bluuebunny/crossref_metadata_2025 huggingface dataset:
Japanese cohort study of first-line chemotherapy (CT) for metastatic colorectal cancer (mCRC) containing fluorouracil, oxaliplatin, and bevacizumab: EMERaLD study, first report.
Authors: Taku Keisei , Ohata Kou , Amano Toraji , Ohashi Yasuo , Yamazaki Kentaro , Watanabe Masaya , Satou Shinsuke , Ooshima Takeshi , Nishikawa Go , Hirano Hidekazu
Published: February 2017

586

Background: An observational cohort study plays a crucial role to understand the current status of clinical practice and can be utilized as database for multi-purpose outcome research. Such database is available in Europe and the United States based on several cohort studies especially in mCRC, while there is no database available including treatments for mCRC patients in Japan. Methods: We planned and conducted a large cohort study to establish database available including treatments for mCRC patients. Major enrollment criteria included documented mCRC and first line CT containing fluorouracil, oxaliplatin and bevacizumab, started treatment in or after January 2010. The primary objectives are to evaluate overall survival(OS), liver metastasectomy rate (LMR), R0 liver resection rate (R0). The secondary objectives are progression-free survival, response rate (RR), and safety. We performed a preplanned interim analysis of 6-month efficacy and safety data after the 500th patient registration. Results: From October 2010 to September 2011, data from 1,353 patients were recruited from 132 centers in Japan, and we analyzed data on 538 patients of them. The background of 538 patients were as the following; male/female, 335/203; median age of 65 (range, 27-85); ECOG PS 0/1/2/3, 453/77/6/2; site of primary tumor colon/rectum/colorectal, 299/238/1; and site of metastatic disease liver/lung/others, 352/162/226; FOLFOX/ CapeOx/ others with bevacizumab, 234/290/14, KRAS-status wild/mutant/unknown, 131/88/319. 6-month efficacy and safety data were OS 97.5%, LMR 15.1%, R0 12.5%, RR 48.3%, G3/4(CTC-AEv4.0) related to bevacizumab; hypertension 1.5%, proteinuria 0.2%, thromboembolism 0.6%, bleeding 1.0%, and gastrointestinal perforation 1.3%. Conclusions: We have started the large Japanese cohort study which investigates first line CT for mCRC. We performed a preplanned interim analysis on 538 patients and there was no difference from past reports. We will further investigate and analyze 2-year efficacy and safety data on all 1,353 patients. This study is sponsored by the Public Health Research Center Foundation CSPOR in Japan. Clinical trial information: UMIN000006392.
Predictors of second- and third-line chemotherapy receipt in stage IV colon cancer Medicare beneficiaries.
Authors: Reese Emily S , Onukwugha Ebere , Hanna Nader , Seal Brian S. , Mullins C. Daniel
Published: February 2017

588

Background: The prognosis for elderly patients with metastatic colon cancer (mCC) is poor with 5-year survival rate of 6 %. There is limited evidence to explain why some elderly mCC patients progress through multiple lines of treatment and others with similar clinical characteristics do not. This study examines the predictors of second- and third-line chemotherapy receipts in Medicare beneficiaries with mCC who initiate treatment. Methods: Using the SEER-Medicare dataset, elderly beneficiaries diagnosed with mCC from 2003-2007, were followed until death or censoring in 2009. Treatment lines were classified in combinations of chemotherapy and biologics. Logistic regression was used to predict receipt of treatment and subsequent treatment. Results: Among 3,266 beneficiaries diagnosed with mCC and initiated therapy, 1,440 progressed to 2nd line treatment and 274 progressed to 3rd line treatment. The strongest predictors of progressing to 2nd line treatment was surgery of the primary tumor site (OR: 2.42, 95% CI: 2.17-2.70) and regional/distal sites (OR: 1.32, 95% CI: 1.14-1.53) and marital status (OR: 1.64, 95% CI: 1.47-1.83). Older beneficiaries (80-84 years (OR: 0.31, 95% CI: 0.26-0.37) and > 85 years (OR: 0.10, 95%CI: 0.08-0.12)) and those with poor performance status indicators (walk aid (OR: 0.46, 95% CI: 0.26-0.82), wheelchair use (OR: 0.43, 95% CI: 0.29-0.64), and use of oxygen (OR: 0.54, 95% CI: 0.41-0.69)) were less likely to proceed to 2nd line treatment. Older age was the biggest predictor of not proceeding to third-line treatment (80-84 years (OR: 0.42, 95% CI: 0.28-0.61) & > 85 years (OR: 0.10, 95%CI: 0.05-0.19)). No variables were statistically significant in predicting receipt of third-line chemotherapy. Conclusions: Surgery of the primary tumor site and of regional/distal sites were the most significant clinical variables predicting whether or not elderly patients proceed to second-line chemotherapy. Sociodemographic variables also predicted receipt of second-line chemotherapy.
Gleason upgrading with time in a large, active surveillance cohort with long-term follow-up.
Authors: Jain Suneil , Vesprini Danny , Mamedov Alexandre , Loblaw D. Andrew , Klotz Laurence
Published: February 2017

