Salvage lenvatinib/everolimus combination therapy after immune checkpoint inhibitor and VEGFR tyrosine kinase inhibitor for metastatic renal cell carcinoma.

Background: The optimal treatment for metastatic renal cell carcinoma (mRCC) patients who have progressed after both immune checkpoint inhibitor (ICI) and VEGFR tyrosine kinase inhibitor (TKI) remains uncertain. Lenvatinib and everolimus (LE) are frequently used in combination as salvage therapy because of their different antitumor mechanisms, but efficacy and toxicity data in this setting are lacking. Methods: We retrospectively reviewed charts from two academic centers for 71 adult mRCC patients who received LE after prior ICI and TKI exposure. We evaluated patient demographics, histology, International mRCC Database Consortium (IMDC) risk group, treatment history, and toxicity details. Outcomes of interest included objective response rate (ORR), time to treatment failure (TTF), overall survival (OS), ≥grade 3 toxicities, and schedule or dosage changes, which were evaluated using descriptive statistics, chi-square test, Cox proportional hazards model, and the Kaplan-Meier method. Results: The median age was 64 (range 31-84). Most patients had clear cell histology (84.5%) and had undergone nephrectomy (80.3%). IMDC risks were favorable (19.7%), intermediate (int) (66.2%), poor (11.3%), and unknown (2.8%). The average ORR was 26.8%, while the median TTF was 5.5 months (95% confidence interval [CI], 3.5-7.6) and the median OS was 9 months (95% CI, 7.6-12.9). Intermediate and poor IMDC risks were independently associated with a significantly worse TTF compared to favorable risk (hazard ratio (HR), 3.03, 95% CI, 1.18-7.79), as was ≥4L treatment vs. 2L/3L treatment (HR, 2.02, 95% CI, 1.08-3.8). Of the 71 patients, 57.7% had ≥grade 3 adverse events, 60% had treatment interruption, 44.3% had dose reduction, and 21% stopped treatment due to intolerance. Conclusions: LE therapy is feasible but has modest efficacies following ICI/TKI treatment. Patients with favorable risk or treated earlier may have a better treatment response. These observations need to be confirmed in prospective studies.

A multicenter study assessing survival in patients with metastatic renal cell carcinoma receiving immune checkpoint inhibitor therapy with and without cytoreductive nephrectomy.

BACKGROUND: Cytoreductive nephrectomy (CN) for the treatment of metastatic renal cell carcinoma (mRCC) was called into question following the publication of the CARMENA trial. While previous retrospective studies have supported CN alongside targeted therapies, there is minimal research establishing its role in conjunction with immune checkpoint inhibitor (ICI) therapy. OBJECTIVE: To evaluate the association between CN and oncological outcomes in patients with mRCC treated with immunotherapy. MATERIALS AND METHODS: A multicenter retrospective cohort study of patients diagnosed with mRCC between 2000 and 2020 who were treated at the Seattle Cancer Care Alliance and The Ohio State University and who were treated with ICI systemic therapy (ST) at any point in their disease course. Overall survival (OS) was estimated using Kaplan Meier analyses. Multivariable Cox proportional hazards models evaluated associations with mortality. RESULTS: The study cohort consisted of 367 patients (CN+ST n = 232, ST alone n = 135). Among patients undergoing CN, 30 were deferred. Median survivor follow-up was 28.4 months. ICI therapy was first-line in 28.1%, second-line in 17.4%, and third or subsequent line (3L+) in 54.5% of patients. Overall, patients who underwent CN+ST had longer median OS (56.3 months IQR 50.2-79.8) compared to the ST alone group (19.1 months IQR 12.8-23.8). Multivariable analyses demonstrated a 67% reduction in risk of all-cause mortality in patients who received CN+ST vs. ST alone (P < 0.0001). Similar results were noted when first-line ICI therapy recipients were examined as a subgroup. Upfront and deferred CN did not demonstrate significant differences in OS. CONCLUSIONS: CN was independently associated with longer OS in patients with mRCC treated with ICI in any line of therapy. Our data support consideration of CN in well selected patients with mRCC undergoing treatment with ICI.

Changes in skeletal muscle and adipose tissue during cytotoxic chemotherapy for testicular germ cell carcinoma and associations with adverse events.

