Comparison of lumen-apposing metal stents versus endoscopic balloon dilation for the management of benign colorectal anastomotic strictures.

BACKGROUND AND AIMS: Limited data exist evaluating lumen-apposing metal stents (LAMSs) with endoscopic balloon dilation (EBD) for the treatment of benign colorectal anastomotic strictures (BCASs). This study compares outcomes of both interventions. METHODS: Patients with left-sided BCAS treated with LAMSs versus EBD were identified retrospectively. The primary outcome was a composite of crossover to another intervention to achieve clinical success or recurrence requiring reintervention. RESULTS: Twenty-nine patients (11 LAMS and 18 EBD) were identified with longer follow-up in the EBD group (734 vs 142 days; P = .003). No significant differences were found in the composite outcome, technical success, clinical success, or components of composite outcome. With LAMS, there was a nonsignificant trend toward fewer procedures (2.4 vs 3.3; P = .06) and adverse events (0% vs 16.7%; P = .26). CONCLUSIONS: LAMS appears to be as effective as EBD for the treatment of BCAS but may require fewer procedures and may be safer than EBD.

Avelumab Plus Axitinib as First-Line Therapy for Advanced Renal Cell Carcinoma: Long-Term Results from the JAVELIN Renal 100 Phase Ib Trial.

BACKGROUND: Progression-free survival was significantly longer in patients who received avelumab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma (aRCC) in a randomized phase III trial. We report long-term safety and efficacy of avelumab plus axitinib as first-line treatment for patients with aRCC from the JAVELIN Renal 100 phase Ib trial (NCT02493751). MATERIALS AND METHODS: In this open-label, multicenter, phase Ib study, patients with untreated aRCC received avelumab 10 mg/kg every 2 weeks plus axitinib 5 mg twice daily or with axitinib for 7 days followed by avelumab plus axitinib. Safety and efficacy were assessed in all patients receiving at least one dose of avelumab or axitinib. RESULTS: Overall, 55 patients were enrolled and treated. Median follow-up was 55.7 months (95% CI, 54.5-58.7). Treatment-related adverse events of any grade or grade ≥3 occurred in 54 (98.2%) and 34 (61.8%) patients, respectively. The confirmed objective response rate was 60.0% (95% CI, 45.9-73.0), including complete response in 10.9% of patients. Median duration of response was 35.9 months (95% CI, 12.7-52.9); the probability of response was 65.8% (95% CI, 46.7-79.4) at 2 years. Median progression-free survival was 8.3 months (95% CI, 5.3-32.0). Median overall survival was not reached (95% CI, 40.8-not estimable); the 5-year overall survival rate was 57.3% (95% CI, 41.2-70.5). CONCLUSION: Five-year follow-up for combination treatment with avelumab plus axitinib in previously untreated patients with aRCC showed long-term clinical activity with no new safety signals, supporting use of this regimen within its approved indication in clinical practice (Clinicaltrials.gov NCT02493751).

Long-term Outcome of Per-oral Endoscopic Myotomy Performed in the Endoscopy Unit With Trainees.

INTRODUCTION: Per-oral endoscopic myotomy (POEM) has been widely adopted for the treatment of achalasia as it provides a precise, tailored myotomy in a minimally invasive endoscopic procedure. Several short-term studies and a few long-term studies have confirmed that POEM is a safe and effective treatment for achalasia. However, the long-term outcome of POEM performed by trainees is unknown. MATERIALS AND METHODS: We conducted a retrospective study of all patients who underwent POEM for achalasia at our tertiary care center during December 2012 and January 2019. All procedures performed with trainees were included. The primary outcome was the clinical response to POEM, defined as an Eckardt score of <3 after POEM. Trainees were trained in performing mucosotomy and submucosal dissection, creating a submucosal tunnel, identifying gastroesophageal junction, and performing myotomy and closure of mucosal incision in a step-by-step fashion. Trainees' performance was evaluated by the mentor based on several key points in each step. RESULTS: A total of 153 consecutive patients with a median age of 57±18 years were analyzed in this study. Of the total patients, 69 (45%) were male. The median length of follow-up after POEM was 32 months (range: 7 to 77 mo). A clinically significant response to POEM was achieved in 95% of patients at year 1, 84% at year 2, 80% at year 3, 79% at year 4, 78% at year 5, and 78% at year 6 and above. All trainees obtained competence within 6 cases for each step and could perform the procedure alone after 20 supervised cases. CONCLUSIONS: Overall, 78% of patients maintained positive clinical response at 6 years following POEM procedure. The recurrence rate of symptoms following POEM was 22% at a 6-year follow-up. This long-term outcome of POEM performed with trainees was comparable to those without trainees in other studies. To our knowledge, this is the longest follow-up and the largest number of patients after the POEM procedure performed with trainees.

