Radical Prostatectomy Without Prior Biopsy in Selected Patients Evaluated by 18F-Labeled Prostate-Specific Membrane Antigen-Ligand Positron Emission Tomography/Computed Tomography and Multiparameter Magnetic Resonance Imaging: A Single-Center, Prospective, Single-Arm Trial.

PURPOSE: This study aimed to verify the feasibility and short-term prognosis of prostatectomy without biopsy. MATERIALS AND METHODS: Patients with a rising PSA level ranging from 4 to 30 ng/mL were scheduled for multiparametric (mp) MRI and 18F-labeled prostate-specific membrane antigen (PSMA) positron emission tomography (PET). Forty-seven patients (cT2N0M0) with Prostate Imaging Reporting and Data System ≥ 4 and molecular imaging PSMA score ≥ 2 were enrolled. All candidates underwent robot-assisted laparoscopic radical prostatectomy without biopsy. Prostate cancer detection rate, index tumors localization correspondence rate, positive surgical margin, complications, postoperative hospital stay, and PSA level in a 6-week postoperative follow-up visit were collected. RESULTS: All the patients with positive mpMRI and PSMA PET were diagnosed with clinically significant prostate cancer. A total of 80 lesions were verified as cancer by pathology, of which 63 cancer lesions were clinically significant prostate cancer. Fifty-one lesions were simultaneously found by mpMRI and PSMA PET. A total of 23 lesions were invisible on either image, and all lesions were ≤ International Society of Urological Pathology 2 or ≤ 15 mm. Forty-five (95.7%) index tumors found by mpMRI combined with PSMA PET were consistent with pathology. Nine patients reported positive surgical margin. CONCLUSIONS: Biopsy-free prostatectomy is safe and feasible for patients with evaluation strictly by mpMRI combined with 18F-PSMA PET/CT.

18 F-DCFPyL positron emission tomography/magnetic resonance imaging-guided ultrasound fusion biopsy is an identical pathway in prostate cancer diagnosis.

BACKGROUND: Prostate biopsy is still unavoidable in patients with a rising prostate-specific antigen even though multiparametric magnetic resonance imaging (MRI) is widely used. 18 F-DCFPyL positron emission tomography (PET)/MRI was proved to be promising both in sensitivity and specificity. But its guiding fusion biopsy and the advantages in the diagnosis of prostate disease is seldom reported. This study aimed to verify the feasibility and advantage of 18 F-DCFPyL PET/MRI-guided fusion targeted biopsy (TB) over whole-mount histopathology (WMH) for prostate cancer diagnosis. METHODS: A prospective study of 94 biopsy-naïve patients were conducted using 18 F-DCFPyL PET/MRI scans and scored on a scale of 1-4. Systematic biopsy was performed for all patients. Patients with suspicious lesions also underwent PET/MRI/transrectal ultrasound-guided fusion biopsy. Patients with pathologically confirmed cancer underwent surgery and WMH sections. Systematic biopsy was compared with TB for the detection of index tumors (ITs). Significant cancer was defined as Grade group (GG) 2 or higher no matter the length of the cancer core. RESULTS: 18 F-DCFPyL PET/MRI detected 30/94 (32%) patients with a score of 4, all of whom were verified to have prostate cancer. While it detected 10 patients with a score of 1 (10.6%), they were shown to have no cancer. The sensitivity and specificity of 18 F-DCFPyL PET/MRI were 94.4% and 75%, respectively, if images with a score of 3 are defined as positive. Systematic biopsy detected 18% (203/1128) samples as prostate cancer; conversely, TB detected 113 samples out of 259 scores (43.6%). A statistically significant difference was seen between the PCa detection rates by TB and SB (p < 0.001). All targeted lesions were pathologically proven to be the IT on WMH. CONCLUSIONS: In biopsy-naïve patients, the ultrasound fusion biopsy targeted by 18 F-DCFPyL PET/MRI is an identical pathway for the detection of prostate cancer.

Vesicoprostatic muscle reconstruction: a step further for immediate and early urinary continence.

