bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular profiling of non-urothelial bladder cancer: Adenocarcinoma and squamous cell carcinoma.
Authors: Geynisman Daniel M. , Arguello David , Reddy Sandeep K. , Gatalica Zoran 
Published: February 2017

423 Background: Adenocarcinoma (ADA) and squamous cell carcinoma (SCC) are rare and often aggressive histologic subtypes of bladder cancer. For advanced disease, no clear standard therapies exist and NCCN guidelines suggest only fluorouracil, cisplatin, paclitaxel and ifosfamide as possible options. Thus, novel therapies based on underlying tumor biology are needed. The purpose of this study was to identify potential therapeutic options for these histologic subtypes, utilizing multiplatform tumor profiling. Methods: 49 ADA and 24 SCC specimenswere tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), gene amplification (CISH or FISH), and protein expression (immunohistochemistry [IHC]). 52% of cases were from metastatic sites. Results: Both ADA and SCC exhibited high rates of TP53 aberrations (82.4% and 72.7%, respectively). Sequencing revealed mutations in BRCA2 (14.3%), SMAD4 (12.5%), PTEN (11.8%), KRAS (8.7%), NRAS (5.6%), and KIT (5.3%) in ADA. In addition, PIK3CA (21.4%), HRAS (18.2%), BRCA1 (16.7%), BRCA2 (16.7%), and FBXW7 (9.1%) mutations were detected in SCC. Amplification in EGFR (27.3%) and ERBB2/HER2 (16.7%) were found in ACA. Meanwhile, only one ERBB2 (6.3%) amplification was found in SCC using ISH. MET was not amplified in either ACA or SCC. For both ACA and SCC, EGFR had the highest level of protein expression (100% and 85.7%, respectively). Of note, PD-1 (44.4% in both) and PD-L1 (11.1% and 22.2% in ACA and SCC, respectively) were expressed in both subtypes. Although differential rates of somatic alterations, amplification, and protein expression were found between ADA and SCC, only TLE3 was significant (19.2% versus 60.0%, respectively, p = 0.0154). Conclusions: Differential results in gene alteration, amplification, and protein expression imply the potential utility of tumor profiling in guiding therapeutic decision-making in ADA and SCC of the bladder. PIK3CA/AKT/mTOR pathway aberrations are similar to what has been reported in urothelial bladder cancer. Targeting the PD-1/PD-L1 axis may be a therapeutic option. Further studies are warranted in both diseases.
First multicenter experience with thermotherapy and mitomycin of high risk NMIBC with a new recirculation system (COMBAT).
Authors: Voegeli Thomas Alexander , Volkmer Bjoern 
Published: February 2017

425 Background: At a temperature of 43° (109°F) cytotoxicity of mitomycin increases 10 fold to tumor cells if used for instillation therapy of superficial bladder cancer (NMIBC).In the last years high organ preservation rates were reported for high risk NMIBC after radiofrequency induced hyperthermia and mitomycin (Synergo System).Unfortunately side effects were frequent and discontinuitation of 40% were reported with this method thus thermotherapy combined with instillation this therapy has not been very common.We here report about the first experience with a newly developed device using a recirculation heating system (COMBAT). Methods: After diagnosis by complete TUR/ReTUR patients received 40 mg mitomycin (mito-extra,medac) via transurethral catheter for 1 h heated up to constant 43° by a circulation pump system (COMBAT). Side effects were recorded pprospectively before and after each teratment and during follow up and success was validated by TUR/biopsy if possible. Results: A total of 20 patients were treated from 11/14-9/15 in 5 institutions. Follow up until now is 1-10 month (mean 8 m). All patients had high risk NMIBC including BCG failures. Therapy must be abondened in 1 patient after the 5th treatment, 50% had dysuria during treatment but symptoms decreased after the last treatment in all patients. 2 patients experienced mild allergic reaction also seen under conventional instillation therapy with mitomycin and were treated by corticosteroids. ReTUR was performed in 17/20 patients and revealed a persistent/recurrent tumor pTa GIII in 1 out of 20 patients. Conclusions: Compared to the microwave driven heating system the new device with recirculation of heated mitomycin seems to have less side effects without major complications. Treatment discontinuitation was recorded in 1/20 patients. Given the assumption that this system has the same high rate of organ preservation as the Synergo System at even much lower costs, it may alter the therapy algorythm in high risk NMIBC. Despite our first promising oncological results further research with longer follow up is necessary.Two prospective randomized studies are now underway in England and Spain and first results are awaited in 2 years.
