bluuebunny/crossref_metadata_2025_split huggingface dataset:
A gene expression signature to predicit overall, prostate cancer, and non–prostate cancer survival.
Authors: Li Chunde , Peng Zhuochun , Skoog Lambert , Hellborg Henrik , Wingmo Inga-lill , Hjelm-Eriksson Marie , Harmenberg Ulrika , Cohn-Cedermark Gabriella , Ährlund-Richter Lars , Pramana Setia , Pawitan Yudi , Nistér Monica , Nilsson Sten 
Published: February 2017

51 Background: For prostate cancer patients, prostate cancer specific and non-prostate cancer specific survival have the same importance. This study aimed at identifying expression biomarkers that can predict prostate cancer specific, non-prostate cancer specific and overall survival at diagnosis. Methods: Selected ESCGPs (embryonic stem cell gene predictors) and control genes were analyzed by multiplex quantitative PCR using prostate fine-needle aspiration samples taken at diagnosis from a Swedish cohort of 189 prostate cancer patients diagnosed between 1986 and 2000. Of all patients, 97.9% had overall and cancer-specific survival data and 77.9% were primarily treated only by hormone therapy. The cohort was divided into one discovery and two validation subsets. Univariate and multivariate Cox proportional hazard ratios and Kaplan-Meier plots were used for the survival analysis. A published dataset was used for external validation. Results: An expression signature of F3, VGLL3 and IGFBP3, was sufficient to categorize the patients into high-risk, intermediate-risk and low-risk subtypes. The median overall survival of the subtypes was 3.23, 4.00 and 9.85 years respectively. The difference corresponded to HRs of 5.86 (95% CI 2.91-11.78, P<0.001) for the high-risk and 3.45 (95% CI 1.79-6.66, P<0.001) for the intermediate-risk compared to the low-risk subtype. This signature is significant in correlation to overall, cancer-specific and non-cancer specific survival in both univariate and multivariate analyses including common clinical parameters. Conclusions: These results suggest that these novel expression biomarkers and the expression signature could be used to improve the accuracy of the currently available clinical tools for predicting overall, cancer-specific and non-cancer specific survival and selecting patients with potential survival benefit from hormone treatment.
A genomic classifier independently prognostic of prostate cancer death in a high-risk surgical cohort.
Authors: Cooperberg Matthew R. , Crisan Anamaria , Mitra Anirban Pradip , Ghadessi Mercedeh , Buerki Christine , Davicioni Elai 
Published: February 2017

60 Background: Biomarkers may improve ascertainment of progression risk after radical prostatectomy (RP). We compared two validated post-RP classifiers: the Decipher genomic classifier (GC) and CAPRA-S (based on standard clinicopathologic parameters), to predict prostate cancer-specific mortality (CSM) in a contemporary cohort of RP patients. Methods: From a cohort of 1,010 RP patients treated from 2000-06, a case-cohort design was used to analyze a subset of 219 men with one or more high risk features and available paraffin-embedded tissue. Median follow-up was 6 years. The GC, derived from expression levels of 22 biomarkers and dichotomized to denote low- and high-risk, and CAPRA-S, calculated from preoperative PSA and pathologic grade and staging variables, scores were determined. The scores were evaluated individually and in combination using concordance index, decision curve, (DC), re-classification, and Cox analyses for prediction of CSM. Results: 212 men had full data available to calculate the CAPRA-S; 27 experienced CSM. The c-index for GC (0.78) and CAPRA-S (0.76) were similar, although GC showed improved calibration and higher net-benefit on DC analysis. In 103 patients with high-risk CAPRA-S scores (≥6), GC scores were likewise high-risk for 49, among whom 19 had CSM events. The other 54 men were reclassified as low-risk by GC; among these only 1 CSM event was observed. In multivariable Cox analysis both GC and CAPRA-S were independently prognostic of CSM, with hazard ratios of 1.62 (p<0.001) and 1.22 (p=0.01), respectively for unit score increases. A combined model defined based on the Cox model as (0.20*CAPRA-S + 5.68*GC) was more accurate than either score alone (p<0.001 by likelihood ratio test). DC analysis indicated greater net benefit for the combined model than for either score alone. Conclusions: In men treated with RP at high risk of recurrence based on clinical and pathologic variables, both GC and CAPRA-S were significant predictors of CSM. Notably, GC was able to 'down-risk' >50% of men stratified to high risk based on CAPRA-S alone. Thus the GC provides independent prognostic information, and a model integrating GC and CAPRA-S may further improve the prediction of lethal prostate cancer.
Dissecting the therapeutic effects of anti-CTLA-4 and ADT in a murine hormone-sensitive prostate cancer.
Authors: Subudhi Sumit Kumar , Montalvo-Ortiz Welby , Scher Howard I. , Allison James Patrick 
Published: February 2017

