bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATDC as a novel oncogene in bladder cancer.
Authors: Palmbos Phillip Lee , Wang Lidong , Yang Huibin , Detzler Taylor , Ney Gina , Lotan Yair , Wilkerson J E , Kunju Priya , Ljungman Mats , Liebert Monica , Simeone Diane M. 
Published: February 2017

269 Background: Bladder cancer is a common and deadly disease, but the molecular events leading to its initiation and progression are incompletely understood. We recently identified Ataxia-Telangiectasia Group D Associated (ATDC) as a novel oncogene which drives tumor proliferation and invasion in pancreatic carcinoma (Cancer Cell, 2009). In this study, we describe the role of ATDC as an oncogene in bladder cancer. Methods: To further determine the oncogenic role of ATDC, we generated ATDC transgenic (tg) mice in which ATDC expression was driven by a CMV promoter and characterized the resulting tumors. Results: The dominant phenotype in these mice was the development of both papillary and invasive urothelial carcinomas (9% and 20% respectively, average age of onset 10-12 months of age). Histologically, these tumors were indistinguishable from human urothelial carcinomas. Gene expression profiling of invasive tumors derived from ATDC tg mice demonstrated a marked overlap with gene signatures of human invasive bladder cancers. Analysis of a human bladder cancer tissue microarray (311 samples) showed elevated expression in 70% (173/252) of muscle-invasive carcinomas, whereas normal bladder had no expression. 22% (5/23) of papillary tumors also expressed elevated levels of ATDC. ATDC was the 11th most highly up-regulated gene in bladder cancers represented in the Oncomine gene expression database. ATDC tg mouse bladder tumors demonstrated loss of p53 signaling and down-regulation of PTEN expression, which was determined to be due to ATDC abrogation of p53 function by cytoplasmic sequestration and ATDC-mediated methylation of the PTEN promoter. Furthermore, ATDC knock-down in invasive cancer cell lines resulted in decreased proliferation, invasion and reactivation of p53-mediated signaling and PTEN expression. Conclusions: ATDC is a novel oncogene that is highly expressed in human bladder cancers and is sufficient to drive the development of invasive bladder tumors in tg mice. The mechanism by which ATDC drives bladder cancer formation involves alterations in p53 and PTEN pathways known to be important in bladder tumorigenesis.
Updated results of a phase I/II trial of intravesical CG0070 in patients with superficial bladder cancer after BCG failure.
Authors: Friedlander Terence W. , Weinberg Vivian K. , Yeung Alex , Burke James , Lamm Donald L. , McKiernan James M. , Nemunaitis John J. , Stephenson Joe , Small Eric Jay , Fong Lawrence , Meng Maxwell V. 
Published: February 2017

271 Background: Loss of retinoblastoma (Rb) tumor suppressor activity occurs commonly in bladder cancer and leads to upregulation of the E2F-1 transcription factor. CG0070 is a replication competent oncolytic adenovirus genetically modified to express GMCSF under control of the human E2F-1 promoter. Updated results from a phase I/II study of CG0070 in patients with recurrent superficial bladder cancer (T1, Ta, Tcis) after BCG treatment are presented here. Methods: The V-0046 phase I/II study previously reported the safety and evidence of efficacy of single and multiple doses of intravesical CG0070. Efficacy was determined using quarterly cystoscopy, biopsy, and/or urine cytology. Tumor Rb status was assessed immunohistochemically in 18 tumors. Results: 35 patients were treated with either a single dose (n=13) of CG0070 ranging from 1x1012 to 3x1013 viral particles (vp) or with weekly x 6 (n=9) or every 4 week x 3 doses (n=13) ranging from 1x1012 to 1x1013 vp per dose. Only one dose limiting toxicity, grade 3 lymphopenia in an every 4 week patient, was observed. The most common adverse events regardless of schedule were flu-like illness, dysuria, hematuria, bladder spasm, and nocturia. Urine GMCSF was detectable in 94% of patients and 58% of patients in the single dose cohort had an increase in CG0070 levels suggesting in-vivo viral replication. The CR rate in the single dose cohort was 23% (3/13), and 64% (14/22) in the multi-dose cohorts. Median follow up for all responders is 9.1 months. Of all responders, 11 recurred with a remission duration ranging from 3.0 - 33.4 months and 6 patients, all in the multiple dose cohorts, remain in remission as of last follow-up with a remission duration ranging from 3.3 – 38.2 months. Phosphorylated (inactive) Rb was detected in 13 of the 18 (72%) patients evaluated. Nine of these 13 patients (70%) had a CR. All patients (5/5, 100%) with known phosphorylated Rb treated in the weekly cohort experienced a CR. Conclusions: CG0070 was well tolerated with minimal local and systemic toxicities. Complete responses were more frequently observed in the multiple-dose cohorts, including durable CRs in patients with phosphorylated Rb. Further study in Rb inactivated tumors is warranted.
Neoadjuvant gemcitabine plus carboplatin followed by immediate radical cystectomy in patients with muscle-invasive bladder cancer: A propensity score analysis.
Authors: Koie Takuya , Okamoto Teppei , Suzuki Yuichiro , Tobisawa Yuki , Yoneyama Tohru , Mori Kazuyuki , Yamamoto Hayato , Hatakeyama Shingo , Yoneyama Takahiro , Kamimura Noritaka , Ohyama Chikara 
Published: February 2017

