bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor protein expression of BRCA1 and development of lethal prostate cancer.
Authors: Ceraolo Carl , Gerke Travis A. , Zareba Piotr , Pettersson Andreas , Stopsack Konrad H. , Chowdhury Dipanjan , Ebot Ericka M. , Flavin Richard , Finn Stephen P. , Kantoff Philip W. , Stampfer Meir J. , Loda Massimo , Fiorentino Michelangelo , Mucci Lorelei A. 
Published: February 2020

65 Background: DNA repair genes including BRCA1 are commonly altered in metastatic prostate tumors. However, mutations and copy number aberrations in these genes are rare in primary tumors. Instead, preliminary studies suggest that higher tumor expression of the BRCA1 protein may be associated with worse prognosis. Methods: We undertook a prospective study of tumor BRCA1 protein expression and lethal prostate cancer among men with clinically localized prostate cancer in the Health Professionals Follow-up Study. We performed immunohistochemical staining for BRCA1 on tumor tissue microarrays using a validated antibody and scored expression as positive or negative. We also assessed tumor proliferation by immunostaining for Ki67, angiogenesis by immunostaining for CD34, and apoptosis using a TUNEL assay. Proportional hazards regression was used to evaluate the association between BRCA1 protein expression and development of lethal prostate cancer (metastasis or cancer-specific death). Results: Ten percent of tumors (60 of 589) stained positive for the BRCA1 protein. BRCA1-positive tumors were characterized by higher Gleason scores, a higher proliferative index, and a higher apoptotic index. During a median follow-up of 14.3 years, 18 men (34%) in the BRCA1-positive group and 74 men (14%) in the BRCA1-negative group developed lethal prostate cancer. There was a strong positive association between BRCA1 protein expression and lethal prostate cancer in both unadjusted analyses (HR 2.71, 95% CI 1.73–4.26) and after adjusting for clinical factors (HR 2.00, 95% CI 1.26–3.18). The positive association with BRCA1 protein expression was also independent of proliferation index. Conclusions: Primary prostate tumors expressing the BRCA1 protein have a highly proliferative phenotype and are more likely to progress to lethal disease, independent of its higher proliferative index. Assessing tumor protein expression of BRCA1 may help elucidate the Janus-faced role of DNA repair pathways in prostate cancer progression.[Table: see text]
Does presence of bone metastases portend worsened prognosis in metastatic renal cell carcinoma? Analysis of the REMARCC (Registry of MetAstatic RCC) database.
Authors: Bradshaw Aaron , Mir Maria Carmen , Autorino Ricardo , Minervini Andrea , Kriegmair Maximilian , Maurer Tobias , Porpiglia Francesco , Van Bruwaene Siska , Linares Espinos Estefania , Hevia Vital , Musquera Mireia , Rousel Eduard , Pavan Nicola , Antonelli Alessandro , Zhang Shudong , Meagher Margaret , Rubio Jose , Albersen Maarten , Furlan Maria , Derweesh Ithaar 
Published: February 2020

655 Background: The presence of brain metastases and bone metastases are generally understood to herald worsened prognosis following nephrectomy in patients with renal cell carcinoma (RCC). However, we sought to determine the effect of bone metastases on outcomes when already present at the time of cytoreductive radical nephrectomy (RN). Methods: Multicenter retrospective analysis of mRCC patients from the REgistry of MetAstatic RCC) REMARCC. Demographics, clinical variables, and outcomes were collected. Patients were stratified into low, medium, and high-risk groups based on Motzer Criteria, and analysis of impact of bone metastases was conducted within each group utilizing Kaplan-Meier analysis (KMA). Multivariable analysis (MVA) was utilized to identify predictors for outcomes. Primary outcome was progression-free survival (PFS) and secondary outcome was overall survival (OS). Results: A total of 447 patients (low- n=30, intermediate- n=208, and high-risk mRCC n=123, median follow-up 14.3 months) were included in the analysis. 124 patients had bone metastases and 323 had mRCC but no bone metastases. No significant demographic differences were noted between groups. KMA (Figure) showed no difference in median PFS for bone metastases vs. non bone metastases groups (6.1 vs. 6.4 months, p=0.973). KMA showed no difference in median OS (25.5 vs. 26.5 months, p=0.958). Similarly, stratification of patients into different Motzer risk categories did not demonstrate difference between bone vs. none bone mRCC for PFS and OS. MVA for PFS demonstrated increasing Motzer risk category (low risk referent vs. intermediate OR 1.89, p=0.006, high risk OR 3.24, p<0.001) as independent predictors. MVA for OS revealed increasing Motzer risk category (low ref, vs. intermediate OR 1.88, p=0.033, high risk 5.17, p<0.001) as being predictive. In neither analysis was presence of bone metastases significant (PFS p=0.690, OS p=0.268). Conclusions: Presence of bone metastases does not independently predict survival or oncologic outcomes in mRCC. While further validation is needed, the prognostic significance of bone metastases may be less than previously thought.
Treatment-free survival after discontinuation of immuno-checkpoint therapy, and outcome of subsequent molecular targeted therapy: Retrospective study of Japanese metastatic renal cell carcinoma patients (after I-O study).
Authors: Tomita Yoshihiko , Kimura Go , Fukasawa Satoshi , Sugiyama Yutaka , Numakura Kazuyuki , Yamana Kazutoshi , Naito Sei , Kabu Koki , Tajima Yohei , Oya Mototsugu 
Published: February 2020

