Targeting STING elicits GSDMD-dependent pyroptosis and boosts anti-tumor immunity in renal cell carcinoma.

While Stimulator-of-interferon genes (STING) is an innate immune adapter cruicial for sensing cytosolic DNA and modulating immune microenvironment, its tumor-promoting role in tumor survival and immune evasion remains largely unknown. Here we reported that renal cancer cells are exceptionally dependent on STING for survival and evading immunosurveillance via suppressing ER stress-mediated pyroptosis. We found that STING is significantly amplified and upregulated in clear cell renal cell carcinoma (ccRCC), and its elevated expression is associated with worse clinical outcomes. Mechanically, STING depletion in RCC cells specifically triggers activation of the PERK/eIF2α/ATF4/CHOP pathway and activates cleavage of Caspase-8, thereby inducing GSDMD-mediated pyroptosis, which is independent of the innate immune pathway of STING. Moreover, animal study revealed that STING depletion promoted infiltration of CD4+ and CD8+ T cells, consequently boosting robust antitumor immunity via pyroptosis-induced inflammation. From the perspective of targeted therapy, we found that Compound SP23, a PROTAC STING degrader, demonstrated comparable efficacy to STING depletion both in vitro and in vivo for treatment of ccRCC. These findings collectively unveiled an unforeseen function of STING in regulating GSDMD-dependent pyroptosis, thus regulating immune response in RCC. Consequently, pharmacological degradation of STING by SP23 may become an attractive strategy for treatment of advanced RCC.

Neoadjuvant therapy in renal cell carcinoma with tumor thrombus: A systematic review and meta-analysis.

To evaluate the efficacy, feasibility and safety of neoadjuvant therapy (NAT) for renal cell carcinoma with tumor thrombus (RCC-TT) in terms of response, perioperative and oncological outcomes, and compare the results between neoadjuvant and non-neoadjuvant groups. Overall, 29 single-arm studies and 5 cohort studies were included. Of the 204 patients undergoing NAT, 16.2% were level I, 35.3% level II, 24.0% level III and 18.6% level IV thrombus. Most of patients underwent preoperative targeted therapy, immunotherapy-based combination therapy was applied in 5.4% patients. The total reduction rate of thrombus level was 29.4%. NAT is associated with a shorter operative time, less blood loss (p<0.05 for both). Rate of complications and oncological outcomes were similar between two groups. Overall, 32.1% (34/106) ≥ grade 3 adverse events occurred in patients undergoing NAT. Neoadjuvant therapy is safe and feasible with acceptable perioperative outcomes in RCC-TT.

Loss of cell division cycle­associated 5 promotes cell apoptosis by activating DNA damage response in clear cell renal cell carcinoma.

Cell division cycle­associated 5 (CDCA5) protein, which is involved in cohesion, contributes to cell cycle regulation and chromosome segregation by maintaining genomic stability. Accumulating evidence indicates that CDCA5 expression is upregulated in a number of types of cancer associated with a poor prognosis. However, the biological function of CDCA5 in clear cell renal cell carcinoma (ccRCC) remains largely unknown. In the present study, The Cancer Genome Atlas data mining revealed that CDCA5 was more highly expressed in ccRCC than in adjacent normal tissues. Importantly, such a high expression was associated with a higher risk of distant metastasis and poorer clinical outcomes. Moreover, the clinical and prognostic value of CDCA5 expression was further investigated using immunohistochemistry on tissue microarrays containing paired tumor tissues and adjacent normal tissues from 137 patients with ccRCC. Functional analyses revealed that CDCA5 knockdown significantly inhibited the proliferation and migration of ccRCC cells, and suppressed the growth of xenografts in nude mice. Mechanistically, CDCA5 knockdown induced severe DNA damage with the persistent accumulation of γ­H2A histone family member X foci, resulting in G2/M cell cycle arrest and finally, in chromosomal instability and apoptosis. CDCA5 knockdown significantly decreased the phosphorylation levels of Stat3 and NF­κB, suggesting that CDCA5 plays a role in regulating the inflammatory response. Collectively, the findings of the present study indicate that ccRCC cells require CDCA5 for malignant progression, and that CDCA5 inhibition may enhance the outcomes of patients with high­risk ccRCC.

