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.

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.

The prognostic impact of lymphovascular invasion for upper urinary tract urothelial carcinoma: A propensity score-weighted analysis.

Lymphovascular invasion (LVI) predicts poor survival in patients with pathologically localized or locally advanced upper urinary tract urothelial carcinoma (UT-UC). However, LVI is associated with high tumor grade, tumor necrosis, advanced tumor stage, tumor location, concomitant carcinoma in situ, lymph node metastasis, and sessile tumor architecture. These factors might interfere with the analysis of the impact of LVI on oncological prognosis. To address this, this study aimed to clarify the relationship between LVI and patient prognosis in UT-UC using propensity score weighting. Data were collected from 789 patients with UT-UC treated with radical nephroureterectomy without chemotherapy. We evaluated the significance of LVI in predicting metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) using propensity score weighting. All weighted baseline characteristics included in the propensity score model were balanced between the LVI (+) and LVI (-) groups. The MFS, CSS, and OS were all significantly poorer in the LVI (+) group. For patients without LVI, the 5-year MFS, CSS, and OS rates were 65.3%, 73.1%, and 67.3%, respectively, whereas the corresponding rates were 50.2%, 63.8 %, and 54.6%, respectively, for patients with LVI. (all P < .001). For patients without LVI, the 10-year MFS, CSS, and OS rates were 61.5%, 69.6%, and 59.2%, respectively, whereas those for patients with LVI were 44.5%, 57.0%, and 42.7%, respectively (all P < .001). LVI is an important pathological feature that predicts metastasis development and worse survival outcome after radical surgery in UT-UC patients.

MicroRNA-26a-5p Restoration Ameliorates Unilateral Ureteral Obstruction-Induced Renal Fibrosis in Mice Through Modulating TGF-ß Signaling.

Renal fibrosis is a hallmark of chronic and progressive renal diseases characterized by excessive fibroblast proliferation, extracellular matrix accumulation, and a loss of renal function, eventually leading to end-stage renal diseases. MicroRNA-26a-5p (miR-26a-5p) downregulation has been previously noted in the sera of unilateral ureteral occlusion (UUO)-injured mice, and exosome-mediated miR-26a-5p reportedly attenuated experimental pulmonary and cardiac fibrosis. This study evaluated the expression patterns of miR-26a in a human tissue microarray with kidney fibrosis and in tissues from a mouse model of UUO-induced renal fibrosis. Histologic analyses showed that miR-26a-5p was downregulated in human and mouse tissues with renal interstitial nephritis and fibrosis. Moreover, miR-26a-5p restoration by intravenous injection of a mimic agent prominently suppressed the expression of transforming growth factor ß1 (TGF-ß1) and its cognate receptors, the inflammatory transcription factor NF-κB, epithelial-mesenchymal transition, and inflammatory markers in UUO-injured kidney tissues. In vitro, miR-26a-5p mimic delivery significantly inhibited TGF-ß1-induced activation of cultured normal rat kidney NRK-49F cells, in terms of downregulation of TGF-ß1 receptors, restoration of the epithelial marker E-cadherin, and suppression of mesenchymal markers, including vimentin, fibronectin, and α-smooth muscle actin, as well as TGF-ß1/SMAD3 signaling activity. Our findings identified miR-26a-5p downregulation in kidney tissues with human interstitial nephritis and UUO-induced mouse kidney fibrosis. MiR-26a-5p restoration may exhibit an antifibrotic effect through the blockade of both TGF-ß and NF-κB signaling axes and is considered a novel therapeutic target for treating obstruction-induced renal fibrosis.

Treatment outcomes with radium-223 in docetaxel-naïve versus docetaxel-treated metastatic castration-resistant prostate cancer patients: Real-world evidence from Taiwan.