276 Background: Standard neoadjuvant chemotherapy has not yet been established for patients with muscle-invasive bladder cancer. Our pervious phase II trial demonstrated the efficacy and safety of neoadjuvant gemcitabine plus carboplatin (GCarb) chemotherapy followed by immediate radical cystectomy (RC) in patients with muscle-invasive bladder cancer. In the present study, we conducted a propensity score analysis to elucidate clinical significance of the present treatment protocol. Methods: The cohort of neoadjuvant group consists of 120 patients with muscle-invasive bladder cancer. They received 2 courses of GCarb therapy consisting of 800 mg/m2 gemcitabine on days 1, 8, and 15 and carboplatin with an AUC of 4 on day 2 between March 2005 and June 2011. After the chemotherapy, RC and bilateral pelvic lymph node dissection (PLND) were performed within an interval of 1 month. The cohort of surgery alone group includes 155 patients with muscle-invasive bladder cancer treated with RC and bilateral PLND between May 1994 and December 2004. Propensity score matching was used to adjust for potential selection biases associated with treatment type. The endpoints were overall (OS) and disease-free survival (DFS). Results: Of the 120 patients who received GCarb and RC, 28 (23.3%) RC specimens showed pT0. Grade 3/4 neutropenia occurred in 40 patients (33.9%) and thrombocytopenia in 23 patients (19.8%). Propensity score-matched analysis indicated 112 matched pairs from both groups. The 5-year OS rate was 91.5% for neoadjuvant GCarb versus 51.3% for surgery alone group (P < 0.0001). The DFS rate was 83.8% for neoadjuvant GCarb versus 53.1% for surgery alone (P < 0.0001). Multivariate analysis revealed that the neoadjuvant GCarb regimen was an extremely strong predictor of the improvement in OS and DFS. Conclusions: Although the present study is not randomized, neoadjuvant gemcitabine plus carboplatin therapy followed by immediate RC achieved significantly longer OS and DFS comparing to surgery alone. The clinical usefulness of the present treatment for the patient with muscle-invasive bladder cancer should be verified by further trials.
Association of DNA repair factors with overall survival in advanced urothelial carcinoma treated with platinum-based chemotherapy.
Authors: Guancial Elizabeth Ann , Werner Lillian , Stack Edward , Lis Rosina , Signoretti Sabina , Loda Massimo , Gallardo Enrique , Rojo Federico , Lloreta Jose , Regan Meredith M. , Park Rachel , O'Brien Robert , Berman David M. , Bellmunt Joaquim , Rosenberg Jonathan E. 
Published: February 2017