First intravesical α-radioimmunotherapy of human urothelial carcinoma in men as a new therapy for carcinoma in situ after BCG failure.
Authors: Autenrieth Michael E , Kurz Florian , Horn Thomas , Seidl Christof , Morgenstern Alfred , Scheidhauer Klemens , Bruchertseifer Frank , Gschwend Juergen E. , Senekowitsch-Schmidtke Reintraud 
Published: February 2017

427 Background: Failure to respond to BCG in patients with carcinoma in situ (CIS) of the urinary bladder is problematic, since those tumours often have the potential to progress to muscle invasion. radical cystectomy remains the mainstay after BCG failure.Because treatment of mice bearing intravesical human bladder cancer xenografts with Bi-213-anti-EGFR-MAb turned out highly efficient (Pfost B et al. 2009, J of Nucl Med 50:1700-1708), the aim of this pilot study was to evaluate tolerability and safety of the α-emitter radioimmunoconjugate in patients after BCG failure. Methods: The alpha-emitter Bi-213 was eluted from a generator system provided by the Institute for Transuranium Elements (European Commission, JRC, Karlsruhe, Germany) and coupled to the anti-EGFR-mAb (Cetuximab, Merck, Germany) via the chelating agent CHX-A”-DTPA. 7 patients suffering from carcinoma in situ of the bladder who had histologically proven residual tumor after BCG induction therapy were included. After emptying the bladder an activity between 9,9 mCi and 22,2 mCi in 40 ml NaCl of Bi-213-anti-EGFR-mAb via a transurethral catheter was instilled. Distribution of Bi-213-anti-EGFR-mAb was monitored by SPECT/CT. Treatment was terminated by emptying of the radioimmunoconjugate from the bladder 120 min after injection. Efficacy was evaluated via endoscopy and histology six weeks after instillation. Results: All patients showed excellent toleration of the treatment without any side effects. SPECT/CT monitoring clearly revealed location of the Bi-213-anti-EGFR-MAb immunoconjugate only in the bladder without extravasation. Treatment resulted in complete eradication of tumor cells in 3 patients and persistent tumor detection in the other 4 patients. Conclusions: Intravesical instillation of Bi-213-anti-EGFR-mAb is a promising therapeutic option for treatment of in situ bladder cancerafterBCG failure for patients who wish to preserve the bladder.
Multicenter prospective phase II trial of neoadjuvant (neo) dose dense gemcitabine and cisplatin (DD-GC) in patients (pts) with muscle-invasive bladder cancer (MIBC).
Authors: Balar Arjun Vasant , Iyer Gopa , Milowsky Matthew I. , Huang William C. , Woods Michael , Donat S. Machele , Herr Harry W. , Dalbagni Guido , Bochner Bernard H. , Ostrovnaya Irina , Al-Ahmadie Hikmat , Rose Tracy Lynn , Riches Jamie Cathleen , Kania Brooke Elizabeth , Regazzi Ashley Marie , McCoy Asia S. , Delbeau Daniela , Rosenberg Jonathan E. , Bajorin Dean F. 
