bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating cell-free DNA profiling of patients with advanced urothelial carcinoma.
Authors: Sonpavde Guru , Nagy Rebecca J , Apolo Andrea B. , Agarwal Neeraj , Pal Sumanta K. , Grivas Petros , Vaishampayan Ulka N. , Lanman Richard Burnham , Talasaz AmirAli 
Published: February 2017

358 Background: Urothelial carcinoma (UC) exhibits one of the highest somatic mutation burdens. Circulating cell-free DNA (cfDNA) is obtained non-invasively from peripheral blood and appears detectable in most patients (pts) with advanced UC. We report cfDNA profiling of patients with advanced UC using biopsy-free cfDNA sequencing. Methods: Twenty-nine patients with advanced UC that underwent cfDNA analysis using Guardant360 were identified. A 68-gene cfDNA next generation sequencing (NGS) panel from a CLIA-licensed, CAP-accredited laboratory (Guardant360) offers complete sequencing for all exons in 29 cancer associated genes, as well as the critical exons in 39 other genes, and copy number amplifications (16), fusions (4) and indels (1) in selected genes, harvested from 20 mL of peripheral blood. The mutant allele fraction (MAF) is defined as the number of mutated cfDNA molecules divided by the number wild type cfDNA molecules at a given nucleotide position. Results: Of 29 patients with advanced UC, cfDNA was detectable in 25 patients (86.2%). Twenty-nine patients were available with bladder primary in 27 pts (93.1%), and the median age was 75 years (range 52-91). The most common recurrent somatic mutations in the 25 patients with ≥ 1 alteration were in TP53 (n = 17), BRCA1/2 (n = 6), FGFR2 (n = 5), EGFR (n = 5), PIK3CA (n = 4), APC (n = 4), KRAS (n = 4), RAF1/BRAF (n = 4), and FGFR3, ALK, PDGFRA, NF1, CDKN2A and ARID1A were observed in 3 patients each. The most common genes with ≥ 2 copy numbers in the 25 evaluable patients were ERBB2 (n = 2) and PIK3CA, EGFR, RAF1, and FGFR1 in one patient each. Analysis of additional patients is ongoing in this expanding dataset. MAF data will be presented. Conclusions: cfDNA is frequently detected in patients with advanced UC, and alterations appear similar to those previously reported from UC tumor tissue. The correlation of cfDNA profiling with tumor tissue profiling within patients and ability to predict response requires study. Given that cfDNA offers a non-invasive means of profiling tumor DNA and MAF, further development of this promising modality is warranted to guide therapy with biologic agents and immunotherapy, and serial monitoring may provide insights regarding tumor biology.
Significance of preoperative butyrylcholinesterase as an independent predictor of survival in patients with muscle-invasive bladder cancer treated with radical cystectomy.
Authors: Koie Takuya , Ohyama Chikara , Hatakeyama Shingo , Imai Atsushi , Yoneyama Takahiro , Hashimoto Yasuhiro 
Published: February 2017

373 Background: Butyrylcholinesterase (BChE) is an alpha-glycoprotein found in the nervous system and liver. Its serum level is reduced in many clinical conditions, such as liver damage, inflammation, injury, infection, malnutrition, and malignant disease. In this study, we analyzed the potential prognostic significance of preoperative BChE levels in patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy (RC). Methods: We retrospectively evaluated 327 patients with MIBC who underwent RC from 1996 to 2013 at a single institution. Serum BChE was routinely measured before operation in all patients. Covariates included age, gender, preoperative laboratory data (anemia, BChE, lactate dehydrogenase, C-reactive protein), clinical T (cT) and N stage (cN), tumor grade, and RC with/without neoadjuvant chemotherapy. Univariate and multivariate analyses were performed to identify clinical factors associated with overall (OS) and disease-free survival (DFS). Univariate analyses were performed using the Kaplan-Meier and log-rank methods, and the multivariate analysis was performed using a Cox proportional hazard model. Results: The median BChE level was 187 U/L (normal range, 168–470 U/L). The median age of the enrolled patients was 69 years, and the median follow-up period was 51 months. The 5-year OS and DFS rates were 69.6% and 69.3%, respectively. The 5-year OS rates were 90.1% and 51.3% in the BChE ≥ 168 and < 168 U/L groups, respectively (P < 0.001). The 5-year DFS rates were 83.5% and 55.4% in the BChE ≥ 168 and ≤ 167 U/L groups, respectively (P < 0.001). In the univariate analysis, BChE, cT, cN, and RC with/without neoadjuvant chemotherapy were significantly associated with both OS and DFS. Multivariate analysis revealed that BChE was the factor most significantly associated with OS, and BChE, cT, and cN were significantly associated with DFS. Conclusions: This study validated preoperative serum BChE levels as an independent prognostic factor for MIBC after RC.
Incidence, characteristics, and implications of thrombo-embolic events in patients with urothelial carcinoma of the bladder undergoing neoadjuvant chemotherapy.
Authors: Duivenvoorden Wilhelmina CM , Daneshmand Siamak , Canter Daniel J. , Lotan Yair , Black Peter C. , Abdi Hamidreza , Van Rhijn Bas W.G. , Fransen van de Putte Elisabeth E. , Bostrom Peter J. , Koskinen Ilmari , Zareba Piotr , Baack Kukreja Janet E. , Kassouf Wassim , Traboulsi Samer , Pinthus Jehonathan H 
Published: February 2017

