bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defining a nine-biomarker panel for predicting bladder cancer outcome in combination with smoking intensity: A report from the Los Angeles Cancer Surveillance Program.
Authors: Mitra Anirban Pradip , Castelao Jose E , Hawes Debra , Tsao-Wei Denice D , Jiang Xuejuan , Shi Shan Rong , Young Lillian L , Datar Ram H , Skinner Eila C , Stein John Peter , Groshen Susan G. , Yu Mimi C , Ross Ronald K , Skinner Donald G , Cortessis Victoria K , Cote Richard J 
Published: March 2020

4575 Background: Urothelial carcinoma of the bladder (UCB) is a disease of alterations in several cellular pathways. Routine molecular profiling studies do not account for smoking, a well established risk factor for UCB, and its influence on outcome. This study assessed the prognostic potential of a multi-pathway protein panel across all UCB stages in a population-based cohort after accounting for clinicopathologic factors and smoking history. Methods: 212 UCB patients from the LA CSP, part of the NCI/SEER cancer registry, were included. "Smoking intensity" analyzed biologic and molecular impact of smoking by combining smoking status, duration of smoking and number of cigarettes smoked daily into a composite covariate. Tumors were profiled for Bax, caspase-3, Apaf-1, Bcl-2, p53, p21, COX2, VEGF and E-cadherin alterations by IHC. Univariate analyses and multivariable modeling examined associations with outcome. Results: Median follow up was 13.2 years. Age, pathologic stage, adjuvant therapy (all p< 0.001) and surgical modality (p = 0.05) were associated with survival. Increasing smoking intensity was associated with worse outcome (P < 0.001). Apaf-1 (p = 0.005), E-cadherin (p = 0.014) and p53 (p = 0.032) were univariately prognostic; E-cadherin remained prognostic after multivariate analysis (p = 0.04). Combined alterations in all 9 biomarkers were prognostic by univariate (p < 0.001) and multivariate (p = 0.006) analysis. A multivariate model that included all 9 biomarkers and smoking intensity was more accurate in predicting prognosis than models comprising of standard clinicopathologic covariates without (p < 0.001) or with (p = 0.018) smoking intensity. Conclusions: The study confirms detrimental effects of smoking on UCB prognosis. Apaf-1, E-cadherin and p53 individually predicted UCB survival. Increasing number of biomarker alterations was significantly associated with worsening survival, although markers contained in the panel were not necessarily prognostic individually. Predictive value of the nine-biomarker panel with smoking intensity was significantly higher than that of routine clinicopathologic parameters alone.
FGFR3 protein expression and gene mutation in primary and metastatic urothelial carcinoma (UC) tumors.
Authors: Rosenberg Jonathan E. , Werner Lillian , Bamias Aristotelis , Choueiri Toni K. , Schutz Fabio A. B. , Park Rachel S. , O'Brien Robert , Guancial Elizabeth Ann , Ross Robert W , Berman David M. , Riester Markus , Lis Rosina , Loda Massimo F. , Stack Edward C. , Michor Franziska , Chehab Nabil , Molins Joaquim Bellmunt 
Published: March 2020

4577 Background: FGFR3 protein expression may represent a valid therapeutic target in metastatic UC. The prevalence of both mutation and overexpression is unknown in metastatic UC. Methods: Tissue microarrays of formalin fixed paraffin-embedded urothelial carcinomas (UC) were stained for FGFR3 by immunohistochemistry (IHC) [primary (n=250); metastatic (n=31); of which (n=14) were paired]. FGFR3 immunostaining was scored as negative or positive based on previously reported scoring systems. FGFR3 mutation in primary tumors was assessed by iPlex and confirmed by hME sequencing (n=141) or Affymetrix OncoScan FFPE Express 2.0 (primary: n=17; metastases n=31). Results: FGFR3 IHC positivity was present in 48% of metastases (95% CI=32-65%) and 26% of primary tumors, (95%=CI 21-32%), though strong staining was rare (<1%). Paired primary and metastatic tumors were both negative in 50% of cases, with 14% positive only in the metastasis, 14% positive only in the primary tumor, and 21% positive in both. If the primary tumor showed staining, 71% of the metastases showed staining. FGFR3 IHC staining did not impact overall survival (p=0.8). FGFR3 mutations were observed in 9.6% of metastatic tumors (95% CI=3.3-25%), compared to 3.5% of primary tumors (95% CI=1.5%-8%). Co-occurrence of mutation and FGFR3 DNA copy number gain was observed in one specimen. Conclusions: FGFR3 IHC staining is present 26 % of primary tumors of patients who go on to develop metastatic disease, and nearly half of metastatic tumor sites. FGFR3 mutation frequency in primary and metastatic tumor specimens is low. Further investigation of the frequency of FGFR3 protein expression in metastases is needed. The presence of FGFR3 protein by IHC staining in primary and metastatic specimens suggests that FGFR3 may represent a therapeutic target even in the absence of mutation. Further functional studies are needed.
