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Ubiquitin-conjugating enzyme E2T (UBE2T), a member of the E2 family, has been reported to be overexpressed in certain tumor types and to have an important role in the Fanconi anemia pathway. However, the role of UBE2T in clear cell renal cell carcinoma (ccRCC) has not been clarified. MicroRNAs (miRNAs) participate in tumorigenesis by binding to genes and proteins that regulate cell proliferation or cell apoptosis. The aim of this study was to determine the role of UBE2T and the relationship between miR-182-5p and UBE2T in ccRCC. In the present study, UBE2T expression levels in ccRCC tissues and cells were assessed using real-time quantitative PCR (RT-qPCR) and western blotting. UBE2T protein expression was assessed in a total of 93 ccRCC patients from Peking University First Hospital (PKU) via immunohistochemistry (IHC). The effects of UBE2T knockdown on ccRCC cells were assessed with MTS assays, wound healing assays, Transwell invasion assays and flow cytometry. The effects of in vivo treatment were evaluated through xenograft experiments. The relationship between miR-182-5p and UBE2T was verified with a dual-luciferase reporter gene assay. We found that UBE2T was highly expressed in ccRCC cells and tissues. High UBE2T expression was positively correlated with advanced pathological stage, histological grade, maximum tumor diameter and distant metastasis. Multivariate analysis revealed that UBE2T expression was an independent risk factor for overall survival (OS) and recurrence-free survival (RFS) in patients with ccRCC. Knockdown of UBE2T significantly suppressed RCC cell proliferation, migration and invasion. Flow cytometry analysis showed that UBE2T knockdown promoted RCC cell cycle arrest at G2/M phase and increased cell apoptosis. The xenograft model confirmed that suppression of UBE2T significantly delayed tumor formation and growth in vivo. In addition, miR-182-5p inhibited UBE2T protein expression by targeting UBE2T mRNA and then inhibited the proliferation, migration and invasion of ccRCC cell. Our research reveals that UBE2T likely plays a critical role in ccRCC progression and may be a potential therapeutic target for ccRCC.

Purpose: To compare the tumor growth kinetics between sporadic clear cell renal cell carcinoma (ccRCC) and Von Hippel-Lindau disease-associated renal cell carcinoma (VHL-associated RCC). To analyze predictive markers for the growth rate of these two types of RCC.Methods: The clinical data of patients with renal tumors who received active surveillance were collected retrospectively. Immunohistochemical staining was utilized to analyze the expression levels of VHL, PBRM1, H3K36me3, and BAP1 in the postoperative specimens.Results: The age of the VHL group was significantly younger than that of the sporadic group (PConclusion: Sporadic ccRCC grew faster than VHL-associated RCC. High histologic grade, low VHL expression and negative PBRM1 expression were predictors of faster growth in sporadic ccRCC. A large initial MTD was a predictor of faster growth for VHL-associated RCC.

Local retroperitoneal recurrence (RPR) after racial nephrectomy (RN) of renal cell carcinoma (RCC) remains a therapeutic challenge and has a poor prognosis. We aimed to compare the oncological outcomes of patients with RPR treated with RPR surgery or targeted therapy alone and assess the prognostic factors of these patients.This is a retrospective multi-center study of patients with RPR after prior RN treated with or without surgical treatment from 2008 to 2020. RPR of RCC is defined as an ipsilateral recurrence confined to the renal fossa, adrenal gland or retroperitoneal lymph nodes after prior nephrectomy, which was diagnosed by cross-sectional imaging. Clinical and pathological features, perioperative complications were reported using descriptive statistics. Cancer-specific survival (CSS) was evaluated by Kaplan-Meier method and studied using Cox proportional hazards model.Median follow-up period was 35 months (IQR 20-61) for the RPR surgery group and 23 months (IQR 9-40.5) for the targeted therapy group. No patients had distant metastatic disease at the time of RPR diagnosis. Treatment with RPR surgery resulted in significantly longer CSS than targeted therapy alone (P.001). In multivariable analysis, high Fuhrman grade, size of RPR tumor, mixed type of RPR, multiple recurrence lesions and the absence of RPR surgery were associated with a significantly increased risk of death from RCC.Aggressive surgical resection of RPR after RN represents a potentially curative treatment for selected RCC patients without synchronous metastases, resulting in significantly longer CSS than targeted therapy alone.

Local retroperitoneal recurrence (RPR) after radical nephrectomy (RN) is rare in patients with renal cell carcinoma (RCC); however, it is associated with poor prognosis and lacks standard treatment. Our study aimed to assess oncological outcomes and prognostic factors of patients that underwent targeted therapy for RPR after RN, and to evaluate the role of presurgical targeted therapy in this context. This was a retrospective multicenter study of 85 patients with RPR treated with targeted therapy for RPR after RN (July 2008-October 2020). Clinical and pathological characteristics were reported using descriptive statistics. Cancer-specific survival (CSS) was examined using the Cox proportional hazards model. The median follow-up time was 50 months (95% confidence interval [CI]: 33.3-66.7) after the RPR diagnosis. The median CSS was 96 months in the presurgical targeted therapy followed by surgical resection group and 42 months (95% CI: 28.8-55.2) in the targeted therapy alone group (P = .0011). In multivariate analysis, International Metastatic RCC Database Consortium classification intermediate/poor risk, number of recurrence lesions and surgical resection were independent predictors of CSS. Presurgical targeted therapy may increase the feasibility of tumor resection for RPR after RN. Patients who underwent surgical resection following presurgical targeted therapy had better CSS than those treated with targeted therapy alone.

