bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient derived xenografts of upper tract urothelial carcinoma: A potential tool for personalized medicine.
Authors: Kim Kwanghee , Murray Katie S , Bagrodia Aditya , Audenet Francois , Jebiwott Sylvia , Gordon Benjamin , Somma Alex , LaRosa Stephen , Dong Yiyu , Alvim Ricardo , Hakimi A. Ari , Hsieh James , Al-Ahmadie Hikmat , Rosenberg Jonathan E. , Solit David B. , Coleman Jonathan 
Published: March 2017

344 Background: Historically, upper tract urothelial carcinomas (UTUC) are treated similarly to urothelial carcinoma of the bladder (UCB). However, compared to UCB, UTUC demonstrates a more aggressive clinical course which may be explained by significant differences in mutational frequencies between UTUC and UCB that were reported using a customized exon capture sequencing assay (the MSK-IMPACT assay). A major limitation in the advancement of the UTUC field is the lack of appropriate models specific to the disease. The objective of this study was to develop and evaluate preclinical models that would recapitulate treatment responses observed in patients. Methods: 35 surgical specimens from nephroureterectomy of patients with UTUC were implanted into immunocompromised NOD-SCID IL2Rg−/− (NSG) mice. The histological and the genomic characterization of patient tumors and PDXs were examined by a board certified pathologist and MSK-IMPACT assay, respectively. Cell lines were also established to assess histologic and genetic fidelity. Chemosensitivity of PDX models was assessed using a 4 week cycle of gemcitabine/cisplatin (or carboplatin) administration and analysis of tumor growth was performed using a Two-way ANOVA test. Results: 12 patient-derived xenograft (PDX) models were established with a success rate of 34% (12/35) and a 14% (3/21) success in developing cell lines. Both models were highly reflective of their original tumors in terms of histology and genomic characteristics in mutation status and copy number alterations. For a representative PDX, chemosensitivity experiments identified gemcitabine/carboplatin as a potentially effective combination, which was also used in the clinical scenario with a therapeutic response. Chemosensitivity of additional PDXs is continuing to be investigated to potentially guide post-operative decision making for treatment of the patient’s clinically. Conclusions: We developed a cohort of stable PDX models and cell lines for UTUC that maintains the genetic characteristics of the patient’s initial tumor. The continued development of these models may facilitate personalized medicine strategies in the treatment of UTUC.
Pertuzumab plus trastuzumab for HER2-positive metastatic urothelial cancer (mUC): Preliminary data from MyPathway.
Authors: Bryce Alan Haruo , Kurzrock Razelle , Meric-Bernstam Funda , Hurwitz Herbert , Hainsworth John D. , Spigel David R. , Bose Ron , Swanton Charles , Burris Howard A. , Guo Shuangli , Yoo Bongin , Beattie Mary Stanley , Tayama Darren , Sweeney Christopher 
Published: March 2017

348 Background: Patients (pts) with mUC have few treatment options beyond the second-line setting. HER2 gene amplification has been reported in a minority of pts with UC, but there have been anecdotal reports of the activity of HER2-targeted agents. MyPathway is a multi-basket study evaluating the efficacy and safety of targeted therapies in non-indicated tumor types harboring relevant molecular alterations. We present preliminary data for pts with HER2-positive mUC receiving HER2-targeted treatment with pertuzumab + trastuzumab. Methods: MyPathway (NCT02091141) is an open-label, multicenter, phase IIA study. Pts in this subset analysis had refractory mUC with HER2 amplification or putative activating mutations by gene sequencing, FISH, or IHC. Pts received standard doses of pertuzumab + trastuzumab without chemotherapy until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed overall response rate (RECIST v1.1). Results: As of July 31, 2016, 12 pts with platinum-resistant HER2-positive mUC (HER2-amplified, n=9; HER2-mutated, n=3) have been enrolled. At a median follow-up of 5.4 (range 0.9–14.5) mos, 1 pt had complete response (CR, ongoing at 12.5 mos), 2 had partial responses (PR; duration of response, 3.7 and 5.5 mos), and 2 had stable disease (SD) for >4 mos (Table). Safety was consistent with the product labels. Conclusions: Preliminary results indicate that the combination of pertuzumab + trastuzumab has activity in previously treated HER2-amplified mUC, including a durable CR in a pt with peritoneal metastases. Accrual to MyPathway is ongoing. Clinical trial information: NCT02091141. [Table: see text]
Targeting ERBB2 mutations in urothelial carcinoma.
Authors: Audenet Francois , Isharwal Sumit , Arcila Maria E. , Funt Samuel , Rosenberg Jonathan E. , Bajorin Dean F. , Bochner Bernard H. , Berger Michael F. , Al-Ahmadie Hikmat , Solit David B. , Iyer Gopa 
Published: March 2017

