bluuebunny/crossref_metadata_2025 huggingface dataset:
Drivers for treatment in an active surveillance cohort.
Authors: Gilbo Philip , Hamilton Mark , Potters Louis , Cox Brett Wayne
Published: February 2018

66

Background: Active Surveillance (AS) for Prostate Cancer (CaP) has become an established management option for patients (pts) with low-risk CaP. We examined the drivers of selecting treatment (tx) over time from a cohort of AS pts seen in a radiation oncology department. Methods: Pts seen in consultation with low-risk CaP were offered AS as one management option. A review of 2,545 pt charts with newly diagnosed CaP from 2010-2016 was undertaken with 794 (31.2%) meeting criteria for AS and ultimately 166 (20.6%) of those patients choosing AS within our department. 22 patients opted to discontinue surveillance before their confirmatory studies. Results: 145 pts elected AS and 66 (45.5%) ultimately required or chose tx. 138 (81.3%) of patients had Gleason 3+3, 28 (17%) had Gleason 3+4 and 3 (1.8%) had Gleason 4+3. The majority (96.4%) were T1c and 112 (67%) were characterized as having NCCN very low risk with a mean PSA of 5.38ng/mL (± 2.38ng/mL). Of the 66 pts who underwent tx, 36 (54.7%) were due to an increase in Gleason score or PSA rise, 14 (21%) electively decided against further AS, 6 (9%) for radiographic progression and 10 (15%) for other. Tx choices are presented in Table 1 with 54 pts (81%) choosing a radiotherapeutic (RT) intervention. The median time to initiate tx was 3.8 years from diagnosis. Conclusions: Men with low-risk CaP and eligible for AS elected AS 21% of the time with slightly less than half of the AS cohort converting to tx within 4 years. The main drivers for tx was either an increase in Gleason score or rise in PSA, followed by patient anxiety regarding diagnosis. Trends over time identified an increase in men electing AS but additional efforts are underway to educate pts on informed decision making and addressing diagnosis anxiety to maintain AS status. A significant proportion of patients chose a RT intervention, perhaps reflecting tx bias towards the physician performing the surveillance. [Table: see text]
Meta-analysis of randomized clinical trials (RCT) for the adjuvant treatment of high-risk clear cell renal carcinoma (RCC) with vascular endothelial growth factor receptor tyrosine-kinase inhibitors (VEGFR TKIs).
Authors: Almeida Daniel Vargas , Oliveira Cleyton Z. , Soares Andrey , Jardim Denis L , Bastos Diogo Assed , Maluf Fernando C. , Werutsky Gustavo , Monteiro Fernando Sabino M , Souza Vinicius Carrera , Fay Andre Poisl , Schutz Fabio A. B.
Published: February 2018

660

Background: A significant proportion of RCC patients with localized disease will eventually recur after a curative intent nephrectomy. VEGFR TKIs have significantly improved the outcomes of patients with advanced disease. RCT are ongoing to evaluate the impact of adjuvant VEGFR TKI on clinical outcome of patients with RCC after definitive treatment . Results from 3 RCT have been already published, but data is controversial. Methods: PubMed databases were searched for articles published from January 1996 to October 2017. Eligible studies were limited to phase 3 RCT of US Food and Drug Administration-approved VEGFR TKIs that reported on patients with RCC treated in the adjuvant setting. Statistical analyses were conducted to calculate the summary hazard-ratio (HR) of disease-free survival (DFS), using 95% CIs by random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results: A total of 4,096 patients from 3 RCT (ASSURE, S-TRAC and PROTECT trials) were included. 2374 patients were randomized to receive sorafenib, sunitinib or pazopanib, and 1722 to receive placebo. The summary HR of DFS for the overall population was 0.88 (95%CI 0.77-1.01; p = 0.0605). When evaluating the report of the ASSURE trial that included only clear cell RCC (n = 3222), the summary HR was 0.85 (95%CI 0.77-0.94; p = 0.0018) favoring adjuvant treatment. No evidence of publication bias was found. Conclusions: This meta-analysis failed to demonstrate a statistically significant improvement in DFS of RCC patients treated with adjuvant VEGFR TKI. However, a statistically significant improvement in DFS was observed when only patients with clear cell histology were evaluated. Longer follow-up of the ongoing trials is necessary in order to better evaluate the impact on overall survival.
Transforming growth factor–β signaling pathways in renal cell carcinoma are regulated by VHL status.
Authors: Ljungberg Borje , Mallikarjuna Pramod , Raviprakash Tumkur sitaram , Landstrom Marene
Published: February 2018

