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.

Case report: Retroperitoneal solid pseudopapillary neoplasm associated with multiple hepatic metastases.

Solid pseudopapillary neoplasm (SPN) is a rare tumor mostly occurring in the pancreas. They are low-grade malignant tumors of the exocrine pancreas that occasionally metastasize, usually to the liver or peritoneum. Additionally, multiple metastases of extrapancreatic SPN to the liver are extremely rare and have been reported before. This study presents a case of a 13-year-old male patient with retroperitoneal SPN and multiple hepatic metastases. The patient presented with abdominal trauma and underwent enhanced CT, which revealed upper pancreatic occupancy and three hypodense foci in the right lobe of the liver. Moreover, increased spleen size was noted. The patient's serum tumor marker CA125 was increased to 39.00 U/mL (N < 35.0 U/mL), and circulating tumor cells were elevated to 10.2 FU/3 mL (N < 8.7 FU/3 mL). The patient underwent retroperitoneal occupancy resection and splenectomy, followed by resection of liver metastases 7 months after the surgery. Furthermore, multiple liver metastases from retroperitoneal SPN were confirmed postoperatively. The patient recovered for 1 year without tumor recurrence. This case emphasizes the importance of evaluating serum tumor markers and medical imaging in young patients as well as the fact that surgery appears to be the preferred treatment option for multiple metastases in SPN.

Risk factors for incident venous thromboembolism in patients with renal tumor and inferior vena cava tumor thrombus: a retrospective case-control study.

BACKGROUND: Venous thromboembolism (VTE) is a principal cause of mortality and adverse oncologic outcomes in patients with renal tumor and inferior vena cava tumor thrombus (RT-IVCTT). However, the preoperative thrombotic risk factors in these patients remain not fully characterized. OBJECTIVES: To identify preoperative thrombotic risk factors in patients with RT-IVCTT. PATIENTS/METHODS: Two hundred fifty-seven consecutive postsurgical patients with RT-IVCTT aged 18-86 years were enrolled between January 2008 and September 2022. Clinicopathological variables were retrospectively reviewed. A multivariate logistic regression model was performed. Preoperative hemoglobin, neutrophils, and serum albumin levels were analyzed as both continuous and categorical variables. RESULTS: VTE was identified in 63 patients (24.5%). On both continuously and categorically coded variables, advanced IVC thrombus (OR 3.2, 95% CI: 1.4-7.0; OR 2.7, 95% CI: 1.2-6.1), renal sinus fat invasion (OR 3.4, 95% CI: 1.6-7.0; OR 3.7, 95% CI: 1.8-7.7), IVC wall invasion (OR 3.6, 95% CI: 1.6-7.9; OR 4.3, 95% CI: 1.9-10.0), IVC blockage status of greater than 75% (OR 5.2, 95% CI: 1.7-15.8; OR 6.1, 95% CI: 1.9-19.7), and higher neutrophils (OR 1.3, 95% CI: 1.0-1.7; OR 2.4, 95% CI: 1.1-5.4) were significantly associated with increased VTE risk in patients with RT-IVCTT. Except hemoglobin, categorically coded serum albumin (OR 0.36, 95% CI: 0.17-0.75) was validated as an independent risk factor for VTE. CONCLUSIONS: This study provided an insight of risk factors contributing to preoperative VTE in patients with RT-IVCTT, which may be beneficial for optimizing strategies to manage VTE in clinical practice.

Assessment of Ki-67 proliferation index in prognosis prediction in patients with nonmetastatic clear cell renal cell carcinoma and tumor thrombus.

