bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of a genomic-clinical classifier model for predicting clinical recurrence of patients with localized prostate cancer in a high-risk population.
Authors: Jenkins Robert B. , Bergstralh Eric J , Davicioni Elai , Karnes R. Jeffrey , Ballman Karla V. , Fink Stephanie , Black Peter C. , Ghadessi Mercedeh , Triche Timothy J. , Klee George G , Kollmeyer Thomas M. , Vergara Ismael A , Crisan Anamaria , Erho Nicholas , Sierocinski Thomas , Buerki Christine , Carlson Rachel , Grill Diane E , Zimmermann Benedikt , Haddad Zaid 
Published: February 2017

175 Background: The efficient delivery of adjuvant and salvage therapy after radical prostatectomy in patients with prostate cancer is hampered by a lack of biomarkers to assess the risk of clinically significant recurrence and progression. Methods: Mayo Clinic Radical Prostatectomy Registry (RP) patient specimens were selected from a case-control cohort with 14 years median follow-up for training and initial validation of an expression biomarker genomic classifier (GC). An independent, blinded case-cohort study of high-risk RP subjects was used to validate GC, comparing the performance of GC to a multivariate logistic regression clinical model (CM) and GC combined with clinical variables (genomic-clinical classifier, GCC) for predicting clinical recurrence (defined as positive bone or CT scan within 5 years after biochemical recurrence). The concordance index (c-index) and Cox model were used to evaluate discrimination and estimate the risk of clinical recurrence. Results: In the training subset (n=359), both GC and GCC had a c-index of 0.90 whereas CM had a c-index of 0.76. In the internal validation set (n=186), GC and GCC had a c-index of 0.76 and 0.75, while CM had a c-index of 0.69. In an independent high-risk study (n=219), GC and GCC had a c-index of 0.77 and 0.76, while CM had a c-index of 0.68. In subset analysis of Gleason score 7 patients within the high-risk group, GC and GCC showed improved discrimination with c-index of 0.78 and 0.76, respectively compared to 0.70 for CM. In the high-risk group, the risk of recurrence by GC model score quartiles at 5 years after RP was estimated at 1%, 5%, 5% and 18%. Conclusions: The GC model shows improved performance over CM in the prediction of clinical recurrence in a high-risk cohort and in subset analysis of Gleason score 7 patients. The addition of clinical variables to the GC model did not significantly contribute to classifier performance in patients with high-risk features. We are further testing the performance of the GC and GCC models and their usefulness in guiding decision-making (e.g., for the adjuvant therapy setting) in additional studies of prostate cancer clinical risk groups.
Comparison of PSA, FDG-PET, and Prostate Cancer Working Group 2 (PCWG2) criteria to interpret apparent progression on first post-treatment bone scan.
Authors: Autio Karen A. , Fox Josef J. , Haupt Eric Conrad , Schöder Heiko , Scher Howard I. , Larson Steven M. , Morris Michael J. 
Published: February 2017

20 Background: The risk of prematurely discontinuing effective therapy in patients with metastatic castrate resistant prostate cancer (mCRPC) because of apparent initial progression on bone scan has repercussions for drug development and clinical practice. We evaluated three methods to distinguish disease progression (POD) from non-progressive bone disease or flare response. Methods: The dataset was comprised of men with mCRPC enrolled in contemporary clinical trials using AR-directed or targeted therapy. To be included, a worsened bone scan (increased size, intensity, or number of lesions) at the time of initial follow-up at 8-12 wks (FU1), a concurrently performed FDG-PET and PSA, and a second follow-up bone scan (FU2) > 6 wks after FU1 were required. Pts were evaluated by three methods: 1) PSA-guided approach: POD was defined as a PSA increase >25% from baseline at FU1; for non-progressors, a special category was created for flare response defined as a PSA decline >50% and a FU2 bone scan documenting stability/improvement; 2) FDG-PET approach: POD was defined as a new bone lesion or increase in SUV >10% at FU1; 3) Bone scan only approach: POD was defined by PCWG2 requiring 2 new bone scan lesions at FU1 and 2 additional lesions at FU2. Results: 66 pts registered to trials conducted between 2007-2011 were examined; 38/66 (57.6%) pts had a worsened bone scan at FU1, 23 of whom had a FU2 bone scan and were considered evaluable for this analysis. Conclusions: Over half of mCRPC pts have a worsening bone scan during the first three months of therapy. PCWG2 controls for flare without use of PSA, confirms radiographic POD, and maintains pts on study longer than use of early post-treatment PSA changes. FDG-PET at first assessment appears to identify an identical percentage of progressors as PCWG2 did at the second assessment. PCWG2 is undergoing prospective validation in phase III trials; the use of FDG PET as an early response biomarker is currently under investigation. [Table: see text]
Relationship of opioid analgesic (OA) use at 3 months and overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Halabi Susan , Kelly William Kevin , Kaplan Ellen B , Small Eric Jay 
Published: February 2017