661

Background: To evaluate the role of pVHL in the regulation of the TGF-β signaling pathways in clear cell renal cell carcinoma (ccRCC) as well as in non-ccRCC, and to evaluate the expression pVHL and the TGF-β pathway components and their association with clinicopathological parameters and patient’s survival. Methods: Snap frozen tissue samples from 143 ccRCC, and 56 non-ccRCC patients were examined by Western blot. Two ccRCC cell lines were utilized for in-vitro studies. Expression levels of pVHL were significantly lower in ccRCC compared with non-ccRCC. Based on the median pVHL level the ccRCCs were divided into pVHL-low and pVHL-high. Results: Non-ccRCCs and pVHL-high ccRCCs expressed similar levels of pVHL. Expression of the ALK5-FL and ALK5-ICD, TGF-βRI, were significantly higher in ccRCC compared with non-ccRCC while pSmad2/3 and PAI-1did not differ. In non-ccRCC patients, expressions of ALK5-FL, ALK-5-ICD, pSmad2/3, and PAI1-1 did not associate to clinicopathological parameters and survival. In the ccRCC pVHL-high, expression of ALK5-ICD and PAI-1 associated significantly only to tumor stage and patients survival. Contrastingly, in ccRCC pVHL-low, ALK5-FL, ALK5-ICD, pSmad2/3 and PAI1 all associated to tumor stage and size, and patient’s survival. In-vitro studies on ccRCC cell lines, A498 and ACHN, revealed that pVHL interacted with ALK5 to downregulate its expression through K48-linked polyubiquitination thus negatively controlling TGF- β induced invasiveness of cells. Conclusions: The pVHL status regulates the TGF-β signaling pathway as well as the aggressiveness of tumors and survival of the ccRCC and non-ccRCC patients.
Impact of tumor size on survival outcome in metastatic renal cell carcinoma patients (mRCC) treated with targeted therapy.
Authors: Xie Wanling , DiNatale Renzo , Hakimi A. Ari , Donskov Frede , Porta Camillo , Reaume M. Neil , Basappa Naveen S. , Hansen Aaron Richard , Rini Brian I. , Beuselinck Benoit , Bjarnason Georg A , Srinivas Sandy , Brugarolas James , Rha Sun Young , Wood Lori , Lalani Aly-Khan A. , Bosse Dominick , Duquette Audrey , Heng Daniel Yick Chin , Choueiri Toni K.
Published: February 2018

667

Background: Recent research suggested that patients (pts) with small renal masses (4cm or less) were at low risk of disease recurrence after surgery. The impact of tumor size on survival in mRCC patients treated with targeted therapy (TKI) is unclear. Methods: Two cohorts were identified from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Cohort 1 pts had initial nephrectomy for M0 RCC and subsequently developed metastasis during follow-up. Cohort 2 pts presented with de novo metastasis with or without cytoreductive nephrectomy. Cox regression was performed to assess the associations of primary tumor size (≤4 vs > 4cm) and overall survival (OS) on first line TKI, adjusted for histology, sarcomatoid features, tumor stage, number of metastasis, IMDC risk groups and age at TKI initiation. Results: 4089 pts with mRCC treated with first line TKI had primary tumor size data available. Patient characteristics were generally balanced between tumor size groups (≤4 vs > 4cm), except pts with ≤4cm tumors were more likely to have single metastasis (29% vs 18%, p = 0.001) and less likely to have IMDC poor risk (32% vs 39%, p = 0.04) in pts from cohort 2. For pts from cohort 1, tumor size at initial nephrectomy did not impact OS after TKI initiation (p = 0.689). However, in pts presenting with de novo metastasis (cohort 2), small primary tumors were associated with improved OS after TKI initiation, but only in T1-2 tumors (Table). Conclusions: Tumor size impacts survival outcome with targeted therapy in mRCC patients presenting with de novo metastasis and T1-2 disease. This may need to be taken in consideration in clinical trial designs. [Table: see text]
Immunologic profile and prognostic significance of tumor-infiltrating lymphocytes in renal cell carcinoma.
Authors: Khan Amir Ishaq , Jansen Caroline Stewart , Wilkinson Carlisle Jennifer , Melnick Kevin Richard , Kim Kyu Seo , Hosseinzadeh Fares , Prokhnevska Nataliya , Bilen Mehmet Asim , Master Viraj A. , Kissick Haydn T.
Published: February 2018

673

Background: Renal cell carcinoma (RCC) has been shown to be a genetically and morphologically heterogeneous cancer. As studies show the significance of tumor-infiltrating lymphocytes (TIL) in cancer, it is critical to examine how the phenotype of TILs manifests in RCC. Such analysis may help explain the role of the immune landscape in developing resistance and its contribution to the high treatment failure observed in immunotherapy for RCC. This study compares the immune phenotype of primary tumors, venous tumor thrombi (VTT), and metastases, as well as multiple sites within primary tumors, and investigates whether inter- and intra-tumoral immune heterogeneity is present in RCC. The association of TIL levels and clinical prognosis will also be assessed and compared with current RCC prognostic scores. Methods: Our cohort included 15 VTT and 6 metastases (3 adrenal, 2 bone, 1 liver) with 20 matched primary tumors, as well as 25 non-metastatic primary tumors. The RCC tissue was collected and digested into single cell suspensions. Suspensions were stained for TIL surface markers and processed using flow cytometry. The data was analyzed to capture %CD8+ and %CD4+ in total tumor. The %CD28+ and %PD1+ of CD8+ cells were measured to describe the co-stimulatory and co-inhibitory receptor expression, respectively. Clinical data was obtained to calculate the Mayo Stage, Size, Grade, and Necrosis (SSIGN) and UCLA Integrated Staging System (UISS) scores for each patient and to evaluate recurrence. Results: Immunologic concordance was observed in all measured parameters (%CD8+, %CD4+, %CD28+, and %PD1+) for primary tumors and VTT, for primary tumors and their metastases, and for different sites within 10 primary tumors. In our overall cohort, %CD8+ was found to be inversely associated with recurrence (p = 0.02). Furthermore, %CD8+ was not significantly associated with patient Mayo SSIGN and UISS scores. Conclusions: Despite the genetic and morphologic heterogeneity seen in RCC, immunologic concordance was observed for both inter- and intra-tumoral analysis. The association between %CD8+ and recurrence presents a novel and objective immune-based prognostic factor for RCC, independent of Mayo SSIGN and UISS scores.
Tumor contact surface area as a predictor of functional outcomes after partial nephrectomy.
Authors: Suk-Ouichai Chalairat , Wu Jitao , Dong Wen , Hajime Tanaka , Caraballo Elvis , Remer Erick M. , Li Jianbo , Isharwal Sudhir , Campbell Steven C.
Published: February 2018

