bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of the orally available MET inhibitor PF-2341066 on tumor burden and metastasis in an orthotopic xenograft model of bladder cancer.
Authors: Sorbellini M. , Giubellino A. , Srivastava G. , Sourbier C. , Pinto P. A. , Linehan W. , Bottaro D. P. 
Published: February 2017

263 Background: Met over-expression has been found in bladder cancer (CaB). However, to date, the effects of Met inhibition in CaB have not been reported. We used a small, orally available, highly specific Met-inhibitor currently on phase 2 clinical trials, to assess its effects in an orthotopic xenograft model of bladder transitional cell carcinoma (TCC). Methods: An orthotopic xenograft murine model of TCC of the bladder was developed with T24-Luciferase positive bladder cancer cells. NIH 3T3 cells producing human hepatocyte growth factor (hHGF) were implanted subcutaneously in mice to provide a source of hHGF. Animals were treated with the selective Met inhibitor (PF-2341066) intra-peritoneally after positive detection of bladder tumor primary and/or metatastatic disease. Fluorescence imaging (Xenogen IVIS) of mice was performed weekly. Mice were euthanized 4 weeks after the start of treatment and their tissues studied histologically. Results: PF-2341066 was found to reduce tumor burden to below detectable levels in both primary and metastatic sites in all mice treated. No noticeable side effects were detected in treated mice secondary to drug administration. Conclusions: This study is the first to test a small orally available Met-selective inhibitor in an orthotopic, HGF-driven model of human CaB. Our results demonstrate that Met-inhibition by PF-2341066 reduces TCC tumor burden supporting its potential use in patients with bladder cancer. No significant financial relationships to disclose.
Early outcomes with neoadjuvant high-dose intensity methotrexate, vinblastine, doxorubicin, and cisplatin (HD-MVAC) or gemcitabine and cisplatin (GC) in muscle-invasive urothelial carcinoma of the bladder: A single-institution experience.
Authors: Mitra N. , Monk J. P. , Pohar K. S. , Shabsigh A. , Sharp D. S. , Abaza R. , Box G. N. , Zynger D. L. , Clinton S. K. , Mortazavi A. 
Published: February 2017

280 Background: Compared to MVAC, HD-MVAC achieves significantly higher complete response rates in patients (pts) with metastatic bladder cancer. Based on current literature, 7%-38% of pts with muscle-invasive bladder cancer achieve pathological down-staging (pT0) with neoadjuvant chemotherapy (NC), which correlates with improved disease-free and overall survival. The role of HD-MVAC has not been evaluated in the neoadjuvant setting. In this retrospective study, we present our data in pts who received NC with HD-MVAC or GC followed by radical cystectomy (RC). Methods: From July 2008 to August 2010, 38 (pts) received 4 cycles of NC with either HD-MVAC or GC for at least T2 bladder cancer followed by RC. The endpoints of interest of this study were the complete pathologic response (pT0) or down-staging to < pT2 (pT0, pTis, and pT1) at RC; and median interval to RC from the time of diagnosis of muscle-invasive bladder cancer and start of NC. Results: Median age at the time of diagnosis was 66 years (35-80 years). Fifteen pts received neoadjuvant HD-MVAC, and 23 received neoadjuvant GC. Clinical T stage at the time of diagnosis was T2 in 29 (76%), T3 in 3 (8%), and T4 in 6 (16%) pts. Down-staging to < pT2 was achieved in 8 (53%) of HD-MVAC pts and 10 (43%) of GC pts. pT0 was achieved in 5 (33%) of HD-MVAC pts and 9 (39%) of GC pts. The median interval from time of diagnosis to RC was 129 days (range 84-154) for the HD-MVAC pts, and 145 days (range 108-252) for the GC pts. The median interval from initiation of NC to RC was 85 days (range 53-122) for the HD-MVAC pts and 107 days (range 60-126) for the GC pts. Overall, NC was well tolerated with 80% of HD-MVAC pts and 78% of GC pts completing the planned chemotherapy. To this date, none of the pT0 pts had recurrence. Conclusions: Both neoadjuvant HD-MVAC and GC appear to be well tolerated, with very promising rate of pathological down-staging. Longer follow-up is needed for the survival outcomes of these patients. A shorter interval from diagnosis and initiation of NC to RC might be responsible for our better outcomes comparing to some historical data. No significant financial relationships to disclose.
Adaptive-predictive organ localization (a-POLO) in the clinic: Updated results in hypofractionated bladder radiotherapy.
Authors: McDonald F. , Lalondrelle S. , Taylor H. , Harris V. , Hansen V. , Khoo V. , Huddart R. A. 
Published: February 2017

