BackgroundA combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study aims to prospectively evaluate the safety, efficacy, and biomarkers of neoadjuvant toripalimab plus axitinib in non-metastatic clear cell RCC.MethodsThis is a single-institution, single-arm phase II clinical trial. Patients with non-metastatic biopsy-proven clear cell RCC (T2-T3N0-1M0) are enrolled. Patients will receive axitinib 5 mg twice daily combined with toripalimab 240 mg every 3 weeks (three cycles) for up to 12 weeks. Patients then will receive partial (PN) or radical nephrectomy (RN) after neoadjuvant therapy. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease-free survival, safety, and perioperative complication rate. Predictive biomarkers are involved in exploratory analysis.ResultsA total of 20 patients were enrolled in the study, with 19 of them undergoing surgery. One patient declined surgery. The primary endpoint ORR was 45%. The posterior distribution of πORR had a mean of 0.44 (95% credible intervals: 0.24–0.64), meeting the predefined primary endpoint with an ORR of 32%. Tumor shrinkage was observed in 95% of patients prior to nephrectomy. Furthermore, four patients achieved a pathological complete response. Grade ≥3 adverse events occurred in 25% of patients, including hypertension, hyperglycemia, glutamic pyruvic transaminase/glutamic oxaloacetic transaminase (ALT/AST) increase, and proteinuria. Postoperatively, one grade 4a and eight grade 1–2 complications were noted. In comparison to patients with stable disease, responders exhibited significant differences in immune factors such as Arginase 1(ARG1), Melanoma antigen (MAGEs), Dendritic Cell (DC), TNF Superfamily Member 13 (TNFSF13), Apelin Receptor (APLNR), and C-C Motif Chemokine Ligand 3 Like 1 (CCL3-L1). The limitation of this trial was the small sample size.ConclusionNeoadjuvant toripalimab combined with axitinib shows encouraging activity and acceptable toxicity in locally advanced clear cell RCC and warrants further study.Trial registration numberclinicaltrials.gov,NCT04118855.

Objectives: To compare the oncologic outcomes and renal function discrepancy of salvage partial nephrectomy (sPN) and salvage radical nephrectomy (sRN) after an initial failed PN.Materials and Methods: Retrospective data from multiple centers between 2008 and 2022 were analyzed in this study. Patients who received sPN or sRN after an initial failed PN were identified. Comparative analysis and propensity score matching (PSM) was performed and the RENAL score, tumor size, and pathological T stage at salvage surgery were used to match the 2 groups. Local recurrence-free survival (LRFS) and recurrence-free survival (RFS) were assessed using the Cox proportional hazards model and log-rank tests. Renal function after salvage surgery was assessed using the Wilcoxon rank sum test.Results: A total of 140 patients who underwent salvage surgery were evaluated, of whom 60 were considered for PSM analysis after matching. At a median follow-up of 27.0 months, LRFS and RFS showed no significant difference between sPN and sRN, either before (LRFS, HR = 0.673 [95% CI: 0.171-2.644], P = 0.610; RFS, HR = 0.744 [95% CI: 0.271-1.344], P = 0.595) or after matching (LRFS, HR = 1.080 [95% CI: 0.067-17.30], P = 0.957; RFS, HR = 1.199 [95% CI: 0.241-5.983], P = 0.822). During long-term follow-up, sPN pre-served renal function (after matching, eGFR, 71.4 vs. 54.0, P < 0.001) and prevented eGFR loss (after matching: 6.6% vs. 25.6%, P < 0.001).Conclusion: Salvage partial nephrectomy offers a better alternative than sRN for recurrence after initial PN, as sPN preserves renal func-tion better while maintaining parallel tumor control and acceptable complication rates. (c) 2023 Elsevier Inc. All rights reserved.

Renal cell carcinoma (RCC) is known to be the most commonly diagnosed kidney cancer. Clear cell RCC (ccRCC) represents approximately 85 % of diagnosed RCC cases. Targeted therapeutics, such as multi-targeted tyrosine kinase inhibitors (TKI) and mTOR inhibitors, are widely used in ccRCC therapy. However, patients treated with mTOR and TKI inhibitors easily acquire drug resistance, making the therapy less effective. Here, we demonstrated that circPTEN inhibits the expression of its parental gene PTEN by reducing methylation of the PTEN promotor and inhibits GLUT1 expression by reducing m6A methylation of GLUT1, which suppresses ccRCC progression and resistance to mTOR inhibitors.

