bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequent expression of androgen receptor (AR) on tumor cells of muscle-invasive (MIUC) and metastatic urothelial carcinoma (mUC): Insights for clinical research.
Authors: Colecchia Maurizio , Lo Vullo Salvatore , Giannatempo Patrizia , Raggi Daniele , Perrone Federica , Nicolai Nicola , Catanzaro Mario , Biasoni Davide , Torelli Tullio , Piva Luigi , Stagni Silvia , Salvioni Roberto , De Braud Filippo G. , Procopio Giuseppe , Mariani Luigi , Necchi Andrea 
Published: September 2018

e16019 Background: Advanced UC treatment is being revolutionized by immunotherapy (IT). However, < 30% of patients (pts) will benefit from IT, and additional therapeutic targets are needed. Findings from analyses supporting an investigator-led, AR-based clinical research program are presented. Methods: From 09/2015, we collected the archival tissue blocks from pts who have been treated or consulted at our center and received platinum-based chemotherapy (CT) for MIUC or mUC. Immunohistochemistry (IHC) was performed on 3µm slides using mouse anti-human AR monoclonal Ab (Dako, clone AR441). ≥1% cutoff for AR+ IHC of tumor cells (TC) was used. AR-expressing pts were further stratified as follows: 1-5%, 5-25%, and 25-100%. Univariable (UVA) and multivariable (MVA) Cox models for overall survival (OS) were fitted, the latter adjusted for clinical stage (MIUC vs mUC), presence of visceral metastases, platinum CT type. OS was calculated from the date of first administration of CT. Exploratory PD-L1 co-expression, by TC or stroma (SP142 Ab, 1% cutoff), was analyzed in all pts. Results: 105 pts (46 MIUC and 59 mUC) had their tumor stained. 80 (76.2%) had bladder primary tumor, 85 (80.9%) had pure UC. 59 received cisplatin and 46 carboplatin. Overall, 37 pts (35.2%) had AR-expressing TC, 17 (16.2%) with ≥25% expression. Cox models were built on 93 pts with follow-up duration of ≥6 months. AR-expressing was equally distributed between MIUC and mUC pts (44.4% and 55.6%). On UVA, AR expression was not associated with OS, neither dichotomizing AR+/AR- pts (p = 0.477) nor after accounting for AR-positivity strata (p = 0.845). The same results were confirmed on MVA (p = 0.505 and p = 0.875). In AR+ vs. AR- pts, PD-L1 was equally expressed in the stroma (67.5 vs 57.9%) but less expressed by TC (39.4% vs 52%). Conclusions: AR is frequently expressed on TC of pts with MIUC and mUC, and AR expression does not seem to be associated with OS in these pts. AR pathway is worthy of clinical studies to synergistically act with anti-PD-L1 therapy. AR sequencing and FISH analysis in positive pts is ongoing, and a clinical program of a named-basis administration of antiandrogen therapy has started at our center.
Cisplatin and gemcitabine versus carboplatin and gemcitabine in metastatic bladder cancer: Survival analysis of veterans' health care data.
Authors: Kunthur Anuradha , Siegel Eric R , Govindarajan Rangaswamy 
Published: September 2018

e16023 Background: Background: Cisplatin and gemcitabine combination chemotherapy is the standard regimen used for the treatment of metastatic bladder cancer. Most Veterans Administration (VA) patients with metastatic bladder cancer are elderly or with poor renal function, and are considered not good candidates for cisplatin administration. It is a common practice to substitute carboplatin for cisplatin in this population. Methods: Methods: We identified stage IV bladder cancer patients treated initially with cisplatin plus gemcitabine (Ci+G) or carboplatin plus gemcitabine (Ca+G) at VA medical centers from 2000 to 2010. The data was obtained via the VA central cancer registry from all VA medical centers across the country. Overall survival (OS) was summarized as Kaplan-Meier medians and compared for difference between platinum groups via Cox regression. Results: Results: 196 subjects () with stage IV bladder cancer were identified. There were 194 males , 78 received Ca+G, 118 received Ci+G. 149 deaths occurred during 197.49 person-years of follow up, for a median OS of 10.35 months. Median OS was 11.14 months with Ca+G versus 10.35 months with Ci+G. Cox regression revealed nearly equal group mortality rates, with Ca+G having a hazard ratio (90% confidence limits) of 1.02 (0.77–1.34) compared to Ci+G ( P= 0.93). Conclusions: Conclusion: Patients treated with Ca+G and Ci+G regimens had similar median OS, supporting the substitution of carboplatin for cisplatin with gemcitabine in this patient population.
Protein kinase D inhibitor CRT0066101 suppresses bladder cancer growth in vitro and in vivo through induction of cell cycle arrest at the G2-M phase.
Authors: Li Qingdi Quentin , Hsu Iawen , Sanford Thomas , Railkar Reema S. , Agarwal Piyush K. 
Published: September 2018

