bluuebunny/crossref_metadata_2025 huggingface dataset:
Defining the genetic evolution of epigenetic alterations in bladder cancer.
Authors: Clinton Timothy Nguyen , Wise Hannah , Almassi Nima , Chavan Shweta S. , Hu Wenhuo , Gao Sizhi Paul , Hanrahan Aphrothiti , Dason Shawn , Pietzak Eugene J. , Carlo Maria Isabel , Funt Samuel Aaron , Teo Min Yuen , Iyer Gopa , Bochner Bernard H. , Rosenberg Jonathan E. , Bajorin Dean F. , Arcila Maria E. , Al-Ahmadie Hikmat , Taylor Barry S. , Solit David B.
Published: February 2020

529

Background: Large-scale efforts have sought to define the genomic landscape of urothelial carcinomas of the bladder with the goal of identifying novel therapeutic targets. Many bladder cancers harbor mutations in genes that regulate chromatin state, such as KDM6A, ARID1A and KMT2D. There remains uncertainty as to the timing at which alterations in chromatin modifying genes (CMG) arise during the evolution of urothelial cancer. Methods: We leveraged a prospective genomic profiling initiative to characterize driver alterations in urothelial cancer. To define the timing at which mutations arose during disease pathogenesis, we performed whole exome (WES) or targeted sequencing analysis of matched pairs of primary and metastatic tumors. Results: CMG mutations were identified in 76% of UC samples in the prospective MSK-IMPACT tumor sequencing cohort (N=1057); most frequent in KDM6A (31%), KMT2D (28%) and ARID1A (27%). Comparison of primary low-grade (N=65), high-grade (N=742) and metastatic (N=250) samples revealed KDM6A, FGFR3 and KMT2C were more frequently mutated in low-grade tumors. WES and targeted sequencing of 63 matched pairs demonstrate a high degree of concordance among likely oncogenic mutations. Notably, 100% (18/18) of pairs were concordant for mutations in KDM6A suggesting that, when present KDM6A mutations arise early during tumor development. Mutations in ARID1A were present only in the metastatic samples of a subset of tumors (29%) suggesting that ARID1A mutations arise later in disease pathogenesis. Several additional oncogenic drivers were found in only the metastatic sample ( FGFR3, TSC1, PIK3CA) of select tumor pairs. Conclusions: Primary and metastatic pairs were largely concordant for known and likely oncogenic mutations. Evolutionary analysis of sequencing data suggested that KDM6A mutations arise early in tumor development whereas ARID1A mutations were enriched and present only in the metastatic samples of a subset of patients. Despite the high frequency of FGFR3 mutations in low grade tumors, discordance of FGFR3 mutational status was observed in small fraction of patients suggesting that profiling of metastatic tumors or cell free DNA would be preferable to identify patients for FGFR inhibitor therapy.
Expression of nectin-4 in bladder cancer with variant histology.
Authors: Hoffman-Censits Jean H. , Choi Woonyoung , Lombardo Kara , Hahn Noah M. , McConkey David James , McGuire Bridget , Parimi (Parini) Vamsi , Matoso Andres
Published: February 2020

546

Background: The antibody-drug conjugate enfortumab vedotin is poised to change the bladder cancer (BC) treatment landscape by targeting Nectin-4, near ubiquitously expressed in urothelial cancer (UC). Less is known about this and other targets in BC with pure or mixed variant histology (VH). Methods: Immunohistochemistry (IHC) was performed on a Ventana Discovery Autostainer (Roche Diagnostics) using an ultraView DAB detection kit (Roche Diagnostics) and a Nectin-4 polyclonal antibody (1:100 dilution; Abcam, Cambridge, UK). The intensity and extent of Nectin-4 expression was determined by the histochemical scoring (H-score) used in preclinical testing, defined as the sum of the products of the staining intensity (score of 0–3) x % of cells (0–100) stained at a given intensity. Specimens were assessed by H score as: negative (0–14), weak (15–99), moderate (100–199), and strong (200–300). Results: Forty UC and VH BC were evaluated for Nectin-4 expression by IHC: 15 small cell (SCBC) (8 pure SCBC, 6 mixed SCBC/UC, 1 SCBC/CIS), 8 carcinosarcomas (CS) (7 pure CS, 1 HGUC/sarcomatoid features), and 17 pure HGUCs. Normal urothelium and stroma were negative. Eight of 8 (100%) pure SCBC were negative for Nectin-4. Six of 7 (85.3%) mixed SCBC+HGUC/CIS had weak staining and 1/7 (14.7%) had moderate staining in the urothelial components (comp) while 7/7 (100%) of the SCBC comp were negative. Seven of 7 (100%) pure CS were negative and 1/1 (100%) mixed CS+HGUC showed weak staining in the HGUC comp while the sarcomatoid comp was negative. Expression in UC was: 1/17 (5.9%) strong, 3/17 (17.6%) moderate, 10/17 (58.8%) weak, and 3/17 (17.6%) negative. Gene expression profiling confirmed Nectin-4 was downregulated in VH compared to UC samples, as was ERBB2 and Trop2. Conclusions: There is heterogeneity of expression of Nectin-4 and other targets in BC with VH compared to UC. This may have therapeutic implications, and highlights need for additional research in VH.[Table: see text]
Validation of 3-factor clinical-genomic model to predict response to atezolizumab as first-line or post-platinum therapy for advanced urothelial carcinoma.
Authors: Sonpavde Guru , Banchereau Romain , Tayama Daren , Shen Xiaodong , Nassar Amin , Kwiatkowski David J. , Price Richard , Mariathasan Sanjeev
Published: February 2020

