Combined inhibition of PI3K and Src kinases demonstrates synergistic therapeutic efficacy in clear-cell renal carcinoma.

Potent inhibitors of PI3K (GDC-0941) and Src (Saracatinib) exhibit as individual agents, excellent oral anticancer activity in preclinical models and have entered phase II clinical trials in various cancers. We found that PI3K and Src kinases are dysregulated in clear cell renal carcinomas (ccRCCs), an aggressive disease without effective targeted therapies. In this study we addressed this challenge by testing GDC-0941 and Saracatinib as either single agents or in combination in ccRCC cell lines, as well as in mouse and PDX models. Our findings demonstrate that combined inhibition of PI3K and Src impedes cell growth and invasion and induces cell death of renal carcinoma cells providing preclinical evidence for a pairwise combination of these anticancer drugs as a rational strategy to improve renal cancer treatment.

Super-selective robot-assisted partial nephrectomy using near-infrared flurorescence versus early-unclamping of the renal artery: results of a prospective matched-pair analysis

ABSTRACT Introduction Super-selective clamping of tumor-specific segmental arteries was developed to eliminate ischemia of the remnant kidney while limiting hemorrhage during partial nephrectomy. The objective is to evaluate the benefice of super-selective clamping on renal functional outcome, compared to early-unclamping of the renal artery. Materials and Methods From March 2015 to July 2016, data from 30 patients undergoing super-selective robot-assisted PN (RAPN) for a solitary tumor by a single surgeon were prospectively collected. Tumor devascularization was assessed using indocyanine green near-infrared fluorescence. A matched-pair analysis with a retrospective cohort undergoing early-unclamping was conducted, adjusting on tumor complexity and preoperative eGFR. Perioperative, oncologic and functional outcomes using DMSA-renal scintigraphy were assessed. Multivariate analysis was performed to identify predictors of postoperative renal function and de novo chronic kidney disease (CKD). Results Super-selective RAPN was successful in 23/30 patients (76.7%), 5 requiring secondary main artery clamping due to persistent tumor fluorescence. Matched-pair analysis showed similar operating time, blood loss, positives margins and complication rates. Super-selective clamping was associated with an improved eGFR variation at discharge (p=0.002), 1-month (p=0.01) and 6-month post-op (-2%vs-16% p=0.001). It also led to a better relative function on scintigraphy (46%vs40% p=0.04) and homolateral eGFR (p=0.04), and fewer upstaging to CKD stage ≥3 (p=0.03). On multivariate analysis, super-selective clamping was a predictor of postoperative renal function. Conclusion Super-selective RAPN leads to an improved preservation of renal function and a reduced risk of de novo CKD stage≥3, while keeping the benefit of main artery clamping on perioperative outcomes.

Super-selective robot-assisted partial nephrectomy using near-infrared flurorescence versus early-unclamping of the renal artery: results of a prospective matched-pair analysis.

INTRODUCTION: Super-selective clamping of tumor-specific segmental arteries was developed to eliminate ischemia of the remnant kidney while limiting hemorrhage during partial nephrectomy. The objective is to evaluate the benefice of super-selective clamping on renal functional outcome, compared to early-unclamping of the renal artery. MATERIALS AND METHODS: From March 2015 to July 2016, data from 30 patients undergoing super-selective robot-assisted PN (RAPN) for a solitary tumor by a single surgeon were prospectively collected. Tumor devascularization was assessed using indocyanine green near-infrared fluorescence. A matched-pair analysis with a retrospective cohort undergoing early-unclamping was conducted, adjusting on tumor complexity and preoperative eGFR. Perioperative, oncologic and functional outcomes using DMSA-renal scintigraphy were assessed. Multivariate analysis was performed to identify predictors of postoperative renal function and de novo chronic kidney disease (CKD). RESULTS: Super-selective RAPN was successful in 23/30 patients (76.7%), 5 requiring secondary main artery clamping due to persistent tumor fluorescence. Matched-pair analysis showed similar operating time, blood loss, positives margins and complication rates. Super-selective clamping was associated with an improved eGFR variation at discharge (p=0.002), 1-month (p=0.01) and 6-month post-op (-2%vs-16% p=0.001). It also led to a better relative function on scintigraphy (46%vs40% p=0.04) and homolateral eGFR (p=0.04), and fewer upstaging to CKD stage ≥3 (p=0.03). On multivariate analysis, super-selective clamping was a predictor of postoperative renal function. CONCLUSION: Super-selective RAPN leads to an improved preservation of renal function and a reduced risk of de novo CKD stage≥3, while keeping the benefit of main artery clamping on perioperative outcomes.