393 Background: Neoadjuvant chemotherapy (NAC), in combination with radical cystectomy (RC), is associated with a significant survival advantage for patients with muscle-invasive bladder cancer. Chemotherapy as well as pelvic surgery are significant risk factors for thrombo-embolic events (TEE). The objectives of this study were to investigate the incidence and characteristics of TEE during and after NAC and subsequent RC for urothelial bladder cancer patients. Methods: A retrospective study was carried out on 827 consecutive patients who underwent NAC and cystectomy for urothelial bladder carcinoma from 2002 to 2014 at ten different tertiary centers across North America and Europe. The median time of follow-up from bladder cancer diagnosis was 13 months (range 1-119 months). The incidence (venous, arterial, port-site or deep vein thrombosis, thrombosis, clinical or incidentally detected pulmonary embolism) and timing of TEE (before or after ( < or > 30 days) RC) and Khorana score (based on baseline hemoglobin, platelet and leukocyte counts, BMI and tumor site, which was established for cancer patients treated with chemotherapy) was determined for all patients. Multivariate analysis was performed on 827 patients. Kaplan Meier survival curves and log rank test were used to compare survival between patients who developed TEE and those who did not. Results: The Khorana criteria indicated intermediate TEE risk in most patients. Khorana risk score was 1 or 2 in 88% of patients. Nevertheless, the incidence of TEE in patients undergoing NAC was 15%. 59 TEE were detected pre-operatively (7.1%), 21 early within 30 days of RC (2.5%) and 36 late post-operatively (4.3%). 32% of the TEE events were detected incidentally by imaging, 68% were detected clinically. Median overall survival of patients who developed TEE was 28 months compared to 71 months for those who did not develop TEE (p = 0.012). Conclusions: This multi-centre retrospective study suggests that TEE are very common in bladder cancer patients undergoing NAC followed by RC and is associated with poorer survival. Further investigation with a prospective prevention trial is warranted.
Single arm phase II study of docetaxel and lapatinib in metastatic urothelial cancer: USC trial 4B-10-4.
Authors: Tang Sujie , Dorff Tanya B. , Tsao-Wei Denice D , Massopust Kristy , Ketchens Charlean , Hu James , Goldkorn Amir , Sadeghi Sarmad , Pinski Jacek K. , Averia Monica , Groshen Susan G. , Press Michael F. , Schuckman Anne K. , Quinn David I. 
Published: February 2017