552

Background: Previously, we reported a 3-factor model including tumor mutation burden (TMB), peripheral blood neutrophil/lymphocyte ratio (NLR) and visceral metastasis status to predict tumor regression (c-statistic=0.90) when using ICIs for mUC regardless of line of therapy. We conducted an external validation of this model to determine its ability to predict response. Methods: We utilized data from a phase II trial, IMvigor210, which evaluated atezolizumab (atezo) for post-platinum pts or as first-line therapy for cisplatin-ineligible pts with mUC. Pts with TMB, NLR, visceral metastasis and RECIST1.1 response status available were evaluable. Tumor genomic analysis was performed using FoundationOne, which sequences 324 cancer-related genes. Multivariable regression studied the association of TMB (<10 vs. ≥10 mutations/megabase), NLR (<5 vs. ≥5) and visceral metastasis status (yes vs.no) with RECIST 1.1 response status (≥partial response [PR] vs no PR). Model discrimination performance was assessed using the concordance (c)-index. Results: A total of 234 pts were evaluable for analysis, of whom 185 (79%) were men. 164 (70.1%) pts received post-platinum therapy and 70 (29.9%) received first-line therapy with atezo. 60 pts exhibited RECIST 1.1 ≥PR. On multivariate analysis, all 3 factors were independently and significantly associated with ≥PR: TMB ≥10 mutations/megabase (HR -4.254, p=2.1 x 10−5), low NLR (HR=2.591, p=0.00958) and absence of visceral metastasis status (HR=4.105, p=4.04 x 10−5). The c-index of this 3-factor model to predict ≥PR was 0.77. Presence of all 3 favorable factors (TMBhigh, NLRlow, no visceral metastases) was associated with ≥PR in 15/21 pts (71.4%), while the absence of all 3 factors (TMBlow, NLRhigh, visceral metastases) was associated with ≥PR in 2/37 pts (5.4%). Conclusions: A 3-factor model combining readily available clinical and genomic variables including TMB, NLR and visceral metastasis status was validated to robustly predict RECIST 1.1 response in pts with mUC receiving atezo as first-line or post-platinum therapy. This model may improve the therapeutic index and cost efficacy of atezo.
Can serum cytokeratin 19 fragments predict postoperative early progression in patients with upper urinary tract urothelial carcinoma?
Authors: Endo Yuki , Kimura Go , Hodotsuka Naoto , Hasegawa Hiroya , Minaguchi Shigehito , Mikami Hikaru , Takeda Hayato , Akatsuka Jun , Hayashi Tatsuro , Kondo Yukihiro
Published: February 2020

557

Background: Current guidelines do not yet provide recommendations for any serum tumor markers in patients with upper tract urothelial carcinoma (UTUC) who received nephroureterectomy (NU). The criteria for adjuvant chemotherapy is also controversial. Previous studies have shown that serum cytokeratin levels (sCK) were correlated with depth of tumor invasion and metastases in patients with bladder cancer. We found that preoperative sCK was correlated with cancer specific survival(CSS) after NU. In this study we evaluated whether postoperative sCK (poCK) could predict early progression in patients who received NU. Methods: 160 patients with UTUC underwent NU from December 2003 to 2014 at our institution. The median age at diagnosis was 73 years (41-89). poCK19 had been measured in 112 patients within 8 weeks after NU. Patients were divided into two groups, a high-group and a low-group based on poCK19 levels (a cut-off value of 3.5 ng/mL). CSS and progression-free survival (PFS) were measured by Kaplan–Meier curves and log–rank test. Multivariate analysis was carried out using the Cox hazards model. Results: Of 112 patients ≤pT1 was 39 (34%), pT2 in 26 (23%), pT3 in 40 (35%), and pT4 in 7 (8%). The 5-year (5y) CSS rate was 86% and the 5yPFS rate was 60%. There were 24 (21%) patients in the high-group and 88 (79%) in the low-group. During the median follow-up period of 34.0 (1-152) months, 39 patients (35%) died. The 5yCSS rate of the high-group was 51%, which is significantly lower than the low-group (86%) (p<0.001). The 1yPFS of the high-group was 66%, which was significantly lower than that of the low-group (86%) (p<0.001). On univariate analysis, positive margin (HR4.0, p<0.001) and poCK19 (HR3.9, p<0.001) were the significant factors for 1yPFS. On multivariate analysis, poCK19 (HR5.3 95%CI (1.8-15.7), p=0.002) and positive margin (HR 4.6 95%CI (1.1-18.9), p=0.032) were also independent factors for 1yPFS. Conclusions: Our study suggests that postoperative sCK19 could predict early progression in patients with UTUC who received NU. Adjuvant chemotherapy might be indicated for patients with high postoperative sCK19 levels independent of pathological findings.
Response to immunotherapy, platinum-based chemotherapy or their combination in metastatic urothelial carcinoma (MUC) with or without FGFR-3 alterations: Single cohort experience.
Authors: Ferrer-Mileo Laura , Rodriguez Adela , González Nuria , Orrillo Mayra , Jiménez Natalia , Marín-Aguilera Mercedes , Rodriguez-Carunchio Leonardo , Prat Aleix , Mellado Begona , Reig Oscar
Published: February 2020

