FGD5 regulates endothelial cell PI3 kinase-ß to promote neo-angiogenesis.

Angiogenesis is required in embryonic development and tissue repair in the adult. Vascular endothelial growth factor (VEGF) initiates angiogenesis, and VEGF or its receptor is targeted therapeutically to block pathological angiogenesis. Additional pro-angiogenic cues, such as CXCL12 acting via the CXCR4 receptor, co-operate with VEGF/VEGFR2 to cue vascular patterning. We studied the role of FGD5, an endothelial Rho GTP/GDP exchange factor (RhoGEF), to regulate CXCR4-dependent signals in the endothelial cell (EC). Patient-derived renal cell carcinomas produce a complex milieu of growth factors that stimulated sprouting angiogenesis and endothelial tip cell differentiation ex vivo that was blocked by EC FGD5 loss. In a simplified model, CXCL12 augmented sprouting and tip gene expression under conditions where VEGF was limiting. CXCL12-stimulated tip cell differentiation was dependent on PI3 kinase (PI3K)-ß activity. Knockdown of EC FGD5 abolished CXCR4 signaling to PI3K-ß and Akt. Further, inhibition of Rac1, a Rho GTPase required for PI3K-ß activity, recapitulated the signaling defects of FGD5 deficiency, suggesting that FGD5 may regulate PI3K-ß activity through Rac1. Overexpression of a RhoGEF deficient, Dbl domain-deleted FGD5 mutant reduced CXCL12-stimulated Akt phosphorylation and failed to rescue PI3K signaling in native FGD5-deficient EC, indicating that FGD5 RhoGEF activity is required for FDG5 function. Endothelial expression of mutant PI3K-ß with an inactivated Rho binding domain confirmed that CXCL12-stimulated PI3K activity in EC requires Rac1-GTP co-regulation. Together, this data identify the role of FGD5 to generate Rac1-GTP to regulate pro-angiogenic CXCR4-dependent PI3K-ß signaling in EC. Inhibition of FGD5 activity may complement current angiogenesis inhibitor drugs.

N6-methyladenosine-modified TRAF1 promotes sunitinib resistance by regulating apoptosis and angiogenesis in a METTL14-dependent manner in renal cell carcinoma.

BACKGROUND: Sunitinib resistance can be classified into primary and secondary resistance. While accumulating research has indicated several underlying factors contributing to sunitinib resistance, the precise mechanisms in renal cell carcinoma are still unclear. METHODS: RNA sequencing and m6A sequencing were used to screen for functional genes involved in sunitinib resistance. In vitro and in vivo experiments were carried out and patient samples and clinical information were obtained for clinical analysis. RESULTS: We identified a tumor necrosis factor receptor-associated factor, TRAF1, that was significantly increased in sunitinib-resistant cells, resistant cell-derived xenograft (CDX-R) models and clinical patients with sunitinib resistance. Silencing TRAF1 increased sunitinib-induced apoptotic and antiangiogenic effects. Mechanistically, the upregulated level of TRAF1 in sunitinib-resistant cells was derived from increased TRAF1 RNA stability, which was caused by an increased level of N6-methyladenosine (m6A) in a METTL14-dependent manner. Moreover, in vivo adeno-associated virus 9 (AAV9) -mediated transduction of TRAF1 suppressed the sunitinib-induced apoptotic and antiangiogenic effects in the CDX models, whereas knockdown of TRAF1 effectively resensitized the sunitinib-resistant CDXs to sunitinib treatment. CONCLUSIONS: Overexpression of TRAF1 promotes sunitinib resistance by modulating apoptotic and angiogenic pathways in a METTL14-dependent manner. Targeting TRAF1 and its pathways may be a novel pharmaceutical intervention for sunitinib-treated patients.

Step-by-step and orderly lowering of the height of inferior vena cava tumor thrombus is the key to robot-assisted thrombectomy for Mayo III/IV tumor thrombus.

