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Introduction: Brachytherapy is a well-established treatment of localized prostate cancer. Few studies have documented long-term results, specifically biochemical progression-free survival (bPFS) in men with brachytherapy alone, with or without short-term androgen deprivation therapy (ADT), or in combination with external beam radiotherapy (EBRT). Our aim was to analyze long-term bPFS of brachytherapy treated patients. Materials and methods: Retrospective analysis of 1457 patients with low and intermediate risk prostate cancer treated with brachytherapy alone (1255) or combined with EBRT (202). Six-months ADT was administrated for all EBRT combined patients and for prostate volume downsizing when >55 cc (328). Failure was by the Phoenix definition. Kaplan-Meier analysis and multivariate Cox regression estimated and compared 10-yr and 15-yr rates of bPFS. Results: Median follow-up was 6.1 yr. Ten and 15-yr bPFS rates of the entire cohort were 93.2% and 89.2%, respectively. On multivariate analysis, PSA density (PSAD), ADT and clinical stage were significantly associated with failure. The most powerful independent factor was PSAD with a HR of 3.5 (95% CI, 1.7–7.4) for PSAD above 0.15. No significant difference was found between low and intermediate risks patients regardless of treatment regimen. However, comparison of two intermediate risk groups, Gleason score (GS) 7, PSA<20 ng/ml versus GS≤6 and PSA = 10–20 ng/ml, revealed 10- and 15-yr bPFS rates of 94.2% and 94.2% compared to 88.2% and 79.9%, (P = 0.022), respectively. ADT improved bPFS rates in low risk patients. The ten and 15-yr bPFS rates were 97.6% and 94.6% compared to 92.3% and 88.2%, (P = 0.020), respectively. Conclusions: Our retrospective large scale study suggests that brachytherapy provides excellent long-term bPFS rates in low and intermediate risk disease. Combination of brachytherapy with EBRT yields favorable outcomes in GS 7 intermediate risk patients and short-term ADT has a positive effect on outcomes in low risk patients. Further prospective studies are warranted to discriminate the role of adding either EBRT and/or ADT to brachytherapy protocols. [ABSTRACT FROM AUTHOR]

Background: Irreversible Electroporation (IRE) is a novel image-guided tissue ablation technology that induces cell death via very short but strong pulsed electric fields. IRE has been shown to have preserving properties towards vessels and nerves and the extracellular matrix. This makes IRE an ideal candidate to treat prostate cancer (PCa) where other treatment modalities frequently unselectively destroy surrounding structures inducing severe side effects like incontinence or impotence. We report the retrospective assessment of 471 IRE treatments in 429 patients of all grades and stages of PCa with 6-year maximum follow-up time. Material and findings: The patient cohort consisted of low (25), intermediate (88) and high-risk cancers (312). All had multi-parametric magnetic resonance imaging, and 199 men had additional 3D-mapping biopsy for diagnostic work-up prior to IRE. Patients were treated either focally (123), sub-whole-gland (154), whole-gland (134) or for recurrent disease (63) after previous radical prostatectomy, radiation therapy, etc. Adverse effects were mild (19.7%), moderate (3.7%) and severe (1.4%), never life-threatening. Urinary continence was preserved in all cases. IRE-induced erectile dysfunction persisted in 3% of the evaluated cases 12 months post treatment. Mean transient IIEF-5-Score reduction was 33% within 12-month post IRE follow-up and 15% after 12 months. Recurrences within the follow-up period occurred in 10% of the treated men, 23 in or adjacent to the treatment field and 18 outside the treatment field (residuals). Including residuals for worst case analysis, Kaplan Maier estimation on recurrence rate at 5 years resulted in 5.6% (CI95: 1.8–16.93) for Gleason 6, 14.6% (CI95: 8.8–23.7) for Gleason 7 and 39.5% (CI95: 23.5–61.4) for Gleason 8–10. Conclusion: The results indicate comparable efficacy of IRE to standard radical prostatectomy in terms of 5-year recurrence rates and better preservation of urogenital function, proving the safety and suitability of IRE for PCa treatment. The data also shows that IRE, besides focal therapy of early PCa, can also be used for whole-gland ablations, in patients with recurrent PCa, and as a problem-solver for local tumor control in T4-cancers not amenable to surgery and radiation therapy anymore. [ABSTRACT FROM AUTHOR]

Background and purpose: In prostate cancer treatment with external beam radiation therapy (EBRT), prostate motion and internal changes in tissue distribution can lead to a decrease in plan quality. In most currently used planning methods, the uncertainties due to prostate motion are compensated by irradiating a larger treatment volume. However, this could cause underdosage of the treatment volume and overdosage of the organs at risk (OARs). To reduce this problem, in this proof of principle study we developed and evaluated a novel adaptive planning method. The strategy proposed corrects the dose delivered by each beam according to the actual position of the target in order to produce a final dose distribution dosimetrically as similar as possible to the prescribed one. Material and methods: Our adaptive planning method was tested on a phantom case and on a clinical case. For the first, a pilot study was performed on an in-silico pelvic phantom. A “library” of intensity modulated RT (IMRT) plans corresponding to possible positions of the prostate during a treatment fraction was generated at planning stage. Then a 3D random walk model was used to simulate possible displacements of the prostate during the treatment fraction. At treatment stage, at the end of each beam, based on the current position of the target, the beam from the library of plans, which could reproduce the best approximation of the prescribed dose distribution, was selected and delivered. In the clinical case, the same approach was used on two prostate cancer patients: for the first a tissue deformation was simulated in-silico and for the second a cone beam CT (CBCT) taken during the treatment was used to simulate an intra-fraction change. Then, dosimetric comparisons with the standard treatment plan and, for the second patient, also with an isocenter shift correction, were performed. Results: For the phantom case, the plan generated using the adaptive planning method was able to meet all the dosimetric requirements and to correct for a misdosage of 13% of the dose prescription on the prostate. For the first clinical case, the standard planning method caused underdosage of the seminal vesicles, respectively by 5% and 4% of the prescribed dose, when the position changes for the target were correctly taken into account. The proposed adaptive planning method corrected any possible missed target coverage, reducing at the same time the dose on the OARs. For the second clinical case, both with the standard planning strategy and with the isocenter shift correction target coverage was significantly worsened (in particular uniformity) and some organs exceeded some toxicity objectives. While with our approach, the most uniform coverage for the target was produced and systematically the lowest toxicity values for the organs at risk were achieved. Conclusions: In our proof of principle study, the adaptive planning method performed better than the standard planning and the isocenter shift methods for prostate EBRT. It improved the coverage of the treatment volumes and lowered the dose to the OARs. This planning method is particularly promising for hypofractionated IMRT treatments in which a higher precision and control on dose deposition are needed. Further studies will be performed to test more extensively the proposed adaptive planning method and to evaluate it at a full clinical level. [ABSTRACT FROM AUTHOR]

Background: Recently, the clinical outcome of prostate cancer treated by hypofractionated radiation therapy has been reported. However, there are few reports from Japan. In Hidaka Hospital, hypofractionated intensity-modulated radiotherapy (HIMRT) for prostate cancer was initiated in 2007. The purpose of this study is to analyze the long-term outcome. Methods: Ninety-two patients with localized prostate cancer treated with HIMRT at Hidaka Hospital between 2007 and 2009 were retrospectively analyzed. HIMRT was delivered using TomoTherapy. The prescription dose was 66 Gy at 95% of the PTV in 22 fractions performed 3 days a week over 7 weeks in all patients. The overall survival rate, biochemical relapse-free rate, and acute and late toxicities were evaluated. Results: The median follow-up duration was 78 (range 14–100) months. The median age at the start of the HIMRT was 72 (range 46–84) years. The disease characteristics were as follows: stage T1c, 45; T2a, 20; T2b, 5; T2c, 1; T3a, 13; T3b, 6; T4, 2; Gleason score 6, 13; 7, 44; 8, 20; 9, 15; 10, 0; pretreatment PSA ≤10 ng/mL, 42; 10 to ≤20, 27; and >20, 23. According to the D’Amico classification system, 10, 37, and 45 patients were classified as low-risk, intermediate-risk, and high-risk. The overall survival rate, the cause-specific survival rate, and the biochemical relapse-free rate at 5 years was 94.7%, 100% and 98.9%, respectively. Severe acute toxicity (grade 3 or more) was not observed. The late urinary toxicity was 52.2% in grade 0, 28.3% in grade 1, 19.6% in grade 2, and 2.2% in grade 3. The late rectal toxicity was 78.3% in grade 0, 7.6% in grade 1, 9.8% in grade 2, and 4.3% in grade 3. Conclusions: The present study demonstrated that HIMRT using TomoTherapy for prostate cancer has a favorable outcome with tolerable toxicity. [ABSTRACT FROM AUTHOR]