282 Background: The A-POLO strategy allows the optimal 'plan of the day' to be selected online for radiotherapy (RT) delivery. The methodology is implemented in a phase II study of patients with muscle-invasive bladder cancer who are not suitable for cystectomy/daily RT and are receiving hypofractionated RT. Methods: Planning scans were performed at 0 and 30 minutes post void (CT0 and CT30). Three conformal plans were created (small, intermediate, large) ( Table ). Patients were prescribed 6Gy weekly for 5–6 weeks. A pre-RT cone beam CT (CBCT) scan and online set-up correction were performed. The plan giving the optimal target coverage was selected by 2 observers. Offline plan selection was also carried out by an independent observer. A post-RT CBCT was acquired to calculate the percentage of the CTV covered by 95% of the dose (V95). The mean A- POLO volume was compared to our previous institutional standard PTV (1.5cm isotropic margins) (PTViso). Outcome data were collected. Results: A total of 77 RT fractions were delivered to 14 patients. The small plan was delivered for 38 (49%) fractions and the large for 6 (8%) fractions. The concordance rate between online and offline plan selection was 71/77 (92%). The mean CTV V95 was 99% (patient mean range 97–100%). The mean time between the pre- and post-treatment CBCT was 15 minutes. The mean reduction between PTViso and mean A-POLO PTV was 42% (range 16– 59%). 2 patients had grade (G) 3 (CTCv3.0) treatment-related acute toxicity. There have been no treatment-related G4 acute or G3 late toxicities. With a median follow-up of 7.3 months 10 patients are alive with 8 disease free (1 local and 1 distant relapse). Conclusions: Implementation of A-POLO RT is feasible, well tolerated, and associated with good concordance in 'plan of the day' selection. An individualized treatment plan can be delivered with each fraction to achieve a reduction in PTV compared to PTViso with maintenance of target coverage. [Table: see text] No significant financial relationships to disclose.
Does induction chemoradiotherapy compromise subsequent radical cystectomy? A single-institutional comparative study on perioperative complications according to the Clavien-Dindo classification.
Authors: Iwai A. , Koga F. , Kawakami S. , Fujii Y. , Masuda H. , Saito K. , Kihara K. 
Published: February 2017

284 Background: Recently, bladder-sparing protocols incorporating TUR + chemoradiotherapy (CRT) have been developed. Patients who achieve CR after CRT are subjects for bladder preservation treatment and those who with non-CR undergo radical cystectomy (RC). However, early studies suggest that RC following pelvic irradiation associates with a higher mortality. To validate the impact of induction CRT on perioperative morbidity of RC, we compared complications of RC in patients treated with or without induction CRT at a single university hospital. Methods: Records of consecutive 193 patients who underwent RC for bladder cancer between April 1989 and May 2010 were reviewed. Induction CRT consists of radiation at 40 Gy to the small pelvis and 2 cycles of concurrent cisplatin at 20 mg/d for 5 days. Any complications occurred within 30 days after RC were graded according to the Clavien-Dindo classification system. Complications of grade I or II were classified as minor and complications of grade III or greater were classified as major. Results: Eighty-seven patients underwent induction CRT (CRT group) while 106 did not (control group). Patients of CRT group had significantly more advanced disease. No patient died within 90 days. Twenty one (11%) patients experienced at least one major complications; there was no significant difference in the incidence of major complications between CRT and control group (14% vs. 8%, p = 0.26). The details were as follows; infectious (3.5% vs. 3.8%, p = 1.0), gastrointestinal (4.6% vs. 0.9%, p = 0.18), surgical (6.9% vs. 3.8%, p = 0.35), cardiovascular (1.2% vs. 0.9%, p = 1.0). There was no significant difference between the incidence of minor complications (61% vs. 51%, p = 0.19). Conclusions: Induction CRT at 40 Gy is unlikely to compromise subsequent RC. No significant financial relationships to disclose.
Bladder preservation with helical tomotherapy-based, image-guided radiotherapy: A clinical study using “plan of the day” adaptive radiotherapy.
Authors: Murthy V. 
Published: February 2017

