bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of stereotactic ablative radiotherapy for extra-cranial oligo-metastatic renal cell cancer.
Authors: Zhang Yuanyuan , Schoenhals Jonathan , Christie Alana , Wang Chiachien , Mohamad Osama , Singla Nirmish , Desai Neil , Choy Hak , Courtney Kevin Dale , Bagrodia Aditya , Margulis Vitaly , Bowman I. Alex , Timmerman Robert D. , Brugarolas James , Hannan Raquibul
Published: March 2019

599

Background: Stereotactic ablative radiotherapy (SAbR) is a standard of care for treating renal cell cancer (RCC) cranial metastasis. We describe the effect of SAbR on oligometastatic extra-cranial RCC disease course. Methods: We retrospectively reviewed 49 patients with oligometastatic RCC with 68 extra-cranial lesions. Patients were treated with SAbR with a curative intent from 2007 to 2017. We analyzed local control, systemic therapy free survival (mPFS), and overall survival. Results: With a median follow-up of 28 months (IQR: 16.0-40.3), the 1-year and 2-year overall survival after SAbR was 93.4% (95% CI: 81.0-97.8), and 83% (95% CI: 67.4-91.5) respectively. The median overall survival was not reached. The median time to systemic therapy was 13.4 months from the first SAbR(95% CI: 8.8-27.6). Median times from the first SabR course to second and third line systemic therapy (or death) were 31.8 months and 45 months, respectively. Patients in the favorable risk group by the Heng’s criteria (HR = 8.67, p = 0.04), with nometastatic disease at diagnosis (HR = 10.38, p < 0.01) and with clear cell histology (HR = 6.15, p < 0.01) exhibited better survival, as shown by univariate analysis. Patients with no metastatic disease at diagnosis (HR = 2.56, p = 0.02) and only one metastasis treated with SAbR (HR = 2.36, p = 0.03) also exhibited better systemic therapy-free survival. SAbR had an excellent local control rate of 94% at 2 years with no reported grade 3 or higher toxicity. Conclusions: SAbR is an effective and safe treatment for oligometastatic RCC, offering excellent local control with minimal toxicity. SAbR delayed the start of systemic therapy for this RCC cohort, offering quality of life benefits for patients without adversely affecting the progression on subsequent lines of systemic therapy. These findings call for prospective verification.
Pembrolizumab (pembro) and cabozantinib (cabo) in patients (pts) with metastatic renal cell carcinoma (mRCC): Phase I results.
Authors: Keeler Molika Emmeline , Kessler Elizabeth Riley , Bernard Brandon , Weisdack Sarah , Breaker Kathryn M. , Wold Mali , Ertz Donna , Weitzenkamp David , Flaig Thomas W. , Lam Elaine Tat
Published: March 2019

600

Background: PD-L1- and VEGF-targeted therapies have improved survival for mRCC pts and mechanisms of synergy have been reported. We conducted a phase I/II study to evaluate the safety and efficacy of pembro and cabo in mRCC pts. Phase I data are presented here. Methods: mRCC pts received pembro and cabo in a standard 3+3 dose escalation to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and objective response rate (ORR). Cabo was dosed at 40mg QD and 60mg QD in the first and second cohorts, respectively. Pembro was dosed at 200mg IV Q3W in all cohorts. The DLT window was 21 days. Scans were obtained every 9 weeks. Treatment beyond progression was allowed. Results: Eight pts (6M, 2F) were enrolled in the dose escalation cohort with cabo 40mg (5 pts) or 60mg (3 pts) and pembro 200mg. Two pts were not evaluable for DLT due to missing ≥25% of the planned cabo doses in C1, not related to DLT. Median age was 52.5 yrs (range 40-68). Seven pts had clear cell RCC and 1 pt had non-clear cell RCC. Seven pts had MSKCC intermediate risk and 1 pt had MSKCC poor risk. All pts had prior nephrectomy. Median number of prior therapies was one (range 1-3). No DLTs were observed. Drug-related G1 and G2 adverse effects included fatigue (87.5%), weight loss (75%), anorexia (50%), diarrhea (50%), dysgeusia (50%), and abnormal LFTs (50%). One pt had SAE of G3 reversible posterior leukoencephalopathy syndrome during C4, attributed to cabo. One pt each developed G3 hypertension, G3 anorexia, and G3 confusion, all occurring outside the DLT window. No dose reductions were needed at the 40mg cohort. One pt in the 60mg cohort required dose reduction to 40mg after C5. All patients were evaluable for response: 2 PR (at 60 mg cohort), 5 SD [median duration SD 18 wks (range 9-36+)], 1 PD; ORR 25%; clinical benefit rate 87.5%. No correlation was seen between PD-L1 status (archival tissue) and response. Conclusions: The MTD was determined to be pembro 200 mg Q3W and cabo 60 QD. Enrollment in the phase II dose expansion is ongoing and the MTD may be adjusted based on additional pt experience and long-term tolerability. There was encouraging early efficacy. This is an investigator-initiated study sponsored by Merck. Clinical trial information: NCT03149822.
Comparison of retroperitoneal and transperitoneal robotic partial nephrectomy by pentafecta perioperative and renal functional outcomes.
Authors: Choi Chang Il , Seo Seong Il
Published: March 2019