INTRODUCTION: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. PATIENTS AND METHODS: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. RESULTS: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. CONCLUSION: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.

Aim: To evaluate the efficacy and safety of second-line treatment with axitinib plus toripalimab in patients with metastatic renal cell carcinoma and failure of VEGFR tyrosine kinase inhibitors. Methods: Data were collected restropectively. Kaplan-Meier analysis and Cox proportional hazards model determined the efficacy outcomes. Results: In 57 patients, objective response rate was 31.6% and median progression-free survival (PFS) was 11.7 months, while median overall survival was not reached. Median PFS was not reached in favorable-risk patients, whereas PFS of 11.0 and 7.8 months were observed in intermediate- and poor-risk patients, respectively (p = 0.011). The treatment-related toxicities were mild in nature. Conclusion: Second-line therapy with axitinib plus toripalimab provided durable response rate, longer PFS and a tolerable safety profile.

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.

You have accessJournal of UrologyCME1 May 2022MP12-11 NEOADJUVANT THERAPY IN THE MANAGEMENT OF LOCAL RETROPERITONEAL RECURRENCE OF RENAL CELL CARCINOMA AFTER RADICAL NEPHRECTOMY Jiwei Huang, Yueming Wang, Cuijian Zhang, Xiaoyi Hu, Ping Wang, Guohai Shi, Jin Zhang, Wen Kong, Yonghui Chen, Yiran Huang, Dingwei Ye, Dan Xia, Jianming Guo, Zhisong He, and Wei Xue Jiwei HuangJiwei Huang More articles by this author , Yueming WangYueming Wang More articles by this author , Cuijian ZhangCuijian Zhang More articles by this author , Xiaoyi HuXiaoyi Hu More articles by this author , Ping WangPing Wang More articles by this author , Guohai ShiGuohai Shi More articles by this author , Jin ZhangJin Zhang More articles by this author , Wen KongWen Kong More articles by this author , Yonghui ChenYonghui Chen More articles by this author , Yiran HuangYiran Huang More articles by this author , Dingwei YeDingwei Ye More articles by this author , Dan XiaDan Xia More articles by this author , Jianming GuoJianming Guo More articles by this author , Zhisong HeZhisong He More articles by this author , and Wei XueWei Xue More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002534.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: 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. This 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 neoadjuvant targeted therapy in this context. METHODS: This was a retrospective multi-center study of 85 patients with RPR treated with targeted therapy for RPR after RN (2008-2020). Clinical and pathological characteristics were reported using descriptive statistics. Cancer-specific survival (CSS) was examined using the Cox proportional hazards model. RESULTS: 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 neoadjuvant targeted therapy followed by surgical resection group and 42 months (95% CI: 28.8-55.2) in the targeted therapy alone group (P = 0.001). In multivariate analysis, International Metastatic RCC Database Consortium classification poor-risk, number of recurrence sites, and surgical resection were independent predictors of CSS. CONCLUSIONS: Neoadjuvant targeted therapy may increase the feasibility of tumor resection for RPR after RN. Patients who underwent surgical resection following neoadjuvant targeted therapy had better CSS than those treated with targeted therapy alone. Source of Funding: This study was supported by grants from the Natural Science Foundation of Shanghai (21ZR1438900), Incubating Program for Clinical Research and Innovation of Renji Hospital (PYXJS16-008 and PYIII20-07), and Basic Oncology Research Program from the Bethune Charitable Foundation (BCF-NH-ZL-20201119-024) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e171 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jiwei Huang More articles by this author Yueming Wang More articles by this author Cuijian Zhang More articles by this author Xiaoyi Hu More articles by this author Ping Wang More articles by this author Guohai Shi More articles by this author Jin Zhang More articles by this author Wen Kong More articles by this author Yonghui Chen More articles by this author Yiran Huang More articles by this author Dingwei Ye More articles by this author Dan Xia More articles by this author Jianming Guo More articles by this author Zhisong He More articles by this author Wei Xue More articles by this author Expand All Advertisement PDF DownloadLoading ...