PURPOSE: To determine the optimal cut-off value of Ki-67 for predicting the survival of patients with clear cell renal cell carcinoma (ccRCC) and tumor thrombus and to explore the correlation between Ki-67 expression and pathological features. PATIENTS AND METHODS: We retrospectively analyzed Ki-67 immunohistochemical staining of ccRCC and tumor thrombus resected from February 2006 to February 2022. The survival rate was evaluated using the Kaplan-Meier method. The optimal cut-off value of the Ki-67 expression for predicting survival was determined by the minimum P-value method. Clinicopathological data were compared based on Ki-67 status (low versus high expression). Univariate and multivariate Cox regression analysis was used to explore independent predictors. RESULTS: A total of 202 patients (median age, 58 years [IQR, 52-65 years], 147 men) with ccRCC and tumor thrombus were included in the study. The optimal cut-off value of Ki-67 for predicting survival was 30%. 159 (78.7%) and 43 (21.3%) patients were included in the low-expression and high-expression groups. Patients with Ki-67 high expression had significantly worse recurrence-free survival (P < 0.001) and cancer-specific survival (P < 0.001). Ki-67 high expression was associated with adverse pathological features, including tumor necrosis, ISUP nuclear grade, sarcomatoid differentiation, perirenal fat invasion, renal pelvis invasion, and inferior vena cava wall invasion (all P < 0.050). Ki-67 expression ≥ 30% (P = 0.016), tumor side (P = 0.003), diabetes (P = 0.040), blood loss (P = 0.016), inferior vena cava wall invasion (P = 0.016), and sarcomatoid differentiation (P = 0.014) were independent predictors of cancer-specific survival. CONCLUSION: The optimal cut-off level of Ki-67 in predicting the prognosis of ccRCC and tumor thrombus was 30%. The high expression of Ki-67 was associated with the aggressive pathological phenotype and poor prognosis.

Predicting recurrence and survival in patients with non-metastatic renal-cell carcinoma after nephrectomy: a prospective population-based study with multicenter validation.

BACKGROUND: Accurate prognostication of oncological outcomes is crucial for the optimal management of patients with renal cell carcinoma (RCC) after surgery. Previous prediction models were developed mainly based on retrospective data in the Western populations, and their predicting accuracy remains limited in contemporary, prospective validation. We aimed to develop contemporary RCC prognostic models for recurrence and overall survival (OS) using prospective population-based patient cohorts and compare their performance with existing, mostly utilized ones. METHODS: In this prospective analysis and external validation study, the development set included 11  128 consecutive patients with non-metastatic RCC treated at a tertiary urology center in China between 2006 and 2022, and the validation set included 853 patients treated at 13 medical centers in the USA between 1996 and 2013. The primary outcome was progression-free survival (PFS), and the secondary outcome was OS. Multivariable Cox regression was used for variable selection and model development. Model performance was assessed by discrimination [Harrell's C-index and time-dependent areas under the curve (AUC)] and calibration (calibration plots). Models were validated internally by bootstrapping and externally by examining their performance in the validation set. The predictive accuracy of the models was compared with validated models commonly used in clinical trial designs and with recently developed models without extensive validation. RESULTS: Of the 11  128 patients included in the development set, 633 PFS and 588 OS events occurred over a median follow-up of 4.3 years [interquartile range (IQR) 1.7-7.8]. Six common clinicopathologic variables (tumor necrosis, size, grade, thrombus, nodal involvement, and perinephric or renal sinus fat invasion) were included in each model. The models demonstrated similar C-indices in the development set (0.790 [95% CI 0.773-0.806] for PFS and 0.793 [95% CI 0.773-0.811] for OS) and in the external validation set (0.773 [0.731-0.816] and 0.723 [0.731-0.816]). A relatively stable predictive ability of the models was observed in the development set (PFS: time-dependent AUC 0.832 at 1 year to 0.760 at 9 years; OS: 0.828 at 1 year to 0.794 at 9 years). The models were well calibrated and their predictions correlated with the observed outcome at 3, 5, and 7 years in both development and validation sets. In comparison to existing prognostic models, the present models showed superior performance, as indicated by C-indices ranging from 0.722 to 0.755 (all P <0.0001) for PFS and from 0.680 to 0.744 (all P <0.0001) for OS. The predictive accuracy of the current models was robust in patients with clear-cell and non-clear-cell RCC. CONCLUSIONS: Based on a prospective population-based patient cohort, the newly developed prognostic models were externally validated and outperformed the currently available models for predicting recurrence and survival in patients with non-metastatic RCC after surgery. The current models have the potential to aid in clinical trial design and facilitate clinical decision-making for both clear-cell and non-clear-cell RCC patients at varying risk of recurrence and survival.

