bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overcoming miR-106a induced radioresistance in prostate cancer: Targeting senescence with KU-55933.
Authors: Hoey Christianne , Ray Jessica , Huang Xiaoyong , Jeon Jouhyun , Boutros Paul Christopher , Liu Stanley K. 
Published: February 2018

77 Background: Prostate cancer is a leading cause of cancer related death in men worldwide, with recurrence being a major clinical problem after radiotherapy. There is an unmet need to better characterize radioresistant tumors and identify biomarkers to improve patient outcomes. Methods: We identified that miR-106a was overexpressed in radiation resistant cell lines compared to parental cells. We analyzed The Cancer Genome Atlas dataset to assess miR-106a expression in normal prostate, and low- to high-grade prostate tumors. To assess the functional role of miR-106a, we performed in vitro and in vivo assays for radiation response, including clonogenic survival, proliferation, senescence, and tumor xenograft growth after radiation. We performed gene array and pathway analyses to identify downstream effectors of miR-106a. Results: MiR-106a expression was significantly higher in prostate tumors with Gleason score > 7 compared to Gleason ≤ 7, suggesting miR-106a is involved in high grade disease. MiR-106a overexpression confers radioresistance in vitro and in vivo, by targeting LITAF. We now extend miR-106a’s effects to upregulation of ATM at the promoter level, thereby increasing ATM transcript and protein in the cell. Unexpectedly, we found that miR-106a’s mechanism of radioresistance through ATM upregulation does not alter DNA damage repair. ATM upregulation affects clonogenic survival through reduced senescence. KU-55933, a specific ATM kinase inhibitor, resensitizes miR-106a overexpressing cells to radiation by inducing senescence, a predominant mode of cell death in prostate cancer. Conclusions: Our research challenges the current paradigm of ATM and DNA damage repair by outlining another mechanism of radioresistance through alteration of senescence. Our findings suggest that miR-106a may be a promising biomarker for high-grade disease and radioresistant prostate cancer. In addition, we have identified a therapeutic intervention for miR-106a induced radioresistance. Improvements in bioavailability of KU-55933 may lead to its clinical use in combination with radiation therapy to radiosensitize miR-106a induced radioresistant prostate cancer.
Impact of percent positive biopsy cores on cancer-specific mortality for patients with high-risk prostate cancer.
Authors: Yang David Dewei , Muralidhar Vinayak , Mahal Brandon Arvin Virgil , Vastola Marie , Boldbaatar Ninjiin , Labe Shelby A , Nezolosky Michelle Daniel , Martin Neil E. , King Martin T. , Mouw Kent William , Orio Peter F , Choueiri Toni K. , Trinh Quoc-Dien , Nguyen Paul L. 
Published: February 2018

78 Background: A high percent positive biopsy cores (PBC), typically dichotomized at ≥50%, is prognostic of worse cancer-specific outcomes for patients with low- and intermediate-risk prostate cancer. The prognostic value of ≥50% PBC for patients with high-risk disease is poorly understood. We examined the association between ≥50% PBC and prostate cancer-specific mortality (PCSM) for patients with high-risk prostate cancer. Methods: We identified 7,569 men from the Surveillance, Epidemiology, and End Results program who were diagnosed with high-risk prostate cancer (Gleason 8-10, prostate-specific antigen > 20 ng/mL, or cT3-T4 stage without evidence of nodal or metastatic disease) in 2010 or 2011 and had 6-24 cores sampled at biopsy. Multivariable Fine and Gray competing risks regression was utilized to examine the association between ≥50% PBC and PCSM, with adjustments for sociodemographic and clinicopathologic factors. Results: Median follow-up was 3.8 years (interquartile range 3.3-4.3 years). 56.2% of patients (4,253) had ≥50% PBC. The 4-year unadjusted cumulative incidences of PCSM were 2.0% (95% confidence interval [CI] 1.5-2.6%) and 5.6% (95% CI 4.9-6.4%) for patients with < 50% and ≥50% PBC, respectively. On multivariable analysis, the presence of ≥50% PBC was associated with a significantly higher risk of PCSM (adjusted hazard ratio [AHR] 1.95, 95% CI 1.43-2.66, P< 0.001). On subgroup analysis, ≥50% PBC was associated with a significantly higher risk of PCSM only for cT1-T2 disease (AHR 2.21, 95% CI 1.59-3.07, P< 0.001) but not cT3-T4 disease (AHR 0.77, 95% CI 0.33-1.81, P= 0.547), with a significant interaction ( Pinteraction= 0.012). Conclusions: In this large, contemporary cohort of patients with high-risk prostate cancer, ≥50% PBC was independently associated with a two-fold increased risk of PCSM for patients with cT1-T2, but not cT3-T4, tumors. Percent PBC should be used to routinely risk stratify men with high-risk disease and identify patients who may benefit from intensification of therapy, such as adding docetaxel or abiraterone to radiotherapy with androgen deprivation therapy, to optimize cancer-specific outcomes.
Results of a phase II trial of neoadjuvant abiraterone + prednisone+ enzalutamide + leuprolide (APEL) versus enzalutamide + leuprolide (EL) for patients with high-risk localized prostate cancer (PC) undergoing radical prostatectomy (RP).
Authors: McKay Rana R. , Xie Wanling , Lis Rosina , Ye Huihui , Zhang Zhenwei , Trinh Quoc-Dien , Chang Steven Lee , Harshman Lauren Christine , Ross Ashley , Pienta Kenneth J. , Lin Daniel W. , Ellis William J , Montgomery Robert B. , Chang Peter , Wagner Andrew , Bubley Glenn , Kibel Adam S. , Taplin Mary-Ellen 
Published: February 2018

