bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using adjuvant radiotherapy to improve cancer-specific survival in patients with highly aggressive prostate cancer: Examining recently released criteria.
Authors: Abdollah Firas , Gandaglia Giorgio , Briganti Alberto , Trinh Quoc-Dien , Nguyen Paul Linh , Hu Jim C. , Montorsi Francesco , Perrotte Paul , Karakiewicz Pierre I. , Sun Maxine 
Published: February 2017

30 Background: Although adjuvant radiotherapy (aRT) after radical prostatectomy (RP) improves biochemical recurrence (BCR)-free survival rates, its effect on cancer-specific mortality (CSM) in patients with prostate cancer (PCa) is still controversial. The aim of our study was to test the effect of aRT on CSM according to a risk score based on the number and nature of adverse pathological characteristics (Gleason score 8-10; pT3b/4, lymph node invasion [LNI]). Methods: Overall, 7,616 patients with pT3/4 N0/1 PCa treated with RP between 1995 and 2009 within the Surveillance Epidemiology and End Results Medicare-linked database were included in the study. Patients were stratified according to the risk score (less than 2 vs. 2 or more adverse characteristics), and the impact of aRT on CSM was examined in each sub-group. Additionally, to evaluate the effectiveness of aRT, we calculated the number needed to treat (NNT), defined as the average number of patients who must be treated to prevent one detrimental outcome. Subsequently, competing-risks regression models were used to test the effect of aRT on CSM rates in the overall population and after stratifying patients according to their risk score (less than 2 vs. 2 or more). Results: The risk score was associated with increasing 10-year CSM rates (P<0.001). When focusing on patients with a risk score 2 or more, 10-year CSM rates were significantly lower for individuals undergoing aRT compared to their counterpart not receiving aRT (6.9 vs. 16.2%, respectively; P=0.002). The corresponding NNT to prevent one death from PCa was 10. Adjuvant RT was not associated with lower CSM rates overall and in patients with a risk score less than 2. This was confirmed in multivariable analyses, where aRT decreased the risk of CSM only in patients with a risk score 2 or more (P≤0.02). Conclusions: Our findings confirm the validity of the previously reported risk score in selecting the most optimal candidates for aRT after surgery in a large contemporary population-based cohort of patients with pT3/4 N0/1 PCa. Patients with two or more adverse pathological characteristics at RP might benefit the most from aRT in terms of reduced CSM.
Using exon-capture, deep sequencing of high-grade bladder urothelial carcinoma to identify recurrent genetic alterations and potential therapeutic targets.
Authors: Kim Philip H. , Sfakianos John P. , Scott Sasinya N. , Iyer Gopa , Cha Eugene K. , Al-Ahmadie Hikmat , Sun Arony J. , Garcia-Grossman Ilana Rebecca , Bambury Richard Martin , Dalbagni Guido , Rosenberg Jonathan E. , Bajorin Dean F. , Berger Michael F. , Solit David B. , Bochner Bernard H. 
Published: February 2017

308 Background: Urothelial carcinoma (UC) is highly lethal malignancy with limited therapeutic options in the advanced setting. Using a targeted, deep sequencing approach, we analyzed high grade bladder tumors to determine the prevalence of known cancer genes and to identify potential targets for therapy. Methods: High-grade bladder UC frozen tumor and matched germline blood was obtained from 109 patients (pts) undergoing transurethral resection or cystectomy. Tumor and normal DNA were analyzed using IMPACT (Integrated Molecular Profiling of Actionable Cancer Targets), a next generation, exon-capture targeted deep sequencing assay designed to identify point mutations, indels, and copy number alterations in the coding regions of 300 cancer-associated genes. Results: Median age was 68 and 82 pts (75%) were male. Mean target coverage for all sequenced exons was 579X. The most commonly mutated gene was TP53 (63 pts, 58%). Alterations in genes regulating cell cycle were also prevalent, including mutations in Rb (25 pts, 23%), and copy number gains of CCND1 (19 pts, 17%) and CCNE1 (8 patients, 7%). Mutations in several chromatin remodeling genes were also highly prevalent, including KDM6A (46 pts, 42%), MLL2 (34 pts, 31%), and ARID1A (31 pts, 28%). Alterations within recognized cancer-related signaling pathways were common. PI3K pathway alterations were prevalent, with PIK3CA mutations found in 25 pts (23%), 23 of which were recurrent missense mutations. Six pts (6%) had mutations in PTEN. Mutations in TSC1 were also found in six pts (6%). Alterations in select MAPK pathway genes were common, including FGFR3 (21 pts, 19%) and ERBB2(15 pts, 14%). Conclusions: High-grade bladder UC is a genetically heterogenous disease. However, over half of the tumors analyzed in this study harbor alterations in genes that have been targeted for therapeutic benefit in other cancers. Results from our targeted exon-sequencing analysis therefore provide a compelling case for clinical trials using novel agents in UC. Moreover, this deep sequencing assay may be used clinically to prospectively identify pts for trials enriched for patients with specific alterations.
Changes in relative conditional survival (RCS) in de novometastatic urothelial carcinoma (mUC): A Surveillance, Epidemiology, and End Results (SEER) database analysis.
Authors: Pal Sumanta Kumar , Vogelzang Nicholas J. , Nelson Rebecca A. 
Published: February 2017