BRCA1, RAP80, and AEG-1 mRNA expression in resectable muscle-invasive bladder cancer (MIBC) patients (p) treated with neoadjuvant cisplatin-based chemotherapy.
Authors: Font Pous Albert , Celiz Pamela , Taron Miquel , Chaib Iman , Gago Jose Luis , Mendez Pedro , Sanchez Jose Javier , Etxaniz Olatz , Cechini Luis , Pardo Nuria , Sanchez Belen , Cuadra Jose Luis , Valverde Ivana , Buisan Oscar , Ibarz Luis , Rosell Rafael 
Published: March 2020

4579 Background: Cystectomy remains the standard treatment in MIBC and only a minority of p are treated with neoadjuvant chemotherapy, suggesting that predictive markers of chemotherapy outcome are needed. Low BRCA1 mRNA expression is associated with an improvement in survival in bladder cancer p treated with cisplatin-based chemotherapy. However, BRCA1 function can be modulated by other DNA repair genes. RAP80 is required for the accumulation of BRCA1 to sites of DNA breaks, and cells depleted of RAP80 exhibit hypersensitivity to irradiation. AEG-1 can induce BRCA1 expression and cause chemoresistance. Methods: Paraffin-embedded pre-treatment tumor samples were collected by transurethral resection from 65 p with resectable MIBC stage T2-4N0M0 treated with neoadjuvant cisplatin-based chemotherapy. Gene expression levels of BRCA1, RAP80 and AEG-1 were quantified by real-time quantitative PCR. Expression levels were divided into terciles and correlated with median survival (MS). Results: 33 p were treated with cisplatin, methotrexate and vinblastine (CMV) and 32 p with cisplatin and gemcitabine. Chemotherapy was followed by cystectomy in 60 p. Overall MS was not reached and 5-year survival was 51%. MS was 45 months (m) and 5-year survival was 27% in 21 p with high BRCA1 mRNA levels vs 168 m and 59% in 44 p with low and intermediate levels (p=0.05). MS was 50 m in 15 p with high AEG-1 levels, 45 m in 15 p with intermediate levels, and was not reached in 18 p with low levels, although these differences were not statistically significant (p=0.3). No differences in MS were observed according to RAP80 mRNA levels. Conclusions: BRCA1 can be a useful marker to predict the efficacy of neoadjuvant chemotherapy. Cisplatin-based chemotherapy should be recommended in p with low/intermediate BRCA1 expression. Further studies with larger numbers of p are warranted to elucidate the role of AEG-1 in this setting.
Phase II trial of neoadjuvant gemcitabine (G) and cisplatin (C) with sunitinib in patients (pts) with muscle-invasive bladder cancer (MIBC).
