Gain of Chromosome 5q Predicts a Favorable Prognosis in Localized Renal Cell Carcinoma.

Approximately 65% of renal cell carcinomas (RCC) are diagnosed at a localized stage. We investigated the chromosome 5q gain impact on disease-free survival (DFS) in RCC patients. Overall, 676 patients with stages 1-2 RCC and having cytogenetic analysis were included. Gain of 5q was observed in 108 patients, more frequently in clear cell (ccRCC) than non-clear cell tumors. Gain of 5q is likely an independent prognostic factor since the concerned patients had a decreased recurrence risk in stages 1-2 RCC, confirmed in multivariable analysis. Detecting 5q gain could enhance recurrence risk assessment, allowing tailored post-surgery surveillance, and reducing unnecessary treatments.

A Phase I, Open-label, Dose-escalation, and Cohort Expansion Study to Evaluate the Safety and Immune Response to Autologous Dendritic Cells Transduced With AdGMCA9 (DC-AdGMCAIX) in Patients With Metastatic Renal Cell Carcinoma.

Expression of carbonic-anhydrase IX (CAIX) in clear cell renal cell carcinoma (RCC) makes it an attractive vaccine target. We developed a fusion-gene construct, granulocyte-macrophage (GM) colony-stimulating factor+CAIX, delivered by an adenoviral vector (Ad) into autologous dendritic cells (DCs) in this phase 1 study. The injected immature DCs were expected to stimulate an antigen-specific immune response against CAIX expressing RCC. Three dose-escalation cohorts (5, 15, and 50×10 cells/administration) were injected intradermally q2wk×3 doses based on a 3+3 design. The primary objective was the safety of the injections. Secondary objectives were immune responses using enzyme-linked immunosorbent spot, a serum biomarker panel, and clinical response. Fifteen patients with metastatic RCC were enrolled, and 9 patients received all 3 doses. No serious adverse events were seen. There were 3 (33%) patients with grade 1 fatigue, 1 of whom subsequently experienced grade 2 fatigue. One patient (11%) experienced grade 1-2 leukopenia. Only 1 patient (11%) experienced grade 2 flu-like symptoms. Of the 9 patients who received treatment, 1 expired of progressive disease, 2 patients were lost to follow-up and 6 patients are alive. Of the 6 patients, 5 have progressive disease, and 1 has completed treatment with stable disease at 27 months follow-up. Immune response measurements appeared more robust in higher dose cohorts, which appeared to be related to patients with stable disease at 3 months. These early data show that autologous immature DC-AdGMCAIX can be safely given to metastatic RCC patients without any serious adverse events with CAIX-specific immune response elicited by the treatment. These preliminary data support further study of Ad-GMCAIX, particularly with combination therapies that may enhance clinical activity.

Evaluation of the prognostic role of co-morbidities on disease outcome in renal cell carcinoma patients.

BACKGROUND: Co-morbidities may induce local and systemic tumor progression of renal cell carcinoma (RCC); however, the prognostic impact of co-morbidities has not yet been well characterized. PATIENTS AND METHODS: RCC patients (n = 2206) surgically treated at three academic institutions in the US and Europe were included in the analysis. Presence of diabetes mellitus, hypertension, chronic kidney disease, chronic obstructive pulmonary disease, coronary heart disease, and hypothyroidism were investigated for their association with clinicopathological features and cancer-specific survival. RESULTS: Hypertension was associated with less advanced T stages (p = 0.025), a lower risk of lymph-node (p = 0.026) and distant metastases (p = 0.001), and improved cancer specific survival in univariable analysis (HR 0.81 95% CI 0.69-0.96, p = 0.013). However, hypertension was not an independent prognostic factor after adjustment for TNM stages, grading, and ECOG performance status (HR 0.95, 95% CI 0.80-1.12; p = 0.530). A correlation between the use of concomitant anti-hypertensive medications and improved survival outcome was not identified. All other investigated co-morbidities did not show significant associations with clinicopathological features or cancer-specific survival. CONCLUSION: Although the investigated co-morbidities are capable or inducing pathophysiological changes that are predisposing factors for tumor progression, none is an independent prognostic factor in patients with RCC.

Melanoma-associated antigen-A and programmed death-ligand 1 expression are associated with advanced urothelial carcinoma.