The KangDuo surgical robot (KD-SR) was recently developed in China.To compare the safety and efficacy of the KD-SR versus the da Vinci Si Surgical System (DV-SS-Si) for robot-assisted partial nephrectomy (RAPN).A double-center prospective randomized controlled noninferiority trial of patients aged 18-75 yr with a suspicion of T1a N0M0 renal cancer (RENAL nephrometry score ≤9) was conducted.RAPN with the KD-SR versus the DV-SS-Si.The primary endpoint was the success rate of operation. The operation was successful if (1) there was no open or laparoscopic conversion, (2) the warm ischemia time was30 min for RENAL nephrometry scores of 4-6 or 40 min for RENAL nephrometry scores of 7-9, and (3) the pathological margin was negative. The secondary endpoint was the estimated glomerular filtration rate (eGFR). A threshold of 10% was set to demonstrate noninferiority.From September 2020 to March 2021, 100 participants were enrolled, of whom 99 (49 in the KD-SR group and 50 in the DV-SS-Si group) were finally included in the full analysis set and 98 (49 in the KD-SR group and -49 in the DV-SS-Si group) in the per-protocol set. Baseline demographic and clinical characteristics were similar between the two groups. All surgeries were completed successfully. The eGFR at postoperative weeks 4-12 and adverse events were similar between the two groups. The docking time and suture time per stitch were longer in the KD-SR group. The main limitation was that a negative margin was considered as the primary outcome rather than survival.The KD-SR achieved noninferior outcomes as compared with the DV-SS-Si regarding safety and efficacy for T1a tumors.The first trial comparing the KangDuo surgical robot (KD-SR) versus the da Vinci Si Surgical System for robot-assisted partial nephrectomy showed that the KD-SR is a viable option for minimally invasive treatment of T1a renal tumors.

Recent studies indicate mammalian target of rapamycin (mTOR) may play an important role in PCa progression and drug resistance. Here, we investigated the effects of a novel mTORC1/C2 dual inhibitor, AZD2014, on naive and docetaxel (Doc)‐pre‐treated castration‐resistant PCa (CRPC) cells and explored its therapeutic potential in CRPCs. In the current study, AZD2014 has a greater inhibitory effect against 4EBP1 and AKT phosphorylation than rapamycin in CRPC cells and prevented the feedback activation of AKT signalling. Importantly, AZD2014 suppressed CRPC cell growth in vitro by suppressing proliferation, apoptosis, cell cycle arrest at G1 phase and autophagy to a greater extent than rapamycin. Moreover, AZD2014 was more efficacious than rapamycin in inhibiting migration, invasion and EMT progression in Doc‐sensitive and Doc‐resistant CRPC cells. Overall, AZD2014 showed significant antitumour effects. Thereby, the current study highlights a reliable theoretical basis for the clinical application of AZD2014 in both Doc‐sensitive and Doc‐resistant CRPCs.

Introduction: To discuss the clinical feasibility and oncologic outcomes of pure transperitoneal laparoscopic radical nephroureterectomy (LSRNU) for upper urinary tract urothelial carcinoma (UTUC).Methods: Between July 2010 and December 2020, 115 patients were admitted to the hospital with a diagnosis of UTUC treated with pure LSRNU by one surgeon. A special laparoscopic bulldog clamp was placed at the bladder cuff before cutting and suturing. The clinical and follow-up data were preoperatively collected and analyzed. Overall survival (OS) and cancer-specific survival (CSS) were estimated by the Kaplan–Meier method.Results All surgeries were completed uneventfully. The mean operative time was 145.69 minutes. The mean estimated blood loss was 56.61 ml. The mean removal time of the drain was 3.46 days. The mean time to liquid diet was 1.32 days, and the ambulation time was 1.50 days. All surgeries were effectively completed, and no case required open conversion. According to the Clavien–Dindo classification system, postoperative complications occurred in two patients (II, III). The mean length of postoperative hospital stay was 5.78 days. The median follow-up duration was 54.50 months. Recurrence in the bladder was 16.0% (15/94), compared with 4.6% (4/87) in the contralateral upper tract. The 5-year OS and CSS rates were 78.9% and 81.4%, respectively.Conclusion Pure transperitoneal laparoscopic RNU is a safe and effective minimally invasive technology for the management of UTUC.

Background To present our experiences with partial nephrectomy (PN) through retroperitoneal approach (RP) with the Kangduo robotic system. Methods From December 2020 to February 2021, the perioperative data of eleven patients underwent PN through RP with the Kangduo robotic system were collected prospectively. Results For the R.E.N.A.L. nephrometry score, 72.7% of patients had a low score (4-6) and 27.3% of patients had a medium score (7-9). Seven tumors were posterior (P), four tumors were on the midline (X). All procedures were completed successfully. The median warm ischemia time was 18.5 (IQR, 13.7-21.0) mins. None of the patients had positive surgical margins at definitive histology (all pT1a). No high-grade perioperative complications or device-related adverse events occurred. At a mean follow-up of 8±0.8 months, no complications occurred in all patients. Conclusions RPPN using the novel Kangduo robotic system is a safe and effective option for managing posterior and lateral renal tumors with R.E.N.A.L. nephrometry scores ≤ 9. This article is protected by copyright. All rights reserved.