602

Background: To compare and analyze surgical, oncological and functional outcomes of transperitoneal (TRPN) and retroperitoneal robotic partial nephrectomy (RRPN). Methods: Out of 566 consecutive patients who underwent RAPN by a single surgeon from December 2008 to July 2017, this study included 523 patients (TRPN 310, RRPN 213) who evaluated preoperative and 1-year postoperative estimated glomerular filtration rate (eGFR). Our primary endpoint was to compare the perioperative and postoperative outcomes of both approaches by the measure of Pentafecta (negative surgical margin, no 30-day complication, warm ischemic time (WIT) ≤25 minutes, return of estimated glomerular filtration rate (eGFR) to > 90% from baseline and no upstaging of chronic kidney disease). Secondary endpoint was to find the factors associated with Pentafecta by multivariate regression analysis. Results: No significant difference was found in terms of age, BMI, laterality, history of hypertension or diabetes, ASA grade, tumor size and RENAL nephrometry score. These outcomes were lower in the RRPN group: operative time [median (IQR) 244 (202-295) vs. 273 (230-314); p < 0.001], WIT [median (IQR) 19 (15-25) vs. 21 (16-27); p < 0.008] and estimated blood loss (EBL) [median (IQR) 100 (60-200) vs. 150 (100-200); p < 0.003]. Hospital stay, baseline eGFR, 1-year postoperative eGFR, the rate of Pentafecta achievement, recurrence and complications were not different. The rate of WIT ≤ 25 minutes was solely significantly different (TRPN 69.7% vs. RRPN 77.9%, p = 0.045) in the Pentafecta criteria. Multivariate analysis revealed tumor size [OR (95% CI) 0.641 (0.536-0.767), p < 0.001) and hospital stays (OR 0.639, p < 0.001) as predictive for lack of Pentafecta. Conclusions: RRPN demonstrated less operative time, WIT and EBL than TPRN. Pentafecta achievements were equivalent in both approaches. Tumor size and hospital stays were found as predictive factors of Pentafecta.
Prognostic role of PD-L1 expression in patients with advanced renal cell carcinoma (RCC) treated with sunitinib.
Authors: Iglesias Clara , Cereceda García Rodrigo Ignacio , Rodríguez Arias Lucía , Alvarez Manceñido Felipe Jose , Blanco Lorenzo Verónica , Faez Laura , Solis-Hernandez Maria Pilar , Fernández Sara , Revuelta Alfonso , Gómez David , del Río Fernández Jorge , Valcárcel González Sena , Contreras Toledo Debora Corina , Mihic Góngora Luka , Esteban Emilio
Published: March 2019

603

Background: the prognosis and treatment of advanced RCC has improved over the last decade due to a number of effective anti-angiogenic and immune checkpoint inhibitors (ICPI) therapies. Certain clinical factors, such as low Karnofsky status (≤ 70%); less than a one year period from diagnosis to treatment administration; low serum hemoglobin; high corrected serum calcium; high lactate dehydrogenase; elevated neutrophil count or platelet count exceeding the upper limit of the normal range, have been able to stratify patients into three distinct prognostic groups: favorable (zero risk factors), intermediate (one to two), and poor risk (more than two). Nowadays, the relationship between PD-L1 expression with treatment response and the survival rate of RCC is a current topic of interest. Methods: a retrospective analysis of 182 patients with advanced RCC who received sunitinb in a single Institution has been conducted with the aim of analyzing PD-L1 as a prognostic factor. To carry out the immunohistochemical analysis, microscopy samples have been treated with the PD-L1 IHC 22C3 pharmDx assay, which is intended to measure the percentage of PD-L1 expression in the primary tumor tissue. Results: a total of 65 patients with primary tumor tissue sampling, who were never treated with (ICPI), were analyzed. Among these, 95% were considered as intermediate or poor risk and 47% had PD-L1 expression. The results have shown that PD-L1 expression is associated with worse progression-free survival (PFS) and overall survival (OS). In patients with no expression of PD-L1, the median PFS was 16.89 months (95% confidence interval 11.0 – 40.87 months) and 12.61 months for those with some % of PD-L1 expression (4.43 – 53.09). (χ² = 1.16; Pr > χ² = 0.20). Likewise, the median OS was 42.28 months (13.76 – 68.13) for patients with no expression of PD-L1 and 24.60 months for those with some % of PD-L1 expression (13.76- not reached) ( χ ² = 0.12; Pr > χ ² = 0.73). Conclusions: patients treated with sunitinib who express PD-L1, have shown shorter PFS and OS. Its validation as an independent prognostic factor, with regard to other standard clinical parameters, must be considered in order to develop a more tailored approach to treatment decision.
Molecular and imaging correlates of exceptional pathologic response to neoadjuvant ADT plus enzalutamide.
Authors: Sowalsky Adam G. , Wilkinson Scott , Ye Huihui , Harmon Stephanie , Turkbey Baris , Carrabba Nicole , Atway Rayann , Chun Guinevere , VanderWeele David James , Karzai Fatima , Madan Ravi Amrit , Pinto Peter A. , Choyke Peter L. , Dahut William L.
Published: March 2019