424 Background: Advanced urothelial cancer progressing after first line systemic therapy is fatal. No agent in the second line or later setting has demonstrated improved survival although taxanes, pemetrexed, gemcitabine & vinflunine have activity & are used as palliative therapy. The Her2 pathway is up-regulated in some urothelial cancers and Her2 targeted therapy has enhanced chemotherapy effect in other cancers. We tested docetaxel with lapatinib, a Her1/Her2 TKI in urothelial cancer patients. Methods: Pts with measurable or evaluable urothelial cancerentered a single arm 2-stage phase II clinical trial, with PFS rate at 12 weeks as the primary endpoint in a Simon 2-stage design of 14+26 patients. The goal was a 12 week non progression rate of 60% - seen as promising compared to a rate of < 40% seen as not. In a 2-stage design if ≥ 6 of 14 patients had not progressed by 12 weeks the trial would continue to 40 pts. Secondary endpts: ORR, safety & OS. First 6 patients were given lapatinib 1250mg PO daily & docetaxel 60mg/m2 IV q3wk; docetaxel dose then increased to 75mg/m2 q3wk. Tumor tissue & circulating microenvironment were evaluated. Results: From July 2011 to July 2013, 15 pts were accrued. Median age 65 y, male 80%, ECOG 0 73%, Caucasian 73%, Mets: Liver 20%, Lung 20%, Bone 20%. PFS at 12 weeks 40%+/-13% - the trial was terminated after first stage. Reason off therapy: PD 10 (67%), toxicity 4 (27%). RECIST 1.1 best response: CR 1 (8%), SD 4 (31%), PD 8 (62%). Median OS: 6.3 (2.2, 12.7), PFS 2.0 (1.3, 6.6) months; 2 pts alive, follow up at 6.9 & 8.1 months. Common toxicities: diarrhea 80% (gr3 33%), vomiting 40% (gr3 26.7%), nausea 67% (gr3 26.7%) & fatigue 73.3% (gr3 6.7%). Conclusions: This phase II study of docetaxel with lapatinib in advanced urothelial cancer patients failed to provide sufficient efficacy for us to complete full accrual. One patient had a complete response and molecular correlatives may shed light on what may have predisposed to this. Intercurrently, another trial of maintenance lapatinib or placebo after chemotherapy in Her2+ patients reports no benefit (Powles ASCO 2015). Lapatinib alone or in combination is not recommended as therapy in urothelial cancer patients unless new tractable markers of response are developed. Clinical trial information: NCT01382706.
GBAS as a novel regulator for targeting centrosome amplification and malignant behavior in bladder cancer.
Authors: Matsumoto Hiroaki , Fujii Nakanori , Kobayashi Keita , Inoue Ryo , Yamamoto Yoshiaki , Nagao Kazuhiro , Matsuyama Hideyasu 
Published: February 2017

429 Background: It has been reported that centrosome amplification (CA) facilitate to enhance the malignant potential and poor prognosis in bladder cancer. Besides Aurora A kinase drives CA, many studies suggest that inhibition of Aurora A is promising approach to concur invasive bladder cancer. We assess the novel molecule that is potential regulator of CA in bladder cancer. Methods: From 2000 to 2008, 57 bladder cancer patients treated in our hospital were included in this study. We obtained tumor sample by TUR or radical cystectomy with informed consent. We evaluated status of CA by fluorescent immuno-cytochemistry using anti pericentrin antibody. Then we performed array CGH to clarify hyper amplification gene in CA patients. By another approach, we identified candidate micro RNAs targeting Aurora A by miRNA tip array using CA+ or CA- bladder cancer cell lines. We performed pathway analysis to investigate potential target for CA regulated genes by both strategy. Finally, we found GBAS gene as a potential regulator for CA. Then, we assessed the function of GBAS gene by repressing or overexpressing in vitro and the status of GBAS expression by immunohistochemistry in tumor sample. Results: In CA- cell lines, GBAS overexpression increased CA rate compared with mock cells. Contrary, GBAS knock down reduced CA rate in CA+ cells. Also, in WST-1 assay, GBAS knock down repressed CA+ cell proliferation. While, GBAS overexpression facilitated migration and invasion in CA- cells. By western blot analysis, GBAS overexpression increased Aurora A expression, while GBAS suppression decreased that expression. GBAS knock down also repressed p53 expression in J82 cells. In immunohistochemistry, the patients with high GBAS expression were significant worse cancer specific survival compared with those of low expression (p < 0.0001). Conclusions: These results suggest that GBAS gene could be a potential regulator of centrosome duplication via Aurora A expression in bladder cancer. Regulation of GBAS is providing pre-clinical proof-of-principle as promising approach for invasive bladder cancer.
Effect of diet on bladder cancer survivors.
Authors: Longo Thomas Andrew , Gopalakrishna Ajay , Fantony Joseph J , Inman Brant Allen 
Published: February 2017