61 Background: Immune checkpoint blockade with anti-CTLA-4 has emerged as a successful, novel form of cancer immunotherapy that acts directly on activated T cells instead of on cancer cells. CTLA-4 blockade can result in durable, long-term responses, but only a subset of patients treated benefit from this approach. Androgen deprivation therapy (ADT) is the first-line treatment for advanced prostate cancer, and it produces some of the most dramatic responses in clinical oncology. Clinically, the combination of ADT and anti-CTLA-4 was found to be more effective than ADT alone. To optimize the development of combination regimens, we examined the kinetics of the immune effects of ADT ± anti-CTLA-4 in a murine model of hormone-sensitive prostate cancer. Methods: Mice with established Myc-CaP prostate tumors were divided into 4 treatment groups: 1) untreated, 2) degarelix, 3) anti-CTLA-4, or 4) degarelix plus anti-CTLA-4. Tumor growth was measured biweekly. Tumor-infiltrating lymphocytes and T cell cytokine production was determined by flow cytometric analysis and serum IFN-gamma levels were assessed by ELISA. Results: We found that degarelix rapidly induces castrate levels of testosterone within 24 hours in mice and maintains these levels for at least 35 days. The combination of degarelix and anti-CTLA-4 improved median overall survival compared to degarelix alone (P<0.030, Mantel-Cox log-rank test). Tumor regression was associated with the production of the Th1-cytokines, IFN-gamma and TNF-alpha by tumor-infiltrating CD4+ and CD8+ T cells within 1 week of treatment initiation. This response peaked at 2 weeks after treatment initiation and was associated with elevated levels of serum IFN-gamma levels. In this model, anti-CTLA-4 monotherapy had no effect on tumor growth rates or intratumoral/sera cytokine levels. Conclusions: The combination of immune checkpoint blockade with anti-CTLA-4 and medical castration with degarelix is therapeutically effective in a murine model of hormone-sensitive prostate cancer, likely through an IFN-gamma-dependent manner. This model can be used to better identify potential post-treatment biomarkers that can be studied for associations with clinical outcomes.
Evaluating the hypothalamic-pituitary-adrenal axis (HPAA) in men receiving ketoconazole for castrate-resistant prostate cancer (CRPC).
Authors: Aggarwal Rahul Raj , Weinberg Vivian K. , Sosa Eduardo V. , Lin Amy M. , Harzstark Andrea Lynne , Small Eric Jay , Fong Lawrence , Hsieh Andrew Caleb , Formaker Carl , Koepfgen Kathryn M. , Friedlander Terence W. , Ryan Charles J. 
Published: February 2017

64 Background: Serum adrenal androgen (AA) levels may be prognostic for survival in men with CRPC treated with androgen synthesis inhibitors (ASIs) including ketoconazole (keto) and abiraterone. We hypothesize that up-regulation of the HPAA and adrenocorticotropic hormone (ACTH) may contribute to therapeutic resistance on ASIs. The current study explores the relationship between ACTH, AA, testosterone (T) and estradiol (E) among CRPC patients (pts) treated with ASI + corticosteroids. Methods: Phase 2 study of keto (400 mg TID) + hydrocortisone (HC) (30 mg/day) in pts with CRPC. Pts who achieved ≥ 30% PSA decline from baseline at week 12 continued keto/HC until progression, at which point HC was replaced by dexamethasone (dex). Serum hormone (H) levels were measured (in AM) at baseline and every 4 weeks using standard assays. Statistical tests include Spearman’s rank test for correlation between baseline H levels; Wilcoxon matched pairs for baseline vs. week 4 distribution; and Fisher’s exact test for associations between H levels (dichotomized at median) with PSA decline. Results: Of 30 pts enrolled and 24 evaluable for PSA response, 13 pts (54%) achieved ≥ 30% PSA decline at 12 weeks. Baseline ACTH was positively correlated with DHEA (r = 0.40; p = 0.04) and cortisol (r = 0.52; p = 0.007). Change from baseline to week 4 in H levels is shown in table. There was a significant increase in pts achieving a PSA decline of ≥ 30% if there was a decrease in E at week 4 vs. no decrease (83% vs. 18%; p = 0.003). Baseline and changes in other H levels were not associated with PSA outcome at week 12. Conclusions: ACTH is positively correlated with DHEA and cortisol in CRPC pts. Declines in E may serve as an additional predictive marker of benefit for ASI therapy. These observations require prospective validation. Analyses exploring changes in ACTH at disease progression and impact of substituting dex for HC are ongoing. Clinical trial information: NCT01036594. [Table: see text]
Quantifying the ki-67 heterogeneity profile in prostate cancer.
Authors: Kamrava Mitchell , Mesko Shane , Banerjee Robyn , Huang Jiaoti , Jeffrey Demanes D. , Marks Leonard S. 
Published: February 2017