OBJECTIVES: The vesicoprostatic muscle (VPM) is a longitudinal smooth muscle that originates from the trigone of the bladder or the opening of the ureter and is involved in urination as part of the detrusor apron. We explored the effect of VPM reconstruction on immediate and early recovery of urinary continence in patients undergoing robot-assisted laparoscopic radical prostatectomy (RALP). PATIENTS AND METHODS: A total of 523 patients with localized prostate cancer were enrolled from June 2018 to June 2020. All patients were diagnosed in our department based on magnetic resonance imaging and pathological findings on prostate biopsy. After 1:1 propensity score matching, 105 patient pairs were matched. The study was approved by our institutional review board and all surgeries were performed by three experienced high-volume surgeons. Demographic data, total operation time, pathological outcomes, the urinary continence rates of the two groups at different times after RALP, and factors influencing postoperative urinary continence after RALP were recorded. Student's t test was used to compare continuous variables and the Pearson χ2 test to compare categorical variables. Logistic regression analysis was used to identify factors affecting immediate and early postoperative urinary control. RESULTS: VPM reconstruction promoted immediate and early recovery of urinary continence (immediate continence, 66.67 vs. 40.00%, P = 0.000; 3-month continence, 80.95 vs. 64.76%, P = 0.008). CONCLUSIONS: VPM reconstruction improved immediate and early urinary continence in patients who underwent RALP.

Adrenocortical carcinoma with venous tumor invasion: is there a role for mini-invasive surgery?

OBJECTIVE: This study aims to investigate early oncologic outcomes in patients with adrenocortical carcinoma (ACC) with venous invasion (VI) treated using both open and mini-invasive approaches. PATIENTS AND MATERIALS: We conducted a retrospective analysis of 4 international referral center databases, including all the patients undergoing adrenalectomy for ACC with VI from January 2007 to March 2020. According to CT scan or MRI, the tumor thrombus was classified into four levels: (1) adrenal vein invasion; (2) renal vein invasion; (3) infra-hepatic Inferior vena cava (IVC); and (4) retro-hepatic IVC. In addition, we divided our patients into patients who had undergone open surgery and mini-invasive surgery. RESULTS: We identified 20 patients with a median follow-up of 12 months. The median tumor size was 110mm. ENSAT stage was II in 4 patients, III in 13 patients, and IV in 3 patients. Tumor thrombus extended in the adrenal vein (n=5), renal vein (n=1), infra-hepatic IVC (n=9), or into the retro-hepatic IVC (n=5). Ten patients were treated with a mini-invasive approach. The patient treated with an open approach reported a more aggressive disease. The two groups did not differ in surgical margins, surgical time, blood losses, complications, and length of stay. The prognosis resulted worse in the patient undergoing open. Kaplan-Meier analysis indicated a difference in OS for the patients stratified by ENSAT stage (Log-rank p=0.011); we also reported a difference in DFS for patients stratified for thrombus extension (p=0.004) and ENSAT stage (p<0.001). CONCLUSION: The DFS of patients with VI from ACC is influenced by the staging and the extension of the venous invasion; the staging influences the OS. The mini-invasive approach seems feasible in selected patients; however, further studies investigating the oncological outcomes are needed. A mini-invasive approach for adrenal tumors with venous invasion is an explorable option in very selected patients.

Genomic profiling of Chinese patients with urothelial carcinoma.

