bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of green tea polyphenol on changes in cancer-related factors in a mouse model of bladder cancer.
Authors: Matsuo Tomohiro , Miyata Yasuyoshi , Nakamura Yuichiro , Takuji Yasuda , Asai Akihiro , Ohba Kojiro , Sakai Hideki 
Published: March 2017

329 Background: Many studies have demonstrated the anti-cancer effects of green tea polyphenol (GTP) in a variety of malignancies including bladder cancer, and epidemiologic studies have shown that green tea consumption reduces cancer risk. New cancer treatment strategies in combination with GTP intake have been recommended for several types of cancer. Thus, GTP is thought to be useful not only for cancer prevention but also for treatment. However, the mechanistic basis of these effects is not well understood. Hence, The aims of this study is to clarify the molecular mechanisms of GTP-induced anti-cancer effects, we used a mouse model of chemically induced bladder cancer. Methods: C3H/He mice (8 weeks old; n = 46) were treated with 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) solution for 14–24 weeks. Mice in the BBN + GTP group (n = 47) were also treated with 0.5% GTP solution over the same period. Tumor cell proliferation, and microvessel density were evaluated along with immunohistochemical analysis of human antigen R (HuR), vascular endothelial growth factor (VEGF)-A, cyclooxygenase (COX)-2, and hemeoxygenase (HO)-1 expression. Results: Cytoplasmic HuR expression in cancer cells was higher at 14 and 24 weeks in the BBN than in the control group and was associated with increased invasion of tumor cells in muscle. However, these effects were not observed in the BBN + GTP group. A multivariate analysis of GTP intake and cytoplasmic HuR expression revealed that GTP was independently associated with COX-2 and HO-1 expression, while cytoplasmic HuR expression was associated with COX-2 and VEGF-A levels. Expression of COX-2 and HO-1 was associated with cell proliferation and that of VEGF-A and HO-1 was associated with angiogenesis. In regard to nuclear HuR, its expression was not associated with any parameters, such as carcinogenesis, muscle invasion, and GTP intake. Conclusions: Our results supported the opinion that GTP intake can suppress tumor progression and malignant behavior in animal model of bladder cancer. In addition, we speculate that GTP directly and indirectly suppresses tumor cell proliferation and angiogenesis via HuR-related pathways in bladder cancer tissue.
Circulating tumor (ct)-DNA alterations in advanced urothelial carcinoma: Association with outcomes and evolution with therapy.
Authors: Grivas Petros , Nagy Rebecca J , Pond Gregory Russell , Gupta Sumati , Wang Jue , Vaishampayan Ulka N. , Pal Sumanta K. , Bilen Mehmet Asim , Naik Gurudatta , Ghatalia Pooja , Gopalakrishnan Dharmesh , Barata Pedro , Lanman Richard B. , Talasaz AmirAli , Sonpavde Guru 
Published: March 2017

334 Background: Cell-free ctDNA may be potentially actionable, prognostic for outcomes and evolve after therapy. We conducted a retrospective study to evaluate these issues and shed light on UC biology. Methods: Patients (pts) with advanced UC who underwent ctDNA analysis for potentially actionable alterations using Guardant360 were identified. Data were requested for prognostic factors, current and prior therapies, TTF (time to treatment failure) and overall survival (OS). A 70-gene ctDNA next generation sequencing panel from a CLIA-licensed, CAP-accredited laboratory (Guardant Health, Inc.) offers complete exon sequencing for 29 cancer genes, critical exons in 39 genes and amplifications (16 genes), fusions (6 genes) and indels (3 genes) harvested from 10 mL of peripheral blood. Alterations were reported and association of non-synonymous potentially functional alterations with outcomes and prior therapy was examined. Results: There were 217 