bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic landscape of metastatic platin-resistant urothelial cancer patients.
Authors: Loriot Yohann , Massard Christophe , Lefebvre Celine , Dogan Semih , Ileanaecaterina Elena , Lacroix Ludovic , Job Bastien , Ngo-camus Maud , Fizazi Karim , Auger Nathalie , Richon Catherine , Koubi-Pick Valerie , Hollebecque Antoine , De Baere Thierry , Vielh Philippe , Ledeley Marie-cecile , Vassal Gilles , Eggermont Alexander M. , Soria Jean-Charles 
Published: February 2017

316 Background: Although several studies have reported genomic characterisation of primary urothelial carcinoma (UC), little is known about the genomic alterations of the metastatic cisplatin-resistant UC. We sought to define the prevalence and co-occurrence of actionable genomic alterations in patients with metastatic cisplatin-resistant lethal UC. Methods: Patients with metastatic UC, who progressed after at least one line of standard therapy, were enrolled in a prospective molecular screening trial (MOSCATO 01) at Gustave Roussy. CT-Scan or ultrasound-guided biopsies were performed in metastases to carry out a comprehensive molecular characterization. DNA was extracted from fresh tumor samples and analyzed by comparative genomic hybridization (CGH) (≥ 30% tumor cells) and by Next Generation Sequencing (NGS) for up to 74 target genes (≥ 10% tumor cells). Whole-exome (WES) and RNA seq sequencing were performed retrospectively in selected cases. Results: From 12/2011 to 12/2013, 30 heavily pretreated patients with metastatic UC were included. Median age was 61 (37-73); all patients had been treated with platin-based chemotherapy with a median number of lines of 2.5 (1-5). A tumor biopsy could be performed in 26 patients (87%). CGH and targeted exome sequencing profiles were assessed in 19 (73%) and 23 (88%) of them, respectively. A total of 19 patients (73%) were profiled for both sequencing and CGH. WES and RNA seq was performed in 16 (62%) pairs of metastatic tissue and normal DNA (Integragen Inc, Hiseq platform). Our analyses identified potential therapeutic targets in 61 % of the tumours, including 31% with targets in the PI3K/AKT/mTOR pathway, 35% with targets in the FGF/FGFR pathway and 15% with targets in the RTK/MAPK pathway (including ERBB2). Others frequent aberrations were found in the chromatin regulatory genes (MLL gene family) and cell-cycle regulatory genes (E2F3, CDKN2A/B genes). FGFR gene fusions were found in 1 out of 16 screened patients (6%) Conclusions: Lethal platin-resistant UC exhibit high-level of genomic heterogeneity. The majority of these tumors harbour actionable genomic alterations that can be targeted with selective agents currently in clinical development (phase I trials) or registered.
Safety of cisplatin in patients with urothelial carcinoma (UC) and renal dysfunction.
Authors: Singh Parminder , Necchi Andrea , Giannatempo Patrizia , Niegisch Guenter , di Lorenzo Giuseppe , Hsu Chiu-Hsieh , Sonpavde Guru 
Published: February 2017

321 Background: Patients (pts) with UC and creatinine clearance (CrCl) < 60 ml/min are considered cisplatin-ineligible. Since the safety of cisplatin use in patients with CrCl < 60 has not been comprehensively studied, we conducted a retrospective study in this population. Methods: Data were requested and retrospectively collected from 5 collaborating institutions. All patients had stage 2 or higher UC and CrCl < 60. Patient characteristics including age, sex, indication for chemotherapy (neoadjuvant, adjuvant or metastatic disease), schedule, total dose of cisplatin, adverse effects, renal function, blood cell counts and radiologic tumor response were collected. Descriptive statistics were employed with no baseline assumptions. Results: 104 patients were evaluable with a mean age of 63.7+ 8.1 yrs (range 41-77yrs) and 63.5% (n=66) were men. Mean CrCl by Cockroft-Gault formula was 50.8 + 8.0 ml/min (range 26-59 ml/min). Baseline ECOG performance status was 0 in 71.8% (n=74); 1 in 20.3% (n=21) and 2 in 7.8% (n=8) of patients. 40.4% (n=42) received chemotherapy for metastatic disease and the rest received perioperative chemotherapy. Of the patients with metastatic disease, 7.1% patient had complete response (CR), 40.5 % patients had partial response. Mean total dose of cisplatin used in all patients was 414.32±198.01 mg, with 81.7% (n=85) patients receiving ≥70mg/m2 dose per cycle. Percentage of patients with any toxicity with baseline CrCl <45 and >45 were 43.5% and 39.5%, respectively (p=0.81). Neutropenic infection occurred in 16.3% and thrombocytopenic bleed in 8.6%. Grade 3 renal toxicity was seen in only one patient (0.96%) and no toxic deaths were reported. Conclusions: This retrospective clinical experience in pts with UC with CrCl <60 ml/min and mostly ECOG-PS 0-1 suggests that cisplatin-based chemotherapy is feasible and warrants exploration given CRs induced in metastatic disease. Incorporation of prophylactic growth factors and modified schedules may mitigate myelosuppression.