61

Background: AR directed therapies are standard of care for metastatic prostate cancer, and their use for high-risk localized disease may improve survival. Previous trials showed that suppression of AR activity resulting in greater pathologic responses improved survival rates. However, the underlying biology and molecular features of exceptionally responding tumors remain unknown. Methods: Men with locally advanced prostate cancer (median Gleason score 8, median PSA 9.58 ng/dl) received mpMRI and MRI/US-fusion targeted biopsies at baseline. Patients received 6 months of ADT plus enzalutamide, then received a second mpMRI, and underwent radical prostatectomy. RP specimens were whole mounted in the same plane as MRI. The location of each tumor on biopsy was mapped to prostatectomy specimens using pathologic and imaging hallmarks. FFPE sections of baseline and post-treatment tumor were stained, laser capture microdissected, and analyzed using whole exome sequencing. Amongst nonresponding patients (residual tumor burden > 0.05 cc) comparison of pre- and post-treatment tumor specimens identified evolutionary phylogenies over space and time representing intrinsic or clonal selection of pre-existing cells. Amongst responding patients, clonal extinction was confirmed by sequencing and immunostaining of surgical specimens. Results: Gleason score at baseline did not differentiate responding and nonresponding patients. Focal ERG staining in biopsies was absent in 100% of responders and present in 60% of responders. Intraductal carcinoma architecture was also absent in all responding tumors. Focal PTEN loss was observed in all nonresponders at baseline. Responding tumor foci were enriched for deletion of chromosome 6q. Comparison of baseline mpMRI sequences indicated a trend towards lower variance on dynamic contract enhanced (DCE) MR and lower local texture heterogeneity metrics in responding lesions. Conclusions: Response to neoadjuvant intense ADT correlates with distinctive pathologic, molecular, and imaging features that can be observed prior to treatment. Selection of patients based on these parameters may improve overall responses to treatment in subsequent clinical trials. Clinical trial information: NCT02430480.
Angiogenic and immunomodulatory biomarkers in axitinib-treated patients (pts) with advanced renal cell carcinoma (aRCC).
Authors: Rini Brian I. , Escudier Bernard , Murphy Danielle , Wang Panpan , Tarazi Jamal Christo , Motzer Robert J.
Published: March 2019

614

Background: Axitinib (axi) is approved for 2nd-line treatment of aRCC. In AXIS trial, median progression-free survival (PFS) was significantly longer in axi- vs sorafenib (sor)-treated pts (hazard ratio [HR] 0.67, 95% CI 0.54–0.81, P<0.0001). Association between mRNA/miRNA expression and clinical outcomes in a subset of axi- or sor-treated pts from AXIS was assessed. Methods: mRNA/miRNA analyses were performed on archival tumor samples. Expression was summarized for responders (complete and partial response) vs non-responders (stable and progressive disease), and for maximum percent tumor change. PFS and overall survival (OS) were analyzed by Kaplan-Meier. Results: Pt characteristics were similar between axi (n=34) and sor (n=33) arms. Association with outcomes is shown in the Table. A correlation was observed for CD68 protein and mRNA expression in axi-treated pts (R=0.4774 P=0.0043 and R=0.3985 P=0.0196, respectively). Both CXCR4 and TLR3 showed differences between treatment arms and association with PFS. TNFSF10 <median, and CD163, CSF1R and miR-221-5p ≥median were associated with shorter OS with axi vs sor ( P<0.05). Clinical trial information: NCT00678392. Conclusions: Immune-related biomarkers were associated with clinical outcomes in axi/sor-treated aRCC pts. Lower CCR7 expression was associated with better response and OS in axi-treated pts. CXCR4 and TLR3 may be predictive of response to axi. Analysis in a larger cohort is warranted.[Table: see text]
A prospective phase II trial of gemcitabine plus axitinib in patients with sarcomatoid type renal carcinoma.
Authors: Park Inkeun , Lee Hyo Jin , Bae Woo Kyun , Yoon Shinkyo , Lee Jae-Lyun
Published: March 2019

616

Background: Sarcomatoid renal cell carcinoma (SRCC) is a rare but very aggressive type of RCC. The treatment option for SRCC is very limited, and there have been anecdotal reports of very good responders to gemcitabine or vascular endothelial growth factor receptor tyrosine kinaase inhibitors (VEGFR TKI). We conducted multicenter phase 2 trial of gemcitabine plus axitinib (GX) in patients (pts) with recurrent or metastatic SRCC to evaluate its efficacy and safety. Methods: Eligibility criteria included histologically confirmed metastatic or recurrent RCC with sarcomatoid component of 25% or more on resected kidney or exclusive sarcomatoid carcinoma on needle biopsy, ECOG PS 0-2, measurable lesion by RECIST v1.1, and adequate cardiac, hepatic, renal and bone marrow function. Pts with uncontrolled hypertension, prior exposure to gemcitabine or VEGFR TKI were exclude. Pts received gemcitabine 1,000 mg/m2 intravenously on days 1 and 8 by 3-week cycle and axitinib 5 mg twice daily. The primary endpoint was objective response rate (ORR) according to RECIST v1.1, and secondary end points were progression-free survival (PFS), overall survival (OS), and toxicity. Results: Twenty-five pts were enrolled between Oct 2014 and Aug 2018. Median age was 61 (range 33-80), and 84% was male. ECOG PS were 1 (92%) and 2 (8%), and 52% had prior nephrectomy. Clear cell carcinoma was the most common histology of carcinoma component, and median percentage of sarcomatoid component was 90% (25-100%). Pts belonged to intermediate (28%) and poor (72%) risk group according to IMDC risk stratification. Median 6 cycles of GX were administered, and 56%, 28%, and 12% of pts achieved PR, SD, and PD, respectively, with an ORR of 56% and median duration of response of 2.5 months. With a median follow-up duration of 21.4 mo, median PFS was 4.9 mo (95% CI, 3.5-13.3), and median OS was 8.4 months (95% CI 3.5-13.3 months). Most adverse events were manageable, and no unexpected toxicities were found. One pt died of grade 5 pneumonia. Conclusions: GX showed promising efficacy in pts with SRCC. GX might be considered as one of treatment options for pts with SRCC, although efficacy of GX should be confirmed in larger trial.
Proposal for tripartite re-classification of T1 renal cell carcinoma into cT1a (very low risk), cT1b (low risk), and cT1c (intermediate risk) substages.
Authors: Bradshaw Aaron , Uzzo Robert , Larcher Alessandro , Eldefrawy Ahmed , Capitanio Umberto , Joshi Shreyas , Ryan Stephen , Meagher Margaret Frances , Cotta Brittney , Yee Addison , Wan Fang , Montorsi Francesco , Derweesh Ithaar
Published: March 2019

