Cabozantinib Plus Nivolumab in Adult Patients with Advanced or Metastatic Renal Cell Carcinoma: A Retrospective, Non-Interventional Study in a Real-World Cohort/GUARDIANS Project.

INTRODUCTION: Combinations of immune-checkpoint inhibitors (ICIs) are the standard of care (SOC) for treatment-naive metastatic renal cell carcinoma (mRCC) patients. In this multicenter study, we evaluated the RW safety and efficacy of cabozantinib plus nivolumab in mRCC patients. METHODS: Data were retrospectively collected from twelve cancer centers in Germany, Switzerland, and Austria. Patients with advanced or mRCC were eligible. The investigator-based objective response rate (ORR) and progression free survival (PFS) were calculated from the start of the treatment to progression or death. Descriptive statistics and Kaplan-Meier (KM) plots were utilized where appropriate. RESULTS: In total, 96 eligible patients (66.6% male) with a median age of 66.0 years were included. The most common histology was clear-cell RCC (ccRCC) in 63.4% (n = 61). A prior nephrectomy was performed in 60.4% (n = 58). ECOG 0-1 was 68.8% (n = 66). A partial response was documented in 43.8% of patients (n = 42), a stable disease in 32.3% (n = 31), and a progressive disease in 8.3% (n = 8) as the best overall response. Response data were not evaluable in 13.5% (n = 13). The median follow-up time was 12.7 months (95% CI, 10.0-15.3). The PFS rate at 6 months was 89.8% in the overall population (86.8% for ccRCC; 90.0% for non-ccRCC). Adverse events (AEs) were reported in 82.3% (n = 79) for all grades and 41.7% (n = 40) for grades 3-5. Elevated liver enzymes (34.4%), diarrhea (31.3%), and hand-foot syndrome (29.2%) were the three most frequent AEs of any grade and causality. DISCUSSION/CONCLUSIONS: In this real-world cohort of mRCC patients, the application of cabozantinib plus nivolumab was shown to be safe and feasible. Our data support the use of cabozantinib plus nivolumab as a first-line standard therapy in mRCC patients. Major limitations were the retrospective data capture and short follow-up time of our study.

A randomized prospective study: assessment of transient ureteral stenting by mono-J insertion after primary URS and stone extraction (FaST 3).

To compare the outcome of a short-term insertion of a mono-J catheter for 6 h following ureteroscopic stone removal to a conventional double-J catheter. This single-center academic study (Fast Track Stent study 3) evaluated stenting in 108 patients with urinary calculi after ureterorenoscopy. Patients were prospectively randomized into two study arms before primary ureterorenoscopy: (1) mono-J insertion for 6 h after ureterorenoscopy and (2) double-J insertion for 3-5 days after ureterorenoscopy. Study endpoints were stent-related symptoms assessed by an ureteral stent symptom questionnaire (USSQ) and reintervention rates. Stone sizes and location, age, operation duration, BMI, and gender were recorded. Of 67 patients undergoing ureterorenoscopy, 36 patients were analyzed in the double-J arm and 31 patients in the mono-J arm. Mean operation time was 27.5 ± 1.3 min versus 24.0 ± 1.3 min, and stone size was 5.2 mm versus 4.5 mm for mono-J versus double-J, respectively (p = 0.06 and p = 0.15). FaST 3 was terminated early due to a high reintervention rate of 35.5% for the mono-J group and 16.7% for the double-J group (p = 0.27). One day after ureterorenoscopy, USSQ scores were similar between the study arms (Urinary Index: p = 0.09; Pain Index: p = 0.67). However, after 3-5 weeks, the Pain Index was significantly lower in those patients who had a double-J inserted after ureterorenoscopy (p = 0.04). Short-term insertion of mono-J post-ureterorenoscopy results in similar micturition symptoms and pain one day after ureterorenoscopy compared to double-J insertion. The reintervention rate was non-significant between the treatment groups most likely due to the early termination of the study (p = 0.27). Ethics approval/Trail Registration: No. 18-6435, 2018.