Published: February 2017

436 Background: Cisplatin-based chemotherapy before radical cystectomy (RC) improves survival in pts with MIBC. DD-GC therapy is active in the metastatic setting [6 cycles (cy), 18 months median survival; Bamias et al, 2012)] and as neo therapy (3 cy, 44% ≤ pT1 rate; Plimack et al, 2014), but the optimal dose and number of cy of neo therapy has not been defined. We prospectively evaluated the activity and safety of 6 cy of neo DD-GC over 12 weeks in MIBC. Methods: Pts with T2-4aN0 disease received six 14-day cy of DD-GC as follows: G 2500 mg/m2 day 1, C 35 mg/m2 days 1 and 2, pegfilgrastim day 3. RC with bilateral pelvic lymph node dissection was planned within 8 weeks of DD-GC completion, regardless of clinical response. The primary endpoint was pathologic response ( ≤ pT1) rate ≥ 55% (exact Binomial one-sided test). Pts not undergoing RC were deemed non-responders regardless of clinical stage after DD-GC. Pts receiving < 3 cy were inevaluable and replaced. All pts were evaluable for toxicity. Results: 49 pts (40 male) were enrolled. Median age was 64 (range: 37-78). Clinical stage was T2N0 (32 pts), T3N0 (12 pts), and T4aN0 (5 pts). Toxicities resulting in cy delay and/or dose modifications included thrombocytopenia (9 pts), renal insufficiency (5 pts), vascular access complication (2 pts), ototoxicity (1 pt), significant urinary symptoms (1 pt), and transient ischemic attack (1 pt). Three pts are inevaluable for the primary endpoint ( < 3 cy). As of 9/7/15, 2 pts are pending RC. Of the 44 pts evaluable for response to date, 31 completed 6 cy of DD-GC, 6 pts completed 5, 3 pts completed 4, and 4 pts completed 3 (median: 6 cy). The median time to RC was 46 days. Four of 44 pts did not undergo RC (consent withdrawal, pt refusal, disease progression prior to RC, death from other causes). Trial accrual has closed with completion of clinical and pathologic data expected by 11/1/15. Of 40 pts with RC pathology available to date, 24 (60%) were ≤ pT1 and 7 (18%) were pT0. Conclusions: Six cy of DD-GC is an active well-tolerated neo chemotherapy regimen in pts with MIBC. The pathologic response rate is encouraging. Thrombocytopenia was the most common toxicity resulting in cy delays/dose modifications. Clinical trial information: NCT01589094.
Racial disparities in quality metrics of muscle invasive bladder cancer (MIBC).
Authors: Mullane Stephanie A. , Meyer Christian , Choueiri Toni K. , Preston Mark A , Nguyen Paul L. , Bellmunt Joaquim , Trihn Quoc-Dien 
Published: February 2017

442 Background: There is conflicting evidence regarding MIBC treatment and outcomes. Our aim was to assess the variation in four quality metrics (neoadjuvant chemotherapy, time to treatment ≤ 3 months, ≥ 10 lymph nodes removed, use of continent urinary diversion) according to race. Methods: Using the National Cancer Database (NCDB), we identified 17,944 MIBC patients undergoing radical cystectomy. Race was stratified into non-Hispanic White (nHW), African-American (AA), Asian (A) and Hispanic/Latino (H). Uni- and multivariable analyzes examined the association between race and receipt of quality metrics, accounting for baseline characteristics. Cox regression model was used to calculate differences in overall survival(OS). Results: Baseline characteristics (insurance status, income, education, age, sex, facility type, Charlston Comorbidity Index) were significantly different between races. We did not observe any difference in the number of quality metrics received ( ≤ 1 vs ≥ 2) according to race (p = 0.161). However, there were significant differences for time to treatment and diversion type (p = 0.002, 0.012). Blacks had a significantly worse OS after adjustment for significant confounders (OR: 1.224, CI: 1.113-1.347). Conclusions: Even after accounting for treatment disparities, AA have a worse OS, warranting further investigation into potential biologic and epidemiologic factors affecting race and MIBC.