73 Background: Ki-67 is a robust predictive/prognostic marker in prostate cancer however tumor heterogeneity may compromise its clinical utility when Ki-67 is determined off of prostate biopsy samples. We examined the variation of Ki-67 in prostate biopsy samples by NCCN risk groups and the location of the highest Ki-67 relative to the most dominant lesion on multiparametric (MP) MRI. Methods: An IRB approved retrospective analysis was done on 77 consecutive men whose prostate biopsies revealed cancer. Using a MRI/US fusion device (Artemis), biopsy cores were obtained systematically and when MRI indicated a lesion, by targeting. Ki-67 staining was determined by a manual semi-quantitative method and reported as % of positive cells. The highest Ki-67 per patient was used to determine inter-prostatic variation. Ki-67 range (highest Ki-67 minus lowest Ki-67 value) was used to determine intra-prostatic variation on a subset of 47 patients with ≥2 positive biopsy cores. Ki-67 range was also used to evaluate intra-lesion variation on 31 MP MRI defined lesions with > 1 targeted positive biopsy core. The relationship of the dominant lesion (lesion with the largest tumor diameter) to the highest Ki-67 in the entire prostate was examined for 10 patients with ≥2 distinct lesions on MP MRI. Analysis of variance (ANOVA) was used to evaluate differences between the means of NCCN-defined risk groups. Results: Inter-prostatic Ki-67 mean±standard deviation (SD) values for low, intermediate and high risk patients were 5.1% ± 3.8%, 7.4% ± 6.8%, and 12.0% ± 12.4% (ANOVA p=0.01). Intra-prostatic mean±SD Ki-67 ranges in low, intermediate, and high risk patients were 2.6% ± 3.4%, 4.6% ± 6.4%, 9.5% ± 10.6% (ANOVA p = 0.0246). Intra-lesion mean±SD Ki-67 ranges in low, intermediate and high risk patients were 1.0%±1.0%, 4.0%±4.29%, and 6.7%±11.51% (ANOVA p=0.39). The dominant lesion harbored the highest Ki-67 30% of the time. Conclusions: High risk patients have significantly higher inter- and intra-prostatic Ki-67 heterogeneity profiles than men with low/intermediate risk disease. The highest Ki-67 is often not located in the dominant MRI defined lesion. This data can inform future biopsy strategies when integrating Ki-67 into clinical practice.
Prediction of patient-reported bowel quality of life (QOL) after dose-escalated radiation therapy (RT) for prostate cancer by rectal dosimetry.
Authors: Stenmark Matthew H. , Conlon Anna S.C. , Daignault Stephanie , Bassetti Michael Frederick , Vance Sean , Marsh Robin , Litzenberg Dale , Ritter Timothy , Feng Felix Yi-Chung , Sandler Howard Mark , Sanda Martin G. , Hamstra Daniel A. 
Published: February 2017