560

Background: Fibroblast growth factor receptor-3 (FGFR-3) is a promising target therapy in metastatic urothelial carcinoma. Its role in patient’s clinical outcome and treatment response is unclear. We present data for overall survival (OS) and response to platinum-based treatment, immunotherapy and combination (platinum plus immunotherapy) in MUC. Methods: Enrolled patients were diagnosed with muscle-invasive urothelial cancer (MIUC) between 2/2009-6/2019 at Clinic Hospital of Barcelona, Spain. All have been screened for FGFR-3 alterations using next-generation sequencing or qualitative real-time polymerase chain reaction-based assays in tumour or blood. Demographic, pathology, treatments and treatment response were collected retrospectively. Results: 101 patients with MIUC were screened, 99% had progressed to metastatic stage. At diagnosis 32.67% were metastatic. 77% were man and median age was 68y (38-85y). Median follow-up (FU) since metastatic disease was 16.25 months (1.2-89.72m) with 69.31% of patients had died at cut-off. 32% presented FGFR-3 alteration (fusion =1 and mutation=31). FGFR-3 altered more frequently had papillary histology than FGFR-3 wild type tumours (69 vs 26%, p<0.05). No statistical differences were detected between both groups for gender, age, stage at diagnosis, median FU, primary tumour site (upper vs lower tract) or previous history of non-invasive urothelial carcinoma. 58% patients received 1st line platinum-based chemotherapy, 25% immunotherapy and 8% the combination of both (9% with other therapies). FGFR-3 altered tended to present more benefit (complete, partial response or stable disease) with platinum-based chemotherapy than FGFR-3 wild type (81% vs 62%) but without reach statistical significance. No differences were detected for immunotherapy or combination therapies. Moreover, OS was similar for FGFR-3 altered (median 14.6m) and FGFR-3 wild- type (median 17.1 m) (HR 0.76, p=0.3). Conclusions: In our series, no significant differences related to response to first line therapy or survival was observed.
FGFR2/3 genomic alterations (GA) in cell-free (cf)DNA from patients (pts) with advanced urothelial carcinoma (aUC).
Authors: Kiedrowski Lesli Ann , Thomas Roby Antony , Vogelzang Nicholas J. , Sonpavde Guru , Gupta Sumati , Gourdin Theodore Stewart , Faltas Bishoy Morris , Nagy Rebecca , Lanman Richard B. , Grivas Petros
Published: February 2020

565

Background: Erdafitinib is approved in pts with aUC with relevant FGFR2/3 GA. BLC2001 trials in pts with activating FGFR2/3 mutations reported 40% ORR to erdafitinib (49% for those with single nucleotide variants [SNVs] and 16% with fusions), 39% stable disease rate, and potentially reduced response to anti-PD-L1. Genomic profiling with plasma cfDNA next-generation sequencing (NGS) is increasingly used to identify targetable GA in pts with advanced solid tumors and presents a minimally invasive option for identification of FGFR2/3 GA. Methods: Genomic data from the Guardant360 database were queried from clinical results released from 10/19/15 - 8/28/19 for clinical samples submitted with diagnoses of aUC or related diagnoses (e.g. bladder cancer, renal pelvis carcinoma). All assays included FGFR2/3 fusions and complete sequencing of all critical exons harboring sensitizing FGFR2/3 SNVs. Results: 1349 results from 1096 unique pts were identified. Somatic GA were identified in 1192 tests (88%) from 997 pts. Fusions and/or nonsynonymous SNVs in FGFR2/3 were identified in 201 pts (20%); 141 pts (14%) had at least one characterized activating FGFR2/3 GA. Of 34 pts (3.4%) with FGFR3 fusions, partners included TACC3 (32), JAKMIP1 (1), and TNIP2 (1). Overall, most SNVs identified in FGFR3 were predicted to be activating (103/125, 82%) whereas in FGFR2 most were variants of uncertain significance (VUS; 62/72, 86%). Of 89 unique variants (59 in FGFR2, 30 in FGFR3), 19 (21%) were activating mutations (7 in FGFR2, 12 in FGFR3). The most common activating SNVs in FGFR3 were S249C (58 pts), Y373C (20) and R248C (10), and in FGFR2 was N549K (4). VUS in both genes were individually uncommon (no VUS recurring in >3 pts). Median copy number-adjusted clonality of SNVs in FGFR3 was higher than those in FGFR2 (0.80 vs 0.20); this remained true when limiting to only characterized activating mutations (0.84 vs 0.17). Conclusions: cfDNA NGS analysis identifies fusions and a broad spectrum of SNVs in FGFR2/3, including heterogeneous subclonal mutations, at a rate similar to reported tissue testing. cfDNA is a minimally invasive option for pts with aUC to assess candidacy for erdafitinib and clinical trials.
Adaptive genetic algorithms combined with high sensitivity single cell-based technology derived urine-based score to differentiate between high-grade and low-grade transitional cell carcinoma of the bladder.
Authors: Alanee Shaheen Riadh , Roumayah Zade , Deebajah Musatafa , Peabody James O. , Mora Rodrigo , Guevara Jose , Francisco Brian , Patterson Bruce Kendrick
Published: February 2020

572

Background: We previously showed that adaptive genetic algorithms (AGA), in combination with single-cell flow cytometry technology, can be used to develop a noninvasive urine-based score to detect bladder cancer with high accuracy. Our aim in this analysis was to investigate if that same score can differentiate between high grade (HG) and low grade (LG) transitional cell carcinoma of the bladder (BC). Methods: We collected urine samples from cystoscopy confirmed HG and LG superficial bladder cancer patients and healthy donors in an optimized urine collection media. We then examined these samples using an assay developed from AGA in combination with single-cell flow cytometry technology. Results: We examined 50 BC and 15 healthy donor urine samples. Patients were majorly White (59.2%), males (61.2%), and had HG BC (66.7%). AGA derived score of 1.1 differentiated between BCa and healthy patients with high precision (AUC 0.92). The median score was 2.8 for LG BC and 6 for LG BC. Mann-Whitney Rank Sum Test indicated that the difference between the median score of HG and LG BC was significant at P value = 0.003. The score performed well independent of patients’ sex or smoking history. Conclusions: Using single-cell technology and machine learning, we developed a new urine-based score that can potentially differentiate between HG and LG bladder cancer. Future studies are planned to validate this score.
Improving quality of health-related quality of life (HRQOL) reporting in phase III randomized controlled trials (RCTs) of metastatic prostate cancer (mPC).
Authors: Jiang Di Maria , Wong Bryan , Morgans Alicia K. , Sweeney Christopher , Fizazi Karim , Chi Kim N. , Powles Thomas , Perlis Nathan , Kulkarni Girish S. , Sridhar Srikala S.
Published: February 2020