Background: Effective interdisciplinary communication of imaging findings is vital for patient care, as referring physicians depend on the contained information for the decision-making and subsequent treatment. Traditional radiology reports contain non-structured free text and potentially tangled information in narrative language, which can hamper the information transfer and diminish the clarity of the report. Therefore, this study investigates whether newly developed structured reports (SRs) of prostate magnetic resonance imaging (MRI) can improve interdisciplinary communication, as compared to non-structured reports (NSRs). Methods: 50 NSRs and 50 SRs describing a single prostatic lesion were presented to four urologists with expert level experience in prostate cancer surgery or targeted MRI TRUS fusion biopsy. They were subsequently asked to plot the tumor location in a 2-dimensional prostate diagram and to answer a questionnaire focusing on information on clinically relevant key features as well as the perceived structure of the report. A validated scoring system that distinguishes between “major” and “minor” mistakes was used to evaluate the accuracy of the plotting of the tumor position in the prostate diagram. Results: The mean total score for accuracy for SRs was significantly higher than for NSRs (28.46 [range 13.33–30.0] vs. 21.75 [range 0.0–30.0], p < 0.01). The overall rates of major mistakes (54% vs. 10%) and minor mistakes (74% vs. 22%) were significantly higher (p < 0.01) for NSRs than for SRs. The rate of radiologist re-consultations was significantly lower (p < 0.01) for SRs than for NSRs (19% vs. 85%). Furthermore, SRs were rated as significantly superior to NSRs in regard to determining the clinical tumor stage (p < 0.01), the quality of the summary (4.4 vs. 2.5; p < 0.01), and overall satisfaction with the report (4.5 vs. 2.3; p < 0.01), and as more valuable for further clinical decision-making and surgical planning (p < 0.01). Conclusions: Structured reporting of prostate MRI has the potential to improve interdisciplinary communication. Through SRs, expert urologists were able to more accurately assess the exact location of single prostate cancer lesions, which can facilitate surgical planning. Furthermore, structured reporting of prostate MRI leads to a higher satisfaction level of the referring physician. [ABSTRACT FROM AUTHOR]

Background: Screening for prostate cancer is frequent in high-income countries, including Switzerland. Notably due to overdiagnosis and overtreatment, various organisations have recently recommended against routine screening, potentially having an impact on incidence, mortality, and surgery rates. Our aim was therefore to examine whether secular trends in the incidence and mortality of prostate cancer, and in prostatectomy rates, have recently changed in Switzerland. Methods: We conducted a population-based trend study in Switzerland from 1998 to 2012. Cases of invasive prostate cancer, deaths from prostate cancer, and prostatectomies were analysed. We calculated changes in age-standardised prostate cancer incidence rates, stratified by tumor stage (early, advanced), prostate cancer-specific mortality, and prostatectomy rates. Results: The age-standardised incidence rate of prostate cancer increased greatly in men aged 50–69 years (absolute mean annual change +4.6/100,000, 95% CI: +2.9 to +6.2) between 1998 and 2002, and stabilised afterwards. In men aged ≥ 70 years, the incidence decreased slightly between 1998 and 2002, and more substantially since 2003. The incidence of early tumor stages increased between 1998 and 2002 only in men aged 50–69 years, and then stabilised, while the incidence of advanced stages remained stable across both age strata. The rate of prostatectomy increased markedly until 2002, more so in the 50 to 69 age range than among men aged ≥ 70 years; it leveled off after 2002 in both age strata. Trends in surgery were driven by radical prostatectomy. Since 1998, the annual age-standardised mortality rate of prostate cancer slightly declined in men aged 50–69 years (absolute mean annual change -0.1/100,000, 95% CI: -0.2 to -0.1) and ≥ 70 years (absolute mean annual change -0.5/100,000, 95% CI: -0.7 to -0.3). Conclusions: The increases in the incidence of early stage prostate cancer and prostatectomy observed in Switzerland among men younger than 70 years have concomitantly leveled off around 2002/2003. Given the decreasing mortality, these trends may reflect recent changes in screening and clinical workup practices, with a possible attenuation of overdiagnosis and overtreatment. [ABSTRACT FROM AUTHOR]

Objectives: No study has reported clinical results of external-beam radiotherapy specifically for T3b prostate cancer. The possibility of escalating the dose to the involved seminal vesicles (ISV) while respecting the dose constraints in the organs at risk is thus so far not clearly demonstrated. The objective of the study was to analyze the dose distribution and the clinical outcome in a large series of patients who received IMRT for T3b prostate cancer. Materials and methods: This retrospective analysis included all patients who received IMRT and androgen deprivation therapy for T3b prostate cancer, between 2008 and 2017, in six French institutions, with available MRI images and dosimetric data. Results: A total of 276 T3b patients were included. The median follow-up was 26 months. The median (range) prescribed doses (Gy) to the prostate and to the ISV were 77 (70–80) and 76 (46–80), respectively. The dose constraint recommendations were exceeded in less than 12% of patients for the rectum and the bladder. The 5-year risks of biochemical and clinical recurrences and cancer-specific death were 24.8%, 21.7%, and 10.3%, respectively. The 5-year risks of local, pelvic lymph node, and metastatic recurrences were 6.4%, 11.3%, and 15%, respectively. The number of involved lymph nodes (≤ 2 or ≥ 3) on MRI was the only significant prognostic factor in clinical recurrence (HR 9.86) and death (HR 2.78). Grade ≥ 2 acute and 5-year late toxicity rates were 13.2% and 12% for digestive toxicity, and 34% and 31.5% for urinary toxicity, respectively. The dose to the pelvic lymph node and the age were predictive of late digestive toxicity. Conclusion: IMRT for T3b prostate cancer allows delivery of a curative dose in the ISV, with a moderate digestive toxicity but a higher urinary toxicity. Lymph node involvement increases the risk of recurrence and death. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate predictors of residual tumor and clinical prognosis in T1a-T1b (incidental) prostate cancer by analysis of specimens from men undergoing surgery for benign prostatic hyperplasia. Materials and methods: We retrospectively reviewed medical records of incidental prostate cancer patients who had undergone radical prostatectomy. Patients whose tumor statuses were further confirmed by prostate biopsy, or who had used androgen deprivation therapy before radical prostatectomy, were excluded. Clinical and pathological parameters were analyzed to evaluate residual tumor and clinical prognosis. We used univariate and multivariate logistic regression analyses, as well as receiver operator characteristics, to predict residual tumor (pT0). Results: The final analysis included 95 patients. Among these patients, 67 (70.53%) exhibited residual tumor, whereas 28 (29.47%) did not (pT0). Pathology findings showed that 44 (65.67%), 16 (23.88%), and 7 patients (10.45%) exhibited Gleason scores of G6, G7, and ≥G8, respectively. Fifty-seven and 10 patients exhibited pathologic T stages T2 and T3, respectively. Mean follow-up duration was 70.26 (±34.67) months. Biochemical recurrence was observed in 11 patients; none were pT0 patients. Multivariate logistic regression showed that low prostate-specific antigen density after benign prostatic hyperplasia surgery and invisible lesion on multiparametric magnetic resonance imaging were significantly associated with pT0. Additionally, a combination of these factors showed an increase in the diagnostic accuracy of pT0, compared with mpMRI alone (AUC 0.805, 0.767, respectively); this combination showed sensitivity, specificity, and positive predictive values of 71.6%, 89.3%, and 94.1%, respectively. Conclusion: Our results suggest that patients with incidental prostate cancer who have both prostate-specific antigen density ≤0.08 after benign prostatic hyperplasia surgery as well as invisible cancer lesion on multiparametric magnetic resonance imaging should be considered for active surveillance. [ABSTRACT FROM AUTHOR]

