bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bladder Cancer Multidisciplinary Clinic (BCMC) model: Impact on imaging, pathology and treatment recommendations.
Authors: Winters Brian , Diamantopoulos Leonidas Nikolaos , Tretiakova Maria S. , True Lawrence D. , Lee Jean H , Zeng Jing , Liao Jay Justin , Cheng Heather H. , Schweizer Michael Thomas , Hsieh Andrew Caleb , Yu Evan Y. , Schade George R , Gore John L. , Lin Daniel W. , Dighe Manjiri , Vakar-Lopez Funda , Russell Kenneth J. , Grivas Petros , Montgomery Robert B. , Wright Jonathan L. 
Published: May 2019

4537 Background: Despite guideline-based standard of care recommendations in BC and upper tract urothelial carcinoma (UTUC), treatment remains variable across US. Experts recommend focusing BC care in tertiary centers. We hypothesized that a BCMC model, with expert central pathology and radiology review, may result in changes in corresponding reports, and, thus, treatment recommendations. Methods: Our BCMC clinic format includes simultaneous consultation with Urologic, Medical and Radiation Oncology, with real time expert genitourinary pathology and radiology review. We retrospectively assessed the concordance between outside (pre-BCMC) imaging & pathology review and BCMC review. Differences between pre- and post- BCMC recommendations on management were also assessed; descriptive statistics were used. Results: We identified 233 BC/UTUC patients (pts) referred to BCMC. Complete radiographic and pathologic data were available for 209 pts. Median age at time of evaluation was 68 (27-93) and 85% were PS ECOG 0-1. After BCMC review of outside records, 112 (53.6%) imaging and/or pathology changes were noted, with 57 (27%) pts upstaged. Overall, imaging interpretation was changed in 25% of cases, and 20% of pts were upstaged. BCMC pathology review resulted in changes in 59 (28%) pts. Among those, 42 (71%) had histologic subtype addition or change, 9 (15%) had LVI/CIS status change, and 2 (3.4%) had low to high grade conversion. In terms of pathology staging, 7 (12%) were downstaged, and 5 (8.5%) upstaged. Further diagnostic work-up was recommended in 71/209 (34%) pts, resulting in upstaging in 11/71 (15.5%) of cases. Pre- and post- BCMC-recommended treatment modality differed in 55/209 (26%) pts, while a new treatment modality was added in 28/209 (13%) pts. These recommendations were followed 91.4% of the time (191/209 pts). Conclusions: BCMC initiation at our institution resulted in imaging and/or pathology diagnostic changes in almost half of cases, with approximately a quarter of pts being upstaged. Findings reveal the importance of expert radiology and pathology review in BC. Further study is needed to confirm the proposed benefits and impact of BCMC on treatment response and outcomes.
Towards the noninvasive identification of pathologic responders to neoadjuvant pembrolizumab in muscle-invasive urothelial bladder cancer (MIBC).
