Benign prostatic hyperplasia (BPH) is an age-related prostate disorder with incompletely defined mechanisms. We integrated laser capture microdissection RNA sequencing, public single-cell RNA sequencing, public spatial transcriptomics, human tissue validation, mouse-model analyses, and in vitro perturbation assays to characterize hypoxia-associated epithelial senescence in BPH. SA-β-gal-positive cells were predominantly epithelial. RNA sequencing of SA-β-gal-positive epithelial cells revealed enrichment of hypoxia/HIF-1, NF-κB, cell-cycle arrest, and senescence-associated programs, with increased HIF1A, senescence-marker, and SASP-associated gene expression. Single-cell and spatial analyses showed coordinated activation of hypoxia-response, NF-κB-related, and senescence-associated programs in luminal epithelial cells or luminal-dominant spots. In 52 human BPH specimens, epithelial HIF-1α staining was modestly but significantly associated with p21, p27, and Rb. In vitro, 1% O₂ exposure or HIF1A overexpression induced senescence-associated phenotypes in BPH-1 and RWPE-1 cells, whereas HIF-1α inhibition or HIF1A knockdown attenuated these effects. NF-κB inhibition or RELA knockdown partially reversed HIF-1α-associated senescence phenotypes. Conditioned media from hypoxia-treated epithelial cells promoted stromal-cell proliferation and SASP-associated cytokine secretion in a partly HIF1A-dependent manner. In a testosterone propionate-induced BPH-like mouse model, HIF-1α or NF-κB inhibition attenuated prostatic hyperplasia, epithelial remodeling, and senescence-marker expression. These findings link hypoxia-associated HIF-1α/NF-κB signaling to epithelial senescence and epithelial-stromal crosstalk in BPH.

Benign prostatic hyperplasia (BPH) occurs when there is an imbalance between the proliferation and death of prostate cells, which is regulated tightly by estrogen signaling. However, the role of G protein-coupled estrogen receptor (GPER) in prostate cell survival remains ambiguous. In this study, we observed that prostates with epithelial hyperplasia showed increased yes-associated protein 1 (YAP) expression and decreased levels of estrogen and GPER. Blocking YAP through genetic or drug interventions led to reduced proliferation and increased apoptosis in the prostate epithelial cells. Interestingly, GPER agonists produced similar effects. GPER activation enhanced the phosphorylation and degradation of YAP, which was crucial for suppressing cell proliferation and survival. The Gαs/cAMP/PKA/LATS pathway, downstream of GPER, transmitted signals that facilitated YAP inhibition. This study investigated the interaction between GPER and YAP in the prostate epithelial cells and its contribution to BPH development. It lays the groundwork for future research on developing BPH treatments.

Several randomized controlled trials (RCTs) demonstrated a significant survival benefit of novel treatment regimens compared with androgen deprivation therapy (ADT) for metastatic hormone-sensitive prostate cancer (mHSPC), especially in high-volume disease (HVD, CHAARTED defined). As an influence on poor prognosis, the treatment for patients with HVD, especially visceral metastasis (VM) needed to be distinguished from mHSPC. This study was conducted to rank the treatment options for patients with HVD and VM, respectively, according to the latest data. We synthesized current evidence based on well-designed RCTs. Only phase III trials were included. A Bayesian network meta-analysis was conducted by using R-4.2.3, and the pooled hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS) with a 95