618

Background: 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 noted 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, Fox Chase Cancer Center, Ospadele San Raffaele) retrospective analysis of patients with cT1 renal cell carcinoma treated between 1987 and 2018. Patients were stratified 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. Results: 3,324 patients were stratified into proposed T1 groups (T1a=578, T1b=2111, T1c=635; median follow-up 50 months). For cT1a, cT1b and cT1c, KMA revealed 5 year RFS of 96.9%, 91.6%, and 80.6% (p<0.001), and 5 year OS of 91.9%, 86.3%, and 76.2% (p<0.001). MVA for RFS revealed increasing age (HR=1.02, p<0.001), diabetes mellitus (HR=1.36, p=0.04), high tumor grade (HR=2.22, p<0.001) and tumor stage (Referent T1a; cT1b HR=2.18 p=0.001, cT1c HR=5.01 p<0.001) as independent risk factors. MVA for OS revealed increasing age (HR=1.05, p<0.001), diabetes mellitus (HR=1.57, p<0.001), high tumor grade (HR=1.34, p=0.002) and tumor stage (Referent T1a; cT1b HR=1.26 p=0.1, cT1c HR=2.050 p<0.001) as risk factors. Conclusions: Subclassification of cT1 renal cell carcinoma into three clinical stage categories corresponds to distinctive tumor groups whose biological potential varies significantly. Division into three distinct categories may enhance risk stratification, refine preoperative counseling, and augment postoperative follow-up protocols by delineating a very low risk and intermediate risk subset of renal tumors. [Table: see text]
The role of radiomics in the preoperative diagnosis of renal cell carcinoma with sarcomatoid dedifferentiation (sRCC).
Authors: Suk-Ouichai Chalairat , Kotrotsou Aikaterini , Idris Tagwa , Abrol Srishti , Umbreit Eric , McIntosh Andrew G. , Wood Christopher G. , Colen Rivka R. , Karam Jose A.
Published: March 2019

621

Background: sRCC is an aggressive renal malignancy, with poor survival and limited response to therapy. Preoperative identification of sRCC would be helpful for counselling patients, and clinical trial enrollment. This study aims at assessing the potential of radiomics to discriminate clear cell sRCC from non-sarcomatoid clear cell RCC (nsRCC). Methods: The study included 49 sRCC and 41 nsRCC patients treated with surgery between 2007-2016, who had contrast-enhanced CT available. An experienced radiologist delineated the entire tumor using 3D Slicer ( http://www.slicer.org ). The extracted 3D region of interest was imported in our in-house radiomic pipeline. A total of 310 features (10 histogram-based and 300 second-order features) were calculated. Second-order radiomic features were calculated using the Grey Level Cooccurrence Matrix (GLCM) and 20 Haralick features were obtained from the GLCM. To account for directionality, the mean, variance and range of the features across different directions were calculated. Finally, different number of gray levels were also considered in the analysis (N = 8, 16, 32, 64, 256). Core features were obtained using a feature selection based on Least Absolute Shrinkage and Selection Operator (LASSO). Selected features were used to build a classification model for prediction of sRCC versus nsRCC (XGboost). To evaluate the robustness of the estimates, Leave One Out Cross-Validation (LOOCV) was conducted on the patient set. Results: Overall, median tumor size was 10.0 cm and most patients had pT3a (68%). There was no significant difference of age, gender, race, tumor size and stages between sRCC and nsRCC cohorts. The prediction of sRCC using LOOCV was significant with p-value < 0.0001. Area under the curve, sensitivity, and specificity for identification of sRCC were 96.8%, 92.6% and 93.8% respectively. Conclusions: This study demonstrates that CT radiomic features can accurately discriminate between sRCC and nsRCC. The proposed tool has the potential to advance clinical management strategies. In addition to being noninvasive, this methodology can be applied to scans obtained during routine clinical care. Further external validation is warranted.
Radiomic correlates of molecular and clinicopathological characteristics in clear cell renal cell carcinoma.
Authors: Coy Heidi , Young Jonathan R , Pantuck Allan J. , Douek Michael , Sisk Anthony , Magyar Clara , Brown Matthew S. , Sayre James , Raman Steven
Published: March 2019

625

Background: Clear cell renal cell carcinoma (ccRCC) is a highly vascularized tumor and has a heterogeneous molecular profile, but the correlation between its tumor biology and radiomic features have only recently been investigated. As 70% of ccRCCs are detected incidentally at imaging, and tumor phenotypes are only available after surgery, a non-invasive biomarker to predict ccRCC phenotypes and aggressiveness on imaging may be clinically valuable, as low grade lesions may undergo active surveillance. Methods: With IRB approval and HIPAA compliance, our study cohort comprised 92 consecutive patients with 102 ccRCCs (mean age, 62 years (SD ± 14.2) with histopathology and molecular endpoints imaged preoperatively on CT with a four-phase renal protocol [unenhanced (U), corticomedullary (C), nephrographic (N), excretory (E)]. Radiomic data was obtained by contouring the entire ccRCC in each phase to obtain a 3D tumor volume of interest (VOI). The mean enhancement in each phase the and wash-in and wash-out of enhancement was calculated for each ccRCC. Molecular data was obtained through immunohistochemistry of resected ccRCCs to assess carbonic anhydrase-IX (CAIX), microvessel density (MVD), phosphatase and tension homolog (PTEN), and tumor grade (TG). Categorical variables were analyzed with logistic regression and odds ratio (OR) was reported. Continuous variables were analyzed with linear regression and Pearson correlation coefficient (r2) was reported. P-values < .05 were considered significant. Results: Significant radiomic associations included TG and 3D tumor enhancement in the C (OR = 4.72, p = .030), N (OR = 17.71, p < .0001), and E phases (OR = 17.10, p < .0001), and wash-in from U to C (OR = 8.27, p = .004). MVD had a significant positive association with 3D tumor enhancement in the C phase (r2= 0.410, p < .0001), wash-in from U to C (r2= 0.435, p < .0001) and wash-out from the C to N (r2= 0.435, p = .001). There were no significant radiomic correlates with CAIX or PTEN expression. Conclusions: A 3D ccRCC VOI on multiphasic CT had significant correlations with TG and MVD, independent of clinical features, potentially becoming a predictive imaging biomarker of ccRCC aggressiveness and clinical outcome.
Improving the definition of high-risk patients for tumor recurrence from clear cell renal cell carcinoma: The U-CISS classification.
Authors: Lebacle Cedric Michel , Kroeger Nils , Pooli Aydin , Liu Sandy , Chamie Karim , Belldegrun Arie S. , Shuch Brian , Drakaki Alexandra , Pantuck Allan J.
Published: March 2019