289 Background: This clinical study assessed the potential of helical tomotherapy-based, image-guided radiotherapy (IGRT) to increase the accuracy of bladder irradiation using a plan of the day adaptive radiotherapy (ART) technique. Methods: Ten patients with stage T2b-T4- N0 M0, histologically proven bladder transitional cell carcinoma, who underwent bladder preservation with trimodality therapy in an ongoing trial, are reported. All patients received a dose of 64Gy/32# to the whole bladder. Seven of these also received a simultaneous integrated boost of 68Gy/32 fractions to tumor bed. The ART technique entailed the generation of six planning PTVs and thus six separate IMRT plans for each patient. All patients underwent daily pre and post treatment MVCT imaging to correct for positioning errors, choose the plan of the day, depending on deformation of the bladder, and verify intrafraction filling at the end of treatment. Margins needed to encompass the bladder wall in each direction during radiotherapy was determined in the following three scenarios: (a) centers with availability of daily IGRT and performing ART, (b) centers with IGRT not doing ART, and (c) centers without IGRT using electronic portal imaging for setup. Results: At a median follow-up of 12.2 months, all patients had a complete response in the bladder and one patient had a pelvic nodal recurrence. No patient developed treatment related grade 3 toxicity. Post treatment MVCT scans (n=315) were used to generate margins for centers with varying resources. Overall, the margin needed to encompass the anterior and superior walls 85 to 95% of the time was more than the other walls (Table, margins for six walls in cm). Maximum geographical miss in spite of IGRT was noted for the superior (13.8%) and anterior walls (10.3%). Conclusions: Plan of the day ART is a feasible and promising technique for optimal treatment and dose escalation in bladder cancer. [Table: see text] No significant financial relationships to disclose.
Targeted combinatorial therapy of androgen receptor in androgen-independent prostate cancer cells.
Authors: Gomez-Pinillos A. , Liu X. , Ferrari A. C. 
Published: February 2017

29 Background: Gain of function of androgen receptor (AR) and PI3K/Akt/mTOR pathway due to loss of PTEN function are interrelated determinants of AIPC progression and resistance to antiandrogens. We determined that histone deacetylase inhibitors (HDACi), known to regulate AR expression and transcriptional activity, restore sensitivity to bicalutamide (Bic) of AIPC cells and the combination is synergistic. We postulate that adding a dual inhibitor of PI3K/mTOR would potentiate growth inhibition and apoptotic response. Methods: Androgen-independent, PTEN null AI-LNCaP (AI-cells) and wt PTEN RV1-cell lines were treated for 72h with the HDACi Panobinostat (PAN), the dual PI3K/mTOR inhibitor BEZ235 (E) and Bic as single agents or in doublet or triplet combinations. Growth was measured by MTT assay, Akt/mTOR pathway target proteins p-Akt, p-4EBP1 and p-S6K by western blot. Activation of ligand-independent AR downstream targets: CDC20, IDI1, CDK1, UBE2C, PRDM4 by qRT-PCR. Apoptosis by oligonucleosome quantification by ELISA was compared to docetaxel. Results: In both cell lines, the IC50s were markedly reduced in response to the doublet combinations and further decreased by the triplet. The isobolograms showed synergy. The apoptosis response increased by two fold in AI and RV1 cells in response to the doublet PAN+E and by four fold with the addition of Bic in AI cells. Only E decreased the protein levels of p473-akt, p-4EBP1, p-S6K markedly while only PAN decreased AR and these levels were not affected by the combinations. However, the triplet but not the doublets decreased by 2-fold the expression of AR targets in AI-cells but not in RV1 cells. Conclusions: The combination of PAN+E is highly effective in AIPC cells regardless of PTEN status but the addition of Bic is essential to maximize the effect in PTEN null AI-cells, suggesting they are more dependent on aberrant activation of AR. [Table: see text] No significant financial relationships to disclose.
Prospective clinical trial of the merits of retroperitoneal lymph node dissection at the time of nephroureterectomy for upper tract urothelial carcinoma.
Authors: Rao S. R. , Correa J. J. , Sexton W. J. , Pow-Sang J. M. , Spiess P. E. 
Published: February 2017