79 Background: Patients with high-risk PC have an increased risk of recurrence and mortality despite therapy. Abiraterone, a CYP17 inhibitor, and enzalutamide, a next generation anti-androgen, have demonstrated improved overall survival in metastatic PC. In this multicenter randomized phase II trial, we evaluate the impact of second generation hormone therapy on RP pathologic outcomes. Methods: Eligible patients had biopsy Gleason score ≥4+3=7, PSA >20 ng/mL or cT3 disease (by prostate MRI). Lymph node were require to be <20 mm. Patients were randomized 2:1 to APE:EL for 6 cycles (24 weeks) followed by RP. All RPs underwent central pathology review. The primary endpoint was the rate of pathologic complete response (pCR) or minimum residual disease (MRD, tumor ≤5 mm). Secondary endpoints include PSA response, surgical staging at RP, positive margin rate, and safety. Results: 75 patients were enrolled at four sites: DFCI/BWH (n=55), BIDMC (n=11), UW (n=5), JHU (n=4). Median age was 62 years. Most patients had NCCN high-risk disease [n=66, 88%; cT3 n=21 (28%), Gleason 8-10 n=59 (79%), PSA >20 ng/mL n=17 (23%)]. All patients completed 6 cycles followed by RP. Median PSA nadir was 0.03 and 0.02 ng/mL and time to nadir was 3.7 and 4.6 months in the APEL and EL arms, respectively. The combined pCR or MRD rate was 30% (n=15/50) in the APEL arm and 16% (n=4/25) in the EL arm. The response difference was 14% (80% CI -3%-30%, p=0.263). 15 patients (14 in APEL; 1 in EL) had grade 3 adverse events (AEs). The most common grade 3 AEs were hypertension (n=7) and ALT increase (n=5). No grade 4-5 AEs occurred. Conclusions: Neoadjuvant hormone therapy plus RP in men with high-risk PC resulted in favorable pathologic responses (≤5 mm residual tumor) in 16-30% with a trend towards improved pathologic outcomes with APEL and acceptable safety profile. Follow-up is necessary to evaluate the impact of therapy on recurrence rates. Clinical trial information: NCT02268175. [Table: see text]
Pilot study of moderately-hypofractionated intensity-modulated radiation therapy over 3 weeks for localized prostate cancer.
Authors: Nakamura Kiyonao , Inokuchi Haruo , Ikeda Itaru , Kamba Tomomi , Inoue Takahiro , Yamasaki Toshinari , Kobayashi Takashi , Ogawa Osamu , Mizowaki Takashi 
Published: February 2018