While radium (Ra)-223 is among the multiple, known life-prolonging treatments in bone-predominant metastatic castration-resistant prostate cancer (mCRPC), optimal treatment sequencing has not been determined, particularly in the Asia-Pacific context. Hence, we aimed to compare treatment outcomes of docetaxel-naïve and post-docetaxel mCRPC patients undergoing Ra-223 therapy in Taiwan. Using a single-center retrospective cohort design, we reviewed records of adult patients receiving Ra-223 for bone-metastatic mCRPC from 2018 to 2021. Patients were categorized into docetaxel-naïve or post-docetaxel groups based on history of docetaxel use preceding Ra-223. We compared the 2 groups in terms of all-cause death, 6-cycle treatment completion, and the following secondary outcomes: pain control, change in biochemical parameters (prostate-specific antigen, lactate dehydrogenase, alkaline phosphatase), biochemical response, and treatment-emergent adverse events. We performed total population sampling and a complete case analysis. We included 48 patients (25 docetaxel-naïve, 23 post-docetaxel) in the study. The mean follow-up duration was 12.4 months for the entire cohort. The docetaxel-naïve group exhibited a significantly lower all-cause mortality rate versus the post-docetaxel group (40.0% vs 78.3%, P = .02), as well as a significantly higher treatment completion rate (72.0% vs 26.1%, P < .01). We did not find significant differences in pain control, change in biochemical parameters, biochemical response, or hematologic treatment-emergent adverse events between the 2 groups. However, the docetaxel-naïve group had a numerically higher pain control rate, numerically greater improvements in alkaline phosphatase and prostate-specific antigen, and numerically lower rates of grade ≥ 3 neutropenia and grade ≥ 3 thrombocytopenia than the post-docetaxel group. Use of Ra-223 in docetaxel-naïve patients with mCRPC led to lower mortality and higher treatment completion than post-docetaxel use. Our study adds preliminary real-world evidence that Ra-223 may be used safely and effectively in earlier lines of treatment for bone-predominant mCRPC. Further large-scale, longer-term, and controlled studies are recommended.

Genetic Interference of FGFR3 Impedes Invasion of Upper Tract Urothelial Carcinoma Cells by Alleviating RAS/MAPK Signal Activity.

Upper tract urothelial cancer (UTUC) is a less common disease in Western countries but has a high level of prevalence in Asian populations. Compared to bladder cancer, unique etiologic and genomic factors are involved in UTUC. Fibroblast growth factor receptor 3 (FGFR3) up-regulation has been proposed as a promising target for bladder cancer therapy. In this study, we aimed to profile the expression of FGFR3 in Asian and Caucasian UTUC tissues and to evaluate the in vitro therapeutic efficacy of small interference RNA (siRNA)-mediated FGFR3 silencing in UTUC treatment. The FGFR3 expression levels in renal pelvis tissues and microarray sections from Asian and Caucasian patients with UTUC, respectively, were measured via immunohistochemistry. The BFTC-909 and UM-UC-14 UTUC cell lines were used to examine the effects of FGFR3 silencing on proliferation, migration, epithelial-mesenchymal transition (EMT) marker expression, and signaling machinery. FGFR3 expression increased as the TNM stage increased in both Asian and Caucasian UTUC tumors, and no statistical difference was identified between the two groups. In vitro studies demonstrated that FGFR3 siRNA delivery significantly inhibited proliferation and migration and suppressed the expression of EMT markers and transcription factors in UTUC cells. Mechanistically, FGFR3 silencing alleviated the constitutive expression of RAS and the phosphorylation of MAPK signaling mediators, including ERK1/2 and JNK1/2. FGFR3 silencing elicited an apoptosis-inducing effect similar to that of FGFR inhibition. Conclusion: siRNA-targeted FGFR3 expression may impede the expansion and invasion of UTUC cells by alleviating the RAS/MAPK signaling pathway. The genetic interference of FGFR3 expression via siRNA in UTUC cells may constitute a useful therapeutic strategy.

Impaired insulin signaling at the bladder mucosa facilitates metabolic syndrome-associated bladder overactivity in rats with maternal and post-weaning fructose exposure.