An Empirical Study on the Operative Treatment of Symptomatic Urolithiasis in Germany.

PURPOSE: The guidelines of the German, European, and American Urological Associations on urolithiasis advise against general ureteral stenting before and after an uncomplicated ureterorenoscopy (URS). However, German and European guidelines state that stenting prior to URS facilitates stone extraction and reduces intraoperative complications. According to the published literature, German practice seems to deviate from recommendations. This nationwide survey aimed to evaluate the treatment modalities of urolithiasis. METHODS: In November 2018 and March 2019, a total of 199 urological hospital departments in Germany were anonymously surveyed about operative care of symptomatic urolithiasis. The response rate was 72.9%. The survey consisted of 25 questions about diagnostics, surgical technique, and aftercare of the URS. This questionnaire is available in the appendix. RESULTS: A primary URS is performed in ≤10% in 49.6% of the hospitals. In every second urological department (49.7%), the German Diagnosis Related Group (G-DRG) system influences the period of pre-stenting before a secondary URS. After a secondary URS, which is performed in 53.8% of the departments in over 80% of the patients, 14% of the departments omit stenting. The standard for stenting seems to be a 28-cm-long 7 Charrière double-J stent in Germany. CONCLUSION: In Germany, the percentage of primary URS is low, and a ureter stenting is performed in most of the urological departments after URS. Delaying therapy due to economic aspects is the standard in almost half of all urological departments.

Quantifying the Overall Survival Benefit With Early Radical Cystectomy for Patients With Histologically Confirmed T1 Non-muscle-invasive Bladder Cancer.

INTRODUCTION: The objective of this study was to examine the overall survival (OS) in patients diagnosed with high-grade T1 non-muscle-invasive bladder cancer treated with early radical cystectomy versus local treatment of the primary tumor, defined as endoscopic management with or without intravesical chemotherapy or immunotherapy. PATIENTS AND METHODS: We identified 4900 patients with histologically confirmed, clinically non-metastatic high-grade T1 bladder cancer undergoing surgical intervention using the National Cancer Database for the period 2010 to 2015. Multivariable logistic regression was used to examine predictors for the receipt of early radical cystectomy (defined as radical cystectomy within 90 days of diagnosis). We then employed multivariable Cox proportional hazards regression models and Kaplan-Meier curves to evaluate the OS according to surgical treatment (early radical cystectomy vs. local treatment). RESULTS: A minority (23.7%) of patients underwent early radical cystectomy. Independent predictors of undergoing early radical cystectomy included lower age, White race, and lower comorbidity status. The median OS was 74.0 months for patients diagnosed with high-grade T1 bladder cancer. The 1- and 5-year survival rates of patients undergoing early radical cystectomy were 94.8% and 71.0%, whereas they were 85.2% and 52.4%, for patients undergoing initial local treatment, respectively (P < .001). Compared with patients undergoing local treatment, patients undergoing early radical cystectomy had a lower risk of all-cause mortality (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91; P = .002). CONCLUSION: In this cohort of patients presenting with high-grade T1 non-muscle-invasive bladder cancer, we found that early radical cystectomy was associated with an OS benefit compared with initial local treatment.

Low-flow lower body perfusion for spinal protection in a frozen elephant trunk simulation model.

