bluuebunny/crossref_metadata_2025_split 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.