BACKGROUNDS: Urothelial carcinoma (UC) is the most common genitourinary malignancy in China. In this study, we surveyed the genomic features in Chinese UC patients and investigated the concordance of genetic alterations between circulating tumor DNA (ctDNA) in plasma and matched tumor tissue. MATERIALS AND METHODS: A total of 112 UC patients were enrolled, of which 31 were upper tract UC (UTUC) and 81 were UC of bladder (UCB). Genomic alterations in 92 selected genes were analyzed by targeted next-generation sequencing. RESULTS: In the study cohort, 94.64, 86.61 and 62.50% of patients were identified as having valid somatic, oncogenic and actionable somatic alterations, respectively. The most frequently altered genes included TP53, KMT2D, KDM6A, FAT4, FAT1, CREBBP and ARID1A. The higher prevalence of HRAS (22.0% vs 3.7%) and KMT2D (59.26% vs 34.57%) was identified in UTUC than in UCB. Comparisons of somatic alterations of UCB and UTUC between the study cohort and western cohorts revealed significant differences in mutant prevalence. Notably, 28.57, 17.86 and 47.32% of the cases harbored alterations in FGFRs, ERBBs and DNA damage repair genes, respectively. Furthermore, 75% of the patients carried non-benign germline variants, but only two (1.79%) were pathogenic. The overall concordance for genomic alterations in ctDNA and matched tumor tissue was 42.97% (0-100%). Notably, 47.25% of alterations detected in ctDNA were not detected in the matched tissue, and 54.14% of which were oncogenic mutations. CONCLUSIONS: We found a unique genomic feature of Chinese UC patients. A reasonably good concordance of genomic features between ctDNA and tissue samples were identified.

Risk Factors Influencing the Thickness and Stranding of Perinephric Fat of Mayo Adhesive Probability Score in Minimally Invasive Nephrectomy.

BACKGROUND Mayo adhesive probability (MAP) score, an accurate and reliable predictor of adherent perinephric fat (APF), consists of posterior perinephric fat thickness and perinephric fat stranding. The present study aimed to identify the potential clinical characteristics associated with these 2 variables to further our understanding of APF. MATERIAL AND METHODS Clinical data of 346 patients subjected to minimally invasive nephrectomy was collected within our prospectively maintained database, between January 2015 and December 2016. Radiological data was assessed by 2 readers in an independent blinded - to each other and APF patient status - fashion. Ordinal logistic regression analyses were performed to evaluate risk factors of posterior perinephric fat thickness and perinephric fat stranding. RESULTS On multivariate analysis, posterior perinephric fat thickness was associated with older age (ß=1.05 [range, 1.03-1.07], P<0.01); male gender (ß=6.06 [3.18-11.54], P<0.01), and higher body mass index (BMI) (ß=1.31 [1.21-1.41], P<0.01). Perinephric fat stranding was associated with older age (ß=1.05 [1.02-1.07], P<0.01), male gender (ß=3.64 [2.09-6.34], P<0.01) and history of diabetes (ß=2.09 [1.24-3.52], P<0.01). MAP score was associated with older age (ß=1.05 [1.03-1.07], P<0.01), male gender (ß=5.07 [2.96-8.71], P<0.01), higher BMI (ß=1.14 [1.07-1.21], P<0.01), history of diabetes (ß=1.72 [1.06-2.78], P=0.03) and alcoholism (ß=1.88 [1.10-3.20], P=0.02). CONCLUSIONS The current study highlights that different risk factors influence the posterior perinephric fat thickness and perinephric fat stranding. Posterior perinephric fat thickness was correlated with age, gender, and BMI, while perinephric fat stranding was associated with age, gender, and history of diabetes.

Hypoxia-induced overexpression of stanniocalcin-1 is associated with the metastasis of early stage clear cell renal cell carcinoma.

