bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring the synergistic effects of cabozantinib (cabo) and a programmed cell death protein 1 (PD1) inhibitor in metastatic renal cell carcinoma (mRCC) with artificial intelligence (AI).
Authors: Costa Luis , Castellano Daniel , Puente Javier , Martin Lidia , Anido Urbano , Gómez Jessica , Duran Ignacio 
Published: March 2021

336 Background: Nonclinical and clinical data suggest that cabo with a PD1 inhibitor provides synergistic antitumor activity in patients with mRCC, possibly by a cabo-induced switch to an immunopermissive tumor microenvironment. We used a complementary, unbiased, AI approach to gain a holistic view of the complex interplay between multiple pathways, cells and molecules and identify the mechanisms that may underpin this synergism. Methods: Biological targets associated with mRCC pathophysiology or drug actions were identified from proteomic, genomic and transcriptomic databases and literature. Using systems- and AI-based technology, the data were integrated using machine learning into mathematical models of the human mRCC protein network topology. The combined effects of cabo and a PD1 inhibitor on biological targets were simulated assuming target receptors were fully activated or fully inhibited. Relevant effects on known cancer processes (e.g. angiogenesis, metastasis, cell proliferation, immune evasion) were identified using artificial neural networks. Biologically plausible synergistic mechanisms were described with sampling methods. Results: Inhibition of VEGF/VEGFR and GAS6/TAMR axes by cabo enhanced the known effects of PD1 inhibitors on immune evasion mechanisms by modulating multiple humoral and cellular components of the innate and adaptive immune responses (Table). PD1 inhibitors further enhanced the anti-angiogenic and tumor pro-apoptotic effects of cabo by modulating pro- and anti-angiogenic factors and T cell cytotoxicity. Conclusions: These data provide a mechanistic rationale and further support for the beneficial combination of cabo and a PD1 inhibitor and may guide future nonclinical and clinical research. [Table: see text]
A dual drug therapy for sunitinib resistant RCC: An in vitro analysis.
Authors: Greenberg Jacob W. , Kim Hogyoung , Moustafa Ahmed A , Barata Pedro C. , Abdel-Mageed Asim , Krane L. Spencer 
Published: March 2021

340 Background: Over the last decade, medical treatment for metastatic renal cell carcinoma has made significant advances through the development of tyrosine kinase inhibitors (TKI) like sunitinib. However, of patients initiated on TKI therapy, 70% respond well while 30% are believed to be primarily resistant to treatment. Additionally, 30% of patients who initially respond to treatment gain secondary drug resistance and present with increased tumor burden. In this study, we seek to develop a combination therapy of Tipifarnib + Sunitinib to target exosome conferred drug resistance. Methods: 786-O, 786-0 Sunitinib Resistant (SR), and 293-T cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 2mM L-glutamine, and 1% penicillin/streptomycin (P/S). Exosomes were collected from conditioned media treated with Tipifarnib and isolated using differential ultracentrifugation. Exosomes were analyzed using the qNano IZON system. Colony forming units assay and Immunoblot analysis were used to further characterize or samples. Results: Exosomes collected from 786-O, 786-0 SR, and 293-T cells treated with 0.5 uM of Tipifarnib were compared using our qNANO IZON system. Exosome concentrations of all cell lines showed a decrease after Tipifarnib treatment. However, our 293-T cells showed a 16% decrease in exosome concentration while our 786-O and 786-0 SR lines displayed a 66% and 75% decrease respectively. To assess the pathway Tipifarnib used to decrease exosome concentrations, immunoblot assay was used after treating cells with 0, 0.1, 0.25, 0.5, 1 uM of tipifarnib. 293-T cells showed a dose dependent increase in ESCRT-dependent marker Alix and no change in either ESCRT-independent marker nSMase or trafficking marker Rab27a. Conversely, our 786-O and 786-0 SR cell lines showed a decrease in all 3 markers: Alix, nSMase, and Rab27a. Furthermore, a colony forming units assay was used to assess the drug combination of tipifarnib + sunitinib ability to alter cell growth. After 48hr, 293-T cell showed no decrease in colony forming units when compared to DMSO control. Our drug combination showed a synergistic ability to decrease colony forming units in the RCC 786-O cell line. 786-O SR cells were resistant to sunitinib treatment, showing comparable CFUs to DMSO control. When treated with the combination of sunitinib and tipifarnib, CTUs of 786-0 SR cells dropped significantly when compared to unaccompanied sunitinib and tipifarnib treatments. Conclusions: Tipifarnib has the ability to attenuate both the exosome ESCRT–dependent and –independent pathways. Our study also showed that when used injunction with sunitinib, tipifarnib is effective at decreasing cell proliferation. This drug combination is also pre-clinically useful in sunitinib resistance cancer cells. We believe this drug combination to be efficacious at decreasing tumor burden through blocking exosome biogenesis and secretion.
DNA damage repair (DDR) pathway alteration in advanced renal cell carcinoma (RCC) is association with good progression-free survival with tyrosine kinase inhibitor (TKI) therapy.
Authors: Zhai Wei , Wang Junyun , He Ning , Zhou Jiale , Wang Jianfei , Xue Yizheng , Yang Zhaolin , Chen Yonghui , Zhang Jin , Haung Jiwei , Kong Wen , Huang Yiran , Xue Wei 
Published: March 2021