1

Background: Active surveillance (AS) is an accepted management strategy for localized prostate cancer. However, the rate of pathological upgrading has not been well described in mature study cohorts. Furthermore, concern exists over the possibility of prostate cancer dedifferentiation with time in patients on AS. Methods: Patients in our prospectively collected AS database with at least one repeat prostate biopsy were included. Linear regression analysis was used to estimate the proportion of patients upgraded (Gleason 6 to 3+4 or higher, Gleason 3+4 to 4+3 or higher) with time from diagnostic biopsy. Results: 593 of 862 patients in our cohort had at least one repeat biopsy. Median follow-up was 6.4 years (max. 20.2 years). The total number of biopsies ranged from 2 to 6. 20% of patients were intermediate risk, 0.3 % high risk, all others low risk. 31.2% of patients were upgraded during active surveillance. The proportion of patients upgraded increased with time, suggesting prostate cancer dedifferentiation occurred at a rate of 1.0%/year (95%CI -0.12 to 2.16%/year). The estimated rate of increase was 2.5 times higher in patients with intermediate risk disease at diagnosis (rate 1.9%/year, 95%CI -0.7-4.6) compared with those with low risk disease (rate 0.75%/year, 95%CI -0.5-2.0). Further analysis is underway. 62% of upgraded patients (n=114) went on to have active treatment. Patients who were upgraded and treated had significantly greater PSA velocities (median 1.2 ng/ml/y vs 0.42 ng/ml/y, p=0.01) and significantly higher Gleason scores when upgraded, than those who remained on surveillance (21.8% vs 2.8% Gleason 8-10, p<0.01). Conclusions: This is the largest re-biopsy cohort, with long-term follow-up, described to date, enabling the first estimates of prostate cancer dedifferentiation in patients on AS. Dedifferentiation rates appear higher in patients with intermediate risk prostate cancer compared with those who are low risk at baseline.
Aldo-keto reductase (AKR) 1C3 as an androgen receptor coactivator.
Authors: Narayanan Ramesh , Yepuru Muralimohan , Wu Zhongzhi , Barrett Christina , Kim Juhyun , Penning Trevor M. , Steiner Mitchell S. , Miller Duane D. , Dalton James T.
Published: February 2017

100

Background: Castration resistant prostate cancer (CRPC) may occur by several mechanisms including up-regulation of the androgen receptor (AR), coactivators, and steroidogenic enzymes, including AKR1C3. AKR1C3 (type 5 17b-hydroxysteroid dehydrogenase) converts weaker 17-keto androgenic precursors to more potent 17-hydroxy androgens and is consistently a major up-regulated gene in CRPC. The objective is to examine the role of AKR1C3 in AR function and CRPC. Methods: AR transactivation studies were performed with GRE-LUC in the presence or absence of AKR1C3 in HEK-293 cells. Gene expression patterns and prostate cancer cell and tumor growth were evaluated in LNCaP and VCaP cells. Molecular studies, including co-immunoprecipitation, chromatin immunoprecipitation and others, were performed to determine AKR1C3 localization and interaction with the AR. Novel small molecule AKR1C3 selective-inhibitors were synthesized and characterized in prostate cancer models. Results: We identified unique AR selective coactivator- and prostate cancer growth-promoting-roles for AKR1C3. AKR1C3 over-expression promotes the growth of both androgen-dependent prostate cancer and CRPC xenografts, with concomitant reactivation of androgen signaling. AKR1C3 interacted with AR in prostate cancer cells and in a human CRPC sample and was recruited to the promoter of an androgen responsive gene, PSA. The coactivator and growth promoting functions of AKR1C3 were inhibited by an AKR1C3-selective competitive inhibitor. Conclusions: AKR1C3 is a novel AR selective coactivator and may represent the first nuclear hormone receptor coactivator that can be pharmacologically targeted.
A randomized phase II, open-label study of sipuleucel-T with concurrent or sequential abiraterone acetate (AA) in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Small Eric Jay , Lance Raymond , Gardner Thomas A. , Karsh Lawrence Ivan , Stubbs Andrew , McCoy Candice , DeVries Todd , Redfern Charles H. , Shore Neal D.
Published: February 2017

114

Background: Sipuleucel-T and AA are both FDA approved for mCRPC. Given that androgen deprivation therapy is immunostimulatory, increased suppression of the androgen axis with AA could provide synergy in combination with sipuleucel-T; however, AA is given with prednisone (P), which may be immunosuppressive. In order to evaluate the impact of concurrent AA + P on product characteristics, a study of sipuleucel-T with concurrent or sequential AA + P was undertaken. Methods: Pts aged ≥18 yrs with asymptomatic or minimally symptomatic mCRPC, and ECOG PS 0/1 were randomized (1:1) to sipuleucel-T (3 infusions at approx 2-week intervals) with up to 26 weeks of AA + P (AA 1000mg QD + P 5mg BID) starting 1 day after the first sipuleucel-T infusion (concurrent arm) or at week 10 (sequential arm). The primary endpoint was cumulative CD54 upregulation (measure of antigen presenting cell activation); secondary and tertiary endpoints included CD54+cell and total nucleated cell (TNC) counts (measures of product potency), safety and efficacy. Results: 29 pts have been enrolled. 16 pts in the concurrent arm (A) and 13 pts in the sequential arm (B) have completed sipuleucel-T treatment at the time of this interim analysis (7 Sept 2012). 27/29 pts received all 3 infusions of sipuleucel-T; 2 pts (both arm A) received only 1 infusion due to insufficient TNC count (n=1) and disease progression 8 days after randomization (n=1). No significant differences in median cumulative CD54 upregulation (31.6 vs 36.6) and CD54+ count (1.9 vs 2.1 x109) were observed between arms A and B, respectively. Increased CD54 upregulation with the 2nd and 3rd treatments were indicative of a prime boost effect in both arms. Similarly, the TNC profile over time was similar for both arms. The overall incidence of adverse events (AEs) was similar in arms A (81%) and B (77%). Common all-grade AEs included muscle spasms (31% vs 23%), oral paresthesia (19% vs 31%), chills (31% vs 8%) and cough (19% vs 15%). Conclusions: These data suggest that sipuleucel-T can be manufactured during treatment with AA + P with product potency and prime boost similar to that of sipuleucel-T alone. Clinical trial information: NCT01487863.
Identification of men with a genetic predisposition to prostate cancer: Targeted screening in men at higher genetic risk and controls—The IMPACT study.
Authors: Eeles Ros A. , Bancroft Elizabeth , Page Elizabeth , Castro Elena , Taylor Natalie
Published: February 2017

