Localized Renal Cell Carcinoma Research Articles

A Bosniak III Cyst Unmasking Tubulocystic Renal Cell Carcinoma in an Adolescent: Management with Selective Arterial Clamping and Robotic Enucleation

The Bosniak classification of renal cysts aims to provide a probabilistic risk assessment indicating the likelihood of malignancy from imaging findings. Originally designed to classify adult renal cysts based on computed tomography findings, the Bosniak classification has been extended to pediatric patients, with some adjustments made with the aim of accommodating magnetic resonance imaging (MRI) and ultrasonography (US). Bosniak IV lesions are rare in adolescents, indicating localized renal cell carcinoma and requiring surgical intervention. In contrast, Bosniak III lesions can be treated conservatively, although there is a lack of specific guidelines on their management. We present a case of a 14-year-old boy with a Bosniak III lesion, which was incidentally detected during the US evaluation of a left varicocele. After a 12-month follow-up, MRI revealed progression to a Bosniak IV cyst. Robot-assisted tumor enucleation was performed with selective artery clamping when the patient was 15. Histopathology showed tubulocystic renal cell carcinoma without adverse features. Immunocytochemistry supported a favorable prognosis of this rare tumor (<1% of renal tumor), thus obviating the need for adjuvant treatment. At the 18-month follow-up, no recurrence or distant metastasis were observed. This case highlights the importance of an aggressive treatment in persistent Bosniak III and Bosniak IV renal cysts in children and adolescents and the necessity to offer a nephron-sparing surgery.

SPP1 expression indicates outcome of immunotherapy plus tyrosine kinase inhibition in advanced renal cell carcinoma

ABSTRACT Clinical guidelines have recently advised combination therapy involving immunotherapy (IO) and tyrosine kinase inhibitors (TKI) as the first-line therapy approach for advanced renal cell carcinoma (RCC). Nevertheless, there is currently no available biomarker that can effectively distinguish the progression-free survival (PFS). RNA-sequencing and immunohistochemistry were conducted on our cohort of metastatic RCC patients, namely ZS-MRCC, who received combination therapy consisting of IO and TKI. We further applied RNA-sequencing, immunohistochemistry, and flow cytometry to examine the immune cell infiltration and functionality inside the tumor microenvironment of high-risk localized RCC samples. SPP1 expression was significantly higher in non-responders to IO-TKI therapy. Elevated levels of SPP1 were associated with poor PFS in both the ZS-MRCC cohort (HR = 2.73, p = .018) and validated in the JAVELIN Renal 101 cohort (HR = 1.61, p = .004). By multivariate Cox analysis, SPP1 was identified as a significant independent prognosticator. Furthermore, there existed a negative correlation between elevated levels of SPP1 and the presence of GZMB+CD8+ T cells (Spearman’s ρ= −0.48, p < .001). Conversely, SPP1 expression is associated with T cell exhaustion markers. A significant increase in the abundance of Tregs was observed in tumors with high levels of SPP1. Additionally, a machine-learning-based model was constructed to predict the benefit of IO-TKI treatment. High SPP1 is associated with therapeutic resistance and unfavorable PFS in IO-TKI therapy. SPP1 expression have also been observed to be indicative of malfunction and exhaustion in T cells. Increased SPP1 expression has the potential to serve as a potential biomarker for treatment selection of metastatic RCC.

Partial Versus Radical Nephrectomy: Comparison of Postoperative Complications and Contribution to Mortality

Background: Partial nephrectomy is the preferred treatment method for certain kidney tumors owing to its nephron-preserving benefit. We aimed to compare the occurrence and importance of complications after radical (RN) or partial (PN) nephrectomy for localized renal cell carcinoma (RCC) and contribution to patient mortality. Methods: All RCC cases were extracted from the National Surgical Quality Improvement Program between 2005 and 2017. All-cause mortality was the primary endpoint that defined a failure to rescue (FTR) after the occurrences of complications. Propensity score matching (PSM) was performed to adjust for confounding variables between the 2 groups. The exclusion criteria included patients on dialysis, those with distant metastases, and those with concurrent procedures. Null hypotheses were rejected when P-values were &lt; .05. Results: The database included 24,830 patients, with 22,015 in the RN group and 2815 in the PN. After PSM, 2226 patients after PN were matched 1:1 to an equal number of patients who underwent RN. Overall, postoperative complications occurred in 20.5% after RN, more frequent than 15.9% after PN (P &lt; .001). While the mortality rates were similar, patients were more likely to experience blood transfusion and reintubation, as well as longer hospital stay after RN, while they were likely to have more infectious complications, including abdominal abscess, and more likely to return to the operating room after PN. In both groups, cardiac and respiratory complications were associated with FTR, leading to mortality. Excessive bleeding (requiring transfusion) was also a significant cause of death after RN but not after PN. Conclusion: When planning PN or RN, patients should be counseled on the risks of their selective procedure and the potential increased mortality risk with certain complications. These risks should be weighed against the benefit of those cancer surgeries.