Partial nephrectomy versus ablative therapy for the treatment of renal tumors in an imperative setting.

PURPOSE: To compare partial nephrectomy (PN) and percutaneous ablative therapy (AT) for renal tumor in imperative indication of nephron-sparing technique (NST). MATERIALS AND METHODS: Between 2000 and 2015, 284 consecutive patients with a kidney tumor in an imperative indication of NST were retrospectively included in a multicenter study. PN [open (n = 146), laparoscopic (n = 9), or robotic approach (n = 17)] and AT [radiofrequency ablation (n = 104) or cryoablation (n = 8)] were performed for solitary kidney (n = 146), bilateral tumor (n = 78), or chronic kidney disease (CKD) (n = 60). RESULTS: Patients in the PN group had larger tumors and a higher RENAL score. There were no differences between the two groups with respect to age, reasons for imperative indication, and preoperative eGFR. Patients in the AT group had a higher ASA and CCI. PN had worse outcomes than AT in terms of transfusion rate, length of stay, and complication rate. Local radiological recurrence-free survival was better for PN, but metastatic recurrence was similar. Percentage of eGFR decrease was similar in the two groups. Temporary or permanent dialysis was not significantly different. On multivariate analysis, PN and AT had a similar eGFR change when adjusted for tumor complexity, reason of imperative indication and CCI. CONCLUSION: In imperative indication of nephron-sparing treatment for a kidney tumor, either PN or AT can be proposed. PN offers the ability to manage larger and more complex tumors while providing a better local control and a similar renal function loss.

High Grade Blunt Renal Trauma: Predictors of Surgery and Long-Term Outcomes of Conservative Management. A Prospective Single Center Study.

PURPOSE: The management of major renal trauma has shifted in the last decade in favor of a nonoperative approach. Our level 1 trauma center promotes this approach with the objective of renal function preservation. However, certain situations still require surgery. In this study we analyze predictors of surgery and long-term outcomes after conservative management. MATERIALS AND METHODS: From January 2004 to March 2015 we prospectively collected data from all patients admitted to our institution for high grade blunt renal trauma (grades IV and V). Nonoperative management was considered successful when patients did not undergo surgical exploration, regardless of angioembolization or endoscopic treatment. RESULTS: Of 306 patients with renal trauma 151 presented with major injuries, including 124 grade IV and 27 grade V. Nonoperative management was successful in 110 (89%) cases of grade IV and 14 (52%) cases of grade V lesions. Deceleration mechanism (p=0.03), associated lesions (p=0.001), percentage of devitalized parenchyma (p=0.012), angioembolization (p <0.001), hemodynamic instability (p <0.001) and low hemoglobin (p=0.001) were more frequent in patients treated surgically. On multivariate analysis grade (OR 7.36, p=0.01) and hemodynamic instability (OR 4.18, p=0.04) were the only independent predictors of surgical treatment. Long-term followup of preserved kidneys revealed a remaining 40% and 0% relative renal function after grade IV and V injuries, respectively. Only devascularized parenchyma greater than 25% predicted the decline of long-term renal function. CONCLUSIONS: Nonoperative management can and should be performed safely in cases of grade IV injuries whenever possible, with valuable long-term renal function. It can also be initiated in grade V cases. However, surgeons should consider nephrectomy with the onset of any suspicious symptoms.

External validation of the RENAL nephrometry score in renal tumours treated by partial nephrectomy.