BACKGROUND: Melanoma-associated antigen-A (MAGE-A) and programmed-death ligand 1 (PD-L1) are present in urothelial carcinoma (UC). We assessed survival outcomes in patients with MAGE-A and PD-L1 expression. METHODS: MAGE-A and PD-L1 expression on neoplastic cells was analyzed using tissue microarrays from patients with UC. We compared differential expression between disease stage and grade. MAGE-A and PD-L1 co-expression was subcategorized. Fisher's exact test was done for categorical variables followed by univariable and multivariable analysis of recurrence-free survival (RFS) and progression-free survival (PFS). RESULTS: Co-expression of MAGE+/PD-L1+ was higher in advanced disease; however, only MAGE+/PD-L1- was associated with shorter RFS [hazard ratio (HR) 1.89; 95% confidence interval (CI) 1.19-2.99; p = .006]. MAGE+/PD-L1+ was associated with the worst PFS (HR 17.1; 95% CI 5.96-49.4; p ≤ .001). MAGE-A expression was more prevalent with high-grade (p = .015), and higher-stage ≥ pT2 (p = .001) disease. The 5-year RFS was 44% for MAGE+ versus 58% for MAGE- patients. On multivariable analysis, MAGE+ was also associated with shorter RFS (HR 1.55; 95% CI 1.05-2.30; p = .03). Similarly, MAGE+ was associated with shorter PFS (HR 3.12; 95% CI 1.12-8.68; p = .03). CONCLUSION: MAGE-A and PD-L1 expression is increased in advanced disease and associated with shorter PFS. Furthermore, MAGE-A expression was significantly associated with higher-grade and -stage disease and associated with shorter RFS and PFS. The worse prognosis associated with MAGE-A+/PD-L1+ provides evidence that a combinatorial treatment strategy co-targeting MAGE/PD-L1 might be feasible. Further studies are needed to validate these findings.

Receptor activator of NF-κB (RANK)-mediated induction of metastatic spread and association with poor prognosis in renal cell carcinoma.

BACKGROUND: Inhibition of the receptor activator of NF-κB ligand (RANKL) has become a standard of care supportive treatment to prevent skeletal related events in cancer patients. Moreover, RANKL inhibition has been implicated with better survival outcome in lung cancer, while RANKL expression induces tumor progression and metastatic spread in vivo in breast cancer. Whether RANK/RANKL may have an impact on the pathogenesis of clear cell renal cell carcinoma (ccRCC) is currently unknown. PATIENTS AND METHODS: A retrospective tissue micro array (TMA)-study was carried out determining the expression of RANK/RANKL in primary tumors of 306 ccRCC patients. Additionally, 24 ccRCC cell lines were employed for in vitro analyses of the RANK/RANKL axis including cell proliferation, migration and anchorage independent growth. RESULTS: RANK (+) vs. RANK (-) tumors had both worse cancer specific survival (CSS) (6.3 vs. 1.3 years; p < 0.001) and recurrence free survival (RFS) (9.9 vs. 5.8 years; p < 0.001). RANK (+) (HR 2.21; p < 0.001) was an independent prognostic factor for CSS and RFS (HR 4.98; p < 0.001). RANKL treatment resulted in increased proliferation, soft agar growth, and colony formation of RANK (+) RCC cell lines, which could be reversed by treatment with an NF-κB inhibitor and with a combination of osteoprotegrin and RANKL in vitro. CONCLUSIONS: RANK is expressed in ccRCC tissue, correlates with clinicopathological features, survival outcome, and when stimulated with RANKL can induce ccRCC progression in vitro. Consequently, RANKL inhibition combined with standard of care treatment may be a promising approach to improve ccRCC patient's survival.

Utility of multiphasic multidetector computed tomography in discriminating between clear cell renal cell carcinomas with high and low carbonic anhydrase-IX expression.