291 Background: DNA repair factors are hypothesized to mediate chemosensitivity to cytotoxic agents that produce DNA damage and may be predictive for response to platinum-based chemotherapeutic regimens. Primary urothelial carcinoma (UC) tumors of patients who developed metastatic disease were evaluated for expression of a panel of DNA repair factors by immunohistochemistry (IHC). Methods: A cohort of 132 clinically annotated, uniformly-treated (platinum-based combination chemotherapy) UC patients who subsequently developed distant metastases with FFPE primary tumor tissue available was identified. Tumor bearing areas were evaluated by a single urologic pathologist. Tissue arrays were constructed for IHC analysis of the following DNA repair factors: ERCC1, Rad 51, BRCA1/2, PAR and PARP1. Tumor was deparaffinized and specific antigen retrieval determined for individual antibodies. Pathologist supervised IHC analysis of nuclear versus cytoplasmic expression was performed using spectral imaging analysis. Overall survival (OS) was defined from start of chemotherapy for metastatic disease to death (N=67) or censored on the last known alive date. Percent of positive nuclear staining was categorized as quartiles or previously identified cut-points. Cox regression evaluated the associations of percent positive nuclear staining levels and OS in multivariable analysis (HRs and 95% CIs included) that controlled for known prognostic variables (performance status and visceral metastases). Results: Higher percentage of nuclear staining of ERCC1 [HR=2.7 (1.5, 4.9), p=0.0007]; Rad51 [HR=5.6 (1.7, 18.3), p=0.005]; and PAR [HR=2.2 (1.1, 4.4), p=0.026] in tumor tissue were associated with poor outcome; each was independent of the other two repair factors and known prognostic variables. Neither nuclear nor cytoplasmic staining for BRCA1/2 or PARP1 reached statistical significance for an association with OS. Conclusions: DNA damage repair factor levels measured by IHC impact outcomes in advanced UC. External validation is ongoing and will be presented. Further studies are required to determine whether these biomarkers are prognostic or predictive in this setting.
Phase II study of docetaxel (D) and oxaliplatin (O) in recurrent metastatic transitional cell cancer (mTCC) of the urothelial tract.
Authors: Chatta Gurkamal S. , Appleman Leonard Joseph , Friedland David , Tribble Gail , Davar Diwakar 
Published: February 2017

296 Background: First-line regimens for mTCC of the bladder are either MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or the cisplatinum-gemcitabine doublet. There is no approved second-line option for mTCC. Both single agent D and O have response rates of 10 to 20%, and O in cisplatin-resistant patients (pts). Hence the combination of D and O may be useful in recurrent mTCC. Methods: The combination of D and O was primarily tested for efficacy in recurrent mTCC. All pts had histologically proven TCC with measurable disease, and had prior treatment with at least 1 platinum-containing regimen. D 60 mg/m2 followed by O 110 mg/m2 were administered every 3 weeks. Pts were evaluated for response every 2 cycles and were treated either till progression or for a maximum of 6 cycles. Results: 22 pts were enrolled of whom 19 were evaluable for response. Median age was 72 years (range 44 – 87). All pts had prior treatment with at least 1 cytotoxic regimen, with 8 pts having received 2 or more prior regimens. The mean number of cycles administered was 3. Of the 19 pts evaluable for efficacy, objective response was documented in two pts (both partial responses), three had stable disease, and the remaining fourteen progressed on therapy for an overall disease stabilization rate of 26%. Median time to progression (TTP) was 3.0 months (95% CI 0.2 to 5.8) and median overall survival (OS) was 7.0 months (95% CI 4.6 to 9.4). Toxicity, evaluated in all 22 patients, was relatively mild: grade 3-4 diarrhea in 6 patients, grade 3-4 hematological toxicity in 4 pts and grade 3-4 fatigue in 1 pt. No grade 3-4 neuropathy was observed and no toxic deaths were noted. The median follow-up period was 7.0 months (95% CI 4.5 to 9.5). Conclusions: The combination of D and O is active in previously treated pts with mTCC. This regimen appears to be well tolerated with overall mild toxicity. Whilst this study was not powered for assessing survival, the presence of stable disease in 26% of pts suggests that further investigation of the combination in carefully selected pts maybe warranted.
Examining the management of muscle-invasive bladder cancer (MIBC) by medical oncologists (MO).
Authors: Apolo Andrea Borghese , Bochner Bernard , Steinberg Seth M. , Bajorin Dean F. , Kelly William Kevin , Quinn David I. , Vogelzang Nicholas J. , Sridhar Srikala S. 
Published: February 2017

