bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic profiling as proof of concept for investigation of collecting duct carcinoma (CDC).
Authors: Procopio Giuseppe , Verzoni Elena , Sepe Pierangela , Mennitto Alessia , Claps Melanie , Guadalupi Valentina , Stellato Marco , Zattarin Emma , De Braud Filippo G. , Sensi Marialuisa , Gargiuli Chiara , Dugo Matteo 
Published: February 2020

714 Background: Collecting duct carcinoma is a rare, highly aggressive and molecularly uncharacterized kidney disease with poor outcome. To date, no standard therapies are available and treatment choice is based on retrospective data. Identifying molecular features of this tumor could provide a biologic rationale for novel targeted systemic therapies. Methods: Total RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissues of 6 CDCs, 5 clear cell renal carcinomas (ccRCCs) and 4 adjacent normal tissues. Samples were profiled by GeneChip Human Transcriptome Array 2.0 (Affymetrix) and constituted the Istituto Nazionale dei Tumori (INT) dataset. Data were pre-processed using the robust multi-array average method and differentially expressed genes were identified according to the limma pipeline. Genes with a false discovery rate < 0.25 were selected. Pathway analysis was performed by gene set enrichment analysis (GSEA), single sample (ss) GSEA, DAVID Bioinformatics Resources 6.8 and Pathfinder Bioconductor package. Moreover, a list of genes representing angiogenesis and immune biology, previously used in the IMmotion150 study, was chosen to explore further functional subcategories of CDC. Available RNA-Seq data of 7 CDCs and 5 matched normal tissue from GSE89122 dataset were used for validation. Results: Comparison of transcriptome profiles of CDCs and ccRCCs versus normal tissue led to the identification of a core of 14 genes specifically up-regulated in CDC, 5 of which (SFN, S100A11, CKAP5, CDH1 and CD44) were significantly involved in extracellular matrix organization. Other deregulated genes were related to immune system, cell cycle progression, glucose and pentose phosphate metabolism and EGFR-signaling. In addition, ssGSEA permitted to identify two major distinct biological subgroups in CDC of both INT and GSE89122 datasets, based on relative expression levels of angiogenesis and immune genes. Conclusions: Our study reveals novel insights into the biology and heterogeneity of CDCs. Although further validation using larger samples is needed, the current findings suggest that this heterogeneity could have clinical implications for the treatment of patients with this rare kidney cancer.
The impact of surgical resection on circulating tumor-reactive cytotoxic T cells for patients with renal tumors.
Authors: Packiam Vignesh T. , Bhindi Bimal , Zhang Henan , Lohse Christine M. , Shah Paras H. , Tsivian Matvey , Pagliaro Lance C. , Costello Brian Addis , Thompson R. Houston , Boorjian Stephen A. , Cheville John , Dong Haidong , Leibovich Bradley C. 
Published: February 2020

725 Background: The impact of surgical resection of renal tumors on peripheral immune related cells is not well characterized, and has potential implications as biomarkers for systemic immune therapy are being developed. We sought to assess the effect of surgical resection on circulating cytotoxic T-cells (CTLs) for patients with renal tumors. Methods: We prospectively enrolled 40 patients undergoing partial, radical, or cytoreductive nephrectomy (PN, RN, CN) for unilateral primary renal tumors between 2016 and 2018. Blood draws were performed pre-op, 1 day post-op, and 3 months post-op. Flow cytometry was performed on peripheral blood mononuclear cells (PBMCs). The % of PBMCs expressing CD11a/CD8 (CTLs) were assessed. The % of CTLs expressing PD-1, Bim (a downstream PD-1 pathway pro-apoptotic mediator), CX3CR1/GZMB (an effector memory T-cell phenotype), and Ki67 (a proliferation marker) were assessed. Median changes in % of CTLs were evaluated with the Wilcoxon signed rank test. Comparisons between aggressive (pT3-4, N1, M1, or aggressive histology (high-grade, coagulative necrosis, sarcomatoid dedifferentiation, or specific RCC-variant histologies)) versus indolent tumors were assessed using the Wilcoxon rank sum test. Results: Twenty, 12, and 8 patients underwent RN, PN, and CN, respectively. Thirty, 7, and 3 patients had clear-cell RCC, non-clear cell RCC, and oncocytoma, respectively. Twenty-three and 17 patients had aggressive and indolent tumors, respectively. While there was no significant change at 1 day, by 3 months there were significantly increased CTLs among PBMCs (+1.3%; p=0.004). There was significant decrease in CX3CR1+GZMB+ CTLs (-2.9%; p<0.001) and significant increase in Bim+ CTLs (+3.0%; p=0.03) at 1 day but not 3 months. Interestingly, Ki67+ CTLs increased at day 1 (+0.6%; p<0.001) but decreased by 3 months (-0.6%; p=0.001). There were no significant changes in PD-1+ CTLs at either time point. There were no significant changes in any CTL characteristics at 1 day or 3 months between aggressive and indolent tumors. Conclusions: These findings characterize changing CTL profiles over time with surgical resection of renal tumors which may help guide biomarker development.
Evaluation of RNA-sequencing (RNA-seq) signatures with pembrolizumab (pembro) in patients (pts) with renal cell carcinoma (RCC) from KEYNOTE-427 cohort A.
Authors: McDermott David F. , Lee Jae-Lyun , Bjarnason Georg A. , Larkin James M. G. , Gafanov Rustem Airatovich , Kochenderfer Mark D. , Malik Jahangeer , Poprach Alexandr , Tykodi Scott S. , Signoretti Sabina , Perini Rodolfo F. , Lunceford Jared , Predoiu Raluca Andreia , Loboda Andrey , Zhao Qing , Snyder Alexandra , Schloss Charles , Atkins Michael B. 
Published: February 2020