The high incidence and vulnerability to recurrence of bladder cancer (BLCA) is a challenge in the clinical. Recent studies have revealed that NFE2L3 plays a vital role in the carcinogenesis and progression of different human tumors. However, the role of NFE2L3 in BLCA has not been elucidated. In this study, NFE2L3 expression was significantly increased in BLCA samples. Its high expression was associated with advanced clinicopathological characteristics and was an independent prognostic factor for overall survival and metastasis-free survival in 106 patients with BLCA. In vitro and in vivo experiments demonstrated that NFE2L3 knockdown inhibited BLCA cells proliferation by inducing the cell cycle arrest and cell apoptosis. Meanwhile, NFE2L3 overexpression promotes BLCA cell migration and invasion in vitro cell lines and in vivo xenografts. Moreover, we identified many genes and pathway alterations associated with tumor progression and metastasis by performing RNA-Seq analysis and functional enrichment of NFE2L3 overexpressing BLCA cells. Mechanistic investigation reveals that overexpression of NFE2L3 promoted epithelial-mesenchymal transition in BLCA cells with decreased expression of gap junction-associated protein ZO-1 and epithelial marker E-cadherin with the elevation of transcription factors Snail1 and Snail2. Finally, we performed a comprehensive proteomics analysis to explore more potential molecular mechanisms. Our findings revealed that NFE2L3 might serve as a valuable clinical prognostic biomarker and therapeutic target in BLCA.

BackgroundRenal cell carcinoma is gradually characteristic of the accumulation of lipid-reactive oxygen species. And, the ferroptosis-related LncRNAs have been reported strongly correlated with tumorigenesis and progression. However, the further functions of ferroptosis-related LncRNAs in clear cell renal cell carcinoma have not been explored. MethodsAfter sample cleaning, data integration, and batch effect removal, we used the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) public database to screen out the expression and prognostic value of ferroptosis-related LncRNAs and then performed the molecular subtyping. The molecular subtyping was developed using the K-means. Then, the KEGG pathway enrichment and statistical analyses of the immune microenvironment and clusters were carried out. The outcomes indicated significant differences in the immune microenvironment and potential therapeutic targets between the two clusters. Then, LASSO Cox regression was performed to establish the 5-LncRNAs-based prognostic signature. The signature could accurately predict patient prognosis and be used as an independent clinical risk factor. And the 5 LncRNAs were validated in the cell lines and clinical samples. We then combined significant clinical parameters in multivariate Cox regression and prognostic signature to construct a clinical predictive nomogram, which provides appropriate guidance for predicting the overall survival of ccRCC patients.ResultsThe prognostic DEFRLncRNAs were identified, and 5 LncRNAs were finally utilized to establish the prognostic signature in the TCGA cohort, which was subsequently validated in the internal and external cohorts. Moreover, we conducted the molecular subtyping and divided the patients in the TCGA cohort into two clusters, showing the difference in the Hallmark pathways, immune infiltration, expression of the immune target, and drug therapy. Furthermore, the nomogram was established better to predict the clinical outcomes of the ccRCC patients. ConclusionsOur study conducted molecular subtyping and established a novel predictive signature based on the ferroptosis-related LncRNAs, which could accurately predict prognosis and potential therapeutic targets in ccRCC patients.

Background: Therapy-related neuroendocrine prostate cancer (NEPC) is a lethal castration-resistant prostate cancer (CRPC) subtype that, at present, lacks well-characterized molecular biomarkers. The clinical diagnosis of this disease is dependent on biopsy and histological assessment: methods that are experience-based and easily misdiagnosed due to tumor heterogeneity. The development of robust diagnostic tools for NEPC may assist clinicians in making medical decisions on the choice of continuing anti-androgen receptor therapy or switching to platinum-based chemotherapy.Methods: Gene expression profiles and clinical characteristics data of 208 samples of metastatic CRPC, including castration-resistant prostate adenocarcinoma (CRPC-adeno) and castration-resistant neuroendocrine prostate adenocarcinoma (CRPC-NE), were obtained from the prad_su2c_2019 dataset. Weighted Gene Co-expression Network Analysis (WGCNA) was subsequently used to construct a free-scale gene co-expression network to study the interrelationship between the potential modules and clinical features of metastatic prostate adenocarcinoma and to identify hub genes in the modules. Furthermore, the least absolute shrinkage and selection operator (LASSO) regression analysis was used to build a model to predict the clinical characteristics of CRPC-NE. The findings were then verified in the nepc_wcm_2016 dataset.Results: A total of 51 co-expression modules were successfully constructed using WGCNA, of which three co-expression modules were found to be significantly associated with the neuroendocrine features and the NEPC score. In total, four novel genes, including NPTX1, PCSK1, ASXL3, and TRIM9, were all significantly upregulated in NEPC compared with the adenocarcinoma samples, and these genes were all associated with the neuroactive ligand receptor interaction pathway. Next, the expression levels of these four genes were used to construct an NEPC diagnosis model, which was successfully able to distinguish CRPC-NE from CRPC-adeno samples in both the training and the validation cohorts. Moreover, the values of the area under the receiver operating characteristic (AUC) were 0.995 and 0.833 for the training and validation cohorts, respectively.Conclusion: The present study identified four specific novel biomarkers for therapy-related NEPC, and these biomarkers may serve as an effective tool for the diagnosis of NEPC, thereby meriting further study.

