bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pazopanib prior to planned nephrectomy in metastatic clear cell renal cancer: A clinical and biomarker study.
Authors: Powles Thomas , Sarwar Naveed , Stockdale Andrew , Boleti Ekaterini , Jones Robert J. , Protheroe Andrew , Chowdhury Simon , Peters John , Oades Grenville , O'Brien Tim S. , Sullivan Mark , Stewart Grant , Aitchison Michael , Sarker Shah-Jalal , Berney Dan , Rofe Charlotte , Sharpe Kevin , Crabb Simon J. 
Published: March 2020

4508 Background: The safety and efficacy of upfront pazopanib, prior to nephrectomy in metastatic clear cell renal cancer (mRCC), has not been prospectively evaluated. The toxicity profile of pazopanib potentially makes it an attractive agent in this setting. Methods: A single arm phase II study (2009-016675-29) evaluated 12-14 weeks of pazopanib prior to planned nephrectomy in 102 untreated patients with mRCC. Patients had MSKCC intermediate (n=80) and poor risk disease (n=22). The Primary endpoint of the trial was to achieve at least a 75% clinical benefit rate (absence of disease progression) with pazopanib at the time of surgery. Sequential tissue was used for biomarker analysis (exploratory endpoint). Tissue from a previous sunitinib trials with a similar design was included for comparative purposes. Results: Overall 81% of patients obtained clinical benefit prior to surgery. The partial response rate of the primary tumor was 14% by RECIST v1.1. The median reduction in the size of the primary tumor was 14% (range 33% to - 41%). No patients became inoperable due to local progression of disease. A nephrectomy was performed in 66% of patients. The two commonest reasons for not having surgery were patient choice (9%) and progression of disease (16%). There were 2 (3%) post operative surgical death. Delayed wound healing occurred in 5%. Progression during the treatment free interval for surgery was 26%. Median PFS has not been reached. Results from biomarker analysis of sequential tissue revealed therapy resulted in a significant decrease in CD31 (-49%), PDL-1 (-31%) and pS6K (-26%), while FGF-2 (+147%), MET (+34%) and Ki-67 expression increased with therapy. Increased ki-67 and CD31 correlated with a poor outcome. Conclusions: Nephrectomy after upfront pazopanib can be performed safely in mRCC and obtains control of disease in the majority of patients. Biomarker analysis shows dynamic changes some of which are prognostically significant. Clinical trial information: NCT01512186.
Randomized phase II CTEP study of MK2206 versus everolimus in VEGF inhibitor refractory renal cell carcinoma patients.
Authors: Jonasch Eric , Corn Paul Gettys , Pagliaro Lance C. , Lara Primo , Wang Xuemei , Do Kim-Anh , Garza Racheal , Bird Shelly , Drabick Joseph J. , Marcott Valerie , Quinn David , Doyle Austin , Tannir Nizar M. 