Cancer CommunicationsVolume 41, Issue 10 p. 1071-1074 LETTER TO THE EDITOROpen Access Clinical outcomes of second-line treatment following first-line VEGFR-TKI failure in patients with metastatic renal cell carcinoma: a comparison of axitinib alone and axitinib plus anti-PD-1 antibody Jiwei Huang, Corresponding Author Jiwei Huang huangjiwei@renji.com orcid.org/0000-0002-1463-670X Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127 P. R. China These authors have contributed equally to this work. Correspondence Jiwei Huang, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, P. R. China Email: huangjiwei@renji.com Shuo Wang, Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P. R. China Email: shuowang11@zju.edu.cn Jianming Guo, Department of Urology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200032, P. R. China Email: guo.jianming@zs-hospital.sh.cn Qiang Wei, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China Email: weiqiang933@126.com Wei Xue, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, China Email: uroxuewei@163.comSearch for more papers by this authorYueming Wang, Yueming Wang Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127 P. R. China These authors have contributed equally to this work.Search for more papers by this authorHaoran Zhang, Haoran Zhang Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China These authors have contributed equally to this work.Search for more papers by this authorXiaoyi Hu, Xiaoyi Hu Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032 P. R. China These authors have contributed equally to this work.Search for more papers by this authorPing Wang, Ping Wang Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003 P. R. China These authors have contributed equally to this work.Search for more papers by this authorWen Cai, Wen Cai Department of Urology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009 P. R. China These authors have contributed equally to this work.Search for more papers by this authorYichu Yuan, Yichu Yuan Department of Urology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009 P. R. China These authors have contributed equally to this work.Search for more papers by this authorHao Zeng, Hao Zeng Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. ChinaSearch for more papers by this authorJin Zhang, Jin Zhang Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127 P. R. ChinaSearch for more papers by this authorWen Kong, Wen Kong Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127 P. R. ChinaSearch for more papers by this authorYiran Huang, Yiran Huang Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127 P. R. ChinaSearch for more papers by this authorShuo Wang, Corresponding Author Shuo Wang shuowang11@zju.edu.cn Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003 P. R. China Correspondence Jiwei Huang, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, P. R. China Email: huangjiwei@renji.com Shuo Wang, Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P. R. China Email: shuowang11@zju.edu.cn Jianming Guo, Department of Urology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200032, P. R. China Email: guo.jianming@zs-hospital.sh.cn Qiang Wei, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China Email: weiqiang933@126.com Wei Xue, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, China Email: uroxuewei@163.comSearch for more papers by this authorJianming Guo, Corresponding Author Jianming Guo guo.jianming@zs-hospital.sh.cn Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032 P. R. China Correspondence Jiwei Huang, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, P. R. China Email: huangjiwei@renji.com Shuo Wang, Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P. R. China Email: shuowang11@zju.edu.cn Jianming Guo, Department of Urology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200032, P. R. China Email: guo.jianming@zs-hospital.sh.cn Qiang Wei, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China Email: weiqiang933@126.com Wei Xue, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, China Email: uroxuewei@163.comSearch for more papers by this authorQiang Wei, Corresponding Author Qiang Wei weiqiang933@126.com Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China Correspondence Jiwei Huang, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, P. R. China Email: huangjiwei@renji.com Shuo Wang, Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P. R. China Email: shuowang11@zju.edu.cn Jianming Guo, Department of Urology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200032, P. R. China Email: guo.jianming@zs-hospital.sh.cn Qiang Wei, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China Email: weiqiang933@126.com Wei Xue, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, China Email: uroxuewei@163.comSearch for more papers by this authorWei Xue, Corresponding Author Wei Xue uroxuewei@163.com Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127 P. R. China Correspondence Jiwei