677 Background: Guidelines for treatment of metastatic renal cell carcinoma (mRCC) recommend nivolumab monotherapy (NIVO) for treated mRCC, and nivolumab + ipilimumab combination therapy (NIVO+IPI) for untreated IMDC intermediate and poor risk mRCC patients. Though molecular targeted therapies (TTs) such as VEGFR-TKIs and mTORi are recommended as subsequent therapy after NIVO or NIVO+IPI, their impact is still unclear. Methods: Japanese mRCC patients treated with TT after NIVO (CheckMate 025) or NIVO+IPI (CheckMate 214) were retrospectively analyzed. Primary endpoints were investigator assessed ORR of the first TT after NIVO, and after NIVO+IPI. Secondary endpoints included treatment-free survival (TFS) after discontinuation of NIVO and NIVO+IPI, and progression-free survival (PFS) and safety of the first subsequent TT after NIVO and NIVO+IPI. Results: Twenty-six patients of CheckMate 025 and 19 patients of CheckMate 214 from 20 centers in Japan were analyzed. Median TFS after ICI discontinuation was 1.0m and 2.5m for CheckMate 025 and CheckMate 214 patients, respectively. Median follow-up period from the start of TT after ICI discontinuation to date of analysis or death was 22.1m for CheckMate 025, and 20.3m for CheckMate 214 patients. As the first subsequent TT after NIVO or NIVO+IPI, axitinib was the most treated therapy for both CheckMate 025 (53.8%) and CheckMate 214 (47.4%) patients. ORR of TT after NIVO and NIVO+IPI was 26.9% and 31.6%, and median PFS was 8.9m and 16.3m, respectively. During the treatment of first TT after NIVO and NIVO+IPI, 98% percent experienced treated-related adverse events, 51% experienced grade 3-4, but no treatment related death. Conclusions: TTs have favorable antitumor activity for mRCC after NIVO and NIVO+IPI, possibly by changing the mode of action. Safety signals of TTs after ICI were similar to the previous reports. These results indicate sequential TTs after ICI may contribute for durable survival benefit.
Evaluation of brain metastasis in JAVELIN Renal 101: Efficacy of avelumab + axitinib (A+Ax) versus sunitinib (S).
Authors: Jonasch Eric , Hasanov Elshad , Motzer Robert J. , Hariharan Subramanian , Choueiri Toni K. , Huang Bo , Haanen John B. A. G. , Albiges Laurence , Venugopal Balaji , Schmidinger Manuela , Larkin James M. G. , Grimm Marc-Oliver , Negrier Sylvie , Wang Jing , Mariani Mariangela , Chudnovsky Aleksander , di Pietro Alessandra , Rini Brian I. 
Published: February 2020