Published: March 2020

4517 Background: Up-regulation of the phosphoinositide-3 phosphate kinase (PI3K) pathway is associated with poorer prognosis in pts with advanced RCC. We hypothesized that optimal blockade of AKT in pts refractory to anti-VEGF therapy eliminates key drivers of tumor growth and proangiogenic signaling, and will prolong progression-free survival (PFS). We tested whether MK-2206, a selective allosteric inhibitor of AKT, will yield superior PFS to everolimus in anti-VEGF therapy refractory RCC pts. Methods: Eligible pts with metastatic RCC who progressed on an anti-VEGF agent were randomized (2:1 ratio) to receive MK2206 or everolimus. Up to two prior therapies allowed. Primary endpoint was PFS. The study had 80% power to detect a 67% increase in PFS with MK2206 over everolimus (8.2 vs. 4.9 mo) with a 1-sided log-rank at alpha= 0.10. One interim futility analysis was planned. Secondary endpoints: safety, overall survival, & response rate. Tumor tissue was collected in correlative analyses. Results: A total of 43 patients were accrued; 42 were evaluable for efficacy. Demographics: Male, 77%;White, 81%; median age 62 (range 41-83). MK2206 was held in 3 pts due to grade 3 rash; 1 came off study for rash. No everolimus pt discontinued study drug due to AEs. 30 events had occurred at first futility analysis. The 1-sided log-rank p-value for rejecting null hypothesis was 0.979, exceeding p-value boundary of 0.6413 for stopping trial. Median PFS for MK2206 was 3.65 mo (95%CI 1.77-5.52) and 7.43 mo for everolimus (95%CI 1.84-13.27). Two out of 29 MK2206 pts demonstrated dramatic response with greater than 50% disease regression and PFS of 8 months and 6 months (ongoing). Conclusions: Monotherapy with MK2206 was not superior to everolimus in this randomized, phase II study. However, dramatic response to MK2206 was seen in a subset of patients. Planned translational studies to allow genotype-phenotype correlations may help explain this observation. Clinical trial information: NCT01239342.
Preliminary HER2 expression data from NeuACT, the phase II randomized, open-label trial of DN24-02 in patients (pts) with surgically resected HER2+ urothelial cancer (UC) at high risk for recurrence.
Authors: Press Michael F. , O'Donnell Peter H. , Plimack Elizabeth R. , Hoffman-Censits Jean H. , Quinn David I. , Sharma Padmanee , DeVries Todd , Chen Melissa , Locker Michael , Bajorin Dean F. 
Published: March 2020

4527^ Background: HER2 overexpression may be a prognostic factor for poor outcomes in pts with high-risk UC. Publications report a wide variability of HER2 expression in UC, with ≥2+ HER2 expression by immunohistochemistry (IHC) reported in <10% to >50% of cases. DN24-02 is an investigational autologous immunotherapy targeting HER2, based on the same manufacturing platform used for sipuleucel-T. NeuACT (N10-1; NCT01353222) is designed to evaluate whether DN24-02 can prolong survival when given as adjuvant therapy following surgical resection in pts with high risk HER2-expressing UC (Bajorin, et al. ASCO 2012). Here we report preliminary data for HER2 expression on primary tumor and positive lymph node samples, and covariate analyses. Methods: Trial eligibility criteria include surgical resection of a primary UC, with either ≥pT2 or pN+ staging, and HER2 expression ≥1+ IHC. Surgical specimens are screened for HER2 expression by central pathology laboratory review and HER2 positivity is scored using the Dako HercepTest system. Results: As of December 2012, tumor specimens from 114 pts have been screened. Of these pts, 84 (74%; 95% CI: 65–82%) had a HER2 expression score ≥1+ in the primary tumor, with 36 (32%) having a 2+ score and 5 (4%) having a 3+ score. Thirty-eight pts also had HER2 expression levels evaluated in lymph node samples. Of these 38 pts, 35 (92%; 95% CI: 79–98%) had a HER2 expression score ≥1+ in the lymph nodes, with 17 (45%) having a 2+ score and 4 (11%) having a 3+ score. Gender, primary tumor site, nodal stage and prior neoadjuvant chemotherapy were not significantly correlated with HER2 expression (p≥0.10). Conclusions: To date, high frequencies (≥74%) of HER2 expression ≥1+ in primary tumor and lymph node samples of UC pts have been observed. No baseline variables, including prior neoadjuvant chemotherapy, appear to affect the rate of HER2 expression. Although preliminary, these data are consistent with prior studies that have noted a higher incidence of HER2 expression in UC lymph node tumor vs. primary tumor and suggest that HER2 protein expression is common in high-risk UC. Clinical trial information: NCT01353222.
Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: A randomized phase II trial: An update.
