MRI-based Bosniak Classification of Cystic Renal Masses, Version 2019: Interobserver Agreement, Impact of Readers' Experience, and Diagnostic Performance.

Background The 2019 Bosniak classification (version 2019) of cystic renal masses (CRMs) provides a systematic update to the currently used 2005 Bosniak classification (version 2005). Further validation is required before widespread application. Purpose To evaluate the interobserver agreement of MRI criteria, the impact of readers' experience, and the diagnostic performance between version 2019 and version 2005. Materials and Methods From January 2009 to December 2018, consecutive patients with CRM who had undergone renal MRI and surgical-pathologic examination were included in this retrospective study. On the basis of version 2019 and version 2005, all CRMs were independently classified by eight radiologists with different levels of experience. By using multirater κ statistics, interobserver agreement was evaluated with comparisons between classifications and between senior and junior radiologists. Diagnostic performance between classifications by dichotomizing classes I-IV into lower (I-IIF) and higher (III-IV) classes was compared by using the McNemar test. P < .05 was considered to indicate a statistically significant difference. Results A total of 207 patients (mean age ± standard deviation, 49 years ± 12; 139 male and 68 female patients) with CRMs were included. Overall, interobserver agreement was higher with version 2019 than version 2005 (weighted κ = 0.64 vs 0.50, respectively; P < .001). Interobserver agreement between senior and junior radiologists did not differ between version 2019 (weighted κ = 0.65 vs 0.64, respectively; P = .71) and version 2005 (weighted κ = 0.54 vs 0.46; P < .001). Diagnostic specificity for malignancy was higher with version 2019 than with version 2005 (83% [92 of 111] vs 68% [75 of 111], respectively; P < .001), without any difference in sensitivity (89% [85 of 96] vs 84% [81 of 96]; P = .34). Conclusion In the updated Bosniak classification, interobserver agreement improved and was unaffected by observers' experience. The diagnostic performance with version 2019 was superior to that with version 2005, with higher specificity. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Choyke in this issue.

Multiparametric MRI Radiomic Model for Preoperative Predicting WHO/ISUP Nuclear Grade of Clear Cell Renal Cell Carcinoma.

BACKGROUND: Nuclear grade is of importance for treatment selection and prognosis in patients with clear cell renal cell carcinoma (ccRCC). PURPOSE: To develop and validate an MRI-based radiomic model for preoperative predicting WHO/ISUP nuclear grade in ccRCC. STUDY TYPE: Retrospective. POPULATION: In all, 379 patients with histologically confirmed ccRCC. Training cohort (n = 252) and validation cohort (n = 127) were randomly assigned. FIELD STRENGTH/SEQUENCE: Pretreatment 3.0T renal MRI. Imaging sequences were fat-suppressed T2 WI, contrast-enhanced T1 WI, and diffusion weighted imaging. ASSESSMENT: Three prediction models were developed using selected radiomic features, radiomic and clinicoradiologic characteristics, and a model containing only clinicoradiologic characteristics. Receiver operating characteristic (ROC) curves and area under the curve (AUC) were used to assess the predictive performance of these models in predicting high-grade ccRCC. STATISTICAL TESTS: The least absolute shrinkage and selection operator (LASSO) and minimum redundancy maximum relevance (mRMR) method were used for the selection of radiomic features and clinicoradiologic characteristics, respectively. Multivariable logistic regression analysis was used to develop the radiomic signature of radiomic features and clinicoradiologic model of clinicoradiologic characteristics. RESULTS: The radiomic signature showed good performance in discriminating high-grade (grades 3 and 4) from low-grade (grades 1 and 2) ccRCC, with sensitivity, specificity, and AUC of 77.3%, 80.0%, and 0.842, respectively, in the validation cohort. The radiomic model, combining radiomic signature and clinicoradiologic characteristics, displayed good predictive ability for high-grade with sensitivity, specificity, and accuracy of 63.6%, 93.3%, and 88.2%, respectively, in the validation cohort. The radiomic model showed a significantly better performance than the clinicoradiologic model (P < 0.05). DATA CONCLUSION: Multiparametric MRI-based radiomic model can predict WHO/ISUP grade in patients with ccRCC with satisfying performance, and thus could help the physician to improve treatment decisions. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Contrast-enhanced ultrasound in detecting wall invasion and differentiating bland from tumor thrombus during robot-assisted inferior vena cava thrombectomy for renal cell carcinoma.