687 Background: Patients (pts) with brain metastasis from renal cell carcinoma (RCC) have poor prognosis and are often excluded from randomized registrational trials. The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) for A+Ax vs S in pts with advanced RCC (Motzer NEJM 2019). The activity of A+Ax in pts with brain metastasis enrolled in JAVELIN Renal 101 is presented. Methods: PFS was compared between treatment arms for the subgroup of pts randomized in JAVELIN Renal 101 with brain metastases at enrollment (pts with brain disease site prior to randomization by blinded independent central review [BICR] or by investigator assessment). PFS time was summarized per BICR assessment by treatment arm using the Kaplan-Meier method. The Cox proportional hazards model was fitted to compute the hazard ratio (HR) and the corresponding CI. In addition, time to brain metastasis was assessed for pts without brain metastasis by BICR at enrollment after treating death as a competing risk. Results: Of all randomized pts (A+Ax arm, N=442; S, N=444), 23 in each arm (5.2%) had asymptomatic brain metastasis at enrollment; of these, pts assigned to A+Ax had a PFS of 4.9 mo (95% CI: 1.6, 5.7) vs 2.8 mo (95% CI: 2.3, 5.6) for pts assigned to S (HR: 0.90; 95% CI: 0.43, 1.88). Among pts without brain metastasis at enrollment, 8 pts on the A+Ax arm and 10 on the S arm developed brain metastasis during the trial, based on BICR assessment; 17/18 occurred ≤12 mo from randomization. The cumulative incidence rate of brain metastasis at 18 mo was 2% (95% CI: 0.6, 3.3) for the A+Ax arm and 3% (95% CI: 1.1, 4.8) for the S arm. Conclusions: In this post hoc exploratory analysis of JAVELIN Renal 101, the observed PFS among pts with brain metastasis at enrollment was similar between the two arms, with HR and median PFS numerically favoring A+Ax. Pts on the S arm had a numerically higher incidence of new brain metastases on trial. Outcomes are poor in pts with advanced RCC and brain metastasis; more effective treatments are needed. Clinical trial information: NCT02684006.
Using high-resolution magic angle spinning magnetic resonance spectroscopy to characterize the metabolomic profile of fat-poor angiomyolipoma and renal cell carcinoma.
Authors: Huynh Melissa Jessica , Gusev Andrew , Palmas Francesco , Vandergrift Lindsey , Wu Chin-Lee , Cheng Leo , Feldman Adam S. 
Published: February 2020

711 Background: Fat-poor angiomyolipoma (AML) can be difficult to differentiate from renal cell carcinoma (RCC) radiographically and may lead to biopsy or unnecessary intervention. In vivoplatforms with the ability to identify tumor histology based on metabolic profiles may avoid unnecessary procedures & their complications. The metabolomics of AML have not been characterized, & research into this area may provide targetable molecules for large AMLs. In this study, we investigate the metabolomic profile of AMLs compared to clear cell RCC (ccRCC) using high resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS). Methods: Tissue samples were obtained from radical or partial nephrectomy specimens that were fresh frozen & stored at -80ºC. Tissue HRMAS MRS was performed by a Bruker AVANCE spectrometer. Metabolomic profiles of RCC & adjacent benign renal tissue were compared, and false discovery rates (FDR) accounted for multiple testing. Regions of interest (ROI) with FDR <0.05 were considered potential predictors of ccRCC rather than AML. The Wilcoxon rank sum test was used to compare median MRS relative intensities for candidate predictors. Logistic regression was used to determine odds ratios for risk of malignancy based on abundance of each metabolite. Results: There were 16 ccRCC samples & 7 AML specimens. Candidate predictors of malignancy rather than AML based on FDR p-values include histidine, phenylalanine, phosphocholine, serine, alanine, glutamate, glutathione, glycerophosphocholine, & glutamine. While an abundance of these metabolites is associated with higher risk of malignancy, the odds ratio was particularly high in the 3.5-3.49 ppm spectral region (OR 2.99x106, 95% CI 3.27, 2.73x1012, p=0.033)in ccRCC samples. Conclusions: HRMAS MRS identified metabolites that may help differentiate fat-poor AML from ccRCC. In particular, metabolites in the 3.5-3.49 ppm spectral region increased the risk of harboring RCC. Our findings may contribute to future in vivostudies to help identify which patients require intervention for malignancy & which may be observed for benign AML without requiring biopsy.
Selective modulation of immune transcripts in extracellular vesicles from plasma of renal cell carcinoma patients receiving nivolumab.
Authors: Verzoni Elena , Shahaj Eriomina , Frigerio Simona , Cova Agata , Squarcina Paola , Pesce Samantha , Vergani Elisabetta , Vallacchi Viviana , Lalli Luca , Pietrantonio Filippo , Di Nicola Massimo A. , Procopio Giuseppe , De Braud Filippo G. , Mennitto Alessia , Claps Melanie , Sepe Pierangela , Rodolfo Monica , Rivoltini Licia , Huber Veronica 
Published: February 2020