Authors: Haggag Rasha Mohamed , Farag Kamel , Abu-Taleb Fouad , Shamaa Sameh , Zekri Abdel-Rahman , ELBolkainy Tarek , Khaled Hussein Mustafa 
Published: March 2020

4537 Background: Bladder carcinoma is still one of the foremost oncologic problems in Egypt. In previous single-arm and double-arm phase II studies, prolonged infusion of low dose gemcitabine and cisplatin proved to be an effective treatment for such patients with advanced disease. Methods: To compare efficacy and safety of both prolonged infusion and standard gemcitabine-cisplatin combination, we updated the data and duplicated the number of patients of our previously published phase II randomized study to 120 untreated patients with stage III/IV bladder cancer. Patients were randomized to receive either gemcitabine (250 mg/m2) 6-hour infusion on days 1 and 8, and cisplatin (70 mg/ m2) on day 2 every 21-day cycle (Arm1) or gemcitabine (1,250 mg/ m2) 30-min infusion on days 1 and 8, and cisplatin (70 mg/ m2) on day 2 every 21-day cycle (Arm 2). Results: The 92 males and 28 females had a median age of 62 years (range 40-85 years). A total of 87 patients had transitional cell, 28 had squamous cell, and 5 had undifferentiated cell carcinoma. Among the 105 evaluable patients (52patients in arm1 and 53patients in arm 2), complete response rate was achieved in 13.5% (7/52 patients of arm 1) and 5.7% (3/53 patients of arm 2). Eighteen patients in arm 1 (34.6%) and 17 patients (32.1%) in arm 2 had partial response on therapy. Thus the overall response rate of patients in arm1 and arm 2 was 48% (25/52 patients) and 37.7% (20/53patients), respectively (p = 0.26). No significant difference in median time to disease progression (26 months versus 24 months, p =0.4), median survival (12 months versus 16 months, p =0.8), and 1-year survival (49.9 % versus 54.7%, p = 0.8) was detected between arms 1 and 2, respectively. No treatment- related deaths occurred. Main hematologic and nonhematologic toxicities were similar in both arms with no statistically signiﬁcant differences. Conclusions: In the treatment of advanced bladder cancer, gemcitabine in low dose and prolonged infusion in combination with cisplatin is not inferior to high-dose short infusion gemcitabine and cisplatin in terms of overall survival, time to disease progression, and response rates with favorable toxicity profile and less financial costs.
A STAT3- and p63-dependent transcriptional network to define a lethal basal subset of human bladder cancers.
Authors: Dinney Colin P.N. , Choi Woonyoung , Porten Sima P. , Roth Beat , Cheng Tiewei , Willis Daniel Levi , Tran Mai Ngoc-Ahn , Lee I-Ling C. , Bondaruk Jolanta E. , Majewski Tadeusz , Zhang Shizhen , Pretzsch Shanna M. , Baggerly Keith A. , Siefker-Radtke Arlene O. , Czerniak Bogdan , McConkey David James 
Published: March 2020

4538 Background: Muscle-invasive bladder cancers (MIBCs) are a heterogeneous group of tumors that display widely variable clinical outcomes and responses to conventional chemotherapy. Methods: We used whole genome mRNA expression profiling and unsupervised hierarchical cluster analyses on a cohort of 73 flash frozen primary tumors to identify 3 distinct subsets of muscle-invasive bladder cancer (MIBC). We confirmed the existence of these 3 subsets in a second cohort of 57 formalin-fixed, paraffin-embedded (FFPE) MIBCs and in 2 other public datasets. Analysis of primary tumors and mechanistic studies in human bladder cancer cell lines identified tumors that respond to FGFR inhibitors or chemotherapy. Results: The first subset was driven by an active "basal" EGFR-STAT3-p63 transcriptional network, and was associated with poor clinical outcomes. High miR-200c expression stratified the survival of these basal tumors. The second subset was characterized by active p53 pathway activation, and tumors and cell lines with these features were resistant to cis-platinum based chemotherapy. The third subset expressed "luminal" markers and active estrogen receptor (ER) and PPARγ signaling, and luminal cell lines were sensitive to fibroblast growth factor receptor (FGFR) inhibition. Conclusions: Molecular subtyping of MIBCs can be used to identify lethal cancers and enrich for tumors that will respond to FGFR inhibitors or conventional chemotherapy.