Background Metastasis is the primary cause of death in renal cell carcinoma (RCC). Loss of cell-to-cell adhesion, including tight junctions (TJs) is the initial step in the process of metastasis. Claudin-7 (CLDN7) is a major component of TJs. However, the clinical significance and its regulation of kidney tumorigenesis remain poorly understood. Methods A total of 120 fresh clear cell RCC (ccRCC) specimens and 144 primary RCC and adjacent nonmalignant renal paraffin specimens were obtained from Department of Urology, Peking University First Hospital. Expression of CLDN7 in ccRCC tissues and cell lines were determined using bioinformatic data mining, quantitative real-time PCR (qRT-PCR), Western blotting and immunostaining. The clinical significance of CLDN7 expression and promoter DNA methylation status was analyzed in ccRCC patients from Peking University First Hospital and The Cancer Genome Atlas. Additionally, the methylation specific-PCR, bisulfite genomic sequencing and demethylation analysis of CLDN7 were performed. Biological functions of CLDN7 were investigated by examining cell proliferation using MTS assays and EdU incorporation assays, cell migration by in vitro wound healing assays and transwell migration assays, cell invasion by transwell invasion assays, and cell apoptosis by flow cytometry. Mouse model experiments were performed to confirm the effects of CLDN7 on tumor growth and metastasis in vivo. The molecular mechanism of CLDN7 function was investigated using gene-set enrichment analysis (GSEA) and high-throughput cDNA sequencing (RNA-Seq) and confirmed by qRT-PCR, Western blot and immunostaining in vitro and in vivo. Results Our findings revealed that CLDN7 is frequently downregulated via hypermethylation of its promoter in ccRCC. CLDN7 can help predict aggressive tumor status and poor prognosis in ccRCC patients. Interestingly, hypermethylation of the CLDN7 promoter was related to advanced ccRCC status and poor prognosis. Moreover, overexpression of CLDN7 induced cell apoptosis, suppressed proliferation, migration and invasion abilities of ccRCC cells both in vitro and in vivo. Additionally, GSEA and RNA-Seq results showed that CLDN7 had negative effects in cancer-associated signaling pathways and (epithelial-mesenchymal transition) EMT-related pathways. These results were validated by qRT-PCR, Western blot and immunostaining. Conclusions We have demonstrated a previously undescribed role of CLDN7 as a ccRCC suppressor and suggest that loss of CLDN7 potentiates EMT and tumor progression. CLDN7 may serve as a functional tumor suppressor in tumor progression and a potential biomarker and target in patients with ccRCC. Electronic supplementary material The online version of this article (10.1186/s13046-018-0924-y) contains supplementary material, which is available to authorized users.

BACKGROUND: Traditional ureteral stricture balloon dilation was performed with fluoroscopic assistance. The use of a C-arm X-ray machine delivered hazardous radiation to both surgeons and patients. In attempt to eliminate the radiation hazard, we developed a F4.5/6.5 ureteroscope assisted intraoperative X-ray free balloon dilation surgical approach to treat ureteral stricture and to verify its safety and efficacy. Specifically, this method had not been previously reported in the literature. METHODS: We demonstrated an intraoperative X-ray free balloon dilation with detailed step-by-step procedures description and video illustration. Clinical data of patients undergoing minimally invasive endourological treatment for ureteral stricture between February 2015 and November 2019 were retrospectively analyzed. All steps of X-ray free balloon dilation were carried out under direct vision of a ureteroscope, and two indwelling F7 ureteral stents were used for 3 months postoperatively. Preoperative, intraoperative, and postoperative clinical data were evaluated, and follow-up results were reported. Successful outcome was defined as disappearance of preoperative symptoms, relief of hydronephrosis and stable of renal function. Univariate and multivariate prognostic analyses were performed. RESULTS: We identified 109 patients who received endourological treatment for ureteral stricture in our hospital’s medical database. After excluding patients undergone simple catheter dilation, endoureterotomy and other treatment method, 76 patients received balloon dilation without intraoperative fluoroscopic guidance were included in our study. 4/76 patients report a grade II complication (urinary tract infections, UTIs) according to Clavien Dindo classification. In the 22.5 months median follow-up time, the one-year cumulative success rate and two-year cumulative success rate were 85.9% and 80.2% (61/76), respectively, and the majority (13/15, 86.7%) recurrence of ureteral stricture or hydronephrosis deterioration were found within two years after surgery. The longer stenotic lesion length (>5 mm) or multiple ureter stenosis and compromised blood supply of ureter were significantly associated with postoperative stenosis recurrence. CONCLUSIONS: X-ray free endoscopic balloon dilation is a safe and effective procedure that could be performed on patients with ureteral stenosis.

BACKGROUND: To evaluate and compare the natural history and growth kinetics of sporadic clear cell renal cell carcinoma (ccRCC) with those of ccRCC in von Hippel-Lindau disease (VHL). METHODS: Sixty patients in the sporadic group with 61 tumors and 15 patients in the VHL group with 30 tumors whom all underwent delayed surgery after at least 12 months of active surveillance (AS) were enrolled to conduct a retrospective cohort study. The growth rate was calculated, and the growth kinetics between the sporadic and VHL groups were compared. The patient and tumor characteristics were reviewed, and their correlation with growth rate was analyzed. RESULTS: The mean growth rate of sporadic ccRCC was 0.91 cm/year (ranging from 0–4.74 cm/year) and that of VHL ccRCC was 0.47 cm/year (ranging from 0.04–1.89 cm/year). The growth rate of sporadic ccRCC showed a tendency of being faster than that of VHL ccRCC but did not reach statistical significance (P=0.07). The factors affecting the growth rate were different between the two groups. For VHL ccRCC, the only factor that correlated with growth rate was initial tumor diameter (P

Background To evaluate the prognostic significance of the novel index combining preoperative hemoglobin and albumin levels and lymphocyte and platelet counts (HALP) in renal cell carcinoma (RCC) patients. Methods We enrolled 1360 patients who underwent nephrectomy in our institution from 2001 to 2010. The cutoff values for HALP, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio were defined by using X-tile software. Survival was analyzed by the Kaplan–Meier method, with differences analyzed by the log-rank test. Multivariate Cox proportional-hazards model was used to evaluate the prognostic significance of HALP for RCC. Results Low HALP was significantly associated with worse clinicopathologic features. Kaplan-Meier and log-rank tests revealed that HALP was strongly correlated with cancer specific survival (P