58

Background: HRQOL data are increasingly used to guide patient care and health policy. However, their utility can be compromised by inadequate quality of HRQOL reporting (QHR). We aimed to evaluate QHR in phase III RCTs of mPC. Methods: A systematic review following PRISMA guidelines identified published manuscripts of phase III RCTs of mPC assessing systemic therapies (excluding androgen deprivation therapy and bone targeting agents) between 1990 - 2019. Supplements, references and companion publications were reviewed. QHR was independently quantified using the Minimum Standard Checklist for Evaluating HRQOL Outcomes in Cancer Clinical Trials (MSC, range 0-11) by 2 investigators. QHR is “probably robust” if MSC score is ≥8 and all 3 mandatory items (baseline compliance, missing data, and psychometric properties) are reported; “limited” if score is 5-7; and “very limited” if score is ≤4. Results: HRQOL was the primary (11%), secondary (61%), explorative (21%), and unspecified (7%) endpoint in 57/76 (75%) RCTs, and reported in 46/57 (81%). Primary HRQOL endpoints were pain palliation only. MSC scores ranged 2 – 11. QHR was mostly limited (Table). Most RCTs did not report mode of administration (82%), rationale for selected instrument (65%), or missing data (59%). Other common limitations were: unreported baseline compliance (35%), lack of culturally validated measure (33%), clinical significance not discussed (33%), no hypotheses stated (28%), and inadequate coverage of HRQOL domains (26%). QHR has improved since 2015, with the median MSC score reaching 8 (Table). Conclusions: QHR has improved considerably over time, with many recent phase III RCTs in mPC reporting “probably robust” HRQOL data. Within existing resource constraints however, nonreporting and methodologic deficiencies still remain. The use of standard checklists may further enhance QHR and promote high quality HRQOL research.[Table: see text]
Genomic landscape of circulating tumor (ct)-DNA alterations in patients with penile cancer.
Authors: Nassar Amin , Agarwal Archana , Nagy Rebecca , Curran Catherine , Abou Alaiwi Sarah , McGregor Bradley Alexander , Talasaz AmirAli , Lanman Richard B. , Sonpavde Guru
Published: February 2020

6

Background: Penile cancer is a rare disease associated with HPV infection and harbors recurrent somatic genomic alterations in the ERBB (HER)-family, CDKN2A, TP53, NOTCH1 and PIK3CA. ctDNA assay allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution. To our knowledge, the genomic alterations observed in ctDNA for penile cancer have not been described before. We report ctDNA profiling of patients with advanced penile cancer. Methods: Sixteen pts with metastatic penile cancer from multiple institutions in the United States that underwent ctDNA analysis using the Guardant360 platform were eligible. Three patients had at least one serial ctDNA sample. De-identified demographic data were collected. Guardant 360 is CLIA-certified ctDNA panel that assesses single nucleotide variants and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants seen at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or reported in OncoKB were considered pathogenic. Results: The median age was 64 years (range 40-77). 4 pts (25%) were documented to be post platinum-based chemotherapy. Among the entire cohort, 51 ctDNA alterations were detected (median=2, range 0-6) in 15/16 patients (94%) across 21 genes (table). Of the 51 alterations, 24 (47%) were actionable and had approved targeted therapies in other cancers. Alterations were most frequently detected in TP53 (9/16, 56%), CDKN2A (5/16, 31%), and TERT promoter (5/16, 31%) (table). In 3 patients with serial samples, 9 novel pathogenic alterations were detected in the second sample including ATM, CDKN2A, ARID1A, CCND1, CDK6, EGFR, PDGFRA, PIK3CA, and SMAD4. Conclusions: ctDNA alterations in patients with advanced penile cancer were frequently detected and appeared similar to previously described tumor tissue analyses. New alterations found on serial ctDNA assays shed light on patterns of tumor evolution and may inform drug development for this challenging orphan malignancy.[Table: see text]
Genetic risk assessment for hereditary RCC: Report from the consensus panel meeting.
Authors: Daneshvar Michael , Mendhiratta Neil , Srinivasan Ramaprasad , Jonasch Eric , Ball Mark Wayne , Metwali Adam R , Brugarolas James , Singer Eric A. , Nathanson Katherine , Pierorazio Phillip M. , Boris Ronald S , Finelli Antonio , Pal Sumanta K. , Hakimi A. Ari , Kutikov Alexander , Iliopoulos Othon , Linehan W. Marston , Shuch Brian M. , Bratslavsky Gennady
Published: February 2020

615

Background: While many genes are now known to be associated with hereditary kidney cancer syndromes, there is a paucity of guidelines or uniform consensus on genetic testing for these patients. An expert panel was organized to assess who, what, when and how patients should be evaluated and what testing should be initiated. Methods: A national, multidisciplinary, panel of experts in urology, medical oncology, clinical geneticists, genetic counselors and patient advocates with background and knowledge in hereditary syndromic kidney cancer convened in person in September 2019. A renal cell carcinoma (RCC) genetic risk assessment questionnaire consisting of 52 questions was compiled prior to the meeting using modified Delphi methodology. The questions were then discussed and reviewed with uniform consensus defined as a minimum of 85% agreement in accordance with the National Comprehensive Cancer Network criteria. Results: The panel consisted of twenty-six attendees represented by urologists (43%), medical oncologist (23%), genetic counselors (13%), clinical geneticists (7%), and patient advocates (3%). The questionnaire consisted of fifty-five statements focusing on who, what, when and how genetic testing should be performed in a patient suspected of hereditary RCC syndrome. A >85% agreement was reached on 30/52 statements with 18/25 (72%) achieving consensus addressing “who”, 2/6 (33%) achieving consensus in “what’ category, 2/7 (29%) in ‘when’ and 4/6 (67%) on how. The questions with least consensus were found in the “what/when?” category with only 4/13 questions with minimum 85% agreement. Specific areas of debate included an age cutoff for prompting a genetic risk assessment as well as need for familial testing in patients with variants of unknown significance. Conclusions: Despite experience of the panel in management of hereditary RCC, the consensus was reached only on 66% of genetic testing. While many issues will need to be discussed further, those statements with consensus may be used to guide physicians and patients on who, what, when and how genetic RCC risk assessment should be performed.
Improving detection of higher-risk or locally advanced disease features in stage I and II renal cell carcinoma.
Authors: Miller Nathan , Derweesh Ithaar , Liu Michael Y. , Bradshaw Aaron , Dutt Raksha , Keiner Cathrine , Meagher Margaret Frances , Ghali Fady , Patel Devin , Wan Fang , Shiehmorteza Masoud
Published: February 2020