pts with 238 samples. ctDNA was detectable in 212 (89%) samples. Median age was 62 (range 39-91). The most common recurrent somatic mutations were in TP53 (n = 122, 57%) ARID1A (n = 47, 22%), NF1 (n = 35, 16%), FGFR2, FGFR3, and BRCA1 (n = 30, 14% each), MET (n = 27, 13%), ERBB2 (n = 25, 12%), PIK3CA (n = 24, 11%), and EGFR (n = 22, 10%). Most common genes with increased copy numbers were ERBB2 (n = 19, 9%) and RAF1 (n = 18, 8%). Clinical data were available for 64 pts, of whom 38 (59%) had prior chemotherapy. FGFR1 alterations noted in 3 of those pts (5%, 2 functional, 1 amplification) were associated with shorter OS (HR 2.95, p = 0.05). Pts with prior chemotherapy showed trend towards frequent alterations in DNA repair genes (45% vs. 23%, p = 0.11). Serial ctDNA profiling of 21 pts receiving therapy revealed the clonal evolution of mutations in BRCA2, NF1 and GATA3. Conclusions: ctDNA was very frequently detected in pts with advanced UC, and alterations were similar to those previously seen in muscle-invasive UC tumor tissue. FGFR1 alterations predicted for unfavorable outcome and DNA repair gene alterations evolved commonly after chemotherapy. Drugs exploiting these targets such as FGFR1 and PARP inhibitors may warrant exploration as salvage therapy in selected pts.
Phase I/Ib study of enzalutamide and gemcitabine and cisplatin in bladder cancer.
Authors: Gupta Shilpa , Fishman Mayer N. , Dhillon Jasreman , Magliocco Anthony Martin , Puskas John , Caceres Gisela , Al-Toubah Taymeyah E , Konety Badrinath R. , Lindemam Matthew , Jha Gautam Gopalji , Zhang Jingsong 
Published: March 2017

338 Background: Metastatic bladder cancer (mBC) is a fatal disease and novel therapies are urgently needed. Preclinical evidence suggests role of AR in BC progression. Enzalutamide (ENZ) is a novel AR antagonist that inhibits nuclear translocation of AR, DNA binding, and co activator recruitment. Our ongoing phase 1 trial is is assessing safety and tolerability of ENZ in combination with gemcitabine and cisplatin (GC) in mBC and explore novel correlatives in tumor tissues and CTCs. Methods: The study has 2 phases, dose escalation phase and dose expansion phase. The dose escalation phase had 2 cohorts testing ENZ at doses of 80 mg and 160 mg respectively with GC (gemcitabine 10000 mg/m2 on days 1 and 8 and cisplatin 70 mg/m2 on day 1 every 21 days). The dose escalation phase allowed both AR + and AR - mBC pts. Patients will be monitored for safety and tolerance with laboratory studies, clinical exam, and CT scans to assess response. Primary objective is safety and tolerability of ENZ and GC. Secondary objectives are objective tumor response, time to progression, and overall survival. Exploratory objectives include qualitative and quantitative evaluation of AR and pAKT expression with AQUA in tumor tissues and correlation with outcomes. CTCs are being evaluated at baseline and cycle 3, including AR expression in CTCs and correlation will be done with tumor AR expression and clinical outcomes. Key eligibility criteria are ECOG PS of 0-1, and no contraindications to study drugs. Results: In the dose expamnsion phase, 3 patients were enrolled in each cohort of 80 mg and 160 mg of ENZ respectively with GC and there were no DLTs or significant AEs related to the combination; the MTD of ENZ is 160 mg. Enrollment on dose expansion phase is ongoing. detectable CTCs were seen in 4/6 BC patients with 2 patients showing AR + CTCs at baseline. Further CTC analysis, including AR expression and tissue analysis for AR and pAKT analysis in tissues is ongoing. (Trial identifier: NCT02300610). Conclusions: This is a first of its kind clinical trial exploring the role of AR signaling in BC and targeting it with ENZ along with GC. The data gathered form this study will help us understand the clinical relevance of targeting AR in BC. Clinical trial information: NCT02300610.