729 Background: We evaluated the association (assoc) of baseline RNA-seq–based signatures with response/resistance to pembro from the phase 2 KEYNOTE-427 study (NCT02853344) in pts with advanced clear cell RCC enrolled in cohort A (n = 110). Methods: In pembro-treated pts with RNA-seq and clinical data (N = 78), we analyzed the assoc of signatures (18-gene tumor T-cell–inflamed GEP; 10 non–T-cell–inflamed GEP canonical signatures [angiogenesis, gMDSC, glycolysis, hypoxia, mMDSC, MYC, proliferation, RAS, stromal/EMT/TGFβ, WNT]) quantifying the TME with clinical outcomes. Canonical signatures were derived from 2 databases (TCGA, Moffit) using an algorithm that included genes based on their correlation to reference signatures in the literature. Signature definitions were finalized before linking to the clinical data, and significance was prespecified at 0.10 given the potential for limited power. Canonical signatures were also analyzed through regression testing of response and the residuals of consensus signatures after adjusting for T-cell–inflamed GEP and IMDC scores in the model. P values were adjusted for multiplicity. Database cutoff date for clinical data: March 12, 2019. Results: Pt characteristics for this analysis were similar to those of the overall cohort A population. T-cell–inflamed GEP was statistically significantly assoc with ORR ( P = 0.021) but not PFS ( P = 0.116). When adjusting for PD-L1 expression (CPS by IHC) and IMDC scores, T-cell–inflamed GEP remained statistically significantly assoc with ORR ( P = 0.059). The angiogenesis signature was not assoc with response. PD-L2 RNA-seq expression was not assoc with response with multiplicity-adjusted P values. Like PD-L1 IHC, PD-L2 RNA-seq expression moderately correlated with T-cell–inflamed GEP and did not show independent predictive value when adjusted for T-cell–inflamed GEP and IMDC scores. Conclusions: RNA-seq–based, T-cell–inflamed GEP was assoc with ORR in pts with clear cell RCC receiving first-line pembro monotherapy; no canonical signatures showed statistical significance. Future directions for these data include whole exome sequencing analysis. Clinical trial information: NCT02853344.
Association of cytoreductive nephrectomy and survival in the immune checkpoint inhibitor era.
Authors: Miccio Joseph , Ma Sung Jun , Oladeru Oluwadamilola Temilade , Yang Daniel X. , Peters Gabrielle W. , Jethwa Krishan , Park Henry S. , Hurwitz Michael E. , Leapman Michael , Sprenkle Preston , Nguyen Paul , Yu James , Johung Kimberly 
Published: February 2020