Androgen deprivation therapy to prevent bladder cancer recurrence.
Authors: Uemura Hiroji , Izumi Koji , Taguri Masataka , Miyamoto Hiroshi , Morita Satoshi , Miyoshi Yasuhide , Hara Yoshinori , Kishida Takeshi , Chiba Kimio , Murai Tetsuo , Hirai Kotaro , Suzuki Kotaro , Fujinami Kiyoshi , Ueki Teiichiro , Udagawa Koichi , Kitami Kazuo , Moriyama Masatoshi , Tsuchiya Futoshi , Ikeda Ichiro , Kobayashi Kazuki 
Published: February 2017

329 Background: Accumulating preclinical evidence indicates the involvement of androgen receptor signals in bladder cancer (BC) development and further suggests androgen deprivation therapy (ADT) as a new therapeutic option for BC. However, the clinical efficacy of ADT in BC recurrence remains unclear. We compared the rates of BC recurrence in prostate cancer (PC) patients between who did and did not receive ADT. Methods: We retrospectively reviewed 20,328 patients with PC diagnosed during1991-2013 and identified 239 (1.2%) men having primary BC. Among them, 162 patients met the inclusion criteria. Using Kaplan-Meier analyses and Cox proportional hazard models, we assessed the prognostic significance of ADT and other clinical variables for recurrence-free survival (RFS) and cumulative recurrence. Results: With a median follow-up of 62 months, 38 (50%) of 76 control patients experienced BC recurrence, while 19 (22%) of 86 did in ADT group. Thus, patients having received ADT showed a significantly lower risk of BC recurrence (5-year actuarial RFS: 76% v 40%; P < 0.001) compared to the control group. ADT patients also had a significantly smaller number of recurrence episodes (5-year cumulative recurrence: 0.44 v 1.54; P < 0.001) compared to control patients. A multivariate analysis revealed ADT as an independent prognosticator (hazard ratio, 0.29; 95% confidence interval, 0.17-0.49) for BC recurrence. Conclusions: This is the first clinical study showing that ADT significantly reduces the risk of BC recurrence. Randomized clinical trials are required to confirm these findings. Clinical trial information: 000012926.
Open versus robot-assisted radical prostatectomy: A contemporary analysis of an all-payer discharge database.
Authors: Leow Jeffrey J. , Trinh Quoc-Dien , Chung Benjamin I. , Chang Steven L. 