12

Background: IMPACT is a multi-national targeted prostate cancer screening study of men with a known germline mutation which is thought to predispose to the disease. The study is recruiting male BRCA1/2 mutation carriers and a control group, who have tested negative for a mutation present in their family, from 52 centres in 17 countries. Methods: Eligible men aged 40-69 years are offered annual serum PSA testing for at least five years. The PSA threshold used to determine prostate biopsy is >3ng/ml. All men are offered a biopsy irrespective of PSA level after 5 years of screening. Men are also invited to take part in a Quality of Life sub-study. Results: To date 1819/ 1850 men have been recruited (593 BRCA1, 580 BRCA2, 638 Controls). 213 presented with a PSA ≥3ng/ml and 159 biopsies have been performed (54 men have either declined the biopsy or are awaiting results) and 60 men have been diagnosed with prostate cancer (31 BRCA2 carriers, 16 BRCA1 carriers and 13 controls). 45% of cases diagnosed in BRCA1/2 carriers were Gleason score ≥7. The estimated positive predictive value (PPV) for PSA screening in Controls was 28%, similar to that in the general population, whilst it was 36% for BRCA1 and 46% for BRCA2. Conclusions: Our preliminary results show that annual PSA screening using a cut-off of 3.0ng/ml detects aggressive prostate cancer in BRCA carriers. Early data indicate that a larger proportion of gene carriers have developed clinically significant prostate cancers (those that would need radical treatment on UK treatment guidelines) compared with the control group. The higher risk of PrCa observed in BRCA1 and BRCA2 carriers will need to be confirmed with further data Acknowledgements: The IMPACT study collaborators and participants, The Ronald and Rita McAulay Foundation, Cancer Research UK, NIHR. Clinical trial information: NCT00261456.
Phase II trial of 177lutetium radiolabeled anti-PSMA antibody J591 (177Lu-J591) for metastatic castrate-resistant prostate cancer (metCRPC): Survival update and expansion cohort with biomarkers.
Authors: Tagawa Scott T. , Akhtar Naveed Hassan , Osborne Joseph , Christos Paul J. , Vallabhajosula Shankar , Goldsmith Stanley J. , Kahn Renee , Ecker Caryn , Beltran Himisha , Morris Michael J. , Milowsky Matthew I. , Bander Neil Harrison , Nanus David M.
Published: February 2017

121

Background: A phase II trial in men with progressive metCRPC receiving a single dose of 177Lu-J591 at 65 mCi/m2 (15 pts) or 70 mCi/m2 (phase I MTD, 17 pts) was performed without selection for PSMA expression, suggesting a larger than expected dose-response (13 vs 47% >30% PSA decline respectively), leading to an expansion cohort to validate the response rate at 70 mCi/m2. Methods: Endpoints: to validate the PSA and/or measurable disease response at 70 mCi/m2, evaluate circulating tumor cell counts (CellSearch) and pre-treatment PSMA imaging with 111In-J591 in the expansion cohort, and examine overall survival (OS) for all pts. Results: 15 additional pts were treated. Expansion cohort demographics were similar to the initial cohorts, and PSA responses and toxicity were similar to the initial cohort treated at 70 mCi/m2 (see Table), with myelotoxicity improving in all following nadir at 1 month. More PSA declines and longer OS were seen at 70 mCi/m2. 12 of 15 pts had baseline and follow up CTC counts at 4-6 weeks: 66.7% had >50% decline and 25% were unchanged at 0 or 1 (one declined 27%). Although 93.3% had accurate targeting (imaging) of known sites of disease, as seen in initial analysis, a trend for fewer > 30% PSA declines was seen with less intense PSMA imaging. Conclusions: Single dose 177Lu-J591 at70 mCi/m2 was generally well tolerated, with predictable, reversible myelosuppression, and demonstrates anti-tumor activity in pts with progressive metCRPC. A dose-response relationship was confirmed for both toxicity and activity, with improved response and OS at 70 mCi/m2. CTC declines are demonstrated. Selection of pts based upon non-invasive testing (PSMA imaging) may improve the therapeutic profile. Clinical trial information: NCT00195039. [Table: see text]
Stratification of risk for patients with prostate cancer at biopsy using CCP score.
Authors: Shore Neal D. , Abbott Brian , Concepcion Raoul S. , Saltzstein Daniel , Kaldate Rajesh R. , Moyes Kelsey , van Breda Arletta , Clark Christopher , Saam Jennifer , Brawer Michael K.
Published: February 2017

127

Background: In the US, most prostate cancers are treated with surgery or radiation, despite many having low malignant potential. If low cancer progression risk can be established, some men can be spared treatment. PSA, Gleason score and clinical stage work well for population risk assessment but lack precision for individuals. Molecular analysis can refine risk assessment as demonstrated by a cell cycle progression score (CCP) predictive of prostate cancer aggressiveness in 4 separate cohorts. In these studies, CCP typically ranged from −2 to +3 with each 1−unit increase corresponding to approximately a doubling of risk. We characterized the CCP distribution using recent samples from a typical US urology multi−centered clinical setting and determined the analytic success rate of the assay. Methods: Formalin fixed, prostate biopsy tissue from 300 patients diagnosed with adenocarcinoma within the last 12 months was analyzed. CCP is calculated by measuring the relative RNA expression of 31 cell cycle progression genes. Patients were recruited from 15 geographically diverse community urology practices. Results: CCP could be measured for 98% of samples (294/300). This study showed a normal distribution for the CCP ranging from −2 to 3.2 (median = −0.3, SD=0.92). There was little correlation of CCP with PSA, age, or body mass index. Correlation with Gleason score was similar to those in prior studies (r=0.494). A relative classification of cancer aggressiveness based on CCP of ~ 1200 patients from multiple cohorts has been developed. The 294 evaluable patients were cross−classified by AUA risk and cancer aggressiveness (see table). CCP further stratified patients within each AUA risk classification. Conclusions: CCP is a novel assay that can facilitate risk stratification for men with prostate adenocarcinoma. [Table: see text]
Comparison of abiraterone acetate (Abi) versus ketoconazole (Keto) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) refractory to docetaxel (D).
Authors: Peer Avivit , Ish-Shalom Maya , Maimon Natalie , Gottfried Maya , Boursi Ben , Leibowitz-Amit Raya , Berger Raanan , Neumann Avivit , Kovel Svetlana , Sella Avishay , Pili Roberto , Hammers Hans J. , Sinibaldi Victoria J. , Carducci Michael Anthony , Eisenberger Mario A. , Keizman Daniel
Published: February 2017