748 Background: Cytoreductive nephrectomy (CN) for patients (pts) with metastatic renal cell carcinoma (mRCC) improved overall survival (OS) in the interferon (IFN) era, but the benefit of CN in the immune checkpoint inhibitor (ICI) era is unknown. Methods: We identified pts with mRCC receiving immunotherapy (IT) from 2004-2015 in the National Cancer Database (NCDB). Pts with partial nephrectomy or ablation were excluded. The ICI era was defined as 2013-2015 based on a high-profile publication in 2012 demonstrating efficacy of ICI in mRCC and the IFN era was defined as 2004-2005 due to FDA approval of sorafenib in 12/2005. Pts receiving CN with TKI were excluded, as prior NCDB study showed an OS benefit to CN in contrast to the results of the CARMENA trial. Univariable (UVA) and multivariable (MVA) associates with OS during each era were identified using Cox regression analysis including age, sex, race, income, insurance, treatment facility type, treatment location, clinical T stage (cT), clinical N stage (cN), histology, Fuhrman grade (FG), other metastectomy, and CN. Results: There was a 65% decline in mRCC pts receiving IT from 2005 to 2006 (end of the IFN era), which remained low (11% rise from 2006-2012) until a 93% rise from 2012 to 2013 (start of the ICI era). 128 of 422 (30.3%) pts in the IFN era received CN compared to 218 of 526 (41.4%) patients in the ICI era, p<0.001. Pts in each era were balanced with respect to median age, race, income, location, cT, and histology, but the ICI era had higher proportions of pts with private insurance, treatment at an academic center, N0 disease, FG 3-4, and other metastatectomy (p<0.05). Most pts with CN in the ICI era had IT after CN (89.9%); this was not coded in the IFN era. In the IFN era, CN compared to IT alone was associated with improved OS on UVA (HR 0.59, 95% CI 0.47-0.73, p<0.001) and MVA (HR 0.62, 95% CI 0.47-0.83, p=0.001). In the ICI era, CN compared to IT alone was associated with improved OS on UVA (HR 0.63, 95% CI 0.49-0.81, p<0.001) but not on MVA (0.82, 95% CI 0.58-1.14, p=0.234). Conclusions: Despite increased utilization of CN for US pts with mRCC treated with IT during the ICI era, the lack of OS benefit in recent years suggests a need for prospective reevaluation of the value CN and its timing with ICI.
Impact of oncological versus nononcological on survival outcomes in African Americans with renal cell carcinoma.
Authors: Meagher Margaret Frances , Bradshaw Aaron , Patil Dattatraya H , Saito Kazutaka , Cotta Brittney , Yasuda Yosuke , Eldefrawy Ahmed , Fujii Yasuhisa , Master Viraj A. , Derweesh Ithaar 
Published: February 2020

749 Background: African-Americans have an increased incidence of renal tumors of lower oncological potential when compared to other ethno-racial groups. Yet, survival outcomes are similar. We investigated the impact of African-American race on overall survival, oncological and functional outcomes, and non-cancer mortality. Methods: Multi-institutional (Emory, TMDU, UCSD) retrospective analysis of patients who underwent partial or radical nephrectomy between 1998-2018. Primary outcome was overall survival (OS). Secondary outcomes were non-cancer mortality (NCM), recurrence free survival (RFS), and eGFR decline. Multivariable logistic regression (MVA) was used to analyze OS, NCM, and RFS, and estimated glomerular filtration rate (eGFR)<45 and <30 ml/min/1.73m2. Results: 3632 patients were grouped into African American (AA, n=531) and Non-African American (NAA, n=3101). No difference was noted between groups with respect to mean tumor size (p=0.31). NAA had a higher proportion of metastases at presentation (9.9% vs. 7.0%, p=0.04). AA race was an independent risk factor for functional decline to de novo eGFR <45 (OR=1.43, p=0.04) and de novo eGFR<30 (OR 2.01, p<0.001). MVA for worsened NCM demonstrated AA race (OR=1.63, p=0.02), increasing age (OR=1.05, p<0.001), male sex (OR=1.56, p=0.01), and hypertension (OR=1.73, p=0.001) to be independent risk factors. Significant factors on MVA for worsened OS included increasing age (OR=1.03, p<0.001), radical nephrectomy (OR=1.47, p=0.01), increasing tumor size (OR=1.11, p<0.001), hypertension (OR=2.63, p<0.001), high tumor grade (OR=1.97, p<0.001), and post-operative eGFR <45 (OR=1.50, p=0.01). MVA for worsening RFS demonstrated high tumor grade (OR=2.04, p<0.001) and increasing clinical tumor size (OR=1.15, p<0.001) to be independent factors. Conclusions: African Americans undergoing surgical management for RCC appear to have similar OS and RFS, but poorer NCM than non-African American patients. The cause of these disparities is multi-faceted but likely is associated with functional decline. Nephron-sparing management when feasible and appropriate should be considered in African-Americans presenting with renal cortical tumors.
Baseline lymphocyte to monocyte ratio (LMR) and systemic inflammation index (SII) as prognostic factors in metastatic renal cell carcinoma (mRCC) patients treated with nivolumab: Preliminary results of the Meet-URO 15 (I-BIO-REC) study.
Authors: Rebuzzi Sara Elena , Buti Sebastiano , Sbrana Andrea , Procopio Giuseppe , De Giorgi Ugo , Vitale Maria Giuseppa , Massari Francesco , Santini Daniele , Cavo Alessia , Banna Giuseppe Luigi , Soraru' Mariella , Cortellini Alessio , Messina Marco , Martelli Valentino , Mollica Veronica , Stellato Marco , Lipari Helga , Catalano Fabio , Signori Alessio , Fornarini Giuseppe 
Published: February 2020