625

Background: Pathologically upstaged T3a renal cell carcinoma (RCC) carries higher oncologic risk than corresponding preoperative clinical stage and presents unique risks from a treatment planning standpoint due to reduced clinician awareness of locally aggressive disease. We sought to identify imaging criteria that predict risk of pathological upstaging of clinical T1 and T2 RCC to T3a and to assess accuracy of CT in detecting T3a RCC. Methods: Single institution retrospective analysis of patients who underwent surgery for RCC. A propensity-score matching process was used to match upstaged patients with non-upstaged (control) patients in a 1:2 fashion. Preoperative CT images were reviewed in a blinded fashion by 2 radiologists for presence of T3a stage imaging criteria. Multivariable analyses assessed risk conferred by imaging features and sensitivity analysis assessed accuracy in detecting T3a RCC. Results: After exclusions, 231 patients were analyzed (mean age 61 years, upstaged 83/control 148, mean tumor size 6.4 cm). In 71/83 (86%) of upstaged tumors, the presence of sinus fat invasion (SFI), perinephric fat invasion (PFI), or venous invasion (VI) was found. The presence of all three was not observed in any non-upstaged tumor. The following features were associated with upstaging: tumor necrosis (OR 2.1, p=0.017), irregular tumor edge (OR 2.9, p<0.001), thickened perirenal fascia (OR 2.6, p=0.001), perinephric stranding (OR 1.8, p=0.043), increased perinephric vascularity (OR 2.02, p=0.021), and perinephric nodules (OR 3.4, p=0.020). The SE/SP for tumor necrosis, irregular tumor edge, thickened perirenal fascia, perinephric stranding, increased perinephric vascularity, and perinephric nodules were 42%/74%, 74%/50%, 48%/74%, 70%/44%, 70%/46%, and 13%/96%, respectively. Conclusions: Upstaged T3a RCC contained several preoperative imaging attributes which were 2-3 times more likely to be present than in non-upstaged tumors. Of these, irregular tumor edge had highest sensitivity, and perinephric nodules had highest specificity. These features should elevate clinical suspicion for T3a disease and may be used to develop a novel risk scoring system. Further investigation is requisite.
An international challenge to use artificial intelligence to define the state-of-the-art in kidney and kidney tumor segmentation in CT imaging.
Authors: Heller Nicholas , McSweeney Sean , Peterson Matthew Thomas , Peterson Sarah , Rickman Jack , Stai Bethany , Tejpaul Resha , Oestreich Makinna , Blake Paul , Rosenberg Joel , Moore Keenan , Walczak Edward , Rengel Zachary , Edgerton Zach , Vasdev Ranveer , Kalapara Arveen , Sathianathen Niranjan J. , Papanikolopoulos Nikolaos , Weight Christopher J.
Published: February 2020

626

Background: The 2019 Kidney and Kidney Tumor Segmentation challenge (KiTS19) was an international competition held in conjunction with the 2019 International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI) and sought to stimulate progress on this automatic segmentation frontier. Growing rates of kidney tumor incidence led to research into the use of artificial inteligence (AI) to radiographically differentiate and objectively characterize these tumors. Automated segmentation using AI objectively quantifies complexity and aggression of renal tumors to better differentiate and describe the tumors for improved treatment decision making. Methods: A training set of over 31,000 CT images from 210 patients with kidney tumors was publicly released with corresponding semantic segmentation masks. 106 teams from five continents used this data to develop automated deep learning systems to predict the true segmentation masks on a test set of an additional 13,500 CT images in 90 patients for which the corresponding ground truth segmentations were kept private. These predictions were scored and ranked according to their average Sørensen-Dice coefficient between kidney and tumor across the 90 test cases. Results: The winning team achieved a Dice of 0.974 for kidney and 0.851 for tumor, approaching the human inter-annotator performance on kidney (0.983) but falling short on tumor (0.923). This challenge has now entered an “open leaderboard” phase where it serves as a challenging benchmark in 3D semantic segmentation. Conclusions: Results of the KiTS19 challenge show deep learning methods are fully capable of reliable segmentation of kidneys and kidney tumors. The KiTS19 challenge attracted a high number of submissions and serves as an important and challenging benchmark in 3D segmentation. The publicly available data will further propel the use of automated 3D segmentation analysis. Fully segmented kidneys and tumors allow for automated calculation of all types of nephrometry, tumor textural variation and discovery of new predictive features important for personalized medicine and accurate prediction of patient relevant outcomes.
Preoperative differentiation of chromophobe renal cell carcinoma from oncocytoma: Aorta-lesion-attenuation difference on multiphasic multidetector computed tomography.
Authors: Hosseiny Melina , Ching Justin , Kooraki Soheil , Raman Steven
Published: February 2020