Intravoxel Incoherent Motion Diffusion-Weighted MR Imaging and Venous Tumor Thrombus Consistency in Renal Cell Carcinoma.

BACKGROUND: Venous tumor thrombus (VTT) consistency of renal cell carcinoma (RCC) is an important consideration in nephrectomy plus thrombectomy. However, evaluation of VTT consistency through preoperative MR imaging is lacking. PURPOSE: To evaluate VTT consistency of RCC through intravoxel incoherent motion-diffusion weighted imaging (IVIM-DWI) derived parameters (Dt , Dp , f, and ADC) and the apparent diffusion coefficient (ADC) value. STUDY TYPE: Retrospective. POPULATION: One hundred and nineteen patients (aged 55.8 ± 11.5 years, 85 male) with histologically-proven RCC and VTT who underwent radical resection. FIELD STRENGTH/SEQUENCES: 3.0-T; two-dimensional single-shot diffusion-weighted echo planar imaging sequence at 9 b-values (0-800 s/mm2 ). ASSESSMENT: IVIM parameters and ADC values of the primary tumor and the VTT were calculated. The VTT consistency (friable vs. solid) was determined through intraoperative findings of two urologists. The accuracy of VTT consistency classification based on the individual IVIM parameters of primary tumors and of VTT, and based on models combining parameters, was assessed. Type of operation, intra-operative blood loss, and operation length were recorded. STATISTICAL TESTS: Shapiro-Wilk test; Mann-Whitney U test; Student's t-test; Chi-square test; Receiver operating characteristic (ROC) analysis. Statistical significance level was P < 0.05. RESULTS: Of the enrolled 119 patients, 33 patients (27.7%) had friable VTT. Patients with friable VTT were significantly more likely to experience open surgery, have significantly more intraoperative blood loss, and significantly longer operative duration. The area under the ROC curve (AUC) values of Dt of the primary tumor and VTT in classifying VTT consistency were 0.758 (95% CI 0.671-0.832) and 0.712 (95% CI 0.622-0.792), respectively. The AUC value of the model combining Dp and Dt of VTT was 0.800 (95% CI 0.717-0.868). Furthermore, the AUC of the model combining Dp and Dt of VTT and Dt of the primary tumor was 0.886 (95% CI 0.814-0.937). CONCLUSION: IVIM-derived parameters had the potential to predict VTT consistency of RCC. EVIDENCE LEVEL: 3 Technical Efficacy: Stage 2.

Venous tumor thrombus consistency: is it a prognostic factor of survival for patients with renal cell carcinoma?

OBJECTIVES: To evaluate whether venous tumor thrombus (VTT) consistency is a risk factor for the patient's prognosis with renal cell carcinoma (RCC). MATERIALS AND METHODS: A total of 190 RCC patients with VTT, who were treated at Department of Urology, Chinese PLA General Hospital, were retrospectively analyzed in this study. The baseline clinical characteristics, postoperative outcomes, and pathological findings were analyzed. Tumor thrombus was classified as solid and friable based on their respective characteristics. Survival curves were estimated using the Kaplan-Meier survival curve analysis, and univariable and multivariable cox proportional hazard regression models were used. RESULTS: Among the total 190 patients included in this study, 145 (76.3%) patients had solid VTT, and 45 (23.7%) patients had friable VTT in their renal veins and inferior vena cava (IVC). There were no significant differences in the age, gender, BMI, symptoms, complex diseases, tumor side, tumor size, TNM stage, Mayo stage, tumor grade, sarcomatous differentiation, pelvic invasion, and sinus fat invasion of patients. Solid VTT consistency was more likely to have a capsule as compared to those with friable VTT (P = 0.007). Kaplan-Meier survival curve analysis demonstrated no statistically significant differences in the overall survival (OS) (P = 0.973) and progression-free survival (PFS) (P = 0.667) of patients. Moreover, VTT consistency was not associated with OS (P = 0.706) of PFS (P = 0.504) in multivariate cox regression analysis. CONCLUSIONS: RCC VTT consistency was not a prognostic risk factor for predicting the OS and PFS of patients.

