bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of myeloid derived suppressor cell (MDSC) populations with clinicopathologic features in urothelial carcinoma (UC).
Authors: Ornstein Moshe Chaim , Diaz-Montero C. Marcela , Rayman Pat A. , Elson Paul , Haywood Samuel , Finke James , Garcia Jorge A. , Rini Brian I. , Stephenson Andrew J. , Campbell Steven C. , Fergany Amr Farouk , Emamekhoo Hamid , Lamenza Marcelo , Stybor Sylvia , Schach Kim , Profusek Pam , Tyler Allison Janine , Ernstoff Marc S. , Grivas Petros 
Published: February 2017

434 Background: MDSC are a heterogeneous population of potent immunosuppressive cells with potential predictive/prognostic significance in solid tumors. The association between MDSC and clinicopathologic features in patients (pts) with UC was investigated. Methods: Peripheral blood from 26 non-metastatic UC pts scheduled to undergo cystectomy or nephroureterectomy at Cleveland Clinic was collected. MDSC were enumerated in fresh unfractionated blood (WB) and in peripheral blood mononuclear cells (PBMC). (T)otal MDSC were defined as CD33+/HLADR-; out of T-MDSC, (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+) and (I)mmature (CD15-CD14-) MDSC were identified. CD11b MDSC (Linlo/HLADR-/CD33+/CD11b+) were identified in WB. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Wilcoxon rank sum test was used to assess associations between MDSC populations and clinicopathologic features. Due to the exploratory nature of the study, p < .10 was considered significant. Results: Of 26 pts, 25 had surgery and 1 is under surveillance. 24 had both WB and PBMC data. 23/26 were men; median age 67. Of 26 pts, all had primarily UC histology; 7 had mixed UC histology, 11 had prior intravesical BCG, 12 neoadjuvant therapy (10 Gem/Cis, 1 Gem/Carbo, 1 unknown). Of 25 pts who had surgery, 5 had pT3/4 stage; 5 had LVI; 9 had CIS. All but 1 had negative LN. Higher levels of specific WB MDSC populations were associated with mixed histology (including squamous), CIS, and higher pT-stage (Table). When compared to a separate cohort of 11 pts with metastatic UC, the % G-MDSC in PBMC was lower in non-metastatic pts (median 0.3 vs. 1.47; p = .05). Conclusions: Although no single MDSC population correlated with all the evaluated clinicopathologic features, higher levels of certain MDSC populations appear to correlate with histology and pT stage. Further validation of blood and tissue is ongoing in a larger cohort. [Table: see text]
External beam radiotherapy and concurrent gemcitabine for muscle-invasive bladder cancer: Toxicities and early outcomes.
Authors: Nack Elana , Rosenberg Jonathan E. , Bochner Bernard H. , Dalbagni Guido , Zelefsky Michael J. , Kollmeier Marisa 
Published: February 2017

443 Background: To report toxicities and early outcomes of external beam radiotherapy (EBRT) with concurrent gemcitabine for muscle-invasive bladder cancer (MIBC) Methods: Between 9/04 - 4/15, 85 patients (median age 77) with MIBC (cT2-T4, Nx-3) underwent transurethral resection (TUR) (39 complete, 43 incomplete, 2 unknown) followed by EBRT (median dose 64.8Gy) with concurrent gemcitabine (20-27 mg/m2) twice weekly. 25 patients (29%) received neoadjuvant chemotherapy. Patients were followed q3 months with imaging, cystoscopy and/or cytology. Early ( < 90 days) and late ( > 90 days) toxicities were graded according to the Common Terminology Criteria for Adverse Events (v4.0). Median followup was 19.5 months; 74 (87%) had > 3 month followup. Kaplan-Meier and Cox regression were used for survival and multivariate analyses. Results: Acute grade ≥ 3 hematologic, gastrointestinal or genitourinary toxicity occurred in 18%, 1.5% and 1.3% of patients, respectively. 73/85 (86%) patients received full EBRT course without interruption. 78/85 (92%) received > 50% of the prescribed gemcitabine. The most common reason for a gemcitabine interruption/dose reduction was hematologic (80%). Late grade 3 toxicity included hematuria (n = 5), urinary obstruction (n = 4) and cystitis (n = 1). The 2-year freedom from in-bladder recurrence and bladder-intact survival was 53% and 60%, respectively. The 2-year distant metastasis-free, disease-specific and overall survivals were 66%, 69% and 62%, respectively. A complete TUR was associated with improvements in 2 year bladder-intact (73% vs 51%, p = 0.01), disease-specific (87% vs 54%, p = 0.001), distant metastasis-free (83% vs 52%, p < 0.0001) and overall survival (78% vs 50%, p = 0.003) compared with incomplete TUR. Neoadjuvant chemotherapy and nodal status had no significant impact on survival outcomes. Conclusions: EBRT with concurrent gemcitabine is well-tolerated for MIBC, even in an elderly population. Hematologic (acute) and genitourinary (late) toxicities are most common. Survival outcomes in this unselected population are comparable to prior trials, although longer followup is needed. A complete TUR prior to chemoradiation is strongly recommended.
Incidence, timing, and risk factors for infection after radical cystectomy: Results from the National Surgical Quality Improvement Program.
Authors: Parker William P. , Tollefson Matthew K. , Heins Courtney N. , Habermann Elizabeth B. , Zaid Harras B. , Frank Igor , Thompson Robert Houston , Boorjian Stephen A. 
Published: February 2017