719 Background: Patients (pts) displaying a full-fledged immune response show high levels of circulating extracellular vesicles (EVs) containing immune transcripts that might be transferred to neighboring cells to amplify immune responses, as in autoimmunity and transplantation. We hypothesized EV immune transcripts could reflect immune activation in cancer pts receiving immunotherapy with immune checkpoint inhibitors (ICI). These RNA-containing EVs may surrogate immune functionality and represent a plasma transcriptional signature of adaptive immunity that can be readily detected by liquid biopsy. Methods: Blood samples from metastatic renal cell cancer pts,treated with ICI nivolumab (n=8) or tyrosine kinase inhibitor cabozantinib (n=9) were collected at baseline, week 4 and 12. EV-RNA was isolated from plasma with membrane affinity spin columns and evaluated for CD274(PD-L1), IFNG, PDCD1 (PD-1), CD3 and GZMB (granzyme B) transcripts by qRT-PCR. Results: All pts showed a statistically significant increase of CD3, IFNG, GZMB, PD-1 and PD-L1 immune transcripts in plasma EVs, evidenced at 4 and 12 weeks of therapy. Treatment subgroup analysis revealed an upregulation of CD3, IFNG, GZMB and PD-1 transcripts only in plasma EVs of patients receiving nivolumab that was more evident in those showing clinical benefit (4/8), while PD-L1 increased significantly during cabozantinib treatment. Upon comparing transcripts with soluble proteins, PD-L1 displayed similar kinetics, while PD-1 increased only as transcript but not as protein, given its potential sequestration by the anti-PD-1 antibody. This effect was detectable only in nivolumab but not in cabozantinib treated pts. Conclusions: Monitoring immune transcripts carried by plasma EVs holds promise as potential tool to assess the entity of the ongoing immune activation during immunotherapy. Plasma EVs may be exploited as indicators of immune response and help to predict clinical efficacy at early on-treatment time points. This approach based on plasma EVs might represent a starting point for the development of a novel strategy to study immune responses in clinical setting.
NF2 mutation-driven renal cell carcinomas (RCC): A comprehensive genomic profiling (CGP) study.
Authors: Yakirevich Evgeny , Perrino Carmen , Necchi Andrea , Grivas Petros , Bratslavsky Gennady , Shapiro Oleg , Jacob Joseph , Sokol Ethan , Vergilio Jo-Anne , Killian Keith , Lin Douglas I. , Ramkissoon Shakti H. , Severson Eric Allan , Chung Jon , Alexander Brian Michael , Elvin Julia Andrea , Schrock Alexa Betzig , Danziger Natalie , Ross Jeffrey S. 
Published: February 2020

726 Background: NF2 genomic alterations (GA) have been associated with aggressive behavior in RCC. Methods: FFPE tissues from 1,386 clear cell (ccRCC), 307 papillary (pRCC), 72 chromophobe (chRCC), 145 sarcomatoid (sRCC), 54 collecting duct (cdRCC),37 medullary (medRCC) and 134 unclassified (nosRCC) underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and MSI was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 140 (7%) RCC featured NF2 GA which were predominantly short variant (SV) mutations. Gender and age were similar with male preponderance in all histologic subtypes. NF2 GA frequency was highest in cdRCC (20%) and sRCC (19%) and lowest in ccRCC (3%). The medRCC at 5% NF2 GA and chRCC at 0% NF2 GA were not further evaluated. VHL and PBRM1 GA were significantly more frequent in NF2 altered ccRCC than all other RCC (P < 0.001). Other mTOR pathway GA were uncommon. Potentially targetable kinase GA in NF2-mutated RCC included BRAF (2% of ccRCC), EGFR (3% of pRCC), ERBB3 (4% of sRCC) and PIK3CA (9% of cdRCC). No NF2 mutated RCC featured MSI -high status and both TMB and PD-L1 expression levels were extremely low in all subsets with exception of high PD-L1 staining in sRCC tumors. Conclusions: cdRCC, sRCC, pRCC and nosRCC are enriched in NF2 GA. Low PBRM1 GA, TMB and MSI- high predict resistance to immunotherapy in NF2 mutated RCC although the high PD-L1 expression in sRCC is noteworthy.[Table: see text]
Validation of the lung immune prognostic index (LIPI) in patients with metastatic renal cell carcinoma treated with nivolumab in the GETUG-AFU 26 NIVOREN trial.
Authors: Lavaud Pernelle , Dalban Cécile , Negrier Sylvie , Chevreau Christine , Gravis Gwenaelle , Oudard Stephane , Laguerre Brigitte , Barthelemy Philippe , Borchiellini Delphine , Gross Goupil Marine , Geoffrois Lionnel , Rolland Frederic , Thiery-Vuillemin Antoine , Joly Florence , Ladoire Sylvain , Tantot Florence , Mezquita Laura , Escudier Bernard , Albiges Laurence 
Published: February 2020