BACKGROUND: Vena cava thrombus is one of the main clinical manifestations of locally aggressive renal cell carcinoma (RCC). Inferior vena cava (IVC) wall invasion and presence of bland thrombus could affect the surgical outcome. This study aims to assess the value of contrast-enhanced ultrasound (CEUS) in detecting wall invasion and differentiating bland thrombus from tumor thrombus during robot-assisted IVC thrombectomy for RCC. METHODS: The intraoperative CEUS findings of 60 patients with RCC accompanied by IVC tumor thrombus were retrospectively analyzed. The CEUS features were compared with the intra- and post-operative pathological findings. CEUS in patients with wall invasion showed that the tumor thrombus was enhanced synchronously with the IVC wall, and the continuity of the IVC wall was lost. In contrast, in patients without wall invasion, CEUS showed that the contrast agent could pass between the tumor thrombus and the IVC wall, and the continuity of IVC wall was good. Typically, contrast-enhanced perfusion was seen in tumor thrombus but not in bland thrombus. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CEUS were statistically analyzed. RESULTS: The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the typical enhancement mode of CEUS were 93.1, 93.5, 93.3, 93.1, and 93.5% in identifying wall invasion and 100, 96, 96.7, 83.3, and 100% in differentiating bland thrombus from tumor thrombus, respectively. There were excellent inter-observer agreements for identifying IVC wall invasion and differentiating bland thrombus from tumor thrombus with kappa coefficients of 0.90 and 0.97. CONCLUSIONS: The present study indicates that intraoperative CEUS plays an important role in robot-assisted IVC thrombectomy for RCC. It can detect wall invasion and differentiate bland thrombus from tumor thrombus, thus offering real-time information to the operator during surgery.

Factors associated with postoperative renal sinus invasion and perinephric fat invasion in renal cell cancer: treatment planning implications.

In patients with renal cell carcinoma (RCC), postoperative upstaging including perinephric fat invasion (PNI) and renal sinus invasion (RSI) leads to unfavorable oncological outcomes. Determining the preoperative risk factors for postoperative upstaging could be beneficial for treatment planning. In this study, 267 RCC patients who underwent radical nephrectomy were studied retrospectively. The RSI incidence was significantly greater than that of PNI. Kaplan-Meier analysis revealed that patients with RSI, PNI, and RSI plus PNI had poorer disease-free-survival than those with neither RSI nor PNI. Univariate and multivariate logistic regression analyses indicated that a tumor extension into the sinus, an irregular tumor-sinus border, and an irregular tumor shape in CT/MRI imaging were independent risk factors for RSI. And a tumor larger than 5 cm, an irregular tumor-perinephric fat border, and a tumor necrosis were independent risk factors for PNI. Subgrouping of patients into low-, moderate-, and high-risk groups according to these factors, revealed a direct association between the risk factors and PNI/RSI incidence. In conclusion, in patients with RCC, preoperative risk factors associated with postoperative upstaging could be assessed by imaging data obtained using CT or MRI. Preoperative Risk group classification would be clinically useful for patient counseling and treatment planning.

Endothelial Delta-like 4 (DLL4) promotes renal cell carcinoma hematogenous metastasis.

The Notch ligand Delta-like 4 (DLL4) plays an important role in tumor angiogenesis, which is required for tumor invasion and metastasis. Here we showed that DLL4 was elevated in endothelium and Notch signaling was activated in renal cell carcinoma (RCC). Exogenous DLL4 induced RCC cell migration and invasion by activating intercellular Notch signaling. Importantly, the DLL4/Notch/Hey1/MMP9 cascades connecting the endothelium to the cancer cells in metastasis were identified. Knockdown of Hey1 decreased expression of MMP9 and attenuated tumor invasion. The clinical investigation on 120 cases of RCC specimens indicated that expressions of Hey1 and MMP9 correlated with DLL4 density. Moreover, univariate and multivariate analyses showed that tumor hematogenous metastasis not only was depended on microvessel density but was also associated with tumor size and DLL4 density. During 4-year surveillance, high-level of DLL4 density was associated with a higher probability of developing metastasis and being sensitive to target therapies. Our data suggest that RCC progression is caused in part by activated DLL4/Notch signaling, interaction of endothelium and cells, which can be therapeutically targeted.