Effects of Retroperitoneal or Transperitoneal Pneumoperitoneum on Inferior Vena Cava Hemodynamics and Cardiopulmonary Function: A Prospective Real-Time Comparison.

Objective: To evaluate the effects of CO2 pneumoperitoneum on venous hemodynamics and cardiopulmonary function during transperitoneal or retroperitoneal laparoscopic surgery. Materials and Methods: A single-institution prospective study. Forty-three patients with renal-cell carcinoma undergoing retroperitoneal (22) or transperitoneal (21) laparoscopic partial nephrectomy were enrolled. Hemodynamic functions were monitored by minimally invasive FloTrac/Vigileo system. Transesophageal echocardiography was used to measure the diameter and blood flow of the inferior vena cava (IVC). Measured parameters were recorded at baseline, 10, 30, 60 minutes following insufflation to 14 mm Hg and 10 minutes following desufflation. Results: For hemodynamic changes in the transperitoneal laparoscopic surgery (TPL) and retroperitoneal laparoscopic surgery (RPL), transperitoneal CO2 insufflation resulted in a rapid parallel increase in central intravenous pressure (CVP), peak airway pressure (AWP), and IVC blood flow velocity after the first 30 minutes of pneumoperitoneum (p < 0.05). In contrast, CVP, AWP, and IVC blood flow velocity increased progressively in RPL. The variation of those parameters was significantly lower than that of TRL (p < 0.001; p = 0.002; p = 0.004). The mean maximum CVP in the two groups was 20 and 16 mm Hg, respectively. The IVC diameter at the cavoatrial junction was significantly reduced in TPL after 10 minutes of insufflation, but it remained unchanged in RPL throughout the surgery. For cardiopulmonary function changes, heart output decreased after a short period of pneumoperitoneum, but no statistical differences were observed between the two groups. The increments of partial pressure of arterial carbon dioxide and end-tidal carbon dioxide tension were significantly higher in RPL than TPL (p < 0.001; p < 0.001). Conclusions: Compared with retroperitoneal pneumoperitoneum, transperitoneal pneumoperitoneum has significant effects on IVC hemodynamics. Elevated intra-abdominal pressure (IAP) causes higher AWP and venous return resistance, which lead to the significant increase of CVP during transperitoneal approach. Adjusting the balance between IAP and CVP might be an effective way to control intravenous bleeding. Clinical Trial Registry: Registration number: ChiCTR2000038291.

Robotic Level IV Inferior Vena Cava Thrombectomy Using an Intrapericardial Control Technique: Is It Safe Without Cardiopulmonary Bypass?

PURPOSE: We introduce an intrapericardial control technique using a robotic approach in the surgical treatment of renal tumor with level IV inferior vena cava thrombus to decrease the severe complications associated with cardiopulmonary bypass and deep hypothermic circulatory arrest. MATERIALS AND METHODS: Eight patients with level IV inferior vena cava thrombi not extending into the atrium underwent transabdominal-transdiaphragmatic robot-assisted inferior vena cava thrombectomy obviating cardiopulmonary bypass/deep hypothermic circulatory arrest (cardiopulmonary bypass-free group) by an expert team comprising urological, hepatobiliary, and cardiovascular surgeons. The central diaphragm tendon and pericardium were transabdominally dissected until the intrapericardial inferior vena cava were exposed and looped proximal to the cranial end of the thrombi under intraoperative ultrasound guidance. As controls, 14 patients who underwent robot-assisted inferior vena cava thrombectomy with cardiopulmonary bypass (cardiopulmonary bypass group) and 25 patients who underwent open thrombectomy with cardiopulmonary bypass/deep hypothermic circulatory arrest (cardiopulmonary bypass/deep hypothermic circulatory arrest group) were included. Clinicopathological, operative, and survival outcomes were retrospectively analyzed. RESULTS: Eight robot-assisted inferior vena cava thrombectomies were successfully performed without cardiopulmonary bypass, with 1 open conversion. The median operation time and first porta hepatis occlusion time were shorter, and estimated blood loss was lower in the cardiopulmonary bypass-free group as compared to the cardiopulmonary bypass group (540 vs 586.5 minutes, 16.5 vs 38.5. minutes, and 2,050 vs 3,500 mL, respectively). Severe complications (level IV-V) were also lower in the cardiopulmonary bypass-free group than in cardiopulmonary bypass and cardiopulmonary bypass/deep hypothermic circulatory arrest groups (25% vs 50% vs 40%). Oncologic outcomes were comparable among the 3 groups in short-term follow-up. CONCLUSIONS: Pure transabdominal-transdiaphragmatic robot-assisted inferior vena cava thrombectomy without cardiopulmonary bypass/deep hypothermic circulatory arrest represents as an alternative minimally invasive approach for selected level IV inferior vena cava thrombi.