E2F1 promotes proliferation and metastasis of clear cell renal cell carcinoma via activation of SREBP1-dependent fatty acid biosynthesis.

Enhanced synthesis or uptake of lipids contributes to rapid cancer cell proliferation and tumor progression. In recent years, cell cycle regulators have been shown to be involved in the control of lipid synthesis, in addition to their classical function of controlling the cell cycle. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and is characterized by lipid-rich cytoplasmic deposition. However, the relationship between altered lipid metabolism and tumor progression in ccRCC is poorly understood. Here, we demonstrated that E2F transcription factor 1 (E2F1), in addition to its key role in regulating the cell cycle, induces extensive lipid accumulation and elevated levels of lipogenic enzymes in ccRCC cells by upregulating sterol regulatory element-binding protein 1 (SREBP1). E2F1 knockdown or SREBP1 suppression attenuated fatty acid (FA) de novo synthesis, cell proliferation and epithelial-mesenchymal transition (EMT) in ccRCC cells. Furthermore, overexpression of E2F1 promoted lipid storage, tumor growth and metastasis in a mouse xenograft model, whereas E2F1 downregulation or SREBP1 inhibition reversed these effects. In ccRCC patients, high levels of E2F1 and SREBP1 were associated with increased lipid accumulation and correlated with poor prognosis. Our results demonstrate that E2F1 can increase proliferation and metastasis through SREBP1-induced aberrant lipid metabolism, which is a novel critical signaling mechanism driving human ccRCC progression.

Androgen receptor modulates metastatic routes of VHL wild-type clear cell renal cell carcinoma in an oxygen-dependent manner.

Recent studies indicated that the androgen receptor (AR) plays important roles in modulating metastasis of VHL-mutant clear cell renal cell carcinoma (ccRCC). However, the precise mechanisms of AR roles in VHL wild-type (VHL-wt) ccRCC, remain unclear. Here we found that AR interacted with VHL to modulate the metastasis of VHL-wt ccRCC via an oxygen-dependent manner. Mechanism dissection revealed that AR could transcriptionally suppress the miR-185-5p expression in the presence of functional VHL-wt protein under a normoxic condition, which might then result in increasing the expression of VEGF-A and VEGF-C via targeting the 3'UTR of mRNAs at a post-transcriptional level. In contrast, under a hypoxic condition, AR could increase miR-185-5p expression to suppress VEGF-C expression, yet this miR-185-5p effect on VEGF-A was reversed via AR's positive regulation on the HIF2α-increased VEGF-A expression that resulted in increasing VEGF-A in the VHL-wt RCC cells. These distinct AR functions under different oxygen conditions may involve the VHL-impacted ubiquitination and nuclear localization of AR. The differential regulation of VEGF-A vs VEGF-C by AR may then result in differential impacts on the ccRCC metastatic destinations of VHL-wt ccRCC cells under different oxygen conditions. These finer mechanisms may help in the development of a novel therapy to better suppress the ccRCC progression under different oxygenization conditions.

Prediction of pentafecta achievement following laparoscopic partial nephrectomy: Implications for robot-assisted surgery candidates.

