bluuebunny/crossref_metadata_2025 huggingface dataset:
Can mpMRI predict biochemical recurrence after radical prostatectomy? Implications for preoperative staging and surgical planning.
Authors: Ho Richard , George Arvin Koruthu , Frye Thomas P , Abboud Steven , Chelluri Raju , Fascelli Michele , Shakir Nabeel Ahmad , Walton-Diaz Annerleim , Sankineni Sandeep , Merino Maria J , Turkbey Baris , Choyke Peter L. , Pinto Peter A.
Published: February 2017

161

Background: Multiparametric magnetic resonance imaging (mpMRI) used in conjunction with MR/TRUS fusion-guided biopsy has improved detection and localization of clinically significant prostate cancer. We aim to evaluate the utility of preoperative MRI characteristics to predict biochemical recurrence (BCR) following radical prostatectomy. Methods: Patients who underwent robotic assisted radical prostatectomy (RARP) between 2007-2014 at the National Institutes of Health were reviewed. We identified patients with BCR defined following the guidelines of the AUA Localized Prostate Cancer Update Panel report (serum PSA ≥0.2 ng/ml with a subsequent confirmatory value). Bivariate analysis and logistic regression were used to determine the association of mpMRI and preoperative patient characteristics with BCR. Results: Of 365 patients who had RARP, 21 met criteria for BCR with a median follow up of 19 months (IQR: 10-34). Mean preoperative PSA (ng/mL) [p<0.001], high MRI suspicion level [p=0.016], presence of extracapsular extension (ECE) on MRI [p=0.003], and total prostate volume by MRI (cc) [p<0.001] were associated with BCR. Increasing MRI suspicion corresponded to increases in rates of BCR within suspicion levels (2.22% of low, 3.88% of moderate, and 10.64% of high). The rates of BCR were significantly greater in men with ECE on final pathology [p<0.001]. Gleason grade trended toward significance [p=0.058]. Controlling for potentially confounding preoperative variables on multivariate analysis, MRI suspicion score, ECE on MRI, and total prostate volume by MRI remained significantly associated with predicting BCR. Conclusions: MRI suspicion score, ECE on mpMRI, and total prostate volume were associated with BCR in patients undergoing RARP. Preoperative mpMRI characteristics aid in risk stratification, patient counseling, and modification of surgical technique in those with high risk imaging features for BCR. The integration of mpMRI characteristics into a comprehensive model of BCR may provide robust tools for preoperative staging and surgical planning.
Validation of the Decipher prostate cancer classifier in intermediate to high-risk men treated with radical prostatectomy but without additional therapy upon PSA rise.
Authors: Ross Ashley , Yousefi Kasra , Trock Bruce J. , Choeurng Voleak , Lam Lucia L.C. , Fedor Helen L. , Ghadessi Mercedeh , Buerki Christine , Glavaris Stephanie , Sundi Debasish , Tosoian Jeffrey , Han Misop , Humphreys Elizabeth B. , Partin Alan W. , Netto George J. , Davicioni Elai , Schaeffer Edward M.
Published: February 2017

173

Background: Radical prostatectomy (RP) is a primary treatment option for men with intermediate and high risk prostate cancer. Though many will be effectively cured with local therapy alone, these men are by definition at higher risk of adverse pathologic findings and clinical disease recurrence. The Decipher test has been previously shown to predict metastatic progression in cohorts that included adjuvant and salvage therapy after RP. Here we evaluate Decipher in a natural history cohort of at risk men who received no additional treatment until the time of metastatic progression. Methods: Men with NCCN intermediate or high risk localized prostate cancer treated with RP at the Johns Hopkins Medical Institute (1992-2010) with at least 5 years of post-operative follow up were identified. Only men with initial undetectable PSA after surgery and who received no therapy prior to metastasis detection were included (n=765). A case-cohort design was used to randomly sample the cohort. The highest Gleason grade cancer tissue was used for RNA extraction and Decipher genomic classifier (GC) scores were calculated with a locked 22-biomarker signature and algorithm. Results: GC results were obtained for 260 patients, 28% had positive margins, 77% had EPE, 28% had SVI, 20% had lymph node invasion and 36% had Gleason ≥8 disease. Median follow up was 9 (IQR 6-12) years and at 15 years post RP the cumulative incidence of BCR, metastasis and prostate cancer specific death was 38%, 21% and 9%. Median GC score was 0.34 (IQR: 0.22-0.52) and was significantly higher among men experiencing metastatic progression during follow up (0.47 vs 0.28 respectively p<0.001). In UVA and MVA (adjusting for clinical covariates), GC had an HR of 1.48 (95% CI: 1.30-1.69, p<0.001) and 1.37 (95% CI: 1.21-1.55, p<0.001) per 10% increase, respectively. Conclusions: The majority of the men in this study had excellent long-term outcomes with surgery alone. Elevated Decipher scores correlated with metastatic events, independent of clinical risk factors. Use of Decipher may allow for selection of candidates for immediate vs. delayed adjuvant or salvage therapy following prostatectomy.
Androgen receptor (AR) based biomarker association with response to abiraterone acetate/prednisone (AA/P) in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Kohli Manish , Wang Liguo , Sicotte Hugues , Qin Rui , Carlson Rachel , Eckel-Passow Jeanette , Tan Winston , Wu Kevin , Dehm Scott , Eiken Patrick W , Jimenez Rafael E. , Cernigliaro Joseph , Quevedo Fernando , Costello Brian Addis , Pitot Henry Clement , Moynihan Timothy J. , Ho Thai Huu , Dronca Roxana Stefania , Bryce Alan Haruo , Wang Liewei
Published: February 2017