Robot-assisted surgery of renal cell carcinoma in comorbid and frail patients

BACKGROUND: Renal cell carcinoma is predominantly observed in elderly patients. Many of them have multiple comorbidities, which can limit the feasibility of surgical treatment. The search for an optimal approach of radical treatment for comorbid and frail patients remains a current challenge. AIM: To evaluate the perioperative outcomes of robot-assisted partial nephrectomy and radical nephrectomy in comorbid and frail patients with renal cell carcinoma. MATERIALS AND METHODS: At the Almazov National Medical Research Centre we retrospectively studied the results of 118 comorbid and frail patients who underwent robot-assisted surgeries for localized renal cell carcinoma from 2012 to 2022. Mean age of men was 65.7 ± 11.4 years, and women was 61.3 ± 13.1 years. Comorbidity was assessed using the Charlson Comorbidity Index (CCI). Frailty was determined using a modified Frailty index (mFI-11). Robot-assisted partial nephrectomy and radical nephrectomy were perfomed by single experienced robotic surgeon. Perioperative functional outcomes were assessed. Renal function was evaluated based on glomerular filtration rate (GFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula before surgery and at 1.3, and 6 months after surgery. RESULTS: Among 118 patients, 71 (60.2%) underwent robot-assisted partial nephrectomy, while 47 (39.8%) underwent radical nephrectomy. Postoperative complications occurred in 15 (12.7%) of patients for robot-assisted surgeries. There were no positive surgical margins. Mortality in the early postoperative period amounted to 1.7% and was associated with the development of acute cardiovascular failure. CONCLUSIONS: Robot-assisted partial nephrectomy and radical nephrectomy for renal cell carcinoma in comorbid and “fragile” patients — the safest and optimal method of treatment, accompanied by minimal perioperative complications and mortality.

Abstract 5151: High serum kidney injury marker-1 and high baseline tumor PD-L1 protein expression levels are independently associated with treatment effect in adjuvant nivolumab plus ipilimumab vs placebo in localized clear cell renal cell carcinoma

Abstract Introduction: CheckMate 914 (CM-914) Part A is a double-blind, phase III randomized trial of the Nivolumab (NIVO) plus Ipilimumab (IPI) vs placebo (PBO) in localized ccRCC. Our prior report from this study suggested a disease-free survival (DFS) benefit for NIVO+IPI among patients with Fuhrman grade 4, TNM stages PT2a and PT4, or sarcomatoid features, although the sample size was limited. It is known that high circulating KIM-1 is associated with worse DFS after nephrectomy. In this exploratory post hoc analysis, we investigated whether high KIM-1 may help identify a subset of patients who benefit from adjuvant NIVO+IPI. Methods: Patients (n=816) with RCC after nephrectomy were randomized in CM-914 Part A to receive NIVO+IPI or PBO as previously described. Assessment of KIM-1 levels was performed using enzyme linked immunoassay (ELISA) on pre-treatment (n=584) and matched on-treatment blood samples (n=584). We used pre-treatment tumor samples to assess PD-L1% tumor cell expression (%TC) in an PD-L1 IHC 28-8 pharm Dx assay. The association between biomarkers and DFS outcomes was investigated by Kaplan-Meier (KM) and Cox proportional hazards analysis. Results: Median baseline serum KIM-1 level was 102 (9.9 - 1055.7) pg/mL. Serum KIM-1 levels were higher in males vs females, ≥65 yrs vs &amp;lt;65 yrs, Asian vs white patients, and patients with partial vs radical nephrectomy. In the PBO arm, subjects with highest quartile of pre-treatment KIM-1 had significantly worse DFS than those from the three lower quartiles. In contrast, this DFS risk among the subjects within the highest KIM-1 quartile was mitigated with NIVO+IPI treatment. Among patients within the highest quartile of pre-treatment KIM-1, there was trend for better DFS for NIVO+IPI versus PBO, HR=0.6 (0.34-1.04). Increase in KIM-1 during study therapy was positively associated with higher DFS rate in both arms. Multivariable analysis showed that PD-L1 %TC was predictive at predefined PD-L1 cutoffs (&amp;gt;=1%, &amp;gt;=5%, and &amp;gt;=10%), associating with improved DFS compared to placebo. Subjects with high PD-L1 expression had a DFS benefit from NIVO+IPI independent of KIM-1. Conclusion: Circulating KIM-1 and tumor PD-L1 expression may enrich for benefit from IO therapy in adjuvant ccRCC and hence holds promise for informing risk stratification and patient inclusion in neoadjuvant or adjuvant clinical trials. Citation Format: Sai Vikram Vemula, Wenxin Xu, Yu Wang, Xiaowen Liu, Jorge Ruiz de Somocurcio, David McDermott, Jun Li, Rupal Bhatt, Chung-Wei Lee, Burcin Simsek, Saurabh Gupta, Robert Motzer. High serum kidney injury marker-1 and high baseline tumor PD-L1 protein expression levels are independently associated with treatment effect in adjuvant nivolumab plus ipilimumab vs placebo in localized clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5151.