Authors: Calareso Giuseppina , Bandini Marco , Raggi Daniele , Farè Elena , Gallina Andrea , Colombo Renzo , Colecchia Maurizio , Luciano Luciano Roberta , Salonia Andrea , Pederzoli Filippo , Ross Jeffrey S. , Madison Russell , Ali Siraj Mahamed , Chung Jon , Montorsi Francesco , Briganti Alberto , Messina Antonella , Necchi Andrea 
Published: May 2019

4540 Background: The possibility to predict the pathologic complete response (pT0) or pT≤1 after neoadjuvant immunotherapy may deeply impact the management of MIBC and orient clinical trials. The PURE01 study ( Necchi, JCO 2018) evaluated preoperative pembrolizumab before radical cystectomy (RC) in T2-3bN0MO patients (pts). The trial was amended to increase the sample size. Methods: Pts were assessed with bladder multiparametric magnetic resonance imaging (mpMRI: T2-weighted imaging, diffusion-weighted imaging, dynamic contrast enhancement [CE]) before and after treatment (3 cycles every 3 weeks) prior to RC. All mpMRI were made with bladder catheterization. We tested the following complete response (CR) definition: any measurable residual disease (T2W, morphology), but no residual restricted diffusion and no early CE signals. Exams were independently assessed by 2 senior radiologists and tested against the pT0/pT≤1 endpoints. Logistic regression models analyzed mpMRI and biomarker data on comprehensive genomic profiling (CGP) with FoundationONE CDx assay and PD-L1 combined positive score (CPS). Results: From 02/17 to 11/18, 84 pts were assessed before and after treatment (168 total mpMRI) and had the pathological response available from RC. Baseline CR (TURB effect) was observed in 14 (16.7%) pts. The mean overall percentage of agreement (OPA) across the mpMRI data was 98.2%. The sensitivity of post-therapy (PT) CR for pT0 response was 0.80 (95%CI: 0.61-0.92); the specificity for pT≤1 response was 0.94 (95%CI: 0.80-0.99). PT-CR was associated with both pT0/pT≤1 endpoints (p < 0.001) after adjusting for clinical T-stage and histology. Baseline CPS≥10 and TMB≥20 mut/Mb were strongly associated with pT0 response (OR: 4.46 and 14.9). mpMRI CR post-pembrolizumab significantly improved the c-index of the CPS/TMB models: up to 0.81 and 0.87 for pT0/pT≤1 endpoints. Conclusions: In post-pembrolizumab MIBC, the proposed definition of radiological CR through mpMRI is endowed with limited inter-observer variability and high accuracy in predicting pT≤1. CPS/TMB-selected pts who achieve CR with mpMRI can be reliably spared any surgical treatment. Clinical trial information: NCT02736266.
Treatment sequencing of anti-PD-1/PD-L1 and carboplatin (carbo)-based chemotherapy (chemo) in cisplatin-ineligible patients (pts) with metastatic urothelial cancer (mUC).
Authors: Wei Xiao X. , Werner Lillian , Teo Min Yuen , Rosenberg Jonathan E. , Koshkin Vadim S , Grivas Petros , Szabados Bernadett , Morrison Laura , Carril Lucia , Castellano Daniel E. , Velho Pedro Isaacsson , Hahn Noah M. , McKay Rana R. , Raggi Daniele , Necchi Andrea , Kanesvaran Ravindran , Alerasool Parissa , Gaines Jacob , Bellmunt Joaquim , Sonpavde Guru 
Published: May 2019

4541 Background: Anti-PD-1/PD-L1 agents and carbo-based chemo are therapy options in 1st-line (1L) setting for cisplatin-ineligible pts with mUC. However, optimal sequencing is unclear. Methods: We conducted a multicenter retrospective analysis of cisplatin-ineligible pts with mUC treated with 1L PD-1/PD-L1 monotherapy followed by carbo-based chemo (IO→Cb) or the reverse order (Cb→IO) without intervening systemic therapy. Perioperative cisplatin-based chemo was allowed if completed > 1 year from 1L mUC therapy initiation. To assess association between overall survival (OS) and therapy sequence, a multivariate analysis (MVA) was performed from initiation of 2L therapy, adjusted for treatment sequence, time interval between initiation of 1L and 2L therapies, Hb ( < 10 vs ≥10 g/dl), ECOG PS (0-1 vs 2-3), and metastatic site (LN/soft tissue only vs non-liver vs liver). Results: 146 pts (IO→Cb n = 43, Cb→IO n = 103) were evaluable with median age 72, 76% men, 78% ECOG PS 0-1, 17.8% with liver metastasis. Baseline factors were balanced except for higher proportion of men in IO→Cb group (91% vs 70%, p = 0.01). Median time interval between initiation of 1L and 2L therapy for IO→Cb and Cb→IO were 15.6mo (4.8-78.1) and 23.0mo (2.1-103.3), respectively. Response rates are summarized (Table). On MVA, treatment sequence was not associated with OS (HR 1.05, p = 0.85). Site of metastasis was the only factor significantly associated with OS (p = 0.002). Conclusions: In our retrospective analysis of cisplatin-ineligible pts with mUC regardless of PD-L1 expression, anti-PD-1/PD-L1 followed by carbo-based chemo or the reverse sequence appeared to confer comparable OS. The observed response rates and time interval between initiation of 1L and 2L therapy are likely contributed by pt selection, where all pts received 2L. Further investigation of the ‘PD-L1 high’ population is warranted, given higher response rates with anti-PD-1/PD-L1 vs ‘PD-L1 low’ population. Ongoing phase III trials will help inform optimal sequencing. [Table: see text]
Clinical and economic outcomes associated with sequential treatment in patients with advanced renal cell carcinoma (aRCC).