200 Background: Baseline pain has been shown to be a significant predictor of overall survival (OS) in mCRPC pts. The objectives of this analysis were to identify predictors of OA use at 3-months after initiating frontline chemotherapy, and to determine if OA use at 3-months predicts overall OS in mCRPC pts. Methods: Data from CALGB 90401, a phase III trial of 1,050 mCRPC pts randomized with equal probability to receive docetaxel, prednisone with either bevacizumab or placebo was analyzed. OA use was collected at baseline and at 3-month follow-up. OA use was classified as: pts not on OA at baseline and at 3-months (OA1); OA at baseline but not on at 3-months (OA2); No OA at baseline but on OA at 3-months (OA3); and OA at both time points (OA4). The logistic regression method was utilized to identify predictors of OA use at 3-months. Furthermore, the proportional hazards model was used to assess the prognostic significance of OA use in predicting OS adjusting for stratification factors. Results: 836 pts had complete OA data. The overall distribution of pts with the associated median survival times is presented in the table. There was a linear trend between OA use and overall survival (log-rank p-value<0.0001). The multivariable hazard ratio (HR) for death was 1.34 (95% CI=1.12-1.61) comparing OA4 vs. OA1. In multivariable logistic regression model, statistically significant predictors of OA at 3-months were OA use at baseline, hemoglobin, and alkaline phosphatase. Conclusions: The strongest predictor of OA use at 3-months was use at baseline. In addition, this analysis shows that OA use after initiating chemotherapy is a statistically significant predictor of overall survival in mCRPC pts. These results require prospective validation. [Table: see text]
Identification of prostate cancer-expressed microRNAs associated with clinical recurrence (cR) and prostate cancer-specific survival (PCSS) following radical prostatectomy (RP).
Authors: Klein Eric A. , Kiefer Mike , Crager Michael , Magi-Galluzzi Cristina , Falzarano Sara Moscovita , Pelham Robert J. , Millward Carl , Cherbavaz Diana B. , Baker Joffre , Shak Steven , Lee Mark 
Published: February 2017

21 Background: We previously identified messenger RNAs (mRNAs) whose expression can distinguish aggressive from indolent prostate cancer. Representing multiple key genomic pathways, these mRNAs are significantly associated with cR and PCSS after RP, providing prognostic information beyond PSA, cT stage and Gleason Score. We evaluated microRNA expression in the same specimens for association with cR and PCSS. Methods: All cT1/cT2 prostate cancer pts treated with RP at Cleveland Clinic from 1987-2004 were identified (n~2,600), of which 127 pts w/ cR and 374 pts w/o cR after RP were randomly selected using cohort sampling. RNA was purified from 2 macrodissected FPE tumor specimens per pt. Expression of 76 test and 5 reference microRNAs was quantified by RT-PCR. Cox regression and control of the false discovery rate (FDR) was used to assess reference-normalized microRNA and mRNA expression for association with cR and PCSS. Results: 106 pts with cR and 310 without cR had sufficient RNA and successful microRNA assays. Analysis of primary Gleason pattern tumor tissue for each pt identified 21 microRNAs associated with cR and 13 microRNAs associated with PCSS, with FDR at 10%; 8 microRNAs were associated with both endpoints. Similar analysis of highest Gleason pattern tumor tissue for each pt identified 22 microRNAs associated with cR (17 overlapping with those for the primary Gleason pattern) and 7 microRNAs associated with PCSS, with FDR at 10%; 4 were associated with both endpoints. miR-1, miR-21, miR-93, and miR-106b were associated with both cR and PCSS in primary and highest Gleason pattern specimens. The 76 microRNAs in this study tended to have weaker association with cR and PCSS than the 732 mRNAs. In multivariate analyses, mRNAs and microRNAs provided prognostic information beyond PSA, cT stage, and biopsy Gleason score. MicroRNAs co-express more frequently with each other than with mRNAs, which may indicate distinct biological regulation. Conclusions: Expression of some microRNAs assayed in FPE prostate tumor tissue was associated with cR and PCSS after RP in this study, and may retain prognostic value in the face of tumor heterogeneity.
Modafinil for fatigue associated with docetaxel-based chemotherapy: A randomized controlled trial.
Authors: Hovey Elizabeth J. , De Souza Paul L. , Marx Gavin M. , Parente Phillip , Rapke Tal , Hill Andrew , Bonaventura Antonino , Michele Antonio , Craft Paul Stanley , Abdi Ehtesham A. , Lloyd Andrew R. 
Published: February 2017