Published: February 2017

33 Background: Robot-assisted radical prostatectomy (RARP) has been rapidly adopted in the US despite the lack of Level 1 evidence. There is no conclusive evidence regarding its morbidity profile compared to open RP (ORP). Our aim was to compare perioperative outcomes of RARP vs. ORP on a contemporary cohort of patients. Methods: Using the Premier Hospital Database, an all-payer discharge database representing over 600 hospitals in the US, we captured men diagnosed with prostate cancer (ICD-9 code 185) who underwent a radical prostatectomy (60.5) from 2003 to 2013.We classified procedures as RARP through a review of the charge description master by identifying supplies unique to robotic procedures. We evaluated 90-day postoperative complications (using Clavien classification), transfusion of blood products, operating room time, length of stay and direct hospital costs. We performed regression analyses, adjusting for potential confounders, accounting for clustering by hospitals and survey weighting to ensure nationally representative estimates. Results: Over the 11-year study period, there was a total of 345,313 ORP and 328,731 RARP. The use of RARP grew rapidly from 2% in 2003 to 85% in 2013 (p<0.001). On adjusted analyses, compared to ORP, RARP patients were less likely to suffer major complications (odds ratio [OR] 0.77, p=0.03), readmissions (OR 0.81, p=0.02), or receive blood products (OR 0.28, p<0.001). RARP patients had shorter LOS (-0.88 days, p<0.001). Mean operating room time for RARP was longer by 71 min (p<0.001); higher surgeon and hospital volume were significant predictors of shorter operating time. 90-day direct hospital costs were higher for RARP (+$4085, p<0.001), primarily attributed to operating room and supplies costs. Conclusions: Our contemporary analysis of men who underwent RP found that the robotic approach appears to confer a perioperative morbidity advantage at a higher cost. The widespread adoption of RARP in the management of localized prostate cancer implies a randomized trial will unlikely be conducted; therefore this large retrospective study may represent the best available evidence for the morbidity and cost profile of ORP vs. RARP.
Feasibility of plasma circulating free RNA (cfRNA) microarray profiling and gene-specific prognostic associations in metastatic urothelial carcinoma (mUC) patients receiving platinum-based chemotherapy.
Authors: Hahn Noah M. , Wang Zhiping , Liu Yunlong , Moore Marietta L. , Prasad Nagendra K 
Published: February 2017

333 Background: The current study was undertaken to determine the feasibility of detection and expression profiling of cfRNA in mUC patients treated with platinum-based chemotherapy. Methods: Plasma samples were identified from consented mUC subjects treated with platinum-based therapy at the IU Simon Cancer Center (IUSCC) from 12/2008 – 8/5/2010. The primary feasibility measure was the detection of cfRNA at any quantitative level. An IUSCC urologic cancer 48-gene array was designed. After cfRNA extraction and cDNA preparation, cDNA were amplified in a specific target amplification step using gene-specific primers for the 48 genes in the array. Gene expression analysis was performed on amplified cDNA using 96.96 format DELTAgene microfluidic Dynamic Array platform (Fluidigm). CT values were calculated for each gene after normalization against expression of internal control gene, GAPDH. To identify associations between individual gene expression and OS, a Cox proportional hazards regression analysis was performed. Results: Plasma samples and OS data were available from 15 pts. Patient demographics included: median age – 70.8, M/F – 14/1, Cisplatin/Carboplatin regimen – 9/6, lymph node/visceral mets – 13/7. Median PFS/OS were 8.7 and 23.0 months respectively. cfRNA was detectable in all 15 patients (100%). Median quantitative cfRNA concentration was 2.68 ng/ml (range 1.9 – 6.3). 96.96 Dynamic Array was performed in all patients. All 48 gene probes passed QC testing and produced CT values suitable for analysis. On univariate analysis, overall survival was significantly associated with presence of visceral metastases and plasma cfRNA expression of AKT1, AKT2, BRCA1, CCND1, HPRT1, HSD3B1, PARP1, and RPA3 (all p < 0.05). Conclusions: Successful extraction of cfRNA suitable for microarray analysis from archived mUC patient plasma samples is feasible. Intriguing hypothesis generating associations between OS and cfRNA expression of genes mediating DNA repair, apoptosis, and cell-signaling pathways were observed. Demonstration of these findings in larger independent patient cohorts is warranted.
Clinical significance of SDF-1 isoforms in bladder cancer.
