bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of cabozantinib plus nivolumab (CaboNivo) and ipilimumab (CaboNivoIpi) in patients (pts) with refractory metastatic urothelial carcinoma (mUC) and other genitourinary (GU) tumors.
Authors: Apolo Andrea B. , Mortazavi Amir , Stein Mark N. , Pal Sumanta K. , Davarpanah Nicole N. , Parnes Howard L. , Ning Yangmin M. , Francis Deneise C , Cordes Lisa M , Monk Paul , Lancaster Tiffany , Costello Rene , Nanda Swati , Bottaro Donald P. , Wright John Joseph , Streicher Howard , Steinberg Seth M. , Berninger Marilise , Lindenberg Liza , Dahut William L. 
Published: March 2017

293 Background: We report the safety and clinical activity of CaboNivo and CaboNivoIpi in pts with mUC and other GU tumors. Methods: Part I included 4 dose levels (DLs) (Cabo PO daily and Nivo IV q2wk): DL1 Cabo40/Nivo1, DL2 Cabo40/Nivo3, DL3 Cabo60/Nivo1, DL4 Cabo 60/Nivo3. Part II included 3 DLs (Cabo PO daily, plus NivoIpi IV q3 wk x 4 doses then Nivo q2wk): DL5 Cabo 40/Nivo1/Ipi1, DL6 Cabo40/Nivo3/Ipi1, DL7 Cabo 60/Nivo3/Ipi 1. Tumors were assessed for overall response rate (ORR) by RECIST 1.1. Adverse events (AEs) were graded (G) by NCI-CTCAE v4.0. Results: From 7/22/15-10/14/16, 40pts [mUC N=14/(plasmacytoid N=1); bladder urachal N=4; bladder squamous cell carcinoma (bSCC) N=2; germ cell tumor (GCT) N=4; castrate-resistant prostate cancer (CRPC) N=9/(neuroendocrine prostate N=1); sarcomatoid renal cell carcinoma (sRCC) N=1; trophoblastic tumor N=1); sertoli cell tumor N=1; and penile SCC N=4] were treated. Median age was 58 (range 31-77); 36 (90%) were male. AEs related to study drugs with [1] CaboNivo included G3 hyponatremia 4/24 (17%), hypophosphatemia 4/24 (17%), lipase increase 3/24 (13%), dehydration 2/24 (8%), diarrhea 2/24 (8%), fatigue 2/24 (8%), HTN 2/24 (8%), thromboembolic event 1/24 (4%), rash 1/24 (4%), chest pain 1/24 (4%), amylase increase 1/24 (4%), hyperthyroid 1/24 (4%), proteinuria 1/24 (4%), thrombocytopenia 1/24 (4%); and G4 pyelonephritis 1/24 (4%); [2] CaboNivoIpi included G3 hypophosphatemia 2/16 (13%), lipase increase 2/16 (13%), fatigue 1/16 (6%), ALT increase 1/16 (6%), and HTN 1/16 (6%). There were 2/40 (5%) G3 immune-related AEs: 1 aseptic meningitis/CaboNivo; and 1 colitis/CaboNivoIpi. There were no G5 toxicities, or DLTs. 38 pts were evaluable for response. ORR was 12/38 (32%): 1 CR (bSCC); 11 PRs (5 mUC, 1 sRCC, 1 urachal, 1 bSCC, 1 CRPC, 2 penile). SD 20/38 (53%); 9/11 responses were ongoing and 26/39 (67%) pts remain on study. Conclusions: CaboNivo and CaboNivoIpi were well tolerated with no DLTs. Responses were seen at all DLs. The recommended dose for Part I is Cabo40/Nivo3 and for Part II is Cabo40/Nivo3/Ipi1. Rare tumors such as bSCC, urachal, and penile cancer demonstrated responses. Clinical trial information: NCT02496208.
Resection margins after radical cystectomy at academic versus community cancer centers.
Authors: Scarberry Kyle , Scarberry Kelly , Agrawal Shree , Kim Simon P. 
Published: March 2017

315 Background: Positive surgical margins are reported in 1-5% of specimens following radical cystectomy (RC) for urothelial carcinoma of the bladder (UC). Negative margin (R0) resection correlates with improved overall survival (OS) following RC in individual institutional analyses compared to microscopic (R1) or grossly (R2) positive margins. The present study hypothesized that RC surgical resection margins vary between treating centers. Methods: Patients with UC undergoing RC were identified from the National Cancer Database (2004-2013). Treating centers were categorized as Academic Cancer Centers (ACC) and Community Cancer Centers (CCC). Rates of R0 vs. R1/2 resection were examined and logistic regression was performed to determine predictive factors for margin status. Results: A total of 40,187 patients were identified with a median age of presentation of 68 years. RC was performed equally at ACC (52%) compared to CCC (48%). Neoadjuvant chemotherapy was utilized more often at ACC (21%) compared to CCC (14%). RC at ACC was associated with higher rates of R0 resections (90%) compared to CCC (88%) (p < 0.001). On logistic regression, after adjusting for age, sex, ethnicity, comorbidities, disease stage, tumor grade, tumor size, and use of neoadjuvant chemotherapy, RC at ACC were associated with decreased risk of experiencing positive margins (OR = 0.79, 95% CI 0.74-0.85). Following multivariate regression, RC performed at ACC were associated with a significant hazard ratio (HR) for survival (HR = 0.88, 95% CI 0.85-0.91). Compared to all variables, R1/2 resection status was the next most significant predictor for poor survival in RC patients (HR = 1.83, 95% CI 1.75-1.91) after cancer stage. Conclusions: Surgical margin is an important, independent risk factor for mortality in patients undergoing RC for UC. RC at ACCs is associated with a higher rate of negative resection margins, suggesting that site of care may impact bladder cancer patient’s oncologic outcomes.
A chemically-modified miR-21 inhibitor (ADM-21) as a novel potential therapy in bladder cancer.
Authors: Drakaki Alexandra , Koutsioumpa Marina , O'Brien Neil A. , Vorvis Christina , Iliopoulos Dimitrios , Slamon Dennis J. 
Published: March 2017

335 Background: MicroRNAs are key regulators of cancer signaling pathways.Targeting their expression has therapeutic potential. MicroRNA-21 (miR-21) acts as an oncogene in several cancers. Here we describe its functional significance in bladder oncogenesis and the therapeutic properties of a novel chemically-modified miR-21 inhibitor (ADM-21). Methods: MiR-21 expression was assessed by RT-PCR in a panel of human bladder cancer tissues and cell lines. Transcriptomic profiling of 28 bladder cancer cell lines performed to identify miR-21-dependent gene signatures. ADM-21 is a chemically-modified (phosphorothioate backbone and locked-nuclei-acid) antisense oligo against miR-21 with high potency and stability.The efficacy of ADM-21 treatment was evaluated in vitro and in vivo. Results: MiR-21 was up-regulated by 5-fold in bladder tumors relatively to normal tissue and by 3-fold in advanced compared to early stage bladder cancers. The 28 cancer cell lines were stratified in 3 groups (high, intermediate, low) according to miR-21 levels. Transcriptomic analysis revealed a 15-gene signature that negatively correlated with miR-21 levels. Protein Phosphatase 2 Regulatory Subunit B Isoform A (PPP2R2A) displayed tumor suppressive properties in bladder cancer. Moreover, PPP2R2A represents a novel miR-21 direct target gene and a negative regulator of the AKT/mTOR pathway. ADM-21 (10uM) treatment suppressed 43.5% the growth and 90% the invasiveness of 5367 bladder cancer cells. Also, intravenous (I.V.) administration of ADM-21 was proven more effective than intraperitoneal (I.P.) administration in mouse xenografts. Specifically, 15mg/kg of ADM-21 (I.V.) every 5 days for 3 cycles reduced 37% and 47% (day 16) the growth rate of tumors originating from injections of 5367 and RT-112 cells, respectively. Conclusions: Integrative analysis of human bladder tumors and cell lines revealed a novel 15-gene signature that correlates with miR-21 levels. PPP2R2A is a miR-21 direct target and regulator of the AKT/mTOR pathway. ADM-21effectively reduces bladder cancer growth in vitro and in vivo. Upon completion of ADM-21 toxicology studies and confirm safety we will design phase I clinical trial for advanced bladder cancer.
Prognostic value of DLL3 expression and clinicopathologic features in small cell bladder cancer (SCBC).
Authors: Koshkin Vadim S. , Elson Paul , Magi-Galluzzi Cristina , McKenney Jesse , Smith Karen Streator , Shadrach Bonnie , Emamekhoo Hamid , Isse Kumiko , Saunders Laura , Kavalerchik Edward , Dylla Scott , Bheddah Sheila , Theiss Noah , Watson Sky , Stephenson Andrew J. , Fergany Amr Farouk , Rini Brian I. , Garcia Jorge A. , Grivas Petros 
Published: March 2017

382 Background: SCBC is rare with limited data on treatment and outcomes. DLL3, a Notch pathway protein, is expressed in small cell lung cancer (SCLC) and neuroendocrine tumors. Phase I/II trials of the anti-DLL3 antibody-drug conjugate, rovalpituzumab tesirine, are ongoing in SCLC and other solid tumors. DLL3 expression in SCBC and its prognostic implications are unknown. Methods: A retrospective review of clinicopathologic features of 63 patients (pts) with biopsy-confirmed SCBC at Cleveland Clinic (1993-2016) was conducted. Percentage (%) of small cell component (SC%) was defined by independent pathology review in all pts. The % of tumor cells expressing DLL3 (DLL3%) was assessed in 53 pts. Multivariable analyses (MVA) were used to identify predictors of overall survival (OS), progression-free survival (PFS) and time to progression (TTP) (p ≤ .05). Results: Median age was 71 (39-90), 83% were men, 77% current/former smokers, 41 (65%) had cystectomy and 22 (35%) only TURBT. Estimated median OS, PFS and TTP were 22.8, 13.7 and 21.1 months from diagnosis. Median SC% was 100% (5-100%) and 79% of tumors were ≥ 50% SC. DLL3 expression of any level was noted in 68% (36/53) of tumors; 58% of tumors had DLL3 expression in > 10% of cells. SC% correlated with DLL3% (r = 0.33, p = .01). In MVA, increased DLL3% was associated with shorter OS and PFS, while increased SC% was associated with shorter PFS and TTP. Higher pT at cystectomy was associated with shorter OS (Table). Conclusions: Higher DLL3 expression and SC% are associated with worse outcomes in SCBC. Most SCBC tumors express DLL3, a therapeutic target tested in clinical trials. Genomic, epigenetic, transcriptomic and PDL1 evaluation in SCBC are also being pursued to define molecular context. DLL3 expression and other prognostic factors. [Table: see text]
Phase II trial of TI-CE high dose chemotherapy (HDCT) with drug monitoring for individual carboplatin dosing in patients with relapsed advanced germ cell tumors: A multicentric prospective GETUG trial.
Authors: Chevreau Christine , Massard Christophe , Flechon Aude , Delva Remy , Gravis Gwenaelle , Lotz Jean-Pierre , Bay Jacques-Olivier , Gross-Goupil Marine , Fizazi Karim , Mourey Loic , Thomas Fabienne , Filleron Thomas , Olivier Pascale , Culine Stephane , Chatelut Etienne 
Published: March 2017

401 Background: HDCT is a valid option of treatment for relapsed advanced GCTs pts. The results of the TICE regimen as salvage therapy in poor risk pts demonstrated a 50% complete response (CR) but with very high variability of measured carboplatin area under the curve (AUC) (between 10.9-36.7 for target AUC = 24 mg.min/mL). We initiated a phase II trial of TICE with therapeutic drug monitoring (TDM) for individual carboplatin dosing in order to target the 3-day AUC to 24 mg/min/mL. Methods: Were included pts with unfavorable relapsed GCTs , secondarily classified according to the International Prognostic Factors Study Group. Pts were treated according the TICE regimen with two cycles combining paclitaxel and ifosfamide followed by three cycles HDCT: carboplatin plus etoposide with stem cell support. Carboplatin dose was adapted on day 3 based on carboplatin clearance (Cl) at day 1, in order to reach the target AUC. The primary endpoint was the CR rate (cCR sCR pCR). A Simon Minimax design was performed using the following hypothesis: p0 = 50%, p1 = 65 α = 5%, β = 10%. Results: Between 03/2009 and 11/2015 101 pts were accrued, 60 pts were treated in first relapse (34 classified as high and very high-risk) and 41 in 2ndor more relapse. 72 pts (71%) received the whole treatment, 12 pts (10%) did not receive any cycle of HDCT. 29pts (26%) stopped treatment earlier, 8 for toxicity. Three pts died on treatment. 35/79 (44.3%) evaluable pts achieved a CR. 19 pts (24%) presented a PRm-. The mean observed carboplatin AUC was 24.5 mg.min/mL (between 18.9 and 28.8) at C1.Following TDM, the modification of the total carboplatin dose during C1 was comprised between -33% and +44%, showing the benefit of TDM in comparison with individual dosing based only on carboplatin Cl predicted according to patient’s renal characteristics. Conclusions: The CR rate observed in this very poor prognosis population was 44.3% and 69.6% CR + PRm-. Carboplatin dose individualization based on TDM allowed to reach more accurately the target AUC compared to previous reports. Clinical trial information: NCT00864318.
Addressing metabolic heterogeneity in clear cell renal cell carcinoma with quantitative magnetic resonance imaging.
Authors: Pedrosa Ivan , Zhang Yue , Udayakumar Durga , Cai Ling , Hu Zeping , Kapur Payal , Diaz de Leon Alberto , Yuan Qing , Yokoo Takeshi , Ye Jin , Mitsche Mathew , Kim Hyeonwoo , McDonald Jeffrey , Xi Yin , Madhuranthakam Ananth J , Lenkinski Robert , Cadeddu Jeffrey A , Brugarolas James , DeBerardinis Ralph 
Published: March 2017

460 Background: Dysregulated lipid and glucose metabolism has been implicated in clear cell renal cell carcinoma (ccRCC) progression. Pre-operative tissue-based assessment of tumor metabolic alterations is challenging due to the characteristic heterogeneity of ccRCC. Non-invasive prediction of metabolic alterations in the whole tumor with an imaging method would be appealing for optimal patient management and possibly selection of targeted neoadjuvant therapy. Methods: In this IRB-approved, HIPAA-compliant study, 43 patients (34 M, 9 F) with pathologically confirmed primary ccRCC underwent pre-surgical MRI to quantify whole-tumor intra-tumoral lipid accumulation (% fat fraction, FF) and tumor enhancement (% enhancement) with Dixon-based MRI and dynamic contrast-enhanced MRI, respectively. All patients signed informed consent. Quantitative MRI measures were also obtained from targeted regions of interest within tumors and correlated to lipid accumulation (Oil Red O, ORO) and mass spectrometry-based lipidomics and metabolomics of tissue samples isolated from anatomically co-registered locations in the same tumor using fiducial markers placed at the time of surgery. Linear regression was performed to correlate FF and ORO %. Univariate statistical differences of the metabolites between two groups were analyzed using Student’s t-test. Results: In vivo tumor FF correlated positively with histologic fat content (Spearman correlation coeff. ρ = 0.86, p <0.0001), spectrometric triglycerides (ρ = 0.56, p = 0.0007) and cholesterol (ρ = 0.47, p = 0.006), respectively; and negatively with spectrometric free fatty acids (ρ = -0.44, p = 0.01) and phospholipids (ρ = -0.65, p = 0.001), respectively. ISUP grade 2 and 3 tumors exhibited marked intra-tumoral FF heterogeneity, whereas grade 4 tumors had reduced lipid accumulation compared to grade 3 (p = 0.016). Aqueous metabolites were different in tumors compared to renal parenchyma and 11 metabolites showed significant correlation with tumor vascularity (FDR p <0.05). Conclusions: MRI-derived FF and tumor enhancement correlated with the altered metabolic features of ccRCC and the metabolic heterogeneity within a given tumor.
Health-related quality of life (HRQoL), treatment satisfaction, and work productivity for patients (Pts) with advanced renal cell carcinoma (aRCC) in a chart review across six countries.
Authors: Hawkins Robert , Doan Justin , Deshpande Chinmay , Solem Caitlyn , Yang Shuo , Jiang Shan , Macahilig Cynthia 
Published: March 2017

487 Background: The humanistic burden of aRCC is not well understood. We describe HRQoL, functional status, treatment satisfaction, and work productivity reported by pts treated with ≥2 lines of treatment (LOT) for aRCC in 6 countries. Methods: Retrospective, observational medical chart review of adults with stage IIIB/IV aRCC who completed the EuroQoL-5D-3L (EQ-5D), Functional Assessment of Cancer Therapy – General (FACT-G)/FACT-Kidney Symptom Index (FKSI-19), Cancer Therapy Satisfaction Questionnaire (CTSQ), and Work Productivity and Activity Impairment (WPAI) questionnaires. FACT-G scores were examined with regression analysis. Results: All measures were impacted by aRCC (Table). Dimensions affected: EQ-5D, pain/discomfort; FACT-G and FKSI-19, functional/emotional; CTSQ, feelings about side effects; WPAI, activity impairment. EQ-5D, FACT-G, FKSI-19 scores were higher (by minimal important difference) in France and Canada vs. other countries. FACT-G scores differed by region, and were higher in Canada and France vs. the USA. Female sex and 2nd LOT were predictors of lower FACT-G score. Conclusions: This study showed a high humanistic burden on aRCC pts across countries. New treatments with reduced side effects and improved effectiveness can help yield improvements in HRQoL, treatment satisfaction, and work productivity. [Table: see text]
Performance of a validated urine exosome gene expression assay to predict high-grade prostate cancer utilizing the International Society of Urological Pathology (ISUP) 2014 grading system.
Authors: Donovan Michael , Torkler Phillipp , Skog Johan , Noerholm Mikkel , Carroll Peter 
Published: March 2017

49 Background: Overdetection and overtreatment of indolent prostate cancer (PCa) remains a significant health issue requiring noninvasive assays to guide the prostate biopsy decision process. We demonstrated that a urine exosome gene expression assay (ExoDx P rostate ( I ntelliScore) (EPI) discriminates GS 7 PCa from GS 6 and benign disease, potentially reducing the number of unnecessary biopsies. The International Society of Urological Pathology (ISUP) proposed a prognostic PCa grading system to accurately reflect the biology of PCa; ISUP separates GS 7 PCa into group 2 (GS 3+4) and group 3 (GS 4+3). We sought to evaluate the performance of the EPI test according to the newly proposed ISUP system. Methods: The 519 patient validation cohort was re-annotated using ISUP and assessed benign (B) +/- ISUP 1 and B+ISUP 1+2 (GS 3+3, GS 3+4) from ISUP 3-5 (GS >= 4+3). We used validated / adjusted cut-points to assess performance with the AUC, sensitivity, specificity and NPV. In addition, we investigated the association of the EPI score with the benign biopsies (BB) and ISUP groups in the combined training and test cohort (n=774). Results: Applying the adjusted cut point (EPI 20) on the 519 ISUP cohort discriminated benign biopsies (BB) + ISUP 1 from >/=ISUP 2, 37% of biopsies avoided, NPV of 90%, equivalent to Gleason grading. Utilizing either the validated (15.6) or adjusted cut points on BB+ISUP 1+ 2 vs. >/=ISUP 3 (dominant pattern 4), 26% vs 37% biopsies avoided, with an improved NPV 98%. In the combined training / test cohort, higher EPI scores were significantly associated with ISUP categories. In this analysis EPI in BB vs. all ISUP groups (p<0.0001); BB+ISUP 1 vs. >/= ISUP2 (p<0.0001) and BB+ISUP 1+2 vs. >/=ISUP3 (p<0.0001); supporting accurate discrimination in high grade PCa. Conclusions: The EPI test is a noninvasive, first-catch non-DRE gene expression assay that accurately discriminates low-grade from high-grade PCa in both ISUP as well as Gleason score based grading systems. The test has the potential to reduce the number of unnecessary biopsies and performs equally well in contemporary approaches to PCa stratification.
Pembrolizumab (pembro) plus low-dose ipilimumab (ipi) for patients (pts) with advanced renal cell carcinoma (RCC): Phase 1 KEYNOTE-029 study.
Authors: Choueiri Toni K. , Hodi F. Stephen , Thompson John A. , McDermott David F. , Hwu Wen-Jen , Lawrence Donald P. , Dawson Nancy Ann , Wong Deborah Jean Lee , Bhatia Shailender , James Marihella , Shu Xinxin , Homet Moreno Blanca , Ibrahim Nageatte , Perini Rodolfo F. , Ribas Antoni , Atkins Michael B. 
Published: March 2017

510 Background: The CTLA-4 antibody ipi and the PD-1 antibody pembro have demonstrated efficacy in pts with advanced malignancies. While these immune checkpoint inhibitors have shown robust activity as monotherapy, combination therapy may further improve outcomes. KEYNOTE-029 (NCT02089685) is a phase 1/2 study designed to assess the safety and efficacy of pembro + ipi or pegylated interferon alfa-2b (IFN-α) in pts with advanced melanoma or RCC. Here we report data from the phase 1 portion of the study in pts with RCC treated with pembro + ipi. Methods: Pts ≥18 years with advanced/unresectable or metastatic clear cell RCC who received ≥1 prior therapy for metastatic disease, had ≥1 measurable lesion per RECIST v1.1, and ECOG PS 0-1 were enrolled. Pts received pembro 2 mg/kg Q3W + low-dose ipi (1 mg/kg Q3W for 4 doses) until disease progression, unacceptable toxicity, investigator/patient decision, or 2 years of pembro treatment. AEs were monitored throughout treatment and for 30 days thereafter and graded per NCI CTCAE v4.0. Primary end point was safety; primary efficacy end point was ORR assessed per RECIST v1.1 by independent central imaging vendor review. Results: As of the March 17, 2016, data cutoff, 10 pts with RCC received pembro + low-dose ipi. 60% were male, 70% were white, median age was 61 years (range, 48-70 years), 40% received 2 prior lines of therapy, and 40% received prior immunotherapy. With a median follow-up of 17.4 months (0.9-23.5 months), 70% of pts experienced treatment-related AEs (TRAEs) of any grade, most commonly fatigue (30%); and 50% experienced grade 3/4 TRAEs, most commonly increased lipase (20%). 50% of pts discontinued pembro because of TRAEs, most commonly increased lipase (40%). There were no treatment-related deaths. ORR was 20% (2 partial responses); median duration of response was not reached (14.1+-17.1 months+). An additional 3 pts had stable disease; disease control rate was 50%. Conclusions: The combination of pembro + low-dose ipi for 4 doses, followed by pembro monotherapy, demonstrates a manageable toxicity profile and preliminary antitumor activity in pts with advanced RCC. Clinical trial information: NCT02089685.