BACKGROUND: In clinical practice, objective basis for the choice between laparoscopic partial nephrectomy (LPN) and robot-assisted partial nephrectomy (RAPN) is scarce. To evaluate surgical outcomes, assess the individual benefit from LPN to RAPN, which can guide clinical decision-making. METHODS: Patients underwent LPN or RAPN for a localized renal mass in our center between Jan 2013 and Dec 2016 were included. The surgical outcome of LPN and RAPN was the pentafecta achievement. A multivariable model was fitted to predict the probability of pentafecta achievement after LPN. Model-derived coefficients were applied to calculate the probability of pentafecta achievement in case of LPN among patients treated with RAPN. Locally weighted scatterplot smoothing method was applied to plot the observed probability of pentafecta achievement against the predicted pentafecta probability in case of LPN. RESULTS: RAPN group had a significantly higher pentafecta achievement (54.6% vs. 41.1%, P < 0.001) than LPN. Multivariable analyses identified that tumor size, distance of the tumor to collecting system or sinus, and preoperative eGFR were independent predictors of pentafecta after LPN. When RAPN was chosen over LPN, the increase in the probability of pentafecta achievement was greatest in intermediate-probability patients. With the increase or decrease of the probability of pentafecta, the benefit of RAPN decreased. CONCLUSION: When pentafecta achievement are assessed, the benefit of RAPN over LPN varies from patient to patient. Patients at intermediate-probability of pentafecta achievement after LPN benefit the most from robotic surgery, which may be the potential ideal candidates for RAPN.

A modified sequential vascular control strategy in robot-assisted level III-IV inferior vena cava thrombectomy: initial series mimicking the open 'milking' technique principle.

OBJECTIVE: To introduce a modified sequential vascular control strategy, mimicking the open 'milking' technique principle, for the early release of the first porta hepatis (FPH) and to stop cardiopulmonary bypass (CPB) in level III-IV robot-assisted inferior vena cava (IVC) thrombectomy (RA-IVCTE). PATIENTS AND METHODS: From November 2014 to June 2019, 27 patients with a level III-IV IVC tumour thrombus (IVCTT) underwent RA-IVCTE in our department. The modified sequential control strategy was used in 12 cases. Previously, we released the FPH after the thrombus was resected and the IVC was closed completely, and CPB was stopped at the end of surgery (15 patients). Presently, using our modified strategy, we place another tourniquet inferior to the second porta hepatis (SPH) once the proximal thrombus is removed from the IVC below the SPH. Then, we suture the right atrium and perform early release of the FPH, and stop CPB. Finally, tumour thrombectomy, vascular reconstruction, and radical nephrectomy are performed. RESULTS: Compared with the previous strategy, the modified steps resulted in a shorter median FPH clamping (19 vs 47 min, P < 0.001) and CPB times (60 vs 87 min, P < 0.05); a lower rate of Grade II-IV perioperative complications (25% vs 60%, P < 0.05); and better postoperative hepatorenal and coagulation function, including better median serum alanine aminotransferase (172.7 vs 465.4 U/L, P < 0.001), aspartate aminotransferase (282.4 vs 759.8 U/L, P < 0.001), creatinine (113.4 vs 295 µmol/L, P < 0.01), blood urea nitrogen (7.3 vs 16.7 mmol/L, P < 0.01), and D-dimer (5.9 vs 20 mg/L, P < 0.001) levels. CONCLUSION: With the early release of the FPH and stopping CPB, the modified sequential vascular control strategy in level III-IV RA-IVCTE reduced the perioperative risk for selected patients and improved the feasibility and safety of the surgery. We would recommend this approach to other centres that plan to develop robotic surgery for renal cell carcinoma with level III-IV IVCTT in the future.

A three-dimensional, anatomy-based nephrometry score to guide nephron-sparing surgery for renal sinus tumors.

BACKGROUND: A quantitative nephrometry scoring system specifically for renal sinus tumors will assist in classifying surgical complexity and treatment planning. METHODS: By using preoperative computed tomography, magnetic resonance imaging, and 3-dimensional image reconstruction, 5 critical components were assessed: the ratio of the sinus area occupied by the tumor in relation to the whole sinus area (R), the compression of the renal segmental vessels or collection system by the tumor (O), the anteroposterior relation of the tumor relative to the segmental vessels or collection system (A), the tumor diameter (D), and whether the tumor affects a solitary kidney (S) ("ROADS"). The ROADS score, indicating low, moderate, or high surgical complexity, was then used to guide surgical strategy planning, including cooling techniques, surgical approaches, and parenchyma incision techniques. A cohort of 134 patients with renal sinus tumors was treated based on their ROADS score and was retrospectively analyzed. RESULTS: The authors successfully performed 113 nephron-sparing surgeries and 21 radical nephrectomies with a complication rate of 7.9%. During follow-up, 3 cases were classified according to surgical margin status because they lacked an intact tumor capsule. There was only 1 case of local recurrence, and there were no cases of metastasis. A high ROADS score was correlated with greater operative complexity, such as longer operation and ischemia times and higher estimated blood loss and complication rates. However, renal function and short-term oncologic outcomes were not related to the score. CONCLUSIONS: The ROADS scoring system provides a standardized, quantitative, 3-dimensional anatomic classification to guide surgical strategy in renal sinus tumors.