BACKGROUND To retrospectively explore the factors influencing Mayo Adhesive Probability (MAP) score in the setting of partial nephrectomy. MATERIAL AND METHODS Data of 93 consecutive patients who underwent laparoscopic and open partial nephrectomy from September 2015 to June 2016 were collected and analyzed retrospectively. Preoperative radiological elements were independently assessed by 2 readers. Ordinal logistic regression analyses were performed to evaluate radiological and clinicopathologic influencing factors of MAP score. RESULTS On univariate analysis, MAP score was associated with male sex, older age, higher body mass index (BMI), history of hypertension and diabetes mellitus, and perirenal fat thickness (posterolateral, lateral, anterior, anterolateral, and medial). On multivariate analysis, only posterolateral perirenal fat thickness (odds ratio [OR]=0.88 [0.82-0.95], p=0.001), medial perirenal fat thickness (OR=0.90 [0.83-0.98], p=0.01), and history of diabetes mellitus (OR=5.42 [1.74-16.86], p=0.004) remained statistically significant. Tumor type (malignant vs. benign) was not statistically different. In patients with renal cell carcinoma (RCC), there was no difference in tumor stage or grade. CONCLUSIONS MAP score is significantly correlated with some preoperative factors such as posterolateral and medial perirenal fat thickness and diabetes mellitus. A new radioclinical scoring system including these patient-specific factors may become a better predictive tool than MAP score alone.

To validate plasma fibrinogen and serum cholesterol levels as prognostic factors for patients with renal cell carcinoma (RCC) and to explore the prognostic value of their combination.Medical data for 1360 RCC patients after nephrectomy were collected. X-tile software was used to determine the cutoff values. The association between clinicopathological factors and fibrinogen and cholesterol levels was determined, and factors predicting survival were examined by multivariate analysis.The median follow-up was 67 months (interquartile range 36-74 months). On univariate and multivariate analysis, both preoperative plasma fibrinogen and serum cholesterol were independent prognostic factors of cancer-specific survival (CSS) and progression-free survival (PFS). By combining the two factors, we developed a novel index, fibrinogen-cholesterol (FC) score and found it to have better prognostic accuracy than the two factors alone. FC was an independent prognostic factor for both CSS (FC score = 1: hazard ratio [HR] = 3.207, 95% confidence interval [CI] = 1.775-5.793; FC score = 2: HR = 5.516, 95% CI = 2.891-10.527) and PFS (FC score = 1: HR = 2.178, 95% CI = 1.545-3.071; FC score = 2: HR = 3.709, 95% CI = 2.355-5.840).Both preoperative plasma fibrinogen and serum cholesterol levels are independent prognostic factors for CSS and PFS in RCC patients after nephrectomy. A novel indicator, FC score, could be considered a novel preoperative prognostic index in RCC.

// Xiaohong Su 1, 2, * , Han Hao 1, 2, * , Xuesong Li 1, 2 , Zhisong He 1, 2 , Kan Gong 1, 2 , Cuijian Zhang 1, 2 , Lin Cai 1, 2 , Qian Zhang 1, 2 , Lin Yao 1, 2 , Yi Ding 1, 2 , Yanqing Gong 1, 2 , Dong Fang 1, 2 , Zheng Zhang 1, 2 , Liqun Zhou 1, 2 1 Department of Urology, Peking University First Hospital, Xicheng, Beijing, China 2 Institute of Urology, Peking University, National Urological Cancer Center, Beijing, China * These authors contributed equally to this work Correspondence to: Liqun Zhou, email: zhoulqmail@sina.com Zheng Zhang, email: doczhz@aliyun.com Keywords: fluorescence in situ hybridization (FISH), upper tract urothelial carcinoma (UTUC), high grade, radical nephroureterectomy (RNU), conservative management Received: September 23, 2016 Accepted: January 24, 2017 Published: February 15, 2017 ABSTRACT Here, we assessed the diagnostic accuracy of fluorescence in situ hybridization (FISH) for detecting aggressive upper tract urothelial carcinoma (UTUC). A total of 210 UTUC patients from a single hospital in China were enrolled in this retrospective study between 2012 and 2016. Patients were classified as FISH-positive or -negative based on FISH analysis of voided urine, and the clinicpathological characteristics of these two patient groups were compared. Patients with positive FISH results had more advanced tumor stages and higher tumor grades than those with negative results. The overall sensitivity of FISH for detecting advanced UTUC was 62.4% (131/210). The sensitivity and positive predictive values of positive FISH results were 76.5% and 59.5% for high-grade UTUC and 71.7% and 58.0% for muscle-invasive UTUC. These data suggest that voided urine FISH results accurately predict advanced UTUC and might help distinguish patients with aggressive disease from those who might benefit from conservative management.