PURPOSE: To investigate if multiphasic multidetector computed tomography (MDCT) enhancement profiles can distinguish clear cell renal cell carcinomas (ccRCCs) with high carbonic anhydrase-IX (CA-IX) expression from ccRCCs with low CA-IX expression. METHODS: With IRB approval for this retrospective study, we derived a cohort of 105 histologically proven ccRCCs with preoperative 4-phase renal mass MDCT from 2001 to 2013. Following manual segmentation, the computer-assisted detection algorithm selected a 0.5-cm-diameter region of maximal attenuation within each lesion in each phase. CA-IX expression level was determined by immunohistochemical staining of tumor specimens. In the high and low CA-IX expression subgroups, the magnitude of enhancement and washout were compared using t tests; the performance of contrast washout in differentiating between subgroups was assessed with logistic regression analysis. RESULTS: ccRCCs with high and low CA-IX expression both exhibited peak enhancement in the corticomedullary phase. ccRCCs with high CA-IX expression demonstrated significantly greater relative nephrographic washout than those with low CA-IX expression (18.4% vs. 7.8%, p = 0.03). ccRCCs with high CA-IX expression had greater relative excretory washout than ccRCCs with low CA-IX expression with a trend toward significance (33.4% vs. 25.2%, p = 0.05). After controlling for tumor size and stage, for distinguishing ccRCCs with high and low CA-IX expression, relative excretory washout had a sensitivity, negative predictive value, accuracy, and positive predictive value of 99% (65/66), 88% (7/8), 69% (72/105), and 67% (65/97), respectively. CONCLUSION: Relative nephrographic and excretory washout may have the potential to help distinguish ccRCCs with high and low CA-IX expression, but this requires further validation.

Overall survival in patients with metastatic renal cell carcinoma and clinical N1 disease undergoing cytoreductive nephrectomy and lymph node dissection.

BACKGROUND: Patients with metastatic renal cell carcinoma (mRCC) have limited treatment options. Cytoreductive nephrectomy (CN) in select patients has been associated with improved survival. We aim to assess the survival in patients with mRCC and cN1 disease who underwent CN with and without lymph node dissection (LND). METHODS: Data were abstracted from the National Cancer Database for patients diagnosed with mRCC and cN1 from 2003 to 2014. Using propensity matching, we compared overall survival (OS) in patients who underwent a LND. Kaplan-Meier survival analysis and multivariable Cox proportional hazards modeling were used. We performed a logistic regression to assess predictors of LND. RESULTS: We identified 1,780 patients in the matched cohort, of which 71% underwent a LND. Patients undergoing LND were younger (P = 0.01) and had similar size tumors (5cm; P = 0.31). Increased LN yield was associated with LND at an academic center (odds ratio = 1.91; 95% CI: 1.51-2.42; P<0.01). LND was associated with worse OS on KM analysis (log rank; P = 0.01). However, on multivariable analysis, we found no significant difference in OS (hazard ratio = 1.10; 95% CI: 0.94-1.29; P = 0.22). However, when adjusting for number of positive LN removed, an increase in LN yield was associated with improved OS (hazard ratio = 0.97; 95% CI: 0.95-0.99; P = 0.01). CONCLUSION: We demonstrate that patients with mRCC and cN1 disease undergoing LND did not have a survival benefit when compared with patients undergoing CN. However, lymph node yield showed an increase in survival when adjusting for the number of positive lymph nodes. Further research and validation of the ideal number of LN removed that may benefit patients is warranted.

Role of surgical approach on lymph node dissection yield and survival in patients with upper tract urothelial carcinoma.

OBJECTIVES: With increasing utilization of robot-assisted surgery in urologic oncology, robotic nephroureterectomy (RNU) is becoming the surgical modality of choice for patients with upper tract urothelial carcinoma (UTUC). The role of surgical approach on lymph node dissection (LND) and lymph node (LN) yield is unclear, and potential therapeutic effects are unknown. Here we analyze the effects of surgical approach on LN yield, performance of LND, and overall survival (OS). METHODS AND MATERIALS: Patients with UTUC who underwent nephroureterectomy from 2010 to 2013 were identified in the National Cancer Database. Outcomes of interest included rate of LND, LN yield, and OS. Logistic regression analyses were used to predict performance of LND. Negative binomial regression was used to derive incidence rate ratios for LN yield. Cox proportional hazards models were used to quantify survival outcomes. RESULTS: A total of 3,116 patients met inclusion criteria. LND was performed in 41% (314/762) of RNU, 27% (380/1385) of LNU cases, and 35% (340/969) of ONU (P<0.001). Compared with an ONU, patients who underwent a LNU had significantly lower odds of receiving a LND (OR = 0.70, 95% CI: 0.55-0.87) and had fewer LNs removed (IRR = 0.69, 95% CI: 0.60-0.80), while RNU trended toward increased LN yield (IRR = 1.14, 95% CI: 0.98-1.33). In a Cox proportional hazards model, increasing LN yield was associated with improved OS in patients with pN0 disease (HR = 0.97 per 1 unit increase in LN yield, 95% CI: 0.95-0.99). CONCLUSIONS: Compared with an ONU, RNU does not compromise performance of a LND and may be associated with improved LN yield. LNU is associated with the lowest rates of LND and LN yield. Increasing LN yield is associated with improved OS in patients with pN0 disease. Despite differential rates of LND and LN yield, surgical approach did not independently affect OS.