Authors: Regan Meredith M. , McDermott David F. , Atkins Michael B. , Ambavane Apoorva , Yang Shuo , Rao Sumati , Michaelson M Dror 
Published: May 2019

4566 Background: Immuno-oncology therapies (IOs) and tyrosine kinase inhibitors (TKIs) are recommended for the treatment of aRCC. As new drugs and combination regimens emerge, there is interest in gaining a deeper understanding of optimal treatment sequencing. We aimed to assess clinical and economic outcomes associated with treatment sequences for untreated aRCC patients with IMDC intermediate/poor risk. Methods: A discrete event simulation model was developed to estimate the total costs and survival (in life-years; LYs) over patients’ lifetimes when receiving sequential treatment with nivolumab + ipilimumab (N+I), sunitinib (SUN), pazopanib (PAZ), or cabozantinib (CAB) as first-line (1L) treatment, and nivolumab (NIVO), axitinib (AXI), PAZ, CAB, or lenvatinib + everolimus (LEN+EVE) as second line (2L). Efficacy inputs were derived from the CheckMate 214 trial and a network meta-analysis based on available literature. Safety and cost data were obtained from literature and publicly available sources. Results: N+I initiating sequences were estimated to provide longer survival in mean LYs and lower mean costs/LY versus sequences with 1L TKIs (table). The estimates of incremental cost-effectiveness ratio (ICER) for N+I initiating sequences with 2L TKI monotherapy were well below the willingness-to-pay threshold of $50,000. Using 2L LEN+EVE, compared with 2L monotherapies, provided an incremental survival gain but at costs/LY close to $100,000. Conclusions: Use of 1L N+I followed by TKI monotherapy is estimated to provide longer survival while being more cost-effective versus TKIs followed by IOs or sequences cycling TKIs, mainly driven by a longer time to 2L treatment and longer treatment-free survival with N+I. Clinical trials with head-to-head comparisons of treatment sequences would be necessary to validate the findings of the study. [Table: see text]
Association of human endogenous retrovirus (hERV) expression with clinical efficacy of PD-1 blockade in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Pignon Jean-Christophe , Jegede Opeyemi , Shukla Sachet A , Braun David A. , Horak Christine , Wind-Rotolo Megan , Ishii Yuko , Catalano Paul J. , Freeman Gordon J. , Jennings Rebecca B , De Cubas Aguirre , Rathmell Kimryn , Choueiri Toni K. , Atkins Michael B. , McDermott David F. , Signoretti Sabina 
Published: May 2019

4568 Background: hERV levels positively correlate with tumor immune infiltrate and were recently shown to be associated with clinical benefit to PD-1/PD-L1 blockade in two small cohorts of patients (pts) with mccRCC (Smith C.C. et al and Panda A. et al; 2018). We tested whether hERV levels correlate with efficacy of nivolumab in a prospective phase II study of pts with mccRCC (Checkmate 010). Methods: Reverse transcribed RNA extracted from 99 FFPE pretreatment tumors were analyzed by RT-qPCR to assess levels of pan- ERVE4, pan- ERV3.2, hERV4700 GAG or ENV, and the reference genes 18S and HPRT1. Normalized hERV levels were transformed as categorical value (high or low) using population quartiles as cutoffs. For each cutoff, samples with non-quantifiable hERV levels for which the limit of quantification was above the tested cutoff could not be categorized and were excluded from analysis. Log rank test was used to test the association of hERV levels with PFS/irPFS (RECISTv1.1/irRECIST) at each cutoff using Holm-Bonferroni correction for Type I error control; adjusted P-values are reported. Fisher’s exact test was then used to explore the association with ORR/irORR (RECISTv1.1/irRECIST). Results: Among the hERV studied, only hERV4700 ENV was significantly associated with PFS/irPFS. At the 25th percentile cutoff, 45 pts had high levels of hERV4700 ENV and 24 pts had low levels of hERV4700 ENV. Median PFS and irPFS were significantly longer in the high- hERV4700 ENV group [7.0 (95% CI: 2.2 - 10.2) and 8.5 (95% CI: 4.2 - 14.1) months, respectively] versus the low- hERV4700 ENV group [2.6 (95% CI: 1.4 - 5.4) and 2.9 (95% CI: 1.4 - 5.7) months, respectively] ( P = 0.010 for PFS and P = 0.028 for irPFS). At the same cutoff, ORR and irORR rates were significantly higher in the high- hERV4700 ENV group [35.6 (95% CI: 21.9 - 51.2) % for both ORR/irORR] versus the low- hERV4700 ENV group [12.5 (95% CI: 2.7 - 32.4) and 8.3 (95% CI: 1.0 - 27.0) %, respectively] ( P = 0.036 for ORR and P = 0.012 for irORR). Conclusions: hERV4700 ENV levels may predict outcome on nivolumab in mccRCC. Validation of our results and correlation of hERV levels with immune markers in a controlled phase III trial (CheckMate 025) is ongoing.
First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): Updated results for KEYNOTE-427 cohort A.
Authors: Tykodi Scott S. , Donskov Frede , Lee Jae-Lyun , Szczylik Cezary , Malik Jahangeer , Alekseev Boris Yakovlevich , Larkin James M.G. , Matveev Vsevolod Borisovich , Gafanov Rustem , Tomczak Piotr , Geertsen Poul F. , Wiechno Pawel J. , Shin Sang Joon , Pouliot Frederic , Alonso-Gordoa Teresa , Silverman Rachel Kloss , Perini Rodolfo F. , Schloss Charles , McDermott David F. , Atkins Michael B. 
Published: May 2019

4570 Background: KEYNOTE-427 (NCT02853344) is an open-label, single-arm, phase 2 study to evaluate efficacy and safety of first-line single-agent pembro, a programmed death 1 (PD-1) inhibitor, in patients (pts) with ccRCC (cohort A) and non–clear cell RCC (cohort B). Updated follow up from cohort A are presented. Methods: Pts with histologically confirmed ccRCC, measurable per RECIST v1.1, and no prior systemic therapy were eligible. Pts received pembro 200 mg IV Q3W for 2 y or until confirmed progressive disease, unacceptable toxicity, or pt decision to withdraw. Primary end point was objective response rate (ORR; per RECIST v1.1 blinded independent central review). Additional end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: 110 pts enrolled; median (range) follow-up was 18.0 (2.5-22.7) mo. Median age (range) was 64 (29-87); 38.2%, 47.3%, and 14.5% had favorable, intermediate, and poor IMDC risk, respectively; 47.3% were PD-L1 positive. Confirmed ORR was 36.4% with 3 (2.7%) CRs and 37 (33.6%) PRs. Median DOR was not reached. Median PFS was 7.1 mo (95% CI, 5.6-11.0) and median OS was not reached. Results by IMDC category are outlined in the table. By PD-L1 status, confirmed ORR was 44.2% and 29.3% for positive and negative, respectively. By sarcomatoid differentiation (n=11), confirmed ORR was 63.6%. Treatment-related AEs occurred in 80.9%, with pruritus (28.2%) and fatigue (28.2%) most commonly reported. One pt died of treatment-related pneumonitis. Conclusions: With a median 18-months’ follow up, first-line pembro monotherapy continued to show antitumor activity in pts with ccRCC. Meaningful responses were observed in pts with intermediate/poor IMDC risk, PD-L1 positive and sarcomatoid differentiated tumors. Safety profile was comparable to previously reported. Clinical trial information: NCT02853344. [Table: see text]
Sequential treatment with pazopanib (PAZO) followed by nivolumab (NIVO) in patients with advanced or metastatic renal cell carcinoma (mRCC): Third interim results of the non-interventional study PAZOREAL.