Objectives: To evaluate the prognosis of non-metastatic T3a renal cell carcinoma (RCC) with partial nephrectomy (PN). Patients and Methods: We retrospectively evaluated 125 patients with non-metastatic T3a RCC. Patients undergoing PN and radical nephrectomy (RN) were strictly matched by clinic-pathologic characteristics. Log-rank test and Cox regression model were used for univariate and multivariate analysis. Results: 18 pair patients were matched and the median follow-up was 35.5 (10-86) months. PN patients had a higher postoperative eGFR than RN patients (P=0.034). Cancer-specific survival (CSS) and recurrence-free survival (RFS) did not differ between two groups (P=0.305 and P=0.524). On multivariate analysis, CSS decreased with positive surgical margin and anemia (both P

Background The aim of the present study was to explore the mechanism underlying the poor efficacy of pyrotinib, propose and validate a strategy for pyrotinib-combined therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). Methods Human GC cell lines and patient-derived xenograft (PDX) models were used to evaluate the antitumor activity and mechanisms of pyrotinib. One pyrotinib-refractory PDX model was established to explore the potential mechanisms underlying drug resistance, propose an optimal therapeutic strategy, and further validate in a phase I clinical trial (NCT03480256). Results Pyrotinib exerted strong antitumor activity in HER2-positive GC cells and PDX models via suppressing the activation of the AKT/S6 signaling pathway. In addition, dysregulation of the cell cycle, represented by aberrant activation of the CCND1-CDK4/6-Rb axis, was found in the pyrotinib-refractory PDX model compared with the parental model. Then, combination therapy of pyrotinib with a CDK4/6 inhibitor (SHR6390) was proposed and its strong tumor growth inhibition was observed in the pyrotinib refractory-PDX model. Three HER2-positive GC patients after multiline therapies were subsequently enrolled in our clinical trial treatment with pyrotinib (400 mg/d for 28 days per cycle) combined with SHR6390 (100 mg/d for 21 days per cycle). After two cycles of therapy, two patients achieved a partial response (PR) and one patient achieved decreased stable disease (SD) with a progression-free survival of 120, 199, and 110 d, respectively. The common adverse events included leucopenia (grade 2 to 3), neutropenia (grade 2 to 4), anemia (grade 1 to 3), and thrombocytopenia (grade 1). Conclusions This representative translational study suggests that a combination treatment of pyrotinib with SHR6390 may serve as a promising strategy for patients with HER2-positive GC after systematic treatment failure. The optimal drug doses and tolerability of this combination treatment will be explored in future studies. Legal entity responsible for the study Zuhua Chen. Funding The National Key Research and Development Program of China (No. 2017YFC1308900, 2017YFC0908400). Disclosure All authors have declared no conflicts of interest.

Introduction: We aimed to compare oncological outcomes by surgery type (segmental ureterectomy [SU] vs. radical nephroureterectomy [RNU]) in a large cohort of patients with upper tract urothelial carcinoma (UTUC) of the distal ureter.Methods: We performed a retrospective analysis of 219 patients with UTUC of the distal ureter among 931 patients with UTUC who underwent SU and RNU. Clinicopathological outcomes were evaluated. Cancer-specific survival (CSS), overall survival (OS), local recurrence-free survival (RFS), intravesical recurrence-free survival (IVRFS), contralateral recurrence-free survival, and distal metastasis-free survival were assessed by the Kaplan-Meier method and Cox regression, estimating hazard ratios (HR) and 95% confidence intervals (CIs).Results: A total of 179 (81.7%) patients underwent RNU and 40 (18.3%) underwent SU: 85 males (47.5%) with RNU and 17 (42.5%) with SU (p=0.568). The median age with RNU and SU was 71 years (range 31–86) and 70 years (range 46–90), respectively (p=0.499). The T stage of the two groups did not differ (p=0.122), nor did mean tumour length (3.35±2.62 vs. 3.25±2.14; p=0.953), grade (p=0.075), tumour necrosis (p=0.634), or followup time (months) (58.1±8.1 vs. 63.7±3.4; p=0.462). The two groups did not differ in CSS (p=0.358) or OS (p=0.206), and surgery type did not predict CSS (HR 0.862; 95% CI 0.469–1.585; p=0.633) or OS (HR 0.764; 95% CI 0.419–1.392; p=0.379). Local RFS was higher with RNU than SU (96.2% vs. 86.0%; p=0.02), but the groups did not differ in IVRFS (p=0.661), contralateral RFS (p=0.183), or distant metastasis-free survival (p=0.078). On multivariate analysis, SU was associated with local RFS (HR 5.069; 95% CI 1.029–24.968; p=0.046) and distant metastasis-free survival (HR 6.497; 95% CI 1.196–35.283; p=0.03). Local RFS was lower with SU than RNU for patients with pT3–4 stage (p=0.006).Conclusions: Long-term oncological outcomes were equivalent with SU and RNU in patients with UTUC of the distal ureter. SU affected local recurrence survival, especially with advanced tumour stage, and distant metastasis survival.

To evaluate the association between tumor squamous and/or glandular differentiation and tumor biological characteristics and to validate the impact of these histologic variants on oncologic outcomes of UTUC patients. We retrospectively analyzed the data of 687 UTUC patients who underwent radical nephroureterectomy in our institute, from Aug 1, 1999, to Dec 31, 2011. All pathologic sections were reevaluated for histologic differentiation variations (squamous and glandular). The clinicopathological variables of patients were reviewed. Among the 687 UTUC patients in our study, 53 (7.7 %) had squamous differentiation, 20 (2.9 %) had glandular differentiation and 8 (1.2 %) had both histologic variants. Patients with mixed histologic variant tended to have significant larger percentage of sessile tumor architecture (58.0 vs 18.2 %), presence of CIS (7.4 vs 2.3 %), advanced T stage, advanced tumor grade and lymph node metastasis (17.3 vs 6.6 %; all p

Aim: We intended to construct DNA methylation-based models for the diagnosis and prognosis of three common urological cancers including prostate adenocarcinoma, renal clear cell carcinoma and bladder urothelial carcinoma. Materials & methods: Total 450K methylation array data from the cancer genome atlas and gene expression omnibus datasets were downloaded. Moderated t-statistics and least absolute shrinkage and selection operator method were used to build diagnosis and prognosis models. Results: Our diagnostic panels including 128 CpG sites had high sensitivity and accuracy in distinguishing samples and could identify lymphatic metastases in prostate adenocarcinoma patients. The prognostic models with 19 CpG sites for renal clear cell carcinoma and 21 CpG sites for bladder urothelial carcinoma were able to distinguish high- and low-risk patients and improve the predictive ability of the tumor node metastasis staging system. Conclusion: DNA methylation may afford reliable biomarkers in the diagnosis and prognosis of common urological cancers.