84 Background: Rectal dose-volume histogram (DVH) parameters and a consensus normal tissue complication probability (NTCP) model predict physician scored toxicity but have not been well studied for patient reported outcomes (PRO) following external beam RT for prostate cancer. Methods: PRO were prospectively collected at baseline and 12 month intervals by expanded prostate cancer index composite (EPIC) for 98 patients from 2004-2009. Linear regression modeling for bowel score at 1 and 2 years was performed using pre-treatment bowel score and DVH parameters [V80 (% of rectal volume >80 Gy), V75, V70, V50, V25, and NTCP]. Results: Median RT dose was 78 Gy with image-guidance in 81%, intensity-modulation in 72%, and pelvic RT in 11%. Rectal DVH parameters are presented in the Table. Pretreatment and 2 year PRO were available for 92% of patients. The mean pretreatment bowel summary score declined from 96.0 (sd 8.0) to 91.8 (13.5) at 2 years. Acute proctitis (grade 1-2) during RT was associated with a decline in 2 year bowel QOL, while acute diarrhea (grade 1-2) was not. At 2 years 63% of patients had a decline <4 points while the remainder had a mean decline of 15.9 (14.2) with 4-6 points having been defined as the minimal clinically significant change. Linear regression modeling, adjusted for pretreatment bowel function, revealed an association between increasing Vdose, NTCP and bowel QOL (Table). Akaike information criterion analysis followed by leave-one-out cross validation, indicated that V75 provided the best predictive model for 2 year bowel QOL followed by NTCP and V70. Conclusions: Most previous studies have highlighted V70 for toxicity (such as rectal bleeding). The association with V75 and rectal QOL has not been previously reported and supports potential changes in how prostate plans are designed to maintain QOL. This is also the first validation of a consensus NTCP model for bowel QOL. [Table: see text]
Association of cross-talk between α1D-adrenergic receptor (α1D -AR) and transient receptor potential vanilloid 1 (TRPV1) with the proliferation of PC3 prostate cancer cells.
Authors: Santoni Giorgio , Farfariello Valerio , Morelli Maria Beatrice , Liberati Sonia , Nabissi Massimo , Santoni Matteo , Piergentili Alessandro , Quaglia Wilma , Amantini Consuelo 
Published: February 2017

87 Background: Growing evidence supports the role of α1-ARs in the direct mitogenic effect of catecholamines on prostate cancer (PC) cell growth. The expression of α1D-AR on PC3 prostate cancer cells and the ability of noradrenalin (NA) to stimulate PC3 cell proliferation in a α1D-AR-dependent manner were reported (Quaglia et al., 2005). In addition, TRPV1 expression was also found in prostate cancers (Sanchez et al., 2006). Aim of this study was to investigate the relationship between α1D-AR and TRPV1 receptors and the involvement of TRPV1 in NA-induced proliferation in PC3 cells. Methods: By western blot analysis and confocal microscopy the expression α1D-AR and TRPV1 and localization in PC3 cells were evaluated. PC3 cells were incubated with NA alone or in combination with WS433 and capsazepine (CPZ), α1D-AR and TRPV1 antagonists. Proton release, calcium influx and cell proliferation were assessed in α1D-AR-, TRPV1- or α1D-AR/TRPV1 double-silenced PC3 cells by cytosensor and cytofluorymetric analyses. Finally, lysates from NA-treated PC3 cells alone or in combination with WS433 or CPZ were blotted with anti-phospho ERK, anti-ERK and anti-phospho-(Ser) PKC substrate Abs and Inositol-1,4,5-trisphosphate [3H] radioreceptor assay were performed. Results: α1D-AR and TRPV1 co-localize and are co-immunoprecipitated in PC3 cells. Treatment of PC3 cells with NA strongly stimulated proton release, calcium influx and cell proliferation that were reverted by α1D-AR WS433 and TRPV1 antagonist. NA-induced increase of survival and proliferation was totally abrogated in α1D-AR/TRPV1 silenced cells. In addition, NA stimulates ERK and PKC substrate phosphorylation that was inhibited by WS433 and CPZ. Finally, CPZ treatment inhibited NA-dependent PLC activation, while WS433 had no effect. Conclusions: A functional and structural cross-talk between α1D-AR and TRPV1 receptors control NA-induced proliferation of PC cells. These data strongly suggest the development of new pharmaceutical approaches based on bifunctional antibodies and molecules recognizing both α1D-AR and TRPV1 receptors.
Phase I trial of total androgen blockade, weekly docetaxel, and image-guided intensity-modulated radiotherapy for localized high-risk prostate adenocarcinoma.
Authors: Ramey Stephen J. , Golshayan Ali Reza , Keane Thomas E. , Kraft Andrew S. , Chaudhary Uzair Bashir , Marshall David T. 
Published: February 2017