Background: Cancer and its treatment affect body systems that are important in preventing falls and controlling balance/walking. This study examined factors associated with self-reported falls and balance/walking difficulty in the past 12 months in older survivors of four major cancers. Methods: This was a cross-sectional study analyzing population-based data from Surveillance, Epidemiology, and End Results–Medicare Health Outcomes Survey (SEER-MHOS). Data from cohorts 9 to 14 (January 2006 to December 2013) were extracted. Inclusion criteria were: age ≥65 years at cancer diagnosis, first MHOS completed during years 1–5 post-cancer diagnosis, first primary breast (n = 2725), colorectal (n = 1646), lung (n = 752), and prostate (n = 4245) cancer, and availability of cancer staging information. Primary outcomes were self-reported falls and balance/walking difficulty in the past 12 months. Multivariable logistic regression was constructed for each cancer type to examine independent factors associated with falls and balance/walking difficulty. Results: In all cancer types, advancing age at cancer diagnosis and dependence in activities of daily living were significant independent factors associated with increased odds of reporting falls and balance/walking difficulty in the past 12 months. Additionally, depression was independently associated with falls and sensory impairment in feet was independently linked to balance/walking difficulty in all cancer types. Other independent factors of falls and balance/walking difficulty varied across cancer types. In breast cancer only, localized or regional cancer stage was significantly associated with increased odds of reporting falls and balance/walking difficulty, whereas treatment with radiation decreased the odds of falling. No association between falls and balance/walking difficulty with time since cancer diagnosis, cancer stage, or cancer treatment was found in colorectal, lung, and prostate cancer. Conclusion: There exists some heterogeneity in factors associated with self-reported falls and balance/walking difficulty between different cancer types. Future research is necessary to ascertain factors predictive of falls and balance/walking difficulty in older cancer survivors, particularly factors related to cancer diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Treatment of metastatic prostate cancer is associated with high personal and economic burden. Recently, new treatment options for castration-resistant prostate cancer became available with promising survival advantages. However, cost-effectiveness of those new treatment options is sometimes ambiguous or given only under certain circumstances. The aim of this study was to systematically review studies on the cost-effectiveness of treatments and costs of castration-resistant prostate cancer (CRPC) and metastasizing castration-resistant prostate cancer (mCRPC) on their methodological quality and the risk of bias. Methods: A systematic literature search was performed in the databases PubMed, CINAHL Complete, the Cochrane Library and Web of Science Core Collection for costs-effectiveness analyses, model-based economic evaluations, cost-of-illness analyses and budget impact analyses. Reported costs were inflated to 2015 US$ purchasing power parities. Quality assessment and risk of bias assessment was performed using the Consolidated Health Economic Evaluation Reporting Standards checklist and the Bias in Economic Evaluations checklist, respectively. Results: In total, 38 articles were identified by the systematic literature search. The methodological quality of the included studies varied widely, and there was considerable risk of bias. The cost-effectiveness treatments for CRPC and mCRPC was assessed with incremental cost-effectiveness ratios ranging from dominance for mitoxantrone to $562,328 per quality-adjusted life year gained for sipuleucel-T compared with prednisone alone. Annual costs for the treatment of castration-resistant prostate cancer ranged from $3,067 to $77,725. Conclusion: The cost-effectiveness of treatments of CRPC strongly depended on the willingness to pay per quality-adjusted life year gained/life-year saved throughout all included costs-effectiveness analyses and model-based economic evaluations. High-quality cost-effectiveness analyses based on randomized controlled trials are needed in order to make informed decisions on the management of castration-resistant prostate cancer and the resulting financial impact on the healthcare system. [ABSTRACT FROM AUTHOR]

Stereotactic body radiation therapy with CyberKnife for prostate cancer has long treatment times compared with conventional radiotherapy. This arises the need for designing treatment plans with short execution times. We propose an objective function for plan quality evaluation, which was used to determine an optimal combination between small and large collimators based on short treatment times and clinically acceptable dose distributions. Data from 11 prostate cancer patients were used. For each patient, 20 plans were created based on all combinations between one small (⌀ 10–25 mm) and one large (⌀ 35–60 mm) Iris collimator size. The objective function was assigned to each combination as a penalty, such that plans with low penalties were considered superior. This function considered the achievement of dosimetric planning goals, tumor control probability, normal tissue complication probability, relative seriality parameter, and treatment time. Two methods were used to determine the optimal combination. First, we constructed heat maps representing the mean penalty values and standard deviations of the plans created for each collimator combination. The combination giving a plan with the smallest mean penalty and standard deviation was considered optimal. Second, we created two groups of superior plans: group A plans were selected by histogram analysis and group B plans were selected by choosing the plan with the lowest penalty from each patient. In both groups, the most used small and large collimators were assumed to represent the optimal combination. The optimal combinations obtained from the heat maps included the 25 mm as a small collimator, giving small/large collimator sizes of 25/35, 25/40, 25/50, and 25/60 mm. The superior-group analysis indicated that 25/50 mm was the optimal combination. The optimal Iris combination for prostate cancer treatment using CyberKnife was determined to be a collimator size between 25 mm (small) and 50 mm (large). [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second most frequently diagnosed cancer and the fifth leading cause of death from cancer in men worldwide. Increased understanding of the prostate cancer metastasis mechanisms will help identify more efficient intervention strategies to prevent or treat this deadly disease in the future. To identify the candidate proteins that contribute to metastasis of PCa, isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis was performed to explore differentially expressed proteins between two homologous human prostate cancer cell lines including highly-metastatic PC-3M-1E8 cell line and poorly-metastatic PC-3M-2B4 cell line. Here, a total of 58 proteins were identified to be significantly differentially expressed between PC-3M-1E8 and PC-3M-2B4 cells, which were further verified using real-time quantitative PCR and western blot analysis. The bioinformatic analysis suggested that the differentially expressed proteins, like MMP1 and FHL1, may contribute to the higher metastatic ability of PC-3M-1E8 cells than PC-3M-2B4 cells. In addition, functional analyses proved MMP1’s positive effect on the higher metastatic ability of PC-3M-1E8 cells than PC-3M-2B4 cells. These findings provided a unique resource to specifically reveal the complex molecular regulatory mechanisms underlying the progression of prostate cancer from poorly-metastatic to highly-metastatic stage. [ABSTRACT FROM AUTHOR]

Single-fiber laser treatment of the prostate has been widely accepted in the clinic due to its minimal invasiveness and high controllability. However, for large tumors, multiple insertions of the laser probe would be needed to achieve full coverage of the tumor, increasing the complexity of the treatment and occasionally resulting in the incomplete killing of tumor cells due to a mismatch between the planned insertion location and the actual probe insertion location. Treatment with a dual-fiber laser results in greater lesion coverage following a single insertion of the probe, with the lesion coverage being even greater than the sum of the coverage of two sequential insertion of a single-fiber laser probe, potentially reducing treatment time and clinical complications. Both theoretical and experimental analyses have been performed to evaluate the proposed dual-fiber laser treatment. A finite element model was established to simulate the treatment process. The simulation results indicated that there is a clear difference between the ablation coverage created using dual-fiber laser ablation and that created using the superposition of sequential single-fiber laser ablation. In addition, the coverage is dependent on the spacing distance between the two fibers. Both ex vivo and in vivo canine prostate tissues were treated by dual-fiber laser ablation, with lesions analyzed by magnetic resonance imaging (MRI), ultrasound imaging, and pathology. The results demonstrate that dual-fiber laser ablation can markedly increase the range of the ablation zone when compared with single-fiber modes. The safety and feasibility of dual-fiber laser treatment has been confirmed, and a treatment plan using dual-fiber laser ablation has also been proposed. [ABSTRACT FROM AUTHOR]

Translation of radiomics into the clinic may require a more comprehensive understanding of the underlying morphologic tissue characteristics they reflect. In the context of prostate cancer (PCa), some studies have correlated gross histological measurements of gland lumen, epithelium, and nuclei with disease appearance on MRI. Quantitative histomorphometry (QH), like radiomics for radiologic images, is the computer based extraction of features for describing tumor morphology on digitized tissue images. In this work, we attempt to establish the histomorphometric basis for radiomic features for prostate cancer by (1) identifying the radiomic features from T2w MRI most discriminating of low vs. intermediate/high Gleason score, (2) identifying QH features correlated with the most discriminating radiomic features previously identified, and (3) evaluating the discriminative ability of QH features found to be correlated with spatially co-localized radiomic features. On a cohort of 36 patients (23 for training, 13 for validation), Gabor texture features were identified as being most predictive of Gleason grade on MRI (AUC of 0.69) and gland lumen shape features were identified as the most predictive QH features (AUC = 0.75). Our results suggest that the PCa grade discriminability of Gabor features is a consequence of variations in gland shape and morphology at the tissue level. [ABSTRACT FROM AUTHOR]