We aim to assess the safety and efficacy of proxalutamide, a novel androgen receptor antagonist, for men with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter, randomized, open-label, phase 2 trial. In our study, the enrolled mCRPC patients were randomized to 100, 200 and 300 mg dose groups at 1:1:1. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate. The secondary endpoints included objective response rate (ORR), disease control rate (DCR) and time to PSA and radiographic progression. Safety and pharmacokinetics were also assessed. Finally, there were 108 patients from 17 centers being enrolled. By week 16, there were 13 (35.1%), 12 (36.4%) and 15 (42.9%) patients with confirmed 50% or greater PSA decline in 100 mg (n = 37), 200 mg (n = 33) and 300 mg (n = 35) groups, respectively. Among the 19 patients with target lesions at study entry, three (15.8%) had a partial response and 12 (63.2%) had stable disease. The ORRs of 20.0%, 22.2%, 0% and DCRs of 80.0%, 88.9%, 60.0% were, respectively, achieved in 100, 200 and 300 mg groups. By the maximum follow-up time of 24 weeks, there were 42.6% and 10.2% of cases experiencing PSA progression and radiographic progression, respectively. Overall, adverse events (AEs) were experienced by 94.4% of patients, most of which were mild or moderate. There were 28 patients experiencing ≥grade 3 AEs. The most common AEs were fatigue (17.6%), anemia (14.8%), elevated AST (14.8%) and ALT (13.0%), decreased appetite (13.0%). These findings preliminarily showed the promising antitumor activity of proxalutamide in patients with mCRPC with a manageable safety profile. The proxalutamide dose of 200 mg daily is recommended for future phase 3 trial (Clinical trial registration no. CTR20170177).

(1) Background: CREB-binding protein (CBP) is a key transcriptional coactivator of androgen receptors (AR). We conducted this study to investigate the effects of CBP on AR expression and proliferation in benign prostatic hyperplasia (BPH) prostate epithelial cells. (2) Methods: By analyzing a published data set, we found that CBP was closely related to the gene expression of AR in prostate cells. We enrolled 20 BPH patients who underwent transurethral resection of the prostate (TURP) in Peking University First Hospital in 2022, and analyzed the expressions of CBP and AR in BPH prostate tissues. Then, we used ICG-001 and shRNA to inhibit CBP in prostate epithelial cells (BPH-1 cells and RWPE-1 cells), and conducted immunofluorescence, cell viability assay, flow cytometry analysis, and Western blot to analyze the effects of CBP on AR expression and proliferation in prostate epithelial cells. We also studied the interaction between CBP and AR through a co-immunoprecipitation assay. (3) Results: CBP is consistent with AR in expression intensity in prostate tissues. Inhibiting CBP decreases AR expression, and induces proliferation inhibition, apoptosis, and cell cycle arrest in BPH prostate epithelial cells. The co-immunoprecipitation assay showed that CBP binds with AR to form transcription complexes in prostate epithelial cells. (4) Conclusions: Inhibiting CBP decreases AR expression and inhibits proliferation in benign prostate epithelial cells. CBP may be a potential target to affect AR expression and the proliferation of prostate epithelial cells in BPH.

Background:To compare the survival outcomes of patients over 85 years of age with bladder cancer.Methods:We used data collected from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier (KM) curves were generated for overall survival with 95% confidence intervals (CIs). Cox proportional hazard models were used to estimate the hazard ratios among cases in different groups.Results:Of the 9,321 patients who met the inclusion criteria, 6,703 (71.9%) were men and 2,618 (28.1%) were women, with a mean (standard deviation) age of 88.68 (3.216) years. The median follow-up time of this cohort was 18 months. In the low-grade non-muscle-invasive bladder cancer (LG NMIBC) group, our analysis showed that no further treatment led to a better prognosis after the first transurethral bladder tumor resection (TURBT). In the high-grade NMIBC (HG NMIBC) cohort, major therapy was correlated with better OS in univariable and multivariable analyses [hazard ratio (HR) 0.450; 95% CI: 0.351-0.577]. Trimodal therapy gave a better prognosis in the muscle-invasive bladder cancer (MIBC) cohort (HR 1.395; 95% CI: 1.147-1.697). In addition, none of the county factors were risk factors for prognosis in multivariable analysis.Conclusions:Minor and major therapies do not have a better prognosis after TURBT in LG NMIBC. Major therapy has better oncological outcomes in LG NMIBC and MIBC than minor therapy. Trimodal therapy leads to longer OS in MIBC. In addition, none of the county factors were risk factors for prognosis.

