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BackgroundThe preoperative C-reactive protein/Albumin (CRP/Alb) ratio has been shown to be valuable in predicting the prognosis of patients with certain cancers. The aim of our study is to explore its prognostic value in patients with renal cell carcinoma (RCC).MethodsA retrospective study was performed in 570 RCC patients underwent radical or partial nephrectomy including 541 patients who received full resection of localized (T1-3 N0/+ M0) RCC. The optimal cutoff value of CRP/Alb was determined by the receive operating characteristic (ROC) analysis. The impact of the CRP/Alb and other clinicopathological characteristics on overall survival (OS) and disease-free survival (DFS) was evaluated using the univariate and multivariate Cox regression analysis.ResultsThe optimal cutoff of CRP/Alb ratio was set at 0.08 according to the ROC analysis. Multivariate analysis indicated that CRP/Alb ratio was independently associated with OS of RCC patients underwent radical or partial nephrectomy (hazard ratio [HR]: 1.94; 95% confidence interval [95% CI]: 1.12-3.36; P = 0.018), and DFS of localized RCC patients underwent full resection (HR: 2.14; 95% CI: 1.22-3.75; P = 0.008).ConclusionElevated CRP/Alb ratio was an independent prognostic indicator for poor OS in patients underwent radical or partial nephrectomy and DFS of localized RCC patients underwent full resection. Overall, CRP/Alb may help to identify patients with high relapse risk.

Background: Although sex bias has been reported in the development and progression of renal cell carcinoma (RCC), the underlying mechanisms remain enigmatic. Here, we investigated the sex differences in the tumor microenvironment (TME) of RCC and explored a promising combination drug regimen to enhance the efficacy of immunotherapy. Methods: Single-cell RNA sequencing (scRNA-seq) data from four published datasets were analyzed to investigate the sex differences in RCC patients, and tumor tissues were collected to validate the sex differences using multiplex immunofluorescence (MxIF) and flow cytometry (FCM). The function of the androgen–androgen receptor axis in sex differences was explored in vivo and in vitro experiments. Results: Our analysis of scRNA-seq data from 220,156 cells, as well as MxIF and FCM assays, revealed that CD8+ T-cells infiltrated highly in the TME of male RCC, but were mostly in an exhausted and dysfunctional state. In vitro and in vivo experiments indicated that the dysfunction and exhaustion of CD8+ T-cells in male TME were induced by androgen. Clinically, higher serum androgen was significantly associated with a worse prognosis in male RCC patients receiving immunotherapy. Androgen receptor inhibitors could activate tumor-infiltrating CD8+ T-cells and enhance the efficacy of immunotherapy of RCC in vivo. Conclusions: Our study delineated the difference in TME between male and female patients with RCC, and demonstrated that the androgen–androgen receptor axis plays an important role in immunosuppression in male RCC. Our findings suggest that androgen receptor inhibitors in combination with immunotherapy may be a promising treatment option for male RCC patients. Highlights: Male renal cell carcinoma is characterized by a heightened degree of malignant cell malignancy, with classical tumorigenic pathways, including EMT, angiogenesis, and TGF-β, highly enriched in the malignant cells. No significant difference in the subsets of infiltrating myeloid cells, indicating that myeloid cells may not play a significant role in the gender bias of renal cell carcinoma. We observed a higher infiltration of CD8+ T-cells in male renal cell carcinoma, most of which were in an exhausted state. The androgen–androgen receptor axis leads to CD8+ T-cell exhaustion in male renal cell carcinoma, resulting in the compromised anti-tumor function of these cells. Androgen receptor inhibitors may hold the potential to alleviate the exhaustion of CD8+ T-cells, paving the way for a promising combination therapy with immune checkpoint inhibitors for immunotherapy. [ABSTRACT FROM AUTHOR]