e16024 Background: Protein Kinase D (PKD) is implicated in tumor growth, death, invasion, and progression. CRT0066101 is an inhibitor of PKD and has antitumor activity in several types of carcinomas. However, the effect and mechanism of CRT0066101 in bladder cancer remain unknown. Methods: The MTS assay was used to evaluate the ability of CRT0066101 to inhibit cellular proliferation in bladder cancer cells. Cell cycle was analyzed by flow cytometry. Protein expression and phosphorylation were assessed by western blotting. Results: We showed that CRT0066101 suppressed the proliferation and migration of 4 bladder cancer cell lines in vitro. We also demonstrated that CRT0066101 inhibited tumor growth in an in vivo mouse model of bladder cancer. To verify the role of PKD in bladder tumor, we found that PKD2 was highly expressed in 8 bladder cancer lines and that RNA interference-mediated silencing of the PKD2 gene dramatically reduced bladder cancer growth in vitro and in vivo, suggesting that the effect of the compound in bladder cancer is mediated through inhibition of PKD2. This notion was confirmed by demonstrating that the levels of PKD2 and phospho-PKD2 (Ser-876) were markedly decreased in CRT0066101-treated bladder cancer. In addition, our cell cycle analysis by flow cytometry revealed that CRT0066101 arrested bladder cancer cells at the G2-M phase. We further validated these data by immunoblotting showing that treatment of bladder carcinoma cells with CRT0066101 downregulated the expression of cyclin B1, cdc2 and cdc25C, but elevated the levels of p27kip1, gadd45a, chk1/2, and wee1. Finally, CRT0066101 was found to increase the phosphorylation of cdc2 and cdc25C, which lead to reduction in cdc2-cyclin B1 activity. Conclusions: These novel findings suggest that CRT0066101 inhibits bladder cancer growth through modulating the cell cycle G2 checkpoint and inducing cell cycle G2-M arrest, which lead to blockade of cell cycle progression. QQL and IH contributed equally to this work.
Health resource utilization and costs for stage IV bladder cancer in community oncology settings.
Authors: Shenolikar Rahul A. , Fisher Maxine D. , Miller Paul J. , Walker Mark Stephen , Fenton Moon Jung 
Published: September 2018

e16032 Background: Current real-world data on patients with metastatic bladder cancer in the community setting are limited. This study describes patient characteristics, health resource utilization (HRU), and costs for this population. Methods: Medical records data from adults diagnosed with stage IV bladder cancer (T4b, node-positive, or distant metastatic disease) between 1/1/2008 and 6/1/2015 were retrospectively collected from a network of 10 US community oncology practices. Patient characteristics, HRU, and costs were assessed. Regression models were used to estimate group effects on utilization and costs through three progression-based lines. Results: Of 508 patients, 75% were male, 79% white, 15% African American, and 71.5% were aged ≥65 years (median age, 71 years; range 35-92 years). Overall, 76.4% were current or past tobacco users. The most prevalent comorbidities were diabetes (23.4%), renal disease (16.5%), and chronic obstructive pulmonary disease (COPD; 12.4%). Overall, 70.1% had distant metastases at diagnosis, including bone (24.0%), lung (23.4%), and liver (14.6%). Of 341 patients analyzed for HRU and cost, 58.9% had hospital visits and 11.7% had emergency department (ED) visits. Age, smoking history, and presence of diabetes were predictors of hospitalization (all P< 0.05). Overall mean monthly total healthcare cost was $18,778 ± $47,006 (median $6285), which was driven by hospitalizations ($14,660 ± 44,686, median $1717). Mean monthly ED cost was $776 ± $5530, median $0. Mean monthly cost for office visits was $186 ± $189, median $152. Procedures in the medical oncology setting had a mean monthly cost of $707 ± $1179, median $395. Other costs included systemic therapy ($267 ± $704, median $117), infused supportive care drugs ($758 ± $1458, median $0), and other drugs ($1422 ± $3745, median $136). Age, presence of diabetes, presence of any comorbidities, body mass index, and impaired composite performance status were predictors of healthcare costs (all P< 0.05). Conclusions: This study showed significant HRU and costs for metastatic bladder cancer patients suggesting high unmet need.
Correlation of tumor enhancement and imaging features on multiphasic multidetector CT with microvessel density as a step toward a minimally invasive method to predict Fuhrman nuclear grade in patients with clear cell renal cell carcinoma.
Authors: Coy Heidi , Young Jonathan , Douek Michael , Magyar Clara , Sisk Anthony , Brown Matthew S. , Sayre James , Raman Steven 
Published: September 2018