8 Background: The purpose of this trial was to prospectively evaluate the short-term outcomes of moderately hypofractionated intensity-modulated radiation therapy (MH-IMRT) for localized prostate cancer. Methods: In November 2013, we started a pilot study of MH-IMRT for prostate cancer. Eligible patients were 50 to 80 years old and had D’Amico’s low- or intermediate-risk disease. Fifty-four Gy in 15 fractions (3.6 Gy per fraction), in which the equivalent total dose in 2-Gy fractions to prostate cancer was estimated about 78 Gy, were delivered over 3 weeks using image-guided IMRT based on daily cone beam CT without intraprostatic fiducial markers. Neoadjuvant androgen deprivation therapy was given 4 to 8 months before the start of IMRT. The primary endpoint was incidence rates of acute toxicities, and the secondary endpoints were incidence rates of late toxicities at 2 years and biochemical relapse free survival (BRFS) at 2 years. Acute toxicities were evaluated based on the Common Terminology Criteria for Adverse Events version 4.0 criteria. Late toxicities were evaluated based on RTOG/EORTC Late Radiation Morbidity Scoring Schema. Biochemical relapse was defined according to the Phoenix definition (absolute nadir + 2 ng/ml). The planned sample size was 25 patients. Results: Twenty-five patients were enrolled in this trial. Twenty-four patients were treated with MH-IMRT, and 1 patient was treated with conventionally fractionated IMRT because his small intestine was close to the target. The median age in the cohort was 71 years old, and median follow-up period was 31 months (range 24-42). Four patients (17%) had low- and 20 (83%) had intermediate-risk disease. No grade ≥3 acute toxicity was observed and the incidence rates of grade 2 acute genitourinary and gastrointestinal toxicities were 21% and 4%, respectively. So far no grade ≥2 late toxicity has been observed and the 2-year BRFS is 95.8%. Transient PSA elevation over 0.4 ng/ml was observed in 11 patients (46%) and in 5 patients (21%) PSA rose ≥1.0 ng/ml above nadir. Conclusions: Sort-term outcome of MH-IMRT delivering 54 Gy in 15 fractions over 3 weeks for prostate cancer was comparable to that of conventionally fractionated IMRT. Clinical trial information: UMIN000012057.
The impact of prostate cancer (PC) margin extent (ME) at radical prostatectomy (RP) on biochemical relapse-free survival (bRFS).
Authors: Seyedin Steven Neema , Mott Sarah L , Snow Anthony N , Russo James Kyle , Watkins John 
Published: February 2018

83 Background: Surgical margin involvement (M+) by PC at RP is associated with suboptimal bRFS; however, the interaction of M+ with coincident high-risk clinicopathologic and treatment factors obscures accurate estimation of recurrence risk. The objective of this study is to determine whether ME permits risk stratification. Methods: Retrospective analysis of clinicopathologic factor association with bRFS. Eligible patients underwent RP alone for clinically localized PC. Patients with metastatic disease, PSA > 30 at diagnosis, pathologic involvement of seminal vesicles or lymph nodes at RP, insufficient follow-up, or receipt of pre-RP or adjuvant therapy were excluded. Slides from RP specimens with close or positive margins were re-reviewed by study pathologists blinded to outcome. Results: From 2002-2010, 667 patients were eligible for analysis. The median age was 61 yrs (range, 43-76), and all had cT1-2 disease (83% T1c), with median PSA 5.6 (0.9-28.0; 85% ≤10). Robot-assisted RP was employed in 141 cases (21%). Two hundred ten patients (31%) had M+, with single maximal ME 3mm (0.1-23), and cumulative ME 4mm (0.1-34). At median follow-up of 102 months (13-184), 149 patients (22%) had recurrence, with estimated 8-year bRFS rates of 85%/56% for M-/+ patients (p < 0.01). Multivariable analysis identified PSA, Gleason score (GS), extraprostatic extension, and M+ as associated with bRFS. Specific to patients with involved margins, the combination of ME and GS permitted recurrence risk stratification, with a low-risk subset identified (GS≤6 and ME < 3mm; Table). Conclusions: The current investigation suggests that GS6 patients with maximal or cumulative ME < 3mm appear to have favorable early 8-year bRFS following RP. GS6 patients with wider ME and GS ≥7 with any extent M+ appear to have suboptimal bRFS. RP pathology reports should include ME details, in order to more precisely estimate risk of subsequent disease recurrence. [Table: see text]
Long-term outcomes of stereotactic body radiotherapy for low- and intermediate-risk prostate adenocarcinoma: A multi-institutional consortium study.
Authors: Kishan Amar Upadhyaya , Katz Alan J. , Mantz Constantine , Chu Fang-I , Appelbaum Limor , Loblaw Andrew , Cheung Patrick , Kaplan Irving D. , Fuller Donald B. , Pham Huong T. , Meier Robert , Buyyounouski Mark K. , Shaverdian Narek , Dang Audrey , Yuan Ye , Bagshaw Hilary , Prionas Nicolas , Kupelian Patrick , Steinberg Michael L. , King Christopher R. 
Published: February 2018