Papillary renal neoplasm with reverse polarity-a comparative study with CCPRCC, OPRCC, and PRCC1.

Papillary renal neoplasm with reverse polarity (PRNRP) is a newly defined entity with distinct histomorphology and recurrent KRAS mutation. In this study, we aimed to identify and analyze the clinicopathological, immunohistochemical (IHC), and molecular features of PRNRP in our center and to evaluate its differential diagnosis with other tumors with which it is easily confused: clear cell papillary renal cell carcinoma (CCPRCC), oncocytic papillary renal cell carcinoma (OPRCC), and papillary renal cell carcinoma type 1 (PRCC1). Nephrectomy specimens of PRNRP (n = 15), CCPRCC (n = 11), and OPRCC (n = 12) were retrieved from our pathology archives. We also selected typical cases of PRCC1 (n = 15) as a control group. PRNRP accounted for 3.05% (15/492) of all PRCC cases at our center. The median follow-up period was 41.3 months. All PRNRP cases were pT1N0M0, and only one involved recurrence (1 year after surgery). IHC analysis showed diffuse staining of CK7, EMA, and GATA3 but weak or negative staining of CD10, CD117, p504s, and vimentin in the PRNRP samples and distinctive IHC features in the other three tumor types. KRAS mutation was detected in 4/10 PRNRP cases. Among the 40 most commonly mutated genes identified, 5 (BCLAF1, PDE4DIP, NCOR1, PARP4, and PABPC1) have actionable alterations. Our study supports the suggestion that PRNRP is an entity distinct from CCPRCC, OPRCC, and PRCC1.

Progressive Obstruction of Inferior Vena Cava by Ameroid Constrictor: The Canine Model of Revealing Hemodynamic and Compensatory Patterns of Tumor Thrombus Formation at the Renal Hilus Level.

Background: To develop an efficient and stable canine model of inferior vena cava (IVC) progressive obstruction at the renal hilus level. Methods: The model was established in two beagles by encircling an ameroid constrictor (AC) on the IVC at the renal hilus level. Abdominal wall varicosity and animal weight variations were observed weekly after operation. Ultrasound examination was performed weekly after surgery to observe the AC position, the diameter, and the velocity in the IVC. Six weeks after surgery, IVC angiography and CT scan were performed to observe the collateral circulation establishment and internal organ variation. Blood samples were taken regularly to monitor for variation in critical biochemical parameters. Renal biopsy was performed at 0, 2, 4, and 6 weeks after surgery. Results: Superficial varicose veins were observed on the abdominal wall at 2 weeks after surgery. Four weeks after operation, the IVC diameter increased by ∼30%, whereas the IVC velocity decreased by more than 50%. Collateral circulation was observed by IVC angiography at 6 weeks through multiple dilated veins along with neovascularization. CT scan showed congestive alteration in the kidney. The body weight, kidney, and liver function were not significantly affected. Chronic congestive renal injury was detected in the renal tubular epithelium by kidney biopsy after surgery. Conclusions: A canine model of IVC progressive obstruction at the renal hilus level was stably and safely established for the first time by using an AC, which may be helpful for preserving pivotal collateral circulation and nontumor-side kidney function in the IVC thrombus surgery.

Loss of CMTM6 promotes DNA damage-induced cellular senescence and antitumor immunity.