Effect of Annexin A2 on prognosis and sensitivity to immune checkpoint plus tyrosine kinase inhibition in metastatic renal cell carcinoma

BackgroundImmunotherapy (IO) plus tyrosine kinase inhibitor (TKI) therapy is the first-line recommendation for advanced renal cell carcinoma (RCC), but no biomarker has been approved for it. Annexin A2 (ANXA2) can induce immune escape in tumors.MethodsTwo independent cohorts of advanced RCC treated by IO + TKI were utilized for survival analysis (ZS-MRCC, n = 45; Javelin-101, n = 726). ANXA2 expression was determined by RNA-sequencing. The impact of ANXA2 on the tumor microenvironment was assessed by RNA-sequencing, flow cytometry and immunohistochemistry in two localized RCC datasets (ZS-HRRCC, n = 40; TCGA-KIRC, n = 530).ResultsANXA2 was upregulated in non-responders of IO + TKI therapy (p = 0.027). High-ANXA2 group showed poor progression-free survival (PFS) in both the ZS-MRCC cohort (HR, 2.348; 95% CI 1.084–5.085; P = 0.025) and the Javelin-101 cohort (HR, 1.472; 95% CI 1.043–2.077; P = 0.027). Multivariate Cox regression determined ANXA2 as an independent prognostic factor (HR, 2.619; 95% CI 1.194–5.746; P = 0.016). High-ANXA2 was correlated with decreased proportion of granzyme B+ CD8+ T cells (Spearman’s ρ = − 0.40, P = 0.01), and increased TIM-3+ (Spearman’s ρ = 0.43, P < 0.001) and CTLA4+ (Spearman’s ρ = 0.49, P < 0.001) tumor-infiltrating lymphocytes. A random forest (RF) score was further build by integrating ANXA2 and immune genes, which stratified patients who would benefit from IO + TKI therapy (low-RF score, IO + TKI vs TKI, HR = 0.453, 95% CI 0.328–0.626; high-RF score, IO + TKI vs TKI, HR = 0.877, 95% CI 0.661–1.165; interaction P = 0.003).ConclusionsUpregulated ANXA2 was associated with poor PFS and therapeutic resistance in RCC treated by IO + TKI therapy, and related with T cell exhaustion. The integrated RF score could stratify patients who would benefit from IO + TKI therapy.

Humoral complementomics – exploration of noninvasive complement biomarkers as predictors of renal cancer progression

ABSTRACT Despite the progress of anti-cancer treatment, the prognosis of many patients with solid tumors is still dismal. Reliable noninvasive biomarkers are needed to predict patient survival and therapy response. Here, we propose a Humoral Complementomics approach: a work-up of assays to comprehensively evaluate complement proteins, activation fragments, and autoantibodies targeting complement proteins in plasma, which we correlated with the intratumoral complement activation, and/or local production, focusing on localized and metastatic clear cell renal cell carcinoma (ccRCC). In two prospective ccRCC cohorts, plasma C2, C5, Factor D and properdin were elevated compared to healthy controls, reflecting an inflammatory phenotype that correlated with plasma calprotectin levels but did not associate with CRP or with patient prognosis. Conversely, autoantibodies against the complement C3 and the reduced form of FH (a tumor neo-epitope reported in lung cancer) correlated with a favorable outcome. Our findings pointed to a specific group of patients with elevated plasma C4d and C1s-C1INH complexes, indicating the initiation of the classical pathway, along with elevated Ba and Bb, indicating alternative pathway activation. Boostrapped Lasso regularized Cox regression revealed that the most predictive complement biomarkers were elevated plasma C4d and Bb levels at the time of surgery, which correlated with poor prognosis. In conclusion, we propose Humoral Complementomics as an unbiased approach to study the global state of the complement system in any pathological plasma sample and disease context. Its implementation for ccRCC revealed that elevated C4d and Bb in plasma are promising prognostic biomarkers, correlating with shorter progression-free survival.