Thrombo-embolic events (TEE) during neoadjuvant chemotherapy for muscle invasive bladder cancer.
Authors: Hussain Syed A. , Gomberg Simon , Probert Cairine , Hickerton Bethan , Jackson Richard , Weston Robin 
Published: March 2017

339 Background: Patients with muscle invasive bladder cancer receiving neo-adjuvant chemotherapy (NAC) prior to radical cystectomy or organ preservation treatment are at higher risk of thrombo-embolic events (TEE). Methods: Retrospective data were collected on patients undergoing NAC prior to radical treatment who had surveillance CT scan chest abdomen pelvis following NAC to assess for response or underwent scan following clinical presentation during NAC requiring imaging. The aim of this study was to document the incidence and characteristics of TEE during NAC prior to radical treatment. Results: Data were collected on 94 patients between January 2012 and December 2015. Median patient age was 67 (IQR: 63, 72) with 28 (30%) females. Chemotherapy received was Cisplatin and Gemcitabine in 90% of cases, Gemcitabine and Carboplatin (9%), and Cisplatin and Etoposide (1%). Performance status was 0 in 59% of cases. G3 disease was recorded in 87%, T2 or T3 in 80% and TCC in 91% of cases. 28 TEE (29.8%, 95 % CI: 20.5%, 39%) were recorded of which 22 (79%) were subclinical TEE and 6 (21%) were clinical TEE. 23 (82%) of TEE were pulmonary emboli, 2 (7%) were concurrent pulmonary emboli and deep vein thombosis, 2 (7%) were abdominal aorta thrombosis, and 1 (4%) was a deep vein thrombosis. Conclusions: Our single centre study demonstrates that the incidence of TEE during NAC prior to radical treatment for bladder cancer is high. Improved imaging techniques lead to reporting of number of sub clinical TEE of uncertain clinical significance. These findings give weight to future prospective clinical trials to investigate the role of anti-coagulation in subclinical TEE and benefit of prophylactic anti-coagulation during NAC.
Difference in toxicity reporting between patients and clinicians during systemic chemotherapy for urothelial carcinoma.
Authors: Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara 
Published: March 2017

347 Background: Symptomatic toxicities associated with anticancer treatments are at high risk of under-reporting by clinicians. However, insufficient evidence is available for urothelial carcinoma. To compare toxicity reporting by patients and clinicians in urothelial carcinoma patients who received systemic chemotherapy. Methods: Between June 2013 and March 2016, 100 urothelial carcinoma patients who received two courses of chemotherapy of gemcitabine plus cisplatin (GCis) or gemcitabine plus carboplatin (GCb) were included in this study. Outcome Measurements and Statistical Analysis: During chemotherapy, patients answered QLQ-C30 quality of life (QOL) questionnaires, which included questions on four toxicity-related symptoms (appetite loss, nausea, constipation, and diarrhea). Clinicians evaluated adverse events using CTCAE v4.0. Differences in toxicity reporting were retrospectively compared between patients and clinicians. Logistic regression analyses were performed to investigate potential factors for under-reporting by clinicians. Results: Toxicity under-reporting was most frequent in diarrhea (44%), followed by appetite loss (39%), constipation (33%), and nausea (22%). In total, toxicity under-reporting was observed in 72% patients. Background-adjusted logistic regression analyses showed that pretreatment QOL items, such as global and symptomatic scores, were selected as potential predictors for toxicity under-reporting by clinicians. Limitations of our study included its retrospective nature and small sample size. Conclusions: Toxicity under-reporting by clinicians is frequent in urothelial carcinoma patients who received systemic chemotherapy. Pretreatment QOL evaluation is essential to identify potential individuals at risk for toxicity under-reporting. Clinical trial information: UMIN000020784.
5-year outcomes from a prospective multi-institutional trial of heterogeneous dosing stereotactic body radiotherapy (SBRT) for low- and intermediate-risk prostate cancer.