e16049 Background: Clear cell renal cell carcinoma (ccRCC) is the most common tumor of the kidney. Up to 70% are incidentally detected on multiphasic CT. The prognosis for patients with ccRCC is related to Fuhrman grade (FG) and is diagnosed by biopsy or excision. There is a great need for a non-invasive method to assess tumor grade which may help inform clinical decision-making. The purpose of our study is to determine if contrast enhancement on CT predicts FG and microvessel density (MVD) of ccRCC lesions and to assess which combination of quantitative and qualitative radiological features and clinical features predict high FG ccRCC lesions. Methods: With IRB approval for this HIPAA-compliant retrospective study, our pathology and imaging databases were queried to obtain a cohort of ccRCC with a preoperative multiphasic (unenhanced (U), corticomedullary (C), nephrographic (N), and excretory (E)) CT scan. Tumors were stained with CD4 to quantify % MVD. Spearman’s rank correlation was calculated to test the strength of the association between CT enhancement, %MVD and FG. Stepwise logistic regression analysis was performed to determine the quantitative and/or qualitative feature with the highest performance in predicting high FG tumor. The multivariate logistic regression analysis was evaluated using ROC curves and AUCs. Results: Our cohort had 127 patients with 89 low-grade tumors and 43 high-grade tumors. The %wash-in of enhancement from the U to the C phase showed a significant correlation with %MVD of the tumor (R2= 0.181,p < . 001) as did enhancement of the tumor in the early C phase with %MVD (R2= 0.159,p < . 001). There was a significant inverse correlation with %MVD and FG (R2= 0.137,p < . 001). T-stage, tumor size, %MVD and presence of renal vein invasion were determined to be significant independent predictors of high grade lesions with an AUC of .838 (95% CI .748-.927). Conclusions: Lower grade ccRCC tumors have a higher MVD. Therefore, contrast material washes in at a faster rate from the UN to the CM phase, enabling low grade to be discriminated from high-grade tumors on CT.
The evolution of clinical trials in renal cell carcinoma: A status report for 2013-2016 from the clinicaltrials.gov website.
Authors: Ghatalia Pooja , Pisarcik David , Koenigsberg Rebecca , Handorf Elizabeth , Geynisman Daniel M. , Zibelman Matthew R. 
Published: September 2018

e16050 Background: The treatment paradigm for renal cell carcinoma (RCC) continues to rapidly evolve. We previously published a snapshot analysis of clinical trials in RCC using the publicly available ClinicalTrials.gov registry. Here we present a 3 year update in order to understand the current trends in RCC clinical research, to identify opportunities for improvement, and to compare this data to the landscape in 2013. Methods: The Website’s advanced search function was used to search for the terms “renal cell carcinoma”, “kidney cancer”, “kidney neoplasm” or “renal neoplasm”. The search was further refined to “open studies”, “interventional” and “age ≥18”. Basket trials with ≥7 tumors with non-RCC tumor histologies, terminated studies and pediatric studies were excluded. The phase, stage, treatment setting, type of intervention, study design, histologies, use of biomarkers, studied outcomes, sponsors and location of the trials were recorded. Results: We locked our search on May 26, 2016 and 165 trials were eligible, compared with 169 trials on Sep 25, 2013. There were more phase I and I/II trials in 2016 compared to 2013 (p = 0.05): phase I (25.6% vs 15.4%) and phase I/II (15.2% vs 9.5%). More clinical trials in 2016 compared to 2013 used immunotherapy (IT) alone or in combination with other drugs (24.2 % vs 10.7%, p = 0.001), and the use of targeted therapy alone (TT) declined (32.9% vs 47.9%, p = 0.005). IT alone was used in 15.2% of current trials, compared to 5.96% in 2013. TT+IT combination trials more than doubled (6.7% vs 2.3%, p = 0.07). The number of trials with treatment in neoadjuvant/adjuvant settings in 2016 and 2013 were similar (9.7% vs 10.6%, p = 0.77), respectively. Compared to 2013, the number of trials with non-clear cell histology remained low (n = 10). Many more trials were sponsored by pharmaceutical industry in 2016 vs 2013 (41.5% vs 16.0%, p = < 0.001). Conclusions: More clinical trials included immunotherapy in 2016 compared to 2013, and there was a significant increase in industry sponsored trials. The increase in industry sponsored studies may reflect use of new expensive drugs. More studies in (neo)adjuvant settings and for non-clear cell histologies are needed.
Trends in exposure to multiple lines of treatment and survival of patients with metastatic renal cell carcinoma: A real-world analysis.
Authors: Ratta Raffaele , Di Maio Massimo , Verzoni Elena , Grassi Paolo , Montone Rosanna , Sorrentino Margherita , Mennitto Alessia , Prisciandaro Michele , De Braud Filippo G. , Procopio Giuseppe 
Published: September 2018