629

Background: Thirty percent of patients with localized clear cell renal cell carcinoma (ccRCC) will ultimately develop recurrence (local or metastatic) after nephrectomy. Current risk stratification systems still misclassify patients. A better stratification is needed to select high-risk patients who may benefit from adjuvant therapy. We sought to improve the existing UISS by the addition of genetic information in a new UCLA cytogenetic integrated staging system (U-CISS). Methods: A total of 240 patients from UCLA with localized ccRCC and cytogenetic analysis on tumor specimen were included in the study. In a continuation of our previous research, cytogenetic (combined loss 3p-14q) and a pathological high-risk feature, microvascular invasion (MVI) were implemented in the UISS. Association with recurrence free survival (RFS) was analyzed in a uni- and multivariable fashion; prognostic accuracy was tested with the c-index. All tumors that had either MVI, combined loss 3p/14q or both in the UISS low-risk group were placed into the U-CISS intermediate group. Tumors with one or both risk factors in the UISS intermediate group were placed into the new U-CISS high-risk group. Results: Fifty patients developed tumor recurrence. On multivariate analysis, combined loss 3p-14q, and MVI were independent prognostic factors. The U-CISS placed significantly better prognosticated RFS in the high-risk group (7/50 (14%) with UISS vs. 23/50 (46%) with U-CISS) and thus, was more accurate in prognosticating RFS. The c-index for recurrence prognostication was improved in the U-CISS (0.70 vs. 0.65 for the UISS). Furthermore, the U-CISS was a better prognostication tool when the intermediate and high-risk group were combined (prognostication of 74% with U-CISS vs. 68% UISS). Conclusions: The use of U-CISS, which integrates genomic alterations with clinical and pathologic features, allowed a re-allocation of patients to create a better stratification of recurrence risk. This new definition of high-risk of recurrence could significantly improve selection of patients who are in greatest need of closer surveillance and/or adjuvant treatment. C.L. and N.K. contributed equally to first authorship.
The role of architectural patterns and cytologic features in the prognosis of clear cell renal cell carcinoma.
Authors: Cai Qi , Christie Alana , Zhou Qinbo , Araj Ellen , Cadeddu Jeffrey A , Margulis Vitaly , Singla Nirmish , Rajaram Satwik , Pedrosa Ivan , Rakheja Dinesh , McKay Renee , Brugarolas James , Kapur Payal
Published: March 2019

632

Background: Clear cell renal cell carcinoma (ccRCC) exhibits a spectrum of clinical behavior and intratumoral heterogeneity histologically. Pathologic grading for ccRCC is primarily based on nucleolar size. Sarcomatoid and rhabdoid changes are known to be associated with aggressive behavior, the significance of the histopathologic heterogeneity occurring in ccRCC remains largely unknown. We evaluated the prognostic role of architectural patterns and cytologic features in ccRCC. Methods: We identified sequential ccRCC cases at our institution between 2006 and 2015 for which follow-up information was available beyond 1.5 years, excepting those who died sooner. Architectural patterns and cytologic features were predefined and quantitated in nephrectomy specimen slides, which were reviewed by an experienced GU pathologist. Nine novel architectural patterns and ten cytologic features were correlated with disease-free survival (DFS) and overall survival (OS). Kaplan-Meier curves were generated to visualize survival distributions. Results: 549 cases met selection criteria and were comprehensively reviewed including 16 grade 1 (2.9%), 278 grade 2 (50.6%), 201 grade 3 (36.6%) and 54 grade 4 (9.8%). Pathologic tumor stage distribution included 63.9% pT1 (n = 351), 6.0% pT2 (n = 33), 27.5% pT3 (n = 151), and 2.6% pT4 (n = 14). Microcystic, tubular, bleeding follicles, and small compact nest patterns (n = 309), were associated with better DFS and OS. In contrast, large nests, thick trabecular, solid sheet, alveolar or papillary/pseudopapillary patterns (n = 240) were associated with worse DFS and OS (p < 0.0001). In addition to multinucleated giant cells, and sarcomatoid and rhabdoid changes, cytologic features including large intracytoplasmic eosinophilic inclusions, voluminous cytoplasm, cytoplasmic spindling, a giant nucleus with perinuclear halo, and a wrinkled nucleus with perinuclear halo were associated with worse DFS and OS (p < 0.0004). Conclusions: Architectural patterns and cytologic features observed in ccRCC predict tumor behavior and are associated with clinical prognosis. Evaluation of histopathologic heterogeneity may shed light on tumor biology and complement prognostic models.
Predictors of prostate cancer-specific anxiety following stereotactic body radiation therapy (SBRT) for clinically localized prostate cancer.
Authors: Salari Kamran , Aghdam Nima , Gersony Luara , Danner Malika , Ayoob Marilyn , Yung Thomas M. , Kataria Shaan , Lei Siyuan , Collins Brian Timothy , Kumar Deepak , Lischalk Jonathan W. , Dritschilo Anatoly , Suy Simeng , Lynch John J. , Collins Sean P.
Published: March 2019