Predictive models for improved prognostication and selection of neoadjuvant and adjuvant systemic chemotherapy in upper tract urothelial cell carcinoma.
Authors: Vernez Simone Lucia , Lotan Yair , Shariat Shahrokh F. , Sagalowsky Arthur I. , Morgan Jacob B , Raman Jay D. , Wood Christopher G. , Weizer Alon Z. , Roscigno Marco , Montorsi Francesco , Bolenz Christian , Kassouf Wassim , Margulis Vitaly , Youseff Ramy F 
Published: February 2017

456 Background: Chemotherapy is still underutilized in management of upper tract urothelial carcinoma (UTUC). We created pre and post-operative predictive tools combining independent prognostics to guide selection of patients for neoadjuvant and adjuvant chemotherapy. Methods: From the UTUC collaboration database (1,453 patients who underwent radical nephroureterectomy [RNU] at 13 academic institutions); a preoperative predictive model was created using 659 patients in whom all preoperative prognostic variables were available and a post-operative model was created using 586 patients with non-metastatic/ high-grade UTU. After multivariable survival analyses, a backward step-down selection process was applied to create a preoperative nomogram. Internal validation was performed using 200 bootstrap resamples. For the postoperative model, TALL score was created based on the sum of the independent prognostic variables. Results: Preoperative model: Grade, architecture and location of the tumor were independently associated with nonorgan confined disease. A nomogram including these 3 variables achieved 76.6% accuracy in predicting nonorgan confined upper tract urothelial cancer. Postoperative model: TALL score (1-7) was the sum of T ( ≤ T1 = 1, T2 = 2, T3 = 3 and T4 = 4), A (papillary = 0 and sessile = 1), LVI (absent = 0 and present = 1) and L (lymphadenectomy = 0 and no lymphadenectomy = 1). Five-year disease-free survival (DFS) and cancer-specific survival (CSS) were stratified into four risk categories according to the TALL score: low (TALL 0-2; 86 % DFS and 90 % CSS), intermediate (TALL = 3; 71 % DFS and 75 % CSS), high (TALL = 4; 57 % DFS and 58 % CSS) and very high risk (TALL ≥ 5; 34 % DFS and 38 % CSS) using Kaplan-Meier survival analyses. TALL score was externally validated in a single-center cohort of 85 UTUC patients. Conclusions: We developed validated multivariable prognostic tools for prediction of locally advanced UTUC and oncological outcomes after RNU for UTUC. These prediction models can be used for patient counseling, selection for neoadjuvant/adjuvant systemic therapies and design of clinical trials.
A non-invasive urine exosome gene expression assay (ExoIntelliScore Prostate) to predict pathologic stage and grade in the prostatectomy specimen.
Authors: Donovan Michael , Eastham James Andrew , Patel Vipul , McKiernan James M , Noerholm Mikkel , Belzer Susan , Bentink Stefan , O'Neill Vince 
Published: February 2017

46 Background: Non-invasive screening tools that add predictive value for identifying high-grade, Gleason score (GS) ≥7 should impact on the current diagnostic and subsequent treatment decision process. We have developed standardized processes to isolate exosomal-RNA from first-catch, non-DRE, urine specimens and have validated a three gene signature (ExoIntelliScore Prostate) that reliably differentiates GS7+ from GS6 and benign at the time of an initial biopsy. In addition to the biopsy outcomes, we sought to understand the performance of the assay in predicting objective pathology in the prostatectomy specimen. Methods: Pre-radical prostatectomy first-catch non-DRE urine specimens were collected from 5 urology practices (academic/community practices) without preservative, stored at 2-8C (up to 2 weeks) and shipped on ice to a central laboratory (Exosome Diagnostics, St. Paul, MN). Exosomes were isolated and RNA extraction performed. RT-qPCR RNA copy numbers of ERG and PCA3 were normalized to SPDEF. Spearman and Pearson correlation along with AUC was used to evaluate performance. Results: Pre-RP urine samples from 430 patients were collected: 16% GS6, 45% GS7 (3+4), 39% (>/=GS4+3) and 85% PSA <10 ng/mL. 359 patients had complete clinical and ExoIntelliScore Prostate assay results with comparable demographics. Importantly, the Exo106 significantly correlated with prostatectomy GS (p=0.025; Spearman’s rank-order). In addition, Exo106 significantly correlated with both tumor volume and pathologic stage (p=0.002, Pearson). Conclusions: A previously validated non-invasive urine exosome gene signature (ExoIntelliScore Prostate) accurately reflects what is present within the prostatectomy specimen with respect to grade, stage and tumor volume. Such information could be incorporated into the treatment decision process, including active surveillance.