675

Background: New baseline GFR is a major factor for cancer survivorship after renal cancer surgery. Parenchymal mass preservation is the predominant factor associated with functional outcomes after partial nephrectomy (PN). Contact surface area (CSA) between the tumor and parenchyma may impact parenchymal preservation and predict functional outcomes after PN. We evaluated CSA as a predictor of parenchymal mass and function preserved by PN. Methods: 419 patients managed with PN had necessary studies to evaluate preoperative and postoperative parenchymal mass and renal function within the operated kidney. Patients with multifocal renal masses were excluded. Parenchymal mass in the operated kidney and CSA were measured using contrast-enhanced CT < 2 months prior and 3-12 months after PN. CSA was calculated using mathematical formula: 2πrd, where r = radius and d = intraparenchymal depth of tumor. Pearson correlation evaluated relationships between CSA and parenchymal mass or GFR preservation. Multivariable linear regression assessed predictors for GFR preservation. Conceptually, the formula for CSA should function best for exophytic tumors, while predictive value for endophytic tumors may not be as strong. Results: Median tumor size and R.E.N.A.L. were 3.5 cm and 8, respectively. Median global/ipsilateral GFR preserved were 89%/79%, respectively. Median ipsilateral parenchymal mass preserved was 85% and significantly higher for exophytic masses (87% vs 83%, p = 0.001). Median CSA was 22.8cm2 and significantly less for exophytic masses (19.8cm2 vs 24.6cm2, p = 0.02). CSA associated modestly with both ipsilateral GFR and mass preserved ( r= 0.25 and 0.36, respectively, both p < 0.001). On multivariable analysis, CSA associated with ipsilateral GFR preserved for exophytic masses (p = 0.011), but not for endophytic ones (p = 0.27). Limitations include retrospective design. Conclusions: CSA associates with parenchymal mass and function saved after PN, although its utility appears to be greatest for exophytic rather than endophytic tumors. Further study will be required to validate the utility of CSA in different clinical settings.
Outcomes of metastatic chromophobe renal cell carcinoma (ChRCC) with sarcomatoid features (SF).
Authors: Ged Yasser , Knezevic Andrea , Chen Yingbei , Redzematovic Almedina , Carlo Maria Isabel , Lee Chung-Han , Feldman Darren R. , Patil Sujata , Motzer Robert J. , Voss Martin Henner
Published: February 2018

678

Background: ChRCC makes up 5-10% of RCC subtypes and is generally thought to confer favorable prognosis. Presence of SF on histologic review can occur in any RCC subtype and is considered a hallmark of aggressive disease. We assessed outcomes in a cohort of patients (pts) with metastatic ChRCC and SF (sChRCC). Methods: Baseline clinical features and details on treatment were collected for pts with newly diagnosed metastatic sChRCC evaluated at Memorial Sloan Kettering Cancer Center (MSKCC) between 2002-17. Overall survival (OS) was calculated for all patients and time to treatment failure (TTF) for those who received first-line therapy at MSKCC. Next generation sequencing (NGS) with MSK-IMPACT was performed in a subset of pts. Results: 27 pts with newly diagnosed metastatic sChRCC were identified; other clinical features are summarized below ( table). 2 pts never received first line therapy based on poor performance status. 16 were treated at MSKCC and received a median of 2 lines of systemic therapy. First line agents included sunitinib (n = 6), pazopanib (n = 2), temsirolimus (n = 2), everolimus + bevacizumab (n = 2), sunitinib + gemcitabine (n = 2) and interferon alpha (n = 2) with median TTF of 2.1 months (0.9-14.5). Across the entire cohort (n = 27), median OS was 7.9 months (95% CI 4.2-11.2) with estimated 1 year OS rate of 25%. By comparison, a cohort of 67 pts with metastatic ChRCC lacking SF also treated at MSKCC 2002-17 achieved median OS of 38.1 months, (HR 4.6; 95% CI: 2.6-8.3; p < 0.001). In the 6 sChRCC pts with NGS analysis, TP53 (n = 4), PTEN (n = 2) and CHEK2 (n = 2) were the most frequently altered genes. Conclusions: Outcome for pts with metastatic sChRCC was poor in contrast to pts with ChRCC lacking SF. The lack of benefit observed across various classes of systemic agents warrants study of underlying biology and novel agents. [Table: see text]
Statin use and risk of renal cell carcinoma in three prospective cohort studies.
Authors: Wilson Kathryn M. , Sanchez Alejandro , Graff Rebecca E. , Signoretti Sabina , Choueiri Toni K. , McDermott David F. , Cho Eunyoung , Preston Mark A
Published: February 2018

679

Background: Evidence on statin use and incidence of renal cell carcinoma (RCC) is mixed. Previous results from the Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS) found a suggestive protective effect in women but not in men (Liu et al, Cancer 2012). We conducted an updated analysis of statin use and risk of total and fatal RCC in the NHS, HPFS, and NHS 2 cohorts, with more than twice as many cases. Methods: We examined the associations between statin use and risk of RCC from 1990 to 2016 in HPFS (men), 1994 to 2016 in NHS (women), and 1999 to 2015 in NHS 2 (women). Information on statin use was collected every two years. We used Cox proportional hazards models, adjusting for known and suspected risk factors, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for use of statins and risk of total and fatal RCC, RCC by stage at diagnosis, and clear cell RCC. We pooled results across cohorts using a random effects model. Results: We documented 661 cases of RCC (310 in HPFS, 255 in NHS, 96 in NHS 2), of which 132 (20%) were fatal. Of the 661 cases, 458 (69%) were clear cell. The pooled multivariable HR for total RCC was 1.01 (95% CI 0.84-1.21) for current statin use, updated over time. Current use was not associated with risk of fatal, advanced (stage T3 or higher), or localized (stage T1 or T2) disease. There were no associations between duration of statin use and risk of RCC; compared to never users, those with less than four years of total use had an HR of 0.91 (95% CI 0.71-1.18), and those with four or more years of use had an HR of 1.03 (95% CI 0.84-1.27). Among men, statin use was associated with increased risk of clear cell RCC (HR for current use: 1.48, 95% CI 1.04-2.11; HR for 4 or more years of use: 1.58, 95% CI 1.05-2.36). Statins were not associated with risk of clear cell RCC in women (HR for current use: 0.77, 95% CI 0.58-1.03; p-value for heterogeneity across cohorts = 0.02). Conclusions: Overall, statin use was not associated with risk of RCC in three large, prospective cohorts of US women and men. Statin use was associated with increased risk of clear cell RCC among men.
Pazopanib with low fat meal (PALM) in advanced renal cell carcinoma (RCC).
Authors: Reimers Melissa Andrea , Daignault Stephanie , Shango Maryann , Dedinsky Rachel , Riddle Liam , Wen Bo , Redman Bruce G. , Alva Ajjai Shivaram
Published: February 2018