Introduction of a tobacco-screening initiative for those at risk for bladder cancer in a high volume urology clinic.
Authors: Bassett Jeffrey C. , Gore John L. , McCarthy William J. , Morrison Christopher , Kwan Lorna , Bennett Carol J. , Cookson Michael S. , Penson David F. , Saigal Christopher 
Published: March 2020

4540 Background: Tobacco use is causal or contributory in 50% of bladder cancer diagnoses. Continued use after diagnosis may negatively impact recurrence, progression, and mortality. Despite its relevance, tobacco screening was infrequently occurring in a regional urology clinic. We hypothesized that the clinic was fertile ground for a tobacco-screening initiative given the number of referrals for bladder cancer, hematuria, and other tobacco-related urologic conditions. Methods: An EMR-based tobacco-screening prompt was designed using the same informatics architecture and clinical reporting system used in primary care. The prompt was introduced for all new patient encounters beginning January 2010. We prospectively collected the proportion of patients asked about tobacco use, advised to quit, and assisted with smoking cessation. Results: For the two years ending December 2011, 4,617 patients were seen in urologic consultation; 31% (n = 1,444) were referred for tobacco-related urologic diagnoses, 36% (n = 518) of whom were referred for bladder cancer or hematuria. The tobacco-screening prompt was used 57% (n = 2,626) of the time. Attending physicians utilized the template in 17% of their encounters, resident physicians in 71%, and nurse practitioners in 97% (p < 0.001). 49% (n = 255) of those referred for bladder cancer or hematuria were screened for tobacco use. Active smokers comprised 21% (n = 558) of screened patients. Relative to former and never smokers, active smokers were more likely referred for bladder cancer or hematuria (p = 0.005). 40% (n = 225) of active smokers desired to quit. Those counseled by an attending physician were more likely ready to quit and trended toward a more intensive cessation program (p = 0.004 and p = 0.07, respectively). Conclusions: Our data suggest that urology clinics may be important sites for tobacco-screening initiatives, particularly for those with tobacco-related urologic diagnoses. Screening patients referred for bladder cancer or hematuria is likely high yield due to the increased proportion of active smokers. Given the disparate utilization of the prompt, identification of provider-level facilitators and barriers to tobacco screening is worthy of study.
A novel phase I trial design featuring a two-dimensional dose-finding algorithm optimizing the dose of gemcitabine and doxorubicin with bortezomib in metastatic urothelial carcinoma (UC).
Authors: Siefker-Radtke Arlene O. , Wen Sijin , Shen Yu , Stigall Kristi , McConkey David James , Millikan Randall E. 