293 Background: The role of retroperitoneal lymph node dissection (RPLND) in patients with upper urinary tract urothelial carcinoma (UUT-UC) remains controversial. The purpose of this prospective study was to assess the safety and feasibility of RPLND at the time of nephroureterectomy (NU) and to determine the incidence of lymph node metastasis and hence the clinical merit of this procedure at the time of NU. Methods: From March 2009 to October 2010, sixteen patients with UUT-UC underwent open (8), laparoscopic (4) or robotic (4) NU with modified RPLND. Each patient received the appropriate modified template dissection depending on the site of the UC. Demographic data, clinical and pathologic stage, histologic nodal status, perioperative complications and recurrence data were documented. Results: On final pathology, 11 (69%) patients had pTa disease, 1 (6%) had pT1, 3(19%) had pT3 disease and 1 (6%) had a benign angioma. The average lymph node count was 8 (range 3–27). No patient had positive lymph node metastasis. The median operative time was 252 minutes (range 146–371). Average EBL was 342 ml (range 100–950). Median hospital stay was 7 days (4–18). Median follow up was 5 months (range 0–16). There were four bladder tumor recurrences and one recurrence in the opposite renal pelvis and ureter. Two patients with pT3 disease as well as the patient with recurrence in the opposite UUT received chemotherapy. Four patients (25%) were given blood transfusions (median 1.2, range 1–2), one patient (6%) developed a chylous leak which resolved in four weeks, one patient (6%) developed postoperative ileus and one patient (6%) had a bowel injury during lysis of adhesions necessitating resection and anastomosis of small bowel. There was no injury to major vessels or other solid organs. Conclusions: Our preliminary results indicate that RPLND during NU for UUT-UC is a safe procedure with minimal morbidity. A larger prospective clinical trial as a multicenter study is required to adequately assess the pathological and treatment related outcomes. No significant financial relationships to disclose.
CD151 as a prognostic indicator in malignancy of the bladder and prostate.
Authors: Williams A. , McPherson V. , Martinez C. , Vasquez C. , Chan S. , Gomez-Lemus J. , Rizkalla K. , Chalasani V. , Rajgopal R. , Zijlstra A. 
Published: February 2017

295 Background: CD151 is a tetraspanin protein linked to cellular growth and motility. Recent work has suggested that CD151 may play a role in metastases in a variety of cancers, but as yet there is no evidence that it plays a role in transitional cell carcinoma of the bladder (TCC) or prostate adenocarcinoma (PCa). We wished to check the protein expression of CD151 in radical cystectomy (RC) and radical prostatectomy (RRP) tumour specimens to look for any association with disease progression and survival. Methods: Tissue was attained from 99 patients who had undergone RRP for PCa (mean follow up 12.4 years) and from 67 patients undergoing RC for TCC (mean follow up 5.75 years). Tissue sections were taken from paraffin embedded slides and imunohistochemical staining performed for CD151. Histological sections from corresponding levels were stained with H&E and compared for CD151 positivity. A database of patient's demographic factors, disease factors and relevant survival information was generated and correlated with disease-free progression and survival. Results: In the RRP group there was a statistically significant difference in CD151 expression between malignant tissue and benign tissue around (p = 0.01) and away from the tumour (p < 0.01). CD151 positivity was statistically associated with biochemical failure p = 0.022 following RRP; Gleason grade and tumor stage were not significantly associated with recurrence in this cohort. CD151 positivity did not correlate with biochemical failure following RC, although tumour stage and nodal status were strong predictors of recurrence. Conclusions: Patients with PCa specimens that stained positively for CD151 were more likely to develop disease recurrence. This study was probably underpowered to show that Gleason score and tumour stage can predict recurrence suggesting that CD151 positivity may be a more sensitive indicator or risk of recurrence in patients following RRP. We speculate that CD151 may have a clinical role in predicting those who may benefit from adjuvant treatment following RRP. While we were able to demonstrate that CD151 seems important in PCa, CD151 does not appear to have any clinical role in predicting recurrence of TCC following RC. No significant financial relationships to disclose.
Tolerability of neoadjuvant chemotherapy with gemcitabine plus cisplatin in elderly (older than age 65) patients (pts) with muscle-invasive urothelial cancer.
Authors: Niedersuess-Beke D. , Gruenberger B. , Puntus T. , Bauer W. , Lamche M. , Schramek P. , Meran J. G. 
Published: February 2017