146

Background: Abi is a standard treatment (tx) in pts with mCRPC refractory to deocetaxel. It is a potent and selective CYP 17 inhibitor that blocks the synthesis of androgens in the testis, adrenal glands, and prostate. However, in many countries where abi has not been approved yet, keto is used as an alternative CYP 17 inhibitor. Although preclinical data suggests that keto is a less specific and potent inhibitor of CYP 17, there are limited clinical data comparing both agents. We aimed to compare the clinical effectiveness of abi vs keto in pts with mCRPC refractory to D. Methods: Records from 156 mCRPC pts treated with keto 200 - 400 mg 3x day, in 4 centers across the US and Israel, were reviewed retrospectively. 26 pts treated post D were individually matched by clinicopathologic factors to pts treated with abi (selected from a multicenter Israeli database, n=120). We compared the PSA response (decrease ≥50% from baseline), biochemical and radiological progression free survival, and overall survival between the groups. Progression free survival and overall survival were determined by Cox regression. Results: The groups were matched by Gleason score, pre-tx disease extent (limited-axial skeleton and/or nodal vs extensive- appendicular skeleton and/or visceral), ECOG PS, pre-tx risk category (favorable, intermediate, poor; Keizman, Oncologist 2012). Furthermore, they were balanced regarding median age (71 abi vs 69 keto), time from primary tx to disease relapse, time to progression on prior GnRH-a and antiandrogen, PSA response and time to progression on prior D, pre-tx pain score/alkaline phosphatase/hemoglobin/ neutrophil to lymphocyte ratio/PSADT/PSA. In the groups of abi vs keto, PSA response was 46% vs 19% (OR 4.4, p=0.043), median biochemical PFS 7 vs 2 months (HR 0.65, p=0.02), median radiological PFS 6 vs 2.5 months (HR 0.63, p=0.016), median overall survival 17 vs 12 months (HR 0.53, p=0.79), and tx interruption d/t adverse events 12% vs 23% (0R 0.6, p=0.023). Conclusions: In mCRPC refractory to D, the outcome of pts treated with abiraterone was superior to ketoconazole.
Prognostic value of free testosterone (FT) levels during salvage chemotherapy with carboplatin plus weekly docetaxel in metastatic castration- and docetaxel-resistant prostate cancer (mDRPC).
Authors: Reuter Christoph W. , Morgan Michael A. , Fenner Martin , Grünwald Viktor , Ganser Arnold
Published: February 2017

152

Background: Recent data suggest that carboplatin plus weekly docetaxel (DC) may be effective in mDRPC. Carboplatin, docetaxel and steroids interfere with testosterone biosynthesis and/or metabolism. In this study the impact of DC treatment on testosterone blood levels was analyzed. Methods: Docetaxel failure/resistance was defined as disease progression during docetaxel treatment according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Since February 2005, 74 consecutive DRPC patients (pts.) were treated with at least 2 cycles of carboplatin AUC5 iv for 30 min on day 1 plus docetaxel at a dose of 35 mg/m2 iv for one hour on days 1, 8, (15) every 4 weeks and prednisone 2x5mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. FT levels were measured before (n=50) and during DC chemotherapy (n=43). Results: Response of prostate-specific antigen (PSAR; ≥50% PSA) was observed in 35/74 (47.3%) pts. At the current analysis the median follow-up time was 16.0 months and 54/74 pts. had died. Median progression-free survival (PFS) was 6.9 months (CI 95% 5.3, 8.4) and median overall survival (OS) was 18.6 months (CI 95% 12.4, 24.7). Median nadir FT levels were 2.8 pmol/L before and below the RIA detection limit of 0.6 pmol/L during DC treatment (p=0.011). While only 4/50 pts. had FT levels <0.6 pmol/L before DC treatment (all under abiraterone therapy), 27/43 pts. had nadir FT values <0.6 pmol/L during DC chemotherapy (p<0.001). FT levels <1 pmol/L during DC treatment were associated with a higher PSA response rate (hazard ratio HR 0.09; CI 0.02, 0.81, p=0.032) and FT levels <0.6 pmol/L with a higher OS (HR 0.45; CI 0.18, 0.98, p=0.045). FT remained statistically prognostic in multivariable analyses. The DC regimen was reasonably well tolerated, with leukopenia/ neutropenia as the most common reversible grade 3/4 toxicity (41.9/37.8%). Conclusions: These data demonstrate for the first time that FT is an important prognostic factor for PSAR and OS in mDRPC pts. receiving chemotherapy.
Association of Gleason 9-10 prostate cancer with worse outcomes compared to Gleason 8 disease.
Authors: Tsao Che-Kai , Gray Kathryn P. , Nakabayashi Mari , Evan Caroline , Galsky Matt D. , Kantoff Philip W. , Oh William K. , Pomerantz Mark
Published: February 2017