445 Background: Radical cystectomy (RC) is the gold standard treatment for muscle-invasive and high-risk non-muscle invasive bladder cancer. However, the procedure has been associated with a high complication rate, including perioperative infection. In addition to resulting in patient morbidity, infections have been suggested as a quality metric. We sought to evaluate the incidence, risk factors, and timing of infection following RC. Methods: The National Surgical Quality Improvement Program (NSQIP) database was queried to identify patients undergoing RC for bladder cancer from 2005-2013 using CPT procedure and ICD-9 diagnosis codes. Infections (urinary tract infection (UTI), surgical site infection (SSI), and sepsis) within 30 days of RC were recorded. Characteristics including age, gender, ethnicity, body-mass index, diabetes, smoking status, renal function, steroid usage, albumin, receipt of perioperative transfusion, and operative time were abstracted, and relative risk of infection was assessed in univariate chi-squared analysis. Results: A total of 3,187 patients were identified, of whom 2604 (81.8%) were male, with a median age of 68.8 years (IQR 62, 77). Postoperative infection was diagnosed in 766 (24%) patients, at a median of 13 days (IQR 8, 19) after RC, with 44.4% occurring prior to hospital discharge. The most common type of infection was SSI (404; 12.7%), followed by sepsis (315; 9.9%), and UTI (309; 9.7%). Factors associated with increased overall infection risk were obesity (RR 1.32; 1.20-1.46; p < 0.001), receipt of a blood transfusion (RR 1.20; 1.10-1.31; p < 0.001), and increased operative time (RR for > 450 min 1.46; 1.26-1.70; p < 0.001). Risk factors for UTI in particular included obesity (RR 1.28; 1.11-1.47; p < 0.001), diabetes (RR 1.38; 1.09-1.75; p = 0.009), and increased operative time (RR for > 450 min 1.45; 1.18-1.78; p < 0.001). Conclusions: Approximately 25% of patients undergoing RC experience an infection within 30 days of surgery, most commonly SSI. Several modifiable risk factors were identified, including blood transfusion and prolonged operative time, that represent potential targets for care improvement.
Programmed death-ligand 1 (PD-L1) characterization of circulating tumor cells (CTCs) and white blood cells (WBCs) in muscle invasive and metastatic bladder cancer patients.
Authors: Anantharaman Archana , Friedlander Terence W. , Lu David , Krupa Rachel , Premasekharan Gayatri , Hough Jeffrey , Edwards Matthew , Graf Ryon , Jendrisak Adam , Louw Jessica , Dugan Lyndsey , Marrinucci Dena C. , Dittamore Ryan Vance , Paris Pamela 
Published: February 2017