Downregulation of FOXO3a promotes tumor metastasis and is associated with metastasis-free survival of patients with clear cell renal cell carcinoma.

PURPOSE: To explore the mechanisms underlying clear-cell renal cell carcinoma (ccRCC) metastasis using transcriptional profiling and bioinformatics analysis of ccRCC samples, and to elucidate the role of FOXO3a in ccRCC metastasis. EXPERIMENTAL DESIGN: Gene expression profiling was performed using four primary metastatic and five primary nonmetastatic ccRCC samples. The mRNA and protein levels of FOXO3a in ccRCC samples were investigated by real-time reverse transcription PCR and immunohistochemistry, respectively. The association between metastasis-free survival of patients with ccRCC and FOXO3a mRNA levels was analyzed. Biologic functions of FOXO3a in renal cancer cell lines were investigated. The influence of FOXO3a on tumor metastasis was also studied in vivo orthotopic xenograft tumor model. Finally, the mechanism by which FOXO3a attenuation could increase invasion and migration of tumor cells was explored. RESULTS: Bioinformatics analysis of the profiling data identified FOXO3a as a key factor in ccRCC metastasis. FOXO3a expression was decreased in primary metastatic ccRCC samples. Patients with low FOXO3a mRNA levels had poor metastasis-free survival (P = 0.003). Knocking down FOXO3a induced tumor cell invasion and migration in the nonmetastatic ccRCC cells. Induced FOXO3a overexpression in SN12-PM6 cells could inhibit tumor metastasis in vivo. Downregulation of FOXO3a increased SNAIL1 expression, thereby activating the epithelial-mesenchymal transition (EMT) of RCC cell lines. CONCLUSIONS: The loss of FOXO3a induced EMT of tumor cells by upregulating SNAIL1, which promoted tumor cells metastasis in vitro and in vivo. Thus, FOXO3a could be considered as an independent prognostic factor in ccRCC metastasis and could be a marker of occult metastases.

Down-Regulated miR-30a in Clear Cell Renal Cell Carcinoma Correlated with Tumor Hematogenous Metastasis by Targeting Angiogenesis-Specific DLL4.

BACKGROUND: Endothelial DLL4 plays an important role in controlling of tumor angiogenesis, which is required for tumor invasive growth and metastasis. However, the regulation of DLL4 in clear cell renal cell carcinoma (ccRCC) has not yet been systematically elucidated. METHODOLOGY: We performed bioinformatical analysis to explore miRNAs targeting DLL4. miR-30a was selected as a representative to validate its functional association in endothelial cell. Then, the expressions of DLL4 and mature miR-30a from 90 cases of ccRCC and 28 cases of nonmatched adjacent non-tumor tissues were measured by quantitative real-time PCR. Finally, the expression of miR-30a was correlated with DLL4 expression, tumor features (metastatic condition and microvessel density), and patient metastasis-free survival. The univariate and multivariate analyses were performed to select the risk factors associated with hematogenous metastasis, respectively. PRINCIPAL FINDINGS: miR-30a negatively regulated DLL4 and inhibited the proliferation and migration of endothelial cells. DLL4 was up-regulated in ccRCC and further increased in hematogenous metastatic cases, while miR-30a was down-regulated in tumor tissues and further decreased in hematogenous metastatic ccRCC (student t test, all p<0.05). Additionally, expression of miR-30a was inversely correlated with expression of DLL4 and microvessel density (linear correlation analysis, both p<0.05). Low-level miR-30a also indicated a higher probability of developing metastasis (log-rank test, p = 0.010). Most importantly, miR-30a expression was an independent predictor of ccRCC hematogenous metastasis by the univariate analysis and binary logistic regression model (both p<0.05). CONCLUSIONS: Down-regulated miR-30a in ccRCC was associated with tumor hematogenous metastasis through increasing microvessel density by targeting angiogenesis-specific DLL4.