157

Background: Use of pathological Gleason score for risk stratification of localized prostate cancer is widely accepted. However, data are lacking regarding differences in presentation and outcome among those with Gleason 8-10 disease. Methods: Using the Dana-Farber Cancer Institute Prostate Clinical Research Information Systems database, we identified a cohort of patients with biopsy Gleason 8-10 disease who received definitive radical prostatectomy (RP) or radiation therapy (RT) (external beam or brachytherapy) for curative intent. The study endpoints, time to biochemical recurrence (BCR), time to metastatic disease (MD), and overall survival (OS) were estimated using the Kaplan-Meier method. Cox proportional hazards model was used to investigate the association of the study endpoints and Gleason score groups (8 vs. 9 and 10) adjusted for clinical and pathological factors including age, PSA at diagnosis, type of local therapy, and tumor stage. Results: We identified 848 patients who received either local definitive RT (n=411) or RP (n=437). Median follow-up from diagnosis was 5.3 years. Patient characteristics at diagnosis (race, age, and clinical stage) were similar between the two groups (Gleason 8 vs. Gleason 9-10). Patients with Gleason 9-10 disease were more likely to receive radiotherapy as primary local therapy (58% vs. 46%, p=0.001), and to receive hormonal therapy as a part of their definitive treatment course (64% vs. 48%, p<0.001). Patients with Gleason 9-10 disease had shorter time to BCR, time to MD, and a trend towards worse OS using multivariate analysis adjusted for significant clinical and pathological factors. (Detailed in table below). Conclusions: In our study, we found that patients with localized Gleason 9-10 disease who were treated with definitive therapy with curative intent had worse outcomes compared to patients with Gleason 8 disease. More aggressive, multimodality treatments may be indicated for men diagnosed with the highest Gleason grades. [Table: see text]
Overtreatment of low-risk prostate cancer in the United States: Incidence, cost, complications, and implications for the screening debate.
Authors: Aizer Ayal A. , Gu Xiangmei , Choueiri Toni K. , Martin Neil E. , Hu Jim C. , Nguyen Paul Linh
Published: February 2017

161

Background: The National Comprehensive Cancer Network (NCCN) recommends active surveillance as the sole option for men with low-risk prostate cancer (LRPC) and a life expectancy <10 years. We sought to describe the incidence, risk factors, cost, and morbidity related to overtreatment of LRPC within the United States. Methods: We used the Surveillance, Epidemiology and End Results (SEER)-Medicare Program to identify 11,744 men ≥66 years with LRPC diagnosed from 2004-2007. Expected survival was estimated using the 2007 Social Security Life Table and was increased and decreased by 50% in men in the upper and lower quartiles of comorbidity, respectively, as specified by the NCCN. Overtreatment was definitive treatment in men with LRPC and life expectancy <10 years. Costs were the amount paid by Medicare in the year following minus the year prior to diagnosis. Toxicities were defined as relevant Medicare diagnoses or interventions. Results: Of 3001 men with LRPC and a life expectancy <10 years, 2011 (67%) were treated definitively. On multivariable logistic regression, men overtreated for prostate cancer were more likely to be younger (p<.001), white (vs black, OR 1.44, 95% CI 1.03-2.02, p=.03), married (OR 1.30, 95% CI 1.05-1.61, p=.02), urban (trend, OR 1.40, 95% CI 0.98-2.00, p=.06), have higher Elixhauser comorbidity (p<.001), and have a higher clinical stage (T2 vs T1, OR 1.57, 95% CI 1.19-2.07, p=.001) and prostate-specific antigen level (OR 1.02, 95% CI 1.02-1.02, p<.001). Relative to expectant management, the mean added cost per definitive treatment was $15,308. When extrapolated nationally the cumulative net cost of overtreatment in men ≥66 years is $32 million per annum. Long-term urinary, erectile, and bowel toxicity occurred in 59.2% and 50.0%, 47.9% and 19.7%, and 7.1% and 17.8% of prostatectomy and radiation patients, respectively. Conclusions: Overtreatment of prostate cancer is partially driven by sociodemographic factors and occurs in a high percentage of men with LRPC and limited life expectancy, with marked impact on patient quality of life and health care costs. Efforts to enhance appropriate management of LRPC would reduce the harms associated with screening.
Effect of Wnt-1 induced signaling protein-2 (Wisp-2/CCN5) on angiogenesis and invasion in prostate cancer.
Authors: Hashimoto Yasunobu , Singh Rajendra , Lokeshwar Bal L.
Published: February 2017