346 Background: Alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may be as potential biomarkers for vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy in renal cell carcinoma. However, biologic significance and relevance to TKI targeted therapy in metastatic RCC are unknown. Methods: Genomic data and treatment outcomes were retrospectively collected for patients with metastatic RCC. Tumor and germline DNA were subject to targeted next generation sequencing across 642 genes of interest, including 60 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) DDR gene alterations present (Mut DDR); (2) wildtype (WT) DDR gene alterations present (WT DDR). Association between DDR status and therapeutic benefit was investigated separately for and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy. Results: Mut DDR were detected in 17/40 patients (42.5%). The most frequently DDR altered genes were TP53. For patients with TKI treatment, Mut DDR status was associated with superior progression free survival (log-rank p = 0.048), but not with superior overall survival (log-rank p = 0.39); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Mut DDR was 2.68 (95% CI: 0.96–7.46; p = 0.059). Conclusions: DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Dysfunction events in these genes may affect outcome with TKI therapy in adanced RCC, and these hypothesis-generating results deserve further study.
Sarcomatoid (srcRCC) versus clear cell (ccRCC) renal cell carcinoma: A comparative comprehensive genomic profiling (CGP) study.
Authors: Bratslavsky Gennady , Jacob Joseph M , Necchi Andrea , Spiess Philippe E. , Grivas Petros , Danziger Natalie , Huang Richard , Mata Douglas A , Decker Brennan James , Ross Jeffrey S. 
Published: March 2021

349 Background: srcRCC is a well-described histologic entity often featuring rapid progression and aggressive clinical course when compared with classic ccRCC. We queried whether CGP would uncover opportunities for targeted and immunotherapy (IO) for srcRCC patients that could individualize their treatment and entry into clinical trials. Methods: Using a hybrid capture-based CGP assay to evaluate all classes of genomic alterations (GA), 160 cases of srcRCC and 1,664 cases of ccRCC were sequenced from FFPE tissue samples. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining set at 1-49% and high staining >50% expression. Results: Gender and age distributions for both tumor types were similar. srcRCC featured significantly higher GA/tumor than ccRCC (P < .0001). CGP revealed major differences with ccRCC associated more frequently with tumor suppressor gene (TSG) losses in VHL, PBRM1, TSC2 and SETD2 (all P < .0001). In contrast, srcRCC is associated with cell proliferation with increased inactivation of cell cycle regulatory genes including TP53, CDKN2A/B, MDM2 and TERT (all P < .0001). RB1 GA in srcRCC may reflect neuroendocrine differentiation occasionally found in these tumors. NF2 GA were more frequent in srcRCC (P < .0001). Conclusions: CGP reveals striking differences between srcRCC and ccRCC which may in part explain the differing histologic appearances and typical clinical course of these 2 aggressive malignancies. ccRCC is driven more by TSG loss and srcRCC is driven more by cell cycle dysregulation. Targeted therapy opportunities were uncommon for both tumor types although each featured biomarkers potentially predictive of mTOR inhibitor responses ( TSC2 in ccRCC and NF2 in srcRCC). Although the higher PBRM1 GA frequency in ccRCC may explain the IO benefit well-known for this tumor type, the srcRCC group features significantly increased TMB, CD274 amplification and PD-L1 staining which may also create IO opportunities for srcRCC patients. [Table: see text]
Distinct cytokines predict response to immunotherapy and targeted therapy in metastatic renal cell carcinoma (mRCC).
Authors: Chehrazi-Raffle Alex , Meza Luis A , Alcantara Marice , Salgia Nicholas , Dizman Nazli , Bergerot Paulo Gustavo , Hsu Joann , Kortylewski Marcin , Pal Sumanta K. 
Published: March 2021