Huang, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, P. R. China Email: huangjiwei@renji.com Shuo Wang, Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P. R. China Email: shuowang11@zju.edu.cn Jianming Guo, Department of Urology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200032, P. R. China Email: guo.jianming@zs-hospital.sh.cn Qiang Wei, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China Email: weiqiang933@126.com Wei Xue, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, China Email: uroxuewei@163.comSearch for more papers by this author Jiwei Huang, Corresponding Author Jiwei Huang huangjiwei@renji.com orcid.org/0000-0002-1463-670X Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127 P. R. China These authors have contributed equally to this work. Correspondence Jiwei Huang, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, P. R. China Email: huangjiwei@renji.com Shuo Wang, Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P. R. China Email: shuowang11@zju.edu.cn Jianming Guo, Department of Urology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200032, P. R. China Email: guo.jianming@zs-hospital.sh.cn Qiang Wei, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China Email: weiqiang933@126.com Wei Xue, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, China Email: uroxuewei@163.comSearch for more papers by this authorYueming Wang, Yueming Wang Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127 P. R. China These authors have contributed equally to this work.Search for more papers by this authorHaoran Zhang, Haoran Zhang Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China These authors have contributed equally to this work.Search for more papers by this authorXiaoyi Hu, Xiaoyi Hu Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032 P. R. China These authors have contributed equally to this work.Search for more papers by this authorPing Wang, Ping Wang Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003 P. R. China These authors have contributed equally to this work.Search for more papers by this authorWen Cai, Wen Cai Department of Urology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009 P. R. China These authors have contributed equally to this work.Search for more papers by this authorYichu Yuan, Yichu Yuan Department of Urology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009 P. R. China These authors have contributed equally to this work.Search for more papers by this authorHao Zeng, Hao Zeng Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. ChinaSearch for more papers by this authorJin Zhang, Jin Zhang Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127 P. R. ChinaSearch for more papers by this authorWen Kong, Wen Kong Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127 P. R. ChinaSearch for more papers by this authorYiran Huang, Yiran Huang Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127 P. R. ChinaSearch for more papers by this authorShuo Wang, Corresponding Author Shuo Wang shuowang11@zju.edu.cn Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003 P. R. China Correspondence Jiwei Huang, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, P. R. China Email: huangjiwei@renji.com Shuo Wang, Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P. R. China Email: shuowang11@zju.edu.cn Jianming Guo, Department of Urology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200032, P. R. China Email: guo.jianming@zs-hospital.sh.cn Qiang Wei, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China Email: weiqiang933@126.com Wei Xue, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, China Email: uroxuewei@163.comSearch for more papers by this authorJianming Guo, Corresponding Author Jianming Guo guo.jianming@zs-hospital.sh.cn Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032 P. R. China Correspondence Jiwei Huang, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, P. R. China Email: huangjiwei@renji.com Shuo Wang, Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P. R. China Email: shuowang11@zju.edu.cn Jianming Guo, Department of Urology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200032, P. R. China Email: guo.jianming@zs-hospital.sh.cn Qiang Wei, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China Email: weiqiang933@126.com Wei Xue, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, China Email: uroxuewei@163.comSearch for more papers by this authorQiang Wei, Corresponding Author Qiang Wei weiqiang933@126.com Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China Correspondence Jiwei Huang, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, P. R. China Email: huangjiwei@renji.com Shuo Wang, Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P. R. China Email: shuowang11@zju.edu.cn Jianming Guo, Department of Urology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200032, P. R. China Email: guo.jianming@zs-hospital.sh.cn Qiang Wei, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China Email: weiqiang933@126.com Wei Xue, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, China