Authors: Boegemann Martin , Bedke Jens , Schostak Martin , Hering-Schubert Christiane , Welslau Manfred , Schleicher Jan , Wolf Thomas , Petzoldt Alexander , Doehn Christian , Grüllich Carsten , Grünwald Viktor , Steiner Thomas , Rogler Anja , Hanson Sven , Klein Dunja , Medinger Tanja , Goebell Peter-Juergen 
Published: May 2019

4574 Background: Randomized clinical trials for the implementation of new therapies include only a selection of patients that are later treated with these new options. Thus, real-world evidence is urgently needed not only to monitor the translation of treatment approaches into routine practice but also to improve cancer treatment and survivorship care on a broader scale. Methods: PAZOREAL is a prospective, multicenter, non-interventional study to evaluate effectiveness [primary time on drug (TD)], tolerability, safety, and quality of life (QoL) in patients (pts) with mRCC, treated with 1st L PAZO followed by 2nd L NIVO or everolimus (EVE). Results: Between Dec. 2015 and Sep. 2017, 421 pts were enrolled and 402 pts started 1st L PAZO treatment (Tx), 127 and 5 pts received NIVO and EVE as 2nd L Tx, resp., 56 entered follow-up. At time of data-cut (08 Nov 2018) median TD was 6.6 months (95%CI 6.0-7.9) for 1st L PAZO and 4.1 months (95%CI 3.2-5.8) for 2nd L NIVO (all pts), 8.1 months (95% CI 6.6-9.5) for PAZO and 3.2 (2.7-6.5) for NIVO Tx for trial eligible pts (39.1% of 402 pts). Median TD for pts with or without prior nephrectomy was 7.6 vs 4.5 months, resp. The clinical benefit rate of 1st L PAZO was 58.2 % (95% CI 53.3-62.9) based on investigator assessment. Median OS of PAZO was 29.5 months (95%CI 23.6-NA) for all pts, 28.2 months (95% CI 22.2-NA) for NIVO in 2nd L. The most commonly reported AEs for PAZO Tx were diarrhea (35%), nausea (20.3%) and fatigue (17.5%). Most common PAZO-related grade 3/4 adverse events were hypertension (5%), hypertensive crisis (2.3%) and GGT increase (1.8%). QoL evaluated by EQ-5D-5L remained stable over different Tx lines. Conclusions: The interim results of the PAZOREAL study confirm a favorable overall survival in pts with mRCC treated with 1st L PAZO in a real-world setting, good benefit-risk profile of PAZO and sustained QoL monitored over several treatment lines. In Germany NIVO as 2nd L Tx is commonly applied after 1st L Tx with PAZO.
Consistent efficacy of nivolumab plus ipilimumab across number of International Metastatic Database Consortium (IMDC) risk factors in CheckMate 214.
Authors: Escudier Bernard , Motzer Robert J. , Tannir Nizar M. , Porta Camillo , Tomita Yoshihiko , Mekan Sabeen Fatima , McHenry M. Brent , Rini Brian I. 
Published: May 2019

4575 Background: The IMDC prognostic model was created based on anti-VEGF treatments for advanced renal cell carcinoma (aRCC), and may not be relevant for immunotherapy. Methods: In a post hoc analysis of CheckMate 214, we compared efficacy with nivolumab + ipilimumab (N+I) vs sunitinib (S) by number of IMDC risk factors present. Results: Among 1096 intent-to-treat (ITT) patients (pts) in both arms, 21%, 61%, and 18% had favorable, intermediate (int), or poor-risk, respectively. Of int-risk pts, 58% had 1 factor (most commonly <1 y from diagnosis [Dx], 52%; Hb < LLN, 27%; or KPS ≤70%, 10%); and 42% had 2 factors (of these pts, the most common combination of 2 factors was <1 y from Dx and Hb < LLN, 59%). Of poor-risk pts, 58% had 3 factors, 29% had 4 factors, and few had 5 (10%) or 6 (3%) factors. Due to small numbers, pts with 4–6 factors were pooled. At 30-mo minimum follow-up, RECIST v1.1-confirmed objective response rate (ORR) and complete response (CR) rate per investigator remained consistently higher with N+I vs S across pts with 1–4 factors, although with S, ORR decreased with increasing number of factors (Table). Improved progression-free survival (PFS) and overall survival (OS) were seen with N+I over S irrespective of the number of factors present, including in pts with only 1 risk factor (Table). Conclusions: N+I showed consistent efficacy across number of IMDC risk factors, while S decreased in efficacy with increasing number of factors. Efficacy of N+I was superior to S in all int- and poor risk pts. These CheckMate 214 results along with prior CheckMate 025 data showing consistent OS benefit with N monotherapy across IMDC risk categories show a need for improved prognostic models for immunotherapies in aRCC. Clinical trial information: NCT02231749. [Table: see text]
Dynamic contrast-enhanced MRI to predict intratumoral molecular heterogeneity in clear cell renal cell carcinoma.
Authors: Udayakumar Durga , Zhang Ze , Dwivedi Durgesh , Xi Yin , Wang Tao , Kapur Payal , Yousuf Qurratulain , Joyce Allison , Hajibeiji Asghar , Fulkerson Michael , Diaz de Leon Alberto , Lewis Matthew , Madhuranthakam Ananth J , Cadeddu Jeffrey A , Bagrodia Aditya , Margulis Vitaly , Brugarolas James , Pedrosa Ivan 
Published: May 2019

4580 Background: Mutation/inactivation of VHL in clear cell renal cell carcinoma (ccRCC) leads to upregulation of hypoxia inducible factors ( HIFs) and angiogenesis. However, ccRCC is characterized by high intra-tumor heterogeneity (ITH). Random small samples such as those in percutaneous biopsies are likely limited for characterization of molecular alterations in heterogeneous ccRCCs. We hypothesize that whole-tumor dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) is useful to noninvasively identify ITH in ccRCC. Methods: This IRB-approved, prospective, HIPAA-compliant study, included 62 ccRCCs. 3T DCE MRI was obtained prior to nephrectomy. Surgical specimens were sectioned to match MRI acquisition plane. 182 snap frozen samples (49 tumors) and adjacent uninvolved renal parenchyma (URP) were collected. RNA isolations, cDNA library preparation and mRNA sequencing were performed using standard protocols. RNA expression in 81 tumor samples were correlated (Spearman ranked) with % enhancement in a region of interest (ROI) drawn in the same location of the tumor on pre- and 3 different post-contrast DCE MRI phases. Gene function overrepresentation (OR) analyses were done on top positively and negatively correlated genes. False discovery rate (FDR) < 0.1 was considered statistically significant. Results: Principal component analysis of > 20,000 genes indicated distinct gene expression in tumors from URP. Unsupervised clustering showed enrichment of ccA samples (better prognosis) compared to ccB samples (worse prognosis). Importantly, ccA and ccB samples coexisted in 25% of tumors. DCE-MRI % enhancement correlated with expression of > 300 genes (p < 0.003, FDR < 0.1). OR analyses placed angiogenic pathway gene processes and the immune/inflammatory response processes within the top 5 positively- and negatively-correlated gene functions, respectively. HIF2 target genes correlated positively with % enhancement. Conclusions: DCE MRI detects specific molecular signatures and may help overcome the challenges of ITH in ccRCC. Further research is needed to explore the potential role of DCE MRI to assess response to antiangiogenic and immune-based therapies.