Differential expression of FOXF1 in bladder cancer metastases and association with established bladder cancer subtypes.
Authors: Sundi Debasish , Choi Woonyoung , Jayaratna Isuru Sampath , McConkey David James , Dinney Colin P. N. 
Published: February 2017

464 Background: FOXF1 is a transcription factor that may act as a tumor suppressor by interaction with p53. We identified FOXF1 to be highly differentially expressed in a discovery set of primary bladder cancers and matched nodal metastases. Here we study FOXF1 in preclinical models and define the association of FOXF1 with clinical bladder cancer phenotypes in several independent cohorts. Methods: Whole genome mRNA gene expression profiling (GEP) using Illumina HT12v3-4 chips was performed on paired primary tumors and nodal metastases from a cystectomy cohort. Among the top differentially expressed genes, FOXF1 was identified as a candidate regulator of cancer cell invasion. Murine orthotopic xenografts were established from human bladder cancer cell lines (UC-3, UC-14), and mRNA expression was assessed by real-time PCR. Four independent clinical cohorts with GEP data were subtyped as luminal, p53-like, or basal according to a validated gene expression signature (Choi et al., Cancer Cell2014). Associations between FOXF1 expression with survival after cystectomy (adjusted Cox models) and bladder cancer subtype (ANOVA) were assessed. High gene expression was defined as expression > median. Results: In the initial discovery set, FOXF1 expression was 3.6-fold lower in nodal metastases than paired primary tumors (n = 33, p < 0.001). Among xenografts with nodal metastases, FOXF1 expression was 1.4-fold lower in the metastases (n = 9, p = 0.0886). In two clinical cohorts (MDA Discovery n = 73 and GSE13507 n = 55), high FOXF1 expression was associated with improved cancer specific survival (HR = 0.35, p = 0.046) and overall survival (HR = 0.45, p = 0.006), respectively. In two other cohorts (MDA Validation n = 57 and GSE32894 n = 93), FOXF1 was not associated with survival after treatment. In all four cohorts, FOXF1 was most highly expressed in tumors subtyped as p53-like (p ≤ 0.0024 for all cohorts). Conclusions: FOXF1 is differentially expressed between primary and metastatic bladder cancer lesions. Across multiple independent cohorts, FOXF1 is more highly expressed among p53-like tumors known to be resistant to neoadjuvant chemotherapy, suggesting that this may be a novel predictive biomarker.
A multiplex immunoassay for the non-invasive detection of bladder cancer.