Email: uroxuewei@163.comSearch for more papers by this authorWei Xue, Corresponding Author Wei Xue uroxuewei@163.com Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127 P. R. China Correspondence Jiwei Huang, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, P. R. China Email: huangjiwei@renji.com Shuo Wang, Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P. R. China Email: shuowang11@zju.edu.cn Jianming Guo, Department of Urology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200032, P. R. China Email: guo.jianming@zs-hospital.sh.cn Qiang Wei, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China Email: weiqiang933@126.com Wei Xue, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong District, Shanghai 200127, China Email: uroxuewei@163.comSearch for more papers by this author First published: 07 August 2021 https://doi.org/10.1002/cac2.12206 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abbreviations VEGFR-TKI vascular endothelial growth factor receptor-tyrosine kinase inhibitor ICI immune checkpoint inhibitor PD-1 programmed cell death protein 1 mRCC metastatic renal cell carcinoma PFS progression-free survival OS overall survival ORR objective response rate IMDC International Metastatic Renal Cell Carcinoma Database Consortium AEs adverse events Dear editor, The prognosis of metastatic renal cell carcinoma (mRCC) has been significantly improved with the development and widespread use of vascular endothelial growth factor (VEGF) pathway inhibitors and mammalian target of rapamycin (mTOR) pathway inhibitors [1]. For the past decade, the standard of care utilized in the first-line setting was VEGF-targeted therapies. Recently, the mRCC treatment landscape has rapidly changed with the exploration of combinations of immune checkpoint inhibitors (ICIs) and anti-VEGF agents [2, 3]. The Keynote-426 trial demonstrated both progression-free survival (PFS) and overall survival (OS) advantages of axitinib plus pembrolizumab over sunitinib for untreated advanced RCC patients [2]. Based on these results, axitinib plus pembrolizumab, cabozantinib plus nivolumab, lenvatinib plus pembrolizumab, and nivolumab plus ipilimumab have been recommended as first-line treatment in recent guidelines [3]. However, axitinib plus pembrolizumab as first-line treatment for mRCC is only approved in limited countries, in which China is not included. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) remain a recommended option as first-line therapy in China and in other countries. Nivolumab, cabozantinib, or axitinib remains the standard care for patients who failed first-line therapy with VEGFR-TKI. Considering that axitinib plus anti-programmed cell death protein 1 (PD-1) antibody was expected to have a better oncological outcome than axitinib alone owing to first-line study results [2], the subsequent therapy algorithm after first-line VEGFR-TKI failure needs to be redefined. So far, there is no research published on VEGFR-TKI and ICI combination therapy after first-line VEGFR-TKI failure.In this context, the present retrospective multi-center study was aimed to compare the objective response rate (ORR), PFS, OS, and toxicities between axitinib plus anti-PD-1 antibody and axitinib alone for mRCC after first-line VEGFR-TKI failure. Clinical data were retrieved from the electronic medical records of mRCC patients treated at 5 participating centers between October 2015 and October 2020. The patient selection and assessments are detailed in the Supplementary file of Patients and Methods. A total of 255 patients were included in this study, of whom 116 received axitinib plus anti-PD-1 antibody combination therapy, and 139 received axitinib alone (Supplementary Figure S1). Anti-PD-1 antibody agents used in this study were used off label, including pembrolizumab (n = 32, 27.6%), nivolumab (n = 6, 5.2%), toripalimab (n = 42, 36.2%), sintilimab (n = 32, 27.6%), and tislelizumab (n = 4, 3.4%). All patients were aware of this situation and signed informed consent before treatment. Supplementary Table S1 shows the baseline characteristics of these 255 patients. The best responses of patients are shown in Supplementary Table S2. According to Response Evaluation Criteria in Solid Tumors version 1.1, only 2 patients in the combination group had complete response (CR), while none in the axitinib group had CR. Meanwhile, 37 patients in the combination group and 28 in the axitinib group were determined to have partial response (PR). The ORR in the combination group was significantly higher than that in the axitinib group (33.6% vs. 20.1%, P = 0.015). After a median follow-up period of 25.7 (95% confidence interval [CI] = 15.4-36.0) months from the start of second-line treatment, the median PFS was 11.7 (95% CI = 9.2-14.2) months for patients treated with combination therapy and 7.5 (95% CI = 5.2-9.8) months for patients treated with axitinib alone. The PFS of the combination group was significantly longer than that of the axitinib group (P = 0.002) (Figure 1A). The median OS