e16064 Background: In recent years, several new agents have been introduced into clinical practice for patients (pts) with metastatic renal cell carcinoma (mRCC). The aim of this study was to describe the difference in terms of exposure to multiple lines of treatment and overall survival (OS) between two groups of pts who started therapy for mRCC in two different periods of time (period 1: 2005-2010 and period 2: 2011-2016). Methods: Data were retrospectively collected from the database of the Istituto Nazionale Tumori of Milan. The proportion of pts who received subsequent lines of treatment after first disease progression (PD) was compared between the two groups of pts. OS was defined as time from the start of first-line treatment to death or last follow-up. Unadjusted and adjusted analyses for Heng risk groups were done. Results: Overall,457 pts with mRCC were evaluated: 274 pts (60%) started treatment in period 1 and 183 (40%) in period 2. Most pts in both groups had intermediate risk (65.7% and 86.3% respectively). The proportion of poor-risk pts was significantly higher in period 1 (21.2% vs 7.7%). Among pts who stopped first-line treatment due to PD, pts in period 2 had a higher chance of receiving second-line treatment as compared to pts of period 1 (80.8% vs 64.7%, 95% CI 1.31-4.04, p = 0.003). Similarly, among those who stopped second-line treatment due to PD, pts in period 2 had a higher chance of receiving a third-line treatment compared to pts in period 1 (71.2% vs 49.3%, 95% CI 1.32-4.87, p = 0.004). In the whole study population, median OS (mOS) was 24.9 months (95% CI 21.6-31.1): 21.7 months (95% CI 18.8-26.3) in pts of period 1 and 38.2 months (95% CI 27.7-49.0) in pts of period 2 (Hazard Ratio [HR] 0.65,95% CI 0.49-0.84, p = 0.001) respectively. When adjusted for Heng groups, OS remained significantly longer for pts of period 2 (HR 0.76, 95% CI 0.57-1.00, p = 0.05). Conclusions: mRCC pts who started a treatment over the last 5 years have been exposed to a higher number of treatment lines as compared to those treated before 2011. Our data suggest that the increase of treatment options as well as a better clinicians’ expertise is associated with a better outcome.
Comparative efficacy and safety of bone-modifying agents for the treatment of bone metastases in patients with advanced renal cell carcinoma: A systematic review and meta-analysis.
Authors: Omae Kenji , Tsujimoto Yasushi , Honda Michitaka , Kondo Tsunenori , Hashimoto Yasunobu , Tanabe Kazunari , Fukuhara Shunichi , Furukawa Toshi 
Published: September 2018

e16067 Background: Bone-modifying agents (BMA) have been well-demonstrated to be effective for preventing and inhibiting skeletal-related events (SRE) in patients with bone metastases of breast or prostate cancer. However, the role of BMA treatment has not yet been clearly defined in patients with bone metastases of renal cell carcinoma (RCC). We, therefore, conducted a systematic review and meta-analysis to evaluate the efficacy and safety of BMA in patients with bone metastases of RCC. Methods: Literature search was conducted on MEDLINE, the Cochrane Central Register of Controlled Trials, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov to identify randomized controlled trials of BMA for the treatment of bone metastases in RCC patients. The primary outcomes were SRE and serious adverse events (AEs). Hazard ratios (HRs) were calculated with a random effects model. The Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach was used to assess the certainty of the evidence. This review was prospectively registered on PROSPERO (No. CRD42016032742). Results: Three studies (259 patients) were identified for the systematic review. Two studies that compared zoledronic acid with placebo or non-zoledronic acid showed that zoledronic acid reduced the SRE risk by 68% (HR 0.32; 95% confidence interval (CI) 0.19–0.55; P < 0.0001). The quality of evidence was moderate. No serious osteonecrosis was reported in both studies. The incidence of serious AEs was identical (80%) on both treatment arms in one study and not reported in the other study. In the remaining study, which compared denosumab with zoledronic acid, analyses of the individual patient data shared through Amgen showed a favorable trend for denosumab in terms of SRE (HR 0.71; 95% CI 0.43–1.17) and serious AEs (risk ratio 0.86; 95% CI 0.68–1.08), but this trend did not reach statistical significance. Conclusions: The moderate-quality evidence indicates that zoledronic acid significantly reduces the risk of SRE among patients with bone metastases of RCC.
Economic burden of empiric drug utilization in metastatic renal cell carcinoma emphasizes the need for early biomarkers of response.
Authors: Chen Viola , Gong Cynthia , Zhang Chiyuan A , Srinivas Sandy , Lee Howard E , Fan Alice C. 
Published: September 2018