Trends in usage of cytoreductive partial nephrectomy and effect on overall survival in patients with metastatic renal cell carcinoma.

PURPOSE: Cytoreductive radical nephrectomy (cRN) improves survival in select patients with metastatic renal cell carcinoma (mRCC). It is unclear, however, whether cytoreductive partial nephrectomy (cPN) compromises oncologic efficacy. We evaluated trends in utilization of cPN and compared overall survival (OS) in patients who underwent cRN or cPN for mRCC. MATERIALS AND METHODS: We queried the National Cancer Database from 2006 to 2013 and identified patients who underwent cPN and cRN for mRCC. We analyzed rates of cPN over time. Logistic regression identified predictors of cPN. We matched patients based on propensity score for treatment. We used matched Kaplan-Meier survival analyses to compare OS, stratified by tumor size. We used multivariable Cox proportional hazards models to determine the effect of cPN and cRN on OS. RESULTS: A total of 10,144 patients met inclusion criteria, with 9,764 (96.2%) undergoing cRN and 381 (3.8%) undergoing cPN. Rates of cPN increased over time from 1.8% to 4.3% over the study period. Treatment at an academic/research facility, papillary and chromophobe histology, and more recent year of treatment were associated with increased odds of cPN. In a matched survival analysis, cPN was associated with improved OS compared with cRN (log rank, P = 0.001). This effect was limited to primary tumors<4cm. In a propensity-score adjusted multivariable Cox model, cPN was associated with improved OS (hazard ratio = 0.81; 95% CI: 0.71-0.93; P = 0.002). CONCLUSIONS: The use of cPN in patients with mRCC is increasing. cPN is associated with improved OS in patients with mRCC, although this effect is limited to patients with primary tumors<4cm.

Adjuvant Therapy for High Risk Localized Kidney Cancer: Emerging Evidence and Future Clinical Trials.

PURPOSE: We reviewed the literature on adjuvant therapies for patients with high risk localized kidney cancer following surgical resection. In this analysis we merge 2 recently published prospective trials with conflicting results within the context of their respective designs. In addition, we spotlight upcoming trials that use novel immunotherapy based checkpoint inhibitors and have the potential to establish a new standard of care. MATERIALS AND METHODS: We searched PubMed® for English language articles published through January 2017 using the keywords "renal cell carcinoma," "kidney cancer," "immunotherapy," "targeted therapy" and "adjuvant therapy." ClinicalTrials.gov was queried for ongoing studies. Relevant data recently presented at major urology and medical oncology meetings are also included. RESULTS: Adjuvant therapies for high risk localized kidney cancer can be grouped into the categories of 1) traditional immunotherapy, 2) inhibitors of the vascular endothelial growth factor and mTOR (mammalian target of rapamycin) pathways, 3) vaccines and antibody dependent cytotoxic agents, and 4) immune checkpoint inhibitors. Several trials of traditional immunotherapy, such as interferon-α and high dose interleukin-2, failed to demonstrate benefit as adjuvant treatment and were associated with significant adverse events. Vascular endothelial growth factor and mTOR inhibitors have less severe toxicity in metastatic disease and, therefore, are natural considerations for adjuvant trials. However, current data are conflicting. The ASSURE (Sunitinib Malate or Sorafenib Tosylate in Treating Patients with Kidney Cancer that was Removed by Surgery, NCT00326898) trial found no recurrence-free survival benefit of sorafenib or sunitinib over placebo, while S-TRAC (Clinical Trial Comparing Efficacy and Safety of Sunitinib versus Placebo for the Treatment of Patients at High Risk of Recurrent Renal Cell Cancer, NCT00375674) revealed that 1 year of sunitinib improved recurrence-free survival by 1.2 years. Vaccine based treatments and antibody dependent cytotoxic agents have had mixed results. New trials evaluating immune checkpoint inhibitors are planned, given the impressive efficacy and tolerability as second line agents in metastatic disease. Future adjuvant trials are likely to be guided by molecular signatures to treat patients most likely to benefit. CONCLUSIONS: Based on the available data, there appears to be no role for traditional immunotherapy as adjuvant treatment in patients with high risk localized kidney cancer following surgical resection. S-TRAC provides evidence that 1 year of adjuvant sunitinib in patients with higher risk locoregional disease increases the median time to recurrence. However, the data on overall survival are immature and adverse effects are common. Results from trials investigating immune checkpoint inhibitors are highly anticipated.

Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) has been previously classified into putative discrete prognostic subtypes by gene expression profiling. To investigate the robustness of these proposed subtype classifications, we evaluated 12 public datasets, together with a new dataset of 265 ccRCC gene expression profiles. Consensus clustering showed unstable subtype and principal component analysis (PCA) showed a continuous spectrum both within and between datasets. Considering the lack of discrete delineation and continuous spectrum observed, we developed a continuous quantitative prognosis score (Continuous Linear Enhanced Assessment of RCC, or CLEAR score). Prognostic performance was evaluated in independent cohorts from The Cancer Genome Atlas (TCGA) (n = 414) and EMBL-EBI (n = 53), CLEAR score demonstrated both superior prognostic estimates and inverse correlation with anti-angiogenic tyrosine-kinase inhibition in comparison to previously proposed discrete subtyping classifications. Inverse correlation with high-dose interleukin-2 outcomes was also observed for the CLEAR score. Multiple somatic mutations (VHL, PBRM1, SETD2, KDM5C, TP53, BAP1, PTEN, MTOR) were associated with the CLEAR score. Application of the CLEAR score to independent expression profiling of intratumoral ccRCC regions demonstrated that average intertumoral heterogeneity exceeded intratumoral expression heterogeneity. Wider investigation of cancer biology using continuous approaches may yield insights into tumor heterogeneity; single cell analysis may provide a key foundation for this approach.

A phase 2 study of TMX-101, intravesical imiquimod, for the treatment of carcinoma in situ bladder cancer.

PURPOSE: Imiquimod is a toll-like receptor agonist with proven antitumor activity as a topical treatment for skin cancer. TMX-101 (Vesimune) is a novel liquid formulation of imiquimod optimized for intravesical delivery. The agent demonstrated safety as an intravesical treatment for non-muscle-invasive bladder cancer in a phase 1 clinical trial. We report the results of a phase 2 prospective multicenter clinical trial assessing the safety and activity of TMX-101. MATERIALS AND METHODS: Patients with non-muscle-invasive bladder cancer containing carcinoma in situ were eligible for inclusion. Enrolled patients received 6 weekly intravesical administrations of 200mg/50ml TMX-101 0.4%. End points included rate of adverse events, changes in urinary cytokine levels following treatment, and clinical response at 6 weeks following final instillation, defined as negative posttreatment bladder biopsy and urine cytology results. RESULTS: A total of 12 patients were enrolled, with 10 available for efficacy analysis. Half of the patients (6/12) had received≥2 prior induction courses of bacillus Calmette-Guerin. All patients received all 6 doses of TMX-101 per protocol. Overall, 75% of patients experienced treatment-related adverse events, only 1 of which was>grade 2 (urinary tract infection). Furthermore, 2 patients demonstrated a negative cytology and biopsy result at 6 weeks following treatment. Significant increases in urinary cytokines, including IL-6 and IL-18, were seen following treatment. CONCLUSION: In this phase 2 pilot study in patients with carcinoma in situ bladder cancer, intravesical TMX-101 was safe and well tolerated with common, mild genitourinary adverse effects. Clinical activity was suggested by the increase in posttreatment urinary cytokines. Complete responders were seen. Further investigation of the agent is warranted.

Serial retrograde instillations of sustained release formulation of mitomycin C to the upper urinary tract of the Yorkshire swine using a thermosensitive polymer: Safety and feasibility.