Conventional imaging examinations are not sensitive enough for the early detection of recurrent or metastatic lesions in renal cell carcinoma (RCC) patients. We aimed to explore the role of 68Ga‐prostate specific membrane antigen (PSMA)‐11 positron emission tomography (PET)/computed tomography (CT) in the detection of primary and metastatic lesions in such patients. We retrospectively analyzed 50 RCC patients who underwent 68Ga‐PSMA‐11 PET/CT from November 2017 to December 2020. We observed a higher median accuracy and tumor‐to‐background maximum standard uptake value (SUVmax) ratio (TBR) of 68Ga‐PSMA‐11 PET/CT in clear cell RCC (ccRCC; 96.57% and 6.00, respectively) than in non‐clear cell RCC (ncRCC; 82.05% and 2.99, respectively). The accuracies in detecting lesions in the renal region, bone, lymph nodes and lungs in ccRCC were 100.00%, 95.00%, 98.08% and 75.00%, respectively, and those in the renal region, bone and lymph nodes in ncRCC were 100.00%, 86.67% and 36.36%, respectively. The median TBRs of the lesions from the above locations were 0.38, 10.96, 6.69 and 13.71, respectively, in ccRCC and 0.13, 4.02 and 0.73, respectively, in ncRCC. The PSMA score evaluated with immunohistochemistry was correlated with the SUVmax (P =.046) in RCC. Higher PSMA scores were observed in ccRCC than in ncRCC (P =.031). 68Ga‐PSMA‐11 PET/CT resulted in changes in clinical management in 12.9% (4/31) of cases because of the discovery of new metastases not detected with conventional imaging. These results indicate that 68Ga‐PSMA‐11 PET/CT is a promising method for the detection of metastatic lesions in ccRCC, especially for those in the bone and lymph nodes. [ABSTRACT FROM AUTHOR]

Background: Locoregional recurrence after nephrectomy for localized renal cell carcinoma (RCC) is rare with diverse manifestations. The selection criteria and efficacy of different treatments are unanswered. The objective was to compare different treatment modalities and present data on stereotactic body radiotherapy (SBRT) for recurrent RCC. Materials and Methods: Patients with locoregional recurrence after nephrectomy without distant metastasis were identified from institutional big data intelligence platform between 2001 and 2020. Patients receiving local therapy (surgery or SBRT) or systemic therapy alone (targeted therapy or PD‐1 inhibitors) were divided into two groups. Progression‐free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier method, Cox regression model. Patients were matched with propensity score matching. Results: Among 106 patients, 33 (31.1%) received systemic therapy alone and 73 (68.9%) received local therapy. Local therapy was surgery in 34 patients (32.1%) and SBRT in 39 (36.8%) patients. Patients treated with systemic therapy alone had more non‐clear cell type (p = 0.044), more advanced T stage (p = 0.006), higher number (p = 0.043) but smaller size of lesions (p = 0.042). Patients receiving local therapy had significantly longer PFS than systemic therapy (19.7 vs. 7.5 months, p = 0.001). After matching, the PFS in the local therapy group remained higher (23.9 vs. 7.5 months, p = 0.001). The 2‐year OS of the local therapy group and systemic therapy group was 91.6% and 71.8%, respectively (p = 0.084). Local therapy was associated with better PFS (HR 0.37; p = 0.0003) and OS (HR 0.23; p = 0.002) in multivariate analysis. Grade 2 or higher toxicities related to local therapy occurred in nine patients. Conclusions: Local therapy could delay disease progression compared with systemic therapy alone. SBRT is safe and effective for locally recurrent RCC. [ABSTRACT FROM AUTHOR]