Authors: Balar Arjun Vasant , Iyer Gopa , Apolo Andrea Borghese , Regazzi Ashley Marie , Garcia-Grossman Ilana Rebecca , Pendse Deepa , Ostrovnaya Irina , Chou Joanne F. , Bochner Bernard , Dalbagni Guido , Herr Harry W. , Milowsky Matthew I. , Bajorin Dean F. 
Published: March 2020

4581^ Background: Response to neoadjuvant chemotherapy (NC) prior to radical cystectomy (RC) predicts improved overall survival (OS) in MIBC. Associations with enhanced survival include complete pathologic response (pT0; Grossman, NEJM 2003) and eradication of the muscle-invasive component (<pT2; Splinter, J Urol 1992). Sunitinib (S) is active in pretreated pts with advanced disease. We tested if S added to GC was safe, improved the rate of pT0, and improved the rate of <pT2. Methods: Cisplatin-eligible pts with cT2-4aN0 bladder cancer received G 1000 mg/m2 and C 35 mg/m2 on day (D) 1 and D8 with S 25 mg orally daily D1-14 of a 21D cycle for 4 cycles. RC plus pelvic lymph node dissection was required to assess response of pT0 or <pT2. A Simon’s Minimax 2-stage design was used to test a null (H0) pT0 rate ≤ 20% against alternative (H1) pT0 rate ≥ 40% with Type I and II error rates of 0.05 and 0.10 respectively. Enrollment to the 2nd stage of 45 patients was planned if ≥ 6 of the initial 24 evaluable pts achieved pT0. Primary endpoint was pT0N0 and secondary endpoints were: response defined as <pT2N0; safety; time to progression (TTP), and OS. Results: 18 pts (15M, 3F), median age 63 (54-76) were enrolled from 6/09 and 10/11 after which financial support was withdrawn. 3 pts were inevaluable for response endpoints due to: 1.) withdrawal of consent, 2.) declining any surgery, 3.) partial cystectomy instead of RC. All 18 were evaluable for safety, TTP and OS. 1 of 15 pts had pT0N0 (6.6%; 95% CI 0.34 – 29.8%) and 5 had <pT2N0 (33%; 95% CI 15-58%). 4 of 5 pts with status <pT2N0 were pTisN0. Median TTP was 10 months (95% CI 3.5-NR). 3 pts were deceased at time of analysis; median OS not reached. Neutropenia due to the 3 drug combination required routine GCSF support on day 8 of each cycle. Grade 3/4 toxicities were anemia (11 pts), neutropenia (6), thromboembolic events (2), febrile neutropenia (2) and infection (2). Conclusions: Despite incomplete accrual, the pT0 rate was low suggesting that S does not add to GC. Residual non-invasive disease (<pT2) was common, including a large proportion of pts with pTisN0. Given these findings, response criteria for future NC studies should consider either <pT2 or < pTis as the primary endpoint.
A phase II trial of neoadjuvant dasatinib (Neo-D) in muscle-invasive urothelial carcinoma of the bladder (miUCB): Hoosier Oncology Group GU07-122 trial.