Risk factors of recurrence after robot-assisted laparoscopic partial nephrectomy for solitary localized renal cell carcinoma

To evaluate the recurrence rate and risk factors of recurrence after robot-assisted laparoscopic partial nephrectomy for solitary renal cell carcinoma (RCC). A total of 1265 cases of initial solitary localized RCC were analyzed. The baseline characteristics, complexity (REANL nephrometry score), intra- and peri-operative outcomes, and recurrence were evaluated. Logistic regression was performed to evaluate the factors affecting recurrence after RAPN for solitary localized RCC. Recurrence after robot-assisted partial nephrectomy (RAPN) occurred in 29 patients (2.29%). The median follow-up was 36.0 months. The N domain (nearness to collecting system/sinus) (odd ratio (OR) 3.517, 95% confidence interval (CI) 1.557–7.945, p = 0.002), operation time (OR 1.005, 95% CI 1.001–1.010, p = 0.013), and perioperative transfusion (OR 5.450, 95% CI 1.197–24.816, p = 0.028) affected recurrence. Distant metastasis among patients with recurrence was significantly associated with nearness to the collecting system/sinus (OR 2.982, 95% CI 1.162–7.656, p = 0.023) and distance between the mass and collecting system/sinus (OR 0.758, 95% CI 0.594–0.967, p = 0.026). Nearness to the collecting system/sinus, operation time, and perioperative transfusion affect recurrence after RAPN for solitary localized RCC. Moreover, the proximity to the collecting system/sinus and distance between the mass and collecting system/sinus were significantly related to distant metastasis after RAPN.

KIDNEY-PAGER: analysis of circulating tumor DNA as a biomarker in renal cancer - an observational trial. Study protocol.

Management of localized renal cell carcinoma (RCC) is challenged by inaccurate methods to assess the risk of recurrence and deferred detection of relapse and residual disease after radical or partial nephrectomy. Circulating tumor DNA (ctDNA) has been proposed as a potential biomarker in RCC. Conduction of an observational study to evaluate the validity of ctDNA as a biomarker of the risk of recurrence and subclinical residual disease to improve postoperative surveillance. Urine and blood will be prospectively collected before and after surgery of the primary tumor from up to 500 patients until 5 years of follow-up. ctDNA analysis will be performed using shallow whole genome sequencing and cell-free methylated DNA immunoprecipitation sequencing. ctDNA levels in plasma and urine will be correlated to oncological outcomes. Residual blood and urine as well as tissue biopsies will be biobanked for future research. Results will pave the way for future ctDNA-guided clinical trials aiming to improve RCC management.

The Role of Targeted Radiation Therapy in the Treatment of Renal Cell Carcinoma

Over the past decade, innovations in radiation technology and technique have led to the increasing use of stereotactic body radiotherapy (SBRT) for the treatment of renal cell carcinoma. We provide an overview of SBRT and review the role of SBRT for treatment of localized and oligometastatic RCC. We also provide a brief overview of the current state of knowledge with regards to the combination of SBRT and novel systemic agents commonly used in the treatment of RCC. As outcomes from trials investigating SBRT mature, showing excellent efficacy and tolerability, it is likely that SBRT use will continue to increase in future years.

Transperitoneal vs retroperitoneal laparoscopic radical nephrectomy: a double-arm, parallel-group randomized clinical trial

ObjectiveTo compare the outcomes of patients undergoing Retroperitoneal laparoscopic Radical nephrectomy (RLRN) and Transperitoneal laparoscopic Radical nephrectomy (TLRN).MethodsA total of 120 patients with localized renal cell carcinoma were randomized into either RLRN or TLRN group. Mainly by comparing the patient perioperative related data, surgical specimen integrity, pathological results and tumor results.ResultsEach group comprised 60 patients. The two group were equivalent in terms of perioperative and pathological outcomes. The mean integrity score was significantly lower in the RLRN group than TLRN group. With a median follow-up of 36.4 months after the operation, Kaplan–Meier survival analysis showed no significant difference between RLRN and TLRN in overall survival (89.8% vs. 88.5%; P = 0.898), recurrence-free survival (77.9% vs. 87.7%; P = 0.180), and cancer-specific survival (91.4% vs. 98.3%; P = 0.153). In clinical T2 subgroup, the recurrence rate and recurrence-free survival in the RLRN group was significantly worse than that in the TLRN group (43.2% vs. 76.7%, P = 0.046). Univariate and multivariate COX regression analysis showed that RLRN (HR: 3.35; 95%CI: 1.12–10.03; P = 0.030), male (HR: 4.01; 95%CI: 1.07–14.99; P = 0.039) and tumor size (HR: 1.23; 95%CI: 1.01–1.51; P = 0.042) were independent risk factor for recurrence-free survival.ConclusionsOur study showed that although RLRN versus TLRN had roughly similar efficacy, TLRN outperformed RLRN in terms of surgical specimen integrity. TLRN was also significantly better than RLRN in controlling tumor recurrence for clinical T2 and above cases.Trial registrationChinese Clinical Trial Registry (https://www.chictr.org.cn/showproj.html?proj=24400), identifier: ChiCTR1800014431, date: 13/01/2018.