Purpose: This observational study investigates the influence of interfractional motion on clinical target volume (CTV) coverage, planning target volume (PTV) margins, and rectum tissue sparing in carbon ion radiation therapy (CIRT). It reports dose coverage to target structures and organs at risk in the presence of interfractional motion, investigates rectal tissue sparing, and provides recommendations for lowering the rate of toxicity. We also propose probabilistic DVH based on cone-beam computed tomography (CBCT) table shifts from photon therapy for consideration in bone-matching CIRT treatment planning to represent probable dose to our CIRT patient population. Methods: At Gunma University Hospital intensity-modulated x-ray therapy (IMXT, aka IMRT) prostate cancer patients are positioned on a table which is shifted twice based on CBCT to align bones and then align prostate tissue to isocenter. These shifts thereby contain interfractional motion. A total of 1306 such table shifts from 85 patients were collected. Normal probability distributions were fit to the difference between bone-matching and prostate-matching CBCT-to-planning CT table shifts (i.e. interfractional motion). Between 2011 and 2016 CIRT prostate patients were treated with three beams to PTV1 (lateral-opposing and anterior) one per day for 9 fractions and two beams for a boost PTV2 (lateral-opposing) one per day for 7 fractions for a prescribed total of 57.6 Gy(RBE) as follows: PTV1 extends the prostate contour by 10/10, 5/10, 6/6 mm in the right/left, posterior/anterior, and superior/inferior directions, respectively, and the proximal seminal vesicles contour by 5 mm superiorly and inferiorly, 3 mm right and left. PTV2 reduces PTV1 posteriorly along a straight line to exclude the rectum and reduces the superior and inferior margins by 6 mm. Probable interfractional motion for 40 patients was simulated using each patient’s own beam data as follows: The previously fit normal probability distributions were randomly sampled 2000 times per patient, and the five beams were shifted and summed with the same relative weighting as in the 16-fraction regimen. The resulting dose distribution was then scaled back down by 16/2000 to match the prescribed number of fractions. We then analyzed the resulting doses to contoured structures. Results: Probable dose to rectum is substantially less than planned: For example, mean+-standard deviation D2% for planned and probable DVH is 51+-1.9 and 45+-2.4, respectively. Cumulative DVH show mean CTV fraction receiving a given probable dose is less than the mean fraction receiving the corresponding planned dose for doses larger than 52 Gy(RBE), up to 19% less at 57.4 Gy(RBE). Our PTV1 margins generally cover 95% of interfractional motion but seminal vesicles and inferior prostate receive less dose than planned due to insufficient PTV2 margins. Conclusion: Assuming rigidly shifting interfractional motion around the prostate region and neglecting minor changes in soft tissue stopping power, interfractional motion resulted in target underdosing but better tissue sparing in all cases. Given our low rates of relapse and recurrence, it appears less curative dose is needed than previously thought or else current planning target margins may be excessive: Planning target volumes should be reconsidered with the adoption of dose verification methods. Our probable dose distributions quantify expected dose for future dose verification studies. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the performance of mpMRI and the 4Kscore test together for the detection of significant prostate cancer. Material and methods We selected a consecutive series of men who were referred for evaluation of prostate cancer at an academic institution and underwent mpMRI and the 4Kscore test. The primary outcome was the presence of Gleason 7 or higher cancer on biopsy of the prostate. We used logistic regression and Decision Curve Analysis to report the discrimination and clinical utility of using mpMRI and the 4Kscore test for prostate cancer detection. We modeled the probability of harboring a Gleason 7 or higher prostate cancer based on the 4Kscore test and mpMRI findings. Finally, we examined various combinations and sequences of mpMRI and the 4Kscore test and assessed the impact on biopsies avoided and cancers missed. Results: Among 300 men who underwent a 4Kscore test and mpMRI, 149 (49%) underwent a biopsy. Among those, 73 (49%) had cancer, and 49 (33%) had Gleason 7 cancer. The area under the curve (AUC) for using the 4Kscore test and mpMRI together 0.82 (0.75–0.89) was superior to using the 4Kscore 0.70 (0.62–0.79) or mpMRI 0.74 (0.66–0.81) individually (p = 0.001). Similarly, decision analysis revealed the highest net benefit was achieved using both tests. Conclusions: The 4Kscore test and mpMRI results provide independent, but complementary, information that enhances the prediction of higher-grade prostate cancer and improves patient’s selection for a prostate biopsy. Prospective trials are required to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: The management of localized prostate cancer is challenging because of the many therapeutic options available, none of which is generally acknowledged as superior to the others in every respect. The selection of the most appropriate treatment should therefore reflect patients’ preferences. Objective: The purpose of the following study was to pilot a new approach for investigating whether urologists who had previously provided patients with therapeutic advice actually knew their patients’ importance weights concerning the relevant aspects of the treatments at issue. Method: Participants were patients recently diagnosed with localized prostate cancer (n = 20), urologists (n = 10), and non-medical professionals (architects, n = 10). These last served as a control group for the urologists and were matched to them for age and gender. Patients’ importance weights were elicited by two standard methods (Direct Rating and Value Hierarchy). Each urologist was asked to estimate (with Direct Rating) his/her patient’s importance weights. The same task was performed by a corresponding architect, who never met the patient and knew only the patient’s age. Univariate and bivariate statistical analyses were performed to investigate the association between importance weights as elicited from patients and as estimated by urologists and architects, as well as to assess whether such agreement was attribute-dependent. Results: Participants found both elicitation methods easy to use. The correlation between patients’ actual importance weights and urologists’ estimates was poor and comparable to that obtained between patients and architects. This result did not depend on the attribute considered, with the sole exception of the attribute “Effectiveness in curing the cancer”, which was evaluated as the most important attribute by the majority of participants. Conclusion: These findings demonstrate the feasibility of the employed methodology and highlight the need to support preference-sensitive decisions in clinical practice by facilitating the elicitation of patients’ importance weights, as well as their communication to physicians. [ABSTRACT FROM AUTHOR]

Background: National guidelines (NICE-CG175) recommended 12 weeks of supervised exercise training for men treated with androgen deprivation therapy (ADT) for prostate cancer to counter debilitating adverse effects of castration. As with other chronic conditions where exercise is indicated, it is uncertain if these services are being delivered in the health services. The aim of this multi-centre investigation was to examine what exercise referral is currently available for men on ADT as provided by the NHS and if a supervised, individually-tailored exercise training package (as per the national NICE guidelines CG175) is embedded within prostate cancer care. Methods: A multi-centre investigation of current National Health Service (NHS) care involving a web-based survey of NHS prostate cancer care, five focus groups involving 26 men on ADT and 37 semi-structured interviews with healthcare professionals (HCPs) involved in the management of prostate cancer. Descriptive statistics and thematic analysis evaluated quantitative and qualitative data, respectively. Qualitative methods followed COREQ standards. Results: HCPs and men on ADT asserted that medical castration has a serious and debilitating impact on many features of men's quality of life. There is support for exercise training programmes as part of cancer care and patients would support their initiation soon after diagnosis. Involving the Multidisciplinary Team (MDT) is proposed as key to this. Critically, traditional values in oncology would need to be overcome for widespread acceptance. Specialist further training for HCPs around behaviour change support could encourage this. Given that these schemes are seen as a fundamental part of cancer care, it is felt the NHS should commission and support provision. 79 representatives of 154 NHS trusts (51%) provided survey data on current delivery: only 17% could provide supervised exercise as per CG175. Conclusions: Evidence-based national exercise guidelines are not being delivered to men on ADT as intended. Traditional values in oncology and the need for NHS financial support are seen as major barriers to provision of current best practice guidelines. Despite this both HCPs and men on ADT are in favour of such programmes being a fundamental part of their cancer care. [ABSTRACT FROM AUTHOR]

Radiation therapy is a useful and standard tumor treatment strategy. Despite recent advances in delivery of ionizing radiation, survival rates for some cancer patients are still low because of recurrence and radioresistance. This is why many novel approaches have been explored to improve radiotherapy outcome. Some strategies are focused on enhancement of accuracy in ionizing radiation delivery and on the generation of greater radiation beams, for example with a higher dose rate. In the present study we proposed an in vitro research of the biological effects of very high dose rate beam on SK-Mel28 and A375, two radioresistant human melanoma cell lines. The beam was delivered by a pulsed plasma device, a “Mather type” Plasma Focus for medical applications. We hypothesized that this pulsed X-rays generator is significantly more effective to impair melanoma cells survival compared to conventional X-ray tube. Very high dose rate treatments were able to reduce clonogenic efficiency of SK-Mel28 and A375 more than the X-ray tube and to induce a greater, less easy-to-repair DNA double-strand breaks. Very little is known about biological consequences of such dose rate. Our characterization is preliminary but is the first step toward future clinical considerations. [ABSTRACT FROM AUTHOR]