Benign prostatic hyperplasia (BPH) is the most common and progressive urological disease in elderly men worldwide. Epidemiological studies have suggested that the speed of disease progression varies among individuals, while the pathophysiological mechanisms of accelerated clinical progression in some BPH patients remain to be elucidated. In this study, we defined patients with BPH as belonging to the accelerated progressive group (transurethral resection of the prostate [TURP] surgery at ≤50 years old), normal-speed progressive group (TURP surgery at ≥70 years old), or non-progressive group (age ≤50 years old without BPH-related surgery). We enrolled prostate specimens from the three groups of patients and compared these tissues to determine the histopathological characteristics and molecular mechanisms underlying BPH patients with accelerated progression. We found that the main histopathological characteristics of accelerated progressive BPH tissues were increased stromal components and prostatic fibrosis, which were accompanied by higher myofibroblast accumulation and collagen deposition. Mechanism dissection demonstrated that these accelerated progressive BPH tissues have higher expression of the CYP19 and G protein-coupled estrogen receptor (GPER) with higher estrogen biosynthesis. Estrogen functions via GPER/Gαi signaling to modulate the EGFR/ERK and HIF-1α/TGF-β1 signaling to increase prostatic stromal cell proliferation and prostatic stromal fibrosis. The increased stromal components and prostatic fibrosis may accelerate the clinical progression of BPH. Targeting this newly identified CYP19/estrogen/GPER/Gαi signaling axis may facilitate the development of novel personalized therapeutics to better suppress the progression of BPH.

Background: Prostate cancer (PCa) is the 2nd leading cause of cancer-related death among men in western countries, and a recently developed powerful antiandrogen enzalutamide (Enz) may extend the castration-resistant prostate cancer (CRPC) patients’ survival extra 4.8 months before development of Enz resistance.Methods: Sequencing analysis, Taqman PCR, absolute real time PCR, PDX animal model and Western blotting were used to detect our newly identified androgen receptor (AR) variant (named ARv33 due to having duplicated exon3) in various PC cell lines and human PCa samples. Genomic PCR, minigene were applied to confirm the mechanism of ARv33 generation. The biological functions of ARv33 were examined in both in vitro and in vivo experiments.Findings: ARv33 is generated via a unique trans-splicing mechanism that occurs rarely in human cells. Human clinical sample survey revealed that ARv33 is expressed in the later PCa stage. Mechanism dissection revealed that Enz/AR could function via transcriptional regulating the lncRNA-LINC00312 to promote splicing of the pre-AR transcript to induce the ARv33, which might then alter the B4GALT1 expression to increase the Enz resistance. Results from preclinical studies revealed that ARv33 could complex with ARv7 to increase the Enz resistance in vitro and targeting ARv33 with ARv33-siRNAs suppressed the EnzR tumor growth in an in vivo xenograft mice model. Together.Interpretation: This newly identified ARv33 plays key roles to alter the Enz resistance and targeting this ARv33 may provide us a new and better therapy to further suppress the CRPC that already developed the Enz resistance.Funding Information: This work was supported by George Whipple Professorship Endowment and China National Natural Science Foundation (81903113).Declaration of Interests: All authors declare there is no potential interest related to this manuscriptEthics Approval Statement: The PCa tissue samples used in the study was approved by the ethics committee of University of Rochester Medical Center (URMC). Animal experiments were performed after the approval from the URMC and the University Committee on Animal Resources (UCAR).

BACKGROUND:Secondary jejunal tumor from renal cell carcinoma (RCC) is extremely rare in clinical practice and is easily missed and misdiagnosed because of the low incidence and atypical symptoms.CASE SUMMARY:A 38-year-old male patient was diagnosed pathologically with left RCC after radical nephrectomy in 2012. The patient then suffered multiple lung metastases 2 years later and was treated with oral sorafenib without progression for 6 years. In 2020, an emergency intestinal segmental resection due to intestinal obstruction was required, and postoperative pathology confirmed a jejunal secondary tumor from RCC. The patient had a smooth recovery following surgery. Three months after surgery, the patient was diagnosed with left adrenal metastasis, and subsequent sintilimab therapy has stabilized his condition.CONCLUSION:This report is written to remind urologists and pathologists of the potential for small intestinal secondary tumors when a patient with a history of RCC seeks treatment for digestive symptoms. Enteroscopy and abdominal contrast-enhanced computed tomography are essential means of examination, but severe cases require immediate surgical intervention despite the lack of a preoperative examination to distinguish tumor attributes.