A phase II study of neoadjuvant tislelizumab and axitinib in patients with locally advanced non-metastatic clear cell renal cell carcinoma (accRCC).

420 Background: PD-1/PD-L1 combined with vascular endothelial growth factor (VEGF) inhibitors improves survival in patients with advanced renal cell carcinoma (RCC), but the role of perioperative application in patients with localized RCC has not been established. In this phase II trial, we investigate the safety and role of tislelizumab and axitinib in downsizing tumors in patients with non-metastatic clear cell RCC prior to surgical resection. Methods: In this investigator-initiated study, 20 patients with high-risk non-metastatic ccRCC (clinical stage T2a-4 and/or N1, M0 lesions) were enrolled to receive 12 weeks of neoadjuvant ticelizumab and axitinib prior to nephrectomy. The primary endpoint was the objective response rate (complete and partial response) after neoadjuvant treatment according to RECIST v1.1. Secondary endpoints were disease-free survival (DFS), overall survival (OS), surgical outcome and safety. Results: By September 2023,13 eligible pts were enrolled. 11 pts have completed neoadjuvant therapy, with a median age of 60 (range 45-73) years, among whom 9 pts underwent surgery as planned without any delay. One patient progressed during treatment and received further systemic therapy. In 9 pts evaluable for efficacy, the investigator-assessed confirmed ORR was 55.5%. The median reduction of primary renal tumor size was 26.2% (range 12.5-45%). Pathologic results showed that one patient (11.1%) achieved a complete response (CR) by RECIST 1.1 and four patients achieved a partial response (PR). One patient who was considered unresectable became resectable at the end of treatment. Two patients were converted from radical to partial nephrectomy. The most common neoadjuvant therapy-related AEs were hematologic toxicity, hypothyroidism, nausea, vomiting, decreased appetite, fatigue, diarrhea, and elevated ALT/AST. There were no Gr4/Gr5 TRAEs. No direct intraoperative complications and no drug-related surgical complications postoperatively. Conclusions: As a neoadjuvant therapy for accRCC, the combination of tislelizumab and axitinib has clinical efficacy and a manageable safety profile. Clinical trial information: NCT05172440 .

Comparison of financial toxicity among patients with non-metastatic versus metastatic renal cell carcinoma.

408 Background: Little is known about the financial impact of renal cell carcinoma (RCC). We sought to ascertain real world data on financial implications and how financial toxicity (FT) impacts quality of life in patients with localized RCC versus patients with metastatic RCC. Methods: An online survey was conducted by the Kidney Cancer Research Alliance (KCCure), a non-profit patient advocacy organization, from 7/22 to 9/22. The survey included questions about costs and financial concerns and the COST questionnaire. Pearson’s correlation (r) and Kendal’s tau test were used to analyze the COST questionnaire, financial burden and hardship. Results: Out of 1062 responders 623 had localized RCC. Out of these patients 395 did not recur and 204 were willing to answer questions related to cost and financial hardship. 289 responders had metastatic disease and were on systemic therapy and 177 pts answered the COST questionnaire. In localized disease 28% reported that their diagnosis has not reduced their income, in 26% the diagnosis had reduced their income very much.31% experienced insurance denials for imaging, 30% faced delays in care due to pre-approval requirements, 45% faced high out-of-pocket costs for medical care. 24% of patients reported taking a hardship withdrawal from a retirement account, 28% stopped funding or lowered contributions to an existing retirement account, 20% borrowed from friends or family. In metastatic patients 14% reported difficulties to pay their premiums. 28% reported that their medical situation has not reduced their income and 26% claimed that their disease reduced their income very much. 36% reported high out of pocket costs are a barrier to care. 44% have received financial support through a manufacturer or a foundation. Median COST score in non-metastatic RCC was 32 (range 19-44)) and was significantly correlated to age, NCCN distress score, risk of recurrence and supplement intake (p &lt; 0.05). Metastatic patients had a significantly higher median COST score of 22 (range 4-36)) that was also correlated to age, NCCN distress score, time since diagnosis and supplement intake (p &lt; 0.05). Conclusions: RCC imposes financial hardship on patients. Younger patients with a higher NCCN distress score and a shorter time since diagnosis are more likely to suffer financial hardships. Patients are willing to pay for supplements. Financial counseling should be considered in these patient subgroups regardless of stage. [Table: see text]

Comparative analysis of outcomes of neoadjuvant and adjuvant systemic therapy in non-metastatic renal cell carcinoma: A propensity score-matched analysis from the INMARC registry.