BACKGROUND: Although metastasis of clear cell renal cell carcinoma (ccRCC) is predominantly observed in late stage tumors, early stage metastasis of ccRCC can also be found with indefinite molecular mechanism, leading to inappropriate clinical decisions and poor prognosis. Stanniocalcin-1 (STC1) is a glycoprotein hormone involved in calcium/phosphate homeostasis, which regulates various cellular processes in normal development and tumorigenesis. This study aimed to investigate the role and mechanism of regulation of STC1 in the metastasis of early stage ccRCC. METHODS: STC1 mRNA and protein expression was determined in ccRCC surgical specimens, RCC cell lines, and human kidney tubule epithelial cell line HKC by real-time polymerase chain reaction (RT-PCR) and western blotting. Immunohistochemistry staining (IHC) and immunofluorescence were also used to examine the expression and localization of STC1 in ccRCC tissues and cancer cells. Knockdown and overexpression studies were conducted in vitro in RCC cell lines using small interfering RNAs (siRNA) and lentiviral-mediated gene delivery to evaluate the role of STC1 in cell proliferation, anchorage-dependent and independent growth, cell cycle control, and migration and invasion. RESULTS: STC1 mRNA and protein expression were significantly up-regulated in tumors when compared with non-tumor tissues, with the greatest increase in expression observed in metastatic tissues. Clinicopathological analysis revealed that STC1 mRNA expression was associated with Fuhrman tumor grade (P = 0.008) and overall Tumor Node Metastasis (TNM) staging (P = 0.018). STC1 expression was elevated in T1 stage metastatic tumors when compared with localized tumors, and was positively correlated with average tumor diameter. Silencing of STC1 expression by Caki-1 and A498 resulted in the inhibition of cell proliferation, migration, and invasion, meanwhile down-regulation of STC1 impaired epithelial-mesenchymal transition (EMT) of ccRCC cell lines. Overexpression of STC1 in Caki-2 enhanced cell growth and proliferation but not migration and invasion. Further investigation identified hypoxia and HIF-1α as candidate regulators of STC1 expression. CONCLUSIONS: Our findings demonstrate a role for STC1 in metastasis of early stage ccRCC and suggest that STC1 may be a biomarker of potential value both for the prognosis of this disease and for guiding clinical decisions regarding surgical strategies and adjuvant treatment.

Transrectal versus transperineal prostate biopsy for cancer detection in patients with gray-zone prostate-specific antigen: a multicenter, real-world study.

Knowledge about the effect of different prostate biopsy approaches on the prostate cancer detection rate (CDR) in patients with gray-zone prostate-specific antigen (PSA) is limited. We performed this study to compare the CDR among patients who underwent different biopsy approaches and had rising PSA levels in the gray zone. Two hundred and twenty-two patients who underwent transrectal prostate biopsy (TRB) and 216 patients who underwent transperineal prostate biopsy (TPB) between June 2016 and September 2022 were reviewed in this study. In addition, 110 patients who received additional targeted biopsies following the systematic TPB were identified. Clinical parameters, including age, PSA derivative, prostate volume (PV), and needle core count, were recorded. The data were fitted via propensity score matching (PSM), adjusting for potential confounders. TPB outperformed TRB in terms of the CDR (49.6% vs 28.3%, P = 0.001). The clinically significant prostate cancer (csPCa) detection rate was not significantly different between TPB and TRB (78.6% vs 68.8%, P = 0.306). In stratified analysis, TPB outperformed TRB in CDR when the age of patients was 65-75 years (59.0% vs 22.0%, P < 0.001), when PV was 25.00-50.00 ml (63.2% vs 28.3%, P < 0.001), and when needle core count was no more than 12 (58.5% vs 31.5%, P = 0.005). The CDR ( P = 0.712) and detection rate of csPCa ( P = 0.993) did not significantly differ among the systematic, targeted, and combined biopsies. TPB outperformed TRB in CDR for patients with gray-zone PSA. Moreover, performing target biopsy after systematic TPB provided no additional benefits in CDR.

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.

Suitability of the MP1000 system for robot-assisted partial nephrectomy: a multicenter randomized controlled noninferiority trial.

PURPOSE: This study aimed to compare the safety and effectiveness of the MP1000 surgical system with the da Vinci Si robot system in robot-assisted partial nephrectomy (RAPN) through a prospective, single-blinded, randomized controlled trial. MATERIALS AND METHODS: A total of 62 patients who were scheduled to undergo RAPN were randomly assigned to either the da Vinci Si robot or MP1000 group. A noninferiority test was conducted with a noninferior intermediate value of 10%. The study compared installation and operation times, estimated blood loss, warm ischemia time, postoperative surgical margin, rate of conversion to open surgery, eGFR level, complications, and other safety indicators between the two groups. RESULTS: All procedures were successfully completed without the need for conversion to open or laparoscopic surgery, and no major complications were observed during the process. The test of noninferiority was achieved. There were no significant differences in median installation time, operation time, complication rate at 3 months, rate of positive surgical margin, and eGFR level at 3 months between the groups. Additionally, no evidence of recurrence was found on imaging in both groups. No difference in National Aeronautics and Space Administration task load index results for ergonomic considerations. A limitation of this study was its small sample size. CONCLUSIONS: The MP1000 system is a suitable platform for RAPN with safety and effectiveness compared with da Vinci Si system.

