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Background: Most safety and efficacy trials of the SARS-CoV-2 vaccines excluded patients with cancer, yet these patients are more likely than healthy individuals to contract SARS-CoV-2 and more likely to become seriously ill after infection. Our objective was to record short-term adverse reactions to the COVID-19 vaccine in patients with cancer, to compare the magnitude and duration of these reactions with those of patients without cancer, and to determine whether adverse reactions are related to active cancer therapy. Patients and Methods: A prospective, single-institution observational study was performed at an NCI-designated Comprehensive Cancer Center. All study participants received 2 doses of the Pfizer BNT162b2 vaccine separated by approximately 3 weeks. A report of adverse reactions to dose 1 of the vaccine was completed upon return to the clinic for dose 2. Participants completed an identical survey either online or by telephone 2 weeks after the second vaccine dose. Results: The cohort of 1,753 patients included 67.5% who had a history of cancer and 12.0% who were receiving active cancer treatment. Local pain at the injection site was the most frequently reported symptom for all respondents and did not distinguish patients with cancer from those without cancer after either dose 1 (39.3% vs 43.9%; P=.07) or dose 2 (42.5% vs 40.3%; P=.45). Among patients with cancer, those receiving active treatment were less likely to report pain at the injection site after dose 1 compared with those not receiving active treatment (30.0% vs 41.4%; P=.002). The onset and duration of adverse events was otherwise unrelated to active cancer treatment. Conclusions: When patients with cancer were compared with those without cancer, few differences in reported adverse events were noted. Active cancer treatment had little impact on adverse event profiles.

To investigate the difference in renal function outcomes for patients with oncocytomas undergoing active surveillance (AS) vs. partial nephrectomy (PN).We reviewed our institutional database for patients with biopsy/surgically confirmed oncocytoma from 2000-2020. The primary outcome was to assess for differences in renal function outcomes in patients undergoing AS vs. PN. We fit two generalized estimating equation (GEE) with an interaction term between follow up time and management strategy to predict 1) mean eGFR for patients managed with AS and PN and 2) the probability of progression to CKD stage III or greater.We identified 114 eligible patients, of which 32 were managed with AS. Median follow-up was 21 months vs. 44 months for PN vs. AS patients. AS patients tended to be older (median: 72 years vs. 65 years, P0.001) and have lower baseline renal function (median: eGFR: 71 mL/min/1.73mIn our institutional dataset, patients undergoing AS or PN with an oncocytoma had similar long-term renal function outcomes. Given similar renal function outcomes in patients undergoing AS and PN, surgery should remain reserved for select patients with oncocytomas.

Background Multi-targeted tyrosine kinase inhibitors (TKIs) are the standard of care for patients with advanced clear cell renal cell carcinoma (ccRCC). However, a significant number of ccRCC patients are primarily refractory to targeted therapeutics, showing neither disease stabilisation nor clinical benefits. Methods We used CRISPR/Cas9-based high-throughput loss of function (LOF) screening to identify cellular factors involved in the resistance to sunitinib. Next, we validated druggable molecular factors that are synthetically lethal with sunitinib treatment using cell and animal models of ccRCC. Results Our screening identified farnesyltransferase among the top hits contributing to sunitinib resistance in ccRCC. Combined treatment with farnesyltransferase inhibitor lonafarnib potently augmented the anti-tumour efficacy of sunitinib both in vitro and in vivo. Conclusion CRISPR/Cas9 LOF screening presents a promising approach to identify and target cellular factors involved in the resistance to anti-cancer therapeutics.

Kidney cancer is one of the 10 most common cancers both in the United States and worldwide. Until this year, there had not previously been a conference focused on translational studies in the broad and heterogeneous group of kidney cancers. Therefore, a group of researchers, clinicians, and patient advocates dedicated to renal cell carcinoma launched the Kidney Cancer Research Summit (KCRS) to spur collaboration and further therapeutic advances in these tumors. This commentary aims to summarize the oral presentations and serve as a record for future iterations of this meeting. The KCRS sessions addressed the tumor microenvironment, novel methods of drug delivery, single cell sequencing strategies, novel immune checkpoint blockade and cellular therapies, predictive biomarkers, and rare variants of kidney cancers. In addition, the meeting included 2 sessions to promote scientific mentoring and kidney cancer research collaborations. A subsequent KCRS will be planned for the fall of 2020.

To investigate the association of surgical approach with outcomes in patients with adrenocortical carcinomas smaller and larger than 6 cm in size.We reviewed the national cancer database for patients undergoing minimally invasive adrenalectomy (MIA) and open adrenalectomy (OA) from 2010 to 2017. To adjust for differences between patients undergoing MIA and OA, we performed propensity score matching within each size strata of ≤6 cm, 6.1 to 10 cm, and 10.1 to 20 cm. We fit generalized estmiating equations with a logit link function to assess for the association of surgical approach with positive surgical margins and a Cox proportional hazards model to assess for the association of surgical approach with overall survival.We identified 364 patients that underwent MIA (182) and OA (182) in the matched cohort. We noted 21% and 18% of patients undergoing MIA and OA had a positive surgical margin, respectively. We did not identify a significant association between surgical approach and positive surgical margins in the cohort as a whole or within each of strata. Furthermore, we did not appreciate a significant association between surgical approach and overall survival in the cohort as a whole or within each size strata.In the National Cancer Database, patients undergoing MIA had similar positive surgical margins and overall survival compared with OA for masses ≤6 cm, 6.1 to 10cm, and10 cm in size. Patients undergoing MIA should be carefully selected with surgical oncologic integrity being the primary determinants of surgical approach.

Item does not contain fulltext INTRODUCTION: We aimed to compare the outcomes of open vs robotic partial nephrectomy (PN), focusing on predictors of Trifecta failure in patients with highly complex renal masses. PATIENTS AND METHODS: We queried the prospectively collected database from the SIB International Consortium, including 507 consecutive patients with cT1-2N0M0 renal masses treated at 16 high-volume referral centres, to select those with highly complex (PADUA score ≥10) tumors undergoing PN. RT was classified as enucleation, enucleoresection or resection according to the SIB score. Trifecta was defined as achievement of negative surgical margins, no acute kidney injury and no Clavien-Dindo grade ≥2 postoperative surgical complications. Multivariable logistic regression analysis was used to assess independent predictors of Trifecta failure. RESULTS: 113 patients were included. Patients undergoing open PN (n = 47, 41.6%) and robotic PN (n = 66, 58.4%) were comparable in baseline characteristics. RT was classified as enucleation, enucleoresection and resection in 46.9%, 34.0% and 19.1% of open PN, and in 50.0%, 40.9% and 9.1% of robotic PN (p = 0.28). Trifecta was achieved in significantly more patients after robotic PN (69.7% vs. 42.6%, p = 0.004). On multivariable analysis, surgical approach (open vs robotic, OR: 2.62; 95%CI: 1.11-6.15, p = 0.027) and tumor complexity (OR for each additional unit of the PADUA score: 2.27; 95%CI: 1.27-4.06, p = 0.006) were significant predictors of Trifecta failure, while RT was not. The study is limited by lack of randomization; as such, selection bias and confounding cannot be entirely ruled out. CONCLUSIONS: Tumor complexity and surgical approach were independent predictors of Trifecta failure after PN for highly complex renal masses.