BACKGROUND: MitoGel is a novel drug formulation intended for the treatment of upper tract urothelial cancer with proven feasibility and safety in an animal model. OBJECTIVE: To evaluate the feasibility, safety, toxicokinetics, and histologic changes associated with serial retrograde MitoGel instillations to the upper urinary tract in a swine model. DESIGN, SETTING, AND PARTICIPANTS: Overall, 27 Yorkshire swine underwent 6 once-weekly unilateral retrograde instillations of MitoGel. Doses of 14, 28, or 56-mg mitomycin C (respective concentrations of 2, 4, and 8mg/ml with 9 animals per group) were evaluated. Additionally, 6 animals received sterile water as a procedure control, and 9 received gel alone (without mitomycin C), as a vehicle control. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Blood and urine samples were collected for determination of MMC toxicokinetics and for hematology, biochemistry, coagulation, and urinalysis throughout the study. Two-thirds of the cohort were euthanized 24 hours after final instillation, and one-third was euthanized 1 month after final instillation. Necropsy was performed to evaluate the histologic effects of treatments. RESULTS AND LIMITATIONS: All animals received all 6 doses of agents per protocol. No mortality, clinical adverse events, or meaningful changes in hematology, chemistry, coagulation, or urinalysis were attributable to MitoGel, RTGel alone, or water instillations. Peak plasma levels of MMC were 2 orders of magnitude less than known toxicity thresholds. MitoGel-related dose-dependent microscopic findings were seen in the treated kidneys and ureters, but were of limited severity, lacked associated clinical adverse findings, and decreased over time. CONCLUSIONS: Serial retrograde instillations of MitoGel to the pyelocaliceal system were technically feasible, and produced no observable adverse clinical, laboratory, or histologic effects.

Immunotherapy for the Treatment of Urothelial Carcinoma.

PURPOSE: We review the biological mechanisms of action, clinical safety and efficacy of immunotherapies for urothelial carcinoma. We also describe current areas of research in immunotherapy, and highlight ongoing trials and promising and novel investigational agents. MATERIALS AND METHODS: Data were obtained by a search of PubMed®, ClinicalTrials.gov and Cochrane databases for English language articles published through February 2016. Applicable abstracts from recent Society of Urologic Oncology, European Association of Urology, American Urological Association and ASCO® meetings were used. RESULTS: Bacillus Calmette-Guérin is one of the most successful immunotherapies in cancer treatment and remains the gold standard of care for patients with high risk, nonmuscle invasive bladder cancer, with initial response rates of approximately 70%. However, with the exception of valrubicin and standard chemotherapeutics there is a paucity of available treatment options for patients with recurrence or progression to more advanced disease. Recently there has been significant interest in novel immunotherapeutic agents in the management of cases where bacillus Calmette-Guérin fails, as well as cases of more advanced cancer. These investigational therapies can generally be classified into several broad categories, including recombinant bacillus Calmette-Guérin and cell wall derived therapies, cytokines, gene therapy, cancer vaccines, immune checkpoint inhibitors, oncolytic viruses, adoptive immunotherapies and immune agonists, as well as several additional immunomodulatory agents. The majority of these agents are currently under investigation in phase I or II clinical trials. Recently investigators reported evidence that inhibition of the PD-1/PD-L1 pathway has clinical activity in patients with advanced bladder cancer. These findings, along with successful phase III trials and U.S. Food and Drug Administration approvals of other checkpoint inhibitors in melanoma, nonsmall cell lung cancer and renal cell carcinoma, ultimately led to Food and Drug Administration approval of atezolizumab for advanced disease, the first new treatment approved for advanced urothelial carcinoma in 20 years. CONCLUSIONS: While bacillus Calmette-Guérin has demonstrated significant clinical efficacy in the treatment of patients with bladder cancer, additional therapies are needed for those in whom bacillus Calmette-Guérin fails, as well as for those with advanced disease. Immunotherapy for urothelial carcinoma remains a promising and active area of research, and numerous agents, particularly the monoclonal antibodies targeting checkpoint inhibition pathways, are showing encouraging signs of clinical activity.

Sustained-release Formulation of Mitomycin C to the Upper Urinary Tract Using a Thermosensitive Polymer: A Preclinical Study.