Purpose: Intermittent androgen deprivation therapy is an effective treatment for metastatic prostate cancer. However, no study to date has evaluated the long-term outcomes of this treatment among patients with prostate cancer after radical prostatectomy. We retrospectively examined the treatment outcomes of patients with prostate-specific antigen recurrence who underwent radical prostatectomy at our department. Materials and methods: Of the 690 patients who underwent radical prostatectomy for local prostate cancer between 1988 and 2011, 129 patients who received androgen deprivation therapy for prostate-specific antigen recurrence were included in this study. Patient characteristics, luteinizing hormone-releasing hormone agonist administration, and outcomes were compared between the intermittent androgen deprivation group (n = 66) and the continuous androgen deprivation therapy group (n = 63). The non-recurrence and overall survival rates were compared between groups. Results: Thirty-six patients (27.9%) experienced recurrence after luteinizing hormone-releasing hormone agonist administration. The 5-year non-recurrence rate and 10-year overall survival rate were higher in the intermittent group (92.9%) than in the continuous group (92.9 vs 57.9%, P < 0.001; and 95.9% vs 84.3%, P = 0.047, respectively). Furthermore, 63 patients (48.8%) showed a PSA nadir of less than 0.01 ng/mL after initiation of luteinizing hormone-releasing hormone agonist; among these patients, the non-recurrence rate was significantly higher in the intermittent androgen deprivation group (P = 0.003). Conclusions: Intermittent androgen deprivation therapy for prostate specific antigen recurrence after radical prostatectomy contributed to improvement of the non-recurrence rate and overall survival, and can be considered an effective therapy for better prognosis. [ABSTRACT FROM AUTHOR]

Background: Limited availability of real-world data that describe treatment patterns of Japanese prostate cancer (PCA) patients. Methods: A biweekly transition analysis of PCA treatment was performed for patients with PCA diagnosis and a specific treatment between 2010 and 2015. To account for different cancer stages, two patient populations were analyzed. The first group consisted of patients on medication for hormone-sensitive prostate cancer (HSPC). The second group is comprised of patients who ended up receiving specific therapy for castration-resistant prostate cancer (CRPC). For each treatment, the average of treatment duration and the portion of patients transitioning to a consecutive treatment was calculated. Results: We identified 59,626 patients from the Japanese administrative database with a PCA diagnosis and specific treatment. In the first year of our observational study 786 patients commenced a HSPC treatment and 695 received a CRPC specific therapy Among the HSPC group, we found that combination hormonal therapy, comprised of a gonadotrophin releasing hormone agonist or antagonist with an antiandrogen was more common than monotherapy. The results of the CRPC group indicated that chemotherapy administration was for a shorter time period in a real-world setting as compared to published clinical studies. Conclusion: Utilizing a novel method to visualize real-world treatment pathways for PCA patients we found that real treatment pathways are in line with international guidelines. [ABSTRACT FROM AUTHOR]

Introduction: Radiotherapy can diminish quality of life (QoL) for prostate cancer patients. Our objective was to evaluate the effect of radiotherapy on QoL in men aged 75 years or older treated with radiotherapy for a localized prostate cancer, and to identify predictors of reduced QoL. Patients and methods: We prospectively administered a battery of geriatric (MNA, GDS, Get up and Go Test, CIRS-G, ADL, IADL, MMSE), toxicity (IPSS; IIEF 5), and QoL (QLQ C30) screening tests in 100 elderly patients before and two months after prostate cancer radiotherapy (NCT 02876237). Patients ≥ 75 years undergoing radiotherapy with a curative intent for localized prostate cancer with or without androgen deprivation therapy (ADL) were eligible for study inclusion. Correlations between patient-assessed QoL and tumor characteristics, radiotherapy treatment or CGA parameters were sought using the Fisher or the Mann and Whitney tests. Changes in QoL parameters over time were analyzed using the Wilcoxon signed-rank test. Results: At study entry, scores for IADL impairments were present in 51%, reduced autonomy in activities of daily living in 16%, cognitive impairment found in 20%, depression-related symptoms in 31%, and 66% of patients had significant co-morbidities. Eight percent were judged to be at risk of fall and 2% were found to be undernourished. Severely impaired (IPSS ≥ 20) urinary function was observed in 11.2% and 13.5% of patients before and two months after completion of radiotherapy respectively. Significantly decreased QoL (> 20 points) at two months after treatment was found in 13% of patients and a moderate but clinically relevant reduction (10 to 20 points) in 17% of patients. No tumor characteristic, treatment, or oncogeriatric parameter was predictive of reduced QoL following prostate cancer radiotherapy. Conclusion: Despite sometimes markedly diminished oncogeriatric parameters, prostate cancer radiotherapy was generally well tolerated in these elderly patients. We found no predictive factor to determine which patients would experience impaired quality of life following radiotherapy. [ABSTRACT FROM AUTHOR]

For CyberKnife-mediated prostate cancer treatment, a tumour-tracking approach is applied to correct the target location by acquiring X-ray images of implanted fiducial markers intermittently. This study investigated the dosimetric impact of intra-fraction prostate motion during CyberKnife treatment. We retrospectively analyzed 16 patients treated using the CyberKnife (35 Gy delivered in five fractions). Using log files of recorded prostate motion, the intra-fraction prostate motion was simulated. We defined the worst-case intra-fraction prostate motion as the difference between pre- and post-deviation on log files and shifted structure sets according to the corresponding offsets for each beam. The dose–volume indices were calculated and compared with the original plan in terms of clinical target volume (CTV), planning target volume (CTV plus a 2-mm margin), rectum, bladder, and urethra. Prostate motions of >3, >5, and >10 mm were observed for 31.3, 9.1, and 0.5% of the 1929 timestamps, respectively. Relative differences between the simulated and original plans were mostly less than 1%. Although significant decreases were observed in D50% and D98% of the target, absolute dose differences were <0.1 Gy compared with the planned dose. The dosimetric impact of intra-fraction prostate motion may be small even with longer treatment durations, indicating that the tumour tracking using the CyberKnife could be a robust system for examining prostate motion. [ABSTRACT FROM AUTHOR]

Objective: To assess whether the use of complementary and alternative medicines therapies (CAMs) for prostate cancer and/or its treatment side effects by long-term survivors is associated with selected socio-demographic, clinical, health-related quality-of-life (HRQOL) and/or psychological factors. Design, setting and participants: The Prostate Cancer Care and Outcomes Study (PCOS) is a population-based cohort study of men with prostate cancer who were aged less than 70 years at diagnosis in New South Wales, Australia. Included in these analyses were men who returned a 10-year follow-up questionnaire, which included questions about CAM use. Methods: Validated instruments assessed patient’s HRQOL and psychological well-being. Poisson regression with robust variance estimation was used to estimate the adjusted relative risks of current CAM use for prostate cancer according to socio-demographic, clinical, HRQOL and psychological factors. Results: 996 of 1634 (61%) living PCOS participants completed the 10-year questionnaire. Of these 996 men, 168 (17%) were using CAMs for prostate cancer and 525 (53%) were using CAMs for any reason (including prostate cancer). Those using CAM for prostate cancer were more likely to be regular or occasional support group participants (vs. no participation RR = 2.02; 95%CI 1.41–2.88), born in another country (vs. Australian born RR = 1.59; 95%CI 1.17–2.16), have received androgen deprivation treatment (ADT) since diagnosis (RR = 1.60; 95%CI 1.12–2.28) or in the past two years (RR = 2.34; 95%CI 1.56–3.52). CAM use was associated with greater fear of recurrence (RR = 1.29; 95%CI 1.12–1.48), cancer-specific distress (RR = 1.15; 95%CI 1.01–1.30), cancer-specific hyperarousal (RR = 1.17; 95%CI 1.04–1.31), cancer locus of control (RR = 1.16; 95%CI 1.01–1.34) and less satisfaction with medical treatments (RR = 0.86; 95%CI 0.76–0.97), but not with intrusive thinking, cognitive avoidance, depression, anxiety or any HRQOL domains. Conclusions: In this study, about one in six long term prostate cancer survivors used CAMs for their prostate cancer with use centred around ADT, country of birth, distress, cancer control, fear of recurrence and active help seeking. [ABSTRACT FROM AUTHOR]