354 Background: ERBB2 encodes human epidermal growth factor receptor 2 (HER2), a member of the EGFR family of receptor tyrosine kinases that signal through the pro-oncogenic MAP- and PI3K-kinase pathways. ERBB2 is altered by amplification and/or overexpression in various cancers, including urothelial carcinoma (UC). These alterations could confer sensitivity to ERBB2 kinase inhibitors in selected patients with UC. Methods: Patients diagnosed with UC were enrolled onto an institutional review board approved prospective sequencing protocol. Tumor and matched germline DNA were analyzed using the MSK-IMPACT assay that detects alterations in 410 oncogenes and tumor suppressor genes, including ERBB2. Results: Overall, 449 samples from 429 patients were sequenced from 2013 to August 2016. Genetic alterations in ERBB2 were found in 78 samples (17%). At the time of sample collection, 24 patients (31%) had non-muscle invasive bladder cancer (NMIBC), 30 patients (38%) had muscle-invasive bladder cancer (MIBC), 18 (23%) had metastatic disease and 7 (8%) had upper tract urothelial carcinoma (UTUC). Sixteen samples (21%) came from metastatic specimens. Of the observed 78 ERBB2 alterations, 20 samples had amplifications (26%) and 58 samples had mutations (74%). Seven samples (9%) had both. We identified 71 missense, 2 inframe and 1 fusion alteration, corresponding to a somatic mutation rate of 13.1%. Thirty-seven mutations (50%) were functionally characterized hot spots that are potentially actionable. Of note, the hot spot mutation S310F/Y was found in 29 samples (37%). Its mutation allele frequency varied significantly. There was a trend towards a higher mutant allele frequency of S310F/Y in higher stage disease without reaching statistical significance (Table). In our cohort, 3 patients were enrolled in clinical trials with ERBB2 kinase inhibitors based upon the presence of an ERBB2alteration. Conclusions: ERBB2is a frequent mutation at different stages of UC. In higher stage disease, clonal selection of the S310F/Y hot-spot mutation may occur and requires further study. [Table: see text]
Prognostic value of PD-1 and PD-L1 expression in patients with high-grade urothelial carcinoma of the upper urinary tract.
Authors: Krabbe Laura-Maria , Heitplatz Barbara , Hutchinson Ryan C , Woldu Solomon L , Preuss Sina , Wood Christopher G. , Karam Jose A. , Weizer Alon Z. , Raman Jay D. , Remzi Mesut , Rioux-Leclercq Nathalie , Haitel Andrea , Roscigno Marco , Bolenz Christian , Bensalah Karim , Sagalowsky Arthur I. , Shariat Shahrokh F. , Lotan Yair , Xylinas Evanguelos , Margulis Vitaly 
Published: March 2017

358 Background: To investigate the prognostic value of PD-1 and PD-L1 expression in patients with high-grade upper tract urothelial carcinoma (UTUC). Methods: Tissue microarrays were created using 448 patients from the International UTUC collaboration who underwent extirpative surgery for high-grade UTUC and stained for PD-1 (antibody (AB): NAT105, diluted 1:250 from Ventana) and PD-L1 (AB: E1L3N prediluted from Cell Signaling). PD-1 and PD-L1 expression was assessed in a semi-quantitative fashion and any percentage of staining of the tumor cells (PD-L1) and tumor-infiltrating lymphocytes (PD-1) was considered positive. Univariate (UVA) and multivariate analyses (MVA) were performed to assess independent prognosticators of oncological outcomes. No funding was received. Results: Median age of the cohort was 69.2 years and 56.5% of patients were male. PD-L1 and PD-1 were positive in 24.1% and 37.5% of patients. PD-L1 positivity was associated with favorable pathological stage, where as PD-1 positivity was significantly associated with pelvicalyceal location, lymph node metastases, non-organ confined disease, presence of lymphovascular invasion, sessile architecture, necrosis, concomitant CIS, and history of non-muscle invasive bladder cancer. PD-L1 positivity was not significantly associated with survival outcomes. In Cox regression UVA, PD-1 positivity was associated with worse recurrence-free survival (RFS) (HR 1.5 (95%CI 1.08-2.14, p=0.016)), cancer-specific survival (CSS) (HR 1.5 (95%CI 1.07-2.19, p=0.021)), and overall survival (OS) (HR 1.5 (95%CI 1.10-1.97, p=0.009)). However in MVA, PD-1 positivity was not found to be an independent predictor of RFS, CSS or OS. Conclusions: PD-1 positivity of tumor-infiltrating lymphocytes was associated with adverse pathological criteria and was a significant prognosticator for RFS, CSS and OS on UVA in patients treated with extirpative surgery for high-grade UTUC in a large, multi-institutional cohort. In MVA, the independent prognostic value of PD-1 was not confirmed. PD-L1 positivity was associated with lower tumor stage, but not with other pathological characteristics or survival outcomes.
Glucose metabolism and bladder cancer.
Authors: Lee Eugene K. , Pirani Karim , Holzbeierlein Jeffrey M. , Martin Paige , Rangarajan Parthasarathy , Hamilton-Reeves Jill , Anant Shrikant 
Published: March 2017