OBJECTIVE: To evaluate the safety and feasibility of single and serial instillations of MitoGel into the upper urinary tract using a preclinical swine animal model. MitoGel is a novel sustained release formulation of mitomycin C (MMC) based on RTGel, a proprietary thermosensitive hydrogel technology. MitoGel is liquid at cold temperatures and solidifies to gel state at body temperature. It is intended as a treatment for upper tract urothelial carcinoma, given its ability to provide sustained release of MMC in the upper urinary tract. MATERIALS AND METHODS: We utilized 23 pigs in a 3-phase design. All animals underwent bilateral nephrostomy tube placement. During phase 1, 3 animals underwent antegrade RTGel instillation, imaging, and euthanasia within 12 hours. In phase 2, 10 pigs underwent single antegrade instillation, unilateral nephrectomy 3 days following instillation, and contralateral nephrectomy and euthanasia 30 days following instillation. During phase 3, 10 animals underwent 6 instillations over 3 weeks, followed by bilateral nephrectomy and necropsy 30 days postinstillation. MitoGel (2 mg/mL and 4 mg/mL), aqueous MMC (2 mg/mL and 4 mg/mL), and RTGel alone were evaluated. RESULTS: MitoGel remained visible within the pelvicalyceal system on fluoroscopic and computed tomography imaging for 4-6 hours. MMC plasma levels were well within acceptable safety thresholds. There was no evidence of urinary obstruction, acute kidney injury, sepsis, or myelosuppression. Histologic changes in the urinary system were mild and transient. CONCLUSION: Antegrade MitoGel delivery to the pelvicalyceal system of Yorkshire swine is feasible and safe. Further evaluation of MitoGel in human clinical trials is warranted.

Adjuvant Weekly Girentuximab Following Nephrectomy for High-Risk Renal Cell Carcinoma: The ARISER Randomized Clinical Trial.

IMPORTANCE: Girentuximab is a chimeric monoclonal antibody that binds carbonic anhydrase IX, a cell surface glycoprotein ubiquitously expressed in clear cell renal cell carcinoma (ccRCC). Its safety and activity in phase 2 studies prompted investigation into its use as adjuvant monotherapy in participants with high-risk ccRCC. OBJECTIVE: To evaluate the safety and efficacy of adjuvant girentuximab on disease-free survival (DFS) and overall survival (OS) in patients with localized completely resected high-risk ccRCC. DESIGN, SETTING, AND PARTICIPANTS: The ARISER trial (Adjuvant Rencarex Immunotherapy Phase 3 Trial to Study Efficacy in Nonmetastatic RCC) was a randomized, double-blind, placebo-controlled phase 3 clinical trial that took place between June 10, 2004, and April 2, 2013, at 142 academic medical centers in 15 countries in North and South America and Europe. Eligible adult patients had undergone partial or radical nephrectomy for histologically confirmed ccRCC and fell into 1 of the following high-risk groups: pT3/pT4Nx/N0M0 or pTanyN+M0 or pT1b/pT2Nx/N0M0 with nuclear grade 3 or greater. Patients were assigned via central computerized double-blind 1:1 randomization to receive either a single loading dose of girentuximab, 50 mg (week 1), followed by weekly intravenous infusions of girentuximab, 20 mg (weeks 2-24), or placebo, stratified by risk group and region. The data were analyzed from March 31, 2012, to April 2, 2013. MAIN OUTCOMES AND MEASURES: Co-primary end points were DFS and OS, based on imaging studies assessed by independent radiological review committee. Secondary end points included safety, assessed as the rate and grade of adverse events. RESULTS: A total of 864 patients (66% male; median [interquartile range] age, 58 [51-65] years) were randomized to girentuximab (n = 433) or placebo (n = 431). Compared with placebo, participants treated with girentuximab had no statistically significant DFS (hazard ratio, 0.97; 95% CI, 0.79-1.18) or OS advantage (hazard ratio, 0.99; 95% CI, 0.74-1.32). Median DFS was 71.4 months (interquartile range, 3 months to not reached) for girentuximab and never reached for placebo group. Median OS was never reached regardless of treatment. Drug-related adverse events occurred in 185 patients (21.6%), reported comparably between arms. Serious adverse events occurred in 72 patients (8.4%), reported comparably between arms. One drug-related serious adverse event occurred in a patient receiving placebo. CONCLUSIONS AND RELEVANCE: Girentuximab had no clinical benefit as adjuvant treatment for patients with high-risk ccRCC. The surprisingly long DFS and OS in these patients represent a challenge to adjuvant ccRCC drug development. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00087022.