Robot-assisted Cavectomy Versus Thrombectomy for Level II Inferior Vena Cava Thrombus: Decision-making Scheme and Multi-institutional Analysis.

BACKGROUND: Robot-assisted thrombectomy (RAT) for inferior vena cava (IVC) thrombus (RAT-IVCT) is being increasingly reported. However, the techniques and indications for robot-assisted cavectomy (RAC) for IVC thrombus are not well described. OBJECTIVE: To develop a decision-making program and analyze multi-institutional outcomes of RAC-IVCT versus RAT-IVCT. DESIGN, SETTING, AND PARTICIPANTS: Ninety patients with renal cell carcinoma (RCC) with level II IVCT were included from eight Chinese urological centers, and underwent RAC-IVCT (30 patients) or RAT-IVCT (60 patients) from June 2013 to January 2019. SURGICAL PROCEDURE: The surgical strategy was based on IVCT imaging characteristics. RAT-IVCT was performed with standardized cavotomy, thrombectomy, and IVC reconstruction. RAC-IVCT was mainly performed in patients with extensive IVC wall invasion when the collateral blood vessels were well-established. For right-sided RCC, the IVC from the infrarenal vein to the infrahepatic veins was stapled. For left-sided RCC, the IVC from the suprarenal vein to the infrahepatic veins was removed and caudal IVC reconstruction was performed to ensure the right renal vein returned through the IVC collaterals. MEASUREMENTS: Clinicopathological, operative, and survival outcomes were collected and analyzed. RESULTS AND LIMITATIONS: All procedures were successfully performed without open conversion. The median operation time (268 vs 190 min) and estimated blood loss (1500 vs 400 ml) were significantly greater for RAC-IVCT versus RAT-IVCT (both p < 0.001). IVC invasion was a risk factor for progression-free and overall survival at midterm follow-up. Large-volume and long-term follow-up studies are needed. CONCLUSIONS: RAC-IVCT or RAT-IVCT represents an alternative minimally invasive approach for selected RCC patients with level II IVCT. Selection of RAC-IVCT or RAT-IVCT is mainly based on preoperative IVCT imaging characteristics, including the presence of IVC wall invasion, the affected kidney, and establishment of the collateral circulation. PATIENT SUMMARY: In this study we found that robotic surgeries for level II inferior vena cava thrombus were feasible and safe. Preoperative imaging played an important role in establishing an appropriate surgical plan.

Initial Series of Robotic Segmental Inferior Vena Cava Resection in Left Renal Cell Carcinoma With Caval Tumor Thrombus.

OBJECTIVE: To present our preliminary experience of robotic left radical nephrectomy (LRN) and segmental inferior vena cava (IVC) resection without caval replacement for left renal cell carcinoma (RCC) with inferior vena cava tumor thrombus. MATERIALS AND METHODS: Between 2017 and 2018, 7 patients underwent segmental IVC resection and LRN robotically. All patients underwent preoperative cavography, demonstrating complete IVC occlusion. Computed tomography-based 3-dimensional reconstruction revealed sufficient collateralization of the IVC and right renal vein (RRV). The cephalic IVC was circumferentially resected and ligated just below the second porta hepatis. The caudal IVC was circumferentially resected above the RRV with preservation of the major collaterals. The RRV was not dissected during the procedure to avoid compromising its neocollaterals. The IVC portion between the RRV and the second porta hepatis was removed en bloc with the tumor thrombus, and the LRN was performed. RESULTS: All cases were successfully performed by robotic surgery without conversion. Median operative time was 420 minutes. Median intensive care unit stay was 3 days. Four grade Ⅱ complications occurred in 2 patients. One patient had mild LEE postoperatively and recovered without special medication. Median preoperative and 3-6 months follow-up serum creatinine was 118.7 µmol/L and 135.2 µmol/L, respectively. No patient needed dialysis postoperatively. One case occurred disease progression. No patient died during the follow-up period. CONCLUSION: Robotic segmental IVC resection for left RCC with inferior vena cava tumor thrombus is feasible in well-selected cases. Three-dimensional reconstruction and cavography are helpful in the preoperative evaluation of neocollaterals in patients with suprarenal IVC occlusion.