Published: March 2020

4548 Background: Preclinical studies suggested that bortezomib (B) enhanced the activity of gemcitabine and doxorubicin (GA) in UC; thus we sought to define possible combinations of bortezomib with this doublet. We employed a novel phase I trial design systematically exploring doses in 2 dimensions. The method estimates an isotoxic curve allowing not only a combination with approximately equal (with respect to single component MTD) contributions of the two components to be found, but also combinations emphasizing one component or the other. Methods: Since 11/06, 74 patients with previously treated metastatic cancer were enrolled (70 UC, 3 prostate, 1 renal). GA was treated as a single component and given in a fixed ratio to a maximum of 900 and 50 mg/m2, and B to a maximal dose of 1.6 mg/m2 IV, with dosing every 14 days. After determining the MTD along the diagonal, we then decreased the dose of B, increasing GA, and vice versa, exploring doses along an isotoxic curve aiming for ≤ 30% dose limiting toxicity (DLT) in cycle 1. The objective response rate (ORR) includes PR or CR, and excludes SD. Results: The MTD along the diagonal for GAB was 756, 42, and 1.4 mg/m2, respectively. Doses maximizing the GA (900, 50) required reduction of B to 1.2 mg/m2. Likewise, doses maximizing B (1.6) required reduction of GA to 559 and 33 mg/m2. The most common DLT were thrombocytopenia 14%, neutropenic fever 5%, and mucositis 1%. There was minimal activity at the on-diagonal MTD with an ORR 1/10. Of the tolerable doses along the isotoxic curve, the greatest activity was seen when maximizing B (1.5-1.6 mg/m2, ORR 7/12 (58%)). The ORR when maximizing GA was 4/10. The most frequent ≥ G3 toxicities include: thrombocytopenia (26%), neutropenia (26%), anemia (24%), fatigue (8%), and neutropenic fever or infection (12%). Treatment was tolerable in poor renal function; 36 patients (49%) had a GFR < 50 ml/min. Conclusions: The combination of GAB has promising activity at doses maximizing proteosome inhibition, despite relatively low doses of GA. Traditional phase 1 design dosing to the MTD "along the diagonal" would have lead to the incorrect conclusion that there was minimal activity. Clinical trial information: NCT00479128.
Investigating serum β-HCG as an independent prognostic factor in patients (pts) receiving chemotherapy (Ct) for transitional cell carcinoma (TCC) of the urothelial tract.
Authors: Crabb Simon J. , Sharp Adam , Head Julia , Chau Caroline , Wheater Matthew , Geldart Thomas R. , Mead Graham 
Published: March 2020

4549 Background: Serum human chorionic gonadotrophin β subunit (β-HCG) has prognostic value in TCC but has not been investigated in pts receiving Ct for this disease. Furthermore prior studies lacked statistical power to test independence from other prognostic variables. Methods: A single institution retrospective clinical database was constructed of pts receiving Ct between 2005 and 2011 for cancer of the urothelial tract. Eligible pts had pure or a component of TCC. Prognostic variables were tested by univariate Kaplan Meier analyses. Statistically significant variables were then assessed by multivariate cox regression analysis. A prospectively defined β-HCG cut-point of < versus ≥ 2 iu/L, either prior to (β-HCGp), or on completion of (β-HCGc) Ct was used. Results: 235 pts were eligible (72% male, 55% ≤70 years, 83% bladder primary). Initial Ct was perioperative (CtPeri) in 46% (7% adjuvant, 39% neoadjuvant). 63% had first line palliative Ct for metastatic disease (CtMet). For CtPeri, ECOG performance status (PS), haemoglobin (Hb), CtPeri regimen and T stage were statistically significant prognostic factors in univariate analyses for overall survival (OS), as were β-HCGp (median OS (mOS) 8.50 v. 1.86 years, p<0.001) and β-HCGc (mOS 4.27 v. 0.66 years, p=0.003). β-HCGp and β-HCGc after CtPeri were also prognostic for relapse free survival and in multivariable analysis remained statistically significant as a prognostic factor for OS (β-HCGp: hazard ratio (HR) 3.13, p=0.001; β-HCGc: HR 4.26, p=0.007). In pts treated with CtMet, PS, alkaline phosphatase, prior CtPeri, visceral metastases, CtMet regimen and β-HCGc (mOS 1.70 v. 1.07 years, p=0.005) were prognostic in univariate analyses for OS. β-HCGc after CtMet was also prognostic for progression free survival and in multivariable analysis remained statistically significant as a prognostic factor for OS (HR 3.47, p<0.001). Conclusions: β-HCG, and specifically its post-Ct level, is an independent prognostic factor for TCC treated with Ct in both curative and palliative settings. Prospective evaluation is warranted for incorporation into treatment selection strategies.
The impact of clinically significant discrepancies from primary pathological review of transurethral bladder resection specimens upon repeat review at a tertiary care center.