314 Background: Currently, no agents are FDA approved for second-line treatment of mUC. Still, many patients receive second-line treatment, with data from phase II studies used as justification for payors. While this practice may not prolong disease-specific survival (DSS) for all mUC patients, assessing RCS may better account for benefit from 2nd line treatment. Methods: The SEER database was queried to compare DSS and 1-year RCS rates in de novo mUC patients diagnosed from 1994-2000 (T1) to those diagnosed from 2001-2009 (T2). The cut-off at 2000 was chosen to account for treatment variations stemming from phase II second-line trials published subequent to this date. DSS rates for T1 and T2 were modeled using Kaplan-Meier methods and compared using the log-rank test. 1-year RCS was computed annually from diagnosis through 5-years post diagnosis. The results were age standardized and compared across time periods using the z-test statistic, with 95% confidence intervals calculated using the log(log()) transformation. Multivariate Cox proportional hazard models were used to assess independent prognostic factors of DSS. Results: A total of 4,465 mUC patients were included, with 1,155 diagnosed during T1 and 3,310 diagnosed during T2. Mean age of the overall cohort was 70, and the majority of patients had poorly differentiated or undifferentiated tumors. Median DSS was 6 months for both T1 and T2 groups (P=NS). 1-year RCS rates at 1, 2, and 3 years post diagnosis, were 46%, 71%, and 76% for T1 patients compared to 39%, 68% and 78% for T2 patients (P=NS for each comparison). On MVA, older age (>65) and undifferentiated histology were independently associated with shorter DSS, while use of radiation and surgery were associated with longer DSS. Time period of diagnosis (T1 vs T2), however, had no impact on DSS. Conclusions: Multiple published phase II studies emerging over the past decade have been used to justify use of post second-line therapies for mUC to payors. In contrast to DSS, our assessment of RCS should better account for the impact of these therapies. The lack of improvement in RCS calls into question the impact post first-line therapies have on the natural history of mUC.
NOTCH2 inhibition on tumor growth and metastasis in bladder cancer.
Authors: Hayashi Tetsutaro , Gust Kilian , Jaeger Wolfgang , Awrey Shannon , Li Na , Altamirano-Dimas Manuel , Buttyan Ralph , Fazli Ladan , Matsubara Akio , Black Peter C. 
Published: February 2017

315 Background: Notch is a family of cell surface receptors that has been demonstrated in several malignancies to regulate differentiation, proliferation, and metastasis. We have investigated the role of Notch signaling in bladder cancer and report here effects of modulating Notch2 in preclinical models of bladder cancer. Methods: Notch2 staining was examined in cystectomy patients by immunohistochemistry (IHC). The high NOTCH2 expressing UM-UC3 and UM-UC13 bladder cancer cells were stably transduced with either Notch2 specific or control shRNA. The low Notch2 expressing RT4V6 and RT112 cells were transduced with NOTCH2 intracellular domain or empty vector. A Notch2 inactivating antibody, NRR2Mab, was provided by Genentech, Inc. (San Francisco, CA). The effects of NOTCH2 overexpression and inhibition were assessed for changes in proliferation under both adherent (AH) and anchorage independent conditions (AI), and invasive activities in vitro, as well as for expression of markers of epithelial to mesenchymal transition (EMT) and stem cell markers. In vivo effects were evaluated in an orthotopic bladder cancer xenograft model with bioluminescence imaging. Results: NOTCH2 overexpression in IHC correlated with higher grade and stage. Both NOTCH2 overexpressing cells showed spindle shaped morphology and increased cell growth in AH and AI and invasion compared to mock cells. This was associated with cell cycle progression and increased expression of EMT and stem cell markers. Stable NOTCH2 knockdown cells and cells treated with NRR2Mab demonstrated decreased growth in AI and invasion, and this was associated with decreased expression of EMT and stem cell markers. In vivo, RT4V6 NOTCH2 overexpression increased xenograft tumor growth and NOTCH2 overexpression increased ki67 positive cells and promoted EMT in IHC. Stable Notch2 knockdown inhibited xenograft tumor growth in UM-UC3 and UM-UC13. NRR2Mab treatment also inhibited UM-UC13 xenograft tumor growth and lymph node metastasis. Conclusions: NOTCH2 plays a crucial role in growth, self-renewal and invasion in bladder cancer. These results provide pre-clinical proof of principle that Notch2 inhibition may be a rational treatment for bladder cancer.
Treatment target development in muscle-invasive bladder cancer.
Authors: Brown Mick D. , Robinson Richard , Hart Claire , Clarke Noel W. 
Published: February 2017