OBJECTIVE: To evaluate the RENAL nephrometry score (RNS) as a predictor of the perioperative outcomes of a partial nephrectomy. PATIENTS AND METHODS: A retrospective review of 177 consecutive patients who were candidates for an open partial nephrectomy (OPN, n = 159) or a laparoscopic partial nephrectomy (LPN, n = 18) from August 2008 to January 2011 was undertaken. Tumour complexity was stratified into three categories: low (4-6), moderate (7-9) and high (10-12) complexity. Complications, and surgical and renal outcomes were recorded and analysed. Predictors of conversion to radical nephrectomy (RN) and complications were assessed using univariate and multivariate logistic regression. Multiple linear regression was used to evaluate the prediction of postoperative estimated glomerular filtration rate (eGFR) and warm ischaemia time (WIT). RESULTS: The median RNS was 7 (interquartile range 6-9). Tumour complexity was assessed as low in 72 (40.6%), moderate in 87 (49.2%) and high in 18 patients (10.2%). There were no significant differences among the three groups with respect to demographic characteristics, operating time, estimated blood loss, transfusion, length of stay, complications and positive surgical margins. Conversion to RN occurred in 29 patients (16.3%). RNS was significantly associated with an increased risk of conversion to RN (odds ratio [OR] = 3.5, P = 0.01 and OR = 6.7, P = 0.005, respectively, for moderate vs low, and high vs low complexity groups). On multivariate analysis, RNS was the only independent predictor of WIT (P = 0.03) and conversion to RN (P = 0.008), but failed to predict postoperative eGFR (P = 0.84) and the occurrence of major complications (P = 0.91). CONCLUSIONS: In the present series, RNS predicted an increased risk of conversion to RN and prolonged WIT. RNS was not a predictor of complications and postoperative renal function.

High-grade renal injury: non-operative management of urinary extravasation and prediction of long-term outcomes.

OBJECTIVE: To predict the outcomes of a non-operative approach to managing urinary extravasation after blunt renal trauma. PATIENTS AND METHODS: A prospective observational study was conducted between January 2004 and October 2011. First-line non-operative management was proposed for 99 patients presenting with a grade IV blunt renal injury according to the revised American Association for the Surgery of Trauma (AAST) classification. Among them, 72 patients presented with a urinary extravasation. Management and outcomes were recorded and compared between patients presenting and those who did not present with urinary leakage. Relative postoperative renal function was assessed 6 months after the trauma using dimercapto-succinic acid renal scintigraphy. Predictors of the need for endoscopic or surgical management and long-term renal function were evaluated on multivariate analysis. RESULTS: Among patients with urinary leakage, endoscopic ureteric stent placement and open surgery were required in 37% and 15%, respectively. On multivariate analysis, fever of >38.5 °C and ureteric clot obstruction were independent predictors of the need for ureteric stent placement. The only predictor of open surgery was the percentage of devitalised parenchyma. Long-term renal function loss was correlated to the percentage of devitalised parenchyma and associated visceral lesions. Urinary extravasation did not predict surgical intervention or long-term renal function loss. CONCLUSIONS: Urinary extravasation after blunt renal trauma can be successfully managed conservatively and does not predict long-term decreased renal function or surgery requirement. A devascularised parenchyma volume of >25% predicts a higher rate of surgery and poorer renal function.

Long-term renal function assessment with dimercapto-succinic acid scintigraphy after conservative treatment of major renal trauma.

PURPOSE: The management of high grade blunt renal injury has evolved with time to become increasingly conservative with the ultimate objective of renal preservation. We evaluated relative renal function with dimercapto-succinic acid renal scintigraphy 6 months after major renal trauma (grade IV or V). MATERIALS AND METHODS: This prospective observational study was done between January 2004 and April 2010. All patients who presented with grade IV or V renal trauma and were treated conservatively were included in analysis. Patient and trauma characteristics, and initial management were recorded. Relative renal function was evaluated by dimercapto-succinic acid renal scintigraphy 6 months after trauma. RESULTS: A total of 88 patients were included in the study. Conservative management was possible in 79 patients (90%), including 69 and 10 with grade IV and V trauma, respectively. Dimercapto-succinic acid renal scintigraphy was done at 6 months for 22 patients (28%). Mean relative renal function for grade IV and V injuries was 39% and 11%, respectively (p=0.0041). The percent of devascularized parenchyma (p=0.0033) and the vascular subtype of grade IV injuries (p=0.0194) also correlated with decreased renal function. No complication or de novo arterial hypertension was noted. CONCLUSIONS: Conservative treatment achieves the objective of renal function preservation for grade IV lesions. Grade V and specific subtypes of grade IV injury have a poor functional outcome. Further study must be performed to determine which patients will benefit from conservative treatment vs early nephrectomy to avoid a longer hospital stay and useless procedures.