108 Background: GT0918 is a 2nd generation of AR antagonist and capability to down-regulate AR level. This study is an open-label, randomized, multicenter, Ph II study to evaluate the safety and efficacy in patients with mCRPC, and to determine the optimal dose for Ph III study. Methods: Patients with historically confirmed mCRPC who progressed after/intolerant to/reluctant to receive Docetaxel and previously treated with abiraterone or enzalutamide were excluded. All the patients received up to 6 cycles or, unacceptable toxicity, or loss of clinical benefit as recommended by PCWG3. Primary endpoint was prostate-specific antigen (PSA) reduction from baseline. Secondary endpoints included time to PSA progression (TTPP), objective response rate (ORR), progression free survival (PFS), disease control rate (DCR) and safety profiles. Results: As of June 30, 2019, 108 treated with GT0918 at three dose levels: 100 mg (n =37), 200 mg (n = 35) and 300 mg (n = 36), the median age of patients was 70.0 years (range 63-77), 88% of patients had stage IV disease at the initial diagnosis and 69.4% had Gleason score ≥ 8. The median duration of disease was 2.88 years. All received prior endocrine therapy, 35.2% received prior chemotherapy, 29.6% received Docetaxel. The median PSA at baseline was 35.285ng/ml, PSA response rate (≥50 % reduction from baseline) was 41.9%. The median time to PSA progression was not reached. There was no significant difference among three arms. Of 19 evaluable patients with target lesions at baseline, the ORR was 15.8% (all were PR) assessed by IRC with RECIST v 1.1, with 20.0% (1/5), 22.2% (2/9), 0 (0/5) at 100, 200, 300 dose level, respectively. The DCR assessed by IRC was 78.9% (CR 0+PR15.8%+SD 63.2%). Of 26 evaluable patients with target lesions at baseline, the ORR was 19.2% assessed by investigators (CR 3.8%+PR 15.4%), with 11.1% (1/9), 20.0% (2/10), 28.6% (2/7) at 100, 200, 300 dose level, respectively. Overall, AEs were experienced by most of patients (94.4 %, n=102). AEs leading to drug interruption were reported in 13 patients (12.0%), 9 (8.3%)of them were suspected to be drug related. AEs leading to discontinuation were reported in 6 patients (5.6%), 3(2.8%) were possibly related to GT0918. 14 patients (13.0%) experienced Grade 3 and 4 AEs. 17 patients (15.7%)experienced SAE, 5(4.6%) of them were suspected to be related to study drug. Most of AEs were mild or moderate. The common suspected AE (≥10%) were asthenia (17.6%, n=19), anemia (14.8%, n=16), AST increased (14.8%, n=16), ALT increased (13.0%, n=14), decreased appetite (13.0%, N=14), white blood cell count decreased (12.0%, n=13), proteinuria (12.0%, n=13). Conclusions: GT0918 showed a manageable safety profile. This study provided preliminary anti-tumor activity in patients with mCRPC. 200mg/day is recommended dose for Ph III trial. Clinical trial information: CTR20170177.

INTRODUCTION:Prostatic stromal tumor of uncertain malignant potential (STUMP) is a rare disease that may coexist with prostate stromal sarcoma (PSS). We aimed to analyze the histological and clinical features of STUMP.METHODS:Twenty-three patients diagnosed with STUMP from 2008 to 2019 were included. Clinicopathological and follow-up information was collected. In the subgroup analysis, we divided the patients into a pure STUMP group (N = 18) and a mixed STUMP (STUMP coexisting with PSS) group (N = 5). Student's t test was used to compare the 2 groups.RESULTS:Patients had a mean age of 55.5 ± 19.4 years and an average follow-up time of 42.3 months. The mean prostate volume was 109.2 ± 73.5 cm3, and the mean prostate-specific antigen was 8.03 ± 10.5 ng/mL. In the subgroup analysis, 16.7% (2/12) of pure STUMP patients had disease progression, while 100% (3/3) of mixed STUMP patients suffered from recurrence. Compared with the pure STUMP group, the mixed STUMP group was younger (37.2 vs. 60.6 years, p = 0.013) and had lower expression of estrogen receptor and progesterone receptor (p = 0.004 and p < 0.001, respectively).CONCLUSION:STUMP is a rare disease with a relatively good prognosis. However, there is still a possibility of disease progression or coexistence with stromal sarcoma. Timely diagnosis and regular monitoring may be helpful in improving treatment outcomes.