359 Background: To understand and evaluate the role of glucose metabolism in bladder cancer growth, in the identification of disease, and development of potential treatment strategies. Methods: UMUC3, T24 and 253JBV cells were grown in varying glucose concentrations (25, 100 and 200mg/dl) and cell proliferation assay with Vi-Cell was performed. Next, we used Qiagen PCR array of glucose metabolic pathway of the UMUC3 cell line under different glucose concentrations. PKM2 is a driver of glycolysis and exists in an inactive dimer or active tetramer. Dimer PKM2 also known as Tumor M2-PK was measured in urine samples of bladder cancer patients using a commercially available ELISA kit (ScheBo Biotech AG). Lastly, Shikonin, a PKM2 inhibitor was evaluated as an inhibitor of bladder cancer cell proliferation using Vi-Cell. Results: Increased glucose concentration 200mg/dl leads to increased proliferation in bladder cancer cells while decreased concentration of glucose; 25mg/dl reduces proliferation compared to control (100). PCR array demonstrates genes in the glycolytic pathway genes are upregulated in cells that are grown in 200mg/dl glucose media and the TCA cycle genes are upregulated in cells that are subjected to the 25mg/dl glucose media when compared to control (100mg/dl). The enzyme pyruvate kinase M2 (PKM2) controls the transition from the glycolytic pathway to TCA cycle. We have found that 9/10 (90%) of bladder cancer urine samples show elevated levels of tumor M2-PK (>104) compared to urine from two normal subjects (~30 units ) using a commercially available ELISA kit. Conclusions: Increased glucose concentration 200mg/dl leads to increased proliferation in bladder cancer cells while decreased concentration of glucose; 25mg/dl reduces proliferation compared to control (100).
Prescribing preferences of U.S. oncologists for patients (Pts) with metastatic urothelial carcinoma (mUC) at first recurrence: Impact of novel agents.
Authors: Lankford Maria L. , Willey Joanne P. , Buettner Arden , Britton Susan Lynne , Scharf Mitch , Dreicer Robert 
Published: March 2017

365 Background: In May 2016 atezolizumab (A) was approved for the treatment of pts with locally advanced or mUC who have disease progression during or following platinum-containing chemotherapy (PCCT), or within 12 months (mos) of neoadjuvant or adjuvant treatment with PCCT. We evaluated prescribing preferences (PPrefs) of 248 U.S-based oncologists for 1strecurrence treatment across a range of clinical scenarios prior to and following A approval. Methods: PPrefs were assessed through a validated, case-based market research tool (Challenging Cases). Assessment dates were 3/5 and 4/30 (PRE-) and 8/6 (POST-approval). Data were acquired using blinded, audience-response technology. A core scenario (CS) and 5 variant scenarios (V1, 2, 3, 4, 5) were utilized. CS: 69-year-old pt with muscle invasive bladder cancer, with a CrCl 62 ml/min, Hgb 12.5, and PS 1, recurs in the liver and bone 18 months after receiving neoadjuvant gemcitabine/cisplatin and a radical cystectomy. V1: Same as CS but with reduced CrCl 48 ml/min. V2: Same as CS but recurrence at 6 months. V3: Same as V2 but multiple comorbidities and PS 2. V4: Same as CS but age 79. V5: Same as V4 but multiple comorbidities. The same query was posed in each setting: What therapy would you choose? Results: See Table. Conclusions: Following the approval of A, overall PPref of most regimens offered decreased across nearly all 1st recurrence scenarios in favor of A. This is particularly stark in platinum unfit (older, comorbid, poor PS) pts. This highlights the previously unmet medical need in the PCCT pre-treated mUC pts. [Table: see text]
Increased utilization of advanced imaging technology and its economic impact for patients diagnosed with bladder cancer in the United States.
Authors: Kosarek Christopher David , Huo Jinhai , Baillargeon Jacques G. , Kuo Yong-Fang , Fang Justin Edwin , Ghaffary Cameron , Kerr Preston , Kim Simon P. , Orihuela Eduardo , Tyler Douglas S. , Giordano Sharon Hermes , Freedland Stephen J. , Kamat Ashish M. , Williams Stephen Bentley 
Published: March 2017