437 Background: Diet has been shown to affect cancer recurrence, progression, and overall survival. A reduction in overall mortality is associated with high intake of vegetables and whole grains, but little is known about the role of other macronutrients. Further, the role of macronutrients in bladder cancer survivors as they move beyond the treatment period is unknown. Methods: After IRB approval, an institutional database was used to identify a large cohort of bladder cancer patients. They were mailed a survey that included the Diet History Questionnaire II (DHQ II). This validated instrument is recommended by the American Cancer Society and National Cancer Institute. It involves 151 questions covering portion size over 134 food items and 8 supplements, and takes a patient roughly an hour to complete. Our cross-sectional survey used the results from the DHQ II to assess compliance with the US Dietary Guidelines for Americans. Results: Out of 962 subjects, 461 completed the survey (48%). Mean age was 73, 80% were male, and 87% were white. The recommended protein intake was met or exceeded 98% of respondents and 66.8% were able to meet the fruit and vegetable recommendations. Similarly, 62.9% met carbohydrate recommendations. Unfortunately, only 44.5% met fat recommendations, and 0.9% met the whole grain recommendations. Recommended sodium intake was exceeded by 62% of subjects. Conclusions: Bladder cancer survivors exhibit poor adherence to standard dietary recommendations, but they represent a unique metabolic state. It is unknown what constitutes a healthy diet in a bladder cancer survivor, but a healthy diet has potential to be a component of survivorship intervention and not merely sustenance. Cancer survivors are an important target population for health promotion efforts and we plan further investigation of diet and its impact on quality of life amongst other lifestyle factors.
Contemporary utilization trends of systemic chemotherapy for upper tract urothelial carcinoma (UTUC).
Authors: Haseebuddin Mohammed , Handorf Elizabeth , Jones Joshua , Kutikov Alexander , Waingankar Nikhil , Ristau Benjamin T. , Haifler Miki , Wong Yu-Ning , Viterbo Rosalia , Greenberg Richard Evan , Uzzo Robert G. , Chen David Y. T. , Smaldone Marc C. 
Published: February 2017

441 Background: There is currently no consensus regarding the use of systemic therapy (ST) for surgically-treated patients with invasive UTUC. Using a large national cancer registry, our objective was to assess temporal trends in utilization of ST for stage II-IV UTUC undergoing definitive resection. Methods: The National Cancer Database (NCDB) was queried for all patients surgically treated (nephroureterectomy, segmental resection) for stage II-IV UTUC from 1998-2012. Temporal trends in receipt of ST [neoadjuvant (NAT), adjuvant (AT), or unknown timing (UKT)] were assessed using chi square analyses. After exclusion of patients receiving NAT or UKT, adjusting for patient and clinicopathologic characteristics, multivariable logistic models were used to examine the association between clinicopathologic characteristics and receipt of ST within 9 months of resection. Kaplan Meier analyses and stratified log-rank tests were performed comparing overall survival (OS) between patients receiving ST < 9 months and those who did not. Results: Of 7,629 patients identified over the study period, 24.1% of patients surgically treated for stage II-IV UTUC received any ST (NAT: 1.44%, AT: 19.11%, UKT: 3.51%). Utilization of any ST significantly increased from 1998-2012 (20.2% vs. 28.7%, p < 0.0001). Following adjustment, patients of increased age (61-70 years: OR 0.62 [CI 0.42-0.91], 71+ years: OR 0.26 [CI 0.17-0.38]) were less likely to receive ST, and patients with high grade (OR 2.46 [CI 1.95-3.09]), Stage III (OR 4.75 [CI 3.89-5.79]), and Stage IV (OR 9.37 [CI 7.49-11.74]) disease were more likely to be treated with ST. When restricted to stage III-IV disease, receipt of ST < 9 months was significantly associated with improved OS after adjustment for age, grade, and charlson index (p < 0.002). Conclusions: In hospitals reporting to the NCDB, while utilization has significantly increased from 1998-2012, less than one third of patients surgically treated for stage II-IV UTUC receive ST. In addition to unmeasured characteristics (decline of renal function following surgery), the lack of explicit guidelines and prospective evidence may contribute to limited use of systemic treatment.
Phase Ib trial of ALT-803, an IL-15 superagonist, plus Bacillus Calmette Guerin (BCG) for the treatment of patients with BCG-naïve non-muscle-invasive bladder cancer (NMIBC).
Authors: Rosser Charles Joel , Nix Jeffrey , Hernandez Liza , Rhode Peter R. , Wong Hing C. 
Published: February 2017