751 Background: Biomarkers to select mRCC patients most likely to benefit to immune-checkpoint inhibitors are still needed. The ongoing retrospective multicentre Meet-URO 15 (I-BIO-REC) study evaluates the prognostic role of peripheral blood cells in mRCC patients treated with nivolumab. Methods:The primary endpoint of the study was median overall survival (mOS) according to baseline neutrophil to lymphocyte ratio (NLR), but here preliminary analyses on baseline LMR and SII (secondary endpoints) are reported. LMR was defined as the ratio of lymphocyte to monocyte (cutoff = 3) and SII as platelet x neutrophil/lymphocyte (cutoff = 1375). Results: From May 2016 to January 2019 189 patients started nivolumab as 2nd (62%), 3rd (25%) and > 3rd (13%) line. Median age was 69 years, 67% were male and 87% had clear cell histology. Baseline IMDC group was favorable in 26%, intermediate in 63% and poor in 11%. Lymph-nodes, visceral and bone metastases were present in 55%, 92% and 37%. mOS and progression-free survival (PFS) were 30.5 months and 9.5 months. Overall response rate (ORR) and disease control rate (DCR) were 28% and 57%. LMR was available in 150 patients: LMR ≥ 3 (44%) correlated with statistically significant longer OS [NR vs 26.8 months, HR 0.50 (0.29-0.88); p = 0.016] but not PFS (10.3 vs 9.9 months, HR 0.87 (0.58-1.31); p = 0.5) with similar ORR (34% vs 33%) and DCR (60% vs 63%) compared to LMR < 3. SII was available in 162 patients. SII < 1375 (82%) correlated with statistically significant longer PFS [11.5 vs 3.4 months; HR 2.16 (1.36-3.43), p = 0.001] and OS [NR vs 9.5 months; HR 3.87 (2.21-6.78), p < 0.001] with higher ORR (35% vs 20%) and DCR (65% vs 40%) compared to SII ≥ 1375. Univariate and multivariate analyses adjusted for IMDC group, line of therapy and metastatic sites, confirmed the statistically significant correlation between SII with PFS and OS, but not for LMR. Conclusions: Preliminary analyses of our study showed a prognostic role of baseline SII, while it is uncertain for LMR in mRCC patients treated with nivolumab.
Improving IMDC criteria in patients with metastatic renal cell carcinoma through the addition of initial metastatic site in bone, brain, and liver.
Authors: Di Nunno Vincenzo , Massari Francesco , Guida Annalisa , Alves Costa Silva Carolina , Derosa Lisa , Mollica Veronica , Colomba Emeline , Escudier Bernard , Albiges Laurence 
Published: February 2020

754 Background: IMDC criteria are largely adopted to estimate patient prognosis. In a retrospective study we assessed that the addition of first site of metastases in brain bone and liver (bbl) metastases as variable improves prognostic stratification of patients (pts) with metastatic renal cell carcinoma (mRCC). We performed a validation study in an external cohort of patients with mRCC. Methods: All consecutive mRCC pts treated at a single institute and included in the local IGReCC database. All pts received at least one line of targeted therapy or ICIs. Primary outcome was OS from first line start. Univariate and multivariate analysis (cox regression model) were performed. Bootstrap was also carried out for validation. Results: 1073 mRCC pts were analysed (808 with known IMDC score). Of 13 initial variables considered for prognostic model, the presence of bbl as first site/s of metastases plus the 6 variables included in IMDC resulted as statistically significant factors associated with OS (table). By including this new parameter we developed a 7-variables based score (IMDC-7). Patients with 0, 1-2 and≥3 positive variable/s were considered as good, intermediate and poor risk patients respectively. 56 (22%) pts moved from good (IMDC) to intermediate (IMDC-7) and 66 (15.4%) pts moved from intermediate (IMDC) to poor (IMDC-7) group (table). Final bias corrected concordance c-index was 0.69 and 0.71 in overall cohort and in pts treated with ICI (n=241). Conclusions: The addition of bbl primary metastases to the others IMDC variables improves prognostic predictive power of the model.[Table: see text]
Recurrence of surgically resected chromophobe renal cell carcinoma: Recommendations for follow-up.
Authors: Vanaclocha Saiz Leyre , Neves Joana B. , Marchetti Marta , Barod Ravi , Patki Prasad , Mumtaz Faiz , Dabestani Saeed , Tran Maxine Gia Binh , Bex Axel 
Published: February 2020