BACKGROUND/PURPOSE: Metabolic syndrome (MetS) and overactive bladder might share common pathophysiologies. Environmental fructose exposure during pre- and postnatal periods of rats may program MetS-associated bladder overactivity. We explored the dysregulated insulin signalling at bladder mucosa, as a common mechanism, in facilitating bladder overactivity in rats with MetS induced by maternal and post-weaning fructose diet. METHODS: Male offspring of Sprague-Dawley rats were subject into 4 groups by maternal and post-weaning diets (i.e., Control/Control, Fructose/Control, Control/Fructose and Fructose/Fructose by diets). Micturition behavior was evaluated. Acidic ATP solution was used to elicit cystometric reflex along with insulin counteraction. Concentration-response curves to insulin were plotted. The canonical signalling pathway of insulin was evaluated in the bladder mucosal using Western blotting. Levels of detrusor cGMP and urinary NO2 plus NO3 were measured. RESULTS: Male offspring with any fructose exposure presents traits of MetS and bladder overactivity. We observed all fructose exposure groups have the poor urodynamic response to insulin during ATP solution stimulation and poor insulin-activated detrusor relaxation in organ bath study. Compared to controls, the Control/Fructose and Fructose/Fructose groups showed the increased phosphorylation levels of IRS1 (Ser307) and IRS2 (Ser731); thus, suppressed the downstream effectors and urinary NOx/detrusor cGMP levels. The Fructose/Control group showed the compensatory increase of phospho-AKT (Ser473) and phospho-eNOS/eNOS levels, but decreased in eNOS, phospho-eNOS, urinary NOx, and detrusor cGMP levels. CONCLUSION: Our results show dysregulated insulin signalling at bladder mucosa should be a common mechanism of MetS-associated bladder overactivity programmed by pre-and postnatal fructose diet.

The lowest level of tumor involvement is a significant prognostic factor for upper tract urothelial carcinoma after radical nephroureterectomy: A large retrospective cohort study.

Purpose: To evaluate the prognostic impact of the lowest level of tumor location for upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). Materials and methods: Data were collected from patients with UTUC treated with RNU (01/2005- 06/2020) at a single center in Taiwan. Patients were stratified by the lowest level of tumor location into three groups: renal pelvis only (RPO), above upper ureter (AUU), and below upper ureter (BUU). We compared characteristics between groups and examined the association of the lowest level of tumor involvement with intravesical recurrence (IVR), systemic metastasis (SM), and cancer-specific mortality (CSM). Results: Overall, 1239 patients (542 RPO, 260 AUU, 437 BUU) were enrolled. Concurrent bladder cancer, multifocality, tumor architecture, lymphovascular invasion, carcinoma in situ, and variant histology were significantly different across different tumor locations. BUU had worse five-year intravesical recurrence (IVR), systemic metastasis (SM) and cancer-specific mortality (CSM) (p < 0.001, p = 0.056 and p = 0.13, respectively). In multivariable models, the lowest level of tumor involvement was an independent predictor of IVR (AUU hazard ratio (HR) = 1.52, p = 0.007; BUU HR = 1.75, p < 0.001), but only BUU was an independent predictor of SM (HR = 1.61, p = < 0.001) and CSM (HR = 1.51, p = 0.008). Conclusion: The lowest level of tumor involvement in UTUC, especially BUU, was associated with a higher risk of IVR, SM and CSM. Assessment of the lowest level of tumor involvement after RNU may help identify patients who require more intensive follow-up.

First-line Immune Checkpoint Inhibitor Versus Immune Checkpoint Inhibitor With Chemotherapy for Cisplatin-ineligible Metastatic Urothelial Carcinoma: Evidence From a Real-world, Multicenter Analysis.

Immune checkpoint inhibitors (ICIs) are widely used for first-line cisplatin-ineligible patients with metastatic urothelial carcinoma (mUC). However, whether to use ICIs as monotherapy or in combination with chemotherapy is still uncertain. We retrospectively analyzed cisplatin-ineligible patients with mUC who underwent first-line ICI monotherapy or ICI plus chemotherapy at 2 medical centers in Taiwan from 2016 to 2021. We calculated the objective response rate, progression-free survival, and overall survival (OS) using the Kaplan-Meier method and Cox regression model for multivariable analysis. In total, 130 patients were enrolled and categorized into 2 groups: an ICI monotherapy group [immunotherapy (IO), n=101] and an ICI plus noncisplatin chemotherapy group [immunotherapy and chemotherapy (IC), n=29]. The median OS of patients in the IO and IC groups was 19.5 and 9.7 months ( P =0.33). Among patients with high programmed cell death ligand-1-expressing tumors, the median OS was significantly prolonged in the IO group compared with the IC group (not reached vs. 6.3 mo, P =0.02). First-line ICI monotherapy demonstrated robust antitumor activity in cisplatin-ineligible patients with mUC. Combining noncisplatin chemotherapy with ICI did not improve clinical outcomes.

Salvage Radiotherapy Plus Androgen Deprivation Therapy for High-Risk Prostate Cancer with Biochemical Failure after High-Intensity Focused Ultrasound as Primary Treatment.