64

Background: Prostate Cancer (PCa) related anxiety varies widely based on management option. SBRT offers a safe and effective treatment for localized PCa. However, there is a paucity of data regarding PCa specific anxiety following SBRT and its relationship with PSA kinetics. In this report we present the results of a mail-in survey conducted amongst the participants of our prospective institutional quality of life (QOL) trial and identify sociodemographic and disease specific predictors of anxiety. Methods: Patients with localized PCa treated with SBRT at a single institution from 2007-2018 were eligible for inclusion in this study. The Memorial Anxiety Scale for PCa (MAX-PC) survey, was mailed to 450 patients on July of 2018. Patient’s total MAX-PC score (scale 0-54) was recorded. A score of ≥ 27 was defined as significant anxiety. Disease specific as well as demographic features were analyzed for possible correlation with self-reported anxiety. Results: By August 31, 2018, 227 patients had responded to the survey . The median score at all time points was 5 (1-41). Stratified by risk grouping; Low, Intermediate, and High Risk patients’ median scores were 7, 4.5 and 6. Six patients had a MAX-PC score≥27. Patients who were at least 2 years out from SBRT treatment had lower mean MAX-PC scores than those who were still within 2 years (6.3 versus 8.1, p = 0.045). Stratified by age, patients > 80 years old had a median score of 2 versus those < 70 with a median score of 6. Caucasian patients had lower mean MAX-PC scores than non-Caucasian patients (6.6 versus 9.1, p = 0.021). Patients who had at least a 0.5 ng/mL increase in PSA in their last 3 measurements had higher mean MAX-PC scores than those who did not (13.0 versus 7.0, p = 0.040). Conclusions: Patients with clinically localized PCa treated with SBRT experience minimal PCa specific anxiety. Anxiety surrounding PCa decreases with time. Non-Caucasian patients tended to have more anxiety than Caucasian patients. Patients who had recent PSA bounces tend to have higher levels of anxiety about their disease. Further follow-up of these patients over time would aid in assessing the progression of PCa specific anxiety as their lives progress.
The mutational burden of targeted genes significantly correlated with overall survival after targeted therapy in metastatic renal cell carcinoma.
Authors: Joung Jae Young , Kim Taek Sang , Park Sang Hyun , Kim Sung Han , Park Weon Seo , Chung Jinsoo
Published: March 2019

643

Background: This study aimed to find the correlation between tumor mutation burden and systemic first line therapeutic response in metastatic tissue samples from patients with metastatic renal cell carcinoma (mRCC). Methods: Between 2005 and 2017, 168 triplet-tissue block samples from 56 mRCC patients were selected for targeted gene sequencing (TGS) using the 88 targeted genes from the National Cancer Center, Korea (NCC) kidney cancer panel. The patients’ medical records, including therapeutic responsive profiles with overall survival (OS) to first-line targeted therapy, were evaluated with the mutational burden of triplet tissue samples using 88 TGS. A few significant target genes associated with therapeutic response towards targeted therapy were identified after comparing the mutational burden of positive for all three blocks and one or two positive blocks (p-value < 0.05). Results: The median PFS for the first-line targeted therapy and OS were 8.7 and 42 months, respectively. MSKCC and Heng risk criteria showed 28.9/65.8/5.3% and 26,3/57.9/15.8% for favorable, intermediate, and poor risk groups, respectively. Also, 55.3% and 52.6% patients received metastatectomy and nephrectomy, respectively. Eighteen (32.1%) patients had all triplet blocks passed for quality check, whereas 21 (37.5%) and 17 (30.4%) patients had two or one passed tissue blocks, respectively. Among the 18 patients with triplet-block, TP53, URB4, PTK2, and SGO2 genes had significant discrimination power for OS on comparing their mutational burden in the three blocks positive group (N = 7) and two or fewer blocks positive groups (N = 11) (p < 0.05). Among the 39 patients with either doublet or triplet blocks passed for quality check, TP53, URB1, PTK2, SGO2, BRAF, NEDD4, PDXDC1, CDH1, FGFR2, RET, RUNX1, and SDHB genes had significant discrimination power for DFS when comparing their mutational burden in the three blocks positive group (N = 7) and two or fewer blocks positive groups (N = 14) (p < 0.01). Conclusions: The study showed the tumor mutational burden of many vital targeted genes to be significantly correlated with OS from metastatic tissues in mRCC.
Immune-related adverse events are associated with improved outcomes in ICI-treated renal cell carcinoma patients.
Authors: Elias Roy , Yan Flora , Singla Nirmish , Levonyack Nicholas , Formella Joseph , Christie Alana , Kapur Payal , Bowman Alex Isaac , Hammers Hans J. , Hannan Raquibul , Brugarolas James
Published: March 2019