Sunitinib is one of the first‐line targeted drugs for metastatic renal cell carcinoma (RCC) with dual effects of antiangiogensis and proapoptosis. Sam68 (Src‐associated in mitosis, 68 KDa), is found being involved in cell apoptosis. This article reveals that Sam68 impacts the sensitivity to sunitinib by mediating the apoptosis of RCC cells. Immunohistochemical staining indicated that the Sam68 expression levels in sunitinib sensitive tumor tissues were markedly higher than those in sunitinib resistant tumor tissues. Sunitinib induced RCC cell apoptosis in a concentration‐dependent manner and inhibited the expression of total and phosphorylated Sam68 (p‐Sam68). Downregulation of Sam68 expression inhibited RCC cell apoptosis induced by sunitinib. While upregulation of Sam68 expression could enhance apoptosis induced by sunitinib. Xenograft models showed that tumors in the Sam68‐knockdown group did not shrink as much as those in the control group after treatment with sunitinib for 4 weeks. Together, our results suggest that Sam68 expression is associated with the sensitivity of ccRCC patients to sunitinib. Sam68 may promote cell apoptosis induced by sunitinib, and the Sam68 expression level may be a biomarker for predicting sunitinib sensitivity in ccRCC patients. [ABSTRACT FROM AUTHOR]

Although high body mass index (BMI) was reported to associate with a better prognosis for metastatic renal cell cancer (mRCC) patients receiving anti-vascular endothelial growth factor (anti-VEGF) therapy, it is an imperfect proxy for the body composition, especially in Asian patients with a lower BMI. The role of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and perirenal fat thickness (PRFT) in mRCC patients was still unknown. Therefore, a multicenter retrospective study of 358 Chinese mRCC patients receiving anti-VEGF therapy was conducted and their body composition was measured via computed tomography. We parameterized VAT, SAT and PRFT according to their median value and BMI according to Chinese criteria (overweight: BMI ≥ 24). We found VAT, SAT, and PRFT (all p < 0.05) but not BMI, significantly associated with overall survival (OS) and progression-free survival (PFS). Multivariate Cox analysis identified PRFT was the independent predictor of OS and PFS, and IMDC expanded with PRFT showed the highest C-index in predicting OS (OS:0.71) compared with VAT, SAT, and BMI. PRFT could increase the area under the curve of the traditional International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model in OS (70.54% increase to 74.71%) and PFS (72.22% increase to 75.03%). PRFT was introduced to improve the IMDC model and PRFT-modified IMDC demonstrated higher AIC in predicting OS and PFS compared with the traditional IMDC model. Gene sequencing analysis (n = 6) revealed that patients with high PRFT had increased angiogenesis gene signatures (NES = 1.46, p = 0.04) which might explain why better drug response to anti-VEGF therapy in mRCC patients with high PRFT. The main limitation is retrospective design. This study suggests body composition, especially PRFT, is significantly associated with prognosis in Chinese mRCC patients receiving anti-VEGF therapy. PRFT-modified IMDC model proposed in this study has better clinical predictive value. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to explore whether complete eradication of tumor burden with stereotactic body radiotherapy (SBRT) would affect the outcomes of oligometastatic renal cell carcinoma (RCC). Materials and methods: Patients diagnosed with extracranial oligometastatic RCC (no more than five metastases) between 2007 and 2019 were reviewed. Those without nephrectomy were excluded. SBRT to all, some and no lesions were defined as complete, incomplete, and no SBRT. Progression-free survival (PFS) and cancer-specific survival (CSS) were analyzed using Kaplan–Meier method, Cox regression model and the Fine and Gray method. Result: A total of 101 patients were included, 51.5% of whom had < 3 metastases. Forty (39.6%) patients received complete SBRT, and 61 (60.4%) received no or incomplete SBRT. The 1-year LC rate was 97.3%. The complete SBRT group had significantly longer PFS (26.0 vs 18.8 months; p = 0.043) and CSS (not reached vs. 55.3 months; p = 0.012) compared with the no or incomplete SBRT group. In multivariate analysis, ECOG 0–1 (HR 0.389, 95% CI 0.167–0.906, p = 0.029) and complete SBRT were prognostic factors for CSS (HR 0.307, 95% CI 0.108–0.876, p = 0.027). Complete SBRT was associated with improved CSS in the subgroups of patients with age < 55 years, ECOG 0–1, clear-cell histology, IMDC intermediate/poor risk, metachronous metastasis, and < 3 lesions. Conclusion: Complete eradication of tumor burden with SBRT was associated with better survival in patients with oligometastatic RCC. The recommendation of SBRT to all lesions should be individualized. [ABSTRACT FROM AUTHOR]

Objectives: Although axitinib has achieved a preferable response rate for advanced renal cell carcinoma (RCC), patient survival remains unsatisfactory. In this study, we evaluated the efficacy and safety of a combination treatment of axitinib and a low dose of pembrolizumab‐activated autologous dendritic cells–co‐cultured cytokine‐induced killer cells in patients with advanced RCC. Methods: All adult patients, including treatment‐naive or pretreated with VEGF‐targeted agents, were enrolled from May 2016 to March 2019. Patients received axitinib 5 mg twice daily and pembrolizumab‐activated dendritic cells–co‐cultured cytokine‐induced killer cells intravenously weekly for the first four cycles, every 2 weeks for the next four cycles, and every month thereafter. Results: The 43 patients (22 untreated and 21 previously treated) showed a median progression‐free survival (mPFS) of 14.7 months (95% CI, 11.16–18.30). mPFS in treatment‐naive patients was 18.2 months, as compared with 14.4 months in pretreated patients (log‐rank P‐value = 0.07). Overall response rates were 25.6% (95% CI, 13.5–41.2%). Grade 3 or higher adverse events occurred in 5% of patients included hypertension (11.6%) and palmar‐plantar erythrodysesthesia (7.0%). Peripheral blood lymphocyte immunophenotype and serum cytokine profile analyses demonstrated increased antitumor immunity after combination treatment particularly in patients with a long‐term survival benefit, while those with a minimal survival benefit demonstrated an elevated proportion of peripheral CD8+TIM3+ T cells and lower serum‐level immunostimulatory cytokine profile. Conclusions: The combination therapy was active and well tolerated for treatment of advanced RCC, either as first‐ or second‐line treatment following other targeted agents. Changes in immunophenotype and serum cytokine profile may be used as prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Background: Stereotactic body radiation therapy (SBRT) and tyrosine kinase inhibitors (TKIs) are effective treatments for metastatic renal cell carcinoma, but data on combining these two modalities are scarce. We aimed to investigate the survival outcomes of SBRT plus TKIs. Methods: Data of patients treated with TKIs from December 2007 to June 2019 were collected. Patients received SBRT plus TKIs (TKI + SBRT group) or TKIs alone (TKI alone group). Local control (LC), time to change of systemic therapy (TTS), and overall survival (OS) were assessed. Results: A total of 190 patients were included, and 85 patients received TKI + SBRT. The 2-year LC rate was 92.8%. The median OS in the TKI + SBRT group was significantly longer than that of the TKI alone group (63.2 vs 29.8 months; P < 0.001). In multivariate analysis, IMDC intermediate (HR 1.96; 95% CI 1.10–3.48; P = 0.022) and poor risk (HR 2.43; 95% CI 1.25–4.75; P = 0.009), oligometastasis (HR 0.41; 95% CI 0.26–0.65; P < 0.001), and the addition of SBRT (HR 0.48; 95% CI 0.31–0.75; P = 0.001) were prognostic factors for OS. Patients with oligometastasis (P = 0.009) and those with IMDC favorable (P = 0.044) or intermediate (P = 0.002) risk had significantly longer OS with TKI + SBRT. The median TTS were 21.5, 6.4, and 9.0 months in patients receiving SBRT before first-line TKI failure, SBRT after first-line TKI failure, and first-line TKI alone (P < 0.001). Five patients (5.9%) experienced SBRT-related grade 3 toxicities. Conclusions: Combining SBRT with TKIs is tolerable and associated with longer OS in selected patients, such as those with oligometastasis and favorable or intermediate risk. [ABSTRACT FROM AUTHOR]