174

Background: AA/P is an FDA approved treatment for mCRPC. Since markers of early resistance to AA/P are unknown, we report initial findings of androgen receptor (AR) based associations with short term (12 week) progression on AA/P. Methods: mCRPC stage patients (pts) initiating pre-chemotherapy AA/P underwent metastatic site biopsies at baseline (pre AA/P) and after 12 weeks. Baseline somatic whole exome DNA, tumor gene expression for AR full length (ARFL), AR splice variant 7 (ARV7) and ARV7/ARFL ratios were compared in progessors versus non-progressors. Progression at or within 12 weeks of AA/P therapy was defined as death or disease progression by PCWG2 “composite progression (CP)” and/or “radiographic progression” endpoints. Wilcoxon rank-sum tests were used to test for differences in the two groups for comparing ARFL, ARV7 expressions and ARV7/ARFL ratios and chi square tests were used for differences in copy number variation. Results: Between 1/2013 and 6/2014, 59 pts were enrolled of which 44 have disease assessment data at the12-week time point. CP was observed in 17/44 patients. DNA seq and clinical data was available for 42/44 pts. Using radiographic progression at 12 weeks, AR Amplification/Gain was observed in 20/26 non-progressors (13 with Amplification) and in 9/16 progressors (P-value = 0.19; OR 2.5). ARFL and ARV7 gene expressions in both groups is provided in table. Conclusions: A trend towards higher ARV7/ARFL gene expression ratio in metastases was observed with early progression on AA/P. AR gain/amplification is observed less often in pts with early progression. Validation of these findings is on-going in this prospective trial. Clinical trial information: NCT# 01953640. [Table: see text]
Cytoreductive radical prostatectomy in patients with prostate cancer and low-volume skeletal metastases: Results of a feasibility and case-control study.
Authors: Heidenreich Axel , Porres Daniel , Kuru T , Pfister David J. K. P.
Published: February 2017

176

Background: Androgen deprivation (ADT) represents the standard treatment for PCA with osseous metastases. We explored the role of cytoreductive radical prostatectomy in PCA with low volume skeletal metastases in terms of a feasibility study. Methods: 32 patients with biopsy proven PCA, minimal osseous metastases (≤ 3 hot spots on bone scan), absence of visceral or extensive lymph node metastases and PSA decrease to < 1.0 ng/ml after neoadjuvant ADT were included in the feasibility study. 38 men with metastatic PCA who were treated by ADT without local therapy served as control group (group B). Surgery-related complications, biochemical progression-free, symptomatic-free, cancer-specific and overall survival were analyzed using descriptive statistical analysis. Results: Mean age was 61 (42-69) and 64 (47-83) years in group A and B, respectively, with similar patient characteristics in terms of initial PSA, biopsy Gleason score, clinical stage, extent of metastatic disease. The mean follow-up was 40.6 (3-71) and 44 (24-96) months in group A and B, respectively. Pathohistology revealed vital PCA with metastatic potential in all 32 patients despite neoadjuvant ADT. 12% of pts in group A developed Clavien grade III complications. According to the ICSmaleSF questionnaire 30/32 (93.7%) pts were continent. Patients in group A experienced significantly better bPFS (36.8 versus 23.1 months, p=0.042), clinical PFS (38.6 versus 26.5 months, p=0.032) and cancer specific survival rate (95.6% versus 84.2%, p=0.043) whereas the overall survival was similar. 0% and 29% of men in group A and B, respectively, underwent palliative surgical procedures for locally progressing PCA. Conclusions: CRP is feasible with good functional and oncological results in well selected men with metastatic PCA who respond well to neoadjuvant ADT. These men have a long life expectancy and CRP reduces the risk of locally recurrent PCA and local complications. CRP might be a treatment option in the multimodality management of PCA with minimal osseous metastases.
Urokinase plasminogen activator receptor (uPAR) as a novel biomarker in prostate cancer.
Authors: Lippert Solvej , Berg Kasper Drimer , Iversen Peter , Høyer-Hansen Gunilla , Christensen Ib Jarle , Brasso Klaus , Røder M. Andreas
Published: February 2017

183

Background: New biomarkers are warranted to distinguish between indolent and aggressive prostate cancer (PCa). The urokinase plasminogen activator receptor (uPAR) plays an important role in pericellular proteolysis by binding urokinase plasminogen activator (uPA). This is required for degradation of the extracellular matrix and for cancer invasion. In addition to binding uPAR, uPA cleaves uPAR liberating uPAR(I) and uPAR(II-III). Intact, uPAR(I-III), and uPAR(II-III) can be liberated from the cell surface resulting in three different uPAR forms in circulation. The different uPAR forms are strong prognostic markers in several cancers. We measured the uPAR forms in plasma from patients with different stages of PCa. Methods: Between February 1, 2012 and October 1, 2014, 400 patients with PCa (se table) had plasma samples obtained. The levels of intact uPAR [uPAR(I-III)], intact uPAR + cleaved uPAR domains II+III [uPAR(I-III) + uPAR(II-III)], and cleaved uPAR domain I [uPAR(I)] were determined in citrated plasma samples with two-site sandwich time-resolved fluorescence immunoassays (TR-FIAs). Results: Plasma uPAR(I-III) + uPAR(II-III) and uPAR(I) were significantly higher in hormone naïve patients and CRPC patients compared to patients with localized disease (see table). Quantification of intact uPAR(I-III) revealed no significant differences between the three groups. Conclusions: Our findings suggest that uPAR(I-III) + uPAR(II-III) and uPAR(I) are associated with higher tumor stage as well as advanced PCa disease. These associations suggest that uPAR domains in plasma harbour prognostic value for PCa patients. Further studies are warranted to validate the use of uPAR forms as biomarkers for PCa. [Table: see text]
Epigenetic field effects: Potential applications for detection of occult high-grade prostate cancer.
Authors: Gaston Sandra Marlene , Grizzle William E. , Van Neste Leander , Bigley Joseph , Yen James , Adams George W , Kearney Gary P
Published: February 2017