Authors: Hahn Noah M. , Daneshmand Siamak , Posadas Edwin M. , Koch Michael O. , Bihrle Richard , Foster Richard , Masterson Timothy A. , Cheng Liang , Liu Ziyue , Breen Timothy , Fleming Mark T. , Lance Ray , Ryan Christopher W. , Corless Christopher L. , Galsky Matt D. , Alva Ajjai Shivaram , Mitchell Carmen , Shen Steven S. , Lerner Seth P. , Sonpavde Guru 
Published: March 2020

4586 Background: Neoadjuvant chemotherapy (NC) preceding radical cystectomy (RC) is an accepted standard for miUCB patients (pts). Dasatinib (D) is an oral tyrosine kinase inhibitor of Src mediated signaling, and has demonstrated promising preclinical anti-tumor activity, providing a rationale to evaluate Neo-D in human miUCB. Methods: A phase II trial was conducted to assess the safety and biologic activity of Neo-D in miUCB. Key eligibility criteria included: miUCB (T2-T4a, N0, M0), unsuitable or willing to forego platinum-based NC, adequate TURBT tissue available, ECOG PS 0-1, creatinine < 2 x ULN. Pts received D 100 mg po once daily for 28 +/- 7 days followed by RC 8-24 hours after the last dose. The primary endpoint was feasibility defined as > 60% of pts completing therapy without treatment-related dose limiting toxicity (DLT) specified as grade 4 hematologic toxicity, grade 3 non-hematologic toxicity, or any grade 2 toxicity > 14 days. Secondary endpoints included the assessment of biologic activity as assessed by pre- and post-treatment tumor tissue immunohistochemistry analysis of Src, pSrc, EPHA2, pEPHA2, FAK, pFAK, AKT, pAKT, CD31, Ki67, TUNEL. Results: The study completed accrual with enrollment of 25pts. 22 and 24 pts were respectively evaluable for feasibility and toxicity endpoints. Patient demographics included: median age – 62, M/F – 20/5, ECOG PS 0/1 – 19/6. Baseline tumor staging included: T2 – 17, T3 – 7. The study achieved its primary endpoint with 15 pts (68%) completing therapy without treatment related DLT’s. DLT’s included: fatigue (2 pts), DVT/PE, abdominal pain, supraventricular tachycardia, enteric fistula, and hematuria (1 pt each). Frequency of highest observed toxicity on study included: Grade 1 – 13%, Grade 2 – 38%, Grade 3 – 46%, Grade 4 – 4%. Among 22 patients, pathologic stage at RC was T1/Tis in 3 pts (14%), ≥T2 in 19 pts (86%), and node positive in 6 pts (27%). Correlative analyses of pre- and post-treatment tumor Src signaling are ongoing and will be updated at the meeting. Conclusions: Neoadjuvant dasatinib preceding RC is feasible in miUCB patients. Tumor tissue correlative studies may provide directions for further development.
Clinical validation of the 7th AJCC-TNM nodal staging system in lymph node-positive patients undergoing radical cystectomy.
Authors: Skinner Eila C. , Bruins Harman Maxim , Dorin Ryan Paul , Rubino Barbara , Miranda Gus , Cai Jie , Daneshmand Siamak 
Published: March 2020

4588 Background: The AJCC TNM staging system for bladder cancer has recently been updated. In the new 7th edition, staging of lymph node (LN) metastases is based on anatomical location instead of size as in the former 6th edition. This study evaluated whether the prognostic value of nodal staging according to the 7th edition is superior to the 6th edition. Methods: Prospectively collected data of patients who underwent radical cystectomy (RC) at a high-volume center between 2002 and 2008 were reviewed. Patients who underwent RC for non-urothelial cancer, received neo-adjuvant therapy or had non-LN metastatic disease at the time of RC were excluded. All patients underwent RC with extended lymphadenectomy up to the inferior mesenteric artery. LNs were submitted in predesignated anatomically defined packets. Detailed data on the number, size and location of LN metastases were recorded. Both the 6th and 7th edition AJCC TNM editions were used to stage LN positive (LN+) disease. Median follow-up time was 2.8 years. Kaplan-Meier analysis was used to estimate overall survival (OS) and recurrence-free survival (RFS). Results: A total of 637 patients were identified of whom 141 patients (22.1%) had LN+ disease. In total, 83 patients (58.9%) received adjuvant chemotherapy. Administration of adjuvant chemotherapy did not differ significantly per N-stage according to both editions. Based on the 6th edition, 31 patients (22.0%) had N1 disease, 105 patients (74.5%) N2 disease and 5 patients (3.5%) N3 disease. Three-year RFS rates for N1, N2 and N3 disease were 51%, 43% and 0% respectively (p = 0.87). Based on the 7th edition, 29 patients (20.6%) had N1 disease, 60 patients (42.6%) N2 disease and 52 patients (36.9%) N3 disease. Three-year RFS rates for N1, N2 and N3 disease were 51%, 42% and 45%, respectively (p = 0.84). Conclusions: Neither the AJCC-TNM 7th edition (location-based) LN staging nor the 6th edition (size-based) staging performed well as a prognostic tool for the patients in this cohort. The new staging system moved a large percent of patients into the N3 category, which did not have a worse prognosis than either the N1 or N2 categories. A better staging system for LN+ bladder cancer patients needs to be developed.
Novel oncogenic function of ATDC in bladder cancer.
Authors: Palmbos Phillip Lee , Wang Lidong , Yang Huibin , Detzler Taylor , Ney Gina , Lotan Yair , Healy Patrick N. , Daignault-Newton Stephanie , Kunju Priya , Kumar Chandan , Ljungman Mats , Liebert Monica , Simeone Diane M. 
Published: March 2020

4591 Background: Bladder cancer is a common and deadly disease, but the molecular events leading to its initiation and progression are incompletely understood. We recently identified Ataxia-Telangiectasia Group D Associated (ATDC) as a novel oncogene which drives tumor proliferation and invasion in pancreatic carcinoma (Cancer Cell, 2009). In this study, we describe the role of ATDC as an oncogene in bladder cancer. Methods: To further determine the oncogenic role of ATDC, we generated ATDC transgenic (tg) mice in which ATDC expression was driven by a CMV promoter and characterized the resulting tumors. Results: Interestingly, the dominant phenotype in these mice was the development of both non-invasive and invasive urothelial carcinomas (9% and 20% respectively, average age of onset 10-12 months of age). Histologically, these tumors were indistinguishable from human urothelial carcinomas. Gene expression profiling of invasive tumors derived from ATDC tg mice demonstrated a marked overlap with gene signatures of human invasive bladder cancers. ATDC was the 11th most highly up-regulated gene in bladder cancers represented in the Oncomine gene expression database. Analysis of a human bladder cancer tissue microarray (311 samples) by IHC showed elevated expression in 70% (173/252) of muscle-invasive carcinomas, 22% (5/23) of papillary tumors and little or no expression in normal bladder urothelium. ATDC tg mouse bladder tumors demonstrated loss of p53 signaling and down-regulation of PTEN expression, which correlated with ATDC induced methylation of the PTEN promoter by DNMT3A. Furthermore, ATDC knock-down in invasive cancer cell lines resulted in decreased proliferation, invasion and reactivation of p53-mediated signaling and PTEN expression. Conclusions: ATDC is a novel oncogene that is highly expressed in human bladder cancers and is sufficient to drive the development of invasive bladder tumors in tg mice. The mechanism by which ATDC drives bladder cancer formation involves alterations in p53 and PTEN pathways known to be important in bladder tumorigenesis.
Interim results of phase II trial of the cyclin-dependent kinase 4/6 inhibitor PD-0332991 in refractory retinoblastoma protein positive germ cell tumors.
Authors: Vaughn David J. , Gallagher Maryann , Lal Priti , Rosen Mark Alan , Hwang Wei-Ting , Einhorn Lawrence H. , O'Dwyer Peter J. 