Comparison of Robot-Assisted and Laparoscopic Partial Nephrectomy for Completely Endophytic Renal Tumors: A High-Volume Center Experience.

Objectives: To compare the perioperative, functional, and oncologic outcomes of robot-assisted partial nephrectomy (RAPN) and laparoscopic partial nephrectomy (LPN) for completely endophytic renal tumors (three points for the "E" element of the R.E.N.A.L. scoring system). Materials and Methods: We retrospectively reviewed patients who underwent either RAPN or LPN between 2013 and 2016. Baseline characteristics, perioperative, functional, and oncologic outcomes were compared. Univariable and multivariable logistic analyses were performed to determine factors associated with pentafecta achievement (ischemia time ≤25 minutes, negative margin, no perioperative complication, return of estimated glomerular filtration rate [eGFR] to >90% from baseline, and no chronic kidney disease upstaging). Results: No significant differences between RAPN vs LPN were noted for operating time (105 minutes vs 108 minutes, p = 0.916), estimated blood loss (50 mL vs 50 mL, p = 0.130), renal artery clamping time (20 minutes vs 20 minutes, p = 0.695), rate of positive margins (3.3% vs 2.0%, p = 1.000), and postoperative complication rates (18.0% vs 21.6%, p = 0.639). RAPN was associated with a higher direct cost ($11240 vs $5053, p < 0.001). There were no significant differences in pathology variables, rate of eGFR decline for postoperative 12-month (9.8% vs 10.6%, p = 0.901) functional follow-up. Multivariate analysis identified that only RENAL score was independently associated with the pentafecta achievement. Conclusions: For completely endophytic renal tumors, both RAPN and LPN have excellent and similar results. Both operation techniques remain viable options in the management of these cases.

Robot-assisted Level III-IV Inferior Vena Cava Thrombectomy: Initial Series with Step-by-step Procedures and 1-yr Outcomes.

BACKGROUND: Level III-IV robot-assisted inferior vena cava (IVC) thrombectomy (RA-IVCT) has been reported in limited series. OBJECTIVE: To report our initial series of level III-IV RA-IVCT with step-by-step procedures and 1-yr outcomes. DESIGN, SETTING, AND PARTICIPANTS: From November 2014 to January 2018, 13 patients with level III-IV IVC tumor thrombi underwent RA-IVCT with a minimum of 1-yr follow-up. SURGICAL PROCEDURE: Level III RA-IVCT requires liver mobilization and clamping of first porta hepatis (FPH), and suprahepatic and infradiaphragmatic IVC. Level IV RA-IVCT requires establishment of cardiopulmonary bypass (CPB). Thoracoscopy-assisted thrombectomy was performed for the intra-atrium part of the thrombus under CPB. Infradiaphragmatic RA-IVCT was completed in a manner similar to that of level III RA-IVCT. MEASUREMENTS: Detailed techniques were described for various scenarios. Baseline and perioperative outcomes were reported, and descriptive statistical analysis was performed. RESULTS AND LIMITATIONS: Median operative time was 465 (interquartile range [IQR]: 338-567) min. Median estimated intraoperative blood loss was 2000 (IQR: 1000-3000) ml. The rates of intraoperative blood transfusion and postoperative transformation to the intensive care unit ward were 92.3% and 100%, respectively. Median FPH blocking time was 40 (IQR: 25-60) min and the CPB time was 72 (IQR: 51-87) min. Three cases had grade IV complications, including two vascular injuries that were treated with intraoperative endoscopic sutures and one perioperative death. The perioperative mortality rate was 7.7%. During an 18-mo follow-up, two patients died and one patient progressed. CONCLUSIONS: Although the risks involved are high, level III-IV RA-IVCT is feasible and serves as an alternative minimally invasive method for selected patients. It also requires more complex techniques and multidisciplinary cooperation. PATIENT SUMMARY: We studied the treatment of patients with level III-IV inferior vena cava (IVC) tumor thrombi using a robotic approach. This technique was feasible for well-selected patients. However, level III-IV robot-assisted IVC thrombectomy requires more complex techniques and multidisciplinary cooperation.