Suitability of the MP1000 Platform for Robot-assisted Prostatectomy: A Prospective Randomised Controlled Trial.

Background and objective: Robot-assisted radical prostatectomy (RARP) is widely used because of the many advantages of a robotic approach. The da Vinci Si robot is one of the most commonly used surgical robot systems, but it may be associated with higher costs owing to the use of consumable surgical supplies. Our aim was to conduct a preliminary investigation of the capability of the MP1000 system for RARP. Methods: In this prospective, multicentre, single-blinded study, we randomly assigned 42 patients scheduled to undergo RARP between April and September 2021 to a da Vinci Si group (control) or an MP1000 group (intervention). Patients underwent RARP performed using the assigned robotic system and were followed up at 3-mo intervals. The primary outcome was the rate of conversion to open/laparoscopic surgery. Secondary outcomes were installation and operation times, intraoperative blood loss, postoperative surgical margin status, hospital stay, incontinence, complications, safety indicators, and surgeon ergonomics. Key findings and limitations: All procedures were successfully completed without conversion to open/laparascopic surgery or major complications. Secondary outcomes, including oncological and ergonomic indicators, did not differ significantly between the groups over the study period. One patient in the control group experienced dysuria (Clavien-Dindo grade 3). No patients had incontinence at 3 mo. A limitation of the study is the small sample size. Conclusions and clinical implications: RARP with the MP1000 system is feasible, safe, and effective in the management of localised prostate cancer. Patient summary: We assessed the effectiveness and safety of the new MP1000 robot system for robot-assisted removal of the prostate in comparison to the da Vinci Si robot. We found no difference in effectiveness or safety among 42 patients with prostate cancer who were assigned randomly to one of the two systems. We conclude that the MP1000 is a suitable robot for this surgery.

Can 18F-PSMA-7Q PET/CT replace prostate biopsy for the diagnosis of prostate cancer?-A single-center retrospective study.

Background: Of the currently available prostate-specific membrane antigen (PSMA) positron emission tomography (PET) tracers, although 68Ga-PSMA-11 and 18F-DCFPyL have been approved by the US Food and Drug Administration (FDA), both tracers are excreted rapidly through the urinary tract, resulting in strong accumulation in the bladder and blurring the prostate.18F-PSMA-7Q is a novel quinoline-containing PSMA PET tracer developed by our team, which is primarily excreted through the liver. It can reduce the incidence of urine-induced false-positives in the prostate. We aimed to explore the diagnostic efficacy of 18F-PSMA-7Q PET/computed tomography (CT), and when 18F-PSMA-7Q PET/CT can be used instead of prostate biopsy to diagnose prostate cancer. Methods: Patients who underwent 18F-PSMA-7Q PET/CT for prostate cancer staging or prostate biopsy guidance at our institution between July 2020 and December 2021 were retrospectively enrolled. Molecular imaging PSMA (miPSMA) scores were assigned for intra-prostatic lesions according to the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria, and the diagnostic efficacy of 18F-PSMA-7Q PET/CT for different miPSMA scores was evaluated using pathological diagnosis as the gold standard. Results: Of the 125 enrolled patients, 101 had prostate cancer, and 24 had prostatic hyperplasia or prostatitis. miPSMA ≥2 was the optimal diagnostic threshold, and area under curve (AUC) was 0.948, the sensitivity and specificity were 91.1% and 83.0%. The prostate cancer detection rates of 18F-PSMA-7Q PET/CT were 14.3% (3/21), 60.0% (6/10), 96.7% (58/60), and 100% (34/34) for patients with miPSMA scores of 0, 1, 2, and 3, respectively. There was no significant difference in the detection rate of prostate cancer between groups with miPSMA scores of 2 and 3, but there were significant differences between any other 2 groups. Conclusions: The prostate cancer detection rate of 18F-PSMA-7Q PET/CT was high for lesions with greater miPSMA scores of 2 and 3. For patients with a high miPSMA score, particularly those with a miPSMA score of 3, prostate biopsy can be omitted and prostate cancer-related treatment can be considered.