The commonly used therapeutic management of PC involves androgen deprivation therapy (ADT) followed by treatment with AR signaling inhibitors (ARSI). However, nearly all patients develop drug-resistant disease, with a median progression-free survival of less than 2 years in chemotherapy-naïve men. Acetyl-coenzyme A (acetyl-CoA) is a central metabolic signaling molecule with key roles in biosynthetic processes and cancer signaling. In signaling, acetyl-CoA serves as the acetyl donor for acetylation, a critical post-translational modification. Acetylation affects the androgen receptor (AR) both directly and indirectly increasing expression of AR dependent genes. Our studies reveal that PC cells respond to the treatment with ARSI by increasing expression of ATP-citrate lyase (ACLY), a major enzyme responsible for cytosolic acetyl-CoA synthesis, and up-regulation of acetyl-CoA intracellular levels. Inhibition of ACLY results in a significant suppression of ligand-dependent and -independent routes of AR activation. Accordingly, the addition of exogenous acetyl-CoA, or its precursor acetate, augments AR transcriptional activity and diminishes the anti-AR activity of ARSI. Taken together, our findings suggest that PC cells respond to antiandrogens by increasing activity of the acetyl-coA pathway in order to reinstate AR signaling.

INTRODUCTION AND OBJECTIVE:Immune checkpoint inhibitors (ICI) are gaining acceptance in the management of metastatic renal cell carcinoma (mRCC) with four FDA approved regimens to date. However, da...

In the National Cancer Database (NCDB), patients treated with minimally invasive adrenalectomy (MIA) for adrenocortical carcinoma (ACC) had similar oncological outcomes and cumulative treatment burden with less morbidity compared with open adrenalectomy (OA). Although OA remains the standard of care for adrenal lesions concerninge for malignancy, MIA in appropriately selected patients may offer equivalent oncological outcomes.We investigated the cumulative treatment burden, oncological effectiveness, and perioperative morbidity in patients undergoing MIA compared with (OA) for patients with ACC.We reviewed the NCDB for patients undergoing surgical resection (MIA vs. OA) for ACC from 2010 to 2017. Inverse probability of treatment weighted logistic regression, negative binomial, and Cox proportional hazards models were fit to assess for an association of surgical approach with cumulative treatment burden (any adjuvant therapy, radiation therapy [RT], and systemic therapy), oncological effectiveness (positive surgical margins [PSM], lymph node yield [LNY], and overall survival [OS]), and perioperative morbidity (length of stay [LOS] and readmission) as appropriate.We identified 776 patients that underwent adrenalectomy for ACC, of which 307 underwent MIA. We noted patients with larger tumors (OR 0.82, 95% CI 0.78-0.86, P.001) were less likely to have MIA prior to IPTW. We did not appreciate a significant association of MIA with cumulative treatment burden or the use of any adjuvant therapy (OR 0.85, 95% CI 0.60-1.21, P = .375), adjuvant RT (OR 0.94, 95% CI 0.59-1.50, P = .801), or adjuvant systemic therapy (OR 0.84, 95% CI 0.58-1.21, P = .352). Patients undergoing MIA had similar oncological effectiveness of surgery and OS when compared with patients which underwent OA. Patients that underwent MIA had a significantly shorter LOS (IRR: 0.74, 95% CI 0.62-0.88, P = .001) and lower odds of readmission (OR 0.46, 95% CI 0.23-0.91, P = .026).Although the standard of care for adrenal lesions suspicious for ACC remains OA, in appropriately selected patients, MIA may offer similar oncological effectiveness and cumulative treatment burden, with less morbidity, than OA.

BRCA1-associated protein 1 (BAP1) is a deubiquitinase that is mutated in 10-15% of clear cell renal cell carcinomas (ccRCC). Despite the association between BAP1 loss and poor clinical outcome, the critical tumor suppressor function(s) of BAP1 in ccRCC remains unclear. Previously, we found that hypoxia-inducible factor 2α (HIF2α) and BAP1 activate interferon-stimulated gene factor 3 (ISGF3), a transcription factor activated by type I interferons and a tumor suppressor in ccRCC xenograft models. Here, we aimed to determine the mechanism(s) through which HIF and BAP1 regulate ISGF3. We found that in ccRCC cells, loss of the von Hippel-Lindau tumor suppressor (VHL) activated interferon beta (IFN-β) expression in a HIF2α-dependent manner. IFN-β was required for ISGF3 activation and suppressed the growth of Ren-02 tumors in xenografts. BAP1 enhanced the expression of IFN-β and stimulator of interferon genes (STING), both of which activate ISGF3. Both ISGF3 overexpression and STING agonist treatment increased ISGF3 activity and suppressed BAP1-deficient tumor growth in Ren-02 xenografts. Our results indicate that BAP1 loss reduces type I interferon signaling, and reactivating this pathway may be a novel therapeutic strategy for treating ccRCC.

Importance: Early in the COVID-19 pandemic, racial/ethnic minority communities disproportionately experienced poor outcomes; however, the association of the pandemic with prostate cancer (PCa) care is unknown. Objective: To assess the association between race and PCa care delivery for Black and White patients during the first wave of the COVID-19 pandemic. Design, Setting, and Participants: This multicenter, regional, collaborative, retrospective cohort study compared prostatectomy rates between Black and White patients with untreated nonmetastatic PCa during the COVID-19 pandemic (269 patients from March 16 to May 15, 2020) and prior (378 patients from March 11 to May 10, 2019). Main Outcomes and Measures: Prostatectomy rates. Results: Of the 647 men with nonmetastatic PCa, 172 (26.6%) were non-Hispanic Black men, and 475 (73.4%) were non-Hispanic White men. Black men were significantly less likely to undergo prostatectomy during the pandemic compared with White patients (1 of 76 [1.3%] vs 50 of 193 [25.9%]; P < .001), despite similar COVID-19 risk factors, biopsy Gleason grade groups, and comparable prostatectomy rates prior to the pandemic (17 of 96 [17.7%] vs 54 of 282 [19.1%]; P = .75). Black men had higher median prostate-specific antigen levels prior to biopsy (8.8 ng/mL [interquartile range, 5.3-15.2 ng/mL] vs 7.2 ng/mL [interquartile range, 5.1-11.1 ng/mL]; P = .04). A linear combination of regression coefficients with an interaction term for year demonstrated an odds ratio for likelihood of surgery of 0.06 (95% CI, 0.01-0.35; P = .002) for Black patients and 1.41 (95% CI, 0.81-2.44; P = .23) for White patients during the pandemic compared with prior to the pandemic. Changes in surgical volume varied by site (from a 33% increase to complete shutdown), with sites that experienced the largest reduction in cancer surgery caring for a greater proportion of Black patients. Conclusions and Relevance: In this large multi-institutional regional collaborative cohort study, the odds of PCa surgery were lower among Black patients compared with White patients during the initial wave of the COVID-19 pandemic. Although localized PCa does not require immediate treatment, the lessons from this study suggest systemic inequities within health care and are likely applicable across medical specialties. Public health efforts are needed to fully recognize the unintended consequence of diversion of cancer resources to the COVID-19 pandemic to develop balanced mitigation strategies as viral rates continue to fluctuate.

Purpose: The use of VEGFR TKIs for the adjuvant treatment of renal cell carcinoma (RCC) remains controversial. We investigated the effects of adjuvant VEGFR TKIs on circulating cytokines in the ECOG-ACRIN 2805 (ASSURE) trial. Experimental Design: Patients with resected high-risk RCC were randomized to sunitinib, sorafenib, or placebo. Plasma from 413 patients was analyzed from post-nephrectomy baseline, 4 weeks, and 6 weeks after treatment initiation. Mixed effects and Cox proportional hazards models were used to test for changes in circulating cytokines and associations between disease-free survival (DFS) and cytokine levels. Results: VEGF and PlGF increased after 4 weeks on sunitinib or sorafenib (P < 0.0001 for both) and returned to baseline at 6 weeks on sunitinib (corresponding to the break in the sunitinib schedule) but not sorafenib (which was administered continuously). sFLT-1 decreased after 4 weeks on sunitinib and 6 weeks on sorafenib (P < 0.0001). sVEGFR-2 decreased after both 4 and 6 weeks of treatment on sunitinib or sorafenib (P < 0.0001). Patients receiving placebo had no significant changes in cytokine levels. CXCL10 was elevated at 4 and 6 weeks on sunitinib and sorafenib but not on placebo. Higher baseline CXCL10 was associated with worse DFS (HR 1.41 per log increase in CXCL10, Bonferroni-adjusted P = 0.003). This remained significant after adjustment for T-stage, Fuhrman grade, and ECOG performance status. Conclusions: Among patients treated with adjuvant VEGFR TKIs for RCC, drug–host interactions mediate changes in circulating cytokines. Elevated baseline CXCL10 was associated with worse DFS. Studies to understand functional consequences of these changes are under way.