328 Background: Outcome for many patients with high-grade muscle invasive bladder cancer (MIBC) remains poor despite aggressive therapy. This study used novel marker approaches to evaluate putative treatment targets, correlating cell line models of bladder cancer with a large scale MIBC tissue microarray (TMA) linked to long-term post-treatment outcomes. Methods: The TMA was constructed from 497 cystectomy specimens from patients with comprehensively documented disease outcome (minimum 5 years follow-up). TMA sections were stained for putative targets using DAB-based IHC. Cellular expression of CYR61 and CTGF was quantified (after targets had been identified using the genetic search programme, Oncomine) using Definiens automated image-analysis (AIA) software. Putative TMA based-targets studied were also evaluated in J82 and T24 bladder cancer cell-lines by siRNA knockdown during proliferation, time course stimulation and Boyden chamber MatrigelÒ invasion assays. Results: CTGF was increased significantly in both cell lines following stimulation with the cMET ligand HGF. siRNA knockdown of CTGF and CYR61 reduced cell proliferation and invasion towards HGF and FCS significantly (p<0.01). AIA demonstrated high sensitivity and specificity (82.5% and 99.8% respectively) for identifying tumour cells. There was no intra-observer variability (ICC=1). CYR61 was associated with significantly improved survival following cystectomy, median 15.2 versus 40.0 months for intermediate/high versus negative/low expression respectively (p=0.004). Conclusions: AIA is robust tool for use in IHC based research. CTGF is an important component of the cMET axis in MIBC. CTGF and in particular CYR61 are promising treatment targets and warrant further investigation in the management of this disease.
Adjuvant chemotherapy for upper-tract urothelial carcinoma: A systematic review and meta-analysis of available studies.
Authors: Leow Jeffrey J. , Chang Steven L. , Choueiri Toni K. , Bellmunt Joaquim 
Published: February 2017

330 Background: Upper-tract urothelial carcinoma (UTUC) accounts for less than 5% of all urothelial cancers. Adjuvant chemotherapy (AC) for UTUC may improve survival outcomes, but currently available evidence is limited. Methods: A comprehensive literature review was performed to identify all studies comparing AC with control for patients with UTUC. The search included the Medline, Embase, Cochrane Central Register of Controlled Trials databases, and abstracts from the American Society of Clinical Oncology meetings up to June 2013. An updated systematic review and meta-analysis was performed. Results: A total of 9 retrospective cohort studies were identified (Table). For disease-specific survival, 6 studies had sufficient data (AC: n=406, control: n=1,227), with a pooled hazard ratio of 0.64 in favor of AC over control (95% CI: 0.41 to 0.99; p=0.047). Between-trial heterogeneity was not significant based on the Cochran Q statistic (p=0.14) and I2 = 40% (95% CI=0-76). Four studies had sufficient data for overall survival (AC: n=228, control: n=685), with a pooled hazard ratio of 1.06 (95% CI: 0.52 to 2.13; p=0.88). Between-trial heterogeneity was observed based on the Cochran Q statistic (p=0.03) and I2(68%, 95% CI: 7-89). There were no randomized trials investigating the role of AC for UTUC. Conclusions: There appears to be a significant benefit in disease-specific survival, but not overall survival, for AC in UTUC. While limited by the retrospective nature of studies and relatively small sample size, this analysis may be helpful in guiding the oncologic management of UTUC. [Table: see text]
Comparison of oncologic outcomes following systemic neoadjuvant chemotherapy and radical cystectomy in patients with mixed histologic variants and pure urothelial carcinoma of the bladder.
Authors: Sverrisson Einar Freyr , Espiritu Patrick , Kim Timothy , Gupta Shilpa , Poch Michael Adam , Spiess Philippe E. , Pow-Sang Julio , Sexton Wade Jeffers 
Published: February 2017

