted and pure laparoscopic radical nephroureterectomy: results from the Taiwan Upper Tract Urothelial Cancer Collaboration Group.

PURPOSE: Laparoscopic radical nephroureterectomy (LNU) has gradually become the new standard treatment for localized upper tract urothelial cancer (UTUC). With more blunt dissection and tactile sensation, hand-assisted LNU might shorten the operative time compared with the pure laparoscopic approach. However, whether the use of the hand-assisted or the pure laparoscopic approach has an effect on oncological outcomes remains unclear. METHODS: We retrospectively identified 629 patients with non-metastatic UTUC who underwent hand-assisted (n = 515) or pure LNU (n = 114) at 9 hospitals in Taiwan between 2004 and 2019. Overall survival, cancer-specific survival, recurrence-free survival, and bladder recurrence-free survival were compared between these two groups using inverse-probability of treatment weighting (IPTW) derived from the propensity scores for baseline covariate adjustment. RESULTS: The median follow-up period was 32.9 and 28.7 months in the hand-assisted and the pure groups, respectively. IPTW-adjusted Cox proportional hazards models showed that the laparoscopic approach (pure vs. hand-assisted) was not significantly associated with all-cause mortality (HR 0.79, 95% CI 0.49-1.24, p = 0.304), cancer-specific mortality (HR 0.88, 95% CI 0.51-1.51, p = 0.634), or extra-vesical recurrence (HR 0.65, 95% CI 0.41-1.04, p = 0.071). However, the pure laparoscopic approach was significantly associated with lower intra-vescial recurrence (HR 0.64, 95% CI 0.43-0.96, p = 0.029) for patients who underwent LNU. Kaplan-Meier curves also revealed that the pure laparoscopic approach was associated with better bladder recurrence-free survival compared with the hand-assisted laparoscopic approach in both the original cohort and the IPTW-adjusted cohort (log-rank p = 0.042 and 0.027, respectively). CONCLUSIONS: The performance of hand-assisted or pure LNU does not significantly affect the all-cause mortality, cancer-specific mortality, or extra-vesical recurrence for patients with non-metastatic UTUC. However, the hand-assisted laparoscopic approach could increase the risk of intra-vesical recurrence for patients who undergo LNU.

Obesity-related indices and its association with kidney stone disease: a cross-sectional and longitudinal cohort study.

Obesity increases the risk of several diseases, including kidney stone disease (KSD). The study aimed to explore the relationship between KSD and various obesity-related indices. A total of 121,605 participants in the Taiwan Biobank from December 2008 to February 2020 were analyzed. The association between self-reported history of KSD and eight obesity-related indices, including body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR), abdominal volume index (AVI), body roundness index (BRI), conicity index, and triglyceride glucose index was examined in cross-sectional analysis; additionally, the risk of developing kidney stones was analyzed in a longitudinal cohort of 25,268 participants without KSD at baseline, which was a subset of the main cohort. Of all participants, 77,904 (64.1%) were female. Overall, 10.7% of males and 4.0% of females had KSD. Multivariate-adjusted logistic regression showed that all obesity-related indices were significantly associated with KSD. During a mean follow-up of 47 months, kidney stones occurred in 642 (2.5%) participants, and after adjusting for confounders, the risk of developing kidney stones was higher in participants with higher BMI, WC, WHtR, WHR, AVI and BRI. BMI, WC, WHtR, WHR, AVI, and BRI were found to be associated with a higher prevalence of kidney stones as well as development of incident kidney stones, which could be used as predictive factors for development of KSD in clinical practice.