We conduct a retrospective analysis of salvage radiotherapy plus androgen deprivation therapy (SRT+ADT) for high-risk prostate cancer patients with biochemical failure after high-intensity focused ultrasound (HIFU) as the primary treatment. A total of 38 patients, who met the criteria of biochemical failure and were consecutively treated with SRT+ADT, were enrolled. All patients received intensity modulated radiotherapy with a median dose of 70 Gy to the clinical target volume. ADT was given before, during or after the course of SRT with the duration of ≦6 months (n = 14), 6−12 months (n = 12) or >12 months (n = 12). The median follow-up was 45.9 months. A total of 10 (26.3%) patients had biochemical failure after SRT+ADT. The cumulative 5-year biochemical progression free survival (b-PFS) and overall survival (OS) rate was 73.0% and 80.3%, respectively. A nadir prostate-specific antigen (nPSA) value 0.02 ng/mL was observed to predict the b-PFS in multivariate analysis. The 5-year b-PFS was 81.6% for those with nPSA < 0.02 compared with 25.0% with nPSA ≧ 0.02. The adverse effects related to SRT+ADT were mild in most cases and only three (8%) patients experienced grade 3 urinary toxicities. For high-risk prostate cancer after HIFU as primary treatment with biochemical failure, our study confirms the feasibility of SRT+ADT with high b-PFS, OS and low toxicity.

MiR-26a-5p as a useful therapeutic target for upper tract urothelial carcinoma by regulating WNT5A/ß-catenin signaling.

The role of miRNAs in cancer and their possible function as therapeutic agents are interesting and needed further investigation. The miR-26a-5p had been demonstrated as a tumor suppressor in various cancers. However, the importance of miR-26a-5p regulation in upper tract urothelial carcinoma (UTUC) remains unclear. Here, we aimed to explore the miR-26a-5p expression in UTUC tissues and to identify its regulatory targets and signal network involved in UTUC tumorigenesis. The miR-26a-5p expression was validated by quantitative real-time polymerase chain reaction (qPCR) using renal pelvis tissue samples from 22 patients who were diagnosed with UTUC and 64 cases of renal pelvis tissue microarray using in situ hybridization staining. BFTC-909 UTUC cells were used to examine the effects of miR-26a-5p genetic delivery on proliferation, migration and expression of epithelial-to-mesenchymal transition (EMT) markers. MiR-26a-5p was significantly down-regulated in UTUC tumors compared to adjacent normal tissue and was decreased with histological grades. Moreover, restoration of miR-26a-5p showed inhibition effects on proliferation and migration of BFTC-909 cells. In addition, miR-26a-5p delivery regulated the EMT marker expression and inhibited WNT5A/ß-catenin signaling and expression of downstream molecules including NF-κB and MMP-9 in BFTC-909 cells. This study demonstrated that miR-26a-5p restoration may reverse EMT process and regulate WNT5A/ß-catenin signaling in UTUC cells. Further studies warranted to explore the potential roles in biomarkers for diagnostics and prognosis, as well as novel therapeutics targets for UTUC treatment.

The Prognostic Impact of Tumor Location in pT3N0M0 Upper Urinary Tract Urothelial Carcinoma: A Retrospective Cohort Study.

Background: We aimed to evaluate the impact of tumor location on cancer outcomes in patients with pT3N0M0 upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU) with bladder cuff excision. Materials and Methods: We retrospectively reviewed 302 patients with pT3N0M0 UTUC who underwent RNU with bladder cuff excision at our institution between 2005 and 2019, including 191 renal pelvis tumors and 111 ureteral tumors. Clinicopathologic characteristics were compared between renal pelvis and ureter urothelial carcinomas. Multivariate Cox proportional hazard regression was used to assess the association between outcomes and clinical factors. Outcomes of interest included intravesical recurrence-free survival (IVRFS), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and cancer-specific survival (CSS), which were measured using the Kaplan-Meier curve with a log-rank test. Results: A total of 302 patients underwent RNU with bladder cuff excision. During the median follow-up of 42.7 months, 70 (23.2%), 95 (31.5%), and 99 (32.8%) patients experienced intravesical recurrence, local recurrence, and distant metastasis, respectively. Seventy (23.2%) patients died from UTUC. Multivariate Cox regression analysis showed that tumor location was an independent predictor of local recurrence (HR = 2.05, p = 0.001), with borderline independent significance in intravesical recurrence (HR = 1.54, p = 0.074) and distant metastasis (HR = 1.45, p = 0.08). Kaplan-Meier analysis showed that ureter tumors had a worse 5-year local recurrence (log-rank p < 0.001) and borderline worse 5-year intravesical recurrence (log-rank p = 0.055) and 5-year distant metastasis (log-rank p = 0.073). Conclusion: Ureter tumors seem to be associated with worse oncological outcomes, especially with local recurrence in UTUC. Further large and long-term studies are warranted for investigating biological differences based on tumor location.