PURPOSE To validate currently used recurrence prediction models for renal cell carcinoma (RCC) by using prospective data from the ASSURE (ECOG-ACRIN E2805; Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) adjuvant trial. PATIENTS AND METHODS Eight RCC recurrence models (University of California at Los Angeles Integrated Staging System [UISS]; Stage, Size, Grade, and Necrosis [SSIGN]; Leibovich; Kattan; Memorial Sloan Kettering Cancer Center [MSKCC]; Yaycioglu; Karakiewicz; and Cindolo) were selected on the basis of their use in clinical practice and clinical trial designs. These models along with the TNM staging system were validated using 1,647 patients with resected localized high-grade or locally advanced disease (≥ pT1b grade 3 and 4/pTanyN1Mo) from the ASSURE cohort. The predictive performance of the model was quantified by assessing its discriminatory and calibration abilities. RESULTS Prospective validation of predictive and prognostic models for localized RCC showed a substantial decrease in each of the predictive abilities of the model compared with their original and externally validated discriminatory estimates. Among the models, the SSIGN score performed best (0.688; 95% CI, 0.686 to 0.689), and the UISS model performed worst (0.556; 95% CI, 0.555 to 0.557). Compared with the 2002 TNM staging system (C-index, 0.60), most models only marginally outperformed standard staging. Importantly, all models, including TNM, demonstrated statistically significant variability in their predictive ability over time and were most useful within the first 2 years after diagnosis. CONCLUSION In RCC, as in many other solid malignancies, clinicians rely on retrospective prediction tools to guide patient care and clinical trial selection and largely overestimate their predictive abilities. We used prospective collected adjuvant trial data to validate existing RCC prediction models and demonstrate a sharp decrease in the predictive ability of all models compared with their previous retrospective validations. Accordingly, we recommend prospective validation of any predictive model before implementing it into clinical practice and clinical trial design.

Cytoreductive nephrectomy (CRN) has long been considered a standard of care in the management of mRCC. This is largely based on randomized trials in the era of interferon (IFN) that demonstrate an improvement in overall survival (OS). With the advent of targeted therapies, the role of CRN has been questioned and multiple retrospective analyses have shown a potential benefit, particularly in intermediate-risk disease. Two long-awaited prospective trials have been published in the past year that explore the role of CRN. The CARMENA trial randomly assigned patients to therapy with sunitinib with or without CRN, showing noninferiority of sunitinib alone versus sunitinib plus CRN with a median OS of 18.4 months versus 13.9 months, respectively (hazard ratio [HR] for mortality, 0.89; 95% CI, 0.71–1.1). The SURTIME trial randomly assigned patients to immediate CRN followed by sunitinib versus a deferred CRN after three cycles of sunitinib. Analysis is limited by early termination as a result of low accrual. Although there was no difference in progression-free survival (PFS), median OS was significantly improved among patients in the deferred CRN arm (HR, 0.57; 95% CI, 0.34–0.95; p = .032). Early systemic therapy is paramount, but there are patients who may derive benefit by incorporating the removal of the primary tumor in their multimodal therapy, perhaps in a deferred setting. As systemic treatment paradigms shift and immunotherapy again moves to the frontline setting with the potential for novel therapeutic approaches, the role of CRN will continue to evolve with the potential to offer surgical interventions with minimal, if any, delay in systemic treatment.

Purpose Partial nephrectomy (PN) is standard for small renal masses, improving renal function by preserving renal parenchyma compared with radical nephrectomy. Recent work demonstrated that postoperative surgeon assessment of volume preservation (SAVP) and 3D imaging measurements agree and correlate with postoperative function. We hypothesize preoperative assessment of volume preservation (PAVP) with PN based on preoperative imaging will reliably indicate postoperative renal function. Materials and Methods Data were collected from 336 patients undergoing PN for suspected renal cancer by 40 surgeons at 12 centers in Europe and the United States within the Surface-Intermediate-Base International Consortium. Surgeons recorded PAVP and SAVP for individual patients; pre- and postoperative glomerular filtration rate (GFR) was estimated by Chronic Kidney Disease Epidemiology Collaboration equations. Correlations between PAVP, SAVP, and postoperative GFR were assessed with linear regression models. Bland–Altman analysis was used to assess agreement between PAVP and SAVP with a significant cutoff of 5%. Results Median PAVP was 90% (interquartile range [IQR] 85%–100%) and SAVP was 90% (IQR: 80%–94%). PAVP and SAVP were moderately correlated (R2 = 0.67, P Conclusion Renal function is closely linked to the amount of parenchymal volume preservation, whether estimated prior to surgery (PAVP) or afterward (SAVP). PAVP provides reasonably accurate information for decision-making in patients considering PN.

Recent adjuvant vascular endothelial growth factor tyrosine kinase inhibitor trials in resected high-risk renal cell carcinoma that compared sunitinib, sorafenib, pazopanib, and axitinib with placebo controls have demonstrated mixed impact on disease-free survival, no improvement in overall survival, and, thus, controversy. Here, we discuss the results and conduct of these trials to provide new insight into the goals and strategies of treating resected renal cell cancer that is at high risk for recurrence. The potential for leveraging what we have learned from these trials to conduct successful contemporary adjuvant and perioperative immune checkpoint inhibition trials and future adjuvant trial design is discussed.

Background Risk stratification for localized renal cell carcinoma (RCC) relies heavily on retrospective models, limiting their generalizability to contemporary cohorts. Objective To introduce a contemporary RCC prognostic model, developed using prospective, highly annotated data from a phase III adjuvant trial. Design, setting, and participants The model utilizes outcome data from the ECOG-ACRIN 2805 (ASSURE) RCC trial. Outcome measurements and statistical analysis The primary outcome for the model is disease-free survival (DFS), with overall survival (OS) and early disease progression (EDP) as secondary outcomes. Model performance was assessed using discrimination and calibration tests. Results and limitations A total of 1735 patients were included in the analysis, with 887 DFS events occurring over a median follow-up of 9.6 yr. Five common tumor variables (histology, size, grade, tumor necrosis, and nodal involvement) were included in each model. Tumor histology was the single most powerful predictor for each model outcome. The C-statistics at 1 yr were 78.4% and 81.9% for DFS and OS, respectively. Degradation of the DFS, DFS validation set, and OS model's discriminatory ability was seen over time, with a global c-index of 68.0% (95% confidence interval or CI [65.5, 70.4]), 68.6% [65.1%, 72.2%], and 69.4% (95% CI [66.9%, 71.9%], respectively. The EDP model had a c-index of 75.1% (95% CI [71.3, 79.0]). Conclusions We introduce a contemporary RCC recurrence model built and internally validated using prospective and highly annotated data from a clinical trial. Performance characteristics of the current model exceed available prognostic models with the added benefit of being histology inclusive and TNM agnostic. Patient summary Important decisions, including treatment protocols, clinical trial eligibility, and life planning, rest on our ability to predict cancer outcomes accurately. Here, we introduce a contemporary renal cell carcinoma prognostic model leveraging high-quality data from a clinical trial. The current model predicts three outcome measures commonly utilized in clinical practice and exceeds the predictive ability of available prognostic models.