470 Background: Novel agents are necessary to treat NMIBC to avoid recurrence and progression. This phase Ib clinical trial evaluated the safety and toleraibility of ALT-803, an IL-15 superagonist, plus BCG in patients with BCG-naïve NMIBC. Methods: This is a Phase Ib trial using the 3+3 design to evaluate intravesical ALT-803 plus BCG 50 mg in BCG-naïve NMIBC patients, who would normally be eligible for intravesical BCG alone. The initial dose of ALT-803 was 100 μg/instillation with 2 dose-escalations allowed (200 μg/instillation and 400 μg/instillation) if dose limiting toxicities (DLTs) were not evident. Patients received intravesical ALT-803 in conjunction with BCG weekly for 6 consecutive weeks (Induction Phase). Patients then had routine follow-up with cystoscopy and voided urinary cytology (VUC) every 3 months for 2 years equating to confirmatory response assessment. Negative cystoscopy, VUC and/or biopsy yielded a complete response (CR). When appropriate for high-risk patients, physicians and patients were encouraged to receive maintenance BCG alone as per common practice patterns. Results: No patient in 100 μg/instillation of ALT-803/BCG and 200 μg/instillation of ALT-803/BCG reported an AE. One patient in 400 μg/instillation/BCG cohort developed a urinary tract infection requiring delay of intravesical treatment by 1 week. No grade 3/4 toxicities were noted. All patients have completed therapy without DLTs. To date, 4 patients have 12 month follow-up and are CR. The remaining 5 patients have no evidence of disease. However, follow-ups are currently approximately 3 months. Corollary immune studies are still pending. Conclusions: Intravesical ALT-803 plus BCG was safe and tolerable in patients with BCG-naive NMIBC. Further evaluation in expansion cohorts in a phase II trial is currently underway. Clinical trial information: NCT02138734.
An open-label, single-group, phase 2 study of brentuximab vedotin as salvage therapy for males with relapsed germ-cell tumors (GCT): Results at the end of first stage (FM12GCT01).
Authors: Necchi Andrea , Magazzu Domenico , Anichini Andrea , Raggi Daniele , Giannatempo Patrizia , Nicolai Nicola , Colecchia Maurizio , Paolini Biagio , Coradeschi Elisa , Tassi Elena , Grazia Giulia , Mortarini Roberta , Calareso Giuseppina , Togliardi Elena , Crippa Flavio , Salvioni Roberto , Gianni Alessandro M. , Valagussa Pinuccia 
Published: February 2017

480 Background: Prognosis of patients (pts) failing multiple chemotherapy (CT) regimens is quite dismal. CD30 is expressed and prognostic in embryonal carcinoma, hence it is a rational target for treatment. Brentuximab Vedotin (BV) is an antibody-drug conjugate consisting of the chimeric anti-CD30 antibody SGN-30 conjugated to an antitubulin synthetic analog (MMAE). A phase 2 trial is ongoing in GCT (NCT01851200). Methods: 24 pts with biopsy-proven CD30+ GCT will receive BV 1.8 mg/Kg IV q3 weeks until disease progression or onset of unacceptable toxicity. Eligibility will include failure of 2 or 3 platinum-based CT (including HDCT). All pts will undergo measurement of serum tumor markers (STM), a computed tomography and a PET scan q6 weeks. An optimal Simon’s 2-stage design will be applied. The primary endpoint is the objective response-rate (ORR; H0: ≤ 5%, H1: ≥ 25%, α and β = 10%). In stage 1, 9 evaluable patients will be accrued. Sequential peripheral blood samples are being collected for immune profiling by flow cytometry of immune cell subsets. Results: From 07/13 to 04/15, 9 pts have been treated, 3 in third-line, and 6 beyond the third-line. 5 had received HDCT. STM decline was obtained in 7 pts (77.8%) after the first dose and in 4 pts (44.4%) after 2 doses (with normalized [1] or still positive [3] STM). ORR was 22.2% (1 CR+1 PR) according to RECIST v1.1, and there were 3 metabolic PR. 3-month PFS was 11.1% (95%CI: 0.6-38.8), 6-month OS was 85.7% (95%CI: 33.4-97.9). 1 case of reversible G3 hyperglycemia was recorded. No BV discontinuation due to toxicity occurred. In 7 evaluable pts, a trend to increasing expression of activation (HLA-DR), proliferation (Ki67), and functional differentiation (Granzyme B) markers in CD4 and CD8 T cells was observed during BV. In CR patient, an increased frequency of naive and central memory T cells was observed after the first cycle of BV, as well as a reduction in the fraction of PD1+/CD8+ T cells. Conclusions: Brentuximab is endowed with potent antitumor activity and meaningful immunomodulatory effects in GCT. The rapid development of resistance is a concern. ORR is pending confirmation in the whole sample size. Clinical trial information: NCT01851200.