683

Background: Pazopanib, a highly lipophilic standard first-line therapy for metastatic RCC, is conventionally taken in a fasting state but has significant gastrointestinal toxicities and 96% of ingested drug is fecally excreted, with major financial implications. Single dose studies with fat meals suggested bioavailability is increased two-fold. We sought to evaluate toxicity/safety, bioavailability and anti-tumor efficacy of daily pazopanib taken with a low fat meal over 12 weeks. Methods: Enrolled pts had unresectable locally advanced or metastatic RCC with clear cell component, RECIST 1.1 measurable disease, ECOG PS ≤2, adequate organ function, and up to 3 prior therapies including VEGF(R) and checkpoint inhibitors. Subjects took pazopanib, starting dose of 400 mg, once daily with low-fat meal ( < 400 cal with < 20% fat/10 g of fat) in 2 wk cycles with MD discretion to dose-escalate q2wks up to 800 mg or irreversibly dose-reduce as low as 200 mg based on tolerance/toxicity for 12 wks. Baseline and end of study echocardiograms, and triplicate ECGs at each cycle start were monitored. Home pill diaries were collected. PK was analyzed in the first 3 cycles. Results: Sixteen pts were accrued: median age 60 (range: 47 – 75),75% men,11 were ECOG PS 0. Most (12/16) subjects with no prior therapy, 13/16 had intermittent Heng risk criteria, 3 favorable; 5 sarcomatoid component. Diet compliance by pill diary was outstanding, except for 1 pt for 1 cycle. Calculated mean daily dose was 535 mg (153-750 mg). Therapy was well tolerated; 5 Grade 3 AEs (1 HTN, 1 chest pain, 2 AST/ALT elevations, 1 Abd pain) occurred. LVEF declined by > 15% in 3 pts but none to < 50%. QTc prolongation > 450 ms did not occur. All but 3 pts completed protocol (off d/t toxicity-HTN, LFTs, chest pain). ORR was PR 5 (31%); SD 7 (44%). PK data and pharmacogenomics CYP3A4 polymorphism data correlated with toxicity. Conclusions: Pazopanib taken with a low fat meal appears to be better tolerated compared to published data on empty stomach administration, especially with fewer GI toxicities, including diarrhea. It also resulted in comparable efficacy with fewer cumulative pills over the 12-week period, with substantial cost implications. Larger trials of pazopanib with low fat meal are warranted. Clinical trial information: NCT02729194.
Adjuvant antiangiogenic agents in post-nephrectomy renal cell carcinoma (RCC): A systematic review and meta-analysis.
Authors: Sonbol Mohamad Bassam , Hilal Talal , Firwana Belal , Ho Thai Huu , Wang Zhen , Joseph Richard Wayne
Published: February 2018

689

Background: The role of antiangiogenic agents in advanced RCC is well established. However, it is still not clear whether this benefit can be extrapolated to the adjuvant setting. In this meta-analysis of 3 randomized control trials (RCTs), we sought to determine the efficacy of these agents in RCC patients who underwent nephrectomy with high risk of relapse. Methods: We searched three databases, including Pubmed, Embase, and Cochrane Central Register of Controlled Trials to identify RCTs comparing antiangiogenic agents to placebo in post-nephrectomy RCC patients. We evaluated: 1) the effect of antiangiogenics in highest risk groups as defined by individual studies; 2) the role of each agent separately; and 3) the effect in clear-cell RCC population. Outcomes of interest included overall survival (OS) and disease-free survival (DFS). The overall effect was pooled using the DerSimonian and Laird random effects models Results: Three RCTs (N = 3693 patients) were identified. All studies were comparing placebo to antiangiogenics: sunitinib, sorafenib, and pazopanib. Overall, antiangiogenics did not improve DFS (HR 0.92, 95% CI 0.78 to 1.07) or OS (HR 0.99, 95% CI 0.79 to 1.25). These results persisted when restricting the analysis to patients with clear cell carcinoma and patients with highest risk of relapse. Similarly, sunitinib did not show any improvement in the entire studied group for either DFS (HR 0.89, 95% CI 0.67 to 1.19) or OS (HR 1.11, 95% CI 0.90 to 1.37). In addition, when restricting the analysis to the high risk group, sunitinib did not show any advantage in terms of DFS (HR 0.85, 95% CI 0.67 to 1.07) and OS (HR 1.04, 95% CI 0.83 to 1.31). Conclusions: Based on the available evidence, antiangiogenics do not seem to add an advantage over placebo in terms of OS and DFS in high risk RCC patients after nephrectomy. Further studies are needed to identify the patient population which might derive a benefit from antiangiogenics in the adjuvant setting.
Can health-related quality of life (HRQoL) predict conditional survival (CS) in metastatic renal cell carcinoma? Results from a large phase 3 trial.
Authors: Doan Justin , Malcolm Bill , Valaitis Eduardas , Hoover Kristopher , George Saby
Published: February 2018

691

Background: In the absence of mature overall survival (OS) endpoints, interim clinical trial data can be used to predict long-term survival in patients (pts) with advanced malignancies and inform trial continuation, treatment preference, and reimbursement decisions. Research shows that HRQoL assessments can be associated with OS, offering potential utility for validated HRQoL scales. We describe a predictive model used to determine the extent to which HRQoL data could predict CS (survival conditional on progression at either 6 or 12 months). Methods: Using pt-level data from a large phase III trial of nivolumab vs everolimus, a simulation approach with a survival random forest algorithm identified factors statistically important in predicting CS from a large number of covariates measured at baseline. Stepwise Cox proportional hazard survival models were fitted using covariates identified as important. Baseline scores and change over time were tested to determine the influence on the predictive power of the HRQoL data. Results: For both nivolumab and everolimus, baseline FKSI values were significant predictors of CS; median survival times roughly doubled for pts with baseline FKSI scores ≥30 vs pts with scores < 30 (nivolumab, 31.3-16.6; everolimus, 26.6-11). Baseline FKSI scores were the most important predictor vs the other baseline covariates from the survival random forest simulation, and a statistically significant covariate when fitting a stepwise Cox proportional hazard survival model. Change in scores over time influenced CS for pts with high baseline scores, and pts who demonstrated improvement in scores vs baseline had significantly higher CS vs pts with low baseline and no improvement in scores vs baseline. However, when examining change in HRQoL score over time, the statistical importance of the covariate begins to diminish due to high correlations with factors such as adverse events and weight change. Conclusions: We found that HRQoL data, specifically the FKSI, could be useful in predicting CS, especially at the onset of a trial. The importance of the FKSI score in predicting CS could be a powerful complement to existing clinical prognostic factors.
Evaluation of serial measurements of C-reactive protein: Albumin ratio in patients with clear cell renal cell carcinoma.
Authors: Patil Dattatraya H , Anastasiades Ella N , Torlak Mersiha , Lay Aaron , Alemozaffar Mehrdad , Pattaras John , Kucuk Omer , Carthon Bradley Curtis , Bilen Mehmet Asim , Ogan Kenneth , Master Viraj A.
Published: February 2018

695

Background: Sequential measurements of prognostic markers is an important protocol for accurate prediction of clinical outcomes in clear cell RCC. We propose that change in value of C-Reactive Protein to albumin ratio before and after surgery would be a good prognostic indicator for assessment of overall survival and risk stratification in clear cell RCC. Methods: Patients that underwent nephrectomy for clear cell RCC between 2007 and 2016 were followed up with CRP-Albumin measurements for 3 post-op visits (1, 3, 6 months). All measurements between post-op day 1 to 21 were excluded from analysis owing to possible confounding effect due to surgical stress. We assessed if change in CRP-Albumin ratio from pre-operative level is associated with any patient and tumor characteristics by fitting linear regression generalized estimating equations models to account for correlation in repeated measures. Average change in level for each post-op visit was used to stratify for an eventual end of follow-up outcome. Results: 302 clear cell RCC patients were treated with nephrectomy with mean age at surgery was 59.9±11 years, and mean BMI of 30.1± 6.6. 103 patients had at least 2 time-points available after surgery. Table 1 depicts mean CRP-Albumin ratio with 95% CI for each visit stratified with vital status. A linear GEE model fitted for baseline factors affecting change in ratio , identified t-stage, Fuhrman nuclear grade, gender, and BMI as significantly associated (p < 0.05). Conclusions: Serial measurement of CRP/Albumin ratio is useful factor for personalized risk-stratification for prognosticating overall survival as well as recurrence in patients with clear cell RCC. Significant effect of T-stage, tumor grade, and BMI depicts close relationship of CA-ratio and established risk predictors. [Table: see text]
Perioperative outcomes of aspirin use in partial nephrectomy.
Authors: Ingham Matthew D. , Krasnow Ross Erik , Mossanen Matthew , Wang Ye , Althaus Adam B. , Chang Steven Lee
Published: February 2018

698

Background: Increasing cardiovascular disease has led to increases in the patient population on anti-platelet therapy who require urologic surgery. We sought to study perioperative outcomes for those undergoing partial nephrectomy (PN) while taking or not taking perioperative aspirin (pASA). Methods: A retrospective review of those undergoing PN was performed on the Premier Hospital Database from 2003 to 2015, with survey projection weighting resulting in a cohort of 10,807 patients. Two groups were formed – those continued on pASA (group 1, n = 774) and those with no pASA (group 2, n = 10,033). In-hospital complication rates were studied: major bleeding, overall transfusion, day-of-surgery transfusion, prolonged ( > 4 days) length of stay (LOS), and prolonged ( > 285 minutes) operative time. We also assessed 90-day rates of: cardiovascular catastrophe, readmission, major complication, and DVT/PE. Unadjusted rates were calculated for all PN patients and further subdivided into open and minimally invasive PN. Adjusted odds ratios (OR) were then calculated between groups 1 and 2. Results: Group 1 was older (58% vs 38% ≥65 years, p < 0.0001), largely male (73.1% vs 58.7%, p = 0.001), and less healthy (34.8% vs 18.4% with a CCI score ≥2, p = 0.003) than to group 2. For in-hospital outcomes, no significant differences were noted. Stratifying by surgical approach, those in group 1 undergoing minimally invasive PN were slightly less likely to require a day-of-surgery transfusion (OR 0.29, CI [0.05-0.99], p < 0.05). For 90-day outcomes, group 1 were far more likely to suffer a cardiovascular catastrophe (OR 7.56, CI [3.38-16.92], p < 0.001) regardless of surgical approach. Conversely, group 1 was slightly less likely to experience readmission (OR 0.48, CI [0.24-0.94], p < 0.05) and was likely driven by those undergoing minimally invasive PN. Conclusions: This large review of academic and community hospitals provides insight into the impact perioperative ASA has on PN outcomes. As noted, in-hospital outcomes were largely equivalent between groups while 90-day cardiovascular catastrophe rates were much higher in the ASA group. Despite this, this study lends support to the belief that pASA should not be considered an absolute contraindication to PN.
TCEB1-mutated renal cell carcinoma in relation to renal cell carcinoma with smooth muscle stroma in tuberous sclerosis complex.
Authors: Parilla Megan , Alikhan Mir , Segal Jeremy , Kadri Sabah , Fitzpatrick Carrie M , Antic Tatjana
Published: February 2018