NutramilTM Complex is a multicomponent food product that meets the requirements of a food for special medical purpose. As a complete, high-energy diet it consists of properly balanced nutrients, vitamins and minerals. The aim of this study was to assess the effect of NutramilTM Complex on breast and prostate carcinoma cells. Our results showed that NutramilTM Complex reduced the viability and proliferation of breast and prostate cancer cells and that this process was associated with the induction of apoptosis via activation of caspase signalling. Data showed elevated levels of p53 tumour suppressor, up-regulation of p38 MAPK and SAPK / JNK proteins and downregulation of anti-apoptotic ERK1/2, AKT1 and HSP27. Treatment with NutramilTM Complex also affected the expression of the BCL2 family genes. Results also showed down-regulation of anti-apoptotic BCL-2 and up-regulation of pro-apoptotic members such as BAX, BAD, BID. In addition, we also observed regulation of many other genes, including Iκβα, Chk1 and Chk2, associated with apoptotic events. Taken together, our results suggest activation of the mitochondrial apoptotic pathway as most likely mechanism of anti-carcinogenic activity of NutramilTM Complex. [ABSTRACT FROM AUTHOR]

Background: In advanced prostate cancer, osteoclast inhibitors prevent and palliate skeletal related events associated with bone metastases. However, it is uncertain whether they play a disease-modifying role earlier in the course of the disease. Methods: Medline, EMBASE, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews and ASCO conference proceedings were searched for randomized controlled trials that compared osteoclast inhibitors with placebo and/or standard of care (SOC) in patients with high-risk, non-metastatic prostate cancer. The primary outcome measure was incidence of new bone metastases; secondary outcomes included overall survival (OS), prostate cancer specific survival, mortality unrelated to prostate cancer, toxicity and health related quality of life outcomes. Results are presented as relative risk (RR) with 95% confidence intervals (CI). Results: Six randomized controlled trials (5947 participants) were included, five evaluating bisphosphonates and one denosumab. Overall, there was no difference in incidence of bone metastases between participants treated with osteoclast inhibitors versus placebo/SOC (RR 1.09, 95%CI 0.84–1.41, p = 0.51) however significant heterogeneity was observed between studies. The denosumab trial was the largest and only positive trial amongst the included studies (RR 0.83, 95%CI 0.73–0.95, p = 0.007). No significant difference was observed in OS (RR 0.99 95% CI 0.89–1.10, p = 0.84) nor prostate cancer specific survival (RR 1.12 95%CI 0.93–1.36, p = 0.24). Most studies reported increased rates of osteonecrosis of the jaw (5% or less) and hypocalcemia (2% or less) with osteoclast inhibitors. Conclusions: While there is limited evidence that bisphosphonates alter the natural history of high-risk, non-metastatic prostate cancer, denosumab delays onset of bone metastases in this patient population. Neither class of osteoclast inhibitor demonstrated an impact on survival outcomes. Future trials with better defined patient selection and a robust definition for high risk disease is critical. [ABSTRACT FROM AUTHOR]

The microenvironment of prostate cancer often includes abundant tumor-associated macrophages (TAMs), with their acquisition of an M2 phenotype correlating with local aggressiveness and metastasis. Tumor-derived M-CSF contributes to TAM M2 polarization, and M-CSF receptor inhibition slows prostate cancer growth in model systems. As additional cytokines can direct TAM M2 polarization, targeting downstream transcription factors could avoid resistance. Klf4 and C/EBPβ each contribute to monocyte development, and reduced expression of macrophage Klf4 or C/EBPβ favors their adoption of a pro-inflammatory M1 state. We find that a Hi-Myc C57BL/6 prostate cancer line grows more slowly in syngeneic Klf4(f/f);Lys-Cre compared with Klf4(f/f) mice when inoculated subcutaneously, but grows equally rapidly in C/EBPβ(f/f);Lys-Cre and C/EBPβ(f/f) hosts. In the absence of myeloid Klf4, TAMs have reduced expression of surface mannose receptor and Fizz1 mRNA, both M2 markers. Global gene expression analysis further revealed activation of pro-inflammatory, pro-atherosclerotic pathways. Analysis of tumor-infiltrating lymphocytes (TILs) demonstrated markedly increased activated CD8 T cell numbers, and CD8 T cell depletion obviated the inhibitory effect of myeloid Klf4 deletion on prostate cancer growth. These findings suggest that reducing expression or activity of the Klf4 transcription factor in tumor myeloid cells may contribute to prostate cancer therapy. [ABSTRACT FROM AUTHOR]

High linear energy transfer (LET) radiation or heavy ion such as carbon ion radiation is used as a method for advanced radiotherapy in the treatment of cancer. It has many advantages over the conventional photon based radiotherapy using Co-60 gamma or high energy X-rays from a Linear Accelerator. However, charged particle therapy is very costly. One way to reduce the cost as well as irradiation effects on normal cells is to reduce the dose of radiation by enhancing the radiation sensitivity through the use of a radiomodulator. PNKP (polynucleotide kinase/phosphatase) is an enzyme which plays important role in the non-homologous end joining (NHEJ) DNA repair pathway. It is expected that inhibition of PNKP activity may enhance the efficacy of the charged particle irradiation in the radioresistant prostate cancer cell line PC-3. To test this hypothesis, we investigated cellular radiosensitivity by clonogenic cell survival assay in PC-3 cells.12Carbon ion beam of62 MeVenergy (equivalent 5.16 MeV/nucleon) and with an entrance LET of 287 kev/μm was used for the present study. Apoptotic parameters such as nuclear fragmentation and caspase-3 activity were measured by DAPI staining, nuclear ladder assay and colorimetric caspase-3method. Cell cycle arrest was determined by FACS analysis. Cell death was enhanced when carbon ion irradiation is combined with PNKPi (PNKP inhibitor) to treat cells as compared to that seen for PNKPi untreated cells. A low concentration (10μM) of PNKPi effectively radiosensitized the PC-3 cells in terms of reduction of dose in achieving the same survival fraction. PC-3 cells underwent significant apoptosis and cell cycle arrest too was enhanced at G2/M phase when carbon ion irradiation was combined with PNKPi treatment. Our findings suggest that combined treatment of carbon ion irradiation and PNKP inhibition could enhance cellular radiosensitivity in a radioresistant prostate cancer cell line PC-3. The synergistic effect of PNKPi and carbon ion irradiation could be used as a promising method for carbon-ion therapy in radioresistant cells. [ABSTRACT FROM AUTHOR]

Hepatoma-derived growth factor (HDGF) is commonly over-expressed and plays critical roles in the development and progression in a variety of cancers. It has previously been shown that HDGF is overregulated in prostate cancer cells compared to normal prostate cells, which is correlated with cellular migration and invasion of prostate cancer. Here, the molecular mechanisms of HDGF in prostate cancer is investigated. It is shown that HDGF knockdown reduces prostate cancer cellular migration and invasion in both androgen-sensitive LNCaP cells and androgen-insensitive DU145 and PC3 cells. Furthermore, Western blot analysis reveals that HDGF knockdown inhibits epithelial-mesenchymal transition (EMT) of prostate cancer cells by upregulation of protein E-cadherin and downregulation of proteins N-cadherin, Vimentin, Snail and Slug. In addition, mechanistic studies reveal that proteins MMP2 and MMP9 are down-regulated. In conclusion, our data suggested that HDGF knockdown inhibits cellular migration and invasion in vitro of prostate cancer via modulating epithelial-mesenchymal transition (EMT) signaling pathway, as well as MMP2 and MMP9 signaling pathway. These results supported that HDGF is a relevant protein in the progression of prostate cancer and may serve as a potentially therapeutic target for prostate cancer as well as its downstream targets. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PC) stratification needs new prognostic tools to reduce overtreatment. Phosphatase of regenerating liver (PRL-3) is a phosphatase found at high levels in several cancer types, where its expression is associated with survival. A recent PC cell line study has shown it to be involved in PC growth and migration. Methods: We used a monoclonal antibody to evaluate the expression of PRL-3 in PC tissue of patients in an unselected cohort of 535 prostatectomy patients. We analyzed associations between PRL-3 expression and biochemical failure-free survival (BFFS), clinical failure-free survival (CFFS) and PC death-free survival (PCDFS). Results: Cytoplasmic PRL-3 staining in tumor cells was significantly correlated to expression of molecules in the VEGFR-axis, but not to the clinicopathological variables. High PRL-3 was not significantly associated with survival in the univariate analysis for BFFS (p = 0.131), but significantly associated with CFFS (p = 0.044) and PCDFS (p = 0.041). In multivariate analysis for the various end points, PRL-3 came out as an independent and significant indicator of poor survival for BFFS (HR = 1.53, CI95% 1.10–2.13, p = 0.012), CFFS (HR = 2.41, CI95% 1.17–4.98, p = 0.017) and PCDFS (HR = 3.99, CI95% 1.21–13.1, p = 0.023). Conclusions: PRL-3 is independently associated with all PC endpoints in this study. Since high PRL-3 expression also correlates with poor prognosis in other cancers and functional studies in PC support these findings, PRL-3 emerges as a potential treatment target in PC. [ABSTRACT FROM AUTHOR]