164

Background: The Wnt-Induced Signaling Protein-2 (Wisp-2/CCN5) is a secreted protein implicated in modification of extracellular matrix, invasion, and angiogenesis. The regulation of Wisp-2 and its function in CaP is poorly explored although it is highly expressed in advanced CaP cells. We discovered recently that a pro-inflammatory chemokine, Interleukin-8 (IL-8) strongly modulates Wisp2 expression in CaP cells. Since chronic inflammation is thought to be significant in CaP metastasis and IL-8 is a major effecter of inflammatory pathway, we investigated the physiological consequence of Wisp-2 modulation in CaP cells. Methods: Quantitative PCR was used to determine the expression of Wisp-2 mRNA and other mRNA in prostate epithelial and cancer cells. Wisp-2 mediated-VEGF secretion was determined by ELISA and endothelial tube formation assay using human vascular endothelial cells. Invasive activity and their attributes were determined using gelatin-zymography for matrix metalloproteinases (MMPs), Matrigel invasion assay and chemotaxis assay. Results: Wisp2 RNA was strongly expressed in two highly metastatic CaP cell lines, DU145 and PC-3 and moderately in less invasive LAPC4 and LNCaP cells. Constitutive autocrine expression or external addition of IL-8 increased Wisp-2 mRNA by ≥15.2 times in LNCaP, and 7.4 times in LAPC4 cells. Depleting Wisp-2 by RNA interference caused 82% reduction of Wisp2 in DU145, and 75% in PC-3. Depletion of Wisp2 did not affect cell proliferation in DU145 and PC3 but it reduced expression of VEGF mRNA by 64% in DU145 and 43% in PC3. Secreted VEGF protein in cultures of DU145 and PC-3 cells showed a decrease of 62% in DU145 and 30% in PC3. Condition medium of Wisp-2 depleted DU145 cell cultures showed 20% decrease in proliferation and vessel formation activity in HUVEC cells. Further, Wisp-2 depletion in DU145 cells resulted in significant decrease in chemoinvasion activity (28%) and secretion of MMP-9 (25%). Conclusions: These results show that Wisp2 is down stream effector of IL-8 and is an important modulator, affecting extracellular matrix to stimulate angiogenesis and invasiveness in CaP cells. Suppression of Wisp-2 in CaP may reduce their metastatic potential.
Specification and validation of prostate cancer quality-of-care e-measures in the Veterans Health Administration (VHA).
Authors: Shelton Jeremy B. , Skolarus Ted A. , Ryoo Joan Joonsun , Malin Jennifer , Antonio Anna Liza M. , He Ren , Saigal Christopher
Published: February 2017

178

Background: Quality measures based on chart abstraction are the “gold-standard,” but the costs of measurement limit widespread adoption. Electronically specified measures (e-measures) promise a way forward, however the fidelity of electronic abstraction compared to chart abstraction is unknown. We sought to validate e-measure versions of VHA-developed prostate cancer quality of care measures. Methods: Quality measures were chart abstracted on 11,263 men in the VHA with incident prostate cancer in 2008. We identified and linked VHA cancer registry and administrative data for the same cohort. E-measures were specified iteratively and validated by comparing accuracy of measure denominators and numerators, and the overall pass rates to chart abstracted results. Results: 3 of 6 quality measures were successfully validated (Table). Conclusions: The VHA’s information technology infrastructure is sufficiently advanced to support valid e-measurement that is equivalent to that performed by chart abstraction, however data availability at this time limits the breadth of e-measurement as compared to chart abstraction. [Table: see text]
Use of microRNA signature to distinguish early from late biochemical failure in prostate cancer.
Authors: Lichner Zsuzsanna , Schaefer Annika , Saleh Carol , Nasser Aurfan , Boles Dina , Al-Haddad Sahar , Kupchak Peter , Dharsee Moyez , Nuin Paulo S. , Evans Kenneth R. , Jung Klaus , Stephan Carsten , Fleshner Neil Eric , Yousef George M.
Published: February 2017

194

Background: With the introduction of PSA testing, the problem of over-treatment emerged in prostate cancer. Only a small subset of prostate cancer patients will require more intensive adjuvant therapy. There is currently no biomarker that can predict disease aggressiveness at the time of surgery. Methods: We analyzed miRNA expression in 41 patients (the discovery set) which were dichotomized into; 'high risk'- experienced biochemical failure within 24 months after radical prostatectomy (n=26) and 'low risk' who did not have biochemical failure for at least 35 months (n=15). The validation set consisted of 72 cases. Total RNA was isolated from FFPE cores. cDNA was prepared for each patients and expression miRNA expression was screened by qRT-PCR –based panel. miRNAs were ranked by non-parametric tests. Linear regression models were built to predict biochemical failure. We used TargetScan for miRNA target prediction. Targets were validated by transient transfection of synthetic miRNA precursors followed by qRT-PCR quantification of the targets. Proliferation was assessed by measuring cell viability. Results: We compared the expression of 754 mature human miRNAs in patients with ‘high’ or ‘low’ risk for biochemical failure. We identified 24 miRNAs that were differentially expressed between the risk groups. We developed three logistic regression models, based on the expression of 2-3 miRNAs (PPV=100% and NPV ranges 86.4-100%). We confirmed the differential expression on the study set and on a larger, independent set of PCa pateints. We also validated one model on an independent set of patients. Further, we show that transfection of miR-152 and miR-331-3p, featured in the logistic regression models, altered proliferation of PCa3 and DU145 cells. Target prediction indicated Erbb3 and Erbb2 as potential direct targets and their mRNA expression significantly reduced when miR-152 and miR-331-3p were overexpressed. Conclusions: Altered miR-331-3p and miR-152 expression represent a potential tool for assessing the risk of early biochemical failure. These miRNAs may act through the Erbb family to induce an alternative way of AR activation.
Utility of blood oxygen level dependent magnetic resonance imaging in the evaluation of tissue oxygenation patterns of prostate cancer.
Authors: Gayed Bishoy A. , Hallac Rami , Youssef Ramy F. , Francis Franto , Yuan Qing , Sims Robert , Ding Yao , Roehrborn Claus G , Mason Ralph , Raj Ganesh
Published: February 2017

198

Background: Tumor hypoxia is associated with worse pathologic features and oncological outcomes. Blood Oxygen Level Dependent (BOLD) MRI evaluates changes in endogenous contrast generated by paramagnetic deoxy-hemoglobin to non-invasively evaluate tissue oxygenation. Prior attempts using carbogen-based (95%O2 + 5%CO2) imaging were limited by patient tolerance. We present the first-in-man evaluation of a novel oxygen breathing challenge technique to monitor tissue oxygenation with BOLD MRI in patients with prostate cancer. Methods: Following IRB approval, 10 patients with clinically localized prostate cancer scheduled for radical prostatectomy underwent preoperative imaging with a 3-Tesla MRI scanner. Images were acquired using a 6-element SENSE body transmit coil and endorectal receive coil. T2* signal intensity is dependent on the concentration of deoxy-hemoglobin. Signal intensity measurements were obtained at different time points. Shorter T2* times imply the presence of hypoxia. Dynamic T2* maps were acquired while subjects breathed air for 2 mins followed by oxygen (15 l/min). Results: 10 patients (median age: 59 years (range 48-73), median PSA 6.9 ng/ml (range 2.5-25), with prostate cancer (Gleason sum 6- 7, 8-9 in 7 and 3 patients respectively) underwent BOLD MRI within 3 weeks of definitive management with a robotic assisted laparoscopic prostatectomy. All patients tolerated BOLD MRI with oxygen challenge without difficulty. Evaluation of BOLD MRI revealed wide variation in T2* values within the prostates from a median of 14.7 ± .71 ms to 44.5 ± 3.3ms. Surrounding muscle T2* values were similar for all patients, indicating that heterogeneous values were specific to each patient’s prostate. Shorter T2* values were seen in Gleason 6-7 than Gleason 8- 9 cancers, indicating more hypoxic areas in these tumors. HIF-1α staining was strongly positive in all tumors. Conclusions: BOLD MRI with oxygen challenge is well tolerated in patients and is a feasible noninvasive technique to study tissue oxygenation in tumors. Differential oxygenation patterns of prostates appear to correlate with pathological features. Further testing is needed to validate these findings.
Impact of magnetic resonance imaging (MRI) in the local staging, risk group classification, and treatment of patients with prostate cancer with combination of high dose rate (HDR) brachytherapy and external beam radiotherapy (EBRT).
Authors: Gomez-Iturriaga Alfonso , Casquero Francisco , Carvajal Claudia , Urresola Arantxa , Canteli Begona , Ezquerro Ana , Hortelano Eduardo , San Miguel Inigo , Cacicedo Jon , Llarena Roberto , Martinez-Indart Lorea , Espinosa Jose Maria , Minguez Pablo , Bilbao Pedro
Published: February 2017

202

Background: To assess the impact of magnetic resonance imaging (MRI) staging for patients undergoing High Dose Rate (HDR) brachytherapy with external beam radiotherapy (EBRT). Methods: Fifty consecutive patients with intermediate risk and high risk prostate cancer underwent staging MRI. The MRI findings were used to guide stage-appropriate treatment recommendations, and to assist in the preplanning and optimization of the brachytherapy isodose distributions. Results: Median age of the patients was 71 years (range 58-78), median pre-treatment PSA was 10.15 ng/ml (3.3-66), median prostate volume was 35cc (14-58). Eighty-four percent of the patients were Gleason ≥ 7. Fifty-two percent had ≥ 50 of cores involved. Fifty four percent of patient’s PSA was ≥ 10 ng/ml. Pre-MRI staging was T1 in 70% of the patients, T2 in 30 %. Of the 50 patients staged by MRI, 70% were upstaged from the digital rectal examination-based clinical stage; 46% of cT1- T2 patients were upstaged to cT3. This upstaging changed the risk group in 56% of the patients while using the NCCN classification and in 24% when the D’Amico classification was used. The treatment reccomendation was modified in 26% and 20% of the patients using the NCCN and the D’Amico classification respectively. Conclusions: Staging MRI impacts in the assessment of the local staging, leading to changes in risk group classification and treatment decision in intermediate and high risk patients undergoing HDR brachytherapy and EBRT.
C35: A new prognostic tool and potential target in prostate cancer.
Authors: Kilari Deepak , Yao Jorge , Scosyrev Emelian , Evans Elizabeth E. , Sahasrabudhe Deepak M.
Published: February 2017

212

Background: Identification and validation of biomarkers can help prognosticate patients and potentially serve as therapeutic targets. C35, a protein encoded by novel gene C17orf37 is located on 17q12 “the hotspot of cancer”. Dasgupta et al. (Oncogene 2009) noted higher expression of C35 in prostate cancer cell lines as compared to minimal expression in normal prostate cells. Furthermore, over expression of C35 enhanced motility and invasion. We hypothesized that C35 expression would correlate with other markers of aggressive clinical behavior and tested this by studying C35 expression in tissue microarrays (TMAs). Methods: TMAs were constructed using tissue samples obtained from normal organs including prostate, primary prostate cancers and prostate cancer from various metastatic sites. The TMAs had triplicates of each specimen which was then stained with rabbit polyclonal anti -C35 antibody. Each sample was scored based on the product of intensity (0-3) and distribution (0-4) of staining, with the maximum score being 12. A blinded review of the final scores and Gleason’s sum were independently conducted by a pathologist. Results: The C35 expression scores were higher in primary prostate cancer compared to benign prostate tissue. The average expression scores increased with increasing Gleason sum. Prostate cancer specimens from the metastatic sites had significantly lower expression scores when compared with the primary prostate cancer specimens. There was minimal to no expression in other normal organs. All these differences were statistically significant (p<0.001). The protein was predominantly cytosolic with membrane localization. Distributions of expression scores according to specimen type are summarized below. Conclusions: C35 expression directly correlates with Gleason sum, a validated prognostic marker. C35 may be a potential target for therapeutic agents. Further studies are needed to determine if increased expression of C35 in normal prostate can predict future development of prostate cancer. [Table: see text]
Diagnostic accuracy of PET scan in salvage lymph node resections in patients with prostate cancer (CaP).
Authors: Pfister David J. K. P. , Piper Charlotte , Porres Daniel , Klotz Theodor , Heidenreich Axel
Published: February 2017