298 Background: Neoadjuvant chemotherapy (NC) for the treatment of MIBC remains underutilized in the United States despite evidence supporting its use. The aim of this project is to examine the current management of MIBC by MO to move towards standardization of practice. Methods: An electronic 26 question survey was emailed to 92 MO belonging to the Bladder Cancer Advocacy Network or the American Society of Clinical Oncology, and posted on the US Oncology portal for 8 wks. The study was approved by the Office of Management and Budget (0925-0046). Percentages are based on the fraction that responded to a given question. Results: Of the 83 respondents: 48% were non-academic. 51% were general oncologists and 45% focused on GU malignancies. The majority of MIBC referrals came from urologists (79%). Initial CT staging with abd/pelvis was required by 88%, CT chest by only 72% and PET by 21%. NC is offered by 79% of MO to all MIBC pts and by 45% to all pts with high grade upper tract urothelial carcinoma. Adjuvant chemotherapy (AC) was offered by 46% to all MIBC pts and by 41% to pts with upper tract disease. NC was not offered if ECOG performance status (PS) was >3 (49%), in T2 disease without lymphovascular invasion (29%), or with GFR of <50 ml/min (35%). Chemotherapy regimens used for NC included gemcitabine/cisplatin (90%); methotrexate/vinblastine/adriamycin/cisplatin (MVAC) (30%), dose dense MVAC (20%); gemcitabine/carboplatin (36%); single-agent gemcitabine (10%), other regimens described include carboplatin/paclitaxel and ifosfamide/doxorubicin/gemcitabine. Response to NC was assessed by CT abd/pelvis (82%), CT chest (39%), cystoscopy (30%) and PET (12%). Pts with pathologic residual disease (>pT2 or positive LN) after NC were generally observed (74%). Conclusions: The majority of MO do offer perioperative chemotherapy for MIBC pts with a trend towards increased use of NC over AC, which follows best evidence. The main reason for not offering perioperative chemotherapy was poor PS. The majority offer cisplatin-based combination therapy by preference. Increasing the rate of referrals of MIBC pts to MO, will result in more pts receiving perioperative cisplatin-based chemotherapy and may lead to better outcomes in this disease.
Impact of multiparametric endorectal coil prostate MRI on disease reclassification among active surveillance candidates: A prospective cohort study.
Authors: Margel David , Yap Stanley , Lawrentschuk Nathan , Klotz Laurence , Haider Masoom A. , Finelli Antonio , Zlotta Alexandre , Trachtenberg John , Fleshner Neil Eric 
Published: February 2017

30 Background: One troubling aspect of active surveillance (AS) is that a subset of patients diagnosed as very-low risk prostate cancer (PCa) appear to be under sampled and, in fact, harbour larger often higher grade cancers.The aim of this study is to report MRI findings among unselected men with low-risk PCa prior to AS. Methods: We prospectively enrolled men with low-grade, low-risk, localized PCa. All patients underwent multiparametric endorectal coil MRI scanning and offered a confirmatory biopsy within one year of MRI. The primary outcome was the impact of MRI in identifying patients reclassified as no longer fulfilling AS criteria by a confirmatory biopsy. We further aimed to identify clinical parameters associated with reclassification. Cohort was stratified as follows: normal MRI; cancer on MRI concordant with initial biopsy (less than 1 cm); cancer on MRI larger than 1cm. We performed a univariate analysis to assess differences in clinical parameters between groups. Results: MRI did not detect cancer in 23 (38%) while MRI and initial biopsy were concordant in 24 patients (40%). MRI detected a 1cm or larger lesion in 13 patients (22%). Eighteen patients (32.14%) reclassified. When no cancerous lesion was identified on MRI only 2 patients (3.5%) reclassified. The positive and negative predictive values for MRI predicating reclassification were 83% (95% CI, 73%-93%) and 81% (95% CI, 71%-91%), respectively. PSA density was elevated among patients with larger than 1 cm MRI lesions compared to those with no cancer on MRI (medians of 0.15 vs 0.07 ng/ml/cc, respectively p=0.016). Conclusions: MRI appears to have a high yield in predicting reclassification among men choosing AS. Upon confirmation of our results MRI may be used to better select and guide patients before AS.
The neoadjuvant management of muscle-invasive bladder cancer (MIBC) in Canada: A national survey of urologists.
Authors: Sridhar Srikala S. , Chi Kim N. , North Scott A. , Black Peter C. , Wood Lori , Hsu Tina 
Published: February 2017