414 Background: Receipt of adjuvant therapy has become a standard of care for management of high risk localized renal cell carcinoma (RCC), with emerging literature demonstrating longer disease-free survival. Neoadjuvant approaches have been utilized investigationally to facilitate complete surgical resections in high risk and complex renal masses. We sought to evaluate outcomes of patients treated with neoadjuvant or adjuvant therapy in non-metastatic RCC utilizing a propensity score model. Methods: We queried the INMARC database for patients with localized surgically treated RCC who underwent systemic neoadjuvant or adjuvant therapy. Neoadjuvant therapy was defined as presurgical therapy given in the setting of localized disease and adjuvant therapy as systemic therapy given postoperatively in the absence of documented metastases. Patients with metastases at time of diagnosis were excluded from the analysis. A propensity score match (PSM) model in a 1:3 ratio was conducted within a caliper width of 0.1 including: age, sex, hypertension, Charlson Comorbidity Index, tumor size, tumor necrosis, stage, surgical margin, tumor grade and type of surgery [radical vs. partial nephrectomy]. Primary outcome was all-cause mortality (ACM), and secondary outcome was cancer-specific mortality (CSM). Multivariable analysis (MVA) via Cox regression was fitted for the outcomes of interest. Kaplan-Meier analysis (KMA) for overall (OS), cancer specific survival (CSS) was conducted for 5-year survival assessment. Results: After PSM 293 patients were analyzed [adjuvant n=203, (69.2%), 109 targeted therapy (TT) vs. 94 immunotherapy; neoadjuvant n=90, (30.7%), 59 TT vs. 31 immunotherapy]; median follow up was 50 (IQR 20-76) months from surgery . MVA revealed adjuvant vs. neoadjuvant (HR 1.98, p=0.007) and positive margin (HR 2.01, p=0.046) to be associated with increased risk of ACM; immunotherapy vs. TT (HR 0.47, p=0.001) was associated with a decreased risk. MVA for CSM revealed that adjuvant vs. neoadjuvant (HR 2.18, p=0.016) and positive margin (HR 2.41, p=0.028) were associated with increased risk of CSM, while immunotherapy vs. TT (HR 0.35, p&lt;0.001) was associated with decreased risk. KMA comparing neoadjuvant vs. adjuvant 5-year OS was 80.4% vs. 64.8% (p=0.04), while CSS was 88.1% vs. 76.2% (p=0.03). Conclusions: In a comparison of patients with localized RCC who underwent adjuvant or neoadjuvant systemic therapy, receipt of neoadjuvant therapy was associated with superior survival outcomes. These findings are hypothesis generating and call for consideration for a clinical trial to compare outcomes of adjuvant vs. neoadjuvant therapy in high-risk localized RCC.

Adjuvant nivolumab monotherapy vs placebo for localized renal cell carcinoma at high risk of relapse after nephrectomy: Results from Part B of the randomized, phase 3 CheckMate 914 trial.

LBA358 Background: CheckMate 914 (NCT03138512) is a phase 3, randomized, double-blind, multicenter, 2-part trial evaluating adjuvant NIVO plus ipilimumab (NIVO+IPI) vs PBO (Part A) or adjuvant NIVO monotherapy vs PBO (and NIVO monotherapy vs NIVO+IPI to assess the contribution of components; Part B) designed in sequence in mutually exclusive patients (pts) with localized RCC at high risk of post-nephrectomy relapse. Results from Part A at 37.0 months median study follow-up (range, 15.4–58.0) showed no disease-free survival (DFS) benefit for adjuvant NIVO+IPI vs PBO in the overall study population ( Lancet 2023;401:821–832). We report primary analyses for Part B of the trial. Methods: Pts eligible for CheckMate 914 included those undergoing radical or partial nephrectomy between 4 and 12 weeks before randomization with negative surgical margins; with predominantly clear cell histology (with or without sarcomatoid features); pathological TNM stage T2a (grade [G] 3/4) N0M0, T2b-T4 (any G) N0M0, or any T (any G) N1M0; and no evidence of residual disease or distant metastases (M0). Pts in Part B were randomized 2:1:1 to NIVO (240 mg every 2 weeks × 12) plus IPI PBO, NIVO (240 mg every 2 weeks × 12) plus IPI (1 mg/kg every 6 weeks × 4), or matching PBO, and stratified by pathological TNM stage and type of nephrectomy. Treatment was planned for 24 weeks (approximately 5.5 months) or until disease recurrence/unacceptable toxicity. The primary endpoint for Part B is DFS per blinded independent central review (BICR) for NIVO monotherapy vs PBO. Secondary endpoints include safety of NIVO monotherapy. Results: In total,619 pts were randomized to NIVO monotherapy (n = 411) or PBO (n = 208). With 27.0 months median study follow-up (range, 18.0–42.4), the primary efficacy endpoint of DFS per BICR with NIVO monotherapy vs PBO was not met (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.62–1.21; P = 0.3962). Median DFS was not reached in either arm; DFS probabilities were 83.3% vs 78.2% (at 12 months) and 78.4% vs 75.4% (at 18 months), respectively. The HR for DFS per investigator was 0.80 (95% CI, 0.58–1.12; P = 0.1936). Median (Q1, Q3) treatment duration was 5.1 (5.1, 5.3) months with NIVO monotherapy and 5.1 (5.1, 5.2) months with PBO. Any-grade treatment-related adverse events (AEs) were reported in 72.5% vs 51.7% of pts treated with NIVO monotherapy (n = 408) vs PBO (n = 207), and grade 3–4 treatment-related AEs were reported in 8.8% vs 1.9%, respectively. Any-grade treatment-related AEs led to discontinuation in 9.6% and 1.0% of pts in the NIVO monotherapy and PBO arms, respectively. Conclusions: Part B of the CheckMate 914 trial of NIVO monotherapy vs PBO in pts with localized RCC at high risk of relapse after nephrectomy did not meet the primary endpoint of DFS. Safety of NIVO monotherapy was consistent with its known profile in advanced RCC. Clinical trial information: NCT03138512 .