Authors: Hupe Marie C , Gosalbez Miguel , Lokeshwar Soum D , Shields John , Yates Travis J , Lokeshwar Vinata B 
Published: February 2017

334 Background: Stroma-Derived Factor (SDF)-1 is a ligand for chemokine receptors CXCR4 and CXCR7. The six known SDF-1 isoforms are generated by alternative mRNA splicing. While SDF-1 expression has been detected in various malignancies, only a few studies have reported differential expression of SDF-1 isoforms and its clinical significance. In this study we evaluated the expression three SDF-1 isoforms (α,β,γ) in bladder cancer (BCa). Methods: Using quantitative PCR, mRNA levels of SDF-1α, SDF-1β and SDF-1γ were measured in bladder tissues (normal: 25; BCa: 44) and urine specimens (n=210; normal: 28; benign conditions: 74; BCa: 57, history of BCa (HxBCa): 35, Hx other Ca: 8; other Ca: 8) from consecutive patients. The transcript levels were normalized to β-actin. Correlation between SDF1-isoform transcript levels and clinical outcome (metastasis and disease specific mortality (DSM)) was evaluated in univariate and multivariate analyses. Results: Among SDF-1 isoforms, only SDF-1β mRNA was significantly overexpressed by 2.5-6-fold in BCa tissues when compared to normal bladder tissues. While SDF-1α was expressed in bladder tissues, SDF-1γ expression was undetectable. In univariate analysis, pathologic stage, lymph node positivity for tumor, SDF-1α and SDF-1β transcript levels significantly associated with metastasis and DSM. However, in multivariate analysis, stage (P=0.005) and SDF-1β levels (P=0.017) were independent predictors of metastasis and DSM. In exfoliated urothelial cells, only SDF-1β mRNA levels were differentially expressed and having 91.2% sensitivity and 73.8% specificity for detecting BCa. In patients with HxBCa, elevated SDF-1β levels indicated 4.3-fold increased risk (chi-square: 15.1; P=0.0001; relative risk = 4.3) for developing recurrence within 6-months. Conclusions: SDF-1 isoforms are differentially expressed in bladder tissues and exfoliated urothelial cells. SDF-1β mRNA levels in BCa tissues predict poor prognosis. Further, SDF-1β mRNA levels in exfoliated cells detect BCa with high sensitivity and are potential predictors of future recurrence. Support: Grant NCI/NIH R01 CA-72821-14; Women’s Cancer Association – University of Miami.
Impact of obesity in patients with metastatic urothelial carcinoma.
Authors: Leiter Amanda , Doucette John , Krege Susanne , Lin Chia-Chi , Hahn Noah M. , Ecke Thorsten , Sonpavde Guru , Bamias Aristotelis , Oh William K. , Galsky Matt D. 
Published: February 2017

346 Background: Obesity has been associated with worse outcomes in patients with clinically localized urothelial cancer. However, the impact of obesity on outcomes of patients with metastatic disease has not previously been evaluated. Methods: Data from 537 patients were aggregated from eight phase II and phase III clinical trials investigating first-line cisplatin-based combination therapy in metastatic urothelial cancer. Chemotherapy regimen, adverse events, treatment response, and survival outcomes were compared across body mass index (BMI) and body surface area (BSA) categories. Results: BMI was classified according to WHO criteria (<18.5 underweight (4.1 % of patients), 18.5-24.99 normal weight (42.8%), 25-29.99 overweight (41.0%), >30 obese (12.1%)). BSA was classified as either below (56.8% of patients) or greater than or equal to (43.2%) the European average (1.91 m2 for males and 1.71 m2 for females). There was no significant difference in number of chemotherapy cycles across BMI and BSA categories. Patients’ treatment regimens significantly differed across BMI (p=0.02) and BSA (p<0.01) categories, with patients with higher BMI category and average or above BSA more likely to receive gemcitabine-cisplatin-based therapy rather than MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin)-based or other therapy regimens. There was no significant difference in adverse events across BMI categories, but the incidence of embolic events was significantly higher in patients with an average or higher BSA (6.6%) than those with a lower than average BSA (2.7%) (p=0.03). There was no significant difference in response rate or survival outcomes (overall and progression-free) amongst BMI and BSA categories. Conclusions: Obese patients with metastatic urothelial cancer on cisplatin-based therapies have similar response rates and survival outcomes to non-obese patients. Toleration of cisplatin-based therapy is similar across BMI and BSA categories, with the exception of a higher incidence of embolic events in patients with an above average BSA.