STAG2 as a prognostic biomarker in low-grade non-muscle invasive bladder cancer.

OBJECTIVE: Improvements to bladder cancer risk stratification guidelines are needed to better tailor post-operative surveillance and adjuvant therapy to individual patients. We previously identified STAG2 as a commonly mutated tumor suppressor gene in bladder cancer and an independent predictor of progression in NMIBC. Here we test the value of combining STAG2 immunostaining with other risk stratification biomarkers in NMIBC, and as an individual biomarker in MIBC. MATERIALS AND METHODS: STAG2 immunohistochemistry was performed on a progressor-enriched cohort of tumors from 297 patients with NMIBC, and on tumors from 406 patients with MIBC from Aarhus University Hospital in Denmark. Survival analysis was performed using Kaplan-Meier survival analysis, the log rank test, and Cox proportional hazards models. RESULTS: STAG2-negative low-grade NMIBC tumors were 2.5 times less likely to progress to muscle invasion than STAG2-positive low-grade NMIBC tumors (Log-rank test, P = 0.008). In a composite group of patients with AUA intermediate and high-risk NMIBC tumors, STAG2-negative tumors were less likely to progress (Log-rank test, P = 0.02). In contrast to NMIBC, we show that STAG2 is not useful as a prognostic biomarker in MIBC. CONCLUSIONS: STAG2 immunostaining can be used to subdivide low-grade NMIBC tumors into two groups with substantially different risks of disease progression. Furthermore, STAG2 immunostaining may be useful to enhance NMIBC risk stratification guidelines, though larger cohorts are needed to solidify this conclusion in individual risk groups. STAG2 is not useful as a biomarker in MIBC. Further study of the use of STAG2 immunostaining as a biomarker for predicting the clinical behavior in NMIBC is warranted.

Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer.

PURPOSE: Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. "Switch maintenance" therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons. PATIENTS AND METHODS: Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS). RESULTS: Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival. CONCLUSION: Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.

Fidelity of a PDX-CR model for bladder cancer.

Patient-derived xenografts (PDXs) are widely recognised as a more physiologically relevant preclinical model than standard cell lines, but are expensive and low throughput, have low engraftment rate and take a long time to develop. Our newly developed conditional reprogramming (CR) technology addresses many PDX drawbacks, but lacks many in vivo factors. Here we determined whether PDXs and CRCs of the same cancer origin maintain the biological fidelity and complement each for translational research and drug development. Four CRC lines were generated from bladder cancer PDXs. Short tandem repeat (STR) analyses revealed that CRCs and their corresponding parental PDXs shared the same STRs, suggesting common cancer origins. CRCs and their corresponding parental PDXs contained the same genetic alterations. Importantly, CRCs retained the same drug sensitivity with the corresponding downstream signalling activity as their corresponding parental PDXs. This suggests that CRCs and PDXs can complement each other, and that CRCs can be used for in vitro fast, high throughput and low cost screening while PDXs can be used for in vivo validation and study of the in vivo factors during translational research and drug development.

STAG2 Is a Biomarker for Prediction of Recurrence and Progression in Papillary Non-Muscle-Invasive Bladder Cancer.