303 Background: There is level 1 evidence and a 5% absolute survival benefit supporting the use of cisplatin-based neoadjuvant chemotherapy (NC) for the management of MIBC. Despite this, it is well known that the majority of eligible patients undergoing cystectomy do not receive NC. We previously surveyed medical oncologists and found that the majority will offer NC to MIBC patients depending on stage, renal function, performance status (PS), and comorbidities. However, the number of MIBC patients being referred for consideration of NC by urologists remains low. The aim of this followup survey to urologists was to better understand their approach to MIBC, and referral patterns for NC. Methods: A survey consisting of 24 questions was administered to Canadian urologists belonging to the Canadian Urologic Oncology Group. Respondents completed the survey and mailed/faxed back their responses. The survey was similar to, but not identical to the previous medical oncology survey. Results: Of the 25 respondents, 21/25 (84%) were academic, >90% were in full-time practice, and 72% were practising for >10 yrs. Most (84%) treated over 20 bladder cancer cases annually. Overall, 22/25 (80%) will offer a NC approach if appropriate. In 2009, 9/24 (38%) sent >6 referrals for NC; 2/24 (25%) sent 5-6 referrals, 6/24 (20%) sent 3-4 referrals, and 5/24 (8%) sent 1-2 referrals. NC was offered as standard of care or to downsize tumors. Initial staging included cystoscopy, CT chest/abdo/pelvis and bone scan. Key factors cited for not offering NC were: T2a disease, GFR <40ml/min, age >85 or PS 3 or 4. Average time from NC to cystectomy was 4-6 wks. Conclusions: The majority of academic urologists in Canada will refer MIBC patients for NC except those with T2a disease, poor renal function, age >85 or poor PS. Non-academic urologists are underrepresented in this survey, and may represent the group facing the greatest challenges in offering NC, due to issues such as access to medical oncology, or lack of local expertise in managing MIBC. Targeting non-academic urologists, and encouraging consultation with a medical oncologist for all patients with MIBC, may lead to increased utilization of NC, and better outcomes in this disease.
Adaptive planning study of “plan of the day” versus “composite planning” for muscle-invasive bladder cancer (MIBC).
Authors: McIntosh David E , Webster Gareth , Stratford Julia , Jegannathen Apurna , Cowan Richard , Logue John P. , Wylie James , Livsey Jacqueline E. , Elliott P. Anthony , Choudhury Ananya 
Published: February 2017

309 Background: Bladder motion during treatment can be considerable resulting in either inadequate coverage of planning target volume (PTV) or significant overdose to organs at risk (OAR). Adaptive radiotherapy planning using either “plan of the day” or “composite planning” may offer a method to reduce PTV, while optimizing the clinical target volume (CTV) coverage and reducing the dose to OAR. Methods: Patients were planned using a radiotherapy CT planning scan (RTP). CTV was defined as whole bladder and this was expanded by 1.5 cm to form the PTV. PTV was treated to 52.5 Gy in 20 fractions over 4 weeks. Off line correction was performed using cone beam imaging (XVI) taken on days 1-3 and weekly thereafter, as a minimum. We performed a retrospective planning study on 8 patients treated for MIBC. For “plan of the day,” 4 separate plans were created by expanding the superior CTV margin by 0.5 cm, 1 cm, 1.5 cm, or 2 cm. All other margins were 1.5 cm in all directions. Composite plans were created from the CTV drawn on the first 3 XVIs. This composite CTV was grown by 5mm to create PTV1 and by 10mm to create PTV2. Subsequent XVIs were assessed to determine if the CTV was encompassed by the 95% isodose for each plan. We compared the PTV for each plan with the standard RTP volume. Results: Preliminary data reveal that the composite plan using a 10mm margin resulted in adequate coverage for all remaining treatments as assessed by XVI. The composite plan with a 5mm margin failed to adequately cover the CTV. Using the composite plan with a 10mm margin the PTV is decreased by a mean of 27.5% compared with conventional planning. Plan of the day resulted in a mean decrease in PTV of 17.0%. Conclusions: This data suggests a potential advantage of adaptive planning with both techniques showing a reduction in PTV compared with conventional planning. This could lead to an associated reduction in dose and toxicity to OAR. Composite planning with a 10mm margin showed the greatest benefit in terms of reduced irradiated volume while adequately covering the CTV. Further studies are needed to investigate any effect on toxicity due to reduced dose to OAR.