OBJECTIVES: The frozen elephant trunk (FET) procedure using isolated selective cerebral perfusion (SCP) at moderate hypothermia is associated with an increased risk for spinal cord ischaemia. The aim of this study was to evaluate the benefit of a combined selective cerebral and low-flow lower body perfusion (CLBP) in a porcine model. METHODS: Twenty pigs (46 ± 5 kg) were cooled on cardiopulmonary bypass (CPB) to 28°C. After aortic clamping and occlusion of the thoracic segmental arteries (TSAT4-T13), a pressure-controlled SCP (50 mmHg) was established for 90 min. Randomly, in n = 10 animals, an additional lower body perfusion (LBP) was performed with 15 ml/kg/min (CLBP). Regional spinal cord blood flow (SCBF), cerebrospinal fluid pressure (CSFP) and motor-evoked potentials (MEPs) were registered at six time points. The animals were sacrificed after 120 min of weaning from CPB, and the spinal cord was analysed histologically using a schematic scoring system (0 = normal, 8 = total necrosis). RESULTS: Isolated SCP led to an SCBF decrease from 18.5 ± 9.4 to 0.9 ± 1.4 ml/min/100 g in the L1-L5 region (P = 0.005). CLBP preserved an almost physiological lumbar SCBF of 11.3 ± 5.3 ml/min/100 g. CSFP decreased in both groups during cooling and SCP/CLBP to 70-80% and increased during reperfusion to 150%, without showing significant differences between groups. The MEP amplitude decreased in both groups, with certain regional differences: T7-T11. MEP recording revealed a more pronounced amplitude decrease in the CLBP group (52.5 ± 2.0 vs 71.3 ± 0.9%), but MEP amplitudes recovered in both groups (SCP: 73.7 ± 0.5 vs CLBP: 82.6 ± 0.1%). During selective hypothermic perfusion, SCP-treated animals showed significant lower MEP amplitudes, when compared with CLBP-treated animals: 60 ± 9 vs 90 ± 3% (P < 0.001). After weaning, CLBP animals showed a better MEP recovery, especially in the L1-L5 region (99 ± 7 vs 70 ± 13%; P < 0.001). The histological analysis did not show significant differences in the necrosis extension in the thoracic spinal cord. A different situation was seen in the L1-L5 area: all animals with isolated SCP, but only 50% of the CLBP animals presented a score of >5. A higher grade of lumbar ischaemia could be seen after isolated SCP (score: 5.9 ± 0.6 vs 3.6 ± 2.9). CONCLUSION: The prolonged SCP provides an insufficient lumbar spinal cord protection during the FET procedure at 28°C. The use of a low-flow LBP in addition to SCP may reduce functional and structural spinal damage.

Spinal cord ischemia after selective cerebral perfusion in a porcine "frozen elephant trunk" simulation model.

BACKGROUND: The "frozen elephant trunk" procedure (FET) represents the therapy of choice for extended aortic diseases. The aim of our study was to analyze whether 90 minutes of selective cerebral perfusion (SCP) at 28 °C followed by permanent occlusion of the thoracic segmental arteries (TSA) would cause spinal cord ischemia in a porcine model. METHODS: 14 pigs (41 ± 3 kg) were cooled on CPB to 28 °C. After aortic clamping, SCP was established for 90 minutes. Randomly, in 7 animals the TSA were clipped (T4-T13); the TSA of 7 animals remained untouched. After the animals were weaned from CPB, hemodynamic data were registered for 120 minutes. Regional spinal cord blood flow (SCBF) was calculated, and motor-evoked potentials (MEP) were assessed at 6 time points. After sacrifice of the animals, the spinal cord was analyzed histologically by use of a schematic grading system (0 = normal; 8 = total necrosis). RESULTS: During SCP the SCBF was maintained at baseline (5.9 ± 2.4 mL/min/100 g) in the T4-T13 region but showed a decrease (from 8.4 ± 4.3 to 1.3 ± 1.5 mL/min/100 g) in the L1-L5 region. During reperfusion it increased, with two to three times higher values in the nonclipped animals. After 90 minutes of SCP, the MEP reached lower levels in the L1-L5 region of the TSA-clipped animals: 59% ± 7% vs 84 ± 15% (vastus medialis muscle) and 48% ± 6% vs 82% ± 26% (tibialis anterior muscle). The MEP recovered only in the nonclipped group. Higher ischemia rates were seen in the L1-L5 region of the TSA-clipped animals (score: 6.0 ± 0.6 vs 2.5 ± 2.3). CONCLUSIONS: 90 minutes of SCP provided sufficient spinal cord protection during arch replacement at 28 °C. In combination with permanent TSA occlusion, the lumbar spinal cord perfusion may be altered, which causes functional and structural damage.