A phase 2 multimodality trial of docetaxel/prednisone with sunitinib followed by salvage radiation therapy (RT) in men with PSA recurrent prostate cancer (PC) after radical prostatectomy (RP).
Authors: Armstrong Andrew J. , Halabi Susan , Healy Patrick , Lee Robert , Koontz Bridget F. , Moul Judd W. , Mundy Kelly , Creel Patricia , Yenser Wood Sarah , Davis Kristen , Reimer Brooke , Nguyen Minh , Spitz Avery N. , Bratt Ellen , Kim Sung , Tran Phuoc T. , Stein Mark N. , Carducci Michael Anthony , George Daniel J. 
Published: February 2017

35 Background: In men with high grade PC and rapid PSA progression after RP, failure rates are unacceptably high despite salvage RT. Androgen deprivation therapy (ADT) is not curative in this setting and we thus evaluated a novel multi-modality approach of systemic chemotherapy and anti-angiogenic therapy prior to prostate bed salvage RT in a multicenter trial. Methods: Eligible men had a rising PSA of 0.1-3.0 ng/ml within 4 years of RP, no metastatic disease except resected positive nodes, no prior ADT, and Gleason 7-10. Men received 4 cycles of docetaxel 70 mg/m2 q3w with prednisone 5 mg bid and sunitinib 37.5 mg qd for 14/21 days each cycle. Salvage RT (66Gy/33fx) to the prostate bed started at day 100. The primary endpoint was progression-free survival at 2 years (PFS2), defined as a confirmed PSA rise above the post-RT nadir or baseline if no nadir occurred, clinical/radiographic progression, or death from date of enrollment. Safety and dose-limiting toxicities were evaluated. This was a single arm prospective open-label phase 2 trial. Results: Thirty-four men accrued in this multisite Dept. of Defense Prostate Cancer Clinical Trials Consortium trial (median age 62, 85% Caucasian, 9% African American); 24% were node positive at surgery, 47% had Gleason 8-10. Median PSA at entry was 0.54 (range 0.2-2.8) and median time since RP was 11 months. The trial was terminated prematurely due to excess dose-limiting toxicity (9 DLT events) including grade 3 events of hand-foot syndrome (n=4), neutropenic fever (n=2), AST increase (n=1), fatigue (n=1), and vomiting with diarrhea (n=1). PFS at 2 years was 48.9% (95% CI: 32.8%, 67.2%) with a median PFS of 26.2 mo (95% CI: 12.5, -). Six men (17.6%) had an undetectable PSA at 2 years. Conclusions: Sunitinib and docetaxel/prednisone followed by salvage RT resulted in excess pre-specified DLTs. However, efficacy data suggests that some men achieved durable long-term disease control with this aggressive approach. Longer-term follow-up and comparative data with salvage XRT and ADT is needed to fully understand the risks/benefits of this combined modality approach in high risk PSA-recurrent PC. Clinical trial information: NCT00734851.
A microdosing study to identify chemoresistance in bladder cancer.