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.

OBJECTIVE:This study evaluated the safety and preliminary efficacy of vorolanib, a novel tyrosine kinase inhibitor, for treatment of patients with advanced solid tumors.METHODS:During dose escalation, patients received increasing doses of oral vorolanib (50-250 mg once daily) in cycles of four weeks for up to one year. During dose expansion, patients received recommended doses (100 and 200 mg) in 4-week cycles. The primary endpoint was to determine the safety and maximum tolerated dose and/or the recommended phase II dose (RP2D). The severity and type of adverse drug reactions (ADRs) were assessed using the Common Terminology Criteria for Adverse Events version 4.0. The second endpoint was preliminary efficacy in terms of objective response and progression-free survival (PFS).RESULTS:No dose-limiting toxicity occurred during dose escalation (50-250 mg). Five (26.3%) patients in the escalation cohort (n=19) and 12 (48.0%) in the expansion cohort (n=25) experienced grade 3 ADRs. The most common ADRs were hair color changes, fatigue, portal hypertension, hypertriglyceridemia, and proteinuria. During dose expansion, the patients treated with 200 mg and 100 mg (once daily) showed an objective response rate of 22.2% and 5.9%, respectively; the disease control rate was 88.9% and 73.3%, respectively; the median PFS was 9.9 [95% confidence interval (95% CI): 7.4-not reached] months and 3.8 (95% CI: 1.9-not reached) months, respectively.CONCLUSIONS:Oral vorolanib at a dose of 200 mg (once daily) exhibited an acceptable safety profile and favorable clinical benefit for patients with advanced solid tumors. The RP2D for vorolanib was determined to be 200 mg as a daily regimen.

斯科特的《逃避统治的艺术》一经出版即获得了学界的诸多关注,成为东南亚研究必读书目之一,但同时也受到学者们不同角度的批评.《逃避统治的艺术》重新定义了“Zomia"即东南亚山地的区域研究内涵,并指出二战前该区域内存在着一种山地居民为免于国家统治而从生计方式、政治结构、历史和宗教等方面建构的“逃避”机制.尽管我们可以指出斯科特使用史实的错误(如坚持“南诏泰族说”)或缺失,也可以批评他忽略了历史变迁的复杂性,但其研究的独到之处依然值得我们借鉴.从方法论来看,斯科特在长期消化文献材料的基础上大胆提出理论假设,这是学术创新的必要路径.斯科特继承了利奇关于克钦人“贡萨”一“贡劳”社会结构的学术遗产,激进地建构了东南亚山地居民以“逃避”为核心的生存模式,堪称西方无政府主义人类学的一次宏伟实验.“Zomia”研究范式也给了我们很多启示,比如应该勇于跨越边界,从关系主义视角来考察研究对象.通过中国西南和东南亚—南亚地区的比较研究,以交互性和流动性为中心考察其历史与当下的政治经济与社会人文形态,探求新的知识生产格局,有望成为中国人类学和民族学作出新贡献的“民族志学术区”.最后,在“post-Zomia"时代,处于各民族国家包围下的山地族群如何在现代化、全球化的时代背景下通过与国家部门和主流社会持续的遭遇、协商和妥协来寻求自身的发展空间,将会成为今后重要的研究方向.