627

Background: Differentiation of benign oncocytoma from chromophobe renal cell carcinoma (chRCC) remains a challenge. This study aimed to investigate whether Aorta-lesion-attenuation difference (ALAD) on multiphasic multidetector CT scan (MDCT) can aid to distinguish oncocytoma from chRCC. Methods: This IRB-approved, HIPAA-compliant study consisted MDCT of 111 patients with pathologically proven chRCC (N: 37) or oncocytoma (N: 74). Regions of interest (ROIs) were placed over the renal mass and Aorta on the same axial MDCT slice of un-enhanced (UE), corticomedullary (CM), nephrographic (NP) and excretory (EX) phases. ROIs were devoid of calcification, necrosis and hemorrhage in lesion or atherosclerotic plaque in Aorta. The difference between Aorta and renal mass Hounsfield unit was calculated in all available phases. SPSS v.18 was used to draw receiver-operating characteristic (ROC) curve to calculate accuracy and optimal cutoff values for differentiation of chRCC from oncocytoma. Results: Mean ALAD was significantly higher in chRCC compared to oncocytoma in CM(P: 0.04), NP (P<0.01) and EX (P<0.01) phases. The area under the curves for ALAD in UE, CM, NP and EX phases were 0.47 (95% CI: 0.36- 0.59, p: 0.68), 0.64 (95% CI: 0.51-0.77, p: 0.03), 0.87 (95% CI: 0.79- 0.95, p< 0.01) and 0.80 (0.70-0.90, P<0.001), respectively. ALAD threshold of 19 in nephrographic phase had sensitivity and specificity of 79% and 78%, respectively, for differentiation of chRCC from oncocytoma. Conclusions: ALAD measured in the nephrogenic phase showed the highest accuracy for differentiation of chRCC from oncocytoma on multidetector CT scan. If validated prospectively, ALAD may act as a useful imaging biomarker to distinguish chRCC from oncocytoma.
Is body mass index (BMI) associated with favorable outcomes in metastatic renal cell carcinoma (mRCC) treated with nivolumab? An ancillary study of the NIVOREN-GETUG AFU-26 trial.
Authors: Colomba Emeline , Dalban Cécile , Flechon Aude , Chevreau Christine , Gravis Gwenaelle , Thibault Constance , Laguerre Brigitte , Barthelemy Philippe , Borchiellini Delphine , Gross Goupil Marine , Geoffrois Lionnel , Rolland Frederic , Thiery-Vuillemin Antoine , Joly Florence , Ladoire Sylvain , Tantot Florence , Escudier Bernard , Albiges Laurence
Published: February 2020

630

Background: Adipose tissue might affect response to immune checkpoint inhibitors (CPI) in cancer patients (pts). Higher BMI is associated with improved outcomes in mRCC under VEGFR TKI but BMI impact under CPI remains unclear. Methods: We analysed BMI in the NIVOREN GETUG AFU 26 study, a prospective study that evaluated the safety and efficacy of nivolumab in mRCC after failure of prior VEGFR inhibitors. We investigated the association between BMI, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). BMI (weight/height 2) was classified according to the World Health Organization (WHO) categories: underweight as BMI < 18.5; normal weight as 18.5 ≤ BMI ≤ 24.9; overweight as 25 ≤ BMI ≤ 29.9 and obesity as BMI ≥ 30. Survival distributions were compared using a Log-Rank test, supported by uni- and multivariate Cox regressions to estimate the Hazard Ratio (HR) and its 95% CIs. Median follow-up (FU) and the 95% CI were calculated using the reverse Kaplan–Meier method. Results: Overall, 708 pts were included in the BMI analysis: 20 pts (2.8%) were underweight, 322(45.5%) had normal weight, 255(36.0%) were overweight and 111(15.7%) obese. Median age was 64 years, 77.3% were male, performance status was ≥ 80% in 81.2%, and IMDC risk group was good, intermediate and poor in respectively 18.2%, 56.4%, 25.4%. Outcomes according to BMI is detailed in table, median FU was 23.9 months (95%CI 23.0-24.5). BMI adjusted to known prognostic factors was not significant in the multivariate analysis. Conclusions: Higher BMI patients seems to have better outcomes with nivolumab in mRCC. Further characterisation is on-going to explore the relation of BMI with established risk factor in pts under CPI in mRCC.[Table: see text]
Effect of obesity on response to checkpoint inhibitors in renal cell cancer.
Authors: Nandagopal Lakshminarayanan , Zakharia Yousef , Yasin Hesham , Nepple Kenneth Gerard , De Shazo Mollie R. , Yang Eddy Shih-Hsin , Garje Rohan , Basu Arnab , Li Peng , Norian Lyse
Published: February 2020

634

Background: Response to checkpoint inhibitors (CPIs) for renal cell cancer (RCC) remains variable, with markers like PDL1 proving unreliable. Preclinical models suggest that obesity could affect CPI outcomes. We conducted a retrospective study on the effect of obesity on outcomes in RCC patients treated with CPIs. Methods: RCC patients treated with nivolumab +/- Ipilimumab at university of Alabama at Birmingham (UAB) and University of Iowa (UIOWA) from 2015 - 2018 were classified according to WHO standard definition of BMI as non-obese (NOB-<30kg/m2) or obese (OB->30Kg/m2). Overall survival (OS) was defined as the interval from the first CPI dose to date of death or to last follow up date if patients were still alive. Progression free survival (PFS) was defined as the interval from the first dose of CPI to date of progression or date of death and censored at last follow-up date if patients were still alive without progression. Multivariable Cox proportional hazard regression model was used to evaluate the association between OS/PFS and obesity status, controlling for age, sex, race and number of prior therapies. All analyses were performed using SAS 9.4. Results: 84 patients with at least 6 months follow-up received a median of 9 doses of CPI with median follow of 72 weeks. 48 patients were NOB while 36 patients were OB, with 40 patients deceased at time of analysis. The most common response was stable disease in 45%, with CR in 5% and PR in 10% for a disease control rate of 63%. The median OS was 30 months in NOB patients and 20 months in the OB group. The 2 yr survival was 59% in the NOB group vs 28 % in the OB group with a HR of 0.60 (0.32-1.14; p=0.12). Median PFS was 13 months in the NOB group vs 7.3 months in the OB group with 2 yr PFS of 28% in the NOB group vs 5.5% in the OB group (HR 0.58 {0.35-0.98}; p=0.04). Conclusions: In this analysis of RCC patients treated with CPI, BMI < 30 predicts better OS and PFS. Further studies are required to better understand the effect of BMI on CPI outcomes in RCC.[Table: see text]
Trends in PRO reporting in clinical trials leading to GU cancer drug approvals from 2007 to 2018.
Authors: Tamil Monica , Safa Houssein , Semaan Adele , Chahoud Jad
Published: February 2020