Purpose: No circulating biomarkers are currently available to identify patients at highest risk of recurrence after nephrectomy for renal cell carcinoma (RCC). Kidney injury molecule-1 (KIM-1) is overexpressed in RCC and its ectodomain circulates in plasma. We investigated whether plasma KIM-1 is a prognostic biomarker in patients with localized RCC after nephrectomy. Experimental Design: The ECOG-ACRIN E2805 (ASSURE) trial evaluated adjuvant sunitinib, sorafenib, or placebo in resected high-risk RCC. KIM-1 levels were measured from banked plasma at trial enrollment 4–12 weeks after nephrectomy. Lognormal accelerated failure time models were used to test for association between KIM-1 and disease-free survival (DFS) as well as overall survival (OS). Results: Plasma from 418 patients was analyzed. Higher post-nephrectomy KIM-1 was associated with worse DFS across all study arms after adjustment for Fuhrman grade, T stage, N stage, and tumor histology [survival time ratio 0.56 for 75th vs. 25th percentile of KIM-1; 95% confidence interval (CI), 0.42–0.73; P < 0.001]. The association between KIM-1 and DFS was stronger among patients with pathologic nodal involvement (Pinteraction = 0.0086). The addition of post-nephrectomy KIM-1 improved the concordance of clinical prognostic models [Stage, Size, Grade, and Necrosis (SSIGN) concordance 0.57 vs. 0.43, P = 0.05; UCLA International Staging System (UISS) concordance 0.60 vs. 0.40, P = 0.0005]. Higher post-nephrectomy KIM-1 was also associated with worse OS after multivariable adjustment (survival time ratio 0.71 for 75th vs. 25th percentile of KIM-1; 95% CI, 0.56–0.91; P < 0.001). Conclusions: Post-nephrectomy plasma KIM-1 is associated with DFS and OS in RCC, and may be a biomarker for microscopic residual disease.

BACKGROUND: Inferior vena cava tumor thrombus (IVC-TT) is a rare yet deadly sequel of renal cell carcinoma (RCC) with limited treatment options. The standard treatment is extirpative surgery, which has high rates of morbidity and mortality. As a result, many patients are unfit or unwilling to undergo surgery and face poor prognosis. This stresses the need for alternative options for local disease control. Our study aims to assess the feasibility and oncological outcomes of stereotactic ablative radiation (SAbR) for IVC-TT. METHODS: A retrospective study reviewing six leading international institutions’ experience in treating RCC with IVC-TT with SAbR. Primary end point was overall survival using Kaplan-Meier. RESULTS: Fifteen patients were included in the cohort. Over 50% of patients had high level IVC-TT (level III or IV), 66.7% had metastatic disease. Most eschewed surgery due to high surgical risk (7/15) or recurrent thrombus (3/15). All patients received SAbR to the IVC-TT with a median biologically equivalent dose (BED(10)) of 72 Gy (range: 37.5–100.8) delivered in a median of 5 fractions (range 1–5). Median overall survival was 34 months. Radiographic response was observed in 58% of patients. Symptom palliation was recorded in all patients receiving SAbR for this indication. Only grade 1–2 adverse events were noted. CONCLUSIONS: SAbR for IVC-TT appears feasible and safe. In patients who are not candidates for surgery, SAbR may palliate symptoms and improve outcomes. SAbR may be considered as part of a multimodal treatment approach for patients with RCC IVC-TT.

Measurement of a tumor’s overall genomic instability has gathered recent interest over the identification of specific genomic imbalances, as it may provide a more robust measure of tumor aggressiveness. Here we demonstrate the association of tumor genomic instability in the prediction of disease recurrence in patients with clinically localized clear cell renal cell carcinoma (ccRCC). Genomic copy number analysis was performed using SNP-based microarrays on tumors from 103 ccRCC patients. The number of copy number alterations (CNAs) for each tumor was calculated, and a genomic imbalance threshold (GIT) associated with high stage and high-grade disease was determined. Cox proportional hazards regression analyzes were performed to assess the effect of GIT on recurrence-free survival adjusting for known confounders. In the cohort, copy number losses in chromosome arms 3p, 14q, 6q, 9p, and 1p and gains of 5q and 7p/q were common. CNA burden significantly increased with increasing stage (p

PURPOSE The previously published single institution randomized prospective trial failed to show superiority in the 5-year biochemical and/or clinical disease failure (BCDF) rate with moderate hypofractionated intensity-modulated radiation therapy (H-IMRT) versus conventionally fractionated IMRT (C-IMRT). We now present 10-year disease outcomes using updated risk groups and definitions of biochemical failure. METHODS Men with protocol-defined intermediate- and high-risk prostate adenocarcinoma were randomly assigned to receive C-IMRT (76 Gy in 38 fractions) or H-IMRT (70.2 Gy in 26 fractions). Men with high-risk disease were all prescribed 24 months of androgen deprivation therapy (ADT) and had lymph node irradiation. Men with intermediate risk were prescribed 4 months of ADT at the discretion of the treating physician. The primary endpoint was cumulative incidence of BCDF. We compared disease outcomes and overall mortality by treatment arm, with sensitivity analyses for National Comprehensive Cancer Network (NCCN) risk group adjustment. RESULTS Overall, 303 assessable men were randomly assigned to C-IMRT or H-IMRT. The median follow-up was 122.9 months. Per updated NCCN risk classification, there were 28 patients (9.2%) with low-risk, 189 (62.4%) with intermediate-risk, and 86 (28.4%) with high-risk prostate cancer. The arms were equally balanced for clinicopathologic factors, except that there were more black patients in the C-IMRT arm (17.8% v 7.3%; P = .02). There was no difference in ADT use ( P = .56). The 10-year cumulative incidence of BCDF was 25.9% in the C-IMRT arm and was 30.6% in the H-IMRT arm (hazard ratio, 1.31; 95% CI, 0.82 to 2.11). The two arms also had similar cumulative 10-year rates of biochemical failure, prostate cancer–specific mortality, and overall mortality; however, the 10-year cumulative incidence of distant metastases was higher in the H-IMRT arm (rate difference, 7.8%; 95% CI, 0.7% to 15.1%). CONCLUSION H-IMRT failed to demonstrate superiority compared with C-IMRT in long-term disease outcomes.

National Comprehensive Cancer Network (NCCN) guidelines recommend confirmatory biopsy within 12 months of active surveillance (AS) enrollment. With10 cores on initial biopsy, re-biopsy should occur within 6 months. Our objective was to determine if patients on AS within practices in the Pennsylvania Urologic Regional Collaborative (PURC) receive guideline concordant confirmatory biopsies.Within PURC, a prospective collaborative of diverse urology practices in Pennsylvania and New Jersey, we identified men enrolled in AS after first biopsy, analyzing time to re-biopsy and factors associated with various intervals of re-biopsy.In total, 1,047 patients were enrolled in AS for a minimum of 12 months after initial biopsy. Four hundred seventy-seven (45%) underwent second biopsy at 1 of the 9 PURC practices. The number of patients undergoing re-biopsy within 6 months, 6 to 12 months, 12 to 18 months, and18 months was 71 (14%), 218 (45.7%), 134 (28%), and 54 (11%), respectively. Sixty percent underwent confirmatory biopsy within 12 months. On multivariate analysis, re-biopsy interval was associated with number of positive cores, perineural invasion, and practice ID (all P0.05). Adjusted multivariable regression did not identify factors predictive of re-biopsy interval.Of patients who underwent confirmatory biopsy at PURC practices, 60.5% were within 12 months per NCCN guidelines. This suggests area for improvement in guideline adherence after enrollment in AS. All practices that offer AS should periodically perform similar analyses to monitor their performance. In an era of value-based care, adherence to guideline based active surveillance practices may eventually comprise national quality metrics affecting provider reimbursement.