Published: March 2020

4596 Background: Deregulation of the retinoblastoma pathway in germ cell tumors (GCT) has been well documented. We previously reported that PD-0332991, a selective oral inhibitor of cyclin-dependent kinase 4/6, led to prolonged disease control in 3 patients (pts) with unresectable growing teratoma syndrome (NEJM, 2009). For these reasons, we initiated a phase II trial of PD-0332991 in pts with refractory retinoblastoma protein (Rb) positive (+) GCT. Methods: Pts with incurable refractory GCT that expressed Rb by immunohistochemistry were treated with PD-0332991 125 mg orally daily for 21 days followed by a 7 day break (cycle = 28 days). Tumor assessments were performed every 2 cycles. The primary endpoint was 6-month progression-free survival (PFS) rate. Results: As of 1/12/2012, archived tumors from 36 pts with refractory GCT were stained for Rb and 35 had ≥ 1+ staining. 18 of planned 24 pts have been enrolled and treated. Pt characteristics: 17 male, 1 female; median age, 31 years (range, 17-56); median ECOG performance status, 1 (range, 0-1); median number of prior chemotherapy regimens, 2 (range, 1-6); median number prior surgeries, 3 (range, 1-6). Pt pathology: mature teratoma (MT), 7; teratoma with malignant transformation (TMT), 7; mixed GCT, 2; late relapse (LR), 2. 16 pts are evaluable; 2 pts are too early to evaluate. 5 of 16 evaluable pts achieved 6-month PFS (3 MT, 1 TMT, 1 LR). Median PFS was 2 months (range, 0-17). No objective radiological responses were observed; 7 patients had best response of stable disease by RECIST criteria (3 MT, 3 TMT, 1 LR). Grade 3 toxicity included neutropenia (4 pts), thrombocytopenia (3 pts), anemia (1 pt), mucositis (1 pt). No grade 4 toxicity was seen. Analysis of archival tumor for predictive biomarkers including Rb and p16 expression is being performed. Conclusions: PD-0332991 has resulted in 6-month PFS in pts with refractory Rb + GCT, including pts with incurable teratomas.
Residual tumor resections (RTR) in patients with germ cell tumors (GCT) after salvage chemotherapy.
Authors: Winter Christian , Bingoel Cigdem , Witthuhn Ralf , De Geeter Patrick , Albers Peter 
Published: March 2020

4601 Background: Residual tumor resections (RTR) after salvage chemotherapy are of utmost importance due to a much higher rate of vital carcinoma in the residual tumor. A complete RTR may lead to an improved long term survival of such patients (pts). Methods: A retrospective analysis was performed in 197 pts who underwent 209 RTRs in 2 referral centers (2003-2011) with identical surgical technique (2 surgeons). The RTR database was queried for pts who received salvage chemotherapy (conventional salvage chemotherapy (CCT) or high-dose salvage chemotherapy (HDCT)) and a subsequent RTR. Results: Sixty (29%) of all RTRs were performed after salvage chemotherapy. In 31 pts (52%) and 29 pts (48%) a CCT and HDCT was used as salvage regimen, respectively.Vital cancer was found in 48% and 45% of pts with CCT and HDCT. Respectively, vital cancer consisted of germ cell cancer and malignant transformed teratoma in 61% and 39% of the cases. In contrast, the percentage of vital cancer in pts after 1st-line treatment was 30% (p= 0.0365).This comparatively high rate is due to a 55% rate of intermediate/poor prognosis pts in the whole group of 209 RTRs. To date we have evaluated the oncological outcome in 171 of 197 pts with a median follow-up of 23 months (1-227). In 142 pts no relapse was observed, whereas in 29 pts a GCT relapse occured (17%), 7 (4.6%) of all evaluated pts had an “in-field”-relapse. 7 pts died due to tumor progression. The relapse rate in pts with RTR after salvage regime was significantly higher compared to RTR pts after primary chemotherapy (37% vs. 13%, p= 0.0008). The „in-field“-relapse rate in pts with RTR after salvage was only in 3.9%, 2 pts died due to tumor progression. Conclusions: Every second pts with RTR after salvage chemotherapy showed vital cancer in the residual tumor. The relapse rate in pts with RTR after salvage chemotherapy was significantly higher compared to RTR pts after first-line chemotherapy (p=0.0008) but the “infield” relapse rate was similar. A complete resection of all residual lesions after salvage chemotherapy is necessary to potentially improve the long-term disease-free survival. This is especially true for pts with malignant transformed teratoma and restricted options for repeated salvage chemotherapy.