446 Background: Recent studies indicate that PD-1 and PD-L1 checkpoint inhibitors have activity in chemotherapy refractory patients with muscle invasive (MIBC) and metastatic (mBCa) bladder cancer. PD-L1 expression on tumor cells or lymphocytes may correlate with response to therapy. To identify potential patients who may benefit from PD-1/PD-L1 targeted immunotherapeutics, we utilized a non-invasive blood test to evaluate PD-L1 protein expression in CTCs and WBCs of bladder cancer patients. Methods: Whole blood from 20 patients with MIBC or mBCa were collected and shipped to Epic Sciences. All nucleated cells were plated onto glass slides and subjected to immunofluorescent (IF) staining and CTC identification using scanners and algorithmic analysis. CTCs, defined as traditional (CK+ CD45- w/ intact DAPI+ nuclei and morphologically distinct) or CK- (CK-, CD45-, DAPI+, intact and distinct) were identified. PD-L1 biomarker characterization was assessed by IF staining. UroVysion FISH testing was used to assess genomic abnormalities in a subset of patient samples. Additionally, WBCs (CD45+ cells) were assessed for PD-L1 expression, relative to healthy controls. Results: Eighty percent of patients had mBCa and 20% had MIBC, 70% percent were men, and themedian age was 67 years, (range 43 to 88). Traditional CTCs were detected in 11/20 (55%) patients. Seven out of 20 (35%) patients had PD-L1+ cells, 4 of these patients had exclusively CK-/PD-L1+ CTCs, a subset of which were confirmed as malignant via FISH. CK- CTCs were detected in 14/20 (70%) patients. Five patients had greater than 4-fold PD-L1 positivity in WBCs as compared to healthy donors. Conclusions: Patients with MIBC and mBCa patients have detectable, heterogeneous CTCs with a population of CK-/PD-L1+ CTCs. Utilization of a liquid biopsy to identify patients with PD-L1+ CTCs and PD-L1+ WBCs may enable patient selection or short term therapeutic monitoring for measuring therapeutic efficacy. Further work will investigate association of PD-L1+ CTCs and WBCs with clinical response to PD-1 checkpoint immunotherapy.
uPAR and mTORC2 as coupled targets for therapeutics development in bladder cancer.
Authors: Hau Andrew M. , Gilder Andrew , Hu Jing-jing , Gonias Steven L. , Hansel Donna E. 
Published: February 2017

447 Background: Bladder cancer currently ranks as the fifth most common and the single most expensive cancer to manage in the United States. Although it is established that invasive behavior is a major predictor of diminished outcomes for patients with bladder cancer, the molecular mechanisms governing bladder cancer cell invasion are not well understood. The urokinase receptor (uPAR) and mammalian target of rapamycin complex 2 (mTORC2) represent two powerful pro-invasion candidates that have increased expression in high-grade, invasive bladder cancer, though the former has not been characterized in detail in bladder cancer. Therefore, the aims of this study are to characterize the uPAR signaling network and delineate the signaling interplay between mTORC2 and uPAR in bladder cancer. Methods: Using immunoblot and RT-qPCR analyses, we evaluated uPAR expression in a panel of immortalized bladder cancer cell lines: UROtsa, RT4, UMUC3, T24 and J82. uPAR influence on mTORC1 and mTORC2 signaling was determined by immunoblot analysis following targeted gene-silencing of uPAR using siRNA. Additionally, the effects of uPAR knockdown on cell migration and invasion were investigated using modified scratch-wound migration and transwell invasion assays. Lastly, signaling interplay between uPAR and mTORC2 was investigated by evaluating the effects of uPAR and mTORC2 silencing on Rac1 activity. Results: uPAR knockdown in a subset (T24 and J82) of invasive bladder cancer cell lines inhibited mTORC2, but not mTORC1, activity as measured by P-AKT S473 and P-S6 levels. We found that uPAR silencing in T24 and J82 cells resulted in significant reductions in cell migration and invasion through Matrigel. This is likely attributed to inhibition of Rac1 and decreased lamellipodia formation. Conclusions: Collectively, our results identify uPAR and mTORC2 as major regulators of bladder cancer cell invasion and that these two systems are linked through Rac1. Further investigation of uPAR and mTORC2 inhibition using uPAR-targeting antibodies and mTOR inhibitors in an in vivo mouse model of bladder cancer will determine if these signaling pathways are therapeutically beneficial for the treatment of bladder cancer.
miRNA expression profiles in high-grade prostatic intraepithelial neoplasia.
Authors: Eminaga Okyaz , Woetzel Fabian , Fries Jochen , Neiss Susanne , Heitmann Michaela , Engelmann Udo , Heidenreich Axel , Warnecke-Eberz Ute 
Published: February 2017