333 Background: Neoadjuvant chemotherapy (CT) is recommended prior to radical cystectomy (RC) in patients with muscle invasive urothelial carcinoma of the bladder (UCB), and has been shown to have modest survival benefit in clinical trials. The purpose of our study was to investigate the response and survival rates in patients with histologic variants (HV) and compare oncologic outcomes to patients with pure UCB. Methods: We performed a retrospective review of 163 patients treated with neoadjuvant CT prior to RC. Twenty-four patients with HV and 139 with pure UCB were identified. Numerous patient demographics, clinical and pathologic characteristics were evaluated including; clinical and pathologic stage, HV, lymphovascular invasion (LVI), margin status, node counts, concomitant carcinoma in situ (CIS), previous intravesical treatments, prior pelvic radiation, completeness of bladder tumor resection (TURBT), and CT regimens. Results: Patients with HV were younger (66.5 versus 71 years, p=0.04) but otherwise there were no significant differences noted between the two groups comparing previous treatments, clinical staging, margin status, node counts, CT regimens, # of neoadjuvant CT cycles, or rates of adjuvant CT administration. Of the 24 HV patients, 11 (47.8%) were downstaged to < pT2 compared to 50 (64.1%) of 139 patients with pure UCB (P=0.37). pT0 rates for HV and pure UCB were 16.7% and 23%, respectively (p=0.60). Twelve (50%) of the HV group compared to 65 (46.8%) of the pure UCB patients (p=0.83), had no evidence of disease at a mean follow up after RC of 19.5 (HV) and 22 (UCB) months. Eight (33.3%) patients with HV died of disease compared to 44 (31.7%) in the UCB group, (p=1.0). There was no significant difference noted in CSS and OS between the 2 groups, although there was a trend towards higher rates of node positive disease (p=0.086) and inferior CSS (p=0.09) in patients with HV compared to patients with pure UCB. Conclusions: Our results indicate that patients with HV experience similar oncologic outcomes from neoadjuvant systemic CT compared to patients with pure UCB.
Comparative effectiveness of radical cystectomy versus bladder-sparing treatment for muscle-invasive urothelial carcinoma: A population-based report.
Authors: Sun Maxine , Gandaglia Giorgio , Karakiewicz Pierre I. , Hu Jim C. , Kim Simon P. , Nguyen Paul Linh , Choueiri Toni K. , Abdollah Firas , Trinh Quoc-Dien 
Published: February 2017

334 Background: Radical cystectomy (RC) represents the standard of care for patients with muscle-invasive urothelial carcinoma of the urinary bladder (UCUB). Alternative organ-conserving treatments such as chemotherapy and/or radiotherapy have gained interest. We sought to compare survival outcomes of patients according to treatment modalities, in a stage-for-stage analysis. Methods: We relied on the Surveillance, Epidemiology, and End Results Medicare-linked database to identify 12,950 patients diagnosed with T2–T4a N0/x M0 UCUB between years 1992 and 2009. Treatment types include RC (n=5207), chemotherapy/radiation (n=2,669), and surveillance (n=5,074). Following instrumental variable analysis, Cox- and competing-risks regression analyses were performed for prediction of overall survival (OS) and cancer-specific mortality (CSM), respectively. All analyses were stratified according to disease stage (T2, T3, T4a). Results: After adjusting for potential confounders, OS was more favorable for RC relative to chemotherapy/radiation (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.02–2.40) or surveillance (HR: 1.82, 95% CI: 1.20–2.78) in patients with T2 UCUB. For the same stage, CSM rates were lower in the surgery group compared to chemotherapy/radiation (HR: 2.05, 95% CI: 1.14–3.67) or surveillance (HR: 1.95, 95% CI: 1.09–3.48). When analyses focused on individuals with more advanced disease (T3–T4a), no statistically significant difference was observed between chemotherapy/radiation relative to RC for both OS and CSM. Conclusions: In the current retrospective population-based cohort, RC was associated with improved survival outcomes relative to its alternative treatment counterparts. However, this effect was only observable in patients with T2 disease. Conversely, no difference between chemotherapy/radiation vs. surgery was noted in patients with more advanced disease stage.
Predictive and prognostic significance of early positron emission tomography/computed tomography (PET/CT) in advanced transitional cell carcinoma.
Authors: Giannatempo Patrizia , Alessi Alessandra , Miceli Rosalba , Raggi Daniele , Farè Elena , Nicolai Nicola , Serafini Gianluca , Padovano Barbara , Piva Luigi , Biasoni Davide , Torelli Tullio , Catanzaro Mario , Stagni Silvia , Maffezzini Massimo , Mariani Luigi , Gianni Alessandro M. , Sonpavde Guru , Salvioni Roberto , Crippa Flavio , Necchi Andrea 
Published: February 2017