Radiotranscriptomics identified new mRNAs and miRNA markers for distinguishing prostate cancer from benign prostatic hyperplasia.

The present study investigated ultrasound (US) phenotypes reflecting prostate cancer (PCa)-related genetic mutations. Herein, integration of radiotranscriptomic data, US and contrast-enhanced ultrasound (CEUS) radiomic images, and RNA sequencing was performed with the aim of significantly improving the accuracy of PCa prognosis. We performed radiotranscriptomic analysis of clinical, imaging, and two genomic (mRNA and microRNA expression) datasets from 48 and 22 men with PCa and benign prostatic hyperplasia (BPH), respectively. Twenty-three US texture features and four microvascular perfusion features were associated with various patterns of 52 differentially expressed genes related to PCa (p < 0.05); 17 overexpressed genes were associated with two key texture features. Twelve overexpressed genes were identified using microvascular perfusion features. Furthermore, mRNA and miRNA biomarkers could be used to distinguish between PCa and BPH. Compared with RNA sequencing, B-mode and CEUS features reflected genomic alterations associated with hormone receptor status, angiogenesis, and prognosis in patients with PCa. These findings indicate the potential of US to assess biomarker levels in patients with PCa.

[Analysis of clinicopathological features and prognosis in 68 patients with chromophobe renal cell carcinoma].

OBJECTIVE: To investigate the clinicopathological features and prognosis of chromophobe renal cell carcinoma (ChRCC). METHODS: The clinical data of 68 ChRCC cases treated in our department between January 2003 and September 2010 were collected and retrospectively analyzed. The prognostic factors were evaluated by Log-rank test. Kaplan-Meier survival curve was used to estimate the survival rate. RESULTS: Fifty cases were treated with radical nephrectomy and 18 with partial nephrectomy. The mean tumor size was 5.7 cm (1.5 - 16.0 cm). The TNM stages were as follows: pT1aN0M0 in 25, pT1bN0M0 in 22, pT2aN0M0 in 9, pT2bN0M0 in 5, and pT3aN0M0 in 7. According to the Fuhrman grading system, 8 patients were classified as grade I, 42 cases were grade II, 14 cases were grade III, and 4 cases were grade IV. The 3-year and 5-year survival rates were 93.0% and 90.0%, respectively. The log-rank test showed that tumor size (> 7 cm vs. ≤ 7 cm) (P = 0.004), TNM stage (T1-2 vs. T3-4) (P = 0.008) and urinary collecting system invasion (P = 0.024) were associated with survival time. The multivariable Cox regression model revealed that tumor size (> 7 cm vs. ≤ 7 cm) was an independent predictor of aggressive ChRCC (P = 0.038). CONCLUSIONS: ChRCC is a distinct type of renal cell carcinoma exhibiting a low degree of malignancy. Most tumors are larger, but predominantly with a favorable prognosis. Fuhrman nuclear grading is not suitable for ChRCC. Tumor size (> 7 cm vs. ≤ 7 cm) is an independent predictor of prognosis of ChRCC.