699

Background: TCEB1-mutated renal cell carcinomas (RCC) are a subtype of RCC which are distinct from both clear cell and clear cell papillary RCCs. These tumors are well-circumscribed, have predominantly tubular and papillary architecture, and have thick intersecting fibromuscular bands imparting a renal angiomyoadenomatous tumor (RAT)-like morphology. Tuberous sclerosis (TSC) patients have an increased risk of developing a number of tumors, including RCC. The histomorphology of RCCs in TSC have been well documented with 30-52% demonstrating “RCC with smooth muscle stroma” morphology, referred to as “TSC-associated papillary RCC (PRCC).” Interestingly the histologic features of TSC-associated PRCC are identical to that of the RAT-like TCEB1-mutated tumors. Methods: A total of 5 patients were found in our archives with histology that matched TSC-associated PRCC /RAT-like morphology. All 5 cases were retrieved and the formalin-fixed, paraffin-embedded blocks were reviewed with a representative block sent for molecular analysis on the UCMC-OncoPlus panel, a 1,213 gene targeted hybrid capture NGS panel. Variant and copy number calling was performed using custom-designed computational pipelines. A subset of cases had additional immunohistochemical stains preformed. Results: These 5 cases all revealed mutations in either TSC1, TSC2 or TCEB1 genes. Conclusions: The TCEB1 gene encodes the protein elonginC, a protein which complexes with VHL. A loss of elonginC results in a VHL complex which is unable to ubiquitinate HIF1-alpha. Non-degraded HIF1-alpha ultimately activates the transcription of a number of genes which lead to tumorgenesis. Interestingly, TSC1 and TSC2 protein products are also responsible for inactivating HIF1-alpha through RHEB/mTORC1/4E-BP1. This intimate molecular relationship with linked pathways of tumorgenesis, coupled identical histomorphology, suggests that TSC-associated PRCC and RAT-like RCC with TCEB1 mutation are the same tumor type.
U-SMART: (UCSD-small mass alt renal score tumor diameter) a novel scoring system of preoperative predictors to stratify oncologic risk of small renal mass.
Authors: Yim Kendrick , Bindayi Ahmet , Ryan Stephen , Reddy Madhumitha , Nasseri Ryan , Wan Fang , Long Christopher , Hamilton Zachary , Derweesh Ithaar
Published: February 2018

700

Background: Small renal masses (SRMs, < 4 cm in diameter) are heterogeneous, with significant proportions of benign as well as high-grade malignancy. We developed a scoring system incorporating patient factors, serum markers, and morphometric characteristics to elucidate benign and high grade pathology and guide decision making. Methods: Single institution retrospective analysis of surgically treated SRMs from 2003-2017. Demographic and clinical factors, including RENAL score, were analyzed. Patients were categorized into 3 groups: benign (BNGN), low grade (LG), or high grade (HG) disease and uni- and multivariable logistic regression were used to screen for association between potential parameters and the 3 groups. Each significant variable was analyzed by risk group and broken into quartiles. The 75th percentile of the HG group was assigned a value of 3. Below the 75th percentile of the BNGN group was assigned a value of 1; values that fell between these cutoffs were assigned 2 points. Tumor diameter was weighted twice that of other factors. Receiver-operating-characteristic (ROC) analysis was used to assess for predictive capability. Results: 312 patients were analyzed (65 BNGN, 204 LG, 43 HG). Factors associated with increased risk of HG were male sex (OR 1.868, p = 0.045), higher ALT (OR 1.036, p = 0.022), higher RENAL score (OR 1.318, p = 0.002), and larger tumor diameter (OR 2.415, p < 0.001). Patients with low (5-8), intermediate (9-11) and high (12-14) scores had 32.8%, 5.2%, and 0% frequency of BNGN pathology. Patients with low, intermediate, and high scores had 7.7%, 18.6%, and 34.9% frequency of HG pathology. ROC analysis revealed AUC of 0.767. Conclusions: Preoperative clinical parameters were incorporated into a model that significantly predicts benign and aggressive pathology for SRMs. This risk stratification may provide a non-invasive method to aid in clinical decision making. External validation is requisite.[Table: see text]
Comparing cabozantinib (C) treatment for a cohort of patients with metastatic clear cell (ccRCC) and variant histology renal cell carcinoma (vhRCC): A retrospective study.
Authors: Lemke Emily , Shah Amishi Yogesh , Msaouel Pavlos , Bilen Mehmet Asim , Jonasch Eric , Venkatesan Aradhana M. , Chandramohan Anuradha , Duran Cihan , Tannir Nizar M. , Campbell Matthew T.
Published: February 2018

702

Background: Both the randomized METEOR and CABOSUN studies in ccRCC found substantial benefit for patients receiving (C). We have previously reported (C) to have significant activity in vhRCC. To date no comparative data exists in evaluating the utility of (C) in ccRCC and vhRCC. Methods: This is a retrospective study of patients with ccRCC and vhRCC who received (C) at a single center from 1/2014-9/2017. Data tabulated included baseline characteristics, toxicity, dose reductions, time on (C) and survival data. A blinded radiologist assessed the radiographic response using RECIST v1.1. Cox regression analysis of time to treatment failure (TTF) in ccRCC and vhRCC was performed, adjusting for age, gender, IMDC score, neutrophil to lymphocyte ratio (NLR), prior TKI treatment, and number of metastatic sites. Statistical analysis were performed using SPSS 23.0. Results:Time to treatment failure was significantly longer in vhRCC compared with ccRCC (16.1 vs 7.64 months, HR 0.42, 95%CI 0.22-0.79, p = 0.007). This difference persisted in the adjusted Cox regression model (HR 0.36, 95% CI 0.15-0.85, p = 0.02). Conclusions: In this retrospective comparative analysis of C treated vhRCC and ccRCC patients, C was found to have substantial activity in both cohorts of patients. The IMDC score was important to predict outcome. Both heavily pretreated patients with ccRCC and those with vhRCC appeared to have substantial benefit.[Table: see text]
Validation of a genomic classifier to predict adverse pathology in men diagnosed with low risk prostate cancer.
Authors: Kim Hyung Lae , Li Ping , Huang Huei-Chung , Deheshi Samineh , Knudsen Beatrice , Abou-Ouf Hatem , Lam Lucia L.C. , Margrave Jennifer , Du Plessis Marguerite , Davicioni Elai , Tosoian Jeffrey J. , Ross Ashley , Davis John W. , Hyndman M. Eric , Klein Eric A. , Bismar Tarek A.
Published: February 2018

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Background: The Decipher 22-feature genomic classifier (GC) has been validated to predict metastasis and prostate cancer specific mortality in needle biopsy (Bx) tissue of men with intermediate and high-risk prostate cancer. We validate GC in diagnostic Bx specimens for the prediction of high-grade/stage (HGS) disease at radical prostatectomy (RP) in men with low and favorable-intermediate (fav-int) NCCN risk group disease. Methods: We identified 176 men diagnosed with low or fav-int NCCN risk group disease who had available Bx GC scores and pathological information after RP from Cedars-Sinai, University of Calgary, Cleveland Clinic, MD Anderson, and Johns Hopkins. The GC score was calculated based on a locked random forest model. Scores range from 0-1 with cut points for GC low, intermediate and high risk groups as <0.45, 0.45-0.6, and >0.6, respectively. The primary endpoint was HGS (Gleason group 3-5 or pT3b or lymph node invasion (LNI)). Univariable (UVA) and multivariable (MVA) logistic regression models were used to evaluate GC and CAPRA. Results: Median age of the cohort was 62 years, 87% and 13% had Bx grade group (GG) 1 or 2 disease. 76% and 24% were NCCN low and fav-int risk, respectively. CAPRA classified 70% as low (0-2) and 30% as average risk (3-5). GC classified 80% low, 16% intermediate and 4% high genomic risk. After RP, 41% had RP GG 1, 46% GG 2 and 13% had GG 3-5 disease. pT3b or positive lymph nodes were observed in 7 men (4%), overall 27 (15%) of men had HGS at RP. In the UVA and MVA, GC was the only significant predictor of HGS with odds ratio (OR) of 1.38 and 1.34 per 10% unit increase, before and after adjusting for CAPRA (p=0.011, 0.027). A low risk score (GC<0.45) had a negative predictive value (NPV) of 92% to identify men who do not have HGS at RP. In exploratory analysis, a very low risk cut-point (GC<0.2) was found which had a sensitivity of 96% and an NPV of 99%. 26% of men had GC<0.2. Conclusions: We validated GC in a multi-institutional study to predict HGS at RP among men with NCCN low and fav-int risk disease with high sensitivity and NPV. Future studies will aim to validate the very low risk genomic cut-point to guide decision-making and follow-up biopsy protocols for men considering or in active surveillance.
Impact of genomic risk scores on treatment decisions following radical prostatectomy in a prospective Medicare registry.
Authors: Gore John L. , Dai Darlene , Den Robert Benjamin , Yousefi Kasra , Le Tiffany , Du Plessis Marguerite , Padre Roanna , Sosu-Sedzorme Worlanyo , Davicioni Elai , Nguyen Paul L. , Ross Ashley
Published: February 2018

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Background: Prostate cancer patients and providers confront uncertainty as they consider adjuvant or salvage radiation therapy (ART, SRT) after radical prostatectomy (RP). We prospectively evaluated the impact of the Decipher RP test, which predicts metastasis risk after RP, on decision-making for postoperative radiation therapy. Methods: Between October 2016 and May 2017, 1,319 patients treated with RP and considering ART or SRT were enrolled into a Medicare Certification and Training Registry (CTR). Providers submitted a management recommendation based on initial clinical and pathology findings prior to obtaining the Decipher RP test and again upon receiving test results. Only Medicare patients that met the Local Coverage Determination inclusion criteria (i.e., non-organ confined prostate cancer or positive margins or rising PSA) and whose provider was certified in the CTR registry were included in the analysis. Results: Based on clinical variables alone, treatment was recommended for 26% of adjuvant and 19% of salvage patients. Obtaining a Decipher score, changed treatment recommendations in 34% (95% CI 30-39%) and 28% (95% CI 19-38%) of men considering adjuvant or salvage therapy respectively. Among men considering ART, 9% of Decipher low risk patients and 45% of Decipher high-risk patients were recommended treatment. Multivariable logistic regression demonstrated that – independent of pathology risk factors, a high-risk Decipher score was associated with an odds ratio of 7.3 (95% CI 3.9-14.2 p < 0.001) in the adjuvant and 5.5 (95% CI, 1.3-27.8, p = 0.026) in the salvage setting. Conclusions: A prospective CTR demonstrated that use of Decipher resulted in significant changes in treatment decisions for Medicare beneficiaries with PCa considering adjuvant and salvage therapies. Ongoing prospective studies aim at determining how increased use of therapy in men with high Decipher risk impacts oncologic outcomes and whether decreased use in Decipher low risk individuals improves health related quality of life without harming patient survival.
Overcoming miR-106a induced radioresistance in prostate cancer: Targeting senescence with KU-55933.
Authors: Hoey Christianne , Ray Jessica , Huang Xiaoyong , Jeon Jouhyun , Boutros Paul Christopher , Liu Stanley K.
Published: February 2018