Searching for new strategies for effective elimination of human prostate cancer cells, we investigated the cooperative cytotoxic action of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and two platinum-based complexes, cisplatin or LA-12, and related molecular mechanisms. We demonstrated a notable ability of cisplatin or LA-12 to enhance the sensitivity of several human prostate cancer cell lines to TRAIL-induced cell death via an engagement of mitochondrial apoptotic pathway. This was accompanied by augmented Bid cleavage, Bak activation, loss of mitochondrial membrane potential, activation of caspase-8, -10, -9, and -3, and XIAP cleavage. RNAi-mediated silencing of Bid or Bak in Bax-deficient DU 145 cells suppressed the drug combination-induced cytotoxicity, further underscoring the involvement of mitochondrial signaling. The caspase-10 was dispensable for enhancement of cisplatin/LA-12 and TRAIL combination-induced cell death and stimulation of Bid cleavage. Importantly, we newly demonstrated LA-12-mediated enhancement of TRAIL-induced cell death in cancer cells derived from human patient prostate tumor specimens. Our results provide convincing evidence that employing TRAIL combined with cisplatin/LA-12 could contribute to more effective killing of prostate cancer cells compared to the individual action of the drugs, and offer new mechanistic insights into their cooperative anticancer action. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the impact of race on the risk of pathological upgrading and upstaging at radical prostatectomy (RP) in an Asian (Korean) and Western (Caucasian) cohort eligible for active surveillance (AS). Materials and methods: We performed a retrospective cohort study of 854 patients eligible for AS who underwent RP in United States (n = 261) and Korea (n = 593) between 2006 and 2015. After adjusting for age, PSA level, and prostate volume, we utilized multivariate logistic regression analysis to assess the effect of race on upgrading or upstaging. Results: There were significant differences between Caucasian and Korean patients in terms of age at surgery (60.2 yr. vs. 64.1 yr.), PSA density (0.115 ng/mL/mL vs. 0.165 ng/mL/mL) and mean number of positive cores (3.5 vs. 2.4), but not in preoperative PSA values (5.11 ng/mL vs. 5.05 ng/mL). The rate of upstaging from cT1 or cT2 to pT3 or higher was not significantly different between the two cohorts (8.8% vs. 11.0%, P = 0.341). However, there were higher rates of upgrading to high-grade cancer (Gleason 4+3 or higher) in Korean patients (9.1%) when compared to Caucasian counterparts (2.7%) (P = 0.003). Multivariate logistic regression analysis showed that age (OR 1.07, P < 0.001) and smaller prostate volume (OR 0.97, P < 0.001), but not race, were significantly associated with upstaging or upgrading. Conclusions: There were no differences in rates of upgrading or upstaging between Caucasian and Korean men eligible for active surveillance. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the major changes of the eighth edition of the American Joint Committee on Cancer (AJCC) pathologic staging for prostate cancer treated with radical prostatectomy. A total of 138,176 patients diagnosed with prostate adenocarcinoma undergoing radical prostatectomy were selected from the Surveillance, Epidemiology and End Results (SEER) database during 2004–2014 period. Excluded were cases with incomplete or unavailable staging, PSA and Gleason score information. Two subgroups were established: group a, T2 stage with PSA≥20ng/ml; group b, T2 stage with Gleason score grade group 5 and PSA<20ng/ml. The median follow-up time was 58 months. The median age at diagnosis for the overall group was 61 years, and the median PSA was 5.7ng/ml. Cancer-specific survival (CSS) at tenth years was 99.3% for T2a/T2b, 99.2% for T2c, respectively. The survival differences between T2a/T2b and T2c did not have statistical significance (P = .323). It was necessary for the current eighth edition to define a single pathologic T2 category, eliminating the subcategories, for all organ-confined disease.CSS at the tenth years was 98.4% for group a, 92.6% for group b, respectively. The prognosis of group a was worse than AJCC II (P = .002). The prognosis of group b was not only worse than AJCC II (P < .001), but also worse than AJCC IIIB. There was necessity to separate the disease with PSA≥20ng/ml or Gleason score grade group 5 from other organ-confined disease. The present study supported the scientificity of the eighth edition of AJCC pathologic staging for prostate cancer. [ABSTRACT FROM AUTHOR]

Tumour necrosis factor α (TNFα) is involved in the pathogenesis of prostate cancer, a disease where disturbances in the endocannabinoid system are seen. In the present study we have investigated whether treatment of DU145 human prostate cancer cells affects anandamide (AEA) catabolic pathways. Additionally, we have investigated whether cyclooxygenase-2 (COX-2) can regulate the uptake of AEA into cells. Levels of AEA synthetic and catabolic enzymes were determined by qPCR. AEA uptake and hydrolysis in DU145 and RAW264.7 macrophage cells were assayed using AEA labeled in the arachidonic and ethanolamine portions of the molecule, respectively. Levels of AEA, related N-acylethanolamines (NAEs), prostaglandins (PG) and PG-ethanolamines (PG-EA) in DU145 cells and medium were quantitated by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS) analysis. TNFα treatment of DU145 cells increased mRNA levels of PTSG2 (gene of COX-2) and decreased the mRNA of the AEA synthetic enzyme N-acyl-phosphatidylethanolamine selective phospholipase D. mRNA levels of the AEA hydrolytic enzymes fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase were not changed. AEA uptake in both DU145 and RAW264.7 cells was inhibited by FAAH inhibition, but not by COX-2 inhibition, even in RAW264.7 cells where the expression of this enzyme had greatly been induced by lipopolysaccharide + interferon γ treatment. AEA and related NAEs were detected in DU145 cells, but PGs and PGE2-EA were only detected when the cells had been preincubated with 100 nM AEA. The data demonstrate that in DU145 cells, TNFα treatment changes the relative expression of the enzymes involved in the hydrolytic and oxygenation catabolic pathways for AEA. In RAW264.7 cells, COX-2, in contrast to FAAH, does not regulate the cellular accumulation of AEA. Further studies are necessary to determine the extent to which inflammatory mediators are involved in the abnormal endocannabinoid signalling system in prostate cancer. [ABSTRACT FROM AUTHOR]

Prostate cancer patients with high WNT5A expression in their tumors have been shown to have more favorable prognosis than those with low WNT5A expression. This suggests that reconstitution of Wnt5a in low WNT5A-expressing tumors might be an attractive therapeutic approach. To explore this idea, we have in the present study used Foxy-5, a WNT5A mimicking peptide, to investigate its impact on primary tumor and metastasis in vivo and on prostate cancer cell viability, apoptosis and invasion in vitro. We used an in vivo orthotopic xenograft mouse model with metastatic luciferase-labeled WNT5A-low DU145 cells and metastatic luciferase-labeled WNT5A-high PC3prostate cancer cells. We provide here the first evidence that Foxy-5 significantly inhibits the initial metastatic dissemination of tumor cells to regional and distal lymph nodes by 90% and 75%, respectively. Importantly, this effect was seen only with the WNT5A-low DU145 cells and not with the WNT5A-high PC3 cells. The inhibiting effect in the DU145-based model occurred despite the fact that no effects were observed on primary tumor growth, apoptosis or proliferation. These findings are consistent with and supported by the in vitro data, where Foxy-5 specifically targets invasion without affecting apoptosis or viability of WNT5A-low prostate cancer cells. To conclude, our data indicate that the WNT5A-mimicking peptide Foxy-5, which has been recently used in a phase 1 clinical trial, is an attractive candidate for complimentary anti-metastatic treatment of prostate cancer patients with tumors exhibiting absent or low WNT5A expression. [ABSTRACT FROM AUTHOR]