Radical Nephrectomy with or without Lymph Node Dissection for pT3 Renal Cell Carcinoma: A Propensity Score-based Analysis.

OBJECTIVES: To study whether radical nephrectomy (RN) with lymph node dissection (LND) can benefit pT3 renal cell carcinoma (RCC) patients versus no LND under the 2018 American Joint Committee on Cancer TNM classification system. Subjects/Patients and Methods: We performed a retrospective cohort study of clinicopathological data for 245 T3 RCC patients, who underwent radical nephrectomy between January 2006 and December 2013 at our center, including 67 (27.1%) who underwent LND. The relationships between the LND and progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) were evaluated using 1:1 propensity score (PS) matching. Then, Kaplan-Meier survival analysis and Cox regression analysis were conducted to study whether these patients can benefit from LND. Depending on the LND number, we divided the cohort into two groups for further comparation. At last, we validated the results with the TCGA database KIRC patients. RESULTS: The median follow-up time was 4.9 years. Sixty-seven pairs of patients were screened by the PS and were further analyzed. We conducted a Cox regression with the survival data and found that the LND group, compared with the non-LND group, showed no survival benefit on PFS, CSS, and OS (p = 0.444, 0.809, and 0.816, respectively). However, the removal of 5 or more LNs showed negative effect on OS (p = 0.0387). TCGA cohort results are mostly consistent with our findings. CONCLUSION: RN with LND cannot improve the PFS, CSS, or OS for pT3 renal cell carcinoma patients.

A systematic review and meta-analysis of clinicopathologic factors linked to oncologic outcomes for renal cell carcinoma with tumor thrombus treated by radical nephrectomy with thrombectomy.

BACKGROUND: There remain discrepancies over the factors that influence oncologic outcomes after radical nephrectomy with thrombectomy (RNTE). To assess significant predictors of oncologic outcomes after RNTE from a systematic review and meta-analysis. METHODS: A comprehensive search of PubMed, Embase, Cochrane Library and Web of Science was performed to identify eligible studies. The endpoints included cancer-specific survival (CSS), overall survival (OS), and recurrence-free survival (RFS). A formal meta-analysis was performed for studies containing non-metastatic and metastatic tumors. Additionally, a sensitivity analysis including the subgroup of studies containing non-metastatic tumors only was conducted. Cumulative analyses of hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were conducted. RESULTS: Overall, 35 retrospective studies of low to moderate risk of bias including 11,929 patients were included. The results indicated that large tumor size, high Fuhrman grade, tumor necrosis, positive lymph node, and metastasis at surgery were adverse significant predictors for both CSS and OS. Also, IVC tumor thrombus, sarcomatoid differentiation, perinephretic fat invasion, and adrenal gland invasion were associated with poor CSS. In the subset of non-metastatic patients, the significant predictors were clinical symptom, thrombus level, Fuhrman grade and adrenal gland invasion for CSS; thrombus consistency, Fuhrman grade and tumor necrosis for OS; tumor size, Fuhrman grade and perinephretic fat invasion for RFS. CONCLUSIONS: A meta-analysis of available data identified significant prognostic factors of CSS, OS and RFS that should be systematically evaluated to propose a risk-adapted approach to postoperative patient counseling, risk stratification, and therapy selection.