641

Background: Having standardized and high quality reporting of patient reported outcomes (PRO), especially in clinical trials that establish standards of care in oncology is important for patient centered care. This study assessed the status of reporting and quality of analysis of PROs in FDA approved drugs for genitourinary malignancies. Methods: We conducted a systematic review of the FDA archives to identify urological cancer drugs approved between 2007-2018. We retrieved the clinical trials that led to these drug approvals from ClinicalTrials.gov and PubMed. We systematically screened for PROs and reviewed their analytic tools and interpretation methods reported in their published manuscripts and study protocols. A clinical trial was considered to include PROs if they were reported in either the primary or a subsequent manuscript. Results: We identified 22 clinical trials leading to FDA approval of urological cancer drugs between 2007-2018. Only 63% of trials had published PROs. PROs were reported in the primary clinical trial manuscripts for two drugs (9%), and in a secondary PRO manuscript for 12 drugs (54%). The median time between the primary and secondary papers was 12 months (IQR:7.5-26 months). Among the 14 published PRO papers, the hypothesis was broad in 79%, and not reported in 21%. PROs were never included as a primary endpoint of a study. Instead, PROs were reported as secondary endpoints in 5 (36%) and as exploratory endpoints in 7 (50%) studies, while two papers (14%) did not mention PRO reporting in their endpoints. The most common PRO instruments were EQ-5D (64%) and FACT-P (50%). In 92% of PRO papers, statistical analyses were conducted to account for missing data. Control for type I error was needed but not done in 57% of the trials. Conclusions: Delays in publication of PROs occur regularly in trials leading to drug approval in GU malignancies. Our study highlights the need to enhance standardization of the analysis and interpretation of PROs to maximize the value of this data for drug development and approval.
Outcome with immune checkpoint inhibitors in metastatic renal cell carcinoma across different treatment lines.
Authors: Bruchbacher Andreas , Franke Johannes , Alic Zumreta , Nachbargauer Sebastian , Fajkovic Harun , Remzi Mesut , Schmidinger Manuela
Published: February 2020

651

Background: The introduction of immune checkpoint inhibitors (ICPI) has led to a paradigm change in the management of metastatic Renal Cell Carcinoma (mRCC). Prospective trials focused on ICPI treatment in first- or second-line. The aim of this analysis was to evaluate the benefit of ICPI across different treatment lines. Methods: This is a single center retrospective study from the Medical University of Vienna which included all mRCC patients who received ICPIs in various treatment lines. Overall response rates (ORR), progression free survival (PFS) and overall survival (OS) were evaluated for the entire cohort and by treatment line. Results: Between January 2014 and October 2019, a total of 113 patients received ICPIs. Ninety-four patients were eligible for full evaluation (83% clear cell and 17% non-clear cell). 26.8%, 61.6% and 14.8% were classified good, intermediate and poor IMDC-risk, respectively. 59%, 20% and 21% were treated with ICPI monotherapy, dual ICPI therapy and ICPI + tyrosine kinase inhibitor, respectively. ORR, median PFS and median OS for the entire cohort was 39.4%, 9.67 months (95%CI: 6.9-12.4 months) and 23.6 months (95%CI: 13.3-33.9 months), respectively. The ORR by treatment line was: 33% in first-line (9 patients), 40.4%, in second- (42 patients), 35% in third- (20 patients) and 43.5% in fourth and beyond-fourth-line (23 patients). The median PFS by treatment line was: 8.6 months, 10.3 months, 7.9 months and 7.23 months, respectively. The median OS was not reached (NR) in first-line and 26.2 months, 18.1 months and 20.7 months in second-, third-, and fourth and beyond- ICPI treatment line, respectively. The global OS for the whole patient cohort calculated from diagnosis of metastasis was 80 months (CL 95%: 50.5 – 109.5 months). Conclusions: ICPIs are active in all treatment lines and should also be offered in heavily pre-treated patients, who have not had access in earlier treatment lines.
Patient-reported outcomes on treatment-related side effects in renal cell carcinoma.
Authors: Battle Dena , Rathmell Wendy Kimryn , Jonasch Eric , Msaouel Pavlos , Stern Adam P. , Zhang Tian , George Daniel J. , Staehler Michael D.
Published: February 2020