645

Background: With the approval of immune-checkpoint inhibitors (ICI) as first and second line agents for treating metastatic renal cell carcinoma (RCC), immune-related adverse events (irAE) are a growing concern. In this study, we present the safety profile and outcomes of 90 patients with RCC treated at two centers, including a university (UT Southwestern/Clements University Hospital) and a county hospital (UT Southwestern/Parkland). Methods: All patients with RCC treated with ICI were identified from 2013 to January 31, 2018. We examined the incidence of any treatment-related adverse events and “select” irAEs and evaluated their impact on patient outcomes and therapeutic decisions. Kaplan-Meier methods and Cox proportional hazards regression models were used to compare overall survival (OS) and time to next therapy (TTNT) by the presence of irAEs. Results: Of 90 patients treated with ICI, 65 (72.2%) patients experienced adverse events, most commonly fatigue (37.8%), nausea (14%), and decreased appetite (12.2%). Select irAEs were seen in 38 (42.2%) with the most common irAEs involving the skin (15.6%), gastrointestinal tract (14%), endocrine organs (11%), and lungs (7.8%). There were 15 (16.7%) grade III/IV irAEs resulting in cessation of therapy for 12 (13.3%) patients. The median OS was 35.9 (95% CI: 24.3-not reached) and 26.5 months (95% CI: 10.2-28.8; p = 0.002) for patients with and without irAEs, respectively. The median TTNT was 17.8 (95% CI: 11.3-29.3) and 6.6 months (95% CI: 4.5-9.6; p = 0.002) for patients with and without irAEs, respectively. In multivariate analysis of irAE status and Heng prognostic score, irAEs were associated with improved OS, HR 0.376 (95% CI 0.179–0.792; p = 0.010) and TTNT, HR 0.482 (95% CI 0.280–0.829; p = 0.008). Conclusions: ICI in RCC is well tolerated with only 16.7% of patients experiencing an adverse event resulting in cessation of therapy. The development of an irAE correlated with both an improved median OS as well as median TTNT, a benefit that persisted after multivariate analysis including Heng prognostic scoring. These findings suggest that the development of irAEs may be an independent positive prognostic factor in patients with RCC treated with ICI.
Cell-free DNA analysis in renal cell carcinoma: Comparison with tumor sequencing and correlation with response to therapy.
Authors: Hamieh Lana , Nassar Amin , Lasseter Kathryn , Ogorek Barbara , McKay Rana R. , Thorner Aaron , Nag Anwesha , Lee Gwo-Shu Mary , Bhatt Rupal Satish , Pomerantz Mark , Freedman Matthew L , Kwiatkowski David J. , Choueiri Toni K.
Published: March 2019

655

Background: Massively parallel sequencing (MPS) of circulating-free DNA (cfDNA) is seeing increasing use in multiple cancer types. There is little data on its use in metastatic renal cell carcinoma (mRCC) as a tool for prognostication and disease monitoring. Methods: cfDNA was extracted from 63 blood samples of 40 metastatic RCC patients (pts). Serial samples were obtained in 12 of 40 (30%) pts (median = 1, range = 1-7). cfDNA was used for targeted MPS using a custom bait-set of 27 genes commonly mutated in RCC. Variants observed in at least 3 reads, in both read directions, and at an allele frequency (AF) of ≥0.5% for single nucleotide variants (SNV), or in 2 reads and AF of ≥0.2% for small indels, were candidate variants validated by Sanger sequencing or amplicon MPS (aMPS). All mutations identified in cfDNA were also assessed in matched patient WBC DNA using aMPS and Sanger sequencing. Tumor specimens from 23 pts were also sequenced in parallel using our institutional OncoPanel assay that assesses 275-447 cancer-associated genes and results were compared with those seen in the cfDNA. Results: Thirty-one of 38 (82%) candidate variants were validated in 17 of 40 pts. Ten of those (32%) from 10 pts were also detected in WBC DNA, 3 of which were germline and 7 were at low mosaic frequency and likely reflected clonal hematopoiesis (CH). The remaining 21 variants validated in cfDNA were in TP53 (6), PBRM1 (3), SETD2 (3), VHL (2), ATM (2), NF2 (2), PTEN (1), PIK3CA (1), and MTOR (1). Two of 17 (12%) pts without tumor mutation analysis had 4 validated variants seen in cfDNA only. 10 of 23 (43%) pts with tumor mutation analysis had one or more variants seen in both tumor DNA and cfDNA. Three of the 23 had mutations seen only in cfDNA. Pts with any mutation in cfDNA (n = 14) had a significantly shorter overall survival in comparison to those without a finding (p < 0.001). Among 12 pts with serial samples, 5 had cfDNA variants identified. Response to therapy correlated with variant prevalence in all 5, including 2 with significant partial responses. Conclusions: This study suggests that paired tumor–cfDNA analysis has value in the assessment of response to therapy in RCC. Further analysis is proceeding.
A multigene expression score for predicting response to anti-PD-1/PD-L1 therapy for clear cell renal cell cancer patients.
Authors: Choudhury Yukti , Tan Kai Wei , Tan Hui Shan , Hong Jian Cheng , Tay Miah Hiang , Tan Min-Han , Tan Puay Hoon , Tan Wan Ling , Ng Quan Sing , Toh Chee Keong , Kanesvaran Ravindran
Published: March 2019

656

Background: Anti-PD-1 inhibitor nivolumab and combination checkpoint inhibition (nivolumab and ipilimumab) are approved for advanced clear cell renal cell cancer (ccRCC), with objective response rates between 25% to 40%. PD-L1 expression is a poor predictor of anti-PD-1/PD-L1 therapy response in ccRCC. Better predictive biomarkers are required. The CLEAR score (CS) is a multigene prognostic expression score for ccRCC (Eur Urol 2015) previously associated with TKI outcomes. Given association of prognosis and clinical benefit, CS was explored as a biomarker for response to anti-PD-1/PD-L1 therapy in this study. Methods: CS is derived from the expression of 8 genes in ccRCC tumor tissue and intervening stroma and includes components of chemokine signaling. Based on this, immunohistochemistry of ccRCC tumor tissue (n = 24; matched CS also derived from same tissue), was done for tumor-infiltrating lymphocytes (CD8+) and PD-L1. Staining intensity was also correlated to CS. In another set of RCC patients who received nivolumab or pembrolizumab after progression on anti-angiogenic therapy (n = 12), correlation of their tumor CS and response outcome to anti-PD-1 therapy was done. Results: CS was significantly higher for ccRCC tumors with higher intratumor and/or stromal CD8+ cell infiltration (p < 0.001). A similar correlation with PD-L1 staining was not observed. Among RCC patients receiving anti-PD-1 therapy, clinical benefit (stable disease or partial response) was characterized by higher CS, regardless of treatment line. When analysis was limited to ccRCC histology, CS were significantly higher (p < 0.05) for responders (n = 2) compared to non-responders (n = 4) to nivolumab treatment. Conclusions: This is the first study reporting the correlation of a multi-gene score (CS) with immune phenotypes in ccRCC. CS correlates well with intratumor/stromal CD8+ cell infiltration, and is a potential biomarker for response to anti-PD-1 therapy. Consistent with clinical trial data, high CS (associated with poor prognostic tumors) correlated with better responses. Studies with a larger cohort of patients are underway to establish the utility of CS in predicting response to anti-PD-1/PD-L1 therapy.
Ten year treatment complication outcomes of radical prostatectomy versus external beam radiation therapy versus brachytherapy for 1,503 patients with intermediate risk prostate cancer.
Authors: Goy Barry W. , Burchette Raoul J.
Published: March 2019