Body Mass Index and Survival in a Prospective Randomized Trial of Localized High-Risk Renal Cell Carcinoma.

BACKGROUND: The relationship between adiposity and renal cell carcinoma is poorly understood. Prior studies have suggested body mass index (BMI) may be associated with indolent disease. METHODS: We reviewed the clinicopathologic records of 845 patients across 14 countries who were enrolled in a prospective, placebo-controlled study of adjuvant girentuximab treatment for high-risk renal cell carcinoma. Clinical features analyzed included age, gender, race, BMI, and performance status. BMI was stratified into <25 kg/m(2), 25.0-29.9 kg/m(2), 30.0-34.9 kg/m(2), and ≥35 kg/m(2) We examined the association of BMI with stage and survival using logistic and Cox regression analyses, respectively. RESULTS: 845 patients were included for analysis. The majority (72%) were overweight/obese. There was an inverse relationship between BMI and lymph node involvement (P = 0.04). Obesity was associated with improved disease-free and overall survival (log rank <0.01 for both). When compared with normal weight subjects, those with a BMI 30-34.9 [HR 0.50; 95% confidence interval (CI) 0.31-0.81] and BMI ≥35 (HR 0.24; 95% CI 0.09-0.60) had significantly improved overall survival. A trend towards improved disease-free survival was found among subjects with BMI 30-34.9 (HR 0.77; 95% CI 0.56-1.05) and ≥35 (HR 0.74; 95% CI, 0.48-1.15). CONCLUSIONS: In a prospective cohort of nephrectomized patients with high-risk disease, obesity is associated with lower risk of lymphatic spread and improved overall survival. IMPACT: This is the first study utilizing data from a prospective randomized trial reporting an association between obesity and improved overall survival for patients with clear cell renal cell carcinoma. Cancer Epidemiol Biomarkers Prev; 25(9); 1326-32. ©2016 AACR.

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.

The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10(-4)), increased frequency of nonsynonymous SSNVs in Pan-Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10(-17)); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers AT-rich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.

Carbonic anhydrase-IX score is a novel biomarker that predicts recurrence and survival for high-risk, nonmetastatic renal cell carcinoma: Data from the phase III ARISER clinical trial.

INTRODUCTION AND OBJECTIVE: With a limited number of prognostic and predictive biomarkers available, carbonic anhydrase-IX (CAIX) has served as an important prognostic biomarker for patients with clear cell renal cell carcinoma (ccRCC). However, studies have recently called into question the role of CAIX as a biomarker for ccRCC. To investigate this uncertainty, we quantified the association of CAIX with lymphatic involvement and survival using data from ARISER study (WX-2007-03-HR)--a prospective trial involving subjects with high-risk nonmetastatic ccRCC. METHODS AND MATERIALS: We reviewed the records of 813 patients enrolled in the ARISER study. Central review of histology, grade, and CAIX staining (frequency and intensity) was performed. CAIX score was derived by multiplying the staining intensity (1-3) by percent positive cells (0%-100%), yielding a range of 0 to 300. We quantified the association of CAIX expression and score with lymphatic spread and survival (disease-free survival [DFS] and overall survival [OS]) using Kaplan-Meier and multivariable propensity score adjusted Cox regression analyses. RESULTS: Median follow-up of the cohort was 54.2 months. Although 56% of subjects with lymphatic involvement had CAIX>85%, only 33% had CAIX score ≥ 200. On multivariable analysis, CAIX>85% was not a statistically significant predictor of DFS and OS (P = 0.06 and P = 0.15, respectively). However, CAIX score ≥ 200, when compared with CAIX score ≤ 100, was associated with improved DFS and OS (P = 0.01 and P = 0.01, respectively) on multivariable analysis. CONCLUSIONS: The largest, multicenter, prospective analysis of patients with high-risk nonmetastatic ccRCC demonstrates the utility of CAIX score as a statistically significant prognostic biomarker for survival. We recommend that CAIX score be quantified for all patients with high-risk disease after nephrectomy.