Matthew Meissner

Identifying the risk of disease progression after surgery for localized renal cell carcinoma

Study Type – Therapy (case series)
Level of Evidence 4

Prognostic serum markers in patients with high-grade upper tract urothelial carcinoma

INTRODUCTION The role of preoperative serum-based markers in predicting survival outcomes of patients has been reported for several cancer types; however, their association with upper tract urothelial carcinoma (UTUC) prognosis is unclear. We evaluated the role of systemic serum-based markers in predicting adverse pathological features and survival outcomes in patients surgically treated for high-grade (HG) UTUC. METHODS We retrospectively reviewed all patients undergoing surgery for HG UTUC between June 2006 and July 2013 at our institution. Comprehensive clinicopathologic data and preoperative serum-based markers including hemoglobin, white blood cell count, platelet count, serum albumin, calcium, and liver function tests were recorded. Associations of serum markers with pathologic features and recurrence-free survival (RFS) were determined by logistic and Cox regression analyses, respectively. The concordance index for the oncologic outcomes model was determined. RESULTS In total, 101 patients were identified with a median follow-up of 18.5 months (range: 1-74mo). In all, 60% of patients had pT2 or less and 11% had nodal metastases. Preoperative elevated alkaline phosphatase (ALP) (≥116IU/l) was associated with multiple adverse pathologic features including advanced T stage, lymphovascular invasion, and histologic necrosis. On univariate analysis, serum markers independently associated with RFS included hemoglobin≤12.9 (hazards ratio [HR] = 2.51; 95% CI: 1.17-5.36, P = 0.018), albumin≤4g/dl (HR = 4.4; 95% CI: 2.04-9.30; P<0.0001), ALP≥116U/l (HR = 13.3; 95% CI: 5.3-33.52, P<0.0001), alanine transaminase≥27 (HR = 2.63, 95% CI: 1.11-6.21, P = 0.028), serum aspartate transaminase≥20 (HR = 2.21, 95% CI: 1.04-4.69, P = 0.038), and corrected calcium≥9.3 (HR = 2.45, 95% CI: 1.01-5.93, P = 0.047). The 2 strongest predictors, albumin and ALP, were combined to form an AA score (range: 0-2), which improved the baseline preoperative clinical model concordance index for prediction of RFS from 0.626 to 0.799. CONCLUSION In HG UTUC, elevated preoperative ALP was associated with adverse pathologic features. Additionally, elevated ALP and low albumin were independently associated with worse RFS and overall survival. These serum-based markers are often measured in the preoperative workup of UTUC, and thus they can be included in future prognostic models to risk stratify patients.

Feasibility of obtaining biomarker profiles from endoscopic biopsy specimens in upper tract urothelial carcinoma: Preliminary results

OBJECTIVE To prospectively evaluate the feasibility of obtaining a reliable histochemical assessment of cell cycle biomarkers from endoscopic biopsy specimens of patients with upper tract urothelial cancer. METHODS Overall, 17 patients were identified who had an available biopsy as well as those who underwent subsequent radical nephroureterectomy (RNU) or segmental ureterectomy (SU) for clinically localized high-grade upper tract urothelial cancer of the renal pelvis or ureter. Of those 17 patients, 15 (88%) had sufficient tissue to undergo immunohistochemical staining. Biopsies were obtained using various endoscopic techniques. Tumor characteristics were recorded and prospectively evaluated for immunohistochemical expression of 5 biomarkers: p21, p27, p53, cyclin E, and Ki67/pRb. Unfavorable prognostic score (PS) was defined as>2 altered markers. RESULTS The median age of the patients was 68 years (range: 53-82y) with 87% being males. Of the 15 specimens, 9 (60%) tumors were organ confined (T≤2 and N0), and all were high grade. Of the 15 patients, 4 (27%), 7 (46.6%), 3 (20%), and 1 (6.7%) individuals had 1, 2, 3, and 5 markers altered on biopsy marker profiling, respectively, with Ki67 being the most frequent alteration (13/15; 87.7%). An overall concordance rate of 60% (9/15) was seen between biopsy and RNU/SU PS. Those patients with favorable biopsy biomarker PS were less likely to display adverse pathological features, with organ-confined disease in 7/11 (63.6%) patients and 9/11 (81.8%) being free of carcinoma in situ in the final specimen. Additionally, 10/11 (91%) had no evidence of necrosis and 7/11 (64%) had no evidence of lymphovascular invasion on final pathologic evaluation. CONCLUSIONS Preliminary results suggest that obtaining interpretable biomarker profile of ureteroscopic biopsy specimens is feasible. Tumor heterogeneity and limited biopsy material may account for the discordance between biopsy and RNU/SU specimens. Meaningful biopsy biomarker profiling could serve as a powerful tool for individualizing treatment regimens and augmenting current predictive variables. Further studies are needed to evaluate clinical applicability.

Editorial Comment to Equivalent survival and improved preservation of renal function after distal ureterectomy compared with nephroureterectomy in patients with urothelial carcinoma of the distal ureter: A propensity score-matched multicenter study

The prevalence of medical renal disease in patients with upper tract urothelial carcinoma (UTUC) is well known and has shown to range between 26% and 52%. Additionally, nearly 78% of patients undergoing radical nephroureterectomy (RNU) are ineligible to receive adjuvant therapy because of renal dysfunction. Hence, implementation of nephron-sparing procedures, such as distal ureterectomy (DU), to adequately preserve renal function is critical. In the current study, Fukushima et al. compared the oncological and functional outcomes of patients with UTUC of the distal ureter treated with either RNU or DU. With a significant median follow up, the authors effectively showed that there were no significant differences in recurrence-free survival (RFS) and disease-free survival in patients undergoing RNU versus DU. Additional subgroup analysis, stratified by stage, yielded the same results. As expected, renal functional outcomes were better preserved in the DU group. Fukushima et al. alluded to several challenging aspects in the management of patients with UTUC – maximizing oncological outcomes while maintaining adequate renal function after surgical extirpation. The challenge with promoting a minimally-invasive or nephron-sparing approach is maintaining the same oncological outcomes as those achieved with the gold standard – RNU. The present study is in line with a recent published series from Bagrodia et al., in which a large analysis from the UTUC Collaboration found no significant difference between segmental ureterectomy and RNU in 5-year cancer-specific survival (67.5% vs 72.1% respectively, P = 0.06) or RFS (69.4% vs 79% respectively, P = 0.06). Additional data by Jeldres et al. suggest that oncological efficacy is equivalent for patients with pT3–4 tumors undergoing RNU or segmental ureterectomy. Patients with UTUC represent a challenging cohort with numerous medical comorbidities including baseline chronic kidney disease. Lane et al. showed that 78% of patients were ineligible to receive adjuvant platinum-based chemotherapy after RNU, documenting a median 21% decrease in glomerular filtration rate. Most concerning, however, was that nearly 60% of patients with cT2–T4 disease were ineligible preoperatively to receive neoadjuvant platinum-based systemic chemotherapy, and this number increased to 78% after RNU. Hence, one must be cognizant that RNU for distal ureteral tumors might render these patients ineligible for adjuvant chemotherapy. The management of UTUC continues to be a challenging endeavor, with significant controversies left to be addressed. However, recent advances in imaging to facilitate accurate staging, elucidation of biomarkers to improve risk stratification and nephron-sparing approaches could help address these challenges. The current study further strengthens the current literature showing that, when feasible, DU is an oncologically and functionally sound treatment modality.

The Adverse Survival Implications of Bland Thrombus in Renal Cell Carcinoma With Venous Tumor Thrombus

OBJECTIVE To characterize the presence of bland (nontumor) thrombus in advanced renal cell carcinoma and assess the impact of this finding on cancer-specific survival. METHODS A multi-institutional database of patients treated with nephrectomy with caval thrombectomy for locally-advanced renal tumors was assembled from 5 tertiary care medical centers. Using clinicopathologic variables including patient age, body mass index, Eastern Cooperative Oncology Group performance status, tumor stage, grade, nodal status and histology, and nearest-neighbor and multiple-matching propensity score matched cohorts of bland thrombus vs nonbland thrombus patients were assessed. Multivariable analysis for predictors of cancer-specific survival was performed. RESULTS From an initial cohort of 579 patients, 446 met inclusion criteria (174 with bland thrombus, 272 without). At baseline, patients with bland thrombus had significantly worse performance status, higher tumor stage, higher prevalence of regional nodal metastases and higher nuclear grade (P < .01 for all). In both nearest-neighbor and multiple-matching propensity score matched cohorts, the presence of bland thrombus presence was associated with inferior median cancer-specific survival (28.1 months vs 156.8 months, and 28.1 months vs 76.7 months, P < .001 for both). The presence of bland thrombus remained independently associated with an increased risk of cancer-specific mortality on multivariable analysis (hazard ratio 4.33, 95% confidence interval 2.79-6.73, P < .001). CONCLUSION Presence of bland thrombus is associated with adverse survival outcomes in patients treated surgically for renal tumors with venous tumor thrombus. These findings may have important implications in patient counseling, selection for surgery and inclusion in clinical trials.

MP72-16 CREATION OF A RENAL MEDULLARY CARCINOMA MOUSE MODEL: FEASIBILITY AND PRELIMINARY RESULTS AFTER TREATMENT WITH ANTI-NEOPLASTIC AGENTS

cell carcinoma (RCC) grown on chicken embryo chorioallantoic membranes (CAM-PDX) as a model of early metastatic disease. METHODS: Clinical grade MV-NIS was grown at Mayo Clinic facilities. Patient tumor cores were obtained from multiple independent sites of the primary tumor at the time of radical nephrectomy. Sectioned tumor fragments were implanted on chicken embryo chorioallantoic membranes and allowed to become vascularized over approximately seven days. In vivo infectivity studies were performed with measles virus expressing green fluorescent protein (MV-GFP), allowing real-time serial visualization of infection using fluorescent stereoscopy. Direct virus inoculation and intravascular administration were utilized. Volumetric Doppler US quantified xenograft vascularity as a measure of treatment response. RESULTS: MV-GFP achieved robust infection of patientderived RCC tumors grown in the CAM model of early metastatic disease, as visualized by fluorescent stereoscopy. The kinetics and distribution of infection varied markedly between direct and intravenous administration, with direct inoculation achieving infection within 24 hours and resulting in near complete infection and xenograft destruction within four days. Intravenous administration achieved infection restricted by neovascularization of the xenograft with delayed kinetics and limited distribution compared to direct administration. Volumetric Doppler ultrasound quantified the vascularization index (percent xenograft volume composed of vasculature), correlating MV infection with decreased xenograft vascularity. CONCLUSIONS: Our data show robust infection and destruction by oncolytic MV of patient-derived RCC xenografts grown in vivo on chicken embryo chorioallantoic membranes. Xenograft destruction was correlated with loss of vascularity as measured by volumetric Doppler ultrasound. Infection was more rapid and widespread after direct inoculation compared to intravenous administration. These data highlight the potential of oncolytic virotherapy as a therapeutic strategy against metastatic RCC. Importantly, the CAM-PDX model allows for rapid and high-throughput analysis of disease response to therapy by individual patient tumors, making in-vivo directed patient-specific treatment approaches a viable option for future oncolytic virotherapy trials.

Adjuvant therapy for advanced renal cell carcinoma

ABSTRACT Introduction: Locally advanced, non-metastatic renal cell carcinoma (RCC) is conventionally managed with surgery. However, patients are at a high risk of RCC recurrence and have poor survival outcomes. An effective adjuvant systemic treatment is needed to improve on these outcomes. Targeted molecular and immune-based therapies have been investigated, or are under investigation, but their role in this setting remains unclear. Areas covered: A comprehensive search of PubMed and ClinicalTrials.gov was performed for relevant literature. The following topics pertinent to adjuvant therapy in RCC were evaluated: strategies for patient selection, cytokine-based immunotherapy, vaccine therapy, VEGF and non-VEGF targeted molecular agents, and immune checkpoint inhibitors. Expert commentary: Strong evidence for the incorporation of adjuvant therapy in high-risk RCC is lacking. Multiple targeted molecular therapies have been examined with only one approved for use. Genetic and molecular-based prognostic models are needed to determine who may benefit from adjuvant therapy. Developing adjuvant therapy strategies in the future depends on the results of important ongoing trials with immunotherapy and targeted agents.

Renal cell carcinoma and pathologic nodal disease: Implications for American Joint Committee on Cancer staging

Lymph node (LN) metastases are associated with poor outcomes for patients with renal cell carcinoma (RCC). This study compared the survival outcomes of patients with stage III, node‐positive disease (pT123N1M0) and patients with stage III, node‐negative disease (pT3N0M0).

Surgical Complications of Presurgical Systemic Therapy for Renal Cell Carcinoma: A Systematic Review

Background: Locally advanced and metastatic renal cell carcinoma (RCC) is associated with poor survival outcomes. The integration of presurgical systemic therapy with targeted molecular agents prior to surgical resection of RCC tumors has been utilized to improve on these outcomes. These agents may be associated with an increased risk of perioperative complications due to their action on angiogenesis and cell proliferation. Objective: To examine the evidence for the incidence and severity of perioperative complications following presurgical targeted therapy for locally advanced or metastatic RCC. Methods: We performed a systematic review of retrospective studies, prospective clinical trials, and meta-analyses using key search terms in PubMed and Medline. Studies were screened for eligibility and data were extracted by the authors. A qualitative analysis was performed and the complications for available targeted agents was reported. Results: Retrospective analyses and small prospective trials indicate varying complication rates and types based on presurgical therapies. While some studies indicate a possible increase in wound-related complications, other studies did not show similar results. Additional unique complications reported include an increase in surgical adhesions. There was not any significant difference in overall or bleeding complications. Conclusions: Overall, these studies demonstrate an acceptable level of surgical complications that should not discourage the clinician considering presurgical therapy. The results of pending trials looking at presurgical therapies will provide further information.

Nephrometry scoring systems: valuable research tools, but can they be applied in daily clinical practice?

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