67

Background: To compare 10 year treatment complication outcomes of radical prostatectomy(RP) vs external beam radiation therapy(EBRT) vs brachytherapy(BT) for patients with intermediate risk prostate cancer(IRPC). Methods: A retrospective analysis was performed on 1,503 IRPC patients who underwent treatment from 2004 to 2007, using univariate comparisons. 819 underwent RP, 574 underwent EBRT, and 110 underwent BT using iodine-125. Urinary and rectal complications for RP were graded as severe if patients required ≥ 3 pads/diapers per day, required chronic use of condom catheter or penile clamp, daily self-catheterization, placement of sling or artificial urinary sphincter, or developed rectal fistula/incontinence. Complications for EBRT and BT were graded as severe if they were classified as grade 3 or 4 on the Radiation Therapy Oncology Group grading system for late effects. For erectile dysfunction, the prevalence of patients requiring injections, pumps or penile implants were calculated after a minimum of 1 year of follow up. Results: Median follow up was 10.0 years for RP, 9.6 for EBRT, and 9.8 for BT. Neoadjuvant androgen deprivation therapy was given in 0.6% for RP patients vs 58.9% of EBRT vs 12.7% of BT, p < 0.0001. Median age for RP vs EBRT vs BT was 62.1, 70.8, 65.3, p < 0.0001. The 10-year prevalence of severe urinary complications for RP vs EBRT vs BT was 10.1%, 12.5%, 4.6%, p = 0.04. The percentage of patients having a pre-treatment American Urological Association(AUA) urinary score for RP vs EBRT vs BT was 7.3%, 11.5%, 97.3%, p < 0.0001. The 10-year prevalence of severe rectal complications for RP vs EBRT vs BT was 0.5%, 1.6%, 0.0%, p = 0.06. The 10-year prevalence of erectile dysfunction devices for RP vs EBRT vs BT was 24.3%, 6.6%, 8.2%, p < 0.0001. Conclusions: After 10 years of follow-up, BT had the lowest rate of severe urinary complications, which may due to using the AUA score to avoid implanting those who had significant baseline obstructive voiding symptoms. EBRT had a higher rate of severe rectal complications. RP had the highest probability of undergoing treatment using erectile dysfunction devices, despite having younger patients.
Factors linked with receiving a lymph node dissection during surgery for nonmetastatic renal cell carcinoma.
Authors: Radadia Kushan Dilip , Rivera-Nunez Zorimar , Kim Sinae , Farber Nicholas , Sterling Joshua , Modi Parth K. , Sharad Goyal , Rahul Parikh , Weiss Robert E. , Kim Isaac , Elsamra Sammy , Jang Thomas , Singer Eric
Published: March 2019

672

Background: The benefit of a lymph node dissection (LND) in renal cell carcinoma (RCC) remains poorly defined. Despite this uncertainty, the American Urological Association (AUA) guideline on localized renal cancer recommends that LND be performed for staging purposes when there is suspicion of regional lymphadenopathy on imaging. Using the National Cancer Database (NCDB), we examined factors associated with the receipt of LND at the time of renal surgery. Methods: The NCDB was queried for non-metastatic patients who underwent partial nephrectomy or nephrectomy for RCC from 2010 to 2014. Patient socio-demographics, clinical characteristics, and treatment factors were extracted. Logistic regression models were used to examine factors associated with the receipt of LND. Results: We identified 110,963 patients who underwent surgery for RCC, of whom 11,867 (11%) had LND performed at the time of surgery. Clinical lymph node (cLN) and pathologic lymph node (pLN) information were available in 11,300 patients, of which 1,725 were preoperatively staged as having positive cLN. In the entire study population, patients who were cLN positive were approximately 19 times more likely to receive a LND at the time of surgery (OR: 18.68, 95%CI: 16.62-21.00). Factors associated with a LND in patients who are cLN negative (n = 106,370) were assessed. Clinical T (cT) stage was the strongest indicator of LND (cT2-4, OR range: 4.87-11.1). Among both cohorts, patients who received surgery at an academic/research institution or traveled farther ( > 31 miles) to a treatment center were more likely to undergo a LND. Patients from both cohorts who underwent robotic or laparoscopic surgery were less likely to receive a LND compared to open surgery. Conclusions: The greatest predictor of LND receipt is being cLN positive. Among patients who are cLN negative, the greatest predictor of LND is cT stage. Predictors of undergoing LND in all patients and those who are cLN negative include treatment center type and distance to the treatment center. Additional studies to determine the accuracy of clinical staging and assess novel preoperative imaging modalities that evaluate nodal involvement are indicated.