e16072 Background: While targeted therapies have significantly changed clinical practice for metastatic renal cell carcinoma (RCC), the economic burden of these drugs is increasing without concomitant advances in strategies for choosing among such agents. We present a model of cost savings using a hypothetical biomarker panel of early response to guide selection of targeted and immune therapies in metastatic RCC patients. Methods: Using the Stanford RCC Outcomes database, we identified patients diagnosed with metastatic RCC who received any of the following: sunitinib, pazopanib, axitinib, sorafenib, cabozantinib, nivolumab, lenvatinib & everolimus, temsirolimus from 2003 through 2016 at Stanford Cancer Center. Primary outcomes included short-term and long-term costs of treatment according to standard-of-care imaging criteria. Drug costs were inferred from the 2017 Veterans Affairs Federal Supply Schedule pricing in USD. A hypothetical biomarker cost was set at $4,620—the current market price of an actively employed diagnostic test in breast cancer, OncotypeDX. These parameters were combined in a Markov model to simulate patient treatment courses and to assess the impact of an early response biomarker on drug expenditures. Results: 370 patients received a range of one to six lines of successive therapy. 170 (45.9%) were long-term patients with cumulative drugs costs totaling $31 million, or on average $185,362 per patient, and $104,521 per individual line of therapy received. 200 (54%) were short-term patients who received less than 3 months of targeted therapy. The costs of such potentially ineffective treatment totaled $4.1 million, or $15,455 per patient per individual line of therapy received. Application of an early biomarker panel at the outset would result in a potential cost savings of up to $6,215 per patient. Conclusions: Bothmetastatic RCC patients and payers suffer high costs from ineffective therapy. Our findings suggest an economic benefit for developing biomarker panels to predict early therapeutic response. Such biomarkers can result in immediate cost savings, and possibly improved quality-of-life for those liberated from unnecessary drug toxicity.
Incidental vs. clinical diagnosis of renal cell carcinoma (RCC): Population, treatment and outcome in a cohort of 828 patients followed at Instituto Oncológico Henry Moore (IOHM).
Authors: Niewiadomski Dario , Acuna Claudia Lorena , Morgenfeld Eduardo L. , Tognelli Flavio , Smolje Leonardo , Montiel Monica , Garcia Gerardi Carlos Fernando , Abal Mariana , Gil Deza Ernesto , Rivarola Edgardo G. J. , Gercovich Felipe G. 
Published: September 2018

e16075 Background: For the past three decades, it has been observed in developed countries an increase in the incidence of RCC, at the expense of small tumors incidentally found. This study compares the epidemiology, treatment and evolution of the patients (pt) with incidental RCC (Group A) or clinical RCC (Group B). Methods: Between 1/1/2001 and 11/30/2016, 29,440 new pt with histological diagnosis of cancer were incorporated to the IOHM database. We selected all those coded under the WHO ICD10 code C64. The medical records were reviewed, registering the epidemiological data, treatments and evolution of each patient Results: We identified 828 pt out of 29,940 pt (2.8%) who met the inclusion criteria. Group A = 507 pt (61%) and Group B = 321 pt (39%). The table below shows the characteristics of both groups. Conclusions: 1) In this cohort the incidental diagnosis of RCC represented 60% of the cases and correlated with early stages and less aggressive tumors. 2) The appropriate selection of patients allowed partial nephrectomies in 103/828 Pt. (12% of the cases). 3) With a median follow-up of 30 months the survival rate of this population exceeded 90% in the early stages and was close to 50% in advanced cases. [Table: see text]