84 Background: While a growing body of evidence supports the use of stereotactic body radiotherapy (SBRT) for the treatment of low- and intermediate-risk prostate adenocarcinoma (PCa), some trepidation exists regarding its long-term efficacy and safety. Methods: Men with low- and intermediate-risk PCa, as defined per the National Comprehensive Cancer Network guidelines, who were enrolled on various institutional phase II trials of SBRT between 2000-2012 were included in a multi-institutional consortium. Biochemical relapse (BCR) was defined as PSA > “nadir +2” or initiation of androgen deprivation therapy (ADT). Toxicity data were scored according to the CTCAE v 3.0 or Radiation Therapy Oncology Group scoring systems. Results: A total of 1644 men were eligible for analysis, with a median followup of 7.2 years. 297 patients (18.1%) had at least 9 years of followup. Fractionation schemes ranged from 33.50-40 Gy in 4-5 fractions. 892 patients had low-risk disease and 752 had intermediate-risk disease. 59 patients (3.6%) received short-term ADT. 100 patients (6.0%) experienced BCR, and 7 (0.4%) experienced distant metastases. No patients died of PCa. By Kaplan-Meier analysis, 5- and 10-year BCR-free survival rates were 98% and 94% in the low-risk group and 96% and 90% in the intermediate-risk group (p < 0.05 by log-rank test). 5- and 10-year overall survival rates were 93% and 86% in the low-risk group and 95% and 91% in the intermediate-risk group (p > 0.05 by log-rank test). Five patients (0.3%) experienced grade 3 acute genitourinary (GU) toxicities, including urinary retention, hematuria, and frequency. 30 (2%) experienced grade 3 late GU toxicity, including urinary strictures, hematuria, and retention. One late grade 4 GU toxicity (hemorrhagic urethritis) and one late grade 4 gastrointestinal toxicity (fistula-in-ano) were seen. Conclusions: To the best of our knowledge, this is the largest analysis of long-term outcomes following SBRT for PCa. The results indicate that SBRT has an efficacy and toxicity profile that compares favorably to more widespread forms of treatment, such as conventionally-fractionated external beam radiotherapy and brachytherapy.
Derivation of dose/volume constraints for the anorectum from clinician-reported outcomes (CRO) in the CHHiP trial of radiotherapy (RT) fractionation.
Authors: Wilkins Anna , Naismith Olivia Frances , Brand Douglas , Fernandez Katie , Hall Emma , Dearnaley David P. , Gulliford Sarah 
Published: February 2018

87 Background: CHHiP (ISRCTN97182923, CRUK/06/016) randomised 3216 men with localised prostate cancer (1:1:1) to 3 RT fractionation schedules: 74Gy/37 fractions (f) over 7.4 weeks, 60Gy/20f/4 weeks and 57Gy/19f/3.8 weeks. Literature-based dose constraints were applied with adjustment for the hypofractionated arms. For standard fractionation the constraints (absolute dose) included V30Gy≤80%, V40Gy≤70%, V50Gy≤60%, V60Gy≤50%, V70Gy≤15%. This study aimed to derive anorectal dose constraints based on prospectively collected CRO. Methods: A case-control study design was used, 4 bowel symptoms were independently evaluated. Cases were patients experiencing a moderate or worse grade symptom 1 to 5 years post RT, who had not had the symptom pre-RT. Controls did not experience the symptom between 1 and 5 years post RT. The anorectum was re-contoured from the anal verge to the recto-sigmoid junction using VODCA software. Dose/volume parameters were extracted and hypofractionated dose schedules were converted to 2Gy equivalent schedules using an α/β ratio of 3Gy. Bootstrapped ROC analysis (1000 replicates, balanced outcomes) was used to derive dose constraints using both the Youden index and “Closest top Left” (CtL). Only AUC with a lower limit of the 95% confidence interval >0.5 were considered statistically significant. Any constraint derived in <99% of bootstraps was excluded. Results: Statistically significant dose constraints were derived for rectal bleeding, increased bowel frequency, faecal incontinence and rectal pain (table). Conclusions: Dose constraints differed between symptoms, indicating potentially different pathogenesis of each radiation-induced side effect. Derived dose constraints were tighter than those used in CHHiP; use of these may reduce anorectal symptoms post RT. Comparable data derived from the hypofractionated cohorts will be presented. [Table: see text]
Contribution of microRNA-200b-3p to radiation therapy resistance in 22RV1 prostate cancer cells.
Authors: Thoms John , Aoki Satoko , Pena Castillo Lourdes 
Published: February 2018

89 Background: Radiation therapy (RT) is a standard treatment option for men with localized prostate cancer. Despite having well-established treatment regimens, such men still fail RT at a rate of up to 30-50%. RT resistant phenotype is a key component leading to treatment failure. MicroRNAs (miRNAs) can influence the response to RT, and the abundance or lack of certain miRNAs can induce a RT resistant phenotype through alteration of survival pathways. We show that altered expression of miR-200b-3p plays an important role in contributing to RT resistance. Methods: RT resistant subline from the parental 22RV1 prostate cancer cell line was generated by exposure to fractionated RT – 22RV1-RT. The global expression level of miRNAs and mRNA was determined, using the Affymetrix GeneChip®: miRNA 4.0 and Human Gene 2.0 ST Arrays. Parental and 22RV1-RT cells were transfected with miR-200b-3p mimics or negative control. The influence of miR-200b-3p on cellular proliferation, morphology, migration, clonogenic survival and response to RT was determined by standard assays. Results: MiR-200b-3p was the only miRNA that was statistically differentially expressed between the two cell lines. There were 39 differentially expressed genes. Of the 65 genes predicted to be regulated by miR-200b-3p as identified from miRTarBase, only Fibronectin 1 (FN1) was in common. FN1 was up-regulated in 22RV1- RT cells. MiR-200b-3p mimics; in comparison to negative control mimics, suppressed cell proliferation in both cell lines. Both cell lines with negative control mimics have fibroblastic-type morphology and display a stretched shape following RT. While, cells transfected with miR-200b-3p mimics demonstrated a round morphology and formed clusters following RT. Over-expression of miR-200b-3p mimics inhibited cell migration synergically with RT and demonstrated a lower degree of clonogenic survival following RT in 22RV1-RT cells compared to negative control mimics. Surprisingly, miR-200b-3p mimics reversed the observed RT resistance and the sensitivity to RT was to the same degree as the parental 22RV1 cells. Conclusions: Together, these data suggest that miR-200b-3p independently contributes to RT resistance in 22RV1 prostate cancer cells.
Microrna-198: A novel tumor suppressor in prostate cancer.
Authors: Ray Jessica , Hoey Christianne , Huang Xiaoyong , Boutros Paul Christopher , Liu Stanley K. 
Published: February 2018

92 Background: microRNAs (miRNAs) are small non-coding RNA molecules which act as repressors of gene function, and have been identified as playing substantial roles in cancer as both tumor suppressors and oncogenes. miR-198 has been reported to be down-regulated in several cancers, with low expression associated with worse overall survival. In addition, miR-198 has demonstrated tumor suppressor effects by altering several hallmarks of cancer. Despite compelling evidence in other cancers, miR-198's role in prostate cancer aggression has not yet been evaluated. Methods: Experiments were conducted by overexpressing miR-198 in three prostate cancer cell lines: DU145, LNCaP and 22RV1. To examine miR-198's effect on hallmarks of cancer in vitro, we used standard protocols to assay proliferation, colony formation, cell cycle profile, migration, and invasive potential. Gene array, qPCR, western blotting, and siRNA knockdown experiments were used to establish miR-198 downstream targets. Results: Overexpression of the candidate tumor suppressor miR-198 diminished proliferation in all prostate cancer cell lines and significantly impaired colony formation in soft agar. Subsequently, miR-198 expression was also demonstrated to reduce growth and tumor formation in vivo using LNCaP xenografts. Gene arrays and in silico target prediction identified several candidate targets, none of which have been previously linked to miR-198. MIB1, an E3 ubiquitin ligase, was the only target we have since identified to be reduced with miR-198 overexpression at both the RNA and protein levels. Knockdown of MIB1 recapitulated miR-198's effects on proliferation and colony formation, and further experiments are underway to demonstrate a direct binding relationship. An additional gene array with MIB1 siRNA will be performed to highlight pathways through which MIB1/miR-198 suppress tumorigenesis. Conclusions: Our evidence supports miR-198 as an important tumor suppressor in prostate cancer, with elevated expression impairing proliferation, colony formation, and in vivo tumor formation. This investigation into miR-198 highlights a potential role as a prostate cancer biomarker, or as a potential target of therapeutics to restore miRNA activity.