352 Background: Previous studies have suggested a link between plasma cytokines and mRCC outcomes with systemic therapy. In a prospective study, we assessed whether plasma cytokines could separately predict outcome with immunotherapy or targeted therapy. Methods: Eligible patients (pts) had histologically proven mRCC with intent to receive a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or an immune checkpoint inhibitor (ICI). Immunologic profiles were evaluated at several time points using a Human Cytokine 30-plex protein assay (Invitrogen). Clinical benefit (CB) was defined as complete response, partial response, or stable disease ≥ 6 months. Results: A total of 56 pts (40:16 M:F) were enrolled; 23 pts and 33 pts received VEGF-TKI and ICI, respectively. The most common VEGF-TKI was cabozantinib; the most common ICI was nivolumab. CB was similar between VEGF-TKI and ICI arms (65% vs 54%). Pts with CB from VEGF-TKIs had lower pretreatment levels of IL-6 (p = 0.02), IL-1RA (p = 0.03), and G-CSF (p = 0.02). Major shifts in plasma cytokines were seen as early as one month; these data will be presented. Conclusions: Distinct plasma cytokines predict benefit with VEGF-TKIs and ICIs. Ongoing work will incorporate analysis of pts receiving VEGF-TKI and ICI combination therapy.
Trends in the use of administrative databases in urologic oncology: 2000 – 2019.
Authors: Leopold Zev , Dave Priya , Menon Adarsh , Patel Hiren V. , Srivastava Arnav , Kim Isaac Yi , Jang Thomas L , Singer Eric A. 
Published: March 2021

356 Background: Administrative databases (AD) provide investigators with nationally representative study populations to answer research questions using large sample sizes. We aimed to quantify the trends and incidence of AD use in published manuscripts in urologic oncology. We examined six commonly used databases: National Cancer Database (NCDB), Surveillance, Epidemiology and End Results Database (SEER), SEER-Medicare (SEER-M), Nationwide Inpatient Sample (NIS), National Surgical Quality Improvement Program (NSQIP), and Premier Healthcare Database (PHD). Methods: A literature review powered by PubMed and DistillerSR from 7/1/2000 to 6/30/2019 aggregated manuscripts that used the aforementioned databases to study a genitourinary malignancy. Included publications were categorized by database used, corresponding author department affiliation, organ, journal, year, and contribution – defined as temporal treatment trends, outcomes and survival, comparative effectiveness research, or cost-effectiveness. Results: There were 2,265 publications across 302 journals that met the inclusion criteria. Between 2000 and 2019 the compound annual growth rate of these publications was 18.7%. SEER contributed most heavily over the study period, with a 14.6% growth rate. NCDB use grew 75.6% annually starting in 2012. Prostate cancer comprised the majority of publications (51.3%), followed by kidney (23.1%) and bladder (22.5%) cancer. Journals publishing these manuscripts had a median impact factor of 3.28 (IQR = 1.84 – 5.74) in 2019. Urologists published 52.5% of AD manuscripts over the study period. Conclusions: Our results show substantial growth in the use of ADs for the study of urologic oncology. Given the broad use of ADs, investigators and specialty societies should advocate for continued improvement in the data captured by them.
Differences in clinical characteristics and outcomes between white (W) and non-white (NW) patients with metastatic germ cell tumor (mGCT) treated at Indiana University (IU).
Authors: Espinoza-Gutarra Manuel Ricardo , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil 
Published: March 2021

376 Background: Patients (pts) with mGCT are curable even when presenting at advanced stages, however its incidence is rising in NW populations. There is lack of data evaluating differences in disease characteristics and outcomes between W and NW pts. Methods: 701 pts with mGCT treated at IU with first-line chemotherapy (FLC) and 462 patients with relapsed mGCT treated with HDCT (high-dose chemotherapy) between 2004 and 2017 at IU were evaluated. Results: Pts treated with FLC had a median follow-up since diagnosis of 4.9 (0.03-19.46) years. 660 (94.1%) W pts and 41 (5.9%) NW (49% Hispanic, 26% Asian, 20% African American and 5% Native American). There were no significant differences in median age at diagnosis, rates of primary tumor site, pathology type (seminoma vs non-seminoma), metastasis sites, mortality, median hCG levels pre-chemotherapy, rates of progression after FLC, or late relapse rates. Higher rates of good risk disease and lower rates of poor risk disease were present among W compared to NW, as well as higher median AFP levels pre-chemotherapy and rates of platinum refractory disease in NW (p<0.05). Patients treated with HDCT had a median follow up time of 2.08 (0.02-14.49) years since diagnosis. 412 (89.1%) were W and 50 (10.1%) were NW (48% Hispanic, 18% Asian, 26% African American, 2% Native American and 6% other). There were no significant differences in rates pathology type, disease risk, tumor markers, platinum refractory disease, completion of 2 cycles of HDCT, progression after HDCT or status at last follow up. W pts were more likely to receive HDCT as initial salvage chemotherapy compared to NW (P<0.05). Conclusions: This single-institution study demonstrates that amongst patients undergoing FLC for mGCT, there were higher rates of poor risk disease and platinum refractory disease amongst NW patients. W patients were more likely to receive HDCT as initial salvage chemotherapy compared to NW patients. However these findings did not reflect a significant difference in disease progression or mortality. [Table: see text]
Longer follow-up data of circulating miR371a-3p expression across the spectrum of germ cell tumors (GCT).
Authors: Nappi Lucia , Thi Marisa , Saxena Neetu , Soleimani Maryam , Eigl Bernhard J. , Chi Kim N. , Gleave Martin , So Alan I. , Black Peter C. , Daneshmand Siamak , Ahmadi Hamed , Hamilton Robert James , Nichols Craig R. , Kollmannsberger Christian K. 
Published: March 2021

379 Background: miR371a-3p (miR371) is overexpressed in seminoma (S) and nonseminoma (NS) active germ cell malignancy (aGCM) and easily detectable in blood. We previously described1 a remarkably high accuracy of miR371 in detecting aGCM in early and advanced stages germ cell tumor (GCT) patients (pts). We here present the updated miR371 expression data with a longer follow-up, particularly relevant to assess miR371 clinical utility to predict GCT relapse in clinical stage I (CSI) and stage IIA pts. Methods:119 samples from 99 pts enrolled in the GU biobank program at the British Columbia Cancer – Vancouver were analyzed. The pts were divided according to their risk of aGCM in low (CSIA NS and CSI S), moderate (CSIB NS, stage IIA markers negative/low elevated S and NS), and high risk (definitively metastatic aGCM) groups. Blood of the low and moderate risk pts was collected post orchiectomy and at the time of the clinical relapse; prior to/post-chemotherapy in the high risk group. Plasma miR371 expression was evaluated by RT-PCR and quantified by ΔΔCT method. Sensitivity, specificity, negative and positive predictive values (NPV, PPV) and AUC of the ROC curve were analyzed. Results: Five (2 moderate - 3 low risks) pts were lost at follow-up and 1 high risk pt had deceased. Overall, 113 samples (50, 36, 27 in the low, moderate, and high risk groups, respectively) were analyzed. The median follow-up from study entry was 30 (6-51), 28 (20-52), and 29 (7-53) months for the low, moderate and high risk, respectively. Seven more relapses occurred: 4 in the low risk (3 S and 1 NS) and 3 in the moderate risk groups (2 NS and 1 S). miR371 was found falsely negative post-orchiectomy in 4 pts and truly negative in 3 relapsed pts (2 pure teratoma and 1 unconfirmed relapse). Serial analysis of the false negative relapsed pts showed that miR371 became detectable at the time of clinical relapse. The operating characteristics of miR371 are summarized in the table below. Conclusions: Our follow-up has exceeded the expected time of relapse even in the low risk pts. The high accuracy of miR371 in detecting aGCM was confirmed with a longer follow up. However, the few false negatives in relapsed pts and the serial analysis suggest a lack of sensitivity in the detection of microscopic disease post-orchiectomy with the current methodology while miR371 high sensitivity was confirmed in presence of radiologic measurable disease (≥ 1 cm). The definitive operating characteristics of miR371 post-orchiectomy and during the follow-up of stages I/ IIA pts will be prospectively validated by the S1823 study that is actively recruiting pts. [Table: see text]
Phase II study of gemcitabine and split-dose cisplatin plus pembrolizumab as neoadjuvant therapy prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC).
Authors: Rose Tracy L , Harrison Michael Roger , Deal Allison Mary , Osterman Chelsea K. , Ramalingam Sundhar , Whang Young E. , Brower Blaine Y , Bjurlin Marc , Smith Angela B. , Nielsen Matthew E. , Tan Hung-Jui , Wallen Eric M. , George Daniel J. , Zhang Tian , Drier Anthony , Kim William Y. , Milowsky Matthew I. 
Published: March 2021

396 Background: Cisplatin-based neoadjuvant chemotherapy is standard of care in MIBC with improved pathologic response and overall survival (OS) compared to RC alone. Pembrolizumab (pembro) is active in high-risk non-muscle invasive and metastatic bladder cancer and is generally well tolerated. This phase II trial evaluated the safety and efficacy of gemcitabine and split-dose cisplatin (GC) + pembro as neoadjuvant therapy prior to RC (NCT02690558). Methods: Patients with clinical T2-4a N0/X M0 urothelial carcinoma of the bladder eligible for RC were enrolled. Patients received pembro 200mg on day 1 with cisplatin 35mg/m2 and gemcitabine 1000mg/m2 on days 1 and 8 every 3 weeks for 4 cycles, followed by RC within 4-8 weeks. The first 6 patients received full-dose cisplatin (70mg/m2 on day 1) and a lead-in pembro dose; this schedule was discontinued for excess toxicity. Primary endpoint was pathologic downstaging rate ( < pT2) with the null and alternative hypothesis rates = 35% and 55%, respectively. Secondary endpoints were toxicity, pT0 rate, event free survival, and OS. Exploratory objectives include association of response with molecular subtype and post-treatment changes in immune microenvironment (predicted neoantigens, immune gene expression, and T cell receptor repertoire). Results: Between May 2016 and July 2020, 39 patients were enrolled (72% cT2, 23% cT3, 5% cT4a) with a median age of 66 and 82% male. Patients received a median of 4 cycles of therapy. All patients underwent RC except one who declined but is included in intention to treat analysis. Rate of < pT2N0 was 56% (22/39) and pT0N0 rate was 36% (14/39). Most common adverse events (AEs) of any grade were thrombocytopenia (29/39; 74%), anemia (27/39; 69%), neutropenia (26/39; 67%), and hypomagnesemia (26/39; 67%). Most common grade 3/4 AEs were neutropenia (16/39; 41%), thrombocytopenia (13/39; 33%), febrile neutropenia (5/39; 13%), and anemia (4/39; 10%). One patient had new onset type 1 diabetes mellitus with ketoacidosis related to pembrolizumab and no patients required steroids for immune-related AEs. Nine patients (23%) discontinued GC + pembro due to AEs, including 4 of the 6 patients who received full-dose cisplatin with pembro lead-in. Survival data are not yet mature and correlative studies are ongoing. Conclusions: Neoadjuvant GC + pembro was generally safe and met its primary endpoint for improved pathologic downstaging. Correlative analyses are ongoing. Additional investigation of this combination is warranted. Clinical trial information: NCT02690558.