Paradigm Shifting Research: Key Studies in Urologic Oncology.

Genitourinary malignancies have a substantial impact on men and women in the USA as they include three of the ten most common cancers (prostate, renal, and bladder). Other urinary tract cancers are less common (testis and penile) but still have profound treatment implications related to potential deficits in sexual, urinary, and reproductive function. Evidenced-based practice remains the cornerstone of treatment for urologic malignancies. The authors reviewed the literature in consideration of the four top articles influencing clinical practice in the prior calendar year, 2022. The PROTECT trial demonstrates favorable 15-years outcomes for active monitoring of localized prostate cancer. The SEMS trial establishes retroperitoneal lymph node dissection as a viable option for patients with seminoma of the testis with limited retroperitoneal lymph node metastases. CheckMate 274 supports adjuvant immunotherapy following radical cystectomy for muscle-invasive bladder cancer with a high risk of recurrence. Data reported from the IROCK consortium reinforce stereotactic ablative radiotherapy as an option for localized renal cell carcinoma. The care for patients with urologic cancers has been greatly improved through advances in surgical, medical, and radiation oncologic treatments realized through prospective randomized clinical trials and large multicenter collaborative groups.

Tumor characteristics associated with detectable circulating tumor DNA preoperatively in patients with renal masses suspicious for RCC.

461 Background: Understanding the specific tumor characteristics associated with detectable ctDNA in the blood of patients with renal cell carcinoma (RCC) is critical to informing future studies seeking to establish the clinical utility of such testing. We characterized pathological and clinical characteristics associated with ctDNA detected preoperatively in patients with renal masses suspicious of RCC. Methods: Using our single institution prospectively maintained database, we identified consecutive patients who underwent partial or radical nephrectomy for non-metastatic suspected RCC (stages cT1b-cT3) during 2022-2023. Included were patients who had undergone tumor-informed ctDNA testing using the commercial Signatera assay (Natera). Baseline characteristics, pathology results, imaging study results, and oncological treatment and follow-up data were collected from the electronic medical records. ctDNA results were collected through the Natera portal. Study findings were reported using descriptive statistics. A p-value of &lt;0.05 was considered statistically significant. R programming language version 4.3 was used for all statistical analyses. Results: A total of 54 patients with a median age of 63 years (IQR 51-71) were included in the study. Twenty-one (39%) were women. The median follow-up time was 4 months (range: 1-21 months). Among the 54 patients, 27 (50%) had detectable ctDNA pre-operatively Post-operative results were available for 33 patients, and 3 (9%) had detectable tDNA (of those 2 had Inferior vena cava involvement). The first patient developed metastatic disease. The two other patients are receiving adjuvant immunotherapy. Analysis of 50 patients with solely malignant RCC revealed that patients with detectable versus undetectable ctDNA were older 67 vs. 54 years (p=0.03), had a higher pathological stage (p= 0.002), larger tumors (7.2 vs. 4.7 cm, p = 0.004), and higher pathological grade (grade 3-4 vs. grade 1-2; p=0.035) (Table 1). All the patients with renal vein or inferior vena cava involvement had detectable ctDNA (n=8). Conclusions: In our cohort, preoperative ctDNA was detectable in 50% of patients with suspected clinically localized RCC. Detectable ctDNA preoperatively correlated with clinically relevant features. The ability of preoperative ctDNA to predict recurrence and survival in patients with clinically localized RCC warrants further evaluation. [Table: see text]

Spatial analysis of the tumor immune microenvironment in papillary renal cell carcinoma.