Recent studies have revealed that chemokine-like factor-like MARVEL transmembrane domain-containing family member 6 (CMTM6) promotes tumor progression and modulates tumor immunity by regulating programmed death-ligand 1 stability; however, its intrinsic functions and regulatory mechanisms in clear cell renal cell carcinoma (ccRCC) remain poorly understood. Here, we show that CMTM6 is upregulated in ccRCC tissues and is strongly associated with advanced tumor grades, early metastases, and a worse prognosis. CMTM6 depletion significantly impaired the proliferation, migration, and invasion of ccRCC cells in vitro and in xenograft mouse models in vivo. In addition, targeting CMTM6 promotes anti-tumor immunity, represented by increased infiltration of CD4+ and CD8+ T cells in syngeneic graft mouse models. Further research revealed that loss of CMTM6 triggered aberrant activation of DNA damage response, resulting in micronucleus formation and G2/M checkpoint arrest, finally leading to cellular senescence with robust upregulation of numerous chemokines and cytokines. Our findings show for the first time the novel role of CMTM6 in maintaining cancer genome stability and facilitating tumor-mediated immunosuppression, linking DNA damage signaling to the secretion of inflammatory factors. Targeting CMTM6 may improve the treatment of patients with advanced ccRCC.

Can the extension of the global value chain production length promote carbon emissions reduction in China's equipment manufacturing industry?

In the context of localization of Global Value Chain (GVC) and stricter carbon emission requirements, the impact of participating in GVC on carbon emission reduction has become one of the most crucial criteria for China's manufacturing industry to consider whether to deepen its participation in GVC. In order to clearly and directly reflect the change in the production distance between the original input and the final product, we use the GVC production length to express the degree of participation in GVC. And in order to make the research more targeted and typical, we select the equipment manufacturing industry as the research object. Using the data from the World Input-Output Database (WIOD), we empirically analyze the GVC production length under different cross-border production activities on the basis of the theoretical mechanism. The results show that the extension of the GVC production length can significantly promote the carbon emissions reduction. In the decomposition part, the extension of simple GVC production length can effectively promote carbon emissions reduction. Therefore, it is suggested that China's equipment manufacturing industry should continue to deeply participate in the high-end production links of GVC and improve its status in the complex GVC production activities.

Genomic Landscape of Chinese Clear Cell Renal Cell Carcinoma Patients With Venous Tumor Thrombus Identifies Chromosome 9 and 14 Deletions and Related Immunosuppressive Microenvironment.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) is associated with a poor clinical outcome. Although several studies have examined the genomic features of ccRCC, the genetic profile of VTT along with its matched primary tumor has not been fully elucidated. MATERIALS AND METHODS: Samples of VTT tissues and matched primary tumor tissues from ccRCC patients (n = 25), as well as primary tumor tissues from patients without VTT (n = 25) were collected and analyzed using whole-exome sequencing. Four additional ccRCC patients who were unfit for surgery were treated with an anti-programmed death receptor-1 (PD-1) monoclonal antibody (Toripalimab, 240 mg, Q3W, IV). RESULTS: By comparing the primary kidney tumors from ccRCC patients with or without VTT, a relatively higher prevalence of BAP1 and KDM5C alterations were found in ccRCC patients with VTT, and these alterations were associated with worse overall survival in the kidney renal clear cell carcinoma (KIRC) database. Based on subclone analysis, VTT was predicted to primarily originate directly from the primary renal mass. A significantly higher prevalence of CELSR2 and TET2 alterations were identified in the VTTs compared with the matched primary tumors. An increased prevalence of DNA damage repair genes, especially those involved in homologous recombination repair and non-homologous end joining, was found in ccRCC patients with VTT. Notably, VTT was characterized by the increase incidence of copy number loss in the whole exome (p < 0.05), particularly in the chromosome 9 and 14 regions. Deletion of chromosome 9 and 14 was associated with worse survival, unfavorable clinical features, and the presence of an immunosuppressive microenvironment, which was characterized by higher infiltration of regulatory T cells, follicular helper T cells, and resting mast cells, but lower counts of resting CD4 memory T cells and CD8 positive T cells. A significantly lower count of CD4+ and CD8+ tumor-infiltrated lymphocytes was identified in the VTT samples comparing with matched primary tumor. Of note, three out of the four ccRCC patients with VTT in our cohort who were treated with the anti-PD-1 therapy exhibited remarkable remission in the renal mass but no notable shrinkage in the VTT mass. CONCLUSION: Our study revealed the genetic profile of Chinese ccRCC patients with VTT, and identified multiple features associated with known poor outcomes, including gene alterations and copy number loss. The deletions in chromosomes 9 and 14, and the associated immunosuppressive microenvironment may indicate limited sensitivity to anti-PD-1/PD-L1 monotherapy in VTT.