Objective: To investigate patient satisfaction after holmium laser enucleation of the prostate (HoLEP) in a prospective study. Subjects and methods: From May 2012 to December 2014, 397 patients underwent HoLEP by a single surgeon and enrolled in our prospective registry. Baseline data included age, PSA, transrectal ultrasonography, the international prostate symptom score (IPSS), and overactive bladder symptom score (OABSS). Subjective assessment of surgical outcomes was performed at 6 months postoperatively using self-administered questionnaires consisting of ‘satisfaction with treatment question’ (STQ), ‘overall response assessment’ (ORA), and ‘willingness to undergo surgery question’ (WSQ). Results: A total of 331 patients (mean age 69.6±7.0 years) were included in the analysis. Mean total prostate volume was 69.5 (±42.2) ml. Mean preoperative IPSS score was 18.5 (±7.8). The STQ showed that most patients (91.8%) were satisfied after the surgery. Only 11 (3.3%) patients responded with ‘dissatisfied’, and no patients replied with ‘very dissatisfied’. The WSQ showed that 311 (94.0%) patients were willing to undergo the surgery again if they had to reconsider the surgical decision. The ORA showed that all patients (99.4%) experienced an improvement. When compared with satisfied patients, neutral/dissatisfied patients had lower IPSS quality of life scores (2.7 vs. 0.9, p<0.001), higher IPSS voiding symptom scores (7.0 vs. 1.4, p<0.001), and more frequent episodes of urgency urinary incontinence in OABSS (1.0 vs. 0.3, p = 0.017) at 6 months postoperatively. Conclusions: The overall level of satisfaction after HoLEP was high. The most common reason for dissatisfaction was the occurrence of urgency urinary incontinence after the surgery. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) poses a major health concern in men worldwide. Retinoic Acid Receptor Responder (RARRES1)/ Tazarotene-induced gene-1 (TIG-1) is a putative tumor suppressor gene that exerts its tumor suppressor function via unknown mechanisms. Epigenetic silencing of RARRES1 leads to its loss in several types of cancer, including PCa. Determining the molecular mechanisms that mediate the tumor suppressor role of RARRES1 in PCa is the focus of our study. Findings: Our data indicates that RARRES1 over expression in PCa cell lines represses mitogen-activated protein kinase (MAPK) activation. RARRES1 expression induces the levels of autophagy-related genes, beclin, ATG3 and increases LC3B-II conversion. A significant induction of SIRT1 along with mTOR inhibition is noted on RARRES1 expression. Furthermore, RARRES1 over expression elevates the levels of the antioxidant enzyme, catalase. Our results also indicate that RARRES1 expression inhibits angiogenesis in endothelial cells. Conclusions: In summary, the data presented here indicate that forced expression of RARRES1 in PCa cells (a) induces ER stress and autophagic response; (b) increases SIRT1 levels; and (c) higher levels of anti-oxidant enzymes. Our study also implicates the role of RARRES1 as a novel anti-angiogenic molecule. Overall this study reports the molecular players that RARRES1 modulates to serve as a tumor suppressor molecule. Future studies will help determine the in vivo mechanisms by which RARRES1 may serve as a target for therapeutic intervention both in cancer and in angiogenesis-related disorders. [ABSTRACT FROM AUTHOR]

Curcumin, an extract from the turmeric rhizome (Curcuma longa), is known to exhibit anti-inflammatory, antioxidant, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Accumulative data indicate that curcumin may induce cancer cell death. However, the detailed mechanism underlying its pro-apoptotic and anti-cancer effects remains to be elucidated. In the present study, we examined the signaling pathways triggered by curcumin, specifically, the exact molecular mechanisms of curcumin-induced apoptosis in highly metastatic human prostate cancer cells. The effect of curcumin was evaluated using for the first time in prostate cancer, a gel-free shotgun quantitative proteomic analysis coupled with Tandem Mass Tag isobaric labeling-based-signaling networks. Results were confirmed at the gene expression level by qRT-PCR and at the protein expression level by western blot and flow cytometry. Our findings revealed that curcumin induced an Endoplasmic Reticulum stress-mediated apoptosis in PC3. The mechanisms by which curcumin promoted cell death in these cells were associated with cell cycle arrest, increased reactive oxygen species, autophagy and the Unfolded Protein Response. Furthermore, the upregulation of ER stress was measured using key indicators of ER stress: Glucose-Regulated Protein 78, Inositol-Requiring Enzyme 1 alpha, Protein Disulfide isomerase and Calreticulin. Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12) and Poly (ADP-ribose) polymerase. The downregulated proteins include anti-apoptotic and anti-tumor markers, supporting their curcumin-induced pro-apoptotic role in prostate cancer cells. Taken together, these data suggest that curcumin may serve as a promising anticancer agent by inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses. [ABSTRACT FROM AUTHOR]

The androgen receptor (AR) transcription factor plays a key role in the development and progression of prostate cancer, as is evident from the efficacy of androgen-deprivation therapy, AR is also the most frequently mutated gene, in castration resistant prostate cancer (CRPC). AR has therefore become an even more attractive therapeutic target in aggressive and disseminated prostate cancer. To investigate mechanisms of AR and AR target gene activation in different subpopulations of prostate cancer cells, a toolkit of AR expressor and androgen response element (ARE) reporter vectors were developed. Three ARE reporter vectors were constructed with different ARE consensus sequences in promoters linked to either fluorescence or luciferase reporter genes in lentiviral vector backbones. Cell lines transduced with the different vectors expressed the reporters in an androgen-dependent way according to fluorescence microscopy, flow cytometry and multi-well fluorescent and luminescence assays. Interestingly, the background reporter activity in androgen-depleted medium was significantly higher in LNCaP cells compared to the prostate transit amplifying epithelial cell lines, EP156T-AR and 957E/hTERT-AR with exogenous AR. The androgen-induced signal to background was much higher in the latter benign prostate cells than in LNCaP cells. Androgen-independent nuclear localization of AR was seen in LNCaP cells and reduced ARE-signaling was seen following treatment with abiraterone, an androgen synthesis inhibitor. The ARE reporter activity was significantly stronger when stimulated by androgens than by β-estradiol, progesterone and dexamethasone in all tested cell types. Finally, no androgen-induced ARE reporter activity was observed in tumorigenic mesenchymal progeny cells of EP156T cells following epithelial to mesenchymal transition. This underscores the observation that expression of the classical luminal differentiation transcriptome is restricted in mesenchymal type cells with or without AR expression, and presence of androgen. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the performance of a model-based optimisation process for volumetric modulated arc therapy applied to prostate cancer in a multicentric cooperative group. The RapidPlan (RP) knowledge-based engine was tested for the planning of Volumetric modulated arc therapy with RapidArc on prostate cancer patients. The study was conducted in the frame of the German RapidPlan Consortium (GRC). Methods and materials: 43 patients from one institute of the GRC were used to build and train a RP model. This was further shared with all members of the GRC plus an external site from a different country to increase the heterogeneity of the patient’s sampling. An in silico multicentric validation of the model was performed at planning level by comparing RP against reference plans optimized according to institutional procedures. A total of 60 patients from 7 institutes were used. Results: On average, the automated RP based plans resulted fully consistent with the manually optimised set with a modest tendency to improvement in the medium-to-high dose region. A per-site stratification allowed to identify different patterns of performance of the model with some organs at risk resulting better spared with the manual or with the automated approach but in all cases the RP data fulfilled the clinical acceptability requirements. Discrepancies in the performance were due to different contouring protocols or to different emphasis put in the optimization of the manual cases. Conclusions: The multicentric validation demonstrated that it was possible to satisfactorily optimize with the knowledge based model patients from all participating centres. In the presence of possibly significant differences in the contouring protocols, the automated plans, though acceptable and fulfilling the benchmark goals, might benefit from further fine tuning of the constraints. The study demonstrates that, at least for the case of prostate cancer patients, it is possibile to share models among different clinical institutes in a cooperative framework. [ABSTRACT FROM AUTHOR]

Background: This meta-analysis was designed to assess the efficacy of the male sling and artificial urinary sphincter on treating post-prostatectomy incontinence by evaluating daily pad use, cure rate, frequency of improvement in incontinence, and quality of life. Methods: Medline, Cochrane, Google Scholar, and ClinicalTrials.gov were searched (until March 31, 2014) for studies that investigated the effectiveness of artificial urinary sphincter or sling surgical treatments for prostate cancer. The primary outcome was daily pad use before and after surgery and secondary outcomes were quality of life before and after surgery, and frequency of cures (no need to use of a pad for at least 1 day) and improvements (decreased pad usage) in incontinence after surgery. Results: We found that that both the sling and artificial urinary sphincter significantly decreased the number of pads used per day by about 3 (P-values <0.001) and increased the quality of life compared with before intervention (P-values < 0.001). In addition, the cure rate and was around 60%. Intervention resulted in improvement in incontinence by about 25% (P < 0.001). Conclusion: Our findings indicate that both sling and artificial urinary sphincter interventions are effective in reducing incontinence and improving the patient’s quality of life. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second leading cause of cancer deaths in men. A better understanding of the molecular basis of prostate cancer proliferation and metastasis should enable development of more effective treatments. In this study we focused on the lncRNA, prostate cancer associated transcript 29 (PCAT29), a putative tumor suppressive gene. Our data show that the expression of PCAT29 was reduced in prostate cancer tumors compared to paired perinormal prostate tissues. We also observed substantially lower levels of PCAT29 in DU145 and LNCaP cells compared to normal prostate (RWPE-1) