Thompson, R. Houston

Abstract Development of effective vaccination approaches to treat established tumors represents a focus of intensive research because such approaches offer the promise of enhancing immune system priming against tumor Ags via restimulation of pre-existing (memory) antitumoral helper and effector immune cells. However, inhibitory mechanisms, which function to limit the recall responses of tumor-specific immunity, remain poorly understood and interfere with therapies anticipated to induce protective immunity. The mouse renal cell carcinoma (RENCA) tumor model was used to investigate variables affecting vaccination outcomes. We demonstrate that although a whole cell irradiated tumor cell vaccine can trigger a functional antitumor memory response in the bone marrows of mice with established tumors, these responses do not culminate in the regression of established tumors. In addition, a CD103+ regulatory T (Treg) cell subset accumulates within the draining lymph nodes of tumor-bearing mice. We also show that B7-H1 (CD274, PD-L1), a negative costimulatory ligand, and CD4+ Treg cells collaborate to impair the recall responses of tumor-specific memory T cells. Specifically, mice bearing large established RENCA tumors were treated with tumor cell vaccination in combination with B7-H1 blockade and CD4+ T cell depletion (triple therapy treatment) and monitored for tumor growth and survival. Triple treatment therapy induced complete regression of large established RENCA tumors and raised long-lasting protective immunity. These results have implications for developing clinical antitumoral vaccination regimens in the setting in which tumors express elevated levels of B7-H1 in the presence of abundant Treg cells.

Objective To demonstrate sarcomatoid differentiation is an independent prognostic feature for patients with grade 4 renal cell carcinoma ( RCC ) with or without distant metastases. To identify independent predictors of survival, evaluate the correlation between the amount of sarcomatoid differentiation and cancer‐specific survival ( CSS ), and to design a multivariate prognostic model for patients with sarcomatoid RCC . Patients and Methods We used the Mayo Clinic Nephrectomy Registry to identify 204 post‐nephrectomy patients with sarcomatoid‐variant RCC , as well as 207 patients with unilateral grade 4 RCC without sarcomatoid features for comparison. All slides were reviewed by one pathologist. CSS was estimated using the K aplan– M eier method. The associations of clinical and pathological features with death from RCC were evaluated using Cox proportional hazards regression models. Results For all patients with grade 4 RCC , the presence of sarcomatoid differentiation was associated with a 58% increased risk of death from RCC ( P < 0.001). For patients with grade 4 non‐metastatic ( M0 ) RCC , the presence of sarcomatoid differentiation was associated with an 82% increased risk of death from RCC ( P < 0.001). For patients with sarcomatoid RCC , the 2009 primary tumour classifications, presence of regional lymph nodes and distant metastases, coagulative tumour necrosis, and the amount of sarcomatoid differentiation were each significantly associated with death from RCC in a multivariate setting. After adjusting for other prognostic variables, each 10% increase in the amount of sarcomatoid differentiation was associated with a 6% increased risk of death from RCC ( P = 0.028). Patients whose tumours contained ≥30% (median amount) sarcomatoid differentiation were 52% more likely to die from RCC compared with patients whose tumours contained <30% sarcomatoid differentiation (hazard ratio 1.52; P = 0.018). Conclusions Among patients with grade 4 RCC , either with or without distant metastases at surgery, sarcomatoid differentiation is significantly associated with adverse survival in a multivariate setting. We also suggest for the first time that the percentage of sarcomatoid differentiation is an independent prognostic feature in a multivariate setting. The 2009 primary tumour classifications, regional lymph node status, the presence of distant metastases classifications, coagulative tumour necrosis, and the amount of sarcomatoid differentiation are independent predictors of survival for patients with sarcomatoid RCC .

Objectives To model renal function after radical nephroureterectomy ( RNU ) for upper tract urothelial carcinoma ( UTUC ). To identify predictors of renal function decline after surgery, thereby allowing the identification of patients likely to be ineligible for cisplatin‐based chemotherapy in the adjuvant setting. Patients and Methods We retrospectively identified 374 patients treated with RNU for UTUC at three centres between 1995 and 2010. Estimated glomerular filtration rate ( eGFR ) was calculated using Chronic Kidney Disease Epidemiology Collaboration equation before RNU and at early (1–5 months after RNU ) and late (>5 months) time points after RNU . Only patients deemed eligible for cisplatin‐based chemotherapy before RNU (preoperative glomerular filtration rate [ GFR ] ≥60 mL/min/1.73 m 2 ) were included. Multivariable analysis identified the preoperative predictors of eGFR after RNU at early postoperative and late postoperative time points. Results A total of 163 patients had an eligible early post‐ RNU eGFR measurement and 172 had an eligible late eGFR measurement. The median eGFR declined by 32% and did not show a significant trend toward recovery over time ( P = 0.4). On multivariable analysis preoperative eGFR and patient age were significantly associated with early and late postoperative eGFR , while C harlson comorbidity index score was significantly associated with late postoperative eGFR alone. Conclusions In patients with normal preoperative eGFR (≥60 mL/min/1.73 m 2 ), renal function decreases by one‐third after RNU and does not show evidence of recovery over time. Elderly patients and those with pre‐ RNU eGFR closer to 60 mL/min/1.73 m 2 (lower eGFR in the present cohort) are more likely to be ineligible for adjuvant cisplatin‐based chemotherapy regimens because of renal function loss after RNU .

Objective To evaluate the association of perioperative blood transfusion ( PBT ) with survival after nephrectomy. Patients and Methods We identified 2318 patients who underwent partial or radical nephrectomy at M ayo C linic between 1990 and 2006. PBT was defined as transfusion of allogenic red blood cells during surgery or postoperative hospitalisation. Survival was estimated using the K aplan– M eier method and compared with the log‐rank test. Cox proportional hazards regression models were used to evaluate the association of PBT with outcome. Results In all, 498 patients (21%) received a PBT . The median (interquartile range) number of units transfused was 3 (2, 5). Patients receiving a PBT were significantly older at surgery ( P < 0.001), more likely to be female ( P < 0.001), with more frequent symptomatic presentation ( P < 0.001), worse E astern C ooperative O ncology G roup performance status ( P < 0.001), and more frequent adverse pathological features, such as high nuclear grade ( P < 0.001), locally‐advanced tumour stage ( P < 0.001) and lymph node invasion ( P < 0.001). The median follow‐up was 9.1 years. Receipt of a PBT was associated with adverse 5‐year cancer‐specific (68% vs 92%; P < 0.001) and overall (56% vs 82%; P < 0.001) survival. On multivariate analyses, PBT remained associated with higher risk of death from any cause (hazard ratio [ HR ] 1.23; P = 0.02). Among patients who received a PBT , an increasing number of units transfused was independently associated with increased all‐cause mortality ( HR 1.08; P = 0.001). Conclusion PBT is associated with a significantly increased risk of mortality after nephrectomy. While external validation is needed, continued efforts to minimise the use of blood products in these patients are warranted.

Abstract Increased angiogenesis and tumor-induced immune evasion are two mechanisms by which clear cell renal cell carcinoma (ccRCC) proliferate and metastasize; however, the relationship between these pathways in human ccRCC is poorly understood. We conducted a nested case–control study using 98 archived tumor samples from patients diagnosed with primary ccRCC between 1990 and 2006, half of which were identified by immunohistochemistry (IHC) as either programmed death ligand 1 (PDL-1)–positive or PDL-1–negative. RNAs were extracted from the formalin-fixed paraffin-embedded tumor slides and the expression of the VEGFA, VEGFR1, VEGFR2, and PDL-1 genes was quantified. We assessed the presence of tumor-infiltrating lymphocytes (TIL) by IHC for CD3, and then analyzed the relationship among VEGFA, VEGFR1, VEGFR2, CD3, and PDL-1. When analyzed as a continuous variable, PDL-1 protein expression by IHC inversely correlates with the expression of the three VEGF-related genes: VEGFA (r = −0.23; P = 0.01), VEGFR1 (r = −0.34; P &lt; 0.001), and VEGFR2 (r = −0.23; P = 0.01). When dichotomized, the PDL-1–positive cohort trended toward a lower expression of VEGFA (fold change = 0.72; P = 0.056) and VEGFR1 (fold change = 0.69; P = 0.057). In addition, there was a significant and positive relationship between the presence of TIL as assessed by IHC for CD3 and PDL-1 by IHC (r = 0.25; P = 0.015), and there was a trend toward an inverse relationship between TIL and VEGFA gene expression (r = −0.18; P = 0.089). In conclusion, this is the first demonstration of an inverse association between the angiogenesis and PDL-1 pathways in tumor samples from primary ccRCC, and this relationship may be related to the immunosuppressive effects of VEGF signaling. Cancer Immunol Res; 1(6); 378–85. ©2013 AACR.