Comparison of Robot-Assisted Laparoscopic Partial Nephrectomy with Laparoscopic Cryoablation in the Treatment of Localised Renal Tumours: A Propensity Score-Matched Comparison of Long-Term Outcomes.

Preserving renal function and controlling oncological outcomes are pertinent when managing renal neoplasms. Cryoablation is the recommended treatment only for clinical T1a stage renal tumour. Here, we compared the outcomes of robot-assisted laparoscopic partial nephrectomy (RaPN) and laparoscopic cryoablation (LCA) in the treatment of patients with localised T1-T2 renal tumours. Overall, 86 patients who received RaPN and 78 patients underwent LCA were included in this study. The intraoperative, postoperative, and oncological outcomes in the LCA group were non-inferior to the RaPN group. Moreover, LCA demonstrated shorter operative time (267.45 ± 104.53 min vs. 138.56 ± 45.28 min, p < 0.001), lower blood loss (300.56 ± 360.73 mL vs. 30.73 ± 50.31 mL, p < 0.001), and slight renal function deterioration because of the reduced invasiveness, without compromising on the oncological outcomes.

The Prognostic Impact of Tumor Architecture for Upper Urinary Tract Urothelial Carcinoma: A Propensity Score-Weighted Analysis.

PURPOSE: To assess the association of tumor architecture with cancer recurrence, metastasis, and cancer-specific survival (CSS) in patients treated with radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC) in Taiwan. MATERIALS AND METHODS: Data were collected from 857 patients treated with RNU between January 2005 and August 2016 in our hospital. Pathologic slides were reviewed by genitourinary pathologists. Propensity score weighting was performed for data analysis. RESULTS: Sessile growth pattern was observed in 212 patients (24.7%). Tumor architecture exhibited a significant association with bladder cancer history, chronic kidney disease (CKD), tumor stage, lymph node status, histological grade, lymphovascular invasion, concomitant carcinoma in situ, and the variant type [standardized mean difference (SMD) > 0.1 for all variables before weighting]. In the propensity score analysis, 424 papillary and sessile tumor architecture were analyzed to balance the baseline characteristics between the groups. Tumor architecture was an independent predictor of metastatic disease and CSS (p = 0.033 and p = 0.002, respectively). However, the associations of tumor architecture with bladder and contralateral recurrence were nonsignificant (p = 0.956 and p = 0.844, respectively). CONCLUSIONS: Tumor architecture of UTUC after RNU is associated with established features of aggressive disease and predictors of metastasis and CSS. Assessment of tumor architecture may help identify patients who could benefit from close follow-up or early administration of systemic therapy after RNU. Tumor architecture should be included in UTUC staging after further confirmation.

High Level of Aristolochic Acid Detected With a Unique Genomic Landscape Predicts Early UTUC Onset After Renal Transplantation in Taiwan.

BACKGROUND: The unusual high dialysis prevalence and upper urinary tract urothelial carcinoma (UTUC) incidence in Taiwan may attribute to aristolochic acid (AA), which is nephrotoxic and carcinogenic, exposure. AA can cause a unique mutagenic pattern showing A:T to T:A transversions (mutational Signature 22) analyzed by whole exome sequencing (WES). However, a fast and cost-effective tool is still lacking for clinical practice. To address this issue, we developed an efficient and quantitative platform for the quantitation of AA and tried to link AA detection with clinical outcomes and decipher the genomic landscape of UTUC in Taiwan. PATIENTS AND METHODS: We recruited 61 patients with de novo onset of UTUC after kidney transplantation who underwent radical nephroureterectomy. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform was developed for the quantitation of AA. Pearson's chi-square test, Kaplan-Meier method, and Cox proportional hazard model were utilized to assess the correlations among AA detection, clinicopathological characteristics, and clinical outcomes. Seven tumors and seven paired normal tissues were sequenced using WES (approximately 800x sequencing depth) and analyzed by bioinformatic tool. RESULTS: We found that high level of 7-(deoxyadenosin-N6-yl)aristolactam I (dA-AL-I) detected in paired normal tissues was significantly correlated with fast UTUC initiation times after renal transplantation (p = 0.035) and with no use of sirolimus (p = 0.046). Using WES analysis, we further observed that all tumor samples were featured by Signature 22 mutations, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-associated gene mutations, p53 mutations, no fibroblast growth factor receptor 3 (FGFR3) mutation, and high tumor mutation burden (TMB). Especially, mammalian target of rapamycin (mTOR) activation predominated in dA-AL-I-detected samples compared with those without dA-AL-I detection and might be associated with UTUC initiation through cell proliferation and suppression of UTUC progression via autophagy inhibition. CONCLUSION: Accordingly, dA-AL-I detection can provide more direct evidence to AA exposure and serve as a more specific predictive and prognostic biomarker for patients with de novo onset of UTUC after kidney transplantation.

