bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atezolizumab (atezo) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): Outcomes by prior therapy.
Authors: Perez-Gracia Jose Luis , Loriot Yohann , Rosenberg Jonathan E. , Powles Thomas , Necchi Andrea , Hussain Syed A. , Morales Rafael , Retz Margitta , Niegisch Guenter , Duran Ignacio , Theodore Christine , Grande Enrique , Thastrom Ann Christine , Li Shi , Abidoye Oyewale O. , Van Der Heijden Michiel Simon 
Published: March 2017

323 Background: Atezo is approved in the US for mUC and non-small cell lung cancer after prior treatment with chemotherapy. > 40% of mUC pts in the Phase 2 IMvigor210 study received ≥ 2prior metastatic regimens (Rosenberg, Lancet 2016). This analysis was performed to assess the impact of prior therapy on atezo outcomes in mUC. Methods: mUC pts in the platinum-pretreated IMvigor210 cohort (NCT02108652) received atezo 1200 mg IV q3w until loss of clinical benefit. Study endpoints analyzed by the number of prior treatment regimens included RECIST v1.1 ORR (central review), complete response (CR) rate, median durations of response (mDOR) and survival (mOS) and adverse event rate. Results: Evaluable pts (N = 310) had a median age of 66 years, and 78% had visceral mets (31% liver). 82% of pts had prior systemic treatment for mUC; number of prior regimens ranged from 1 to ≥ 4 (Table). 73% of pts received prior cisplatin, and 26% had carboplatin (no cisplatin). Objective responses, including CRs, occurred regardless of the number of prior therapies and were ongoing in 65% of responders at the July 4, 2016 data cut off (median follow-up, 21 mo [range, 0.2+-24.5]). mDOR was not reached in any subgroup based on number of treatments, except in pts who received only perioperative chemotherapy (mDOR, 16 mo [95% CI: 6.2, NE]). Similarly, mOS was generally consistent despite number of prior regimens (Table). Atezo remained generally well tolerated with similar overall safety and tolerability by line of therapy. Conclusions: Clinically meaningful benefit was observed in pts treated with atezo notwithstanding number of prior systemic mUC regimens. Minimally and heavily pre-treated pts had durable responses, encouraging OS and no major differences in safety signals. Clinical trial information: NCT02108652. [Table: see text]
Molecular subtyping of metastatic urothelial bladder cancer.
Authors: Ackerman Charlotte , Mariathasan Sanjeev , Nickles Dorothee , Gomez De Liano Lista Alfonso , Wimalasingham Akhila Ganeshi , Szabados Bernadett , Powles Thomas 
Published: March 2017

326 Background: TCGA molecular sybtyping is established in metastatic urothelial bladder cancer (UBC). It remains unclear if it is of prognostic importance with chemotherapy in metastatic UBC. Data into immune therapy suggests TCGA subtyping is predictive to response. Methods: Archival formalin-fixed paraffin embedded (FFPE) tissue were analysed from 170 patients that had consented into a clinical trial (NCT00949455) after first line chemotherapy for metastatic disease. Gene expression levels were quantified by NanoString technology. Molecular subtypes were assigned according to The Cancer Genome Atlas (TCGA) subtypes. Clinical information was available for all patients and analysis on individual genes were explored. Results: 170 patients were analysed, 75% male. 107 (64%) patients received cisplatin based first-line chemotherapy, with 36% receiving carboplatin based regimen. Median overall survival (OS) was 15.73 months [95% CI: 13.87-17.58], and median progression free survival (PFS) was 10.71 months [95% CI: 8.97-12.45]. Samples were initially clustered into luminal (n=109) and basal (n=61) subtypes. Response to first line chemotherapy occurred in all subtypes but was shown to be significantly higher in the luminal subtype versus the basal subtype [58% vs 20%, p=0.01]. PFS was superior in luminal subtypes [11.8 months vs 8.9 months, p=0.005]. Exploratory analysis showed that luminal II subtype had the best outcome for OS [20.3 months, p=0.03] compared to the other subtypes. Outcomes with other genes including immune markers were explored. TCGA outcomes can be summarised in the table. Conclusions: In metastatic urothelial cancer, TCGA subclassifying influences outcome of patients post chemotherapy. [Table: see text]
Assessing bone response to cabozantinib in patients (pts) with metastatic urothelial carcinoma (mUC) using 18F-Sodium Fluoride (NaF) PET/CT.
Authors: Lin Jeffrey , Lindenberg Liza , Steinberg Seth M. , McKinney Yolanda , Weaver Juanita , Francis Deneise C , Berniger Marilise Anne , Parnes Howard L. , Davarpanah Nicole N. , Choyke Peter L. , Apolo Andrea B. 
Published: March 2017

328 Background: NaF PET/CT is a radiotracer used for the assessment of bone metastases (mets). The goal of our study was to assess bone mets using NaF PET/CT imaging in mUC pts treated with cabozantinib. Methods: We conducted a single-arm phase II trial of cabozantinib in pts with mUC. Pts with known bone mets underwent a NaF PET/CT scan at baseline and every 8 weeks until progression. At each scan, we captured, the number of lesions per pt and per anatomical site, the maximum standardized uptake values (SUV), and serum alkaline phosphatase (AP). Bone responses (bone response (BR), stable disease (SD), progressive disease (PD)) were assigned to each pt based on the NaF report. Change from baseline to the time of best response for SUV, the number of lesions, and AP were compared between BR + SD vs PD were analyzed using an exact Wilcoxon rank sum test. The Kaplan-Meier method was used to determine the association of progression free survival (PFS) or overall survival (OS) with baseline SUV and number of lesions. Results: 68 pts enrolled on study, 22 pts had bone mets at baseline (6 bone only and 16 with bone and soft-tissue mets) (median OS 4.6 mo (95% CI: 3.4-7.7 mo), and median PFS 2.0 mo (95% CI: 1.8-3.9 mo)) of which 15 pts had follow up NaF scans. At baseline, 147 total lesions were analyzed, and the lesion distribution was: spine 29%, ribs 21%, pelvis 18%, skull 11%, femur 6%, scapula 3%, humerus 3%, sternum 3%, sacrum 3%, fibula 1%, and clavicle 0.7%. 5/15 pts had BR (and remained on study 238, 252, 182, 161, and 56 days), 4/15 SD, and 6/15 PD at best response. Sites of PD occurred in bone 10/22, bone and soft-tissue 5/22, and soft-tissue 7/22. The percent difference in number of lesions among responders and non-responders was 43% (p = 0.0039). At baseline, there was no association with PFS or OS and number of lesions (p = 0.84, p = 0.97), SUV (p = 0.83, p = 0.97), or AP (p = 0.97, p = 0.33). Conclusions: Pts with mUC and bone disease have poor overall outcome. Most bone lesions were found in the spine, ribs, and pelvis. Larger studies are needed to assess the correlation of NaF response with clinical outcome in mUC. We have an ongoing study using NaF PET to assess bone mets in mUC treated with cabozantinib/nivolumab/ipilimumab. Clinical trial information: NCT01688999.
Is neoadjuvant chemotherapy beneficial before radical cystectomy? Examining the external validity of the SWOG-8710 trial.
Authors: Hanna Nawar , Trinh Quoc-Dien , Sammon Jesse , Seisen Thomas , Vetterlein Malte , Moreira Raphael Brandao , Preston Mark A , Lipsitz Stuart R. , Bellmunt Joaquim , Menon Mani , Choueiri Toni K. , Abdollah Firas 
Published: March 2017

331 Background: The use of neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) is supported by results from several randomized control trials, including SWOG-8710. We sought to test the applicability of the SWOG-8710 study in the general population. Methods: We used the National Cancer Data Base (NCDB) to identify patients with non-metastatic muscle-invasive urothelial carcinoma of the bladder who underwent RC between 2004 and 2012. The primary endpoint was overall survival (OS). Secondary endpoints were rates of downstaging (pT0), positive pathologic lymph nodes (pN+), margin status, postoperative readmission, length of hospital stay (LOS), and 30 and 90-day postoperative mortality rates. OS comparison using Cox regression analysis was conducted. Furthermore, logistic regression models examining secondary outcomes were fitted. To adjust for potential selection bias, propensity score weighted analyses were performed. Results: Of 8732 patients who underwent RC, 1619 (19%) received NAC. Compared to the SWOG-8710 cohort, our population was older, more commonly female (p=0.002), and had higher clinical stage (p<0.001). Following propensity score adjustment, receipt of NAC was associated with an OS benefit (Hazard Ratio [HR]: 0.88, p=0.017). On secondary outcome analysis, higher downstaging rates (Odds Ratio [OR]: 5.03, p<0.001) and lower 30-day (OR: 0.49, p=0.019) and 90-day (OR: 0.61, p=0.009) postoperative mortality rates were recorded in patients who received NAC. Conclusions: Despite baseline differences between patients from the SWOG-8710 trial and general urologic practice, NAC is associated with an OS advantage relative to RC alone. Continued efforts should focus on promoting the use of NAC in appropriate patients.
Impact of variant histology on disease-specific mortality and survival in patients with non-muscle invasive bladder cancer (NMIBC): A population-based analysis.
Authors: Tripathi Abhishek , Preston Mark A , Hirsch Michelle S. , Trinh Quoc-Dien , Stewart James A. , Bellmunt Joaquim , Choueiri Toni K. , Kibel Adam S. , Harshman Lauren Christine 
Published: March 2017

332 Background: Prior studies have reported that variant histology is associated with poor outcomes in NMIBC. We utilized the Surveillance, Epidemiology and End Results (SEER) database to compare disease specific survival (DSS) and mortality (DSM) among the different variant histologies and urothelial carcinoma (UC). Methods: Patients diagnosed with NMIBC (Ta, Tis, T1) between 2004 and 2012 were eligible for analysis. Patients were separated into cohorts based on histology: UC and variant histology which included micro-papillary variant (MPV), neuroendocrine (NEC), squamous (SCC), adenocarcinoma (AC) and other variants (e.g., lymphoepithelial, giant cell, undifferentiated/anaplastic, sarcomatoid). Univariate and multivariable Cox proportional hazard analysis was used to evaluate the impact of variant histology on DSM after adjusting for other covariates. DSS was estimated amongst the different histologic and treatment groups using the Kaplan-Meier method and compared using Log-rank test. Results: We identified 111,756 patients, who were predominantly Caucasian (90%) and older than 70 years (57.5%; n=64,314). Variant histology accounted for 1.2% (n=1354) of cases. AC and SCC were the most common variant subtypes (26.4%; n=357 and 25.6%; n=347 respectively) followed by NEC (11.2%; n=151) and MPV (7.1%; n=96). On multivariable analysis adjusting for age, sex, race, T-stage, histologic grade and number of primary tumors, all variant subgroups except MPV were associated with increased DSM compared to UC (p<0.001). SCC had the worst 5-year DSS (53.8%; P<0.001) followed by NEC (65.1%) and AC (77.8%). Compared to treatment with TURBT or intravesical BCG, cystectomy was associated with improved DSS for variant histology patients with T1 tumors (75.8% vs. 66.3%; P<0.001). Conclusions: Variant histology, specifically SCC and NEC, was associated with significantly worse 5-year DSS in NMIBC. MPV, which is generally thought to be aggressive, had outcomes comparable to UC. Cystectomy was associated with improved DSS in patients with T1 disease and should be considered for NMIBC with variant histology.
Effect of defective ERCC2 on cisplatin and ionizing radiation (IR) sensitivity in bladder cancer cells.
Authors: Li Qiang , Bell Andrew , Jordan Emmet , Gao Sizhi Paul , Ma Jennifer , Pietzak Eugene J. , Dalbagni Guido , Bochner Bernard H. , Rosenberg Jonathan E. , Bajorin Dean F. , Solit David B. , Riaz Nadeem , Iyer Gopa 
Published: March 2017

333 Background: Genetic alterations within ERCC2 correlate with extraordinary responses to neoadjuvant cisplatin-based chemotherapy and bladder-sparing ionizing radiation (IR) in muscle-invasive bladder cancer (MIBC). Two studies correlated ERCC2 mutations with pathologic response to chemotherapy and improved disease-free and bladder intact survival following trimodality therapy. We sought to characterize the biological significance of these mutations in bladder cancer cells using CRISPR/Cas9-mediated ablation of ERCC2 function. Methods: The ERCC2 T484A/M point mutation was the most common alteration (4 of 36 patients) within a prospectively collected cohort of 299 bladder cancer patients sequenced at our institution. We infected the ERCC2 wild-type KU19-19 bladder cancer cell line with a CRISPR/Cas9 lentivirus targeting residues 481-487 of ERCC2 and identified a cell clone harboring an ERCC2 in-frame deletion (M483_T484del). Following exposure to cisplatin and IR, cell viability was examined using Cell-titer Glo and clonogenic assays. Apoptosis was gauged by subG1 cell fraction measurement by flow cytometry. Results: ERCC2 mutant cells exhibited significantly increased cisplatin sensitivity compared to parental cells (IC50 0.3uM vs 2.0uM, p < 0.0001). Cisplatin treatment after 48 hours resulted in increased apoptosis in ERCC2 mutant vs parental cells (sub-G1 fraction 52% vs 16%, p = 0.01). ERCC2 mutant cells were more sensitive to combined IR (2 Gy) and cisplatin (1uM) compared to parental cells (SF2Gy (surviving fraction) 17 % vs 60%). Conclusions: ERCC2 mutations enhance cisplatin and IR sensitivity in a bladder cancer cell line model. ERCC2 alterations are likely the genetic basis for extraordinary response to cisplatin chemotherapy and IR in MIBC patients. Prospective genetic sequencing may help select ERCC2 mutant MIBC patients who are most likely to respond to chemotherapy or trimodality bladder-sparing therapy.
Perioperative and readmission rates in open and robotic assisted radical cystectomy: A National Cancer Database analysis.
Authors: Kosinski Kaitlin E. , Fazzari Melissa , Kongnyuy Michael , Katz Aaron E , Corcoran Anthony T 
Published: March 2017

337 Background: Perioperative mortality and readmission rates are evolving metrics of care being monitored in radical cystectomies (RC). We aim to evaluate these outcomes in open radical cystectomies (ORC) and robotic assisted radical cystectomies (RARC) reported in the National Cancer Database adjusted by surgery type. Methods: Using the National Cancer Database, patients treated with RC from 2003 to 2010 were identified. We evaluated the association between 90-day conditional mortality and readmission with respect to surgery type, adjusted by patient (age, gender, race/ethnicity, Charlson-Deyo score, tumor type, clinical stage, margin status and receipt of neoadjuvant chemo-or radiotherapy) and facility characteristics (overall cystectomy volume and facility type [Academic/Research, Comprehensive Community, or other]). Results: 16,923 RC cases (13,236 ORC, 3,687 RARC) were identified with 480 deaths (3.6%) after ORC and 99 deaths (2.7%) after RARC within 90 days, conditional upon surviving 30 days post-surgery. Comparing <3 ORC/year to >20 ORC/year, 90-day overall conditional mortality rates decreased from 4.0% to 2.5%. In stratified analyses, 90-day conditional mortality rates decreased from 4.2% to 2.7% for ORC and 2.7% to 2.0% for RARC. Center volume was strongly associated with 90-day conditional survival (p=0.002), independent of surgery type. In multivariable analysis of 90-day conditional mortality, age (OR=1.03, 95% CI: 1.02-1.04, p<0.0001), comorbidites (OR=1.4, 95% CI: 1.12-1.6, p=0.0005), margin rates (OR=3.5,95% CI: 2.9-4.3, p<0.0001) as well as facility volume (OR=0.99, 95% CI: 0.98-1.00, p=0.001), were predictive of 90-day conditional mortality. Cystectomy volume did not predict 30 day readmission, but Charlson-Deyo score 1-2 (OR=1.274, 1.112-1.461 95% CI, p=0.0005) and receipt of neoadjuvant chemo- or radiotherapy (OR=1.161, 1.032-1.307 95% CI, p=0.0134) were significantly associated with 30-day readmission. Conclusions: Patients were less likely to incur death following robotic or open cystectomy within 90 days as institutional cystectomy volume increased. 30 day readmission rates were not influenced by institutional cystectomy volume.
Measuring and improving symptom burden in radical cystectomy patients undergoing traditional care compared to enhanced recovery.
Authors: Kukreja Janet Baack , Chang Courtney M , Chen Ting Yu , Shi Qiuling , Wang Xin Shelley , Navai Neema , Kamat Ashish M. , Dinney Colin P.N. , Shah Jay Bakul 
Published: March 2017

340 Background: Bladder cancer is a disease of the elderly associated with high morbidity in those undergoing radical cystectomy (RC). The Optimized Surgical Journey (OSJ) uses enhanced recovery after surgery (ERAS) principles for RC patients to improve postoperative pain and shorten hospital stay. There have been few patient reported outcomes studied in OSJ and ERAS patients. The MD Anderson Symptom Inventory (MDASI) is patient reported outcome measures used for clinical and research purposes related to cancer and its treatment. Our objective was to determine if patient reported outcomes using MDASIs are different in patients following the OSJ compared to a traditional care pathway. Methods: From July 2013 to November 2015, MDASIs were collected from 160 RC patients preoperatively and on postoperative days (POD) 1 through 3. The MDASI consists of 19 core symptom burden related questions and 6 questions analyzing how symptoms have interfered with the patient’s life. Using a 0-10 scale, patient’s rate their symptoms. T-test, Man-Whitney where appropriate and logistic regression were used for multivariable cross sectional analysis. Results: The most bothersome symptoms were abdominal discomfort, disturbed sleep, dry mouth, fatigue, and drowsiness. Nausea, vomiting, bowel pattern, bowel control and appetite were all found to be insignificant. Abdominal discomfort was reported significantly less in OSJ patients on PODs 1 and 2 (p = 0.032 and 0.001, respectively). In multivariable analysis OSJ status was predictive of less abdominal pain (p < 0.001). Dry mouth was also significantly burdensome on PODs 1 and 2 (p = 0.022 and < 0.001, respectively) in non-OSJ patients. Less dry mouth was also predicted by OSJ status in multivariable analysis (p = 0.014). Disturbed sleep, fatigue, and drowsiness were significantly less in patients on the OSJ POD 2. Mood was better in OSJ patients PODs 2 and 3 (p = 0.016). Conclusions: The OSJ can significantly reduce the burden of symptoms in RC patients immediately postoperatively. MDASIs maybe a helpful tool to measure symptom burden. This information can be used in the future to create additional interventions for improvement in RC patient recovery experiences.
Updated meta-analysis (MA) of salvage therapy for metastatic urothelial cancer (mUC): Comparing outcomes of immunotherapy (IT) versus single agent and doublet chemotherapy (CT).
Authors: Necchi Andrea , Raggi Daniele , Sonpavde Guru , Giannatempo Patrizia , Mariani Luigi , Galsky Matt D. , Bellmunt Joaquim , Miceli Rosalba 
Published: March 2017

341 Background: Doublet CT demonstrated improved overall response rate (ORR) and progression-free survival (PFS) compared to single agent CT in a MA of patients (pts) receiving II line CT in trials of mUC ( Raggi et al, Ann Oncol 2016). We aimed to update the analyses adding trials of salvage IT. Methods: We searched for arms of phase 2 or 3 studies of salvage single agent anti-programmed cell death-1/Ligand-1 (PD-1/PD-L1) agents pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, single agent CT and doublet CT. Random-effects models were used to pool trial level data according to treatment arm, including ORR, median PFS (mPFS), median overall survival (mOS). Univariable (UVA) and multivariable (MVA) analyses were performed, adjusting for ECOG-PS 2 and liver metastases. Results: 7 IT trials were analyzed (n=1,041), 22 arms received single agent CT (n=1,202), and 24 doublet CT (n=708). The pooled ORR was: 21.2% (95%CI: 14.9-29.2) with IT, 14.2% (95%CI: 11.1-17.9) with single agent CT and 31.9% (95%CI: 27.3-36.9) with doublet CT. Pooled mPFS was 1.8, 2.69 and 4.05 months, respectively. Pooled mOS was 8.27, 6.98 and 8.50 months. Pooled median ORR and mOS of IT for PD-L1+ pts were: 30.7% (95%CI: 23.2-39.2) and 11.60 months. Results of UVA and MVA are shown in the table. Only UVA was possible for PD-L1+ pts. Conclusions: Among trials of salvage therapy for mUC, IT was associated with significantly higher ORR and mOS in PD-L1+ pts compared with single agent or doublet CT, while significant differences were not seen in unselected pts. These results are hypothesis-generating and suggest the importance of developing companion predictive biomarkers. [Table: see text]
The impact of MRE11 in nuclear to cytoplasmic ratio on outcomes in muscle invasive bladder cancer an analysis of NRG/RTOG 8802, 8903, 9506, 9706, 9906, and 0233.
Authors: Magliocco Anthony Martin , Moughan Jennifer , Simko Jeff , Efstathiou Jason A. , Gray Phillip J , Hagan Michael P , Kaufman Donald S , Tester William J. , Zietman Anthony L. , McCarthy Susan M , Hartford Alan C , Patel Ashish Bharat , Rosenthal Seth A. , McGowan David G , Greenberg Richard H , Schwartz Michael A , Augspurger Mark E , Keech John A. , Winter Kathryn A , Shipley William U. 
Published: March 2017

343 Background: Biomarkers are needed to help select patients (pts) with muscle invading bladder cancer (MIBC) for bladder sparing chemotherapy and radiation treatment (CRT). Higher MRE11 expression has been identified as a potential RT response marker in MIBC. MRE11 protein is involved in the DNA double strand break repair mechanism. This analysis evaluates associations between MRE11 expression and outcome in pts from 6 NRG/RTOG bladder-sparing RT protocols. Methods: Archival tissue via TMA or unstained slides was used. Cases were stained with anti MRE11 antibody Rabbit mAb, clone EPR3471 (Epitomics at 1:1500 dilution). Slides were scanned on an Aperio FL instrument and analyzed via Automated Quantitative Image analysis (AQUA). MRE11 scores were determined within the nucleus and cytoplasm of urothelial cells and a ratio of nuclear to cytoplasmic (N/C) score calculated. A ratio was used to normalize scores and overcome pre-analytical variation. MRE11 N/C was analyzed by quartile cut points. Cumulative incidence was used to estimate disease-specific mortality (DSM; failure=bladder cancer death) and Fine-Gray models were used to evaluate associations between MRE11 and DSM. Cox models were used for overall survival (OS; death) and bladder-intact survival (BIS; cystectomy/death). Results: Out of 465 eligible pts, tissue was available and MRE11 N/C determined for 135. Analyzable pts were less likely to be white (p=0.0001) and more likely to be T2 (p=0.0003). Median MRE11 N/C was 2.41 (min-max: 0.69-6.03). Pts with MRE11 N/C ≤ 1.49 (lower quartile) were associated with significantly higher DSM (HR= 2, 95% CI: 1.1, 3.8, p=0.03). The 4-year DSM was 41% for pts with MER11 N/C ≤ 1.49 vs. 21% for pts with MER11 N/C was >1.49. MRE11 N/C was not associated with OS or BIS. Conclusions: AQUA analysis allows precise measurement of this marker in tissue samples. Low expression of MRE11 N/C (≤1.49) is associated with significantly higher DSM. This adds further evidence of MRE11 as a potential RT response biomarker for selection of pts most likely to respond to bladder-sparing CRT. Supported by NCI grants U10CA180868, U10CA180822, UG1CA189867,U24CA196067.