755 Background: Post-operative follow-up protocols for renal cell carcinoma (RCC) are based on outcomes of the clear cell subtype and often rely on variables not applicable to chromophobe RCC (chRCC), such as Fuhrman nuclear grading. We aimed to evaluate predictors of recurrence to guide follow-up regimes in the context of chRCC. Methods: Combined retrospective analysis of non-metastatic surgical cases with a final diagnosis of chRCC from an institutional database at a UK tertiary high-volume centre (June/2013 to March/2019) and from the international collaborative database RECUR (12 institutes across 8 European countries; 2006 to 2011). TNM risk group, tumour size, histopathological features, cancer specific survival (CSS) and recurrence free survival (RFS) were analysed. Kaplan Meier plots and Cox regression analysis were performed to determine factors associated with recurrence (local or distant). Results: 295 cases were identified (57.3% male, median age 60). After a median follow up of 58 months, 17 (5.8%) recurrences were observed, the majority of which were distant recurrences (n = 13). CSS was 96.3%. Tumours staged ≥pT2b (HR 13.7; 95%CI 3 to 63.1; p = 0.001), with coagulative necrosis (HR 3.9; 95%CI 1.3 to 11.1; p = 0.012) and sarcomatoid differentiation (HR 33; 95%CI 8.1 to 134.6.1; p = 0.000) were more likely to recur during follow-up. Only two cases of pT1a lesions had local recurrence, both after a positive surgical margin. All patients with early recurrences ( < 18 months after surgery; n = 6) had tumours staged ≥pT2b with coagulative necrosis; sarcomatoid differentiation was also present in 3 cases. Conclusions: Recurrence of surgically resected chRCC is not common. For patients with pT1 lesions, negative margins, no coagulative necrosis or sarcomatoid features, prognosis is excellent. Follow up can be curtailed to avoid excess radiation exposure and patient anxiety.
Predicting long-term results with circulating tumor cells in patients with de novo androgen sensitive prostate cancer treated with hTERT peptides vaccine.
Authors: Lilleby Wolfgang , Guldvik Ingrid Jenny , Hole Knut H. , Olaussen Richard , Mills Ian G. , Stensvold Andreas , Seierstad Therese , Tran Phuoc T. , Inderberg Else Marit 
Published: February 2020

98 Background: Androgen deprivation, radiotherapy and chemotherapy improves survival in advanced prostate cancer (PC), but many patients still progress and experience toxicity from treatment. We investigated the clinical utility of a medical wire, collecting circulating tumor cells (CTCs) from a peripheral vein, to predict oncologic outcomes prior to treatment with a hTERT peptide vaccine. Methods: Twenty-three patients with advanced PC with non-visceral spread and unselected HLA-type were eligible. One patient progressed before initiation of the vaccination (median FU 60 months). The hTERT peptides vaccine schedule started one week after inclusion with a total of 13 vaccinations (N=22). Patients with no signs of deterioration during the vaccine schedule received image-guided radiation to the prostate (2Gy/37f, n=20). Vaccine response was evaluated by T-cell proliferation assay. CTCs were enriched from the peripheral blood using EpCAM as antibody (CellCollector, Gilupi, Potsdam, Germany). Kaplan-Meier outcome curves were constructed for prostate cancer-specific survival (PCSS) and overall survival with stratification by immune response, CTCs (no/yes), PSA and comparison of patient subsets using the log-rank test. Results: Median age of the cohort was 67 years (range 51-78 years).The mean time from CellCollector after ADT to start vaccine was 2,95 months (SD+-1,78 months). The mean yield of CTCs was 3 cells (range 0 - 22). The detection of CTCs showed an inverse trend towards immune response (p=0.07). None of the patients with a positive CellCollector finding and a PSA below ≤0.2 (n=9) had died of prostate cancer during the observation period of 5 years, patients with no CTCS and a PSA >0.2 (n=14) had an estimated median PCSS of 39 months (log-rank test 0=0.007, Fig. 1). The overall survival analysis showed that 6 out of 9 patients with CTCs compared to 5 out of 14 patients in the CTCs negative group were alive at 5 years FU (log-rank-test=0.159). Conclusions: Patients with a de novo diagnozed metastatic prostate cancer and a positive CTC burden do better when subsequently treated with the hTERT vaccine than those with a negative CTC finding. Clinical trial information: NCT01784913.