Authors: Barlow Lamont J. , Shapiro Edan , Ahn Jennifer , Benson Mitchell C. , McKiernan James M. 
Published: March 2020

4552 Background: Internal review of outside pathology slides is a common practice among urologic oncologists at tertiary care facilities, and discrepancies have a potential to directly affect the choice of treatment. While repeat prostate biopsy review has been extensively studied, there is little data available on the impact of repeat reviews of bladder biopsies. The purpose of the current study is to perform a standardized comparison of original and internal pathology reviews of identical bladder specimens to characterize the impact of repeat review on treatment decisions. Methods: Using the Columbia Urologic Oncology Database, a retrospective analysis of 91 consecutive patients who underwent bladder resections at outside institutions from 2008-2012 with secondary referral to a single urologist and internal review at our institution was conducted. Characteristics of both original pathology reports and internal reviews were collected and compared by blinded reviewers. A discrepancy in one of the following characteristics was considered treatment-altering: presence of muscularis in specimen or tumor involvement in muscularis. Additional clinically-significant discrepancies including presence of secondary histology, carcinoma in situ, lymphovascular invasion, micropapillary features, tumor stage, and overall accumulative discrepancy rate were also analyzed. Results: Median time from original procedure to internal review was 34 days (range: 9-368). 56/91 (62%) patients had at least one of the predefined clinically-significant discrepancies. 27/91 (30%) patients had at least one treatment-altering discrepancy, including 25 with discrepant muscle in specimen and 11 with discrepant muscle invasion. Regarding tumor stage, 8 patients were upstaged, 71 were unchanged, and 12 were downstaged on internal review. Conclusions: Repeat pathologic review of primary bladder specimens at a tertiary care center has the potential to alter clinical care for the majority of patients. Further studies are needed to determine if these discrepancies and the decisions they influence have a significant impact on patient outcomes.
A retrospective analysis of patients with poor-risk germ cell tumor (PRGCT) treated at Indiana University from 2000 to 2010.
Authors: Adra Nabil , Albany Costantine , Sonnenburg Daniel , Tong Yan , Hanna Nasser H. , Einhorn Lawrence H. 
Published: March 2020

4557 Background: PRGCT represents 14% of germ cell tumors, with 2-year PFS of 50%. PRGCT is defined by primary mediastinal non-seminomatous germ cell tumor (PMNSGCT), non-pulmonary visceral metastasis (NPVM), AFP > 10,000 or hCG > 50,000. This analysis attempts to identify subsets of patients with more or less favorable outcomes among the poor risk groups. Methods: Retrospective analysis of all patients with testicular cancer seen at Indiana University (IU) from 2000-2010. 291 patients with PRGCT identified of whom 79 received initial therapy at IU. We analyzed the following variables: primary site testis/retroperitoneal (T/RP) vs. PMNSGCT, pulmonary vs. NPVM, and the amplitude of serum tumor markers. We identified groups of patients according to the level of tumor marker elevation with cutoff points of AFP 20,000 and hCG 200,000. Results: Mean age 29, mean AFP 8,283, mean hCG 185,667. 24% had PMNSGCT, 48% NPVM, 11% AFP>20,000, and 25% hCG>200,000. When hCG was analyzed as a continuous variable, every 10,000 unit increase in hCG caused the hazard of progression to increase by 1% (p value 0.01). Patients with NPVM had significantly worse PFS. NPVM with elevated hCG had worse outcome than NPVM with normal hCG. This did not correlate as well with AFP. PFS was worse with NPVM than elevated pre-chemotherapy tumor markers. Multiple different criteria for poor risk disease carried significantly worse impact on PFS and OS when compared to having a single criterion for poor risk disease. Conclusions: Our data indicate that patients with NPVM or more than one criteria for PRGCT have a worse outcome compared to other PRGCT subgroups. [Table: see text]