Safety and Efficacy of Immune Checkpoint Inhibitors for Patients With Metastatic Urothelial Carcinoma and End-Stage Renal Disease: Experiences From Real-World Practice.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are used widely for treating metastatic urothelial carcinoma (mUC). In practical settings, evidence is lacking on the efficacy of ICIs in some difficult-to-treat patients, such as those with end-stage renal disease (ESRD). Herein, we evaluate the safety and efficacy of ICIs for patients with mUC and ESRD. METHODS: For this retrospective study, patients with mUC who were given ICIs at Kaohsiung Chang Gang Memorial Hospital and Linkou Chang Gung Memorial Hospital between April 2016 and November 2019 were consecutively enrolled. All clinicopathologic data, treatment responses, and adverse events were recorded. The immune-related adverse events (AEs), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between ESRD and non-ESRD groups. RESULTS: In total, 129 patients with mUC were enrolled, with 11 patients categorized as the ESRD group. Among these patients with ESRD receiving ICIs, 7 of 11 (63.6%) had high-grade (grade ≥3) AEs, chiefly hematologic toxicity. Some rarely encountered AEs were noted, including toxic epidermal necrolysis, tuberculosis reactivation, ascites, and cytokine release syndrome. Patients in the ESRD group had numerically higher ORR (54.5% vs. 28.8%, p = 0.09), PFS (7.1 vs. 3.5 months, p = 0.42), and OS (not reached vs. 15.4 months) than the non-ESRD group. A multivariate Cox regression model demonstrated that leukocytosis (hazard ratio [HR]: 2.63; 95% confidence interval [CI]: 1.23-5.63; p = 0.01) and neutrophil-to-lymphocyte ratio (HR 2.91; 95% CI: 1.30-6.53; p = 0.01) were independent prognostic factors. CONCLUSION: Administration of ICIs in patients with mUC and ESRD demonstrated a modest antitumor activity, and should be used with caution for increasing risk of hematologic toxicity.

Galectin-1 Overexpression Activates the FAK/PI3K/AKT/mTOR Pathway and Is Correlated with Upper Urinary Urothelial Carcinoma Progression and Survival.

Galectin-1 (GAL1) is a ß-galactoside-binding protein involved in multiple aspects of tumorigenesis. However, the biological role of GAL1 in upper tract urothelial carcinoma (UTUC) has not been entirely understood. Herein, we investigated the oncological effects of GAL1 expression in tumor specimens and identified related gene alterations through molecular analysis of GAL1. Clinical parameter data and tumor specimens were collected from 86 patients with pT3N0M0 UTUC who had undergone radical nephroureterectomy. We analyzed the difference in survival by using Kaplan-Meier analyses and Cox proportional regression models and in GAL1 expression by using immunohistochemical (IHC) methods. Public genomic data from the Cancer Genome Atlas (TCGA) and GSE32894 data sets were analyzed for comparison. Using four urothelial carcinoma (UC) cell lines (BFTC-909, T24, RT4, and J82) as in vitro models, we evaluated the functions of GAL1 in UC cell growth, invasiveness, and migration and its role in downstream signaling pathways. The study population was classified into two groups, GAL1-high (n = 35) and GAL1-low (GAL1 n = 51), according to IHC interpretation. Univariate analysis revealed that high GAL1 expression was significantly associated with poor recurrence-free survival (RFS; p = 0.028) and low cancer-specific survival (CSS; p = 0.025). Multivariate analysis revealed that GAL1-high was an independent predictive factor for RFS (hazard ratio (HR) 2.43; 95% confidence interval (CI) 1.17-5.05, p = 0.018) and CSS (HR 4.04; 95% CI 1.25-13.03, p = 0.019). In vitro studies revealed that GAL1 knockdown significantly reduced migration and invasiveness in UTUC (BFTC-909) and bladder cancer cells (T24). GAL1 knockdown significantly reduced protein levels of matrix metalloproteinase-2 (MMP-2) and MMP-9, which increased tissue inhibitor of metalloproteinase-1 (TIMP-1) and promoted epithelial-mesenchymal transition (EMT). Through gene expression microarray analysis of GAL1 vector and GAL1-KD cells, we identified multiple significant signaling pathways including p53, Forkhead box O (FOXO), and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT). We validated microarray results through immunoblotting, thus proving that downregulation of GAL1 reduced focal adhesion kinase (FAK), p-PI3K, p-AKT, and p-mTOR expression. We concluded that GAL1 expression was highly related to oncological survival in patients with locally advanced UTUC. GAL1 promoted UC invasion and metastasis by activating the FAK/PI3K/AKT/mTOR pathway.