368 Background: This study examined utilization patterns and predictors for use of positron emission tomography-computed tomography (PET/CT), magnetic resonance imaging (MRI), and computed tomography (CT) among Medicare beneficiaries diagnosed with bladder cancer. Methods: We used the Surveillance, Epidemiology and End Results (SEER)-Medicare linked databases to analyze claims data for 36,855 patients aged 60-90 years diagnosed with bladder cancer from 2004 to 2011. The Cochran-Armitage test for trend was used to determine whether significant changes in the proportion of patients receiving advanced imaging after cancer diagnosis occurred during the time interval; trends in the usage of the imaging modality types were assessed. Multivariable logistic regression modeling was conducted to analyze potential demographic and clinical predictors associated with receipt of advanced imaging. The costs of imaging were measured using Medicare payments. Results: While the overall trend of imaging use remained essentially unchanged over the study period, there was a significant decrease in the proportion of patients who received conventional imaging modalities (MRI and CT; P < .05) and a significant increase in the proportion of patients receiving the more advanced imaging modality (PET/CT; P < .0001). On multivariable analysis, receipt of PET/CT was significantly higher in female patients, Non-Hispanics, residents in West Census region, patients with higher grade tumors, those diagnosed with advanced stage disease, hydronephrosis, and those that received radical cystectomy and chemotherapy. In the cost analysis, the estimated national excess medical spending for advanced imaging was $6.1 million. Conclusions: The sharp increase of advanced imaging (PET/CT) and substantial costs associated with this rapid adoption as we have documented suggests that further efforts should be made to evaluate the clinical and economic benefits of PET/CT imaging and to elucidate its appropriateness of use among bladder cancer patients.
Dissecting the genomic landscape of metastatic bladder cancer using circulating tumor DNA.
Authors: Struss Werner J. , Vandekerkhove Gillian , Annala Matti , Todenhoefer Tilman , Beja Kevin , Eigl Bernhard J. , Wyatt Alexander William , Black Peter C. 
Published: March 2017

378 Background: To date, only limited data are available on genomic alterations present in metastatic lesions of patients with metastatic urothelial carcinoma (mUC). The constant release of cell free DNA (cfDNA) from tumor cells into the peripheral blood stream may provide a valuable source for detection of cancer associated somatic copy number variations and mutations. The aim of this project was to evaluate the feasibility of detecting clinically relevant genomic alterations in mUC by next-generation sequencing (NGS) of circulating cfDNA. Methods: Peripheral blood (20ml) was collected from 15 patients with mUC before chemotherapy. Plasma cfDNA was isolated using the QIAAmp Circulating Nucleic Acid Kit. Germline control DNA was extracted from peripheral blood mononuclear cells (PBMCs) using the DNEasy Kit (Qiagen). We performed deep (>500X) targeted DNA sequencing on cfDNA and germline DNA using a custom NimbleGen SeqCap EZ Choice Library and Illumina sequencers. Our custom panel included 50 bladder cancer-relevant genes, including key tumor suppressors (e.g. TP53, RB1, CDKN2A), cell cycle drivers (e.g. CCND1, CCNE1), DNA repair genes (e.g. ATM, BAP1, ERCC2), PI3K pathway genes (e.g. PIK3CA, PTEN, AKT1), and other oncogenic pathways (e.g. RAS/RAF, EGFR, ERBB2, PPARG, FGFR3). Results: Somatic mutations and/or copy number changes were detected in 14/15 samples, with a median variant allele frequency >5%. The overall mutational landscape was highly consistent with bladder cancer, including mutations in TP53 and ARID1A (and other chromatin modifiers), as well as hotspot activating mutations in PIK3CA. Typical copy number changes, including focal amplifications of ERBB2, KRAS, and CCNE1 were detected. We identified complex gene rearrangements, including an activating FGFR3 fusion in one case. Extended analyses with a larger patient population are currently pending. Conclusions: Non-invasive characterization of genomic changes in peripheral blood of patients with mUC using NGS of plasma cfDNA is feasible in a high proportion of patients. Analysis of cfDNA might therefore provide an improved understanding of genomic changes in mUC and could be developed as a biomarker to help guide the use of targeted therapies.
Comprehensive genomic sequencing of urothelial tumors to identify rare driver genomic alterations in SMARCB1 in a subset of patients.
Authors: Gupta Sumati , Albertson Daniel Joseph , Gaston David , Heilbrun Marta Elise , Agarwal Neeraj , Liu Ting , Miller Vincent A. , Ross Jeffrey S. , Millis Sherri Z. , Ali Siraj Mahamed 
Published: March 2017