Background 5-Hydroxymethylcytosine (5hmC) is converted from 5-methylcytosine (5mC) by a group of enzymes termed ten-eleven translocation (TET) family dioxygenases. The loss of 5hmC has been identified as a hallmark of most types of cancer and is related to tumorigenesis and progression. However, the role of 5hmC in bladder cancer is seldom investigated. Vitamin C was recently reported to induce the generation of 5hmC by acting as a cofactor for TET dioxygenases. In this study, we explored the role of 5hmC in bladder cancer and the therapeutic efficacy of vitamin C in increasing the 5hmC pattern. Results 5hmC was decreased in bladder cancer samples and was related to patient overall survival. Genome-wide mapping of 5hmC in tumor tissues and vitamin C-treated bladder cancer cells revealed that 5hmC loss was enriched in cancer-related genes and that vitamin C treatment increased 5hmC levels correspondingly. Vitamin C treatment shifted the transcriptome and inhibited the malignant phenotypes associated with bladder cancer cells in both in vitro cell lines and in vivo xenografts. Conclusions This study provided mechanistic insights regarding the 5hmC loss in bladder cancer and a rationale for exploring the therapeutic use of vitamin C as a potential epigenetic treatment for bladder cancer. Electronic supplementary material The online version of this article (10.1186/s13148-018-0527-7) contains supplementary material, which is available to authorized users.

Table S1. The clinicopathological features of 120 ccRCC patients from Peking University First Hospital. (DOCX 14 kb)

Table S3. Correlation between CLDN7 expression and 653 clinicopathological features in 534 ccRCC patients from TCGA. (DOCX 15 kb)

Table S4. Correlation between CLDN7 promoter DNA methylation site (cg00072720) and clinicopathological features in 319 ccRCC patients from TCGA. (DOCX 15 kb)

Aim: We conducted this study to identify gene promoter methylation status and clinical predictors for upper tract urothelial carcinoma (UTUC) patients. Materials & methods: Using methylation-sensitive PCR, we examined ten genes promoter methylation status in 687 UTUC patients. Results: A methylated promoter of three genes to predict higher tumor stage (T3 and T4), five genes to predict higher tumor grade (G3) and one gene to predict pN+ were certified in this study. Nine factors were significantly associated with poor cancer-specific survival. Six factors were considered as predictors to develop bladder recurrence after surgery. Conclusion: Methylation occurs commonly in UTUCs, may affect carcinogenic mechanisms, and is a well predictive factor for cancer-specific survival and bladder recurrence in UTUCs.

To evaluate the association and interaction of five single-nucleotide polymorphisms (SNPs) in three genes (CFH, ARMS2, and ARMS2/HTRA1) with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) in Chinese population.A total of 300 nAMD and 300 PCV patients and 301 normal subjects participated in the present study. The allelic variants of rs800292, rs2274700, rs3750847, rs3793917, and rs1065489 were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Gene-gene interactions were evaluated by the data mining approach multifactor-dimensionality reduction (MDR) method.The risk alleles of CFH rs800292, rs2274700, ARMS2 rs3057847, and ARMS2/HTRA1 rs3793917 showed significant difference between nAMD or PCV patients and controls (all P0.01). The homozygosity of risk alleles for rs800292, rs2274700, rs3750847, and rs3793917 were significantly different between nAMD patients and controls (all P0.01), and predisposed to PCV patients (all P0.01). After cross-validation consistency (CVC) and permutation tests, the two-locus model rs2274700_rs3750847 has a balanced accuracy of 64.37% in predicting nAMD disease risk. The one-marker model, rs3750847, and two-locus model rs2274700_rs3750847 has a balanced accuracy of 66.07% and 65.89% in predicting PCV disease risk, respectively. Furthermore, CFH rs1065489 did not show significant association with nAMD (P0.01), but was strongly associated with PCV in Chinese patients (P0.001).In this study, we found that the interaction of ARMS2 and ARMS2/HTRA1 is significantly associated with nAMD, and the interaction of CFH and ARMS2 is pronounced in PCV development in Chinese population.

Objective. To investigate the efficacy of surgery in the treatment of metastatic renal cell carcinoma (mRCC) and to identify prognostic factors. Methods. A single center retrospective study of 96 patients with mRCC from December 2004 to August 2013. Results. The median follow-up time was 45 months. Thirty-one (32.3%) of the patients received complete resection of metastatic sites, 11 (11.5%) of the patients underwent incomplete resection of metastatic sites, and 54 (56.3%) of the patients received no surgery. In the univariate Kaplan-Meier analysis, the median overall survival times of the three groups were 52 months, 16 months, and 22 months, respectively (p<0.001). The difference in the overall survival time was statistically significant between complete resection and no surgery groups (HR = 0.43, p=0.009), while there was no significant difference between the incomplete metastasectomy and no surgery groups (HR = 1.80, p=0.102). According to the multivariate Cox regression analysis, complete metastasectomy (HR = 0.49, p=0.033), T stage > 3 (HR = 1.88, p=0.015), disease free interval p=0.003), and multiorgan involvement (HR = 2.00, p=0.011) were significant prognostic factors. Conclusion. In the era of targeted therapy, complete metastasectomy can improve overall survival. Complete metastasectomy, T stage > 3, disease free interval

