bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of leptomeningeal carcinomatosis (LC) in advanced prostate cancer patients: Characteristics of six cases in a single institution.
Authors: Sperlich C. , Fontaine A. , Ayllon J. , Van Campenhout I.
Published: February 2017

218

Background: In the past months, we have noticed an increasing number of leptomeningeal carcinomatosis (LC) in patients known for advanced prostate cancer (PC). This complication has only been reported in a few patients.

Methods: We identified and reviewed the charts of all patients known for advanced PC who later developed LC. We report their characteristics as well as survival.

Results: Between March 2009 and April 2010, we identified 6 patients known for advanced PC that showed evidence of LC (median time from diagnosis of prostate cancer to development of LC, 55.8 months). Disease was already metastatic to other sites in all of them, and all had previously showed evidence of castrate refractory prostate cancer (CRPC). All patients maintained LHRH agonist therapy and were treated with prednisone once they showed evidence of CRPC. Most had also been treated with docetaxel (n=5), zoledronic acid (n=4; the remaining 2 patients received either zoledronic acid or denosumab as part of a protocol) and/or other (dasatinib/placebo as part of a protocol, n=1; sunitinib as part of a protocol, n=1). LC was diagnosed a median of 21.2 months after evidence of CRPC, based on clinical findings (cranial nerve[s] involvement [n=6] and nausea and/or ataxia [n=2]) and magnetic resonance imaging (MRI). 2 patients underwent lumbar puncture (negative results). Treatment administered for LC included dexamethasone (n=1), radiation therapy (n=1), or both (n=2). Two patients with poor performance status did not receive any treatment. All patients assessable for response (n=3) showed a partial improvement in their symptoms, but not complete resolution. Median overall survival from development of CRPC and from diagnosis of LC is 23.9 months and 2.7 months, respectively.

Conclusions: LC is a newly described site of metastasis in patients with advanced CRPC. It is associated with a late onset and a very poor prognosis.

[Table: see text]
Pathohistologic findings in patients with nonseminomatous germ cell tumors (NSGCT) who undergo postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for small tumors.
Authors: Pfister D. J. , Busch J. , Winter C. , Schmelz H. U. , Dieckmann K. , Albers P. , Schrader M. , Heidenreich A.
Published: February 2017

224

Background: The current guidelines recommend the resection of all visible residual tumors in NSGCT after a cisplatin based chemotherapy. There are controversial data concerning the necessity of PC-RPLND in patients with residual tumours less than one centimetre in diameter. The aim of our study was to evaluate the pathological findings in a modern series with regard of the residual tumour size.

Methods: A retrospective analysis of the patient's charts was performed including patients who underwent PC-RPLND between 1989 and 2010. Of 408 patients 330 had a NSGCT, 78 patients had a pure seminoma or a primary extragonadal germ cell cancer and were excluded from analysis. The tumour size at the time of surgery was available in 261 patients in the remaining 69 pateints no preopretive data with regard to the tumour size were recorded in the radiology reports. Due to the location of the residual tumour a median laparotomy, a thoracoabdominal approach was used. In one center a laparoscopic approach was preferred.

Results: Mean tumour diameter was 4.7 (0 to 32) cm. The patients were stratified in three groups: group 1 n=28 (RT<=1cm), group 2 n=23 (RT>1<=1.5cm) and group 3 n=209 (RT>1.5cm). The histological specimens contained teratoma in 21.4%, 39.1%, 44.5% respectively, viable cancer in 10.7%, 17.4% and 22% respectively, and fibrosis/necrosis in 64.3%, 52.2% and 37.8% respectively in the three grpups respectively.

Conclusions: The finding of both teratoma and viable cancer decreases with decreasing sizes of the residual tumour. Nevertheless lesions <= than 1 cm still harbour a significant pathohistology in one third of the patients. As a consequence PC-RPLND must not be omitted even in small RT.

No significant financial relationships to disclose.
Capsaicin, a novel radiosensitizer, acts via a TRPV6 mediated phenomenon.
Authors: Klotz L. , Venier N. , Colquhoun A. J. , Sasaki H. , Loblaw D. A. , Fleshner N. , Venkateswaran V.
Published: February 2017

23

Background: Radiosensitizing agents sensitize cells to the lethal effects of ionizing radiation (IR). This permits use of lower doses of radiation to achieve equivalent cancer control thereby minimizing adverse effects to normal tissues. Given their lack of toxicity compounds occurring naturally in the diet make ideal potential radiosensitizing agents. Capsaicin, a compound found in the Capsicum sp. of plants, is a widely consumed food additive in areas with low PCa incidence. Traditionally capsaicin is used to treat chronic pain syndromes; however, recently evidence using in vitro PCa models describes its anti-carcinogenic potential. The transient receptor potential vanilloid-receptor (TRPV)-1 and TRPV6 cation selective channels are thought to be partly responsible for mediating these effects. TRPV-1 and TRPV-6 expression is up-regulated in PCa tissue correlating directly with increasing tumor grade. This suggests TRPV1 and/or TRPV6 may be potential therapeutic targets for capsaicin mediated interventions in PCa patients. As IR and capsaicin both promote apoptosis and inhibit cell cycle progression in vitro we hypothesize an at least additive effect of combining these two therapies.

Methods: Using clonogenic assays we assessed the effect of ionizing radiation (1-8 Gy) and/or capsaicin (1-10μ M) on colony formation rates in 4 human PCa cell lines (LNCaP, PC3, PC3AR2, DU145). Proliferative, apoptotic, TRPV-6 protein markers were assessed using Western blot analyses.

Results: Exposure of cells to capsaicin (1-10μ M) or IR (1-8Gy) caused significant dose-dependent inhibition of colony formation (p<0.001). Combining capsaicin with IR resulted in further significant inhibition of colony formation rates (P<0.001). Western blot analyses showed LNCaP cells treated with capsaicin and/or IR to have increased expression of pro- apoptotic proteins BAX and Bad, tumor-suppressor proteins p21 and p27 and reduced androgen-receptor. Additionally, capsaicin monotherapy caused a dramaticalteration in TRPV1 and TRPV6 expression.

Conclusions: These studies confirm the radiosensitizing capacity of capsaicin in PCa cells in vitro. Ongoing studies are further delineating the mechanism of interaction of these treatment modalities.

No significant financial relationships to disclose.
Alterations in genes regulating cell cycle and apoptosis in high-grade urothelial carcinoma.
Authors: Al-Ahmadie H. , Iyer G. , Lin O. , Gopalan A. , Fine S. , Tickoo S. , Reuter V. E. , Bajorin D. F. , Milowsky M. I. , Solit D. B.
Published: February 2017

237

Background: Dysregulations of cell cycle and inhibition of apoptosis are crucial factors in tumorigenesis of multiple malignancies, including urothelial carcinoma (UC). Deletions of TP53 and CDKN2A and amplification of MDM2 have been observed in UC, but their exact frequency and functional consequence is less known. We sought to determine the frequency of copy number alteration (CNA) and mutations of genes that regulate cell cycle or apoptosis in a panel of 96 cases of high-grade UC (HGUC) of bladder.

Methods: 96 frozen cases of HGUC were studied, including 11 bladder small cell carcinomas. DNA was isolated and analyzed for CNA by comparative genomic hybridization (CGH) using a one million oligonucleotide probe array from Agilent. The targeted genes included TP53, MDM2, CCND1, CCNE1, CDKN2A/B, E2F3 and Rb1. Traditional Sanger sequencing for mutations within TP53, Rb1, and CDKN2A was also performed.

Results: The frequency of CNA and mutations are listed in the table. Overall, 54 of 96 cases (56%) showed CNA (45) or mutation (13). Deletion of CDKN2A/B and amplification of E2F3 were the most common alterations in cell cycle regulatory genes (13 cases each, 14%), followed by amplification of CCND1 (11 cases, 11%). There was no co-amplification of CCND1 and CCNE1 in any sample. Rb1 deletion was present in five cases. CNA in E2F3 and Rb1 were mutually exclusive in 14 of 16 cases (88%) and were both present in two cases only. Mutations in TP53 were noted in 13 cases and deletions in nine. Amplification of MDM2 was noted in four cases, none of which overlapped with TP53 deletions or mutations. Overexpression of E2F3 was significantly more common in small cell carcinoma (5/11) compared to conventional UC (8/85, p = 0.006).

Conclusions: Regulators of cell cycle and apoptosis are amplified, deleted or mutated in more than half of cases (56%) of high-grade urothelial carcinoma. The overwhelming majority of these abnormalities are nonoverlapping. Amplification of E2F3 seems to be overrepresented in small cell carcinoma of bladder.

[Table: see text]

No significant financial relationships to disclose.
Use of immunocytology to predict bladder cancer presence in patients with asymptomatic hematuria.
Authors: Cha E. K. , Tirsar L. , Shariat S. F. , Christos P. J. , Mazumdar M. , Hennenlotter J. , Schwentner C. , Mian C. , Lodde M. , Schmitz-Drager B. J.
Published: February 2017

242

Background: The uCyt immunocytology assay detects cellular biomarkers for bladder cancer (BCa) in exfoliated urothelial cells. We assessed the performance of uCy for detecting BCa in patients undergoing initial evaluation for asymptomatic hematuria.

Methods: Data from 1,182 subjects without a history of BCa undergoing evaluation for hematuria were collected at three centers: EuromedClinic/Urologie24, University of Tübingen, and Central Hospital of Bolzano. All subjects underwent standard workup (i.e., voided cytology, upper tract imaging, and cystoscopy) and immunocytology.

Results: Overall, 245 subjects had BCa (20.7%). The sensitivity/specificity/negative predictive value for uCyt and cytology were 82.4%/86.6%/95.0% and 46.5%/94.9%/87.2%, respectively. uCyt (OR 18.3, p<0.001) and cytology (OR 2.9, p<0.001) were associated with BCa in a multivariable analysis. The base model (age, gender, smoking status, type of hematuria) predicted BCa with an accuracy of 74.1%. Addition of cytology to the base model improved predictive accuracy (PA) to 83.5% (p<0.001), while addition of uCyt to the base model improved PA to 90.1% (p<0.001). Addition of uCyt to Model 1 significantly improved PA (+7.6%, p<0.001), but addition of cytology to Model 2 did not (+1.0%, p=0.057). uCyt performed equally well in patients with microscopic and gross hematuria (OR 30 vs. 27), while cytology did not (OR 18 vs. 12).

Conclusions: uCyt is a strong, independent predictor of BCa in patients with hematuria; it outperforms cytology. uCyt may help with patient counseling, quality of care optimization (referral prioritization), and possibly sparing unnecessary hematuria workup in patients at extremely low risk of BCa.

[Table: see text]

No significant financial relationships to disclose.
Meta-analysis of randomized trials comparing cisplatin versus carboplatin-based regimens for the first-line therapy of metastatic transitional cell carcinoma of the urothelium (TCCU).
Authors: Sonpavde G. , Galsky M. D. , Chen G. J. , Bellmunt J. , Roth B. J. , Petrioli R. , Hutson T. E. , Dogliotti L. , Dreicer R. , Oh W. K.
Published: February 2017

247

Background: Cisplatin-based chemotherapy is the first-line treatment standard for metastatic TCCU, although carboplatin is substituted for cisplatin-ineligibility, tolerability, and ease of administration. Since definitive data comparing cisplatin- versus carboplatin-based chemotherapy are lacking, a meta-analysis of published randomized trials was performed.

Methods: PubMed was searched for articles published in the English language from 1966 until 2010 and abstracts presented at the American Society of Clinical Oncology Annual Meeting between 2000 and 2010 were searched to identify relevant trials. Eligible studies included prospective randomized trials evaluating cisplatin- versus carboplatin-based regimens in cisplatin-eligible patients with metastatic TCCU. Individual patient data were not available and progression and survival data were inconsistently reported. Therefore, the analysis focused on overall (OR) and complete response (CR). The Mantel-Haenszel method was used for combining trials and calculating pooled risk ratios (RR).

Results: A total of 286 patients with metastatic TCCU from 4 randomized trials (3 phase II and 1 phase III trial) were included. Chemotherapy regimens included MVEC (methotrexate, vinblastine, epirubicin, cisplatin) vs. MVECa (methotrexate, vinblastine, epirubicin, carboplatin), MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) vs. MCAVI (methotrexate, carboplatin, vinblastine), MVAC vs. paclitaxel plus carboplatin, and gemcitabine plus cisplatin vs. gemcitabine plus carboplatin. Cisplatin-based chemotherapy was associated with a significant improvement in the likelihood of CR (RR=3.973 [95%CI: 1.562 – 10.110], p =0.004) and OR (RR=1.336 [95%CI: 1.043 – 1.712], p=0.025).

Conclusions: Cisplatin-based as compared with carboplatin-based combination chemotherapy significantly increases the likelihoods of both OR and CR, in patients with metastatic TCCU. In the absence of definitive phase 3 trials, these results support cisplatin-based regimens as the preferred first-line treatment for cisplatin-eligible patients with metastatic TCCU.

No significant financial relationships to disclose.
Androgen-regulated metabolome in prostate cancer.
Authors: Putluri N. , Zhang Y. , Putluri V. , Vareed S. , Vasu V. T. , Fischer S. M. , Chad C. , Sreekumar A.
Published: February 2017

25

Background: Prostate cancer (PC) is the second most prevalent cancer among American men which is primarily treated by androgen ablation therapy. Although a number of patients respond to this regimen, a significant subset fail and the tumor invariably progresses into a hormone refractory metastatic state, which is lethal. Earlier we had reported the first unbiased metabolomic signature for localized and metastatic prostate cancer tissues. Advancing further, we attempt to delineate the subset of metabolome in prostate cancer which is regulated by androgen-action.

Methods: Androgen responsive (R22V1, LnCap and VCAP) and independent (PC3, DU145) PC cells and benign prostate epithelial cells (RWPE) were profiled for their metabolomic alterations using mass spectrometry. Extracted metabolome from these cells were profiles using a combination quadrupole-time-of-flight (Q-TOF) and triple quadrupole (QQQ) mass spectrometers coupled to reverse phase and aqueous normal phase chromatography. The metabolomic profiles were analyzed to delineate class-specific signatures which were interrogated for altered bioprocesses using Oncomine Concept Map (OCM, www.oncomine.org ). The androgen receptor (AR) regulated metabolome was verified using treatment of PC cells with synthetic androgen, R1881.

Results: A total of 3,092 metabolites (113 named) were detected across the 4 cells lines, of which 869 compounds were significantly (ANOVA P<0.01) different between androgen responsive and non-responsive cells. The differential compendia included 28 named metabolites, including sarcosine which was earlier shown to be elevated during PC development and progression. Bioprocess mapping of AR-regulated metabolome revealed enrichment of amino acid metabolism and methylation potential, both of which were earlier defined to be the hallmarks of PC development and progression.

Conclusions: The study defines AR-regulated metabolic signature which portrays enrichment of amino acid metabolism and methylation potential that are hallmarks of PC development and progression.

No significant financial relationships to disclose.
Risk-specific intensity of surveillance practices in non-muscle-invasive bladder cancer: Results from the BCAN/SUO/AUA/LUGPA electronic survey.
Authors: Smith A. , Nielsen M. E. , Ferguson J. , Manvar A. , Pruthi R. , Wallen E. , Lotan Y.
Published: February 2017

251

Background: The ideal surveillance regimen for patients with non-muscle-invasive bladder cancer (NMIBC) is uncertain. Given different grade- and stage-specific risks of recurrence and progression, there is some question whether it might be acceptable to pursue less intensive surveillance practices for patients with lower risk disease, and there is a paucity of data on current patterns of care in this area of practice.

Methods: An electronic survey was developed by the Bladder Cancer Advocacy Network (BCAN) to elicit self-reported practices of cystoscopy, cytology, and radiographic testing in the setting of surveillance for patients with a history of NMIBC. The survey was circulated to urologists via the AUA, SUO and LUGPA distribution lists. 512 respondents completed the survey.

Results: Among respondents, 66% report performing cystoscopy every 3 months on all patients for at least the first two years following diagnosis of NMIBC. The remaining 33% report performing surveillance cystoscopy less frequently, 95% of whom report doing so in the setting of low grade pathology. Similarly, 51% report using cytology with every cystoscopy, 23% do so for all high grade cases, and 30% report not using cytology with every cystoscopy. In the absence of recurrence for patients with an initial high grade diagnosis, upper tract reimaging is performed annually in 48%, biannually in 37% and never in 3%. The corresponding figures for patients with an index diagnosis of low grade disease are 14%, 37% and 28%, respectively. In the event of a recurrence in the bladder, 80% of respondents report reimaging the upper tracts for patients with high grade disease, versus 45% in the event of a low grade recurrence.

Conclusions: A substantial number of urologists responding to a survey report using relatively less intensive surveillance practices in patients with lower risk NMIBC. These results suggest a lack of consensus on the ideal intensity of evaluation in this setting, and provide a basis for prospective studies to validate the safest and most cost-effective strategies for surveillance.

No significant financial relationships to disclose.
Evaluation of the insulin-like growth factor receptor I and Pyk2 kinase in urothelial carcinomas and effect on motility and invasion of urothelial carcinoma-derived cells.
Authors: Morrione A. , Genua M. , Iozzo R. V. , Gomella L. G.
Published: February 2017

254

Background: We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial-carcinoma-derived cells without affecting cell proliferation, suggesting that the IGF-IR may play a more prominent role in promoting the transition to the invasive phenotype in bladder cancer.

Methods: IGF-IR levels in cancer and normal bladder tissues were analyzed by immunohistochemistry. IGF-IR and Pyk2 signaling pathways were studied in several urothelial carcinoma-derived cancer cells using biochemical assays and siRNA approaches. Pyk2 expression in a bladder tissue array was analyzed by immunofluorescence and by AQUA (Automated Quantitative Analysis).

Results: In this studywe demonstrated by immunohistochemical analysis that the IGF-IR expression increased with grade in bladder cancer tissues compared to non-malignant controls. Increased IGF-IR expression in non-tumorigenic T24 urothelial carcinoma cells promoted anchorage independent growth, while IGF-IR targeting in metastatic T24T cells inhibited colony formation in soft-agar. We also discovered that the focal adhesion protein Pyk2 is activated by IGF-I in urothelial carcinoma-derived cells. Using siRNA approaches, we demonstrated that Pyk2 is critical for IGF-IR-dependent motility and invasion and regulates IGF-I-dependent activation of the Akt and MAPK pathways in urothelial cancer cells. Using immunofluorescence and AQUA analysis we also discovered that Pyk2 is overexpressed in bladder cancer tissues compared to normal tissue controls. In urothelial carcinoma-derived tissues there is also increased Pyk2 localization in the nucleus compared to normal tissue controls.

Conclusions: Our results provide the first evidence for a role of the IGF-IR and Pyk2 in motility and invasion of bladder cancer cells, and support the hypothesis that the IGF-IR and Pyk2 may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia. The IGF-IR and Pyk2 could also serve as novel tumor biomarkers for diagnosis and possibly prognosis of bladder tumors.

No significant financial relationships to disclose.
Investigating the Nrf2 transcription factor as a regulator of cisplatin resistance in urothelial carcinoma (UC) cells.
Authors: Crabb S. J. , Hayden A. , Gould K. , Andrews L. , Packham G.
Published: February 2017

256

Background: Nrf2 controls expression of multiple target genes, each containing an antioxidant response element (ARE). These targets mediate cellular protection through antioxidant response, cellular detoxification (including glutathione conjugation), and altered drug uptake/efflux. Some targets (e.g., metallothionein, glutathione reductase) are associated with UC characteristics, outcomes, and chemotherapy resistance. Nrf2 regulation is partially understood and includes negative regulation by Keap1 and phosphorylation. De-novo or acquired cisplatin resistance is a problem in UC. We hypothesised that it might be mediated by Nrf2.

Methods: Nrf2 expression was assessed in UC clinical samples by immunohistochemistry. We then utilised a panel of UC cell lines, including a cisplatin resistant RT112 sub-line (RT112CP), to test Nrf2 axis expression and activation correlated to cisplatin sensitivity/resistance. Effects of AKT or HER2 kinase activity on Nrf2 activation were tested by chemical inhibition.

Results: In UC clinical samples we detected Nrf2 over-expression in 64% of cancers compared to surrounding normal tissue. Varied Nrf2 expression levels were also detected in different UC cell lines whereas Keap1 demonstrated an inverse profile of both RNA and protein expression. Nrf2 expression was 4 fold greater in RT112CP cells which exhibited comparative cisplatin resistance (10 fold greater IC50 in proliferation assays) compared to parental cells. Nrf2 over expression was functional in this model system as indicated by increased activity in ARE luciferase reporter assays, raised expression of Nrf2 transcriptional targets (metallothionein, glutathione reductase) and glutathione levels. Furthermore, depletion of Nrf2 in RT112CP cells by siRNA or transfection of a dominant negative Nrf2 construct partially restored cisplatin sensitivity. Finally chemical inhibition of AKT or HER2 reduced Nrf2 activation in ARE reporter assays.

Conclusions: Nrf2 is overexpressed in a subset of UC. In cell line models it is functionally activated and contributes to cisplatin resistance, which is reversible. This might be amenable to detection and therapeutic reversal in the clinic.

No significant financial relationships to disclose.
Can we reliably identify patients for radical cystectomy without neoadjuvant chemotherapy?
Authors: Dickstein R. J. , Grossman H. B. , Pretzsch S. M. , Karam J. A. , Millikan R. E. , Dinney C. P. , Kamat A. M.
Published: February 2017

258

Background: When neoadjuvant chemotherapy is administered prior to radical cystectomy in patients with muscle-invasive urothelial cancer, the patients who benefit most are those with pathologic T3-4 or N+ disease. Thus, some advocate reserving neoadjuvant chemotherapy for patients considered high risk based on presence of the following clinical parameters: lymphovascular invasion, hydroureteronephrosis, presence of a palpable or visible mass on exam under anesthesia or imaging (suggesting cT3 disease), and/or variant histology. The goal of this study was to report the outcome of patients who were classified as “not high risk” (i.e., lacking the above-mentioned criteria) and underwent radical cystectomy without neoadjuvant chemotherapy.

Methods: On retrospective review of 858 patients who underwent radical cystectomy from 2000 to 2008, we identified 174 patients with muscle-invasive disease (cT2) who were classified as “not high risk” (i.e., did not have lymphovascular invasion, hydroureteronephrosis, variant histology, and/or palpable or visible mass on imaging studies) and underwent radical cystectomy without neoadjuvant chemotherapy. Endpoints of interest included pathologic upstaging (≥ pT3), pathologic lymph node positivity, need for adjuvant or salvage chemotherapy, disease recurrence, and disease specific survival (DSS).

Results: Of the 174 patients, 155 (88.6%) were male and the median age was 67.6 years (range 39-86). At radical cystectomy, 75 patients (42.9%) were upstaged (pT3N0: 45; pT4N0: 6; pTxN+: 24). Thirteen patients (7.4%) received adjuvant chemotherapy for adverse pathology. After a median interval of 27 months, 38 patients (21.7%) developed recurrent disease; isolated pelvic recurrences: 4, distant recurrences: 34, and 2 had both. Eighteen patients with recurrent disease went on to receive salvage chemotherapy. Overall, 25 patients (14.3%) died of disease with a 5-year DSS of 82.3%.

Conclusions: Although clinical understaging remains a problem in the management of patients with muscle-invasive urothelial cancer, our criteria for selection of patients for primary radical cystectomy without neoadjuvant chemotherapy results in a cohort with a 5-year DSS of 83%.

No significant financial relationships to disclose.
Radiosensitization of MYC-overexpressing prostate cancer cells by statins.
Authors: Salih T. , Aziz K. , Thiyagarajan S. , Armour M. , Shanmugam B. , Zeng J. , Adam S. J. , Felsher D. W. , DeWeese T. L. , Tran P. T.
Published: February 2017

26

Background: Studies have shown a link between HMG-CoA reductase inhibitors (statins) and decreased cancer risk in various cancers including prostate cancer. Recent clinical studies have shown improved outcome for men on statin therapy receiving definitive radiation therapy compared to radiation therapy alone for prostate cancer. The oncogene Ras can be inhibited by statin treatment and in turn also result in targeted downregulation of Myc. Inactivation of Myc has been shown to induce tumor regression in transgenic mouse models of different cancers.

Methods: Utilizing both in vitro and in vivo models, we studied in MYC over-expressing prostate cancer cells statin induced cytotoxicity and radiosensitization. We studied the effect of statin treatment with and without radiation treatment on in vitro cell death and clonogenic survival and correlated effects to levels of MYC and phospho-MYC. We constructed mutant cell lines to specifically examine the MYC-dependent effects of statins on prostate cancer cell cytotoxicity and radiosensitization. We performed similar studies in vivo using subcutaneous tumor grafts.

Results: Statin treatment alone of prostate cancer cells resulted in increased cell death and decreased clonegenic survival. Statin treatment further sensitized prostate cancer cells to ionizing radiation as shown through colony formation assays. These cellular effects were associated with decreased levels of active MYC as confirmed by western and phospho-western analysis. Statin-induced cell death and decreased MYC levels could be rescued with the HMG-CoA bypass product mevalonate. Finally, flank tumor graft experiments demonstrated the ability of statins and radiation to delay tumor growth in vivo.

Conclusions: Our preliminary data have implicated MYC as a potential critical target for the cytotoxic effects of statins on prostate cancer cells. The prevalence of MYC overexpression in human prostate cancers is as high as 80%. Thus the ability of statins to radiosensitize MYC overexpressing prostate cancer cells may provide a mechanistic explanation to the improved outcomes for men taking statins while on radiation therapy and now may afford us a molecular biomarker to examine this phenomenon in the clinic.

No significant financial relationships to disclose.
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.