654

Background: Effective management of treatment related toxicities is crucial to maximizing patient outcomes and enhancing quality of life in renal cell carcinoma. Little is known about patient perception and reporting of side effects in a real world setting outside clinical trials. We sought to gather independent data from online patient communities to estimate gaps in communication and reporting. Methods: KCCure conducted an anonymous online survey from 07/19 to 09/19 using questions related to side-effect experience and management. Results: 1,136 patients (median age 57 years [range 28-86], 54% male) participated, 411 patients on systemic therapy were asked about side-effects. 47% of patients reported bothersome side effects impacting their daily lives. The most poorly managed side-effect was fatigue (25%), followed by taste alteration (15%) and loss of appetite (15%). Only 50% of patients are confident their medical oncologist will offer help for side effects, and 20% are worried that reporting side effects may result in dose reduction or treatment discontinuation. 6% of patients don’t talk about their side effects. Patients who identified as non-white (Hispanic, African American, Asian/Pacific Islander and Native American) were three times less likely to talk about side effects. 51% indicated the best advice on managing treatment related side effects was provided by their medical oncologist; 40% seek advice from online patient communities and 35% from advocacy organizations. Only 8% used manufacturer support websites. 13% had never had any concomitant medication prescribed to manage side effects. Major unreported side effects are sexual dysfunction, cognitive impairment and vision disturbances. Conclusions: The majority of patients experience treatment related side-effects on a regular basis, but underreporting may be significant due to a variety of factors, including fear of dose-reduction or discontinuation. Sexual side-effects are underreported. Future studies need to explore differences in reporting for minority populations as well as side effect experiences according to the class of agent prescribed, and the setting in which treatment occurs.
Impact of diabetes mellitus on functional and survival outcomes in renal cell carcinoma: An international multicenter study.
Authors: Dutt Raksha , Meagher Margaret Frances , Patil Dattatraya , Saito Kazutaka , Patel Devin , Ghali Fady , Keiner Cathrine , Miller Nathan , Bradshaw Aaron , Wan Fang , Yasuda Yosuke , Fujii Yasuhisa , Master Viraj A. , Derweesh Ithaar
Published: February 2020

666

Background: Functional decline is an important consideration in the surgical treatment of renal cell carcinoma (RCC). While radical nephrectomy (RN) may be associated with increased risk of functional decline compared to partial nephrectomy (PN), the modifying effect of DM, an independent risk factor of chronic kidney disease (CKD), is not completely understood. We investigated the relationship between DM and decline in kidney function following surgery for RCC, and impact on overall survival (OS) in patients with RCC. Methods: A multicenter dataset of RCC patients undergoing PN and RN was utilized. The cohort was divided based on DM status [DM vs No DM (NDM)]. Multivariable analysis (MVA) elucidated potential variables associated with decline in kidney function [de novo estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73m2 and de novo eGFR < 30 ml/min/1.73m2] and worse all-cause mortality (ACM). Kaplan-Meier analysis (KMA) was used to investigate OS rates in DM and NDM patients undergoing RN and PN. Results: 2928 patients were analyzed (DM = 406, NDM = 2522). On MVA, independent risk factors associated with eGFR < 45 included age (OR = 1.07, p < 0.001), DM (OR = 1.88, p < 0.001), tumor size (OR = 1.03, p = 0.032), and RN (OR = 1.54, p < 0.001). Variables associated with eGFR < 30 included age (OR = 1.05, p < 0.001), African American race (OR = 2.18, p < 0.001), and DM (OR = 2.09, p < 0.001). MVA for ACM revealed age (OR = 1.02, p = 0.002), HTN (OR = 2.47, p < 0.001), tumor size (OR = 1.12, p < 0.001), tumor grade (OR = 1.87, p < 0.001), RN (OR = 1.55, p = 0.011), eGFR < 45 (OR = 1.40, p = 0.03), and eGFR < 30 (OR = 1.87, p = 0.026) to be independently associated. On KMA, 5-year OS stratified by DM status showed that DM is associated with worse OS for RN patients (p = 0.047), but not for PN patients (p = 0.944). Conclusions: Presence of DM is an independent risk factor for renal functional decline and development of worsening CKD is a risk factor for worsening ACM. Furthermore, decreased survival in DM patients was associated with RN recipients but not with PN recipients. Presence of DM may be considered a strong indicator for nephron preservation management strategies when safe and feasible in RCC patients.
Acute interstitial nephritis (AIN) following immune checkpoint inhibitor (ICI) therapy in metastatic RCC (mRCC) as a potential predictor of response.
Authors: Patel Viral M. , Elias Roy , Formella Joseph , Schwartzman William , Christie Alana , Hammers Hans J. , Brugarolas James
Published: February 2020

674

Background: ICIs such as nivolumab (N) have improved outcomes in mRCC patients (pts), but are also associated with immune-related adverse events. As has been shown in melanoma, we hypothesized that pts experiencing an autoimmune reaction directed against the tissue of origin may be more likely to benefit from ICI. Specifically, we evaluated whether pts with nivolumab-induced AIN (N-AIN) exhibited improved outcomes. Methods: We identified all patients with mRCC at UT Southwestern Medical Center from 2014 - 2018 who received at least one dose of N. We extracted creatinine (Cr) values over the entirety of each pt's N treatment course from the electronic medical record. Pts with a 1.5 fold Cr increase over baseline were investigated. The diagnosis of N-AIN was made by biopsy or by clinical criteria (timing of kidney injury, laboratory analysis, and exclusion of other causes). Results: We identified 177 mRCC pts who received at least one dose of N, 36 of whom had at least a 1.5 fold increase in Cr over baseline while on treatment. Of those, two had biopsy-proven AIN and one was clinically diagnosed, resulting in an incidence of 1.7%. Two received N monotherapy after first line, and the third in combination with ipilimumab as initial therapy. The earliest case of N-AIN occurred 1.5 months from N onset, and the others were diagnosed at 11 and 12 months. Of the 3 pts, one had a partial response lasting 2 years, and the other two had a complete response which is ongoing in both pts with over 2 years of follow up. In all 3 cases, N-AIN was treated with cessation of N and prednisone with a return to baseline kidney function. None required dialysis. Conclusions: AIN is a rare event with N, but it may portend a higher likelihood of response. One possible explanation is antigenic crossover between normal renal tubular cells and mRCC, resulting in a robust immune response.