Each year Clinical Cancer Advances: ASCO’s Annual Report on Progress Against Cancer highlights the most important clinical research advances of the past year, including the Advance of the Year, and identifies priority areas where ASCO believes research efforts should be focused moving forward. In 2020, ASCO names the Refinement of Surgical Treatment of Cancer as the Advance of the Year. Years of progress in developing new systemic cancer therapies has not only improved patient survival and quality of life but is now transforming surgical approaches to cancer treatment. The emergence of novel systemic therapies combined in new and better ways is significantly changing the role of cancer surgery. ASCO’s selection of Refinement of Surgical Treatment of Cancer as the 2020 Advance of the Year recognizes recent strides seen in the effectiveness of these treatments in reducing the amount of surgery, and even the need for it, while increasing the number of patients who can undergo surgery when needed. Other advances highlighted in the report include progress in cancer prevention, molecular diagnostics, and cancer treatment—surgery, radiotherapy, combination therapy, immunotherapy, and other types of therapies. The report also features ASCO's 2020 list of Research Priorities to Accelerate Progress Against Cancer. These priorities represent promising areas of research that have the potential to significantly improve the knowledge base for clinical decision-making and address vital unmet needs in cancer care. A MESSAGE FROM ASCO’S PRESIDENT Shortly before I was elected President of ASCO, I attended the 65th birthday party of a current patient. She had been diagnosed 10 years earlier with metastatic breast cancer and hadn’t been sure she wanted to move forward with further treatment. With encouragement, she elected to participate in a clinical trial of an investigational drug that is now widely used to treat breast cancer. Happily, here we were, celebrating with her now-married daughters, their husbands, and three beautiful grandchildren, ages 2, 4, and 8. Such is the importance of clinical trials and promising new therapies. Clinical research is about saving and improving the lives of individuals with cancer. It’s a continuing story that builds on the efforts of untold numbers of researchers, clinicians, caregivers, and patients. ASCO’s Clinical Cancer Advances report tells part of this story, sharing the most transformative research of the past year. The report also includes our latest thinking on the most urgent research priorities in oncology. ASCO’s 2020 Advance of the Year—Refinement of Surgical Treatment of Cancer—highlights how progress drives more progress. Surgery has played a fundamental role in cancer treatment. It was the only treatment available for many cancers until the advent of radiation and chemotherapy. The explosion in systemic therapies since then has resulted in significant changes to when and how surgery is performed to treat cancer. In this report, we explore how treatment successes have led to less invasive approaches for advanced melanoma, reduced the need for surgery in renal cell carcinoma, and increased the number of patients with pancreatic cancer who can undergo surgery. Many research advances are made possible by federal funding. With the number of new US cancer cases set to rise by roughly a third over the next decade, continued investment in research at the national level is crucial to continuing critical progress in the prevention, screening, diagnosis, and treatment of cancer. While clinical research has translated to longer survival and better quality of life for many patients with cancer, we can’t rest on our laurels. With ASCO’s Research Priorities to Accelerate Progress Against Cancer, introduced last year and updated this year, we’ve identified the critical gaps in cancer prevention and care that we believe to be most pressing. These priorities are intended to guide the direction of research and speed progress. Of course, the effectiveness or number of new treatments is meaningless if patients don’t have access to them. High-quality cancer care, including clinical trials, is out of reach for too many patients. Creating an infrastructure to support patients is a critical part of the equation, as is creating connections between clinical practices and research programs. We have much work to do before everyone with cancer has equal access to the best treatments and the opportunity to participate in research. I know that ASCO and the cancer community are up for this challenge. Sincerely, Howard A. “Skip” Burris III, MD, FACP, FASCO ASCO President, 2019-2020

Clinical interest in poly(ADP-ribose) polymerase 1 (PARP-1) has increased over the past decade with the recognition of its roles in transcription regulation, DNA repair, epigenetic bookmarking, and chromatin restructuring. A number of PARP-1 inhibitors demonstrating clinical efficacy against tumors of various origins have emerged in recent years. These inhibitors have been essentially designed as nicotinamide adenine dinucleotide (NAD+) mimetics. However, because NAD+ is utilized by many enzymes other than PARP-1, NAD+ competitors tend to produce certain off-target effects. To overcome the limitation of NAD-like PARP-1 inhibitors, we have developed a new class of PARP-1 inhibitors that specifically targets the histone-dependent route of PARP-1 activation, a mechanism of activation that is unique to PARP-1. Novel histone-dependent inhibitors are highly specific for PARP-1 and demonstrate promising in vitro and in vivo efficacy against prostate and renal tumors. Our findings suggest that novel PARP-1 inhibitors have strong therapeutic potential for the treatment of urological tumors.

Cisplatin-based neoadjuvant chemotherapy (NAC) has demonstrated an overall survival (OS) benefit in muscle invasive bladder cancer (MIBC). However, only a subset of patients (25–50%) have pathologic complete response at cystectomy. Using a cohort of patients (n = 58) from two phase II trials, our group previously reported that mutations in the ATM, RB1, and FANCC genes correlate with complete response to cisplatin-based NAC, and consequently improved overall and disease specific survival. These trials enrolled patients with T2-T4 (N0 or N1) MIBC and treated them with dose dense NAC with MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) or Gem/Cis (gemcitabine and cisplatin) with plan for curative cystectomy. Updated long-term follow up (median follow-up = 74 months) shows that patients with mutations in ATM, RB1 or FANCC maintained significantly greater OS and DSS. The 5-year-survival rate for patients with at least one mutation was 85% compared to 45% for patients without a mutation. Based on the association with response, long-term OS and DSS, we propose that these alterations may be useful as predictive biomarkers to allow clinicians to prioritize patients who are most likely to benefit from NAC prior to radical cystectomy. PATIENT SUMMARY: (2–3 short sentences in plain English to describe your findings to a non-medical audience. For example: “In this report we looked at the outcomes from invasive bladder cancer in a large European population. We found that outcomes varied with patient age and treating centre. We conclude that the best outcomes are seen in younger patients treated at high volume hospitals.”): In this report we looked at the outcomes for patients with muscle-invasive bladder cancer treated with cisplatin-based chemotherapy before surgery (neoadjuvant) who had mutations in a set of DNA damage repair genes (ATM, RB1, FANCC) compared to those who did not. We found that patients who had at least one mutation in one of these genes survived longer after receiving cisplatin chemotherapy before surgery than patients who did not.

Background Partial nephrectomy (PN) is recommended for localized T1a (≤4 cm) renal masses and is preferred over radical nephrectomy (RN) for amenable T1b/T2 (>4 cm) tumors. The objective of the current study was to assess overall survival (OS) differences between PN and RN in patients with T1 and T2 renal cell carcinoma (RCC). Methods The National Cancer Data Base was queried for patients with T1 and T2 RCC who underwent PN or RN from 2004 to 2014. Trends in surgery were evaluated using Cochran-Armitage tests. Differences in OS were assessed using adjusted Kaplan-Meier methods. The effects of procedure on OS were analyzed using propensity score-based, weighted Cox proportional hazards models. Results In total, 212,016 patients with T1 and T2 RCC who underwent either RN (59.7%) or PN (40.3%) were included. The use of PN rose from 2004 to 2014 (T1a: from 40.6% to 71.4%; T1b/T2: from 8.4% to 26.5%; P Conclusions Receipt of PN is associated with improved OS in patients with T1a RCC. No procedure-related differences in OS were observed for patients age ≥75 years who had tumors measuring >4 cm. Decisions to undergo PN for T1b/T2 tumors should be based on individualized risk assessment.