Purpose: Most bladder cancers are early-stage tumors known as papillary non-muscle-invasive bladder cancer (NMIBC). After resection, up to 70% of NMIBCs recur locally, and up to 20% of these recurrences progress to muscle invasion. There is an unmet need for additional biomarkers for stratifying tumors based on their risk of recurrence and progression. We previously identified STAG2 as among the most commonly mutated genes in NMIBC and provided initial evidence in a pilot cohort that STAG2-mutant tumors recurred less frequently than STAG2 wild-type tumors. Here, we report a STAG2 biomarker validation study using two independent cohorts of clinically annotated papillary NMIBC tumors from the United States and Europe.Experimental Design: The value of STAG2 immunostaining for prediction of recurrence was initially evaluated in a cohort of 82 patients with papillary NMIBC ("Georgetown cohort"). Next, the value of STAG2 immunostaining for prediction of progression to muscle invasion was evaluated in a progressor-enriched cohort of 253 patients with papillary NMIBC ("Aarhus cohort").Results: In the Georgetown cohort, 52% of NMIBC tumors with intact STAG2 expression recurred, whereas 25% of STAG2-deficient tumors recurred (P = 0.02). Multivariable analysis identified intact STAG2 expression as an independent predictor of recurrence (HR = 2.4; P = 0.05). In the progressor-enriched Aarhus cohort, 38% of tumors with intact STAG2 expression progressed within 5 years, versus 16% of STAG2-deficient tumors (P < 0.01). Multivariable analysis identified intact STAG2 expression as an independent predictor of progression (HR = 1.86; P = 0.05).Conclusions: STAG2 IHC is a simple, binary, new assay for risk stratification in papillary NMIBC. Clin Cancer Res; 24(17); 4145-53. ©2018 AACR.

Urinary Bladder Cancer in Egypt: Are There Gender Differences in Its Histopathological Presentation?

We investigated gender differences in the histopathologic presentation of bladder cancer cases in Egypt, where both urothelial cell carcinoma (UC) and squamous cell carcinoma (SCC) types are highly prevalent. We used logistic regression to estimate the unadjusted (OR) and adjusted odds ratio (AOR) and 95% confidence interval (CI) of the associations between gender and different histopathologic and sociodemographic parameters of 2,186 confirmed cases of primary bladder cancer (1,775 males and 411 females; 784 SCC and 1,402 UC). There were no statistically significant gender differences in tumor grade, stage, mucosal ulcer, or inflammatory cystitis, regardless of the cancer type, but men were less likely than women to have undergone cystectomy with pelvic lymphadenectomy. Having Schistosoma haematobium (SH) ova in the bladder tissue was significantly associated with male gender in the fully adjusted model of either SCC (AOR (95% CI) = 2.12 (1.15-3.89)) or UC cases (3.78 (1.89-7.55)). Compared to females, male cases were significantly older at time of diagnosis and smokers. In Egypt, regardless of the type of bladder cancer (SCC or UC), male more than female cases had evidence of SH infection, but not other histopathologic differences, in bladder tissue specimens.

Outcomes and quality of life assessment after per oral endoscopic myotomy (POEM) performed in the endoscopy unit with trainees.

BACKGROUND: Per oral endoscopic myotomy (POEM) has emerged as a promising option for the treatment of achalasia. This study assessed POEM training process, outcomes, and improvement in quality of life after POEM performed by an interventional endoscopist (mentor) with trainees. METHODS: We performed a retrospective review of data for patients who underwent POEM with involvement of trainees. Trainees were trained in performing mucosotomy, submucosal dissection, creating submucosal tunnel, identifying gastroesophageal junction, myotomy, and closure of mucosal incision in a step-by-step fashion. Trainees' performance on each step was evaluated by the mentor based on several key points in each step. The short form 36 (SF36) was obtained before and certain times after the primary POEM procedure was performed. RESULTS: Sixty-two patients, 26 males and 36 females with a mean age of 59 years, who underwent POEM were enrolled. A checklist included all related items for each step was established. All trainees obtained competence within 6 cases for each step. 61/62 (98.3%) patients had a significant improvement in the Eckardt's score post POEM: 9.3 ± 1.5 prior to POEM and 2.6 ± 1.2 after the POEM (P = 0.001) and a decrease in mean lower esophageal sphincter pressure (LES): pre- and post-procedure mean LES pressures were 28.5 ± 11.4 and 12.1 ± 4.5 mmHg, respectively (P = 0.001). The SF-36 questionnaire demonstrated a significant improvement in quality of life and comparable with those without trainees in other studies. CONCLUSION: This preliminary study showed for the first time that training for POEM can be performed in a step-by-step fashion, learning mucosal incision, submucosal dissection, myotomy, and mucosal incision closure from an expert interventional endoscopist without increasing adverse events. The checklist for each step could be used as an important guide in training POEM. The outcomes of POEM in this study were similar to those reported by others without trainees. Further multiple center studies are needed to verify this training process and to establish a formal training protocol.

Intrapancreatic Enteric Duplication Cyst Masquerading as Groove Pancreatitis.

Intrapancreatic enteric duplication cysts are exceedingly rare, and the clinical presentation varies. We present a 48-year-old man with significant alcohol and tobacco abuse and a diagnosis of groove pancreatitis complicated by a pancreatic duct stricture, pseudocyst, and recurrent biliary obstruction. Due to failure of endoscopic therapy and concerning findings on endoscopic ultrasound with negative pathology, he underwent a pancreaticoduodenectomy. Pathology revealed an intrapancreatic enteric duplication cyst, minimal chronic pancreatitis changes associated with pancreaticobiliary strictures, and no evidence of malignancy. This rare diagnosis should be considered in the differential for patients with idiopathic recurrent pancreaticobiliary duct strictures and pancreatic pseudomasses.

Utilization and predictors of expectant management among elderly men with low-and intermediate-risk localized prostate cancer in U.S. urological practice.

INTRODUCTION: Expectant management (EM) reduces overtreatment in low-risk but not intermediate-risk localized prostate cancer (PCa). We assessed the use and predictors of EM to understand its uptake in U.S. practice. METHODS: Using the U.S. SEER-Medicare database, we conducted a retrospective cohort study of men 66 years and older diagnosed with low-risk (N=25,506) or intermediate-risk (N=25,597) localized PCa between 2004 - 2011 and followed through December 31, 2012. We defined EM as no definitive therapy (DT) and at least one prostate-specific antigen (PSA) test or re-biopsy 4 - 12 months post diagnosis; or receiving DT after PSA testing or re-biopsy 7 - 12 months after diagnosis. We performed separate analyses for low-risk and intermediate-risk groups using multiple logistic regressions. RESULTS: For men diagnosed with PCa in 2004-2011, EM increased from 22% to 43% in the low-risk group and from 15% to 18% in the intermediate-risk group. In the low-risk group, EM increased with patients' age (adjusted odds ratio [aOR] = 1.26 for 71-75 years; 2.21 for 76-80 years; 6.33 for older then 80, p<0.0001, compared to 66-70 years). EM uptake was higher among men with comorbidities (aOR=1.29), and residing in the Pacific region (aOR=0.56, compared to the East Coast). CONCLUSIONS: In U.S. practice, the utilization of EM steadily increased in low-risk PCa and remained low in the intermediate-risk group over time. While patients with advanced age or comorbidities were more likely to receive EM, its use varied substantially by geographic region. Our findings bring attention to the presence of multiple barriers for EM implementation.

Physicians' Perceptions of Factors Influencing the Treatment Decision-making Process for Men With Low-risk Prostate Cancer.

OBJECTIVE: To assess physicians' attitudes regarding multiple factors that may influence recommendations for active surveillance (AS) vs active treatment (AT) given the central role physicians play in the treatment decision-making process. MATERIALS AND METHODS: We conducted semistructured interviews to assess factors that physicians consider important when recommending AS vs AT, as well as physicians' perceptions of what their patients consider important in the decision. Participants included urologists (N = 11), radiation oncologists (N = 12), and primary care physicians (N = 10) from both integrated and fee-for-service healthcare settings. RESULTS: Across the specialties, quantitative data indicated that most physicians reported that their recommendations for AS were influenced by patients' older age, willingness and ability to follow a surveillance protocol, anxiety, comorbidities, life expectancy, and treatment preferences. Qualitative findings highlighted physicians' concerns about malpractice lawsuits, given the possibility of disease progression. Additionally, most physicians noted the role of the healthcare setting, suggesting that financial incentives may be associated with AT recommendations in fee-for-service settings. Finally, most physicians reported spouse or family opposition to AS due to their own anxiety or lack of understanding of AS. CONCLUSION: We found that patient and physician preferences, healthcare setting, and family or spouse factors influence physicians' treatment recommendations for men with low-risk PCa. These were consistent themes across physician subspecialties in both an Health Maintenance Organization and in fee-for-service settings.