96 Background: High-risk prostate cancer patients have high rates of treatment failure and improved outcomes are needed. Docetaxel has shown efficacy in hormone-resistant prostate cancer and can act as a radiosensitizer. Dose escalation studies with radiation therapy have found improved freedom from failure rates. The addition of androgen deprivation therapy (ADT) improves overall survival. Therefore, this phase I study was designed to find the maximum tolerable dose (MTD) of weekly docetaxel when combined with high-dose image-guided intensity-modulated radiotherapy (IGRT) and ADT in patients with high-risk prostate cancer. Methods: Men with high-risk adenocarcinoma of the prostate (≥T2c, or PSA ≥20ng/ml, or Gleason ≥8) were treated with weekly docetaxel (given at 10-30 mg/m2, increasing by 5 mg/m2until the MTD was reached) concurrently with IGRT of 77.4 Gy in 43 fractions to the prostate and 45 Gy in 25 fractions to the proximal seminal vesicles. ADT consisted of a gonadotropin-releasing hormone agonist (GnRHa) and bicalutamide beginning 2 months before chemoradiation and continuing 2 months concurrently. The GnRHa was then continued for an additional 24 months. Results: 19 patients began combined chemoradiation between April 2006 and December 2010. Median follow-up is 32 months. No dose-limiting toxicities (DLTs) were seen in patients treated with docetaxel doses up to 25 mg/m2. However, at the 30 mg/m2level, 2 of 4 patients experienced DLTs of both grade 3 fatigue and grade 3 upper GI toxicity, indicating the MTD had been exceeded. At last follow-up, 2 patients had died, one from metastatic prostate cancer and the other from heart failure. A second patient demonstrated biochemical failure by the Phoenix criteria at 46 months, giving an actuarial biochemical disease-free survival (bDFS) at 3 years of 94.7%. All patients had ≥grade 2 erectile dysfunction but no other ≥grade 2 long-term toxicities were identified. Conclusions: Weekly docetaxel may be combined with high-dose IGRT and long-term ADT up to a MTD of 25 mg/m2. Long-term side effects with this regimen were minimal, and bDFS rate is encouraging. Clinical trial information: NCT00099086.
Axitinib with or without dose titration for first-line metastatic renal cell carcinoma (mRCC): Unblinded results from a randomized phase II study.
Authors: Rini Brian I. , Gruenwald Viktor , Fishman Mayer N. , Melichar Bohuslav , Ueda Takeshi , Bair A. H. , Chen Ying , Bycott Paul W. , Pavlov Dmitri , Kim Sinil , Jonasch Eric 
Published: February 2017

LBA349 Background: Patients receiving the 5-mg twice daily (BID) axitinib starting dose exhibit variable drug exposure; prior pharmacokinetic analyses indicate higher exposure is associated with better outcomes in mRCC. Dose titration based on individual tolerability may optimize exposure and improve efficacy. Methods: Patients (N=213) with treatment-naïve mRCC received axitinib 5 mg BID for a 4-week lead-in period. Then, patients with 2 consecutive weeks of blood pressure ≤150/90 mmHg, no axitinib-related toxicities >grade 2, no dose reductions, and ≤2 antihypertensive medications were randomized (double-blind) to axitinib 5 mg BID + dose titration to 10 mg BID maximum with axitinib or placebo. Those not eligible for randomization continued axitinib 5 mg BID or lower. Primary endpoint was objective response rate (ORR) in randomized arms. Progression-free survival (PFS), overall survival, and safety were secondary endpoints. Assuming response rate under the null hypothesis is 0.15, this study had ≥80% power (1-sided type I error 10%) to detect a ≥25% absolute improvement in ORR with active vs placebo titration. Results: In all, 56 patients each were randomized to active and placebo titration arms, 91 were not randomized, and 10 withdrew during the lead-in period. As of Oct 12, 2012, ORR (95% confidence interval [CI]) was 54% (40–67) in the active titration arm vs 34% (22–48) in the placebo titration arm (1-sided P=0.019), and 59% (49–70) in the non-randomized arm. Median PFS (95% CI) from first dose was 14.5 mo (9.2–24.5) in the active titration arm vs 15.7 mo (8.3–19.4) in the placebo titration arm (hazard ratio favored active titration, 0.85; 95% CI, 0.54–1.35; 1-sided P=0.244), and 16.6 mo (11.2–22.5) in the non-randomized arm. Most frequent all-grade, all-causality adverse events in active titration, placebo titration, and non-randomized arms, respectively, were diarrhea (61% vs 63% vs 63%), hypertension (61% vs 43% vs 82%), and fatigue (45% vs 46% vs 54%). Conclusions: Axitinib is effective and well tolerated in first-line mRCC with prolonged median PFS in all treatment arms compared to historical controls. Axitinib dose titration significantly improved ORR vs placebo. Clinical trial information: NCT00835978.