471 Background: Spatial analysis of the tumor immune microenvironment (TIME) has yet to be explored in papillary renal cell carcinoma (pRCC). We utilized multiplex immunofluorescence (mIF) and spatial transcriptomics using spatial molecular imaging (SMI) to evaluate TIME properties in pRCC and contrasted these results with clear cell RCC (ccRCC). Methods: Tumor specimens were obtained from localized RCC tumors. mIF was performed on regions of interest (ROIs) selected from matched compartments from tumor, stroma, and tumor/stromal subsets of the interface. Two antibody panels were used for markers against T cells and B cells/macrophages. Marker abundance and clustering differences between pRCC and ccRCC were evaluated across ROIs. Select markers were also explored across pathologic tumor staging in pRCC. The SMI platform used for validation utilized probes against 959 transcripts. Cells were phenotyped using InSituType using the Kidney Cell Atlas as a reference. Cell clustering was quantified by univariate and bivariate Ripley’s K using the spatialTIME package in R. Results: mIF was performed on 1178 ROIs from 16 pRCC tumors and 70 ccRCC tumors. Compared to ccRCC, pRCC immune cell abundance was statistically lower amongst many T cell types and M2-like macrophages (Figure). M1-like macrophages were the only cell line seen at higher levels in interface compartments only. Increased macrophage clustering was observed in pRCC, including doubly positive M2-like macrophages in interface compartments (p=0.001 and 0.007). Higher abundance of CD8+ and FOXP3+ T cells in pRCC was associated with worse clinical stage, but no trend was seen with marker clustering. Four ROIs from 2 pRCC patients underwent SMI validation. On SMI of the tumor compartment, T cells were clustered with other T cells, B cells, and M1 macrophages. Conclusions: Compared to ccRCC, pRCC has fewer T cells and macrophages but more macrophage clustering. Using spatial transcriptomics, we found significant clustering between T cells, macrophages, and B cells in pRCC.

Key parameters that influence surgical strategy in localised kidney cancer.

423 Background: The goal of this studywas to select the key factors affecting choice between radical nephrectomy (RN) and partial nephrectomy (PN) for patients with localized RCC based on clinical and nephrometry data. Methods: A special retrospective cohort study was conducted in National Cancer Institute of Ukraine, which results were further validated on patient dataset in urological department of University Clinic of Cologne. The Institutional Review Boards and the local ethics committees of both high-volume centres approved the study. The main nephrometry parameters of tumor location in the kidney were analysed according to the R.E.N.A.L nephrometry score. The remaining functional parenchymal volume (RFPV) was calculated using the special formula. To determine the relationship between the risk of RN or PN, the multivariate predictive modelling method containing 12 parameters was used (Artificial Neural Networks [ANN]). Data validation based on referential centre experience using ROC-curve analysis to detect clinical applicability of the null hypothesis was performed. Results: Based on the analysis, for polary and laterally located tumors, the risk of RN was conditioned only by RFPV. The average critical value of RFPV for polar lesions was X6crit = 58% (in X6 &lt; X6crit, RN was predicted); for lateral tumors - X6crit = 67% (in X6 &lt; X6crit, RN was predicted). For medial location, the risk of RN only depended on the tumor size. Average critical value of the tumor size in the medial location was X7crit = 38 mm (in X7 &gt; X7crit, RN was predicted). Based on the ROC curve comparison, there were no statistically significant differences between the AUCLin_12 and AUCMLP_3 (p = 0.12); thus, the reduced amount of the factor indicators from 12 to 3 did not worsen the model predictive qualities. Designed during primary analysis hypothesis was successfully validated in a referent centre on the cohort of 300 patients. Out of the cohort - 14 (4.6%) patients experienced false positive/negative outcome, which resulted in a radical/partial nephrectomy out of the hypothesis margins. Predictive model is characterized by high sensitivity (95.2%) and specificity (95.4%) in selecting patients for partial nephrectomy. Conclusions: For the polar and lateral tumor locations, the functioning parenchymal volumes of over 58 and 67% respectively serve as PN indications. However, for the medial lesions, the primary PN indication is a tumor size less than 38 mm.

Treatment of localized renal cell carcinoma

Both partial nephrectomy (pNx) and total nephrectomy (TNx) are the mainstay of the surgical treatment of renal cell carcinoma. In smaller masses, ablative treatment as well as surveillance are possible options. The aim of this article is to provide acloser look at the surgical methods, active surveillance and ablative options as well as the current evidence to support their use. This study is based on aselective literature review regarding pNx and TNx for renal cell carcinoma using the PubMed database and the review of current European and American guidelines on surgical treatment and conservative options for renal cell carcinoma. The choice of surgical method depends on the intrarenal tumor configuration as well as patient comorbidities. While pNx is used for smaller localized masses TNx is usually performed in larger more complex tumors. Both methods can be performed using aminimally invasive (laparoscopic or robotically assisted) or an open approach. In patients with severe comorbidities or alimited life expectancy, local ablative treatment options as well as surveillance strategies are suitable strategies.