OBJECTIVES: To quantify changes in body composition during cytotoxic chemotherapy for germ cell carcinoma of the testis (GCT) and evaluate associations between change in skeletal muscle and adipose tissue and chemotherapy-associated adverse events. MATERIALS AND METHODS: This retrospective single-institution study evaluated men with GCT treated with cytotoxic chemotherapy from 2005 to 2018. We measured skeletal muscle index (SMI [cm2/m2]), skeletal muscle density (SMD [Hounsfield Units (HU)]), skeletal muscle gauge (SMG [cm²*HU/m²]), fat mass index (FMI [kg/m2]), visceral adipose index (VAI [cm2/m2]), and subcutaneous adipose index (SAI [cm2/m2]) on axial computed tomography images at the level of the third lumbar vertebra within 75 days before and after chemotherapy. Chemotherapy-associated adverse events (AE) were graded based on the Common Terminology Criteria for Adverse Events (CTCAE v5.0.) Changes in body composition were quantified. Predictors of change in body composition were evaluated with multivariable linear regression. Associations between baseline or change in body composition and AEs were estimated with multivariable logistic regression adjusting for age, comorbidity, performance status, stage, and number/type of chemotherapy cycles. RESULTS: 141 patients (median age, 30 years [IQR 25-39]) including 86 patients (61%) with non-seminomatous GCT were included. Patients received a median of 3 cycles of cisplatin-based chemotherapy, and 124 patients (88%) completed planned chemotherapy. Median observed changes in SMI, SMD, and SMG were -6% (P<0.0001), -2% (P=0.07), and -7% (P<0.0001), respectively, while FMI increased 5.3% (P<0.0001). Overall, 120 patients (85%) experienced at least one AE including one or more ≥grade 3 AE in 57 patients (48%). Decrease in SMI (OR: 0.89, P=0.02), decrease in SMG (OR: 0.88, P=0.01,) and post-chemotherapy SMG (OR: 0.94, P=0.05) were independently associated with higher incidence of AEs, while pre-chemotherapy skeletal muscle parameters and post-chemotherapy SMI and SMD were not associated with AEs (P>0.05 for all). Preoperative adipose tissue or change in adiposity was not associated with incidence of AEs. CONCLUSIONS: In men with GCT receiving cytotoxic chemotherapy, a decrease in skeletal muscle mass and quality during chemotherapy were associated with a higher incidence of chemotherapy-associated AEs. Adipose tissue was not associated with the incidence of AEs.

Ureteral Injuries Secondary to Blunt Abdominal Trauma: A 15-Year Review of Presentation, Management, and Outcomes at a Level 1 Trauma Center.

OBJECTIVE: To report our contemporary experience with ureteral injuries secondary to blunt trauma, with diagnostic methods and management stratified according to injury severity. MATERIALS AND METHODS: We performed a retrospective 15-year study (4/2005-4/2020) at a regional level I trauma center. Patients were categorized as having a partial or complete transection injury. Treatment success was defined as the absence of hydronephrosis or obstruction on follow-up imaging. RESULTS: Eighteen patients suffered 10 partial and 9 complete ureteral transections. All 16 patients who underwent initial evaluation with computed tomography were correctly graded as having partial or complete transections, and there were no missed injuries. Treatment of partial transections included observation (3/9), retrograde double-J stent placement (4/9), and Heineke-Mikulicz pyeloplasty (2/9). At a median follow-up of 9 (IQR 2-59) months, 8/9 (89%) partial transections were treated successfully. Treatment of complete transections included pyeloplasty (3/9), ureteroureterostomy (4/9), and ureteroneocystostomy (1/9). One patient who underwent attempted reconstruction 6 days after trauma required nephrectomy. At a median follow-up of 32 (IQR 4-82) months, 7/8 (89%) reconstructed complete transections were treated successfully. CONCLUSION: Computed tomography with delayed phase imaging is a sensitive test to detect ureteral injuries after blunt trauma, and computed tomography can distinguish between partial and complete transections. Partial transection injuries secondary to blunt trauma may be amenable to ureteral stent placement or close observation in select cases. Good intermediate-term outcomes can be achieved with early surgical intervention in the case of complete transections.

Computed tomography-based volume calculations of renal ischemia predicts post-traumatic renal function after renal infarction injury.

OBJECTIVES: To describe a systematic method to quantify the severity of renal infarction injury and assess its association with post-traumatic renal function after blunt trauma. METHODS: We retrospectively reviewed all patients who suffered an AAST grade IV renal infarction injury without active bleeding secondary to blunt trauma between 1/2010 and 10/2020. Only patients with a pre-traumatic eGFR within 12 months of injury and post-traumatic eGFR within 3-12 months were included. Percentage of renal ischemia was defined as: (ischemic volume/total volume) × 100%. Two radiologists reviewed computed tomography images to determine ischemic and overall cross-sectional areas using the polygon region of interest tool. These areas were multiplied by slice thickness to obtain ischemic and total volumes. Intraclass correlation coefficient was used to assess consistency between radiologists. Linear regression analyses were used to assess the association between percentage of renal ischemia and post-traumatic renal function. RESULTS: Thirty-five of 140 (25.0%) patients met inclusion criteria. The median (IQR) pre-trauma eGFR was 107.7 ml/min/1.73m2 (90.6-121.8), percentage of renal ischemia was 8.4% (2.9-30.1), and decrease in eGFR after trauma was 12.9 ml/min/1.73m2 (0.4-32.6). There was excellent reliability in calculating ischemic volume (ICC = 0.987) and total kidney volume (ICC = 0.995) between two radiologists. When adjusting for pre-traumatic eGFR, patient age, and injury severity score, a 10% increase in ischemic volume was associated with a post-injury eGFR value that was 8.0 ml/min/1.73 m2 (95% CI - 11.2, - 4.7) lower. CONCLUSIONS: CT-based volume calculation of renal ischemia may be utilized to quantify kidney injury and be associated with post-traumatic renal function loss.