Authors: Rosser Charles Joel , Shimizu Yoshiko , Furuya Hideki , Bryant-Greenwood Peter , Chan Owen , Dai Yunfeng , Thornquist Mark , Goodison Steve 
Published: February 2017

471 Background: Urine based assays that can non-invasively detect bladder cancer (BCa) have the potential to reduce unnecessary and invasive procedures. The purpose of this study was to develop a multiplex immunoassay that can accurately and simultaneously monitor 10 diagnostic urinary protein biomarkers for application as a non-invasive test for BCa detection Methods: A custom electrochemiluminescent (ECL) multiplex assay was constructed (Meso Scale Diagnostics, LLC, Rockville, MD) to detect the following urinary proteins; IL8, MMP9, MMP10, ANG, APOE, SDC1, A1AT, PAI1, CA9 and VEGFA. Voided urine samples from two cohorts (cohort #1 n = 62 and cohort #2 n = 200) were collected prior to cystoscopy and samples were analyzed blinded to the clinical status of the participants. Means (±SD) and receiver operating characteristic (ROC) curve analysis were used to compare assay performance and to assess the diagnostic accuracy of the diagnostic signature. Results: Comparative diagnostic performance analyses revealed an AUROC value of 0.9258 for the multiplex assay and 0.9467 for the combination of the single-target ELISA assays (p = 0.625), so there was no loss of diagnostic utility for the MSD multiplex assay. Analysis of the independent 200-sample cohort using the multiplex assay achieved an overall diagnostic sensitivity of 0.85, specificity of 0.81, positive predictive value 0.82 and negative predictive value 0.84. Conclusions: It is technically feasible to simultaneously monitor complex urinary diagnostic signatures in a single assay without loss of performance. The described protein-based assay has the potential to be developed for the non-invasive detection of BCa.
Comprehensive genomic profiling (CGP) of advanced nonseminomatous testicular germ cell tumors (NSGCT) to reveal clinically relevant genomic alterations (CRGA) to guide targeted therapy.
Authors: Elvin Julia Andrea , Patterson Christina , Chalmers Zachary Rockow , Ali Siraj Mahamed , Brennan Timothy , Chmielecki Juliann , Stephens Phil , Boyle L. Eamonn , Ross Jeffrey S. , Miller Vincent A. 
Published: February 2017

477 Background: NSGCT, the most common solid malignancy in U.S. men ages 18-35, has a > 95% 5-year survival due to exquisite chemosensitivity; however, chemoresistant recurrences still contribute to 400 NSGCT deaths/year. We queried CGP results of the largest collection to date of recurrent NSGCT (n = 28) to identify targeted therapy options for this subset of high risk patients. Methods: DNA was extracted from 28 FFPE NSGCT clinical specimens. Hybridization captured libraries of 236 (FoundationOne, n = 20) or 305 (FoundationOne, n = 8) genes, plus select introns frequently rearranged in cancer were sequenced to high ( > 605x), uniform coverage. All classes of genomic alterations (GA; base subs, in/dels, rearrangements, and copy number alterations) were evaluated. CRGA were defined as GA associated with on-label targeted therapies and targeted therapies in mechanism-driven clinical trials. CGP coverage data was used to assess for chromosome 12p arm amplifications. Results: 28 samples (29% primary, 71% metastasis) from patients (avg 33.7 y) with recurrent NSGCT of predominant pattern of yolk sac tumor (43%), embryonal carcinoma (18%), choriocarcinoma (18%), or unspecified/mixed (21%) were profiled. 57% of NSGCT had chromosome 12p amplification ( > 6 copies). 89% had at least one GA not localized to chromosome 12p, including CRGA of CRKL (11%), MCL1 (11%), MDM2 (11%), GNAS (11%), KRAS (SV 7%), AURKA (7%), KIT (7%). CRGA in each of: AKT1, AKT2, BRAF, ERBB2, NF1, PIK3R2, PDGFRA, STK11 were identified in a single case. To date, we are aware of one patient in whom treatment with everolimus was initiated on the basis of the CGP results (inactivating point mutations in STK11 and PIK3R2) and who experienced marker stabilization lasting 5 months suggesting a biologic effect of this therapy. Conclusions: GA not accounted for by 12p amplification are present at a higher frequency than previously reported in recurrent or treatment-resistant NSGCT. The prevalence of CRGA and clinical response to targeted therapy in one such patient support the utility of CGP to identify additional therapeutic options for high risk NSGCT and warrants additional study.