Background: Statin use is widespread among the general population. Data suggest a potentially beneficial effect of statin therapy on renal function following surgery. The impact of statins on post-partial nephrectomy (PN) renal function is unknown. We hypothesized that perioperative statin use may be associated with reduced rates of acute kidney injury (AKI) in patients undergoing PN. Objectives: To evaluate the effect of perioperative statin use on AKI rates in patients undergoing PN. Materials & Methods: 1,056 patients undergoing PN were identified from a prospectively-maintained institutional renal mass database. Exclusion criteria included lack of preoperative serum creatinine (Cr), concurrent surgeries, and those with baseline Cr

Introduction and objectives Renal mass biopsy (RMB) has not been widely adopted in evaluating small renal mass due to concerns for safety, efficacy, and its perceived lack of consequence on management decisions. We assess the potential cost savings and morbidity avoidance of routine RMB on cT1 renal masses undergoing robotic-assisted partial nephrectomy (RAPN). Methods We identified n = 920 consecutive RAPN pT1 renal masses and n = 429 consecutive RMBs for cT1 renal masses over 12 years. Using a novel pathological-based risk classification system for cT1 renal masses, we evaluated the morbidity and costs of our RAPN and RMB cohorts. We then define four clinical scenarios where RMB could potentially delay and/or avoid intervention in our pT1 RAPN cohort and model potential complications prevented and cost savings utilizing common clinical scenarios. Results Using our risk stratification system in RAPN patients, final histology was classified as benign in n=174 (18.9%) cases, very low-risk (n = 62 [7%]), low-risk (n = 383 [42%]), and high-risk (n = 301 [33%]), respectively. We identified n = 116 (12.6%) Clavien graded peri-operative complications. In our RMB patients, 120 (27.9%), 17 (3.9%), 240 (55.9%), 52(12.1%) were benign, very low, low and high-risk tumors. The median total direct cost for RAPN was $6955/case compared to $1312/case for RMB. If we established a primary goal to avoid immediate extirpative surgery in benign renal tumors, in the elderly (>70 y) with very low-risk tumors and/or those with high renal functional risks (≥ CKD3b), or competing risks (ASA ≥ 3), RMB could have reduced direct costs by approximately 20% and avoided n = 39 Clavien graded complications, seven readmissions, three transfusions, and two returns to the OR. With the additional cost of performing RMB on those not initially biopsied, the net cost saving would be approximately $1.2 million with minimal added complications while still treating high-risk tumors. Conclusions Routine RMB before intervention results in cost-saving and complication avoidance. Given the limitations of biopsy, shared decision-making is mandatory. Biopsy should be considered prior to intervention in at-risk populations.

Introduction: SETD2 encodes a histone H3-K36 methyltransferase which is frequently inactivated in clear cell renal carcinomas (ccRCCs) and papillary RCCs via 3p deletion/LOH and deleterious mutations. Histone H3-K36 trimethylation is facilitated by SETD2, which is necessary for proper pre-mRNA intron splicing. Improperly spliced mature-mRNA may lead to aberrant translation of retained introns (ATaRI), which represents potential therapeutic vulnerabilities. We explored this hypothesis using real world data and RCC models. Methods and Results: Gene set enrichment analysis comparing SETD2-mutant to WT tumors using samples from the TCGA KIRC data set revealed that the untranslated protein response (UPR) was strongly enriched, as well as several immunotherapy-relevant pathways. This suggested that peptides arising from ATaRI may be present, since they would not be expected to fold properly and thus need to be addressed by the UPR pathway to maintain homeostasis. To investigate this further, we generated Setd2-isogenic RENCA cells using CRISPR. Knockout was confirmed by sequencing and immunoblot. H3K36 trimethylation was decreased or eliminated in monoclonal knockout cell lines, confirming a functional effect. Markers of UPR activation, including cleaved Atf6 and Atf4, were found to be upregulated in Setd2-mutant RENCA cells compared to controls as measured by immunoblot. Cleaved ATF6 is known to translocate to the nucleus to take part in a UPR transcriptional program. Consistent with this, ATF6 was found to localize to the nucleus in Setd2-knockout cells using immunofluorescence. Interestingly, CHOP, another downstream effector of the UPR pathway which predominantly regulates cell death, did not become upregulated in Setd2-knockout cells, suggesting activation of a compensatory cell survival pathway. Conclusions: We identify activation of the UPR upon Setd2 loss and suggest that activation of part of the UPR pathway may represent a new therapeutic vulnerability for exploitation as a rationale for personalized medicine. We continue to evaluate the generation of peptides arising from ATaRI in Setd2-mutant contexts. Citation Format: Alexander Metz, Robert Uzzo, Philip Abbosh. SETD2 loss in renal carcinoma cells induces the unfolded protein response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2027.

Background: The proto-oncogene c-MYC, located on chromosome 8q, can be upregulated through gain of 8q, causing alteration in biology of renal cell carcinoma (RCC). The aim of this study was to evaluate the prevalence of c-MYC through chromosome 8q gain and to correlate findings with cancer-specific mortality (CSM), and overall survival (OS). Methods: Cytogenetic analysis by conventional or Chromosomal Genomic Microarray Analysis (CMA) was performed on 414 renal tumors. Nonclear and nonpapillary RCC were excluded. Impact of gain in chromosome 8q status on CSM, OS, and its correlation with clinicopathological variables were evaluated. CSM and OS were assessed using log-rank test and the Cox proportional hazards model. Results: A total of 297 RCC tumors with cytogenetic analysis were included. Gain of 8q was detected in 18 (6.1%) tumors (9 clear cell and 9 papillary RCC), using conventional method ( n = 11) or CMA ( n = 7). Gain of 8q was associated with higher T stage ( p < 0.001), grade ( p < 0.001), nodal involvement ( p = 0.005), and distant metastasis ( p < 0.001). No association between gain of 8q and age ( p = 0.23), sex ( p = 0.46), and Charlson comorbidity index (CCI, p = 0.59) were seen. Gain of 8q was associated with an 8.38-fold [95% confidence interval (CI), 3.83–18.34, p < 0.001] and 3.31-fold (95% CI, 1.56–7.04, p = 0.001) increase in CSM and decrease in OS, respectively, at a median follow up of 56 months. Conclusion: Chromosome 8q harbors the proto-oncogene c-MYC, which can be upregulated by gain of 8q. Our findings suggest that gain of 8q, can predict aggressive tumor phenotype and inferior survival in RCC.

Introduction To evaluate if interruptions of external beam radiation therapy impact outcomes in men with localized prostate cancer (PCa). Methods We included men with localized PCa treated with three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) of escalated dose (≥74 Gy in 1.8 or 2 Gy fractions) between 1992 and 2013 at an NCI-designated cancer centre. Men receiving androgen deprivation therapy were excluded. The non-treatment day ratio (NTDR) was defined as the number of non-treatment days divided by the total elapsed days of therapy. NTDR was analysed for each National Comprehensive Cancer Network (NCCN) risk group. Results There were 1728 men included (839 low-risk, 776 intermediate-risk and 113 high-risk), with a median follow up of 53.5 months (range 12–185.8). The median NTDR was 31% (range 23–71%), translating to approximately 2 breaks (each break represents a missed treatment that will be made up) for 8 weeks of RT with 5 treatments per week. The 75 percentile of NTDR was 33%, translating to approximately 4 breaks, which was used as the cutoff for analysis. There were no significant differences in freedom from biochemical failure, freedom from distant metastasis, cancer specific survival, or overall survival for men with NTDR ≥33% compared to NTDR