20

Background: Needle biopsy (Bx) pathology is central to the diagnosis and management of prostate cancer (PCa), but Bx sampling error can result in an underestimate of Gleason grade (GS). Epigenetic DNA hypermethylation markers associated with PCa are commonly observed in histologically benign tissue adjacent to a cancer focus. Such field effects are the basis for a diagnostic test in which the absence of GSTP1, APC and RASSF1 hypermethylation in benign Bxs is associated with a low risk of “missed” PCa. Relatively low methylation thresholds are used for the current epigenetic test (ConfirmMDx) that is designed to be sensitive to any occult cancer, regardless of GS. We are evaluating new prototype epigenetic tests that are designed to be sensitive to the GS of an occult PCa. Methods: DNA was extracted from prostate bx tissue prints and used for quantitative methylation-specific PCR for GSTP1, APC and RASSF1. Results were computed as levels of marker methylation relative to a common reference gene. Each of 12 cores was tested from a series of 102 Bx patients: 20 diagnosed with no cancer (Group 1), 46 with GS 6 PCa (Group 2) and 36 with GS 7 PCa (Group 3). Results: For all 3 markers, we observed a positive correlation between the highest level of hypermethylation in the benign cores and in the same-patient cancer cores. This correlation was strongest for APC (P <0.0001). For GSTP1 and APC, hypermethylation intensity in the benign cores was also positively correlated with the overall GS. Interestingly, for each marker, the GS 6 cores from Group 3 (overall diagnosis GS 7) showed significantly higher levels of hypermethylation than the GS 6 cores from Group 2 (overall GS 6). The strongest correlation between the level of GS 6 core hypermethylation and overall GS was observed for GSTP1(P=0.0002). Conclusions: For GSTP1, APC and RASSF1, the intensity of field effect hypermethylation in benign Bx cores was positively correlated with the level of hypermethylation present in the cancer cores from the same patient. In GS 6 cancer cores, the intensity of hypermethylation is higher in subjects who also have cores of GS 7 than in subjects with GS 6 cores only. Both findings support the feasibility of an epigenetic test that is sensitive to the GS of an occult PCa.
Stage at presentation and survival outcomes of patients with Gleason 8 to 10 prostate cancer and low PSA.
Authors: Falchook Aaron David , Martin Neil E. , Chen Ronald C.
Published: February 2017

21

Background: Low prostate specific antigen (PSA) levels among men with Gleason 8-10 prostate cancer may be a result of cellular de-differentiation rather than low disease burden. We hypothesized that men with Gleason 8-10 prostate cancer and low PSA have increased risk for advanced disease and worse survival outcomes. Methods: Men diagnosed from 2004-2006 with Gleason 8-10 prostate adenocarcinoma in the Surveillance Epidemiology & End-Results (SEER) database were included. Patients were stratified by PSA at diagnosis: 0.1-3.9 ng/mL, 4.0-9.9 ng/mL, 10.0-19.9 ng/mL, and ≥ 20.0 ng/mL. Outcomes examined by PSA group included: clinical TNM stage, pathologic stage (for patients who received prostatectomy), and overall survival (for patients with N0 and M0 disease). Results: 18,491 patients were included. Men with PSA <4 were more likely than PSA 4-9.9 to present with clinical T3-4 disease (26 vs. 22%, p<.001), nodal (6 vs. 4%, p<.001) and distant (6 vs. 3%, p<.001) metastasis (Table). For patients who underwent radical prostatectomy, PSA <4 was more likely than PSA 4-9.9 to have pathologic nodal metastasis (10 vs. 7%, p<.001). With a median follow-up of 6 years, 6 year OS was 89.8% (PSA<4) vs. 92.3% (PSA 4-9.9) for prostatectomy patients (Logrank p=.02), and 73.6% vs. 79.3% for radiotherapy (p= 0.01). Conclusions: Patients with Gleason 8-10 cancer and PSA<4 have a more aggressive presentation and worse survival than those with PSA 4-9.9; these low PSA cancers behave more like those with PSA >10. Further study is needed to evaluate any biologic basis for inferior outcomes among men with high Gleason score and low PSA. [Table: see text]
Oligometastatic prostate cancer: An evaluation of stereotactic body radiotherapy (SBRT) as an alternative to palliative androgen deprivation therapy.
Authors: Henderson Daniel Robert , Tree Alison , Taylor Helen , Khoo Vincent , Van As Nicholas John
Published: February 2017