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Background: PET-CT scans in patients with CaP are often used to identify either local recurrent disease or suspected lymph node metastases in early biochemical recurrent disease. The diagnostic accuracy is controversial. We want to show our experience of PET-CT and its diagnostic accuracy in salvage lymph node dissection. Methods: 21 patients treated with radical prostatectomy between 1997 and 2009 presented with PET-CT´s and biochemical recurrent disease and were treated by salvage lymph node dissection to prolong the time to either androgene deprivation or chemotherapy. Diagnostic accuracy was correlated per patient and per lymph nodes. Results: Mean PSA at time of lymph node dissection was 2,73 (0,4-8,4)ng/ml. 17 (81%) received prior radiotherapy and 6 (29%) received androgene deprivation. In total 203 lymph nodes were resected with 58 (29%) harbouring metastasis in 15 (71%) patients. This leads to a Sensitivity, Specifity, positive and negative predictive value of 69%, 12%, 76% and 88% concerning lymph node detection and 70%, 0%, 93% and 0% concerning the calculation per patient. At time of analysis follow-up was available in 5 patients with a biochemical recurrence free survival of 5 (3-12) months. Conclusions: The value of PET-CT in salvage lymph node dissection is under debate and must be questioned according to our results in this setting.
Patient-reported quality of life in men with TURP undergoing proton therapy for prostate cancer.
Authors: Lee Derek , Hoppe Bradford S. , Smith Tamara L. , Morris Christopher G. , Nichols Romaine Charles , Henderson Randal H. , Mendenhall William M. , Williams Christopher R. , Li Zuofeng , Mendenhall Nancy Price
Published: February 2017

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Background: We report on quality of life (QOL) and early toxicity following proton therapy (PT) among men with prostate cancer who underwent transurethral resection of the prostate (TURP) prior to treatment. Methods: Between 2006 and 2010, 1,540 patients were treated definitively with PT for prostate cancer at UFPTI and enrolled on a prospective IRB-approved outcomes protocol. One hundred of the men had received a TURP before PT. Baseline comorbidities, medications, expanded prostate index composite (EPIC) score, international prostate symptom score (IPSS), and CTCAE vs.3 toxicity assessment were collected prospectively. The Kaplan-Meier product limit method was used to estimate freedom from toxicity. Results: Men who had TURP prior to PT had lower EPIC scores at baseline and at all followup points for urinary function, urinary incontinence, and urinary summary (Table). The TURP group also had lower EPIC bowel bother, bowel function, and bowel summary at baseline, 6-month, and 1-year followup. EPIC urinary bother, urinary irritation/obstruction, and subscales did not show a statistically significant difference at baseline, but they did show lower scores for the TURP group at variable follow-up time points. The IPSS scores among the TURP group did not show a statistical difference from the non-TURP group, except at the 6-month follow-up time point. Toxicity assessment showed that the 2-year and 3-year cumulative incidence of grade 3 GU toxicity rate in the pretreatment TURP group were 14% and 18%, respectively. Conclusions: Pretreatment TURP was associated with both a high incidence of physician-assessed toxicity and inferior patient-reported QOL scores both before and after PT treatment. Studies investigating QOL and toxicity after specific prostate cancer therapies should stratify patients by pretreatment TURP. Longer follow-up and further evaluation of risk factors for grade 3 GU toxicity among this cohort are needed. [Table: see text]
Dosimetic quality and evolution of edema after prostate brachytherapy for small prostates: Implications for the use of newer isotopes.
Authors: Kovtun Konstantin , Wolfsberger Luciant D. , Niedermayr Thomas , Neubauer Emily , Murciano-Goroff Yonina R. , Beard Clair , D'Amico Anthony Victor , Martin Neil E. , Orio Peter F. , Nguyen Paul Linh
Published: February 2017

232

Background: Prostate brachytherapy is often avoided in men with small prostate volumes (PV) due to concerns about suboptimal dosimetry. We characterized prostate swelling and dosimetry in patients with small PVs compared with large PVs. Methods: We studied twenty-five patients with PV <25 cc (range 15.1-24.8) and sixty-five patients with PV >=25 cc (range 25.0-66.2) who underwent brachytherapy. Gland size was based on the contoured volume on a 3D transrectal ultrasound before the procedure. Ultrasound-guided brachytherapy was performed under intra-operative planning with loose Iodine-125 seeds to a prescription dose of 145 Gy. Patients underwent CT and MRI scans on post-implant Days 1 and 30 for dosimetric study. MRI was used to contour the prostate and then fused with the CT for dosimetry. Results: Small PVs had greater Day 1 post-implant swelling than patients with large PVs (32.5% increase in volume vs. 23.7%, p=0.04) but Day 30 swelling was minimal and not significantly different (4.4% increase in volume vs. 1.6%, p=0.44) for small and large PVs respectively. Small PVs had greater seed and needle density at implant (p<0.001). Small PV patients had larger Day 1 hot spots in the prostate at (V150 = 59.6% vs. 53.0, p=0 .022) which resolved by Day 30 (V150 = 70.9% vs. 67.1, p=0.20). Rectal and urethral doses were nearly identical by Day 30 (Small PV RV100 = 0.32 cc, Large PV RV100 = 0.33 cc, p=0.99; small PV UV150 = 0.20, large PV UV150 = 0.20, p=0.91). Day 1 swelling created cold areas (rate D90>140 Gy = 88.0% and 90.6% for the small and large PV groups respectively, p=0.71), but day 30 dosimetry was excellent (rate D90>140 Gy = 100% for both groups). Conclusions: While smaller prostates have more immediate post-operative swelling, good Day 30 dosimetry can be achieved in small prostates, which makes them excellent candidates for treatment with I-125 seeds (t½ = 60 days). Due to the increased short-term swelling, small prostates may be suboptimal candidates for implants done with shorter half-life sources such as cesium-131 (t½ = 9.7 days), where the majority of the dose may be delivered to an edematous gland.