Risks of Serious Toxicities from Intermittent versus Continuous Androgen Deprivation Therapy for Advanced Prostate Cancer: A Population Based Study.

PURPOSE: Randomized trials have shown that intermittent androgen deprivation therapy for patients with advanced prostate cancer may improve sexual and physical functioning compared to continuous androgen deprivation therapy without compromising survival. To our knowledge it is unknown whether intermittent androgen deprivation therapy alters the risk of serious toxicities associated with continuous androgen deprivation therapy. MATERIALS AND METHODS: We performed a population based cohort study of 9,772 men 66 years old or older who were diagnosed with advanced prostate cancer from 2002 to 2011 and treated with androgen deprivation therapy. Intermittent androgen deprivation therapy was defined as a single 90-day interval between 2 androgen deprivation therapy sessions during which patients visited their physicians or underwent prostate specific antigen testing. Outcomes included acute myocardial infarction, stroke, heart failure, type 2 diabetes and fracture. We used Cox proportional hazard models to estimate the HRs of the comparative risk of serious toxicities between intermittent and continuous androgen deprivation therapy. RESULTS: A total of 2,113 (22%), 769 (9%) and 899 men (9%) had a new cardiovascular event, diabetes or fracture, respectively, within 5 years of starting androgen deprivation therapy. Compared to the continuous androgen deprivation therapy group, the intermittent therapy group was at lower risk for serious cardiovascular events (HR 0.64, 95% CI 0.53-0.77), particularly in reducing the risk of heart failure (HR 0.62, 95% CI 0.49-0.78) and fracture (HR 0.52, 95% CI 0.38-0.70, each p <0.0001). CONCLUSIONS: Intermittent androgen deprivation therapy was associated with a lower risk of heart failure and fracture compared to continuous androgen deprivation therapy. This raises toxicity concerns for continuous relative to intermittent therapy and suggests that intermittent androgen deprivation therapy may represent a safer therapeutic choice in elderly men with advanced prostate cancer.

Emerging monoclonal antibodies for the treatment of renal cell carcinoma (RCC).

INTRODUCTION: Advanced renal cell carcinoma (RCC) was considered refractory to most cancer therapies until the 1980s, after which immune modulating agents and targeted agents were developed. Recently the rapid development of therapeutic monoclonal antibodies targeting immune checkpoint pathways has provided significant clinical benefit in patients with many distinct cancer types. Nivolumab, an anti-PD1 monoclonal antibody showed improvement in response rate and overall survival in patients with previously treated RCC and received US FDA approval in late 2015. Current efforts with anti-PD1-based therapy include combinations with ipilimumab and with VEGF pathway blockers in the hopes on building on the activity of single agent therapy. AREAS COVERED: We describe our current understanding of tumor immunology including the basis of the tumor-specific immune response and the adaptive mechanisms used by the tumor for immune escape. We describe the mechanisms of action as well as the therapeutic application of the antibodies, ipilimumab, nivolumab and atezolizumab in patients with RCC. We identify key areas of active research in biomarker development and combination therapies. EXPERT OPINION: Clinical trials and the field of RCC therapeutics are expected to move in the direction of combination therapies using immune checkpoint inhibitors, extending overall survival as a benchmark for new drug approvals, and biomarker validation for improved selection of patients for specific therapies.

Soft computing model for optimized siRNA design by identifying off target possibilities using artificial neural network model.