341 Background: A risk-adapted treatment for TCC may guide new trial designs for early-recognized unresponsive patients (pts). We aimed to prospectively identify early fluorodeoxyglucose (FDG)-PET/CT as a predictor of response and outcome. Methods: Pts with newly-diagnosed advanced/metastatic TCC receiving first-line chemotherapy underwent CT and FDG-PET/CT at baseline, a restaging with PET/CT after 2 cycles only (PET2), and a CT (± FDG-PET/CT) at the end of treatment and during follow up. The endpoints were PET2 metabolic response, RECIST response, progression-free (PFS) and overall survival (OS). Univariable (UVA) and multivariable (MVA) Cox models were fitted. Prespecified variables were presence of visceral metastases, nodal or soft tissue disease, and PET2 response. Results: In the time-frame 05/2010-10/2012, 31 pts with ECOG-PS 0 received a modified MVAC regimen according to Institutional protocol, every 3 weeks. After 2 cycles of MVAC, 6 patients (19.3%) had a complete (CR) and 17 (54.8%) a partial metabolic response (PR) (74% total responders; 95% CI, 55.4-88.1%), 4 had stable disease (SD), 4 progressed. Metabolic response (CR + PR) was associated with final CT response (p=0.007 at Fisher exact test). Metabolic CR was followed by a RECIST CR in all but one cases and metabolic progression at PET2 corresponded to a RECIST PD in all four patients and they all switched to second line chemotherapy. Median follow up was 18 months (IQR: 10-47). Those with metabolic response had a median (95% CI) PFS of 8 (7-11) months compared to 3 (2-5) months of patients without response (p=0.024). PET2 responders had a significant benefit in 8-month PFS (p<0.001) and 15-month OS (p=0.016 at Klein test). A significant association was observed between PET2 response and longer PFS in both UVA and MVA (p=0.027 and p=0.023, respectively). Results are limited by small numbers. Conclusions: PET2 response might confer an independent prognostic impact on PFS and OS. Results warrant a validation series, a comparison with the impact of early RECIST response as well as a detailed cost-efficacy analysis prior to devise a new strategy of first-line treatment.
Clinical evaluation of cisplatin sensitivity germ line polymorphisms in neoadjuvant chemotherapy (NAC) for urothelial cancer (UC).
Authors: O'Donnell Peter H. , Garcia-Grossman Ilana Rebecca , Cao Hongyuan , Ostrovnaya Irina , Plimack Elizabeth R. , Stratton Kelly Lynn , Manschreck Christopher , Smith Norm D. , Steinberg Gary D. , Joseph Vijai , Offit Kenneth , Stadler Walter Michael , Bajorin Dean F. 
Published: February 2017

342 Background: Cisplatin-based NAC in UC confers a survival benefit, but prediction of which patients (pts) will benefit is not possible. We attempted to validate pharmacogenomic (PGx) markers of cisplatin sensitivity derived from a cell-based model and previously associated with response in a population of pts receiving NAC. Methods: Three germline single nucleotide polymorphisms (SNPs) were previously associated with pathologic response at cystectomy in a single-institution discovery set of 59 cT2 UC pts. These SNPs were tested for association with NAC response in a prospectively-identified, multi-institution, independent cohort. The primary analysis tested for association between rs244898 and rs7937567 and pathologic complete response (pT0). A replication set of 134 pts would provide 80% power to detect effects of both SNPs at p=0.05 independently using a multivariate logistic model. Results: N=146 pts with ≥cT2 N0 disease were identified from three institutions. All pts received ≥3 cycles of cisplatin-based NAC and underwent definitive surgery. Rates of pT0 and <pT2 were 26% and 50%, respectively, comparable to the discovery population. Though each SNP had a >5 odds ratio of effect on pT0 in the discovery set, neither was associated with achievement of pT0 in the replication set. The third SNP (rs10964552) which was associated with pathologic downstaging in the discovery set, also failed to replicate. All three SNPs were in Hardy-Weinberg equilibrium, and minor allele frequencies were similar between discovery and validation. Conclusions: Three germline SNPs previously associated with platinum sensitivity in pre-clinical and clinical models were not associated with NAC response in a large replication cohort of UC pts. Reasons for failure may include unmeasured clinical differences between the pt cohorts, a higher proportion of MVAC use in the replication set compared to gemcitabine/cisplatin in discovery pts, or simply spurious association in the discovery cohort. These results emphasize the need for replication when evaluating PGx markers, and demonstrate that multi-institutional efforts are feasible and will likely be necessary to achieve advances in UC PGx.