BACKGROUND:The distribution characteristics of inflammatory cells in hyperplastic prostatic tissue and its influences on disease development remain unknown. We aimed to explore the infiltration characteristics of different inflammatory cells in histological structures of benign prostatic hyperplasia (BPH) in combination with clinical data.METHODS:The present study included 76 cases of BPH patients underwent transurethral resection of prostate (TURP). Hematoxylin-eosin staining was performed to identify the degree of general inflammation in prostatic tissues. The infiltration of T-lymphocytes (CD3), B-lymphocytes (CD20), and macrophages (CD68) were recorded by immunohistochemistry.RESULTS:The present study included 76 BPH patients with the mean age of 69.5 years old (range, 49-83 years) and the mean prostate volume of 91.9 mL (range, 24-218 mL). Periglandular inflammation was the most common pattern, being presented in 94.7% (72/76) patients, followed by stromal inflammation (67/76, 88.2%) and glandular inflammation (57/76, 75.0%). However, the stroma presented the highest rate of severe inflammation (14.6%). And the grades of glandular inflammation and stromal inflammation were independently correlated with prostate volume. T-lymphocytes, B-lymphocytes and macrophages had different infiltrated patterns in histological structures of prostate. And stromal hyperplasia dominated BPH was only significantly correlated with the T-lymphocytes infiltration condition (P=0.001). Meanwhile, overweight patients had more severe glandular inflammation in the prostate (P=0.010). The grade of glandular inflammation could independently increase prostate-specific antigen (PSA).CONCLUSIONS:We characterized infiltrated patterns of different inflammatory cells in histological structures of hyperplasic prostatic tissues from surgically treated BPH specimens. The role of inflammation in BPH development was highlighted by its correlation with the prostate volume, metabolism and PSA level.

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III (PD59)1 Apr 2020PD59-03 HYPOXIA INDUCE NEUROENDOCRINE DIFFERENTIATION OF PROSTATE CANCER VIA ANDROGEN RECEPTOR RELATED SIGNALS Yun Cui*, Yin Sun, Yang Yang, Shuai Hu, Yinong Niu, Xiaodong Zhang, Shuyuan Yeh, Chawnshang Chang, and Jie Jin Yun Cui*Yun Cui* More articles by this author , Yin SunYin Sun More articles by this author , Yang YangYang Yang More articles by this author , Shuai HuShuai Hu More articles by this author , Yinong NiuYinong Niu More articles by this author , Xiaodong ZhangXiaodong Zhang More articles by this author , Shuyuan YehShuyuan Yeh More articles by this author , Chawnshang ChangChawnshang Chang More articles by this author , and Jie JinJie Jin More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000969.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Development of the neuroendocrine differentiation (NED) in prostate cancer (PCa) has been linked to the failure of androgen deprivation therapy. And it was also regarded as the main origin of neuroendocrine PCa, which is a terminal lethal cancer with little effective therapies. This study aimed to study the role of hypoxia, especially hypoxia induced androgen receptor (AR) signals, in the NED of PCa and explore the potential way to restrain NED development. METHODS: Hypoxia was achieved by maintaining the cells at 1% O2, 5% CO2 and 94% N2 in a hypoxic chamber with oxygen sensor controls. Immunohistochemistry, immunoprecipitation assay, chromatin immunoprecipitation assay, CRISPR-CAS9 mediated gene transactivation, orthotropic xenograft, cell culture, quantitative RT-PCR, immunoblotting, bioinformatics analysis, lentivirus packaging and luciferase reporter assay were used to study hypoxia induced NED of PCa in vivo and in vitro. RESULTS: PCa performed NED under hypoxia condition with morphology change and neuroendocrine-related marker increasing. In vitro studies indicated that hypoxia induce NED via suppressing the AR signals. And mechanism dissection demonstrated hypoxia could suppress AR protein via AKT/MDM2 mediated ubiquitination of the AR protein. AR could regulate miRNA-449c-5p which suppress ASCL1 expression at the transcriptional level. Importantly, human clinical data survey also revealed a positive correlation between hypoxia and NED. In vivo orthotropic xenograft indicated miR-449c-5p could suppress NED development in PCa. CONCLUSIONS: Results from human clinical data survey and preclinical studies conclude that hypoxia may increase NED via altering the AKT/MDM2/AR/miRNA-449c-5p/ASCL1 signals in PCa, and targeting these newly identified AR-mediated signals with miRNA-449c-5p may help us to better suppress PCa progression via reducing the development of NED. Source of Funding: Beijing Natural Science Foundation (No. 7184214) © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1205-e1206 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yun Cui* More articles by this author Yin Sun More articles by this author Yang Yang More articles by this author Shuai Hu More articles by this author Yinong Niu More articles by this author Xiaodong Zhang More articles by this author Shuyuan Yeh More articles by this author Chawnshang Chang More articles by this author Jie Jin More articles by this author Expand All Advertisement PDF downloadLoading ...