BACKGROUND: The surgical management of Mayo III/IV tumor thrombi is difficult and risky, and robotic surgery is even more difficult. The purpose of this study was to introduce the step-by-step and orderly lowering of the height of inferior vena cava tumor thrombus, which was the core technique of robot operation for Mayo III/IV tumor thrombus. METHOD: A total of 18 patients were included in this study. The average tumor thrombus height was 2.4 cm above the level of the second porta hepatis (SPH), and 9 patients were prepared for cardiopulmonary bypass (CPB) before surgery. During the operation, the height of the tumor thrombus was lowered orderly for 2-3 times, and the blood flow blocking method was changed sequentially. The CPB was required when tumor thrombus in the atrium; After the height of the thrombus was lowered to the atrium entrance, CPB was stopped and the blood flow was blocked in the upper- and retro-hepatic inferior vena cava (IVC); After the tumor thrombus continued to descend to the lower part of the SPH, liver blood flow could be restored, and then, the blood flow was simply blocked in the retro-hepatic IVC to complete the removal of the thrombus and the repair or resection of the IVC. Finally, the diseased kidney and renal vein were removed. RESULTS: All operations were successfully completed, and 2 cases were transferred to laparotomy. Seven cases received CPB, while the other 11 did not. 15 patients underwent two times of the lowering of the tumor thrombus, 2 patients underwent one time and 1 patient underwent three times. The mean liver/IVC dissociation and vascular suspension time was 22.0 min. All patients had less than Clavien-Dindo grade III complications, no serious complications occurred during operation, and no patient died within 90 days. CONCLUSIONS: The step-by-step and orderly decline of tumor thrombus height is the key to the success of robot Mayo III / IV tumor thrombus surgery. This method can shorten FPH and CPB time and improve the success rate of surgery.

Let-7d inhibits intratumoral macrophage M2 polarization and subsequent tumor angiogenesis by targeting IL-13 and IL-10.

The microRNA let-7d has been reported to be a tumor suppressor in renal cell carcinoma (RCC). Tumor-associated macrophages (TAM) are M2-polarized macrophages that can enhance tumor growth and angiogenesis in many human cancers. However, the role of let-7d in TAM-associated RCC progression remains elusive. First, we observed a strongly inverse correlation between let-7d expression and microvessel density in RCC tissues. Furthermore, the proliferation, migration, and tube formation of HUVECs were significantly inhibited by conditioned medium from a coculture system of the phorbol myristate acetate pretreated human THP-1 macrophages and let-7d-overexpressing RCC cells. Moreover, the proportion of M2 macrophages was significantly lower in the group that was cocultured with let-7d-overexpressing RCC cells. Subcutaneous xenografts formed by the injection of let-7d-overexpressing RCC cells together with THP-1 cells resulted in a significant decrease in the M2 macrophage ratio and microvessel density compared with those formed by the injection of control RCC cells with THP-1 cells. In silico and experimental analysis revealed interleukin-10 (IL-10) and IL-13 as let-7d target genes. Importantly, the addition of IL-10 and IL-13 counteracted the inhibitory effects of the conditioned medium from the coculture system with let-7d-overexpressing RCC cells in vitro. Additionally, overexpression of IL-10 and IL-13 reversed the effects of let-7d on macrophage M2 polarization and tumor angiogenesis in vivo. Finally, the expression of IL-10 and IL-13 were inversely correlated with the expression of let-7d in RCC clinical specimens. These results suggest that let-7d may inhibit intratumoral macrophage M2 polarization and subsequent tumor angiogenesis by targeting IL-10 and IL-13.

The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol.

BACKGROUND: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE). METHODS: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging. DISCUSSION: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21 .

Multi-omics analysis of tumor angiogenesis characteristics and potential epigenetic regulation mechanisms in renal clear cell carcinoma.

BACKGROUND: Tumor angiogenesis, an essential process for cancer proliferation and metastasis, has a critical role in prognostic of kidney renal clear cell carcinoma (KIRC), as well as a target in guiding treatment with antiangiogenic agents. However, tumor angiogenesis subtypes and potential epigenetic regulation mechanisms in KIRC patient remains poorly characterized. System evaluation of angiogenesis subtypes in KIRC patient might help to reveal the mechanisms of KIRC and develop more target treatments for patients. METHOD: Ten independent tumor angiogenesis signatures were obtained from molecular signatures database (MSigDB) and gene set variation analysis was performed to calculate the angiogenesis score in silico using the Cancer Genome Atlas (TCGA) KIRC dataset. Tumor angiogenesis subtypes in 539 TCGA-KIRC patients were identified using consensus clustering analysis. The potential regulation mechanisms was studied using gene mutation, copy number variation, and differential methylation analysis (DMA). The master transcription factors (MTF) that cause the difference in tumor angiogenesis signals were completed by transcription factor enrichment analysis. RESULTS: The angiogenesis score of a prognosis related angiogenesis signature including 189 genes was significantly correlated with immune score, stroma score, hypoxia score, and vascular endothelial growth factor (VEGF) signal score in 539 TCGA KIRC patients. MMRN2, CLEC14A, ACVRL1, EFNB2, and TEK in candidate gene set showed highest correlation coefficient with angiogenesis score in TCGA-KIRC patients. In addition, all of them were associated with overall survival in both TCGA-KIRC and E-MTAB-1980 KIRC data. Clustering analysis based on 183 genes in angiogenesis signature identified two prognosis related angiogenesis subtypes in TCGA KIRC patients. Two clusters also showed different angiogenesis score, immune score, stroma score, hypoxia score, VEGF signal score, and microenvironment score. DMA identified 59,654 differential methylation sites between two clusters and part of these sites were correlated with tumor angiogenesis genes including CDH13, COL4A3, and RHOB. In addition, RFX2, SOX13, and THRA were identified as top three MTF in regulating angiogenesis signature in KIRC patients. CONCLUSION: Our study indicate that evaluation the angiogenesis subtypes of KIRC based on angiogenesis signature with 183 genes and potential epigenetic mechanisms may help to develop more target treatments for KIRC patients. Video Abstract.

Varying Outcomes among Patients with Large Angiomyolipomas according to the Treatment Method.

PURPOSE: This study aimed to evaluate the outcomes of large angiomyolipoma (AML) treatment by selective arterial embolization (SAE) versus nephron-sparing surgery (NSS) using a robotic surgical system. MATERIALS AND METHODS: Between January 2011 and June 2018, we retrospectively reviewed 25 patients who underwent robot-assisted partial nephrectomy (RAPN) or SAE for large AMLs. Ten patients underwent RAPN, and 15 underwent SAE. Patient demographics, AML characteristics, and operative and postoperative clinical outcomes were recorded and analyzed. Outcomes were compared between patients who underwent RAPN and patients who underwent SAE. Specifically, changes in renal function and size were evaluated after the treatment. RESULTS: The mean age of the patients was 52.9 years, and 22 of 25 patients were female. The mean maximum AML diameter on computed tomography was 8.9 cm, and 8 patients had multiple masses. Twenty-two of 25 patients had moderate to high RENAL complexity. Patients who underwent SAE had more symptoms (p = 0.018) and higher RENAL complexity scores (p = 0.013) on average. On average, tumor size decreased by 99% among RAPN patients and by 58% among SAE patients (p = 0.001). Although the mean pretreatment estimated glomerular filtration rate (eGFR) was higher among RAPN patients (99.8 vs. 80.0 mL/min/1.73 m2, p = 0.043), there were no significant changes in eGFR in either group after the treatment. One patient in the RAPN group experienced complications, but the postoperative ileus resolved without intervention. CONCLUSIONS: Both RAPN and SAE were effective and feasible treatment options for large AMLs. The AML characteristics and the condition of the patient might be important in determining the appropriate treatment method.

Papillary vs clear cell renal cell carcinoma. Differentiation and grading by iodine concentration using DECT-correlation with microvascular density.

OBJECTIVES: Various imaging methods have been evaluated regarding non-invasive differentiation of renal cell carcinoma (RCC) subtypes. Dual-energy computed tomography (DECT) allows iodine concentration (IC) analysis as a correlate of tissue perfusion. Microvascular density (MVD) in histopathology specimens is evaluated to determine intratumoral vascularization. The objective of this study was to assess the potential of IC and MVD regarding the differentiation between papillary and clear cell RCC and between well- and dedifferentiated tumors. Further, we aimed to investigate a possible correlation between these parameters. METHODS: DECT imaging series of 53 patients with clear cell RCC (ccRCC) and 15 with papillary RCC (pRCC) were analyzed regarding IC. Histology samples were stained using CD31/CD34 monoclonal antibodies; MVD was evaluated digitally. Statistical analysis included performance of Mann-Whitney U test, ROC analysis, and Spearman rank correlation. RESULTS: Analysis of IC demonstrated significant differences between ccRCC and pRCC (p < 0.001). A cutoff value of ≤ 3.1 mg/ml at IC analysis allowed identification of pRCC with an accuracy of 86.8%. Within the ccRCC subgroup, G1/G2 tumors could significantly be differentiated from G3/G4 carcinomas (p = 0.045). A significant positive correlation between IC and MVD could be determined for the entire RCC cohort and the ccRCC subgroup. Limitations include the small percentage of pRCCs. CONCLUSIONS: IC analysis is a useful method to differentiate pRCC from ccRCC. The significant positive correlation between IC and MVD indicates valid representation of tumor perfusion by DECT. KEY POINTS: • Analysis of iodine concentration using DECT imaging could reliably distinguish papillary from clear cell subtypes of renal cell cancer (RCC). • A cutoff value of 3.1 mg/ml allowed a distinction between papillary and clear cell RCCs with an accuracy of 86.8%. • The positive correlation with microvascular density in tumor specimens indicates correct display of perfusion by iodine concentration analysis.

Weakly-supervised convolutional neural networks of renal tumor segmentation in abdominal CTA images.

BACKGROUND: Renal cancer is one of the 10 most common cancers in human beings. The laparoscopic partial nephrectomy (LPN) is an effective way to treat renal cancer. Localization and delineation of the renal tumor from pre-operative CT Angiography (CTA) is an important step for LPN surgery planning. Recently, with the development of the technique of deep learning, deep neural networks can be trained to provide accurate pixel-wise renal tumor segmentation in CTA images. However, constructing the training dataset with a large amount of pixel-wise annotations is a time-consuming task for the radiologists. Therefore, weakly-supervised approaches attract more interest in research. METHODS: In this paper, we proposed a novel weakly-supervised convolutional neural network (CNN) for renal tumor segmentation. A three-stage framework was introduced to train the CNN with the weak annotations of renal tumors, i.e. the bounding boxes of renal tumors. The framework includes pseudo masks generation, group and weighted training phases. Clinical abdominal CT angiographic images of 200 patients were applied to perform the evaluation. RESULTS: Extensive experimental results show that the proposed method achieves a higher dice coefficient (DSC) of 0.826 than the other two existing weakly-supervised deep neural networks. Furthermore, the segmentation performance is close to the fully supervised deep CNN. CONCLUSIONS: The proposed strategy improves not only the efficiency of network training but also the precision of the segmentation.

Comparison of three dimensional reconstruction and conventional computer tomography angiography in patients undergoing zero-ischemia laparoscopic partial nephrectomy.

BACKGROUND: With the development of three dimensional (3D) reconstruction and printing technology, it has been widely using in the field of urology. However, there have been few studies reporting the role of 3D reconstruction in zero-ischemia partial nephrectomy (PN). The aim of this study was to assess the role of 3D reconstruction and conventional computer tomography angiography (CTA) in zero-ischemia laparoscopic partial nephrectomy (LPN). METHODS: A total of 60 consecutive patients undergoing zero-ischemia LPN between October 2017 and March 2018 who underwent CTA (CTA group including 30 patients) and 3D reconstruction (3D group including the remaining 30 patients) preoperatively were included. 3D reconstruction and CTA images were prepared which were used to demonstrate the number and spatial interrelationships of the location of renal tumors and tumor feeding arteries. These radiological findings were directly correlated with intraoperative surgical findings at laparoscopy. Baseline, perioperative variables and the rate of accurate tumor feeding artery orientation were compared between groups. RESULTS: All LPNs were completed without conversion to renal hilar clamping or open surgery. Preoperative 3D reconstruction identified that 15 patients had only one tumor feeding artery, 12 had two, and another 3 had three, while the conventional CTA revealed that 22 patients had one tumor feeding artery, 8 had two (P > 0.05). The mean operation time was shorter and estimated blood loss was less in the 3D group (P < 0.05) and the rate of accurate tumor feeding artery dissection was higher in the 3D group (91.7%) in comparison with the CTA group (84.2%). The baseline characteristics and renal function outcomes had no statistical differences between groups. CONCLUSIONS: 3D reconstruction can provide comprehensive information for the preoperative evaluation and intraoperative orientation about tumor feeding arteries that may facilitate tumor resection during zero-ischemia LPN for renal tumors.

[Impact of partial nephrectomy in a hybrid operating room on the activity of kidney cancer surgery]. / Évaluation de l'utilisation de la salle hybride sur l'activité de chirurgie en cancérologie rénale.

INTRODUCTION: Partial nephrectomy (NP) after embolization of tumor vessels (NPESH) in a hybrid room combines embolization of tumor vessels and enucleation of the tumor under laparoscopy in the same operative time. The purpose of this study was to assess the impact of the use of NPESH in the management of patients treated with surgery for a localized kidney tumor. MATERIAL AND METHODS: Using the uroCCR database, we included all consecutive patients operated in a university hospital for localized kidney tumor. From 2011 to May 2015, patients were treated by Standard Partial Nephrectomy (NPS) Laparoscopic or Open and from May 2015 to May 2019 by NPESH. We evaluated characteristics of patients, tumors, perioperative data and complications. These data were compared by Student and Khi2 tests. RESULTS: 87 NPS were performed during Period 1 and 137 NPS were performed during period 2. The ASA score of patients undergoing NPESH was higher than NPS (P<0.0001). The tumor complexity and median tumor size were similar in the two groups (P=0.852 and P=0.48). The complication rate for NPS and NPESH was 55.2% and 33.6% (P=0.002). There were less severe complications in the NEPSH group (P=0.012). The median length of stay was 8 and 4 days for the NPS and NPESH groups (P<0.0001). Positive surgical margins were 2 (2.3%) and 6 (4.6%) for the NPS and NPESH group (P=0.713). DISCUSSION: NPESH is an efficient technique compared to NPS. It seems to be an interesting alternative to limit renal ischemia, complication rate and length of stay for the management of localized kidney tumors.

PinX1 represses renal cancer angiogenesis via the mir-125a-3p/VEGF signaling pathway.

BACKGROUND: PIN2/TRF1-interacting telomerase inhibitor 1 (PinX1) is a tumor suppressor in various tumors. However, the molecular mechanism underlying PinX1's role in cancer development and progression remains unclear. In this study, we aimed to uncover the new molecular mechanism and role of PinX1 in renal cell carcinoma (RCC) progression. METHODS: We used miRNA microarray to detect the different expressed miRNAs upon PinX1 knockdown. Chromatin immunoprecipitation and Luciferase reporter assays were taken to identify the molecular mechanism of PinX1 in regulating mir-125-3p. In situ hybridization was performed to analyze the expression of mir-125a-3p in RCC using tissue microarray. The correlations between the mir-125a-3p expression level and clinicopathological features were evaluated using the χ2 test. The role and molecular mechanism of PinX1 in RCC angiogenesis were investigated through a series of in vitro and in vivo experiments. RESULTS: In this study, we discovered a new molecular mechanism of PinX1, in which PinX1 transcriptionally activated mir-125a-3p expression, thereby inhibiting the expression of vascular endothelial growth factor (VEGF), which is the target gene of mir-125a-3p. PinX1 also repressed tumor angiogenesis by increasing the mir-125a-3p expression in renal cancer. Moreover, the loss of mir-125a-3p expression was manifested in patients with RCC, and low miR-125a-3p levels correlated with poor survival of these patients. CONCLUSIONS: PinX1 represses renal cancer angiogenesis through mir-125a-3p/VEGF signal pathway. The miR-125a-3p may be a candidate clinical prognostic marker and a novel therapeutic target in RCC.

Apelin and apelin receptor expression in renal cell carcinoma.

BACKGROUND: The APLNR (apelin receptor) has been shown to be an essential gene for cancer immunotherapy, with deficiency in APLNR leading to immunotherapy failure. The aim of this study is to investigate the expression of APLN (apelin) and APLNR in patients with renal cell carcinoma (RCC), and its association with clinicopathological parameters and survival. METHODS: Three well-characterised patient cohorts with RCC were used: Study cohort 1 (clear-cell RCC; APLN/APLNR mRNA expression; n = 166); TCGA validation cohort (clear-cell RCC; APLN/APLNR mRNA expression; n = 481); Study cohort 2 (all RCC subtypes; APLNR protein expression/immunohistochemistry; n = 300). Associations between mRNA/protein expression and clinicopathological variables/patients' survival were tested statistically. RESULTS: While APLN showed only very weak association with tumour histological grade (TCGA cohort), APLNR/mRNA protein expression correlate significantly with ccRCC aggressiveness. APLNR is expressed in tumour vasculature and tumour cells at different levels, and these expression levels associate with tumour aggressiveness in opposing directions. APLNR expression was negatively correlated with PD-L1 expression by tumour cells in a subset of patients with ccRCC. APLNR expression in either compartment is an independent prognostic factor for survival of patients with ccRCC. CONCLUSION: The APLNR/APLN-system appears to play an important role in ccRCC, warranting further clinical investigation.

Enhancing Antitumor Immunity with Antiangiogenic Therapy: A Clinical Model in Renal Cell Carcinoma?

Combination therapies involving antiangiogenic agents plus immune checkpoint inhibitors have recently demonstrated clinical efficacy in advanced renal cell carcinoma (RCC). This commentary summarizes the clinical advances and reviews the potential implications for RCC and other advanced solid tumors.

Volumetric imaging: a potential tool to stage upper tract urothelial carcinoma.

PURPOSE: To investigate whether volumetric imaging of tumor vasculature can be used to phenotypically characterize advanced upper tract urothelial carcinoma, and if this technique can distinguish aggressive invasive tumors from non-aggressive superficial ones. METHODS: In a pilot study, two TaG1 and two T3G3 formalin-fixed paraffin-embedded (FFPE) tumor samples were examined using the DIPCO pipeline (Tanaka et al. in Nature Biomed Eng 1(10):796-806. https://doi.org/10.1038/s41551-017-0139-0 , 2017). Briefly, punch biopsies of FFPE tumors were deparaffinized, cleared, immunolabeled with the vessel marker CD34 and imaged with a light-sheet microscope. Thereafter, the three-dimensional (3D) vasculature of the tumors was analyzed and characterized using a specialized image processing software. RESULTS: We found that T3G3 tumors had increased CD34 density kurtosis and skewness compared to TaG1 tumors. This suggests that analysis of the 3D vasculature can distinguish between high-grade invasive and low-grade superficial tumors. CONCLUSIONS: Volumetric imaging of tumor samples may represent novel methodology that can complement conventional histopathology. Volumetric imaging enabled us to differentiate between invasive and non-invasive upper tract urothelial carcinoma. The method is of particular interest in diagnostic work-up of patients with upper tract urothelial carcinoma as previous findings indicate that volumetric imaging of vascular patterns could be used to differentiate superficial and invasive urothelial carcinoma, irrespective of if the tumor sample was deep or superficial. However, further and more extensive studies are required before this method can be applied clinically.

Extrahepatic Clinical Application of Vessel Tracking Software and 3D Roadmapping Tools: Preliminary Experience.

This article demonstrates the use of a representative commercially available automated vessel-tracking software originally intended for liver-only application (Vessel Assist Flight Plan for Liver; GE) in 4 patients. Treatment settings included embolization of small bowel hemorrhage source, treatment of renal cell carcinoma, management of symptomatic benign prostate hypertrophy, and detection with subsequent closure of a mesenteric pseudoaneurysm. All patients were treated successfully.

Dual-Energy CT Material Density Iodine Quantification for Distinguishing Vascular From Nonvascular Renal Lesions: Normalization Reduces Intermanufacturer Threshold Variability.

OBJECTIVE: The purpose of this study was to determine whether a single, uniform normalized iodine threshold reduces variability and enables reliable differentiation between vascular and nonvascular renal lesions independent of the dual-energy CT (DECT) platform used. MATERIALS AND METHODS: In this retrospective, HIPAA-compliant, institutional review board-approved study, 247 patients (156 men, 91 women; mean age ± SD, 67 ± 12 years old) with 263 renal lesions (193 nonvascular, 70 vascular) underwent unenhanced single-energy and contrast-enhanced DECT scans. One hundred and six nonvascular and 38 vascular lesions were scanned on two dual-source DECT (dsDECT) scanners, and 87 nonvascular and 32 vascular lesions were scanned on two rapid-kilovoltage-switching single-source DECT (rsDECT) scanners. Optimal absolute and normalized (to aorta) lesion iodine thresholds were determined for each platform type and for the entire cohort combined. RESULTS: Mean optimal absolute discriminant thresholds were 1.3 mg I/mL (95% CI, 1.2-1.9 mg I/mL), 1.6 mg I/mL (95% CI, 0.9-1.5 mg I/mL), and 1.5 mg I/mL (95% CI, 1.4-1.7 mg I/mL) for dsDECT, rsDECT, and combined cohorts, respectively. Optimal normalized discriminant thresholds were 0.3 mg I/mL (95% CI, 0.2-0.4 mg I/mL) for both the dsDECT and rsDECT cohorts, and 0.3 mg I/mL (0.3-0.4 mg I/mL) for the combined cohort. The AUC, sensitivity, and specificity for the combined optimal normalized discriminant threshold of 0.3 mg I/mL was 0.96 (95% CI, 0.92-1.00), 0.93 (0.84-0.97), and 0.95 (0.91-0.98), respectively. Normalization resulted in decreased variability and better lesion separation (effect size, 1.77 vs 1.69, p < 0.0001). CONCLUSION: The optimal absolute discriminant threshold for evaluating renal lesions varies depending on the type of DECT platform, though this difference is not statistically significant. Variation can be reduced with a better separation of vascular and nonvascular lesions by normalizing iodine quantification to the aorta.

Volume Computed Tomography Perfusion Imaging: Evaluation of the Significance in Oncologic Follow-up of Metastasizing Renal Cell Carcinoma in the Early Period of Targeted Therapy - Preliminary Results.

INTRODUCTION: The aim of this study was to assess the significance of volume computed tomography perfusion imaging of metastasizing renal cell carcinoma (mRCC) in the early period after the initiation of targeted therapy. METHODS: Blood flow (BF), blood volume, and clearance (CL) were calculated in 10 patients with histologically verified mRCC before and 1 month after initiation of targeted therapy using compartmental analysis algorithms. In addition, the longest diameter of tumor was measured for both time points and compared. Correlation test was performed between perfusion parameters and size changes with time to progression (TTP). RESULTS: Blood flow and CL were significantly lower after therapy initiation, whereas blood volume and the long diameter remained unchanged. Median values before and after 4 weeks of therapy were 144.2 versus 99.4 mL/min/100 mL for BF (P = 0.009) and 115.5 versus 46.8 mL/min/100 mL for CL (P = 0.007). Changes in BF and CL showed very strong negative correlation with TTP (r = -0.838, P = 0.009 and r = -0.826, P = 0.011, respectively). CONCLUSIONS: Our preliminary study results indicate that volume computed tomography perfusion may assess targeted therapy response of mRCC earlier than the currently used Response Evaluation Criteria in Solid Tumors. In addition, changes in BF and CL may be a promising parameter for prediction of TTP.

Clear cell papillary renal cell carcinoma in a transplant kidney.

Large renal cell carcinomas (RCC) arising in allograft kidney transplants are rarely encountered. The distinct RCC sub-type, clear cell papillary RCC (CP-RCC), has mostly been described in non-immunosuppressed patients. Here we report the presentation, management and pathologic diagnosis of a large (11.2 cm, pT2b), multifocal, CP-RCC in a poorly functioning renal allograft of a 63-year-old woman 19 years following kidney transplant. Preoperative angiographic kidney embolization was successfully performed prior to allograft nephrectomy, with an excellent surgical, oncologic and clinical outcome.

Preclinical impact of high dose intermittent antiangiogenic tyrosine kinase inhibitor pazopanib in intrinsically resistant tumor models.

Antiangiogenic tyrosine kinase inhibitors (TKIs) target vascular endothelial growth factor receptors and other receptor tyrosine kinases. As a result of toxicity, the clinical failures or the modest benefits associated with antiangiogenic TKI therapy may be related in some cases to suboptimal drug dosing and scheduling, thereby facilitating resistance. Most antiangiogenic TKIs, including pazopanib, are administered on a continuous daily basis. Here, instead, we evaluated the impact of increasing the dose and administering the drug intermittently. The rationale is that using such protocols, antitumor efficacy could be enhanced by direct tumor cell targeting effects in addition to inhibiting tumor angiogenesis. To test this, we employed two human tumor xenograft models, both of which manifest intrinsic resistance to pazopanib when it is administered continuously: the VHL-wildtype SN12-PM6-1 renal cell carcinoma (RCC) and the metastatic MDA-MB-231/LM2-4 variant breast cancer cell line, when treated as distant metastases. We evaluated four different doses and schedules of pazopanib in the context of primary tumors and advanced metastatic disease, in both models. The RCC model was not converted to drug sensitivity using the intermittent protocol. Using these protocols did not enhance the efficacy when treating primary LM2-4 tumors. However, one of the high-dose intermittent pazopanib protocols increased median survival when treating advanced metastatic disease. In conclusion, these results overall suggest that primary tumors showing sensitivity to continuous pazopanib treatment may predict response to this drug when given at high doses intermittently in the context of advanced metastatic disease, that are otherwise resistant to the conventional protocol.