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.

Prognostic role of bland thrombus in patients treated with resection of renal cell carcinoma with inferior vena cava tumor thrombus.

OBJECTIVES: To assess the impact of the presence of bland thrombus (BT) on prognosis of patients treated with resection of renal cell carcinoma (RCC) with inferior vena cava tumor thrombus (IVCTT). MATERIALS AND METHODS: The medical records of a total of 145 consecutive postsurgical RCC patients with level I-IV IVCTT were reviewed from January 2008 to August 2018. Associations of BT with clinicopathological variables were estimated by chi-square test or Student's t-test. Kaplan-Meier method and multivariate Cox proportional hazard model were used. The eighth TNM staging system, "Spiess PE" model, University of California at Los Angeles Integrated Staging System and Stage, Size, Grade, and Necrosis (SSIGN) score were selected to assess whether BT could improve their predictive abilities. RESULTS: BT was observed in 34 (23.4%) patients and was significantly associated with increased levels of IVCTT (P = 0.004) and invasion of IVC wall (P = 0.030). Multivariable Cox analyses revealed that tumor grade, T stage, M stage, tumor thrombus consistency and BT were independent risk factors for both progression-free survival and overall survival. The concordance indexes ranged from a low of 0.652 in TNM to a high of 0.731 in SSIGN, and integrating BT into each base model led to an increased predictive accuracies of 6.2% for TNM (P = 0.025), 4.0% for "Spiess PE" model (P = 0.069), 2.1% for University of California at Los Angeles Integrated Staging System (P = 0.149) and 1.2% for SSIGN (P = 0.290), respectively. CONCLUSIONS: Presence of BT was independently associated with survival in postsurgical patients with RCC-IVCTT. Routine consideration of BT as an adjunct to TNM staging system may be suggested.

Robotic Retroperitoneal Versus Transperitoneal Inferior Vena Cava Thrombectomy: Right-Sided Cases with Level I-II Tumor Thrombus.

Objectives: To compare the perioperative hemodynamic consequences and oncology outcomes of robotic retroperitoneal vs transperitoneal inferior vena cava (IVC) thrombectomy (IVCT) for right renal cell carcinoma (RCC) with IVC tumor thrombus (IVCTT) that located below the first porta hepatis. Patients and Methods: Between January 2018 and June 2019, 35 patients of right RCC with IVCTT that located below the first porta hepatis underwent robotic retroperitoneal IVCT (16 patients) or transperitoneal IVCT (19 patients). We have described the procedures of transperitoneal IVCT earlier. The main procedure of robotic retroperitoneal IVCT include circumferential dissection of the IVC, sequentially clamping subhepatic IVC, the left renal vein and the caudal IVC with vessel loops, IVCT, IVC repair, and radical nephrectomy (RN). The following parameters were compared between the two groups: baselines characteristic, perioperative consequences, and hemodynamic changes. Results: Retroperitoneal and transperitoneal cohorts were comparable in terms of IVC thrombus length (3.2 vs 4.0 cm), IVC block time (18 vs 16 minutes, p = 0.64), postoperative hospital stay (6 vs 6 days, p = 0.67), postoperative complications (0 vs 0), and recurrence or metastasis rate (0 vs 0) for patients with similar baseline characteristic. The retroperitoneal cohort tended to less blood loss (160 vs 240 mL, p = 0.024), shorter operative time (130 vs 145 minutes, p = 0.003), lower central venous pressure (p < 0.05), and smaller diameter of IVC (p < 0.05). Conclusions: Robotic retroperitoneal RN and IVCT is feasible for patients of right RCC with IVCTT located below the first porta hepatis and is superior to transperitoneal IVCT in terms of bleeding control and operation time for skilled surgeons.