BACKGROUND The current study was performed to examine temporal trends and compare overall survival (OS) in patients undergoing radical cystectomy (RC) or bladder-preservation therapy (BPT) for muscle-invasive urothelial carcinoma of the bladder. METHODS The authors reviewed the National Cancer Data Base to identify patients with AJCC stage II to III urothelial carcinoma of the bladder from 2004 through 2013. Patients receiving BPT were stratified as having received any external-beam radiotherapy (any XRT), definitive XRT (50-80 grays), and definitive XRT with chemotherapy (CRT). Treatment trends and OS outcomes for the BPT and RC cohorts were evaluated using Cochran-Armitage tests, unadjusted Kaplan-Meier curves, adjusted Cox multivariate regression, and propensity score matching, using increasingly stringent selection criteria. RESULTS A total of 32,300 patients met the inclusion criteria and were treated with RC (22,680 patients) or BPT (9620 patients). Of the patients treated with BPT, 26.4% (2540 patients) and 15.5% (1489 patients), respectively, were treated with definitive XRT and CRT. Improved OS was observed for RC in all groups. After adjustments with more rigorous statistical models controlling for confounders and with more restrictive BPT cohorts, the magnitude of the OS benefit became attenuated on multivariate (any XRT: hazard ratio [HR], 2.115 [95% confidence interval [95% CI], 2.045-2.188]; definitive XRT: HR, 1.870 [95% CI, 1.773-1.972]; and CRT: HR, 1.578 [95% CI, 1.474-1.691]) and propensity score (any XRT: HR, 2.008 [95% CI, 1.871-2.154]; definitive XRT: HR, 1.606 [95% CI, 1.453-1.776]; and CRT: HR, 1.406 [95% CI, 1.235-1.601]) analyses. CONCLUSIONS In the National Cancer Data Base, receipt of BPT was associated with decreased OS compared with RC in patients with stage II to III urothelial carcinoma. Increasingly stringent definitions of BPT and more rigorous statistical methods adjusting for selection biases attenuated observed survival differences. Cancer 2017;123:4337-45. © 2017 American Cancer Society.

Background The programmed death 1 (PD-1) checkpoint inhibitors (CKIs) can lead to immune-related adverse events (irAEs). We sought to evaluate whether the development of irAEs correlates with treatment response in non-melanoma malignancies. Materials and Methods We conducted a retrospective study of patients who received anti-PD-1 CKI monotherapy at Fox Chase Cancer Center. Endpoints included overall response rate (ORR), time to next therapy or death (TTNTD), and overall survival (OS). Fisher's exact tests and logistic regression models were used to determine the association between irAE incidence and ORR, and Kaplan-Meier curves with log-rank tests and Cox regression models were used for the comparison of TTNTD and OS. Results Between November 2011 and November 2016, 160 patients were treated with >1 dose of an anti-PD-1 CKI. Seventy-three (46%) were treated on a clinical trial. Immune-related adverse events were noted in 64 patients (40%), with steroids required in 36 (23%). Of the 142 patients evaluable for clinical response, 28 patients (20%) achieved a partial response at first scan. An association between irAEs and ORR was seen in clinical trial patients (p = .007), but not in non-trial patients (p = .13). When controlling for clinical trial participation and cancer type using multivariate analysis, low-grade irAEs had higher ORR (p = .017) and longer TTNTD (p = .008). No association between irAE incidence and OS was seen (p = .827). Immune-related adverse events that required steroid treatment were marginally associated with increased TTNTD (p = .05, hazard ratio 0.62) but were not associated with OS (p = .13). Conclusion We demonstrate several positive associations between the development of irAEs and clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which further validation is required.

Anatomic tumor complexity can be objectively measured and reported using nephrometry. Various scoring systems have been developed in an attempt to correlate tumor complexity with intraoperative and postoperative outcomes. Nephrometry may also predict tumor biology in a noninvasive, reproducible manner. Other scoring systems can help predict surgical complexity and the likelihood of complications, independent of tumor characteristics. The accumulated data in this new field provide provocative evidence that objectifying anatomic complexity can consolidate reporting mechanisms and improve metrics of comparisons. Further prospective validation is needed to understand the full descriptive and predictive ability of the various nephrometry scores.

Background: Radical cystectomy is associated with perioperative complication rates exceeding 50% in some series. Readmission rates are increasingly used as a surgical quality metric. White blood cell count is a crude surrogate for physiologic processes which may reflect postoperative complications leading to readmission. Objective: We assessed the association between final white blood cell count at discharge and risk of readmission following radical cystectomy. Methods: Records on 477 patients undergoing radical cystectomy from 2006–2013 were reviewed. Final white blood cell count was defined as the last documented value during index admission. Univariate analysis was performed using Fisher’s exact, Wilcoxon rank sum test, and Spearman’s coefficient tests where appropriate. Multivariable logistic regression models were used to test the associations between final white blood cell count and readmission. Results: 34% of patients were readmitted within 90 days of surgery. Amongst this cohort, a cutoff final white blood cell count of 9000/mm3 was identified, with a significantly higher proportion of patients with values >9000/mm3 experiencing readmission than those with values≤9000/mm3 (42% vs 28%, p = 0.004). Other perioperative variables associated with an increased readmission rate included initial hospital length of stay≤10 days, and receipt of a continent diversion. Following adjustment, final white blood cell count >9000/mm3 was associated with increased risk of readmission (OR 2.09, 95% CI 1.23–3.53, p = 0.006). Conclusions: Final white blood cell count is associated with hospital readmission following radical cystectomy. This metric may provide important guidance in discharge algorithms.

Rates of kidney cancer have been increasing, with small incidental tumors experiencing the fastest growth rates. Much of the increase could be due to increased use of CT scans, MRIs, and ultrasounds for unrelated conditions. Many tumors might never have been detected or become symptomatic in the past. This suggests that many patients might benefit from less aggressive therapy, such as active surveillance by which tumors are surgically removed only if they become sufficiently large. However, it has been difficult for clinicians to identify subgroups of patients for whom treatment might be especially beneficial or harmful. In this work, we use a principal stratification framework to estimate the proportion and characteristics of individuals who have large or small hazard rates of death in two treatment arms. This allows us to assess who might be helped or harmed by aggressive treatment. We also use Weibull mixture models. This work differs from much previous work in that the survival classes upon which principal stratification is based are latent variables. That is, survival class is not an observed variable. We apply this work using Surveillance Epidemiology and End Results-Medicare claims data. Clinicians can use our methods for investigating treatments with heterogeneous effects.

Background: Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs. Methods: We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib. Results: The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet. Conclusions: The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients.

Purpose To provide recommendations for the management options for patients with small renal masses (SRMs). Methods By using a literature search and prospectively defined study selection, we sought systematic reviews, meta-analyses, randomized clinical trials, prospective comparative observational studies, and retrospective studies published from 2000 through 2015. Outcomes included recurrence-free survival, disease-specific survival, and overall survival. Results Eighty-three studies, including 20 systematic reviews and 63 primary studies, met the eligibility criteria and form the evidentiary basis for the guideline recommendations. Recommendations On the basis of tumor-specific findings and competing risks of mortality, all patients with an SRM should be considered for a biopsy when the results may alter management. Active surveillance should be an initial management option for patients who have significant comorbidities and limited life expectancy. Partial nephrectomy (PN) for SRMs is the standard treatment that should be offered to all patients for whom an intervention is indicated and who possess a tumor that is amenable to this approach. Percutaneous thermal ablation should be considered an option if complete ablation can reliably be achieved. Radical nephrectomy for SRMs should only be reserved for patients who possess a tumor of significant complexity that is not amenable to PN or for whom PN may result in unacceptable morbidity even when performed at centers with expertise. Referral to a nephrologist should be considered if chronic kidney disease (estimated glomerular filtration rate < 45 mL/min/1.73 m2) or progressive chronic kidney disease occurs after treatment, especially if associated with proteinuria.