296 Background: Urothelial cancer (UC) is a common tumor with a peak in the seventh decade. Locally advanced disease has a significant risk for developing metastases. Neoadjuvant, platinum-containing, combination chemotherapy improves survival over radical cystectomy (RC). Chemotherapy with gemcitabine plus cisplatin (GC) shows equivalent efficacy with less toxicity to methotrexate-vinblastine-doxorubicin- cisplatin (MVAC) in metastatic setting. Methods: We prospectively evaluated 23 elderly pts (8 female, 15 male) with a median age of 72 years, WHO performance status 0/1, with muscle invasive UC who received neoadjuvant GC (gemcitabine 1,000 mg/m2 days 1, 8, 15 and cisplatin 70 mg/m2, day 2 q28) for 3 cycles between 2006 and 2010 prior to RC. Assessments included toxicity of GC, pathologic response, progression free survival (PFS) and overall survival (OS). Results: 21 (91.3%) out of 23 pts finished intended chemotherapy. Two refused chemotherapy due to personal reasons. According to CTCAE guidelines 43.5% developed grade 3 hematologic toxicities; 13% developed grade 4 thrombopenia. Grade 3 non-hematologic toxicities included nausea in 2 patients. In 2 (8.7%) pts grade 4 thromboembolic events occurred. There was no treatment related febrile neutropenia or death. 15 (71.4%) of the pts underwent RC. 5 (23.8%) pts refused RC due to personal reasons. 1 of them agreed second look TURB. 1 patient underwent palliative radiotherapy due to progression of disease. Out of the 16 pts 43.75% achieved pathological response (18.75% pT0 stage and 25% pT1 stage). 56.25% had muscle invasive UC. 18.75% of them nodal positive disease. All 7 pts achieving < pT2 pathologic stage remained progression-free at a median follow up of 16 months. Pts > pT2 stage had a median PFS of 14 months. Median OS was not reached yet. Conclusions: Neoadjuvant GC is a well tolerated regiment in elderly pts and it seems to be less toxic than MVAC. Prophylactic anticoagulation during treatment should be considered. Although pathologic response is lower than in previously published retrospective data we recommend neoadjuvant treatment with GC in elderly pts. [Table: see text]
Planning outcomes and acute toxicity of intensity-modulated radiotherapy (IMRT) for treatment of bladder and pelvic lymph nodes.
Authors: Harris V. , McDonald F. , Hansen V. , Taylor H. , Huddart R. A. 
Published: February 2017

297 Background: We implemented an IMRT protocol for simultaneous treatment of bladder and pelvic lymph nodes (LN) and report the planning outcomes and acute toxicity of patients treated using this technique. Methods: 13 patients were treated with a 5-field step and shoot IMRT technique. Inclusion criteria were: radiological evidence of pelvic LN metastases; stage T3/T4; high risk pathology or post-cystectomy with persistent/recurrent disease. Anisotropic margins were applied to the whole bladder CTV (0.5 cm laterally/inferiorly, 1 cm posteriorly, 1.5 cm superiorly/anteriorly) to create PTV1. 0.5 cm margins were applied to the pelvic LN CTV to create PTV2. PTVs 1/2 were prescribed 52 Gy in 32 fractions. 1 cm margins were applied to the involved bladder to create PTV3 (prescribed 64Gy). 0.5 cm margins were applied to the involved LN volumes to create PTV4 (prescribed 60 Gy). Post cystectomy patients were planned using PTVs 2/4 only. Dose volume histograms for organs at risk (rectum, femoral heads and other bowel) were calculated and compared with local dose constraints. Acute toxicity was assessed according to common toxicity criteria v3.0 and recorded weekly during treatment. Treatment verification was performed by cone beam CT. Results: All treatment plans achieved target coverage of > 95% volume to > 95% prescription dose for each PTV. All patients achieved rectal and femoral head dose constraints. 2 patients did not meet V45 other bowel constraints but proceeded with treatment as all other dose limits were achieved. At the time of abstract submission 13 patients had completed treatment. 2 were treated for relapse post-cystectomy and did not have GU toxicities recorded. Maximum experienced acute toxicities were recorded. 9/11 patients experienced acute GU toxicity (G1=3, G2=1, G3=5). 6/13 patients experienced acute GI toxicity (G1=3, G2=3). 9/13 patients developed other acute toxicities (G1=7, G2=2). No patients developed ≥G3 non-GU toxicity. Conclusions: Bladder and pelvic LN IMRT allows patients with high risk locoregional bladder cancer to meet preset dose constraints, appears feasible and has a comparable rate of acute toxicity to conventional bladder-only radiotherapy treatment. No significant financial relationships to disclose.