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.

Gender effect on the oncologic outcomes of upper urinary tract urothelial carcinoma in Taiwan.

PURPOSE: Upper urinary tract urothelial carcinoma (UTUC) is a relatively uncommon malignancy in Western countries, affecting more men than women. By contrast, UTUC is relatively common in Taiwan and diagnosed more often in women than in men. Previous studies regarding the gender effect on cancer behaviour with UTUC have been controversial. Investigation of female predominance of UTUC in Taiwan may help improve UTUC management in Taiwan as well as understand the gender effect on urothelial carcinoma. METHODS: Between January 2005 and December 2015, 828 patients with localized UTUC treated with radical nephroureterectomy were enrolled. Cox regression analysis was performed to assess the independent roles of perioperative factors on local recurrence and systemic recurrence. RESULTS: Multivariate analysis revealed the male gender had a trend associated with higher systemic recurrence (P = 0.096) and independently associated with higher bladder recurrence (P = 0.011) and cancer-specific mortality (P = 0.014), even after taking smoking and other established prognostic factors into consideration. Bladder cancer history and multifocal disease are strongly associated with bladder recurrence. CONCLUSION: Compared with female UTUC patients, male UTUC patients in Taiwan were associated with more bladder recurrences and higher cancer-specific mortality and had a trend associated with more systemic recurrences.

Modest dose anti-thymocyte globulin administered intraoperatively is safe and effective in kidney transplantations: a retrospective study.

BACKGROUND: Anti-thymocyte globulin (ATG) as induction therapy in renal transplantation is facing the dilemma of reducing the incidence of acute rejection (AR) and delayed graft function (DGF) or increasing risks of infection and malignancy. The purpose of this study was to delineate the safety and efficiency of the optimal ATG dosage. METHODS: We retrospectively evaluated 91 deceased donor kidney transplant recipients (KTRs) in our institution between March 2011 and January 2019. The patients were classified into three groups based on induction therapy: (1) Group 1: modest-dose ATG (three mg/kg) intraoperatively (N = 21); (2) Group 2: low-dose ATG (1-1.5 mg/kg) intraoperatively (N = 23); (3) Group 3: basiliximab 20 mg both on day 0 and 4 (N = 47). In Groups 1 and 2, all patients received a daily low-dose program (1-1.5 mg/kg each day) with target dosage of six mg/kg. Induction therapy was combined with standard immunosuppressive regimen consisting of calcineurin inhibitors, mycophenolate/the mammalian target of rapamycin inhibitors and corticosteroids. RESULTS: There was no significant difference in patient characteristics among groups. The outcomes of infection rate, biopsy-proven acute rejection, post-transplant diabetes mellitus, graft survival, and patient survival were similar among groups. Compared to the daily low-dose ATG regimen, the intraoperative modest-dose regimen did not cause more dose interruption and hence was more likely to reach the target ATG dosage. The intraoperative modest-dose regimen also seemed to reduce the rate of DGF. DISCUSSION: In recent years, a trend of using a "lower" dose of ATG has seemed to emerge. Our results suggest intraoperative modest-dose ATG followed by daily low-dose ATG regimen was safe and effective in cadaveric renal transplantations for preventing DGF, AR, and graft loss.