The efficacy of partial nephrectomy (PN) in setting of pT3a pathologic-upstaged renal cell carcinoma (RCC) is controversial. We compared oncologic and functional outcomes of radical nephrectomy (RN) and PN in patients with upstaged pT3a RCC.This was a multicenter retrospective analysis of patients with cT1-2N0M0 RCC upstaged to pT3a postoperatively. The primary outcome was recurrence-free survival, with secondary outcomes of overall survival and de novo estimated glomular filtration rate (eGFR) 60. Multivariable analysis was performed to identify predictive factors for oncologic outcomes. Kaplan-Meier analyses (KMA) were obtained to elucidate survival outcomes.A total of 929 patients had pT3a upstaging (686 [72.6%] RN; 243 [25.7%] PN; mean follow-up, 48 months). Tumor size was similar (RN 7.7 cm vs. PN 7.3 cm; P = .083). PN had decreased ΔeGFR (6.1 vs. RN 19.4 mL/min/1.73mIn pathologically upstaged pT3a RCC, PN did not adversely affect risk of recurrence and provided functional benefit. Surgical decision-making in patients at risk for T3a upstaging should be individualized and driven by tumor as well as functional risks.

Purpose: Rocapuldencel-T is an autologous immunotherapy prepared from mature monocyte-derived dendritic cells (DC), coelectroporated with amplified tumor RNA plus CD40L RNA. This pivotal phase III trial was initiated to investigate the safety and efficacy of a combination therapy dosing regimen of Rocapuldencel-T plus sunitinib in patients with metastatic renal cell carcinoma (mRCC). Patients and Methods: Patients received either Rocapuldencel-T plus standard of care (SOC) or SOC treatment alone. The primary objective compared overall survival (OS) between groups. Secondary objectives included safety assessments, progression-free survival (PFS), and tumor responses based on RECIST 1.1 criteria. Exploratory analyses included immunologic assessments and correlates with OS. Results: Between 2013 and 2016, 462 patients were randomized 2:1, 307 to the combination group and 155 to the SOC group. Median OS in the combination group was 27.7 months [95% confidence interval (CI) 23.0–35.9] and 32.4 months (95% CI, 22.5–) in the SOC group HR of 1.10 (95% CI, 0.83–1.40). PFS was 6.0 months and 7.83 months for the combination and SOC groups, respectively [HR = 1.15 (95% CI, 0.92–1.44)]. The ORR was 42.7% (95% CI, 37.1–48.4) for the combination group and 39.4% (95% CI, 31.6–47.5) for the SOC group. Median follow up was 29 months (0.4–47.7 months). On the basis of the lack of clinical efficacy, the ADAPT trial was terminated on February 17, 2017. Immune responses were detected in 70% of patients treated with Rocapuldencel-T, and the magnitude of the immune response positively correlated with OS. In addition, we report the survival-predictive value of measuring IL-12 produced by the DC vaccine and the observation that high baseline numbers of T regulatory cells are associated with improved outcomes in DC-treated patients, but are associated with poor outcomes in patients receiving SOC treatment. No serious adverse events attributed to the study medication have been reported to date. Conclusions: Rocapuldencel-T did not improve OS in patients treated with combination therapy, although the induced immune response correlated with OS. Moreover, we identified two potential survival-predictive biomarkers for patients receiving DC based immunotherapy, IL-12 produced by the DC vaccine and higher numbers of T regulatory cells present in the peripheral blood of patients with advanced RCC.

The objective of the study was to evaluate the frequency and the outcomes of whole chromosome 9 loss in 103 patients with clear cell renal cell carcinoma (ccRCC) using Single nucleotide polymorphism-based chromosome microarray (CMA) analysis. Our study, demonstrated chromosome 9 loss is associated with higher grade, advanced stage and poor outcome in ccRCC and can potentially be used as a major prognostic predictor in ccRCC patients. BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies in humans and is usually associated with poor outcomes. Cancers are considered to be genetic diseases. Therefore, a better understanding of genetic alterations that are related to disease progression or poor prognosis can help to more precisely identify high-risk patients and treat them more effectively. The aim of this study was to examine the frequency of whole chromosome 9 loss (monosomy of chromosome 9) and its prognostic value in patients with ccRCC. METHODS: Single nucleotide polymorphism-based CMA analysis was performed on 103 resected specimens from ccRCC patients who had undergone partial or radical nephrectomy between January 2002 and March 2017 at Fox Chase Cancer Center (FCCC). Monosomy 9 was correlated with clinicopathological parameters and recurrence-free survival. RESULTS: Chromosome 9 loss was detected in 31 (30%) out of 103 tumors. Tumors with chromosome 9 loss had higher histologic grade (3 and 4, p

INTRODUCTION AND OBJECTIVES:Level 1 evidence shows that mTOR inhibition is associated with clinically significant reductions in tumor size in angiomyolipomas (AMLs) associated with Tuberous Scleros...

INTRODUCTION AND OBJECTIVES:Criteria for staging of T1 renal tumors into T1a (≤4cm) and T1b (4cm< and ≤7cm) have remained unchanged since 1997. Advancements in tumor biology have led to great understanding of the heterogeneous potential of T1 renal tumors. We hypothesized that a three-tier classification may more rationally risk stratify T1 renal masses than the current T1a/T1b system.METHODS:Multicenter (UCSD, Emory, Fox Chase Cancer Center, Ospadele San Raffaele) retrospective analysis of patients with cT1 renal cell carcinoma (RCC) undergoing partial or radical nephrectomy. Patients were stratified by tumor size into three groups cT1a (≤2cm, very low risk), cT1b (2cm< and ≤5cm, low risk), and cT1c (5cm< and ≤7cm, intermediate risk). Primary outcome was recurrence-free survival (RFS). Secondary outcome was overall survival (OS). Multivariable Cox Regression analysis (MVA) and Kaplan-Meier analyses (KMA) were utilized for outcomes.RESULTS:4710 patients were stratified into proposed T1 groups (T1a=856, T1...

Despite improvements in medical management of advanced prostate cancer (aPC), it continues to be a leading cause of cancer death in men. Contemporary management of men with aPC is complex and requires resources to be more readily available at high-volume facilities.To determine the relationship between facility volume and survival in men with aPC.The National Cancer Database (NCDB) was queried from 2004 to 2013 for aPC, defined as T4, N+, or M+ disease, identifying 64815 patients. Six predefined patient cohorts were evaluated. Cohort "A" included all patients with aPC. "B" cohorts included only M0 patients. "C" cohorts included only M1 patients. Facilities were divided into quartiles based on median treatment volume (patients/yr).Diagnosis and management of aPC at an NCDB-reporting facility.Overall survival (OS) was assessed as a function of facility volume. Multivariable Cox regression models were fitted. Cox regressions using natural cubic splines were used to test for nonlinear relationships between volume and OS.OS improved as facility volume increased (top quartile vs bottom quartile, hazard ratio 0.82, 95% confidence interval 0.77-0.88, p0.001) and was consistent across patient cohorts. Spline models demonstrate a continuous decrease in hazard of death as volume increases. Limitations include the retrospective analysis and a lack of precise treatment information.In this retrospective analysis of nearly 65000 men who presented with aPC, we demonstrate an association between higher facility volume and improvements in OS. This OS advantage persisted with similar magnitudes of effect after narrowing the cohorts by disease and treatment characteristics.In this retrospective review of the National Cancer Database, we analyzed the association between treatment facility volume and survival in men who are diagnosed with advanced prostate cancer. We found that survival improved as volume increased, indicating a possible imbalance of resources and expertise that favors higher-volume facilities.