Abstract Background We performed a pooled analysis of the COMPARZ study assessing efficacy and safety of pazopanib versus sunitinib in treatment-naïve Chinese patients with locally advanced and/or metastatic renal cell carcinoma (a/mRCC). Methods In the COMPARZ study, patients were randomized (1:1) to receive pazopanib 800 mg once daily (QD) continuously or sunitinib 50 mg QD in 6-week cycles (4 weeks on, 2 weeks off). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), and safety. PFS and ORR were assessed by independent review committee (IRC) and local investigators. Results Of the 209 Chinese patients (pazopanib, [n = 109] and sunitinib, [n = 100]), 155 (74%) were males and median age was 57 years (range, 18–79). Median PFS was 13.9 months for pazopanib versus 14.3 months for sunitinib per investigator assessment and 8.3 months in both arms per IRC assessment; PFS hazard ratio was 1.17 (investigator) and 0.99 (IRC). Median OS was not reached in pazopanib arm and was 29.5 months in sunitinib arm. ORR was significantly higher in pazopanib arm versus sunitinib arm (investigator: 41% versus 23% [P = 0.0052]; IRC: 35% versus 20% [P = 0.0203]). Pazopanib was generally well tolerated in Chinese patients with a/mRCC. Most frequent AEs in the pazopanib arm were diarrhea and hair color changes whereas the most frequent AEs in the sunitinib arm were decreased platelets, decreased neutrophil count, and thrombocytopenia. Conclusion The results of the pooled analysis were consistent with the overall population in the COMPARZ study, and confirmed similar PFS and OS of pazopanib and sunitinib in the Chinese patients. Trial registration clinical trials.gov, NCT00720941 (August 14, 2008) and NCT01147822 (May 19, 2010).

BACKGROUND:To develop successful prognostic models for grade 4 renal cell carcinoma (RCC) following partial nephrectomy and radical nephrectomy. METHODS:The nomograms were established based on a retrospective study of 135 patients who underwent partial and radical nephrectomy for grade 4 RCC at the Department of Urology, Peking University First Hospital from January 2013 to October 2018. The predictive performance of the nomograms was assessed by the calibration plot and C-index. The results were validated using bootstrap resampling. RESULTS:Aspartate transaminase (AST), the maximum diameter of tumor (cutoff value =7 cm), lymph node metastasis, and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group were independent factors for determining the overall survival (OS) and cancer-specific survival (CSS) in multivariate analysis. AST, the maximum diameter of the tumor (cutoff value =7 cm), and lymph node metastasis were found to be independent variables for progression-free survival (PFS) in multivariate analysis. These variables were used for the studies to establish nomograms. All calibration plots revealed excellent predictive accuracy of the models. The C-indexes of the nomograms for predicting OS, CSS and PFS were 0.729 (95% CI, 0.659-0.799), 0.725 (95% CI, 0.654-0.796) and 0.702 (95% CI, 0.626-0.778), respectively. Moreover, the recurrence rate was not associated with open or laparoscopic radical nephrectomy in our cohort (P=0.126). CONCLUSIONS:We have developed easy-to-use models that are internally validated to predict postoperative 1-, 3-, and 5-year OS, CSS, and PFS rates of grade 4 RCC patients. The new models could aid in identifying high-risk patients, making postoperative therapeutic and follow-up strategies as well as predicting patients' survival after externally validated. Besides, our study shows that the recurrence rate is not associated with open or laparoscopic radical nephrectomy.