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Background: Prostate cancer is a leading cause of cancer related death in men worldwide, with recurrence being a major clinical problem after radiotherapy. There is an unmet need to better characterize radioresistant tumors and identify biomarkers to improve patient outcomes. Methods: We identified that miR-106a was overexpressed in radiation resistant cell lines compared to parental cells. We analyzed The Cancer Genome Atlas dataset to assess miR-106a expression in normal prostate, and low- to high-grade prostate tumors. To assess the functional role of miR-106a, we performed in vitro and in vivo assays for radiation response, including clonogenic survival, proliferation, senescence, and tumor xenograft growth after radiation. We performed gene array and pathway analyses to identify downstream effectors of miR-106a. Results: MiR-106a expression was significantly higher in prostate tumors with Gleason score > 7 compared to Gleason ≤ 7, suggesting miR-106a is involved in high grade disease. MiR-106a overexpression confers radioresistance in vitro and in vivo, by targeting LITAF. We now extend miR-106a’s effects to upregulation of ATM at the promoter level, thereby increasing ATM transcript and protein in the cell. Unexpectedly, we found that miR-106a’s mechanism of radioresistance through ATM upregulation does not alter DNA damage repair. ATM upregulation affects clonogenic survival through reduced senescence. KU-55933, a specific ATM kinase inhibitor, resensitizes miR-106a overexpressing cells to radiation by inducing senescence, a predominant mode of cell death in prostate cancer. Conclusions: Our research challenges the current paradigm of ATM and DNA damage repair by outlining another mechanism of radioresistance through alteration of senescence. Our findings suggest that miR-106a may be a promising biomarker for high-grade disease and radioresistant prostate cancer. In addition, we have identified a therapeutic intervention for miR-106a induced radioresistance. Improvements in bioavailability of KU-55933 may lead to its clinical use in combination with radiation therapy to radiosensitize miR-106a induced radioresistant prostate cancer.
Impact of percent positive biopsy cores on cancer-specific mortality for patients with high-risk prostate cancer.
Authors: Yang David Dewei , Muralidhar Vinayak , Mahal Brandon Arvin Virgil , Vastola Marie , Boldbaatar Ninjiin , Labe Shelby A , Nezolosky Michelle Daniel , Martin Neil E. , King Martin T. , Mouw Kent William , Orio Peter F , Choueiri Toni K. , Trinh Quoc-Dien , Nguyen Paul L.
Published: February 2018

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Background: A high percent positive biopsy cores (PBC), typically dichotomized at ≥50%, is prognostic of worse cancer-specific outcomes for patients with low- and intermediate-risk prostate cancer. The prognostic value of ≥50% PBC for patients with high-risk disease is poorly understood. We examined the association between ≥50% PBC and prostate cancer-specific mortality (PCSM) for patients with high-risk prostate cancer. Methods: We identified 7,569 men from the Surveillance, Epidemiology, and End Results program who were diagnosed with high-risk prostate cancer (Gleason 8-10, prostate-specific antigen > 20 ng/mL, or cT3-T4 stage without evidence of nodal or metastatic disease) in 2010 or 2011 and had 6-24 cores sampled at biopsy. Multivariable Fine and Gray competing risks regression was utilized to examine the association between ≥50% PBC and PCSM, with adjustments for sociodemographic and clinicopathologic factors. Results: Median follow-up was 3.8 years (interquartile range 3.3-4.3 years). 56.2% of patients (4,253) had ≥50% PBC. The 4-year unadjusted cumulative incidences of PCSM were 2.0% (95% confidence interval [CI] 1.5-2.6%) and 5.6% (95% CI 4.9-6.4%) for patients with < 50% and ≥50% PBC, respectively. On multivariable analysis, the presence of ≥50% PBC was associated with a significantly higher risk of PCSM (adjusted hazard ratio [AHR] 1.95, 95% CI 1.43-2.66, P< 0.001). On subgroup analysis, ≥50% PBC was associated with a significantly higher risk of PCSM only for cT1-T2 disease (AHR 2.21, 95% CI 1.59-3.07, P< 0.001) but not cT3-T4 disease (AHR 0.77, 95% CI 0.33-1.81, P= 0.547), with a significant interaction ( Pinteraction= 0.012). Conclusions: In this large, contemporary cohort of patients with high-risk prostate cancer, ≥50% PBC was independently associated with a two-fold increased risk of PCSM for patients with cT1-T2, but not cT3-T4, tumors. Percent PBC should be used to routinely risk stratify men with high-risk disease and identify patients who may benefit from intensification of therapy, such as adding docetaxel or abiraterone to radiotherapy with androgen deprivation therapy, to optimize cancer-specific outcomes.