The ability of small interfering RNA (siRNA) to do posttranscriptional gene regulation by knocking down targeted genes is an important research topic in functional genomics, biomedical research and in cancer therapeutics. Many tools had been developed to design exogenous siRNA with high experimental inhibition. Even though considerable amount of work has been done in designing exogenous siRNA, design of effective siRNA sequences is still a challenging work because the target mRNAs must be selected such that their corresponding siRNAs are likely to be efficient against that target and unlikely to accidentally silence other transcripts due to sequence similarity. In some cases, siRNAs may tolerate mismatches with the target mRNA, but knockdown of genes other than the intended target could make serious consequences. Hence to design siRNAs, two important concepts must be considered: the ability in knocking down target genes and the off target possibility on any nontarget genes. So before doing gene silencing by siRNAs, it is essential to analyze their off target effects in addition to their inhibition efficacy against a particular target. Only a few methods have been developed by considering both efficacy and off target possibility of siRNA against a gene. In this paper we present a new design of neural network model with whole stacking energy (ΔG) that enables to identify the efficacy and off target effect of siRNAs against target genes. The tool lists all siRNAs against a particular target with their inhibition efficacy and number of matches or sequence similarity with other genes in the database. We could achieve an excellent performance of Pearson Correlation Coefficient (R=0. 74) and Area Under Curve (AUC=0.906) when the threshold of whole stacking energy is ≥-34.6 kcal/mol. To the best of the author's knowledge, this is one of the best score while considering the "combined efficacy and off target possibility" of siRNA for silencing a gene. The proposed model shall be useful for designing exogenous siRNA for therapeutic applications and gene silencing techniques in the area of bioinformatics. The software is developed as a desktop application and available at http://opsid.in/opsid/.

Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies.

Despite extensive investigation over the past three decades, cancer immunotherapy has produced limited success, with few agents achieving approval by the Food and Drug Administration and even the most effective helping only a minority of patients, primarily with melanoma or renal cancer. In recent years, immune checkpoints that maintain physiologic self-tolerance have been implicated in the down-regulation of anti-tumor immunity. Efforts to restore latent anti-tumor immunity have focused on antibody-based interventions targeting CTL antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on T lymphocytes and its principal ligand (PD-L1) on tumor cells. Ipilimumab, an antibody targeting CTLA-4, appears to restore tumor immunity at the priming phase, whereas anti-PD-1/PD-L1 antibodies restore immune function in the tumor microenvironment. Although ipilimumab can produce durable long-term responses in patients with advanced melanoma, it is associated with significant immune-related toxicities. By contrast, antibodies targeting either PD-1 or PD-L1 have produced significant anti-tumor activity with considerably less toxicity. Activity was seen in patients with melanoma and renal cancer, as well as those with non-small-cell lung, bladder and head and neck cancers, tumors not previously felt to be sensitive to immunotherapy. The tolerability of PD-1-pathway blockers and their unique mechanism of action have made them ideal backbones for combination regimen development. Combination approaches involving cytotoxic chemotherapy, anti-angiogenic agents, alternative immune-checkpoint inhibitors, immunostimulatory cytokines and cancer vaccines are currently under clinical investigation. Current efforts focus on registration trials of single agents and combinations in various diseases and disease settings and identifying predictive biomarkers of response.

New agents and new targets for renal cell carcinoma.

The vascular endothelial growth factor (VEGF) pathway blockers and mammalian target of rapamycin (mTOR) inhibitors have dramatically improved the treatment options and outcome for patients with advanced renal cell carcinoma (RCC). However, because the vast majority of patients will still succumb to their disease, novel treatment approaches are still necessary. Efforts to identify novel therapeutic target treatments are focused on better understanding unique aspects of tumor cell biology guided the Cancer Genome Atlas analyses and the interaction of the tumor with its microenvironment. Areas of promising investigation include a) the identification of mechanisms of acquired resistance to VEGF pathway inhibition and developing agents targeting these in combination with VEGF receptor (VEGFR) pathway blockade; b) the identification of novel therapeutic targets, particularly for patients with VEGF pathway blocker refractory disease; and c) the development of novel immunotherapies, particularly those involving checkpoint inhibitors used alone or in combination with other immunotherapies of VEGF pathway blockers. Specific targets or agents of interest include angiopoietins (trebaninib), c-Met (cabozantinib), activin receptor-like kinase-1 (ALK-1; dalantercept), interleukin (IL)-8, and HDM2 for acquired resistance to VEGF pathway inhibition; hypoxia inducible factor-2 alpha (HIF-2 alpha), TORC1/2, and the Hippo pathway for novel targets, and PD1 and PDL1 antibodies given either alone or in combination with other checkpoint inhibitors, other immunotherapies, or VEGF pathway blockers for novel immunotherapies. In addition, the application of genetic, immunologic, or other biomarkers developed in the context of this research has the potential to select patients with specific tumor types for therapy targeted to specific vulnerabilities within the tumor or tumor microenvironment. Together, these developments should enable the transition to a new era of rational and more effective therapy for patients with advanced RCC.