45 Background: High-grade prostatic intraepithelial neoplasia (HGPIN) is widely believed to be a precursor of prostate cancer (PCa). However, little is known about the expression of miRNAs variations in HGPIN compared to normal tissues and PCa. Methods: The expression data of 1054 miRNAs from TCGA were applied to identify relevant miRNAs associated with tumor progression (i.e., miR-98-5p, miR-183-5p, 345-5p, miR-143 miR-210-3p and miR-378-3p). miRNA were isolated by miRNeasy FFPE kit (Qiagen, Hilden, Germany) from paraffin-embedded tissues (FFPE) of prostate specimens with PCa, HGPIN and normal tissues. Early-stage PCa was defined as PCa with pT2 tumor stage, Gleason score <=7a (3+4) and PSA level <10 ng/ml. Quantitative miRNA expression data were acquired and analyzed using a real-time TaqMan-based PCR with the ABI Prism 7900HT (Life Technologies, Darmstadt, Germany). ANOVA analysis were performed to evaluate the expression of miRNAs between HGPIN, Normal and PCa tissues. All statistical analysis was performed using SPSS (IBM, Armonk, USA). P values were adjusted using the false discovery rate for multiple comparisons. The small nuclear U6 RNA was used as an endogenous control. Results: The expression of miR-143-3p, miR-210-3p and miR-345-5p and miR-98-5-p were varied between normal tissue, HGPIN and early-stage PCa. Interestingly, decrease in expression of miR-143.-3p, miR-98-5p and miR-210-3p was associated with tumor development (Normal tissues > HGPIN > early-stage PCa) (FDR<0.001). Furthermore, overexpression of miR-345-5p was observed in normal tissues compared to HGPIN and early-stage PCa, which both showed similar expression level of miR-345-5p. No significant differences in expression of miR-375, miR-183-5p and miR-378-3p were observed between HGPIN and PCa. These miRNAs were interacted with genes related to HIF-1 signaling pathway, p53 signaling pathway, androgen receptor signaling pathway, intrinsic apoptotic signaling pathway, RNA transcription, homologous recombination and non-homologous end-joining. Conclusions: HGPIN shows an altered expression of miRNAs interact with genes related to hypoxia, androgen receptor signaling pathway, cell cycle and epigenetic regulation.
Impact of multidisciplinary bladder cancer care for muscle invasive bladder cancer: A propensity score matched analysis of survival outcomes.
Authors: Kulkarni Girish S. , Hermanns Thomas , Li Kathy , Wei Yanliang , Bhindi Bimal , Kuk Cynthia , Sridhar Srikala S. , van der Kwast Theodorus , Chung Peter W. M. , Bristow Robert G. , Warde Padraig Richard , Milosevic Michael F. , Fleshner Neil Eric , Jewett Michael A.S. , Zlotta Alexandre 
Published: February 2017

455 Background: We started in 2008 a Multidisciplinary Bladder Cancer Clinic (MDBCC), where complex bladder cancer patients are assessed concurrently by urologic and radiation oncologists, with support from medical oncologists. Patients have the opportunity to discuss various treatment options including radical cystectomy (RC) or bladder sparing trimodal therapy (TMT; endoscopic resection, radiotherapy and chemotherapy). Although reports have shown comparable outcomes of TMT to cystectomy, no direct comparison to RC has been published and no randomized studies are available. We report our long term outcomes of multidisciplinary care, comparing TMT to surgery using propensity-matched analyses. Methods: Patients seen in our MDBCC receiving TMT for MIBC from 2008 to 2012 were identified and matched, using propensity scores, to patients operated by RC. Matching occurred on age, ECOG status, Charlson comorbidity score, cT stage, cN stage and date of treatment. Overall survival (OS) and disease-specific survival (DSS) were assessed with Cox Proportional hazards modeling and competing risk analysis, respectively. Results: Between 2008 and 2012, 248 patients were assessed in the MDBCC. Of these, 162 (65%) had MIBC. Nearly half (80) opted for radiotherapy +/- concurrent cisplatin chemotherapy and 49 underwent full bladder preservation with TMT as their primary therapy. We matched 48 TMT patients with 48 RC patients with no imbalances. Median age of the cohort was 67.5 years with 29.2% cT3/cT4. With a median follow up time of 3.62 years, there were 19 (39.6%) deaths (7 from bladder cancer) in the RC group and 15 (31.3%) deaths (6 from bladder cancer) in the TMT group. 5 year DSS was 85.2% and 84.7% with TMT and surgery, respectively (p > 0.05). There was no statistically significant difference in DSS between the two groups (HR for TMT 1.31 (0.40-4.23), p = 0.66) or in OS (HR for TMT 0.77 (0.34-1.75), p = 0.53). Conclusions: Bladder cancer patients benefit from a multidisciplinary approach.. In selected patients with MIBC, chemo-radiation yields survival outcomes similar to matched RC patients. BC patients should be offered the possibility to discuss various treatment options.
The impact of histological variants on bladder cancer survival: A population-based analysis.
Authors: Gelpi-Hammerschmidt Francisco , Rodriguez Dayron , Tinay Ilker , Allard Christopher Brian , Blute Michael , Kibel Adam S. , Chang Steven Lee , Trinh Quoc-Dien , Preston Mark A 
Published: February 2017