was not reached in the combination group and was 21.4 (95% CI = 13.7-29.1) months for patients treated with axitinib alone (Figure 1B). No significant difference in OS was found (P = 0.201). FIGURE 1Open in figure viewer PFS, OS, and subgroup analysis of 255 mRCC patients who received axitinib alone or axitinib plus anti-PD-1 antibody following first-line VEGFR-TKI failure. A. Kaplan-Meier PFS curves of patients treated with combination therapy and axitinib alone. B. Kaplan-Meier OS curves of patients treated with combination therapy and axitinib alone. C. Subgroup analysis of PFS. D. Subgroup analysis of OSAbbreviations: PFS, progression-free survival; OS, overall survival; mRCC, metastatic renal cell carcinoma; PD-1, programmed cell death protein 1; VEGFR-TKI, vascular endothelial growth factor receptor-tyrosine kinase inhibitor; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium. Figure 1C shows the subgroup analysis of PFS with respect to baseline characteristics and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) classification using Cox proportional hazards model. Factors favoring combination therapy included IMDC intermediate risk (hazard ratio [HR] = 0.490, 95% CI = 0.288-0.833) and poor risk (HR = 0.516, 95% CI = 0.279-0.956). However, in the subgroup analysis of OS (Figure 1D), the advantage of combination therapy was only observed in IMDC intermediate-risk mRCC (HR = 0.346, 95% CI = 0.133-0.905). Furthermore, the combination therapy significantly prolonged PFS in patients with (HR = 0.407, 95% CI = 0.167-0.995) or without sarcomatoid features (HR = 0.626, 95% CI = 0.421-0.931). Next, we evaluated the associations between clinical characteristics and survival. IMDC risk, discontinuation of first-line therapy due to AEs, and second-line regimen were significantly associated with PFS (Supplementary Table S3); IMDC risk was identified as an independent predictor of OS (Supplementary Table S4). At the time of data analysis, in the combination therapy group, adverse events (AEs) led to discontinuation of either drug in 11 (9.5%) patients, discontinuation of both drugs in 6 (5.2%) patients, and dose reduction of axitinib in 9 (7.8%) patients. While in the axitinib group, 17 (12.2%) patients required dose reduction, and 10 (7.2%) needed drug discontinuation. Major treatment-related adverse events are presented in Supplementary Table S5. In the present study, axitinib plus anti-PD-1 antibody showed ORR and PFS benefits over axitinib alone in mRCC patients. One concern is whether the benefits of the combination therapy could be observed across all IMDC risk categories. We found that the combination therapy prolonged PFS in the IMDC intermediate- or poor-risk subgroup, but not in the favorable-risk subgroup. However, the OS benefit was only observed in the IMDC intermediate-risk subgroup, probably due to the small number of patients at IMDC poor risk and short follow-up period. According to the subgroup analysis of the Keynote-426 study [4], pembrolizumab plus axitinib prolonged both OS (HR = 0.52, 95% CI = 0.37-0.74) and PFS (HR = 0.67, 95% CI = 0.53-0.85) in patients with IMDC intermediate or poor risk, which were similar to our findings. Based on these results, we speculate that patients with IMDC favorable risk mRCC might have no added benefit from the combination therapy after first-line TKI failure given the high cost of ICI-based therapy and immune-related AEs [5, 6], while patients with IMDC intermediate- or poor-risk mRCC might benefit most from the combination therapy. In patients with mRCC treated with TKIs, sarcomatoid features had been reported to be associated with poor prognosis [7], but recent studies suggested that ICI-based combination therapy could dramatically improve the outcomes of these patients [4, 8]. The subgroup analysis of the Keynote-426 study [4] showed a benefit in PFS (HR = 0.54, 95% CI = 0.29-1.00) with combination therapy compared to sunitinib alone in patients with sarcomatoid features, which was similar to our results. Some side effects of combination therapy seemed to add up numerically [2, 9, 10]. The rate of grade ≥3 liver enzyme elevation was significantly higher in the combination group than in the axitinib group, which was consistent with historic comparisons such as the Keynote-426 study [2]. The limitation of this study was represented by the relatively short follow-up, the retrospective design, and selection bias. The OS data were not mature in the combination group. In addition, patients who received cabozantinib, ICI alone, or ICI combination as second-line therapy were not included in this study because cabozantinib and anti-CTLA-4 antibodies were not commercially available in China during the study period. Nevertheless, the ideal order of sequential therapy remains unclear, and the combinational use of axitinib plus anti-PD-1 antibody in this setting should be validated in future prospective studies as a standard of care. In conclusion, among mRCC patients with first-line VEGFR-TKI failure, second-line treatment with axitinib