DMDRMR promotes angiogenesis via antagonizing DAB2IP in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) patients are highly angiogenic and treated by targeted therapies against VEGFA/VEGFR signaling pathway. However, tumors with such targeted therapies remain a significant clinic challenge. Understanding the underlying mechanism against angiogenesis is highly desired. Here, we demonstrated that the lncRNA DMDRMR serves as a sponge of miR-378a-5p to increase EZH2 and SMURF1 expression, thus promoting EZH2-mediated transcriptional repression of DAB2IP and SMURF1-mediated degradation of DAB2IP. Consequently, this axis activates VEGFA/VEGFR2 signaling pathway, resulting in angiogenesis and resistance of tumor cells to sunitinib in ccRCC. Moreover, the competing endogenous RNA regulatory axis of DMDRMR is clinically relevant to ccRCC pathogenesis and prognosis of patients with ccRCC. Our results support that the DMDRMR/miR-378a-5p/DAB2IP axis may serve as a novel target for combination diagnosis or therapy of ccRCC patients. Our findings may have highly clinical relevance for future translation to develop the targeted therapies for patients with ccRCC.

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.

DMDRMR-Mediated Regulation of m6A-Modified CDK4 by m6A Reader IGF2BP3 Drives ccRCC Progression.

Aberrant N 6-methyladenosine (m6A) modification has emerged as a driver of tumor initiation and progression, yet how long noncoding RNAs (lncRNA) are involved in the regulation of m6A remains unknown. Here we utilize data from 12 cancer types from The Cancer Genome Atlas to comprehensively map lncRNAs that are potentially deregulated by DNA methylation. A novel DNA methylation-deregulated and RNA m6A reader-cooperating lncRNA (DMDRMR) facilitated tumor growth and metastasis in clear cell renal cell carcinoma (ccRCC). Mechanistically, DMDRMR bound insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) to stabilize target genes, including the cell-cycle kinase CDK4 and three extracellular matrix components (COL6A1, LAMA5, and FN1), by specifically enhancing IGF2BP3 activity on them in an m6A-dependent manner. Consequently, DMDRMR and IGF2BP3 enhanced the G1-S transition, thus promoting cell proliferation in ccRCC. In patients with ccRCC, high coexpression of DMDRMR and IGF2BP3 was associated with poor outcomes. Our findings reveal that DMDRMR cooperates with IGF2BP3 to regulate target genes in an m6A-dependent manner and may represent a potential diagnostic, prognostic, and therapeutic target in ccRCC. SIGNIFICANCE: This study demonstrates that the lncRNA DMDRMR acts as a cofactor for IGF2BP3 to stabilize target genes in an m6A-dependent manner, thus exerting essential oncogenic roles in ccRCC.

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.

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.

Leukemia Inhibitory Factor Promotes Castration-resistant Prostate Cancer and Neuroendocrine Differentiation by Activated ZBTB46.

PURPOSE: The molecular targets for castration-resistant prostate cancer (CRPC) are unknown because the disease inevitably recurs, and therapeutic approaches for patients with CRPC remain less well understood. We sought to investigate regulatory mechanisms that result in increased therapeutic resistance, which is associated with neuroendocrine differentiation of prostate cancer and linked to dysregulation of the androgen-responsive pathway. EXPERIMENTAL DESIGN: The underlying intracellular mechanism that sustains the oncogenic network involved in neuroendocrine differentiation and therapeutic resistance of prostate cancer was evaluated to investigate and identify effectors. Multiple sets of samples with prostate adenocarcinomas and CRPC were assessed via IHC and other assays. RESULTS: We demonstrated that leukemia inhibitory factor (LIF) was induced by androgen deprivation therapy (ADT) and was upregulated by ZBTB46 in prostate cancer to promote CRPC and neuroendocrine differentiation. LIF was found to be induced in patients with prostate cancer after ADT and was associated with enriched nuclear ZBTB46 staining in high-grade prostate tumors. In prostate cancer cells, high ZBTB46 output was responsible for the activation of LIF-STAT3 signaling and neuroendocrine-like features. The abundance of LIF was mediated by ADT-induced ZBTB46 through a physical interaction with the regulatory sequence of LIF. Analysis of serum from patients showed that cases of higher tumor grade and metastatic prostate cancer exhibited higher LIF titers. CONCLUSIONS: Our findings suggest that LIF is a potent serum biomarker for diagnosing advanced prostate cancer and that targeting the ZBTB46-LIF axis may therefore inhibit CRPC development and neuroendocrine differentiation after ADT.