211 Background: Chemotherapy-induced fatigue is a common complaint for patients with cancer. We investigated whether modafinil, a psychostimulant, could reduce fatigue in patients on chemotherapy. Methods: A multicenter, randomized, double-blind, placebo-controlled, parallel group study was conducted in patients with metastatic prostate or breast cancer suffering significant chemotherapy-related fatigue whilst undergoing docetaxel-based chemotherapy. Patients were enrolled at the start of their 3rdor subsequent cycles of docetaxel which was continued for up to four further cycles (defined here as ‘treatment periods’). Patients were randomized 2:1 to receive modafinil 200mg daily or placebo for 15 days during each treatment period. Fatigue was evaluated by the MD Anderson Symptom Inventory (MDASI). The primary endpoint was MDASI area under the curve (AUC) during the first 7 days of study medication for the first two treatment periods (possible range 0-70). Other validated tools were used to record disturbances in sleep, mood and functional status. Results: Eighty-three patients (65 with prostate cancer) were randomized and received at least one dose of study medication. The number of grade 3 or 4 adverse events (AEs) was 16/55 (29.1%) in the modafinil group and 5/28 (17.9%) in the placebo group. The toxicity profile was largely consistent with docetaxel-based chemotherapy and with previously reported AEs associated with modafinil use in the community; 11 AEs were possibly related to docetaxel; 1 to modafinil and 9 to neither treatment. Conclusions: Managing chemotherapy-related fatigue remains a major challenge. Despite not reaching the primary endpoint, there was a consistent trend towards improvement of chemotherapy-related fatigue in the modafinil arm. Further studies are needed to better understand the clinical implications of these findings. Funding sanofi-aventis; Study ID NCT00917748 . [Table: see text]
Role of lymphotoxin-a and interleukin-17A in human prostate cancer.
Authors: Burbridge Sophie , Goldstein Robert Michael , Cahill Declan , Chowdhury Simon , Maher John 
Published: February 2017