plus anti-PD-1 antibody may prolong PFS and increase ORR as compared with axitinib alone. ACKNOWLEDGEMENTS Not applicable. AUTHORS' CONTRIBUTIONS J.H., S.W., J.G., Q.W. and W.X. designed the research. W.X., S.W., J.G., Q.W. and W.C. provided executive support and data surveillance and performed the patient selection process. Y.W., H.Z., X.H., P.W., W.C. and Y.Y. acquired and analyzed the data. J.H., Y.W., H.Z., X.H., P.W., W.C. and Y.Y. wrote the manuscript. H.Z., J.Z., W.K., J.Z. and Y.H. revised the manuscript. All authors reviewed the manuscript critically and approved the content. COMPETING INTERESTS The authors declare that no competing interests exist. AVAILABILITY OF DATA AND MATERIALS Not applicable. CONSENT FOR PUBLICATION Not applicable. ETHICS APPROVAL AND CONSENT TO PARTICIPATE This study was conducted in accordance with the ethical standards of the Declaration of Helsinki and approved by the independent ethics committee of all 5 participating centers. FUNDING This study was supported by Shanghai Science and Technology Commission Research Project (21ZR1438900) and the Incubating Program for Clinical Research and Innovation of Renji Hospital (PYXJS16-008, PYIII20-07). CONFLICT OF INTEREST DISCLOSURES The authors have declared no conflicts of interest. Supporting Information Filename Description cac212206-sup-0001-FigureS1.pptx57 KB Supporting Information S1 cac212206-sup-0001-SuppMat.docx41.4 KB Supporting Information S2 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Choueiri TK, Motzer RJ. Systemic Therapy for Metastatic Renal-Cell Carcinoma. N Engl J Med. 2017; 376(4): 354- 366. https://doi.org/10.1056/NEJMra1601333Google Scholar 2Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019; 380(12): 1116- 1127. https://doi.org/10.1056/NEJMoa1816714Google Scholar 3Bedke J, Albiges L, Capitanio U, Giles RH, Hora M, Lam TB, et al. The 2021 Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibitor-based Combination Therapies for Treatment-naive Metastatic Clear-cell Renal Cell Carcinoma Are Standard of Care [published online ahead of print, 2021 May 29]. 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目的 探讨肾部分切除术治疗cT2期肾癌的疗效.方法 回顾性分析2007年1月至2018年10月在仁济医院接受肾部分切除术的60例cT2期肾癌患者的临床资料,其中男性46例,女性14例;年龄26～79岁,中位年龄58岁;左侧35例,右侧25例;肿瘤最大直径7.1～11.2 cm,中位数为7.9 cm.25例患者接受开放肾部分切除术,33例患者接受腹腔镜肾部分切除术,2例患者接受机器人辅助肾部分切除术.观察肾功能结果、并发症发生率及癌症控制效果等指标.结果 59例术后病理切缘阴性,1例阳性.术前的肾小球滤过率估值(eGFR)的中位数为96.07(40.40～181.44)mL/(min·1.73 m2),最后一次肾功能评估的eGFR中位数为79.40(6.03～182.81)mL/(min·1.73 m2).共有22例患者术后出现并发症,严重并发症(CCS分级Ⅲ级及以上)的发生率为10％.2年总生存率为97.4％,2年肿瘤特异性生存率为97.4％,2年无进展生存率为93.0％.结论 肾部分切除术可以安全地用于合适选择的cT2期肾癌,具有良好的肾功能保护效果、可接受的并发症发生率和癌症控制效果.

Objective:To investigate the effect of selective clamping of renal arterial branches in robotic-assisted laparoscopic partial nephrectomy(RAPN) for renal hilar tumors.Methods:14 patients with renal hilar tumor who received robotic-assisted laparoscopic partial nephrectomy from April 2017 to June 2019 in our hospital were retrospectively analyzed. 8 males and 6 females were included. The median age was 55.5 years, ranged from 45 to 69 years. The median diameter of the tumor was 3.6 cm with 9 on the left and 5 on the right. 8 cases with T 1a tumors and 6 cases with T 1b tumors were included. The median preoperative serum creatine and estimated glomerular filtration rate(eGFR) was 73 μmol/L and 92.97 ml/(min·1.73 m 2), respectively. The spherical hat RAPN was performed in 14 cases under the general anesthesia. The surgical approach was chosen based on the localization of kidney. The main renal artery, target arterial branch and venous branch were exposed. According to the preoperative image, the target arterial branch was blocked. Results:Robotic-assisted partial nephrectomy with clamping of renal arterial branches was successfully completed in 13 cases, with 1 converted to the conventional method in which the main renal artery was clamped. No case was converted to open surgery or radical nephrectomy. The median operation time was 120(90-160) min. The median blood loss was 120(10-400) ml. There was no intraoperative blood transfusion. The median warm ischemic time was 21.5(13-35) min. The median postoperative hospital stay was 2.5(2-4) days. No major complication was observed after surgery. Pathologic studies revealed 9 cases of clear cell carcinoma, 1 case of papillary cell carcinoma, 1 case of multilocular cystic renal neoplasm of low malignant potential, 1 case of MiT family translocation renal cell carcinoma, 1 case of renal angioleiomyolipoma and 1 case of metanephric adenoma. Surgical margins were negative in all cases. The median follow-up period was 17(2-28) months with no recurrence or metastasis. The median postoperative serum creatine and eGFR was 79(54-129)μmol/L and 84.24(55.53-122.47)ml/(min·1.73 m 2), respectively. Conclusions:Selective clamping of renal arterial branches in robotic-assisted laparoscopic partial nephrectomy for renal hilar tumors has the advantage of minimal invasion, high safety, preservation of postoperative renal function and good effect.

Purpose: Aiming to improve the drug loading capacity of dendritic nanoparticles and enhance delivery efficacy in drug-resistant cancer, we developed and optimized a more advanced dendritic, redox-responsive, supramolecular (Dr.S) system for intravenous RAD001 administration. Materials and methods: The Dr.S system was engineered by linking 3rd generation polyamidoamine dendrimers (G3 PAMAM) with 8-arm polyethylene glycol (PEG) to encapsulate a molecular targeted agent RAD001. The drug-loading capacity was measured by ultraviolet-visible spectrophotometry. In vitro release behavior was determined with a two-compartment model, and the in vivo distribution pattern was tracked by Cy5.5 fluorescence. The therapeutic effect of Dr.S/RAD001 was evaluated in RAD001-resistant cancer cells and tumor-bearing nude mice, respectively. Results: The Dr.S system encapsulating RAD001 with a loading efficiency of 10.6% formed a core-shell structure, by shifting hydrophobic PAMAM/RAD001 components towards inner space and exposing the hydrophilic PEG on the surface. The Dr.S/RAD001 system could respond to a lysis-mimicking reduction stimulus, and functionally release cargoes to facilitate tumor accumulation and cellular internalization. These features contributed to the enhanced anti-tumor activity of RAD001 in renal cancers in vitro and in vivo. The Dr.S/RAD001 system also reversed acquired RAD001-resistance by a 60-fold increase in tumor accumulation of the therapeutics. Conclusion: The functional Dr.S/RAD001 system enables lysis-triggered release of RAD001 to achieve better tumor accumulation, which helps overcome acquired drug resistance in renal cancers.

Objective:To study the pathological characteristics, diagnosis and treatment of primary adenocarcinoma of renal pelvis and ureter.Methods:The clinical pathological characteristics, treatment and prognosis of 5 patients with adenocarcinoma of upper urinary tract treated between January 2007 and May 2019 was retrospectively reviewed. There were 4 male and 1 female patients, with a median age of 60 years. The major symptoms were hematuria in 5 cases and low back pain in 4 cases. All cases underwent B-ultrasound and CT examination, and 4 cases accepted cystoscopy. Preoperative diagnoses were ureter tumor in 2 cases, renal pelvis tumor in 1 case, renal tumor in 1 case and renal calculus in 1 case.Results:5 cases were treated with surgery. Radical nephroureterectomy was performed in 3 cases, and nephrectomy in one case. 1 case underwent first-stage percutaneous nephrolithotomy and second-stage radical nephroureterectomy due to the discovery of tumor. 1 case was treated with radiotherapy and immune checkpoint inhibitor postoperatively. The mean diameter of the tumors was 4.4 cm. There were 3 renal pelvis adenocarcinomas and 2 ureter adenocarcinomas confirmed by pathologic examination, including 3 cases of pT 3 stage and 1 case of pT 4 stage. Lymph node metastasis was found in 2 cases. Immunohistochemistry revealed that CDX2(+ ), p63(-), GATA3(-), β-catenin(-)were the common features of five cases. The median survival was 12 months with a median follow-up of 6 months. 2 cases died of tumor progression within 1 year. Conclusions:Adenocarcinoma is an extremely rare malignancy, typically associated with long-standing calculi and chronic inflammation. Given the fact that clinical and imaging findings are nonspecific, the diagnosis is based on pathologic examination, supported by glandular structure of histology. Immunohistochemical staining exhibited CDX2 and CK20 positivity and β-catenin negativity, moreover, GATA3, p63 and CK7 was usually negative or partially positive. Surgery is the foremost choice of treatment. The prognosis is correlated with subtypes, whereas the overall prognosis is poor due to high rates of recurrence and metastasis.