Authors: Fuller Donald B. , Kane Brent L. , Medbery Clinton A. , Underhill Kelly , Gray James R. , Peddada Anuj , Chen Ronald C. 
Published: March 2017

35 Background: SBRT is an emerging treatment for prostate cancer, but long-term reporting remains sparse. We present a prospective Phase II trial with 90% treated in community facilities. Methods: 14 institutions enrolled 259 patients - 112 low-risk; 147 intermediate-risk. The regimen emulated a high-dose rate brachytherapy (HDR) regimen - 38 Gy/4 fractions delivered by robotic SBRT. Androgen deprivation therapy was not allowed. HDR-like heterogeneous prostate dosing was used (Dmax >57 Gy). Toxicities were assessed by CTCAE v3.0 and quality of life assessed by Expanded Prostate Cancer Index Composite (EPIC). Biochemical recurrence was defined by Phoenix criteria. Results: Median follow-up is 5 years. 5-yr Grade 2 GU toxicity was 13.7% and GI toxicity 4.5%, with Grade 3 rates of 3% (GU) and 0% (GI) (one Gd 4 GU event). 5-yr median PSA was 0.1 ng/mL with further subsequent decrease (7 y = 0.035 ng/mL). 5-yr biochemical disease-free survival (bDFS) = 100% for low-risk and 88.5% for int-risk. 6 patients developed distant metastasis and one died of disease. Median EPIC GU obstruction and GI scores were similar at baseline vs. 5 years. 2% of patients had baseline GU incontinence requiring pad use vs 10% at 5 yrs. Of baseline potent men, 46% remained so at 5 yrs (66.7% for those age ≤65 vs. 37.1% age >65 at treatment). Conclusions: This is the first report of 5-year median follow-up outcomes post heterogeneous dosing SBRT for early prostate cancer. This treatment produces a low PSA nadir vs other forms of radiotherapy, with a favorable long-term result that appears reproducible in the community. Clinical trial information: 00643617. [Table: see text]
Comprehensive genomic profiling of relapsed and refractory small cell neuroendocrine carcinoma of the urinary bladder.
Authors: Pal Sumanta K. , Hoffman-Censits Jean H. , Elvin Julia Andrea , Vergilio Jo-Anne , Suh James , Ramkissoon Shakti , Ali Siraj Mahamed , Schrock Alexa Betzig , Fisher Hugh A.G. , Mian Badar , Nazeer Tipu , Fabrizio David , Frampton Garrett Michael , Stephens Phil , Miller Vincent A. , Gay Laurie M. , Ross Jeffrey S. 
Published: March 2017

350 Background: Small cell neuroendocrine carcinoma of the bladder (SCCB) is rare but aggressive form of genitourinary cancer that can arise de novo or in conjunction with urothelial carcinoma (UCB). Methods: DNA was extracted from 40 microns of FFPE specimen from 29 cases of relapsed, refractory and metastatic SCCB and 1,113 UCB. Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of > 503X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations (GA), including base substitutions, insertions and deletions (short variants; SV), fusions, and copy number changes including amplifications (amp) and homozygous deletions. Results: 29 SCCB cases were confirmed on routine histology and featured positive IHC staining for chromogranin, synaptophysin or both. Patients had a mean age of 68.1 years (range 49-90 years) and 25 (86%) were male. At the time of CGP, 3 (10%) SCCB were Stage III and 26 (90%) were stage IV. The primary SCCB was used for sequencing in 14 (48%) of cases and a metastasis sample in 15 (52%). The 29 SCCB featured 2.86 GA/case.The genomics of SCCB differed significantly from UCB (Table). The most frequent clinically relevant GA in SCCB were RICTOR amp (21%) and PIK3CA (10%), BRCA1, HGF, FBXW7 and CCND2 SV (7% each). The relatively high TMB in SCCB (7% TMB > 20 mut/Mb and 28% TMB > 10 mut/Mb) is similar to that seen in UCB. No SCCB cases were MSI-high. ERBB2 and FGFR1 GA frequencies (both 3%) in SCCB were lower than in similarly studied UCB. Conclusions: SCCB differs in genomic landscape from UCB in having higher frequencies of TP53 and RB1 GA and lower frequencies of FGFR3 and ERBB2 GA. However, like UCB, SCCB shares the presence of multiple GA associated with potential responses to targeted therapies and high TMB associated with response to immune checkpoint inhibitor therapy. [Table: see text]
Sarcopenia as a useful predictor of postoperative complications following radical cystectomy: An assessment of preoperative CT scans.