MRI radiomics-based nomogram for individualised prediction of synchronous distant metastasis in patients with clear cell renal cell carcinoma.

OBJECTIVE: To evaluate the performance of a multiparametric MRI radiomics-based nomogram for the individualised prediction of synchronous distant metastasis (SDM) in patients with clear cell renal cell carcinoma (ccRCC). METHODS: Two-hundred and one patients (training cohort: n = 126; internal validation cohort: n = 39; external validation cohort: n = 36) with ccRCC were retrospectively enrolled between January 2013 and June 2019. In the training cohort, the optimal MRI radiomics features were selected and combined to calculate the radiomics score (Rad-score). Incorporating Rad-score and SDM-related clinicoradiologic characteristics, the radiomics-based nomogram was established by multivariable logistic regression analysis, then the performance of the nomogram (discrimination and clinical usefulness) was evaluated and validated subsequently. Moreover, the prediction efficacy for SDM in ccRCC subgroups of different sizes was also assessed. RESULTS: Incorporating Rad-score derived from 9 optimal MR radiomics features (age, pseudocapsule and regional lymph node), the radiomics-based nomogram was capable of predicting SDM in the training cohort (area under the ROC curve (AUC) = 0.914) and validated in both the internal and external cohorts (AUC = 0.854 and 0.816, respectively) and also showed a convincing predictive power in ccRCC subgroups of different sizes (≤ 4 cm, AUC = 0.875; 4-7 cm, AUC = 0.891; 7-10 cm, 0.908; > 10 cm, AUC = 0.881). Decision curve analysis indicated that the radiomics-based nomogram is of clinical usefulness. CONCLUSIONS: The multiparametric MRI radiomics-based nomogram could achieve precise individualised prediction of SDM in patients with ccRCC, potentially improving the management of ccRCC. KEY POINTS: • Radiomics features derived from multiparametric magnetic resonance images showed relevant association with synchronous distant metastasis in clear cell renal cell carcinoma. • MRI radiomics-based nomogram may serve as a potential tool for the risk prediction of synchronous distant metastasis in clear cell renal cell carcinoma.

Sarcomatoid variant urothelial carcinoma of the bladder: a systematic review and meta-analysis of the clinicopathological features and survival outcomes.

BACKGROUND: A systematic review and meta-analysis was performed to compare the clinicopathological features and survival outcomes between sarcomatoid variant (SV)-urothelial carcinoma of the bladder (UCB) and conventional UCB (C-UCB). METHODS: A comprehensive search of PubMed, Embase, and Cochrane Library was performed. Endpoints included clinicopathological features and survival outcomes (overall survival [OS], cancer-specific survival [CSS], and progression-free survival [PFS]). The survival benefits of neoadjuvant chemotherapy (NAC) or adjuvant chemotherapy (AC) for SV-UCB also have been studied. RESULTS: A total of 8 observational studies were included. Patients with SV-UCB had a higher rate of ≥ stage pT3 (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.64-2.59; p < 0.001) and a lower rate of concomitant carcinoma in situ (OR, 0.25; 95% CI, 0.09-0.72; p = 0.010). The other clinicopathological variables were similar between SV-UCB and C-UCB. With unadjusted data, patients with SV-UCB had a significant inferior OS (HR, 1.24; 95% CI, 1.07-1.44; p = 0.004) and CSS (HR, 2.08; 95% CI, 1.63-2.66; p < 0.001). However, after adjusted, SV-UCB had worse OS (HR, 1.41; 95% CI, 0.95-2.08; p = 0.090) and CSS (HR, 1.54; 95% CI, 0.95-2.52; p = 0.080) approaching the borderline of significance. For SV-UCB, NAC (HR, 0.73; 95% CI, 0.51-1.05; p = 0.090) and AC (HR, 0.88; 95% CI, 0.66-1.17; p = 0.370) seemed to have no benefit on OS. CONCLUSIONS: Compared to C-UCB, SV-UCB was associated with more advanced disease and more inferior OS and CSS. NAC and AC had no survival benefit for SV-UCB.

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.