735 Background: The Lung Immune Prognostic Index (LIPI) is a prognostic score combining pretreatment dNLR (neutrophils/ (leucocytes-neutrophils) and LDH correlated to immune checkpoint inhibitors (ICI) benefit in several advanced cancers. We aimed to correlate LIPI score with Nivolumab (N) benefit in metastatic clear cell renal cell carcinoma (mccRCC) patients. Methods: We investigated the LIPI score in the GETUG-AFU 26 NIVOREN phase II trial assessing the activity and safety of N after failure of upfront VEGF-targeted therapies. A dNLR ≥ 3 and LDH ≥ upper superior limit were analyzed for the LIPI, and patients were stratified into 3 groups (good (GG), intermediate (IG) and poor (PG)) (Mezquita et al, JAMA Oncol 2018). The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and objective response rate (ORR). Results: Overall, 619 pts were included. Median age was 64 years old, 22.1% pts had received more than 2 previous lines and IMDC risk groups were 18.3%, 56.5% and 25.0% for good/intermediate and poor risk respectively. Median (m) follow up was 23.7 months (mo). The mPFS with N was 4.0 mo and mOS was not reach. LIPI classified 364 pts (58.8%) as GG, 216 pts (34.9%) as IG and 39 pts (6.3%) as PG. The PFS and OS results are summarized in the Table. In multivariate analysis, LIPI score remains an independent prognostic factor after adjustment for sex, age, ECOG PS and IMDC. ORR did not seem to be influenced by the LIPI groups. Conclusions: We report for the first time that LIPI score is associated with PFS and OS in patients treated with N for mccRCC. LIPI score appears as an independent prognostic factor even after adjustment for established risk factors. External validation in a VEGF-targeted therapy cohort is ongoing and will contribute to evaluate the predictive value of LIPI in mccRCC.[Table: see text]
Cognitive status of prostate cancer (PCa) patients aged 60 years and older initiating gonadotropin-releasing hormone agonist (GnRHa) therapy, by age group.
Authors: Rozet Francois , Hennequin Christophe , Roupret Morgan , Pello Leprince Ringuet Nathalie , Houchard Aude , Mongiat Artus Pierre 
Published: February 2020

74 Background: Age is a risk factor for both PCa and cognitive impairment. Moreover, androgen deprivation therapy (ADT) is suspected to alter cognition, but little is known about the cognitive status of men starting ADT. Our purpose was to analyze cognitive status in 3 groups of age ([60-70[, [70-75[ and ≥ 75 years). Methods: Initiated in March 2018, a prospective, multicenter, longitudinal, non-interventional study is conducted in France (PRISME, NCT03516110). Urologists, radiation oncologists and medical oncologists recruited patients aged 60 years and older, with histologically confirmed PCa, candidate for GnRHa therapy. Patients were included (1:2:1) in prespecified age groups ([60-70[, [70-75[, ≥ 75 years). Cognitive status was evaluated through Mini Mental State Evaluation (MMSE) questionnaire (scores 0-30), and through a visual analog scale (VAS) measuring satisfaction of patients with memory (score 0-10 cm). Significant differences (*) were concluded in case of non-overlapping of the means 95% CIs. Results: 528 patients were included in the pre-planned interim analysis of baseline results. Mean (±SD) age was 72.9±6.5years. There were 145, 207 and 176 patients, in the [60-70[, [70-75[ and ≥75y age groups, respectively. 93.8% of patients had a Karnofsky score ≥ 80%; 73.4% had at least one comorbidity at baseline and 67.9% were receiving at least one concomitant systemic treatment. Reason for GnRHa initiation was high risk localized or locally advanced tumor (57.6%), metastatic stage (19.8%), biochemical recurrence after local treatment (14.7%). Mean [95% CI] MMSE score was significantly* lower in the ≥75y age group (26.1 [25.5-26.8]) than in the [60-70[ (27.6 [27.0-28.1]) and [70-75[ (27.5 [27.1-28.0]) age groups. Cognitive impairment (MMSE < 26) concerned 18.2%, 17.6% and 32.0% of patients, respectively. Similarly, memory VAS mean score was significantly* lower in the ≥75y age group (6.4 [6.0-6.8]) than in the [70-75[ age group (7.2 [6.9-7.5]). Conclusions: Analysis of the cognitive status of 3 age groups at initiation of GnRHa therapy showed a higher rate of cognitive impairment in the eldest group. Clinical trial information: NCT03516110.