Authors: Hennig Martin Jp , Hupe Marie C , Hensen Bennet , Jansen Max Clemens , Kramer Mario W , Kuczyk Markus A , Merseburger Axel Stuart 
Published: March 2017

351 Background: Muscle-invasive urothelial carcinoma is usually treated with radical cystectomy (RC). However, patients face a relevant risk of postoperative complications on variable factors. Recent reports described that sarcopenia, which is defined by a loss of sceletal muscle body composition, may enhance risk stratification. Methods: Our retrospective study includes 200 patients (154 men, 46 women, mean age: 67.9 years) which were treated with RC between 2005 and 2014. Median follow-up time was 26 months. Computed tomography (CT) scans were performed within 60 days prior to surgery. Lumbar skeletal muscle index (SMI) were measured with MeVisLab 2.7 by manually segmentation of preoperative CTs. The fat mass index (FMI) was calculated based on the same CT slides. Cut off points were developed for men and women separately. Additionally, short-, mid- and long-term complications were assessed using the Clavien-Dindo classification. Results: SMI (cm2/m2), FMI (kg/m2) and BMI (kg/m2) for men were calculated with mean scores of 52.8, 9.6 and 26.7, respectively. The corresponding calculated means for women were 38.9, 10.0 and 26.1. The SMI for short- and mid-term complications was statistically significant (p < 0.01) when applied on patients with a BMI over 25 kg/m2. Using Kaplan-Meier plots none of the other markers (BMI and FMI) correlated with complications or overall survival (OS). Conclusions: The presence of sarcopenia assessed by CT may improve risk stratification in patients undergoing radical cystectomy. BMI and FMI may not be used in risk stratification models, even though further validation for subgroups is needed. Future research is needed to validate the current findings. Noninvasive and semiautomatic calculation of SMI in preoperative CT scans may improve risk stratification in patients undergoing radical cystectomy and thus could reduce morbidity and mortality.
Association of preoperative neutrophil-to-lymphocyte ratio with survival outcomes in patients undergoing radical cystectomy, regardless of neoadjuvant chemotherapy status.