Purpose Cryoablation and radio frequency ablation are attractive modalities for small renal masses in patients with substantial comorbidities. However, salvage extirpative therapy for local recurrence after thermal ablation can be challenging due to associated perinephric fibrosis. Materials and Methods Patients with thermal ablation refractory tumors requiring surgical salvage from 1997 to 2013 were identified and retrospectively reviewed. Results A total of 27 patients were treated surgically after cryoablation (18) or radio frequency ablation (9) failed. Subjective assessment indicated moderate/severe fibrosis in 22 cases (81%). Partial nephrectomy was preferred in all patients but was not possible in 12, primarily due to unfavorable tumor size/location. In the intended partial nephrectomy group (15) open surgery was performed in all patients and completed in 14, with the procedure aborted in 1 due to extensive perinephric fibrosis. Radical nephrectomy was planned in 12 patients, of whom 8 were treated laparoscopically with 1 requiring conversion to open. Median estimated blood loss was 225 ml. Overall 17 patients experienced no complications and 4 had minor complications. However, 6 patients experienced more significant complications (Clavien III-IVb). Since January 2008 partial nephrectomy was performed more frequently (12 of 17, or 71% vs 2 of 10, or 20% for previous cases, p=0.02). Conclusions Surgical salvage after failed thermal ablation is feasible in most instances, and partial nephrectomy is often possible but can be challenging due to associated perinephric fibrosis. The difficulty of surgical salvage should be recognized as a potential limitation of the thermal ablation treatment strategy. Prospective studies of thermal ablation vs partial nephrectomy should be prioritized to provide higher quality data about the merits and limitations of each approach. [ABSTRACT FROM AUTHOR]

Background: In the current Tumour-Node-Metastasis (TNM) classification system for renal cell carcinoma (RCC), both renal sinus fat invasion (SFI) and perinephric fat invasion (PFI) are defined as T3a, suggesting that the prognosis should be similar for the two pathologic findings. Several studies, however, have reported a worse prognosis for SFI in patients with a T3a tumor. In order to compare the prognosis of these two pathologic findings (SFI versus. PFI) in a more comprehensive way, this meta-analysis was performed. Methods: To identify relevant studies, Medline, Embase, Cochrane Library, and Scopus database were searched from the inception until October 2014. A meta-analysis was performed using Review Manager 5.2 and STATA 11. Pooled Odds ratio (OR) and/or hazard ratio (HR) with 95% confidence interval (CI) were calculated to examine the risk or hazard association. Results: A total of 6 studies including 1031 patients qualified for analysis. T3a RCC patients with SFI were significantly associated with poor cancer specific survival(CSS) (HR: 1.47, 95% CI: 1.19–1.83; P<0.001) compared to those with PFI. In T3aNx/N0M0 subgroup, SFI patients also showed a worse prognosis than those with PFI (CSS, HR: 1.94, 95% CI: 1.21–3.12; P = 0.006). T3a RCC patients with SFI had higher Furhman grade, greater possibility of lymph node metastasis, sarcomatoid differentiation and tumour necrosis. Main limitation is the relatively small number of included studies. Conclusion: The present meta-analysis suggested that SFI is associated with worse CSS in patients with pT3a RCC. However, due to the small number of included studies, future studies with a large sample size are required to further verify our findings. [ABSTRACT FROM AUTHOR]

Purpose Preservation of renal function is prioritized during surgical management of localized renal cell carcinoma. VEGF targeted agents can downsize tumors in metastatic renal cell carcinoma and may do the same in localized renal cell carcinoma, allowing for optimal preservation of renal parenchyma associated with partial nephrectomy. Materials and Methods Localized clear cell renal cell carcinoma patients meeting 1 or both of the following criteria were enrolled in a prospective phase II trial, including radical or partial nephrectomy likely to yield a glomerular filtration rate of less than 30 ml/minute/1.73 m 2 , or partial nephrectomy high risk due to high complexity (R.E.N.A.L. 10 to 12) or tumor adjacent to hilar vessels. Pazopanib (800 mg once daily) was