229

Background: Oligometastatic prostate cancer (OPC) can be defined as 1-3 sites of metastasis, typically occurring some years after radical treatment for primary disease. Standard treatment is long-term palliative androgen deprivation therapy (ADT). Although effective, this treatment can have a significant impact on quality of life. We hypothesized that ablative treatment with SBRT may delay disease progression, and therefore the need for palliative ADT. Methods: A single-institution case series 2011-present. Eligible patients had metachronous OPC diagnosed by F-choline PET/CT and were ADT-naïve in the palliative setting. Stereotactic body radiotherapy was given to a dose of 30 Gy in 3 fractions using a robotic radiosurgery system (Cyberknife). ADT-free survival was calculated as the time from completion of treatment for oligometastatic disease to initiation of ADT with palliative intent. Follow up with clinical review and PSA was undertaken at four weeks, then three monthly, with F-choline PET/CT restaging as indicated. Palliative ADT was initiated for metastatic disease not amenable to further SBRT. Results: Twenty one patients received SBRT for ADT-naïve OPC. Median time from primary treatment to oligometastatic relapse was 59.7 months. Median PSA doubling time was 4.1 months. Six patients received a short course (3-6 months) of ADT with SBRT. Sites treated: bone (8) and lymph node (20). At a median follow up of 16.7 months, 81% (17) remained ADT-free. Median ADT-free survival was 28 months (95% CI: 10 - 43 months). All but one patient had a PSA response, with a median reduction of 84%. There were no local failures. Incidence of grade 1 and 2 CTCAE toxicity was 29% (6) and 5% (1), respectively. No toxicity of grade 3 or above was observed. Conclusions: SBRT for OPC is well tolerated. A clinically significant delay in initiation of palliative ADT was observed in patients with ADT-naïve oligometastatic disease. In view of this potential to improve patients’ quality of life, randomised trials against a standard of care are justified.
The presence of intraductal carcinoma of the prostate in needle biopsy as a prognostic parameter for prostate cancer patients with distant metastasis.
Authors: Kato Masashi , Tsuzuki Toyonori , Kimura Kyosuke , Sassa Naoto , Yoshino Yasushi , Fukatsu Akitoshi , Kimura Tohru , Ishida Ryo , Gotoh Momokazu
Published: February 2017

237

Background: The presence of intraductal carcinoma of the prostate (IDC-P) is an adverse prognostic factor for prostate-specific antigen (PSA) failure, progression-free survival, and cancer-specific survival (CSS) in localized prostate cancer patients. However, there is no data indicating whether the presence of IDC-P can influence outcome in prostate cancer patients with distant metastasis at presentation. We aimed to evaluate whether IDC-P in needle biopsies is also an adverse prognostic parameter for CSS in prostate cancer patients with distant metastasis. Methods: We retrospectively evaluated 159 prostate cancer patients with distant metastasis who presented at the hospitals that the authors are affiliated with between 2002 and 2012 and reviewed the slides prepared from prostate needle biopsy specimens. Data on the patient age, performance status, clinical T stage, serum PSA, C-reactive protein, alkaline phosphatase (ALP), hemoglobin (Hb), albumin, serum calcium, biopsy Gleason score (> 8 or not), the presence of Gleason pattern 5, the percent of the core involved with cancer, and the maximum percent of a core involved with cancer were analyzed. Patient characteristics were analyzed using the Fisher's exact test. Multivariate Cox proportional hazard regression models were developed to predict CSS. Results: Patient median age was 73 years (range 47–90 years). The median serum PSA was 290 ng/mL (range 4.18–10,992 ng/mL). The median follow-up period was 36 months (range 3–120 months). IDC-P component was detected in 103 (64.8%) patients. There were 82 patients who died of the disease and 6 patients who died of other causes. Using univariate analysis, IDC-P (p = 0.0001), the presence of Gleason pattern 5 (p = 0.005), the percent of the core involved with cancer (p = 0.002), Hb (p = 0.001), and high ALP (p = 0.002) were all shown to be significantly associated with CSS. In the multivariate analysis, only IDC-P (p = 0.016; hazard ratio, 2.187) was significantly associated with CSS. Conclusions: The presence of IDC-P in needle biopsy is a prognostic parameter for CSS in patients with distant metastasis at presentation.
Sequential use of new agents (NAs) after docetaxel (DOC) first line in metastatic castration-resistant prostate cancer (mCRPC) patients (pts): A pooled-analysis of the published studies.
Authors: Maines Francesca , Caffo Orazio , Veccia Antonello , Bria Emilio
Published: February 2017

258

Background: NAs have recently demonstrated a survival advantage in mCRPC pts progressing after DOC: two hormonal NAs (HNA), abiraterone and enzalutamide, and one chemotherapeutic agent, cabazitaxel (CAB). Recent evidences of possible cross-resistance has opened a debate about the best strategy when these drugs are used sequentially. We performed a pooled analysis of the published studies in order to assess if one of the following sequence strategy was potentially better than the others: a) HNA→ HNA, b) HNA → CAB or c) CAB → HNA. Methods: We evaluated the studies reporting clinical outcomes of a single NA administered after sequential treatment with docetaxel followed by another NA in mCRPC pts. All studies reporting monthly overall survival (OS) rates were considered eligible for the analysis; data were extracted, cumulated and weighted by taking into account each trial sample. We also evaluated possible differences in terms of factors able to produce potential patient-selection biases (age, Performance Status, visceral metastases and Gleason score). Results: Ten retrospective studies met the selection criteria of our analysis. They reported the outcomes of 735 pts who have received HNA → HNA (320 pts), HNA→ CAB (249 pts), and CAB → HNA (166 pts). No statistically significant differences were observed in terms of selection factors. Cumulative OS rates (with CIs), according to treatment sequence, are summarized in the Table. Conclusions: Our data seems to confirm a potential cumulative survival benefit of sequential use of NAs without a clear superiority of a single strategy over the others after DOC first-line in mCRPC patients. This conclusion is tempered by the retrospective nature and the potential selection biases. Nevertheless, a possible OS advantage could be observed when a CAB-based sequence is adopted. [Table: see text]
Phase I trial of weekly cabazitaxel with concurrent intensity-modulated radiation therapy (IMRT) and androgen deprivation therapy (ADT) for the treatment of high-risk prostate cancer (PCa).
Authors: Lin Jianqing , Den Robert Benjamin , Showalter Timothy Norman , Hoffman-Censits Jean H. , McGuire Monica , Kennedy Brooke , Hurwitz Mark , Trabulsi Edouard John , Lallas Costas D. , Yang Hushan , Birbe Ruth C. , Chervoneva Inna , Dicker Adam , Kelly William Kevin
Published: February 2017