Authors: Chow Helen , Wang Sisi , Zhang Hongyong , Zimmermann Maike , Lin Tzu-yin , Scharadin Tiffany , Malfatti Michael , Evans Christopher P. , Cimino George , Turteltaub Kenneth , de Vere White Ralph , Henderson Paul T. , Pan Chong-Xian 
Published: February 2017

356 Background: DNA adduct formation and incorporation of gemcitabine into genomic DNA are critical steps in cancer cell response to platinum (Pt) and gemcitabine chemotherapy, respectively. We hypothesize that levels of Pt-DNA adducts and gemcitabine in genomic DNA below a threshold are predictive of chemoresistance. Accelerator mass spectrometry (AMS) is an ultrasensitive method for measuring radiocarbon. By measuring 14C bound to DNA, AMS was used to quantify carboplatin-DNA damage and gemcitabine incorporation into DNA after mice or patients received nontoxic “microdoses” of 14C-labeled carboplatin or gemcitabine. Methods: Cancer cells and mice bearing tumor xenografts were treated with one microdose (1% of the therapeutic dose) or therapeutic dose of [14C]carboplatin or [14C]gemcitabine. Carboplatin-DNA adducts and gemcitabine incorporation in DNA were correlated with cell/tumor response to chemotherapy. In the Phase 0 trial, patients with advanced bladder or non-small cell lung cancer were treated with one microdose of [14C]carboplatin followed by tumor sampling 24 hours later. Carboplatin-DNA adducts and other relevant parameters, such as pharmacokinetics and repair of DNA damage, were measured and correlated with cancer response to chemotherapy. Results: The levels of microdose-induced carboplatin-DNA damage were linearly proportional to that caused by the therapeutic dose (R2=0.92, p<0.001); and correlated with chemoresistance to carboplatin. Low gemcitabine incorporation into DNA correlated to gemcitabine resistance in patient-derived bladder cancer xenografts (p<0.001). In the Phase 0 trial, 18 patients have been enrolled. DNA damage induced by carboplatin was measured by AMS in peripheral blood mononuclear cells and, in some patients, in tumor tissues; and will be correlated with cancer response to chemotherapy. The pharmacokinetics and DNA adduct levels were linear between microdose and therapeutic doses. No microdose-related toxicity was observed. The radiation exposure was less than that of one chest X-ray per microdose. Conclusions: The levels of DNA damage induced by nontoxic microdosing carboplatin can potentially predict chemoresistance. The current status of the Phase 0 trial will be presented. Clinical trial information: NCT01261299.
miR125 and miR200a as potential circulating miRNA biomarkers in metastatic urothelial carcinoma patients treated with docetaxel.
Authors: Mullane Stephanie A. , Zhou Chensheng Willa , Martin-Doyle William , Loda Massimo , Choueiri Toni K. , Bellmunt Joaquim , Bowden Michaela 
Published: February 2017

364 Background: Docetaxel is frequently used as second-line therapy in advanced bladder cancer. The response rate is 10-15% with a median PFS of 2.5 months and without data showing improvement of QoL, however, some selected patients derive significant benefit. Understanding the mechanisms underlying the sensitivity of docetaxel in bladder cancer will help to customize treatment in second line. Circulating miRNAs have been shown to be predict outcome in GU malignancies (for example, prostate cancer). Using circulating miRNA can identify patients who will respond to therapy non-invasively. The main aim of our study was identify circulating miRNAs predicting docetaxel response in urothelial carcinoma (UC). Methods: We obtained pre- and post-treatment plasma samples from patients included in the zactima phase II clinical trial assigned to the placebo + docetaxel arm. RNA from plasma was extracted and RT-PCR was performed on both the pre- and post-treatment samples looking at miRNAs known to be important in docetaxel response1(miR125, miR27a, miR34a, miR429, miR141, miR200a, miR200c, miR 146a, and miR9). Samples were normalized by the mean global miRNA levels. We divided patients based on progression free survival (PFS) as good responders (>4 months PFS or 6 cycles) versus poor responders (<2 months PFS or progression at first evaluation). Differences in miRNA levels were assessed using the student t test (p<0.05). Results: miR125 and miR200a were shown to be significantly different between the poor and good responders (p=0.056 and p=0.028, respectfully) in the pre-docetaxel samples. Higher expression of both miRNAs correlated with a good response in our small patient cohort. Additional analysis comparing pre- and post-miRNA levels will be presented. Conclusions: miR125 and miR200a are potential extracellular biomarker to docetaxel treatment in metastatic UC.