Authors: Kukreja Janet Baack , Podolnick Jason M , Wang Xuemei , Chen Hsiang-Chun , Navai Neema , Kamat Ashish M. , Dinney Colin P.N. , Shah Jay Bakul 
Published: March 2017

352 Background: Pre-operative neutrophil-to-lymphocyte ratio (NLR) has been found to be associated with adverse pathological results and poor long-term outcomes in patients treated with radical cystectomy (RC) for urothelial bladder carcinoma (BC). Prior studies have determined inclusion based on neoadjuvant chemotherapy (NAC) status. This study aimed to evaluate pre-operative NLR in a large cohort without exclusion as a predictor of long-term outcomes in patients undergoing RC for BC. Methods: A retrospective cohort study was performed of 1243 patients undergoing RC between 2000 and 2011. NLR was summarized using descriptive statistics. Univariate classification and regression trees analysis (CART) was applied to identify subgroups of patients using pre-surgery NLR as the covariate and overall survival (OS) or disease specific survival (DSS) as the outcome of interest. The probabilities of OS and DSS were estimated using the Kaplan-Meier method. Results: The median follow-up time among survivors was 7 years. 863 (69%) patients died and 380 (31%) were alive at last follow-up. The median OS was 5.2 years (95% CI: 4.9-5.5 years). Using CART analysis, the strongest association with OS was the cutoff point 3.09. 767 (62%) patients had pre-surgery NLR < 3.09 and 475 (38%) had pre-surgery NLR ≥ 3.09. The overall survival was found to be significantly associated with NLR < 3.09 vs. ≥ 3.09 (p < 0.001). The median OS for patients with NLR < 3.09 and ≥ 3.09 was 5.9 years (95% CI: 5.3-6.3 years) and 4.2 years (95%:3.3-4.7 years), respectively. Patients with NLR < 3.09 and ≥ 3.09 had 5-year OS of 56% and 44%, respectively. DSS was found to be significantly associated with NLR ≥ 3.09 vs. < 3.09 (p < 0.001). The median DSS for patients with pre-surgery NLR < 3.09 and ≥ 3.09 were 15.6 years and 7.5 years, respectively. Conclusions: The NLR significantly predicts OS and DSS in RC patients. NLR should be taken into consideration as NAC and adjuvant treatments are considered in BC patients to help improve survival.
Survival for patients with residual tumor at radical cystectomy following chemotherapy: A matched analysis to cystectomy-only patients.
Authors: Bhindi Bimal , Frank Igor , Mason Ross , Tarrell Robert F. , Thapa Prabin , Cheville John C. , Costello Brian Addis , Pagliaro Lance C. , Karnes Jeffrey , Thompson Robert Houston , Tollefson Matthew K. , Boorjian Stephen A. 
Published: March 2017

355 Background: While neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) improves survival compared to RC alone for urothelial carcinoma of the bladder (UCB), the bulk of this survival benefit has been attributed to patients who achieve ypT0 status at RC. The implications of having residual UCB (rUCB) at RC after NAC are less clear. As such, we evaluated whether the outcomes for patients with rUCB after NAC differ from stage-matched RC patients who did not receive NAC. Methods: Patients undergoing RC for UCB between 1981-2010 at Mayo Clinic were identified. All RC pathology was re-reviewed by a single genitourinary pathologist. Patients who received NAC were matched 1:2 to patients not exposed to NAC based on pT and pN-stage, margin status, and year of RC. Kaplan Meier and Cox regression analyses were used to evaluate the associations between NAC and cancer-specific (CSS) and overall survival (OS), stratified by presence of rUCB (i.e. (y)pT0N0 and non-(y)pT0N0). Results: We matched 111 patients who underwent NAC + RC to 222 RC-alone patients. Median age was 68 years (IQR 60,74); 59 (18%) were female. Median follow-up among survivors was 7.2 years (IQR 6,16). A total of 248 patients died; 148 died from UCB. In patients without rUCB at RC, there were no differences in 5-yr CSS (86% vs. 90%, p=0.85) or OS (82% vs. 84%, p=0.46) between patients who did and did not receive NAC. Moreover, on multivariable analysis, NAC exposure was not associated with CSS (HR=1.0; 95%CI 0.3-3.1; p=0.9) or OS (HR=0.9; 95%CI 0.4-1.9; p=0.8) in this subgroup. Among patients with rUCB, receipt of NAC was associated with significantly worse 5-yr CSS (32% vs. 56%, p<0.001) and OS (25% vs. 48%, p<0.001). NAC exposure remained independently associated with worse CSS (HR=2.2; 95%CI 1.6-3.1; p<0.001) and OS (HR=2.0; 95%CI 1.5-2.7; p<0.001) among these patients. Conclusions: While patients who achieve a complete response to NAC have excellent survival outcomes, patients with residual UCB at RC after NAC have a worse prognosis compared to stage-matched RC patients not exposed to NAC. Such patients should be considered for enrolment in novel adjuvant therapy trials.