212 Background: Infiltrating immune cells have been implicated in prostate carcinogenesis. Murine studies suggest that B-cell-derived lymphotoxin (LT)a may be a key effector in the evolution to castrate-resistant prostate cancer (CRPC) (Ammirante et al, Nature 2011). Lymphotoxin a has also been implicated in the progression of murine fibrosarcoma, where it complements interleukin (IL)-17A, to synergistically enhance NFkB signaling. This interaction may also apply to human prostate cancer since IL-17-producing Th17 cells are abundant in these tumors. However, the role of LTα in human as distinct from murine prostate cancer remains unclear. Clinical validation is vital since murine models poorly recapitulate the behavior of prostate cancer in man. Methods: Serum levels of LTα and IL-17A were measured by ELISA in patients with benign (n=22) and malignant prostate disease (n=87). Samples were from 29 early prostate cancer patients (amenable to radical therapy), 28 with androgen-sensitive (AS) disease and 30 with CRPC. Data were not normally distributed and thus were analyzed by Mann-Whitney U test. Results: Serum LTαand IL-17A were significantly elevated in patients with both CRPC and early stage prostate cancer, compared to those with benign disease. LTαwas significantly raised in CRPC compared to AS disease. IL-17A was significantly higher in the early stage disease compared to AS prostate cancer. Conclusions: Based upon these data, we hypothesize that B-cell derived LTα synergises with Th17 derived IL-17A from the earliest stage of primary tumor development. In support of this, blockade of LTα in prostate cancer-prone (TRAMP) mice delays primary tumor onset and inhibits metastasis. Furthermore, NSAIDs protect more strongly against lifetime risk of prostate cancer in those individuals with an LTα over-producer polymorphism. Prostate cancer preferentially metastasizes to local lymph nodes and bone – sites at which mature B-cells are plentiful. Consequently, tumor-trophic effects of LTα would become increasingly efficient with disease progression. Our data are incompatible with and thus refute the clinical relevance of a role for androgen ablation in promoting LTα-driven CRPC.
Patient-reported toxicity after treatment for prostate cancer (PC).
Authors: Hill-Kayser Christine E. , Vachani Carolyn , Hampshire Margaret K. , DiLullo Gloria A , Metz James M. 
Published: February 2017

221 Background: PC patients may be at risk for significant late effects after treatment, the impact of which may difficult to evaluate in the clinical setting. This Internet based study evaluates patient perceptions of toxicity after treatment for PC. Methods: Patient-reported data was gathered via a convenience sample frame from PC survivors voluntarily utilizing a publically available, free, Internet-based tool for creation of survivorship care plans. Available at www.livestrongcareplan.com, the tool allows survivors to enter data regarding diagnosis, demographics, and treatments, and provides customized guidelines for future care. During use of the tool, PC survivors are queried regarding late effects associated with specific treatments, and asked to answer “yes,” “no,” or “I don’t know.” They are also asked to score urinary and sexual symptoms using adapted scales. Results: Of 4378 survivors using this tool from 4/10-7/11, 203 (5%) had a diagnosis of PC. Median diagnosis age was 59 and median current age 63. 47% reported having undergone radical prostatectomy (RP) and 53% radiation (RT). RT was delivered via x-ray (80%), brachytherapy (15%), protons (3%), and combinations (3%). Hormonal treatment was delivered to 50%. Erectile dysfunction was reported by 65% of PC survivors using this tool, 80% of those having undergone RP, and 52% of those RT. Of men reporting ED, 97% reported that they could have an erection prior to PC treatment. Survivors treated with RP most commonly reported urinary incontinence (42%) and dry ejaculation (27%). Survivors treated with RT reported urinary incontinence (14%) and chronic diarrhea (10%). Most (75%) survivors reported they would share the care plan with their healthcare team; of 25% who reported that they would not, the most common reason was “I did not think they would care.” Conclusions: Survivors using this tool anonymously and voluntarily report significant toxicity after PC treatment, including ED and urinary incontinence. Not all survivors appear comfortable discussing these issues with healthcare providers. This tool offers a unique way for survivors to report their experiences; the data reported here may be of significant impact in future study of quality of life, patient counseling and survivor care.
Effect of Wnt signaling protein (Wisp2/CCN5) on angiogenesis and invasion in prostate cancer.
Authors: Hashimoto Yasunobu 
Published: February 2017

227 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 IL-8 is a major effecter of inflammatory pathway, we investigated the physiological consequence of Wisp-2 modulation in CaP cells. We hypothesised that Wisp-2 is a down-stream effector of IL-8 induced angiogenesis and invasion. Methods: Quantitative PCR (qPCR) 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 (HUVEC). Invasive activity and their attributes were determined using gelatin-zymography for matrix metalloproteinases (MMPs), and Matrigel invasion 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.
Transperineal sector biopsies: Their role in prostate cancer active surveillance.
Authors: Vyas Lona 
Published: February 2017