Objective To describe a modified suture technique for transperitoneal laparoscopic dismembered pyeloplasty (TPLDP) that can be consistently replicated. Methods Between June 2010 and April 2014, 21 men and 7 women with primary pelviureteric junction obstruction underwent our modified TPLDP suture technique performed by the same surgeon. In our method, the dismembering should be performed after performing half of anastomosis to achieve the maintenance of correct orientation and the prevention of torsion of anastomosis. We defined the success criteria as complete clinical resolution of flank pain for the patients with flank pain and complete radiologic resolution for the asymptomatic patients. Results The mean overall operative time for our technique was 137.3 minutes. The mean operative time for procedures on the left side was longer than on the right side ( P = .02). The mean suture time was 37.2 minutes. The mean estimated blood loss was 29.4 mL, and the crossing vessel was found in 7 of 28 patients (25.0%). No open conversion was required. The mean follow-up time was 21.0 months. Only 1 patient still had frequent and intolerable flank pain after surgery whose treatment was unsuccessful. The rest of the patients got complete clinical or radiologic resolution. The success rate was 27 of 28 (96.4%). Conclusion Our modified TPLDP suture technique is feasible and seems to be safe and to allow high success rate for the treatment of pelviureteric junction obstruction. Sizable sample and further analysis about technique will be completed in the future.

Background To explore the prognostic significance of preoperative prognostic nutritional index (PNI) in bladder cancer after radical cystectomy and compare the prognostic ability of inflammation-based indices. Methods We retrospectively analyzed data for 516 patients with bladder cancer who underwent radical cystectomy in our institution between 2006 to 2012. Clinicopathologic characteristics and inflammation-based indices (PNI, neutrophil/lymphocyte ratio [NLR], platelet/lymphocyte ratio [PLR], lymphocyte/monocyte ratio [LMR]) were evaluated by pre-treatment measurements. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan–Meier method and compared by log-rank test. Multivariate analysis with a Cox proportional hazards model was used to confirm predictors identified on univariate analysis. The association between clinicopathological characteristics and PNI or NLR was tested. Results Among the 516 patients, the median follow-up was 37 months (interquartile range 20 to 56). On multivariate analysis, PNI and NLR independently predicted OS (PNI: hazard ratio [HR] = 1.668, 95% CI: 1.147–2.425, P = 0.007; NLR: HR = 1.416, 95% CI:1.094–2.016, P = 0.0149) and PFS (PNI: HR = 1.680, 95% CI:1.092–2.005, P = 0.015; NLR: HR = 1.550, 95% CI:1.140–2.388, P = 0.008). Low PNI predicted worse OS for all pathological stages and PFS for T1 and T2 stages. Low PNI was associated with older age (>65 years), muscle-invasive bladder cancer, high American Society of Anesthesiologists grade and anemia. Conclusion PNI and NLR were independent predictors of OS and PFS for patients with bladder cancer after radical cystectomy and PNI might be a novel reliable biomarker for bladder cancer.

Objective. To evaluate the feasibility of an internal suspension technique in retroperitoneal laparoscopic partial nephrectomy for the management of renal ventral tumors. Methods. Between January 2013 and July 2016, a total of 145 patients underwent retroperitoneal laparoscopic partial nephrectomy with or without internal suspension technique. For patients who underwent internal suspension technique, the surgeons preserved the external fat of the renal tumor as a suspension traction measure when separating the kidney. Propensity score matching (PSM) was performed according to age, gender, body mass index, tumor size, tumor location, and RENAL nephrometry score. Patient characteristics and intraoperative and postoperative outcomes were compared between the groups. Results. After PSM, 32 patients treated with the internal suspension technique were compared with 32 cases treated without such technique. Baseline characteristics were statistically similar for the cohorts. The use of our new technique resulted in shorter warm ischemia time (WIT: 15.0 versus 19.0 minutes, P=.002) and tumor resection time (4.0 versus 7.5 minutes, P<0.001). The rate of WIT >25 minutes decreased (6.3% versus 25%, P=.04) and the trifecta outcomes were significantly improved (87.5% versus 62.5%, P=.02). Conclusion. Internal suspension technique is a feasible and safe procedure in retroperitoneal laparoscopic partial nephrectomy for renal ventral tumors.

Introduction We compared the prognostic significance of inflammatory and nutritional scores, including the prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio in patients with renal cell carcinoma (RCC) undergoing nephrectomy. Patients and Methods We retrospectively analyzed the data from 1360 patients with RCC undergoing nephrectomy from 2001 to 2010. The PNI was calculated as the serum albumin level (g/L) + 5 × lymphocyte count (10 9 /L). The receiver operating characteristic (ROC) curve analysis was used to determine the cutoff values. The areas under the ROC curve (AUCs) were calculated to compare the predictive ability of the indexes. Univariate and multivariate analyses were used to identify the prognostic factors for overall survival (OS) and progression-free survival (PFS). Results The median follow-up period after surgery was 67 months (range, 2-108 months). The PNI had the largest AUC for both OS and PFS. On univariate analysis, each index was associated with OS and PFS. On multivariate analysis, PNI, rather than other inflammatory and nutritional scores, remained as a risk factor for OS (hazard ratio [HR], 1.645; 95% confidence interval [CI], 1.153-2.348; 2 P = .006) and PFS (HR, 1.705; 95% CI, 1.266-2.296; 2 P Conclusion The preoperative PNI might be a good prognostic factor for both OS and PFS in RCC patients undergoing nephrectomy.