A matched-pair comparison between bilateral intrafascial and interfascial nerve-sparing techniques in extraperitoneal laparoscopic radical prostatectomy.

The aim of this study was to validate the advantages of the intrafascial nerve-sparing technique compared with the interfascial nerve-sparing technique in extraperitoneal laparoscopic radical prostatectomy. From March 2010 to August 2011, 65 patients with localized prostate cancer (PCa) underwent bilateral intrafascial nerve-sparing extraperitoneal laparoscopic radical prostatectomy. These patients were matched in a 1:2 ratio to 130 patients with localized PCa who had undergone bilateral interfascial nerve-sparing extraperitoneal laparoscopic radical prostatectomy between January 2008 and August 2011. Operative data and oncological and functional results of both groups were compared. There was no difference in operative data, pathological stages and overall rates of positive surgical margins between the groups. There were 9 and 13 patients lost to follow-up in the intrafascial group and interfascial group, respectively. The intrafascial technique provided earlier recovery of continence at both 3 and 6 months than the interfascial technique. Equal results in terms of continence were found in both groups at 12 months. Better rates of potency at 6 months and 12 months were found in younger patients (age ≤ 65 years) and overall patients who had undergone the intrafascial nerve-sparing extraperitoneal laparoscopic radical prostatectomy. Biochemical progression-free survival rates 1 year postoperatively were similar in both groups. Using strict indications, compared with the interfascial nerve-sparing technique, the intrafascial technique provided similar operative outcomes and short-term oncological results, quicker recovery of continence and better potency. The intrafascial nerve-sparing technique is recommended as a preferred approach for young PCa patients who are clinical stages cT1 to cT2a and have normal preoperative potency.

[Expression analysis of NOTCH1/HES1/PTEN signaling pathway in invasive bladder transitional cell carcinoma].

OBJECTIVE: To explore the role of NOTCH1/HES1/PTEN signaling pathway in invasive TCCB (bladder transitional cell carcinoma). METHODS: The expressions of NOTCH1, HES1 and PTEN were detected in 36 cases of invasive TCCB tissues and 10 cases of normal bladder samples by real-time q-polymerase chain reaction (q-PCR) and Western blot. Then NOTCH1-ORF plasmid and its blank vector pCMV6-Entry were transfected into T24 cell respectively. And the expressions of three above-mentioned target genes were measured by real-time q-PCR and Western blot. Furthermore, cell proliferation, cell apoptosis and cell cycle were analyzed respectively by MTS assay and flow cytometry. RESULTS: Compared with normal bladder samples, the higher levels of both mRNA and protein of NOTCH1 and HES1 were detected in invasive TCCB tissues while there was a lower expression of PTEN (P < 0.05). The mRNA expression levels of NOTCH1 and HES1 were 4.22 and 3.75 folds respectively higher than those of normal tissues. In NOTCH1-overexpressed T24 cell, the expression of HES1 was 5.43 folds higher than that of the blank vector control group while the expression of PTEN declined to 41.76% (P < 0.01). MTS assay showed that the NOTCH1-ORF transfection obviously promoted cell proliferation in T24 cell (P < 0.01). CONCLUSION: NOTCH1 gene may function as an oncogene by regulating HES1/PTEN in invasive TCCB and its aberrant activation promotes cell proliferation.

Role of spinal cord in regulating mouse kidney: a virally mediated trans-synaptic tracing study.

OBJECTIVE: To determine the spinal innervation and neuronal connections is important for studying renal metabolic responses. MATERIALS AND METHODS: In this study, the spinal cords of 10 adult male C57BL/6J strain mice were mapped retrograde using injections of pseudorabies virus (PRV)-614. The virus, injected into the kidney, was specifically transported to the spinal cord. RESULTS: At 5 days after injection of the PRV-614, PRV-614-positive cells were found in the intermediolateral cell column, the intercalates nucleus, or the central autonomic nucleus of spinal cord segments T4-L1, and most PRV-614-labeled cells were found in the T9 segment. CONCLUSION: Our results revealed neuroanatomical circuits between kidney and the spinal intermediolateral cell column neurons.