385 Background: Multiple genomic alterations leading to overlapping dysregulation of cell cycle, kinase and phosphotidyl \inositol-3-OHkinase signaling and chromatin remodeling are the hallmark of urothelial carcinoma (UC). ARID1A and SMARCA2 loss are frequently altered leading to SWI/SNF nucleosome-remodeling complex dysregulation in urothelial cancers. Mutations affecting components of the SWI/SNF complex lead to aggressive de-differentiated neoplasms. SMARCB1 loss has been implicated in malignant rhabdoid tumors, epithelioid sarcoma and renal medullary carcinoma. Upper tract UC patients with SMARCB1 loss may represent a novel, rare subset. Methods: Tissue from UC patients (n=1099) was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities; 315 genes frequently altered in cancer were assayed. One patient had an advanced poorly differentiated neoplasm and received conventional chemotherapy. Results: CGP identified 10 (1%) patients with SMARCB1 alterations and different patterns overall in GAs. Three patients (1 kidney, 1 ureter, and 1 bladder) had bi-allelic loss of SMARCB1, and 7 others had a loss of function alteration with loss of heterozygosity. These patients with SMARCB1 bi-allelic loss had few or no additional alterations, notably no alterations in TP53, CDKN2A/B, or TERT, which are observed in greater than 50% of urothelial tumors, or RB1 alterations observed in ~22% of UC. The patient treated with cisplatin based chemotherapy achieved a pathologic CR. Conclusions: Genomic profiles of tumors from patients with UC revealed a rare population of patients with alterations impacting chromatin regulation and tumor suppression, specifically through loss of SMARCB1. Tumors with SMARCB1 loss have a very low burden of genetic alterations and SMARCB1 loss or deletion may be the sole driving mutation. Conventional chemotherapy may be effective. Inhibitors of EZH2, HDAC and CDK4 may be potential treatment strategies to target this subset of tumors.
Impact of histologic subtype on bladder cancer outcome.
Authors: Washington Samuel L , Sanford Thomas , Leapman Michael S. , Meng Maxwell V. , Porten Sima P. 
Published: March 2017

391 Background: Variant histology is increasingly recognized but its impact on outcomes is less well known compared to urothelial carcinoma (UC). We aim to evaluate the impact of variant histology on bladder cancer outcomes using the National Cancer Database (NCDB), a U.S. population-based cohort capturing approximately 70% of newly diagnosed cancer cases. Methods: We identified patients with bladder cancer from 2004 to 2013 treated with radical cystectomy. We compared clinical and pathologic characteristics between those with UC and those with variant histology. Chi-square test was utilized for categorical variables and Independent Samples t-test for continuous variables. Multivariable Cox regression was used with hazard ratios (HR) and 95% confidence intervals (CI) to identify independent predictors of overall survival. Results: A total of 40,918 patients were identified with mean age 67 years, with male (75%) and Caucasian (90.9%) predominance. Median follow-up was 36.9 months (IQR 16.1-67.5). Squamous cell carcinoma (4.4%), small cell carcinoma (1.6%) and micropapillary (0.9%) were the most common variant histologies. Variant histology was found more commonly in women (35.6% vs 23.4%, p < 0.05), black (8.8% vs 5.6%, p < 0.05), stage pT3 or T4 (67% vs 50.2%, p < 0.05) and node positive (30.8% vs 26.9%, p < 0.05). In adjusted models squamous cell carcinoma (HR 1.3, 95% CI 1.2-1.4), small cell carcinoma (HR 1.6, 95% CI 1.5-1.8) and black ethnicity (HR 1.2, 95% CI 1.1-1.2) were independent predictors of increased mortality risk while micropapillary was associated with decreased risk (HR 0.8, 95% CI 0.7-1.0) after controlling for age, gender, surgical margin status, pathologic T stage, pathologic N stage and history of chemotherapy. All associations remained statistically significant (p < 0.05). Conclusions: Non-urothelial histology was associated with worse overall survival in patients with bladder cancer treated with radical cystectomy; however, contrary to some previous reports, micropapillary variant was associated with lower risk of death. In addition, black ethnicity was associated with worse survival. Further investigation is needed to explore the impact of variant histology as well as other socioeconomic factors on survival after cystectomy.