458 Background: We evaluated the clinical and prognostic impact of bladder cancer histologic variants (BCHV) using a large population-based cancer database. Methods: Using the Surveillance, Epidemiology, and End Results database (SEER), we identified bladder cancer patients from 2001-2012, and categorized them according to histological differentiation. 5 year disease-specific survival (DSS) was calculated using the Kaplan-Meier method. Cox proportional hazards regression model was used to predict association with disease-specific mortality (DSM). In addition, we fitted multivariate logistic regression models to predict the impact of histological variants on muscle-invasive status (MI), nodal involvement (NI), and metastatic disease (MD). Results: The cohort included 175,544 urothelial (96.3%) and 6,714 non-urothelial (3.7%) cancers. The latter were divided into: 2,382 squamous cell carcinoma, 1,648 adenocarcinoma, 888 small cell, 912 sarcomatoid, 292 signet-ring cell, 314 neuroendocrine and 278 micropapillary bladder tumors. Urothelial cancers overall had the best 5-year DSS. Of the non-urothelial variants, micropapillary and squamous had the best and worst DSS respectively (p < 0.001). On multivariable analysis predicting DSM, micropapillary and squamous variants had the best and worst prognosis respectively (HR 0.79, p = 0.102 and HR 2.63, p < 0.001), compared to urothelial tumors. On multivariable analysis predicting MI, NI, and MD: squamous (OR 22.76, p < 0.001), micropapillary (OR 3.17, p < 0.001) and adenocarcinoma (OR 4.14, p < 0.001), had higher likelihood respectively, compared to urothelial tumors. Conclusions: Despite accounting for a minority of bladder cancers, BCHV are associated with worst outcomes. It is essential to recognize the potential implications of these variants when deciding treatment. Additional studies are warranted to better characterize the clinical impact of these variants.
Afatinib activity in platinum-refractory metastatic urothelial carcinoma (UC) patients with ErbB alterations: Results of a phase II trial.
Authors: Choudhury Noura , Campanile Alexa , Antic Tatjana , Wade James Lloyd , Stadler Walter Michael , Nakamura Yusuke , O'Donnell Peter H. 
Published: February 2017

459 Background: Metastatic UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ErbB3 are frequent in UC and may represent viable therapeutic targets. We studied whether afatinib, an oral, irreversible Erb family blocker, has activity in UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance.The primary endpoint was 3-mo progression-free survival (PFS3) using a Simon two-stage design, with the trial proceeding to stage II if ≥ 30% pts in stage I had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman) of available archival tumor tissue. Results: The initial enrollment goal of 23 ptswas met: 18 M/5 F, median age 67 (36-82), ECOG 0 in 26%/1 in 74%, Hb < 10 g/dl in 17%, liver metastases in 30%, median time from prior chemotherapy = 3.6 mo. No unexpected toxicities were observed; 2 pts required dose-reduction (grade 3 fatigue, grade 3 rash). 5/23 pts (21.7%) had PFS3 (1 partial response (PR), 4 stable disease). Notably, 5/7 pts (71.4%) with ErbB molecular alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 4.6 (ongoing) and 3.9 (ongoing) mo respectively) while 0/16 without alterations reached PFS3 (p < 0.001, Fisher’s exact). The 2 pts with alterations (both HER2 amplified) who did not reach PFS3 had liver metastases. All 3 pts with ErbB3 somatic mutations were responders. One pt with both HER2 amplification and R103G ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. Average time to progression/discontinuation was 4.9 mo in pts with molecular alterations vs 1.7 mo for pts without alterations (p = 0.03). Conclusions: Afatinib demonstrates significant activity in platinum-refractory UC pts with HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. A follow-on phase II study of afatinib in marker-selected refractory UC pts is underway. Clinical trial information: NCT02122172.