228 Background: Many men with low risk prostate cancer on transrectal biopsy appear suitable for active surveillance (AS). Under staging and grading at diagnosis can result in delayed treatment and risk of poorer oncological outcomes. In most AS series about 30% men have active treatment at a median of two years for presumed disease progression/choice but this may represent disease mischaracterised at initial biopsy. So it is essential to accurately stratify patients before surveillance. We have routinely offered transperineal sector prostate biopsies (TPSB), using 24-32 cores, to all patients considering AS. Methods: 350 patients with apparent low to intermediate risk prostate cancer after transrectal prostate biopsy (TRUS Bx) underwent transperineal sector biopsies. Results: Median age 64 yrs (38–84). Median PSA 7.2 ug/l (0.14–58). 190 had Gleason 3+3, 115 had Gleason 3+4 and 45 >3+4 disease. 145 (41%) patients elected for definitive treatment, in 112 because there was an upgrade or higher disease volume compared with the original TRUS Bx. 33 patients chose definitive treatment rather than continued AS. 205 (59%) patients entered our AS programme, in 25 follow up data is incomplete leaving 180 for analysis. 61 have had repeat TPSB within our protocol and at a median follow up at 2 years in 56/61 (92%) the Gleason score and volume of disease was unchanged. Only 5/180, 2.8% have had treatment for disease progression and additionally 4/180 (2.2%) have chosen active intervention over continued surveillance, despite no evidence of progression. Conclusions: TRUS biopsies under-estimate Gleason grade or cancer volume compared with TPSB. In our cohort of AS patients only 2.8%, at a median follow up of two years, have transferred to definitive treatment for disease progression. TPSB provides the best method to exclude higher risk disease from AS programmes.
Use of the slope of the DVH curve for predicting late rectal toxicity in IMRT for patients with localized prostate cancer.
Authors: Crehange Gilles , Walker Paul M , Gauthier Mélanie , Mirjolet-Didelot Céline , Petitfils Aurelie , Martin Etienne , Chamois Jérôme , Khoury Cedric , Maingon Philippe 
Published: February 2017

230 Background: Dose volume specific endpoints (DVSE) have been demonstrated to be reliable and reproducible for predicting late toxicity with conformal 3D-RT. New highly sophisticated delivery techniques such as IGRT or IMRT or combined IG-IMRT can spare rectum more efficiently while substantially increasing the delivered dose to the prostate. The purpose of this study is to investigate whether the slope of the DVH curve could predict late rectal toxicity more accurately than DVSE in prostate cancer (PCa) patients. Methods: Charts from164 men with complete DVH data who had a localized PCa were treated with exclusive IG-IMRT. The rectum was defined as a cylindrical structure around the outer rectal wall and contoured from the ischial tuberosities to the rectosigmoid junction. A set of DVSE were registered (V75, V70, V60). Four distinct DVH groupings were defined for each DVSE: [0–5%], ]5–10%], ]10–15%] and ]15–20%]. In parallel, we decided to calculate the slope of the DVH curves encompassing the 3 DVSE: 60Gy, 70Gy and 75Gy. The median dose prescribed to the prostate was 78Gy (min. 74Gy – max. 78Gy). Late toxicity was retrospectively scored according to the CTC v.3.0 morbidity grading scales. Univariate analysis using a logistic regression was performed to determine the relationship between DVSE, the slope 60-75Gy and the appearance of any late rectal toxicity (grade ≥ 1). Results: With a median follow-up of 38.3 months [5.25 – 87.3], the rates of grade (G) 1, G2 gastrointestinal toxicity were 20.4%, 2.4%. No grade 3 or 4 occurred. For the rectum, the average Dmean, D98, V75, V70 and V60 were 39.9 Gy [25.7–61.1], 8.9Gy [1.0–38.8], 1.1Gy [0.0–33.3], 6.0 Gy [0.0–44.0] and 19.0 Gy [1.0–70.0]. DVH groupings for V75, V70 and V60 were not predictive of any G≥1 late rectal toxicity (p= 0.836, p= 0.580 and p= 0.152, respectively). The slope 60-75Gy was significantly correlated with late rectal toxicity ≥ G1 (OR= 0.55, [CI95%: 0.33–0.92], p= 0.024). Conclusions: DVSE could be irrelevant with IG-IMRT, thus jeopardizing the clinical benefit of dose escalation. The slope of the curve predicts more accurately late toxicity when attempting to optimize dose distribution.