26

Background: Cabazitaxel (C) improves overall survival and has been approved in second line chemotherapy for patients (pts) with metastatic castrate resistant PCa. We hypothesized that C is a radiosensitizer and performed a phase I trial of weekly C with standard IMRT and ADT for pts with high risk localized PCa. Methods: Conventional “3 + 3” design. Pts with newly diagnosed high risk PCa defined as either Gleason score (GS) 8 – 10, or T3/T4 with GS 7, or PSA > 20 with GS 7 are eligible. Dose escalation occurred only after all the cohort pts completed weekly C ( 4 cohorts at the dose of 4, 6, 8 and 10 mg/m2) and the total planned dose IMRT. ADT was started two months prior to C and IMRT then continued on for a total of 24 months. Daily bicalutamide started within 1 day to 2 weeks prior to LHRH agonist therapy and stopped on the last day of IMRT for approximately 4 month duration. IMRT is delivered to a total dose of 75.6 Gy at 1.8 Gy daily fraction for 8.5 – 9 wks. The primary objective of this study was to determine the safe dose of the combination of weekly C with IMRT and ADT . Results: At present, 14 pts of mean age 62 yrs (range 53 – 82), T2 - T4; mean PSA 89 (range 4 – 253); and median GS 9 (GS 7 – 10) were enrolled and 10 pts completed the chemo-radiation therapy. Grade 3 dose-limiting toxicites in the first two pts at the 8 mg/m2 C dose level were diarrhea and elevated transaminase, thus the maximum tolerable dose (MTD) of C with IMRT was determined to be 6 mg/m2. An expansion cohort is ongoing. In this dose level, there were ≤ grade 2 toxicities only (diarrhea, hypophosphatemia and leukopenia). No long term toxicities are observed. Standardized measurement of health status and quality of life will be presented. Conclusions: Concurrent weekly C with current standard IMRT is feasible with no unexpected toxicity. In combination with IMRT and ADT, the MTD of weekly C is 6 mg/m2 in pts with newly diagnosed high risk PCa. Clinical trial information: NCT01420250.
In vivo assessment of the therapeutic effects of lyophilized leech saliva extract from (Huridinaria manillensis) on LNCaP tumor xenograft model in nude mice.
Authors: Ammar Amr , Hessein Mohamed , Guns Emma , Chin Mei , Helaluddin Abul Bashar , Abdualkader Abdulrahman , Alaama Mohamed , Merzouk Ahmed , Ghawi Abbas , Kucuk Omer
Published: February 2017

271

Background: Ancient traditional physicians from many countries used leeching to treat a wide range of diseases for thousands of years. A large number of peptides and proteins have been identified and characterized in leech saliva extract (LSE), including anti-thrombotic agents, cancer metastasis inhibitors and anti-microbials Currently, leech therapy is established as an important tool in microsurgery and reconstructive operations having demonstrated superior clinical outcomes for the optimal salvage of grafted tissues. Methods: In the current study, we have determined the in vivo efficacy of LSE from (Huridinaria manillensis) on castration resistant LNCaP xenograft mouse model. Mice were divided into three groups of six, mice were subcutaneously injected with either LSE (5 mg/kg), docetaxel (10 mg/kg), or vehicle once a week. PSA and tumor volume were measured weekly. After four weeks of treatment, mice were euthanized, tumors and organs were collected for transcriptome and immunohistochemical (IHC) analysis. Results: There was a significant decrease in the tumor volume and PSA with either docetaxel (10mg/kg) or LSE (5 mg/kg) treated groups compared to the control. While there was no significant difference between the anti-tumor activity of docetaxel (10mg/kg) and LSE (5 mg/kg). IHC showed significant increase in caspase-3 and significant decrease in Ki-67 and PCNA expression in the LSE treated mice compared to the control group. Interestingly, transcriptome analysis of tumor samples showed that LSE modulated cytokine production, monocyte adhesion, steroidogenesis, and P38 MAPK signaling pathways. Conclusions: LSE has significant anti-tumor activity in LNCaP tumor xenograft models with no apparent side effects. This can be attributed, at least partly, to its inhibition of cellular proliferation, induction of apoptosis, modulation of immunity and steroidogenesis.
Quantitative imaging by automated bone scan index (BSI) as a response biomarker in standard clinical care of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide.
Authors: Anand Aseem , Lindgren Belal Sarah , Reza Mariana , Edenbrandt Lars , Bjartell Anders
Published: February 2017

288

Background: Enzalutamide (ENZ), an androgen receptor antagonist therapy, was approved for patients (pts) with mCRPC. However, in standard of care for mCRPC pts, change in prostate specific antigen (PSA) is not accepted as an efficacy response measurement and the radiological change is inadequately measured in an interpreter-dependent subjective analysis of bone scan. Therefore, an objective efficacy response biomarker is warranted. In this registry study, we evaluated BSI as a quantitative analysis of bone scintigraphy, to access response in mCRPC pts being treated with ENZ. Methods: Pts with mCRPC, at Skåne University Hospital (SUH), Sweden, who initiated treatment with ENZ after failing chemotherapy were eligible for the study. Primary objective was to associate the change in BSI and PSA, after 12 weeks (wks) of treatment with EZN, with overall survival (OS). Automated BSI generated by EXINI boneBSI platform is quantitative representation of tumor burden as a percent of total skeletal mass. Bivariate cox regression analysis was used to evaluate the association of BSI and PSA with OS. Results: Thirty-five pts, who initiated ENZ treatment at (SUH), were eligible for the BSI analysis. Follow-up scans for the BSI analysis were available from 24 pts. Median baseline BSI value was 2.92 (range: 0.0 - 11.72) and at follow-up the median BSI value was 2.83 (range: 0.0 - 12.65). OS was associated with BSI at both baseline and at follow-up as opposed to that of PSA (table 1). The change in BSI between baseline and follow-up was also significantly associated with OS, whereas the change in PSA was not. Conclusions: Automated BSI and its relative change were observed to be associated with OS in mCRPC pts receiving ENZ as standard of care treatment. The result deserves further validation, in controlled investigational studies, of BSI as a quantitative imaging biomarker indicative of efficacy response to second-line treatment in mCRPC pts. [Table: see text]
Effect of AXIN2 expression on prostate cancer recurrence and an invasive, tumorigenic phenotype.
Authors: Hu Brian Robin , Fairey Adrian S , Madhav Anisha , Yang Dongyun , Li Meng , Groshen Susan G. , Stephens Craig , Kim Philip , Virk Navneet , Wang Lina , Martin Sue Ellen , Erho Nicholas , Davicioni Elai , Jenkins Robert B. , Den Robert Benjamin , Xu Tong , Xu Yucheng , Gill Inderbir S , Quinn David I. , Goldkorn Amir
Published: February 2017

29

Background: Better biomarkers are needed in prostate cancer (PCa) to predict disease recurrence and guide optimal therapy. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor cancer phenotype impact PCa biology and clinical outcomes in localized disease. Methods: Genes associated with self-renewal, drug resistance, and tumorigenicity were analyzed by qRT-PCR on PCa mRNA from radical prostatectomy (RP) specimens (+/- disease recurrence). Wilcoxon rank sum two-sample test, multivariable recursive partitioning, and bootstrap internal validation measured and confirmed associations with recurrence. Further validation was conducted in external cohorts and in-silico, as well as in vitro and in vivo using siRNA knockdown and lentiviral overexpression to determined the effect of gene expression on PCa proliferation, invasion and tumor growth. Results: Four candidate genes were differentially expressed in PCa recurrence, and of these, low AXIN2 expression was internally validated. Validation in external cohorts demonstrated low AXIN2 expression was associated with more aggressive prostate cancer and was independently associated with biochemical recurrence (BCR) and metastasis-free survival (MFS) after RP. In vitro, low AXIN2 expression was associated with a cancer stem-like cell-surface signature, and siRNA knockdown of AXIN2 resulted in significantly greater invasiveness. Conversely, ectopic overexpression of AXIN2 significantly reduced cell proliferation and tumor growth in mice. Conclusions: Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts. AXIN2 expression levels in PCa cells significantly impacted invasiveness, proliferation and tumor growth. AXIN2 represents a putative biomarker and potential therapeutic target in early prostate cancer.
Genomic landscape of high-grade T1 micropapillary bladder tumors.
Authors: Bellmunt Joaquim , Guo Guangwu , Mullane Stephanie A. , Orsola Anna , Werner Lillian , Van Hummelen Paul , Thorner Aaron , Loda Massimo , Choueiri Toni K. , Barletta Justine A. , Kwiatkowski David J. , Meyerson Matthew , Van Allen Eliezer Mendel
Published: February 2017

299

Background: The genomic landscape of high-grade T1 micropapillary bladder tumors (HGT1micropap) is unknown. Clinically, micropapillary bladder cancer is an aggressive and possibly lethal disease. Our main objective was to assess the genomic landscape of HGT1micropap through identifying mutations, insertions/deletions (indels), translocations, and copy number variations (CNVs). Methods: We prospectively identified nine HGT1micropap with 45.4 months of median follow up. Patients were treated in a uniform manner using TUR, BCG, and appropriate follow up. We performed whole exome sequencing using Ilumina Exome _v5 plus translocation. Mutations and indels were called using the Firehose pipeline. CNVs were called using ExomeCNV. We examined the mutational landscape and compared the genomic alterations to TCGA (>T2, n=131)2 and publicly available data on non-muscle invasive bladder tumors (Ta/T1, n=37)1. Results: Within the HGT1micropap, mutations on TP53, KMT2D, TSC1, and ATM were suggested to occur more frequently compared to the NMIBC control group1. FGFR3 was seen at the expected frequency for NMIBC. The mutations of interest are presented in Table 1 with the percentage seen in the other cohorts. Of interest, TSC1 was seen in higher frequency in micropapillary than in the NMIBC or the TCGA cohort2. We did not see any patterns between CNVs and mutations. We also saw two patients with severe chromothripsis. 3 patients had loss of chromosome 9 or 9q without any other severe chromosome alterations. CNV alterations will be presented and compared to MIBC. Conclusions: In this preliminary analysis, our HGT1micropap, showed a mutational landscape more similar to MIBC compared to NMIBC bladder landscape. We did not find any clear driver of the micropapillary histology at the exome level in this limited sample of patient, which may indicate that tumor heterogeneity or epigentic changes may be driving this aggressive phenotype. [Table: see text]
Clonality of bladder tumors following radical nephroureterectomy: Against the field defect hypothesis.
Authors: Cha Eugene K. , Sfakianos John , Scott Sasinya N. , Murugan Paari , Iyer Gopa , Bagrodia Aditya , Shah Ronak , Bajorin Dean F. , Rosenberg Jonathan E. , Berger Michael F. , Al-Ahmadie Hikmat , Bochner Bernard H. , Coleman Jonathan A. , Solit David B.
Published: February 2017

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Background: Urothelial carcinoma is characterized by multifocal and metachronous tumors. To explain this phenomenon, two hypotheses have been proposed: the ‘field defect’ hypothesis - urothelial cells are primed to undergo transformation by exposure to carcinogens, and the clonal, or ‘single progenitor cell,’ hypothesis - tumors arise from intraluminal seeding of transformed cells. Methods: To examine their clonal relationships, we compared the genomic profiles of primary upper tract urothelial carcinoma (UTUC) tumors and metachronous bladder tumors (intravesical recurrences) in patients treated with radical nephroureterectomy (RNU) and subsequent transurethral resection. Specimens were analyzed using a next-generation, targeted sequencing assay designed to identify point mutations, indels, and copy number alterations in 341 cancer-associated genes. Results: We analyzed 16 primary UTUC tumors and 41 intravesical recurrences in patients treated with RNU. The median number of intravesical recurrences per patient was 2 (range 1-7) and the interval from RNU to intravesical recurrence ranged from 3.5 months to 129 months. With an average sequencing coverage of 516x, we found strong evidence delineating the clonal relationship between primary UTUC tumors and subsequent bladder tumors. The majority of somatic mutations present in the primary UTUC tumors (median=7, range 4-39) were detected in all subsequent bladder tumors (128/146, 88%). In an illustrative case, one patient followed with periodic cystoscopy/cytology who had been NED for 5.5 years then developed 7 bladder tumors over the next 44 months, each with the identical mutation profile (8 mutations) as the primary tumor. Conclusions: We demonstrate that bladder tumors following RNU represent true intravesical recurrences, with almost all tumors sharing the same somatic mutation profile as the primary UTUC tumor. This has important implications for surgical techniques to minimize the risk of intraluminal seeding, the delivery of intravesical therapy following RNU, and the development of strategies employing systemic chemotherapy or targeted agents.
Urinary EGFR as a marker of urinary bladder cancer.
Authors: Regan Hannah Louise , Ward Douglas G , Bryan Richard T
Published: February 2017

327

Background: Better biomarkers must be found to develop clinically useful urine tests for urothelial bladder cancer (UBC). Our objective was to identify proteins released by bladder cancer cells in vitro and assess their potential as urinary biomarkers. EGFR was identified as a promising biomarker and is overexpressed in numerous cancers including UBC. EGFR is a member of the ErbB family of transmembrane tyrosine kinase receptors. It is a 170kDa protein that facilitates cell growth and differentiation by acting upon downstream signaling pathways. Methods: We used shotgun proteomics to identify the proteins released into culture media by 8 UBC cell lines. These data were compared with protein expression data from the Human Protein Atlas. EGFR was measured by ELISA in the urine of 436 patients with primary bladder cancer (prior to commencing treatment) and 60 non-UBC control subjects (all samples were obtained from the Bladder Cancer Prognosis Programme). Outcomes were, presence of bladder cancer (yes/no) and bladder cancer-specific survival. Data were analysed with Mann-Whitney tests and Cox multivariable modelling. Results: EGFR was selected as a candidate biomarker because it was released by 5 out of 8 bladder cancer cell lines, but not by a ‘normal urothelium’ cell line, and is documented as highly overexpressed in UBC in the Human Protein Atlas. A soluble form of EGFR is detectable in urine and is increased in some patients with high-grade bladder cancer. With a cut-off defined as mean + 2 SD (630pg EGFR/mg creatinine), elevated urinary EGFR was an independent indicator of poor bladder cancer-specific survival with a hazard ratio of 2.89 (95% CI 1.81-4.62, p<0.001). In multivariable models urinary EGFR and EpCAM (previously reported) are strong independent predictors of bladder cancer-specific survival. Urinary EGFR is not useful as a diagnostic marker. Conclusions: Aggressive bladder cancers shed the ectodomain of EGFR into urine. Measuring urinary EGFR and EpCAM may represent a simple and useful approach for fast-tracking the investigation and treatment of those patients with the most aggressive bladder cancers, expediting their care to improve outcomes.
Who should be performed perioperative chemotherapy in upper-tract urothelial cancer? Risk classification for selecting candidate using preoperative factors.
Authors: Nagao Kazuhiro , Inoue Ryo , Inamoto Teruo , Takahara Kiyoshi , Matsumoto Hiroaki , Yamamoto Yoshiaki , Kobayashi Keita , Sakano Shigeru , Azuma Haruhito , Matsuyama Hideyasu ,   Yamaguchi Uro-Oncology Group
Published: February 2017

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Background: The patients with advanced upper tract urothelial carcinoma (UTUC) have poor prognosis. Previous reports have not shown that neoadjuvant chemotherapy for UTUC improves patient survival and it is difficult to select appropriate candidates for neoadjuvant chemotherapy. We aimed to predict appropriate candidates for neoadjuvant chemotherapy. Methods: We reviewed the data of 536 patients with UTUC undergone total nephroureterctomy in the cohort of Yamaguchi Uro-Oncology Group (Group 1) and 150 cases in the cohort of Osaka Medical College (Group 2). We performed a multivariate analysis to the Group 1 to decide independent predictive factors and validated them in another cohort (Group 2). We evaluated the clinical significance of the predictive factors in cancer-specific survival (CSS) and overall survival (OS) between the cohort with and without perioperataive chemotherapy. Results: Multivariate analysis showed ≥cT3, cN+ and elevated CRP (≥0.31mg/dl) could become independent prognostic factors in Group 1, which showed 0.70 of AUC in predicting cancer death. We validated these factors in Group 2 and confirmed that they also showed 0.78 of AUC in predicting cancer death. Then, we divided the patients into 4 risk groups based on the number of the predictive factors: score 0 (202 cases), score 1 (152 cases), scores 2 (51 cases) and scores 3 (30 cases). Kaplan-Meier Curve showed that 5 year CSS in score 0, 1, 2, and 3 were 84.7%, 67.7%, 32.2% and 22.0%, respectively. Finally, we analyzed the difference in CSS and OS between the 138 cases with and 296 cases without perioperative chemotherapy. A significant difference in CSS and OS between the cases with and without perioperative chemotherapy was shown only in the cases with all the predictive factors: score 3. Additionally, fraction of patients with lymphovascular invasion of the surgical specimen were significantly increased with score advance. Conclusions: Survival in the patients with UTUC was predictable by preoperative factors. The patients with all the predictive factors, ≥cT3, cN+ and elevated CRP, were supposed to be the best candidates for neoadjuvant chemotherapy against UTUC.
Weekly paclitaxel versus ADT alone in localized high-risk prostate cancer: Results of a single-institution phase II trial.
Authors: Saldana Carolina , Salomon Laurent , Rousseau Benoit , Chaubet-Houdu Marie , Joly Charlotte , Ploussard Guillaume , Allory Yves , Tournigand Christophe , de la Taille Alexandre
Published: February 2017

37

Background: Adjuvant chemotherapy’s role after radical prostatectomy (RP) remains controversial in localized high-risk prostate cancer (HRPC). This phase II trial assessed the combination of weekly paclitaxel (WP) with androgen deprivation therapy (ADT) in this population. Methods: All eligible patients (pts) had undergone a laparoscopic RP with pelvic lymph node dissection for a localized HRPC defined with ≥1 of the following criteria: T3b-T4 post-operated Gleason score (GS) ≥8, PSA≥ 20 ng/mL, pN+, in Henri Mondor Hospital. Pts were randomly assigned to either triptoreline 11.25mg every 3 months during 3 years and 8 cycles of WP 100 mg/ m2 (WP arm, n=21) or triptoreline alone (ADT arm, n=26). The primary endpoint is disease free survival (DFS); events=PSA relapse, clinical and radiographic relapse, death. The planned number of pts was 152. Toxicity results indicated a good tolerability with neutropenic fever in 4.3% (n=1), and no negative impact on QoL in the WP arm (Ploussard, Prostate Cancer Prostatic Dis. 2010). Here we report 8-year DFS and overall survival (OS) results. Results: Between February 2005 and October 2007, 47 pts were enrolled. This trial was terminated prematurely because of slow accrual. After a mean follow-up of 8.4 y, we identified a PSA relapse in 25 pts (53%) and castrate-resistant prostate cancer occurred in 6 pts. No statistically difference was found in terms of either biochemical or clinical DFS (bDFS, cDFS) and OS: 8-year bDFS rate: 50% [n=11/22] in the WP arm vs 46% [n=12/26] in the ADT arm (p=0.79); 8-year cDFS rate: 95.4% [n=21/22] in the WP arm vs 88.5% [n=23/26] in the ADT arm (p=0.38). The 8-year OS rate is 90.9% (n=20/22) and 84.6% (n=22/26) respectively with no difference between treatment arms (p=0.51). No clinical, histological or biological variable demonstrated a difference in either 8-year bDFS, cDFS or OS rate. Conclusions: Provided that this trial is probably underpowered to detect a DFS benefit, adjuvant weekly paclitaxel after RP was not associated with any significant reduction in the risk of biological relapse or death compared to ADT alone in patients with localized HRPC. Chemotherapy should be only proposed in dedicated clinical trial for localized HRPC.
Dacomitinib (PF-0299804) in untreated patients (pts) with advanced or metastatic penile squamous cell carcinoma (PSCC): Early findings of an open-label, single-group, phase II trial (HER-Uro01).
Authors: Necchi Andrea , Giannatempo Patrizia , Raggi Daniele , Nicolai Nicola , Torelli Tullio , Catanzaro Mario , Piva Luigi , Biasoni Davide , Stagni Silvia , Colecchia Maurizio , Calareso Giuseppina , Togliardi Elena , Marchiano' Alfonso , Crippa Flavio , Salvioni Roberto
Published: February 2017

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Background: Prognosis of pts with advanced/metastatic PSCC is poor and chemotherapy exerts a low efficacy. PSCC is consistently depending on the epidermal growth-factor receptor (EGFR) pathway and early signals of activity of anti-EGFR targeting have been reported. Dacomitinib is a potent, irreversible TKI of human EGFR/HER1, HER2 and HER4. The primary objective of the trial will be to investigate the activity of PF-0299804 until surgical removal of nodal disease (locally-advanced setting) or until disease progression/onset of unacceptable toxicity (metastatic setting) (ClinicalTrials.gov NCT01728233). Methods: 37 pts with clinical N2-3or metastatic disease will receive oral dacomitinib 45 mg daily. Further eligibility requirements are ECOG-PS≤1, locoregional relapse after prior surgery, and no prior systemic therapy. Computed tomography (CT) and PET scans are scheduled at baseline and every 2 months. Simon’s Optimal 2-stage design is applied. The primary endpoint is the response-rate (CR/PR according to RECIST v1.1, H1:20%, H0: 5%). In stage 1, 12 evaluable patients will be accrued. Results: From 06/13 to 07/14, 9 pts were enrolled. Median age was 55 yrs (IQR: 54-72). 4 had received inguinal/pelvic lymphadenectomy, 4 had inguinal+pelvic nodes, 7 bilateral disease, and 2 distant mets. One patient achieved a PR, 6 a SD, 2 PD. 5 pts had a metabolic PR. After a median follow-up of 5 months, 4 pts (44.4%) are still progression-free (2-month PFS was 77.8%, 95%CI: 36.5-93.9). Skin toxicity was observed in 5 cases (4 G1, 1 G3), G2 diarrhea in two, and bleeding of cutaneous mets in one case. Conclusions: The minimum requirements to move to the second stage and full accrual have been met. Dacomitinib is showing activity in patients with PSCC. Further understanding of drug activity will come from the body of translational imaging and molecular characterization of tumors from enrolled patients. Clinical trial information: NCT01728233.