administered for 8 to 16 weeks with repeat imaging at completion of therapy, followed by surgery. Results A total of 25 patients enrolled with a median tumor size of 7.3 cm and a median R.E.N.A.L. score of 11. Of index lesions 80% were high complexity and 56% of patients had a solitary kidney. Patients received a median of 8 weeks of pazopanib. The median interval from treatment start to surgery was 10.6 weeks. R.E.N.A.L. score decreased in 71% of tumors and 92% of patients experienced a reduction in tumor volume. Six of 13 patients for whom partial nephrectomy was not possible at baseline were able to undergo partial nephrectomy after treatment. The mean parenchymal volume that could be saved with surgery increased from an estimated 107 to 173 cc (p = 0.0015). In 5 patients a urine leak developed, which was managed conservatively, and 7 received a transfusion, of whom 1 required embolization. Conclusions Neoadjuvant pazopanib resulted in downsizing localized renal cell carcinoma, allowing for improved preservation of renal parenchyma and enabling partial nephrectomy in a select subset of patients who would otherwise require radical nephrectomy. [ABSTRACT FROM AUTHOR]

Background Chronic kidney disease (CKD) can be associated with a higher risk of progression to end-stage renal disease and mortality, but the etiology of nephron loss may modify this. Previous studies suggested that CKD primarily due to surgical removal of nephrons (CKD-S) may be more stable and associated with better survival than CKD due to medical causes (CKD-M). Objective We addressed limitations of our previous work with comprehensive control for confounding factors, differentiation of non–renal cancer-related mortality, and longer follow-up for more discriminatory assessment of the impact of CKD-S. Design, setting, and participants From 1999 to 2008, 4299 patients underwent surgery for renal cancer at a single institution. The median follow-up was 9.4 yr (7.3–11.0). The new baseline glomerular filtration rate (GFR) was defined as the highest GFR between the nadir and 42 d after surgery. Three cohorts were retrospectively evaluated: no CKD (new baseline GFR >60 ml/min/1.73 m 2 ); CKD-S (new baseline GFR<60 but preoperative >60 ml/min/1.73 m 2 ); and CKD-M/S (new baseline and preoperative GFR both <60 ml/min/1.73 m 2 ). Cohort status was permanently set at 42 d after surgery. Intervention Renal surgery. Outcome measurements and statistical analysis Decline in renal function (50% reduction in GFR or dialysis), all-cause mortality, and non–renal cancer mortality were examined using a multivariable Cox proportional hazards model. Results and limitations CKD-M/S had a higher incidence of relevant comorbidities and the new baseline GFR was lower. On multivariable analysis (controlling for age, gender, race, diabetes, hypertension, and cardiac disease), CKD-M/S had higher rates of progressive decline in renal function, all-cause mortality, and non–renal cancer mortality when compared to CKD-S and no CKD (hazard ratio [HR] 1.69–2.33, all p < 0.05). All-cause mortality was modestly higher for CKD-S than for no CKD (HR 1.19, p = 0.030), but renal stability and non–renal cancer mortality were similar for these groups. New baseline GFR of <45 ml/min/1.73 m 2 significantly predicted adverse outcomes. The main limitation is the retrospective design. Conclusions CKD-S is more stable than CKD-M/S and has better survival, approximating that for no CKD. However, if the new baseline GFR is <45 ml/min/1.73 m 2 , the risks of functional decline and mortality increase. These findings may influence counseling for patients with localized renal cell carcinoma and higher oncologic potential when a normal contralateral kidney is present. Patient summary Survival is better for surgically induced chronic kidney disease (CKD) than for medically induced CKD, particularly if the postoperative glomerular filtration rate is ≥45 ml/min/1.73 m 2 . Patients with preexisting CKD are at risk of a significant decline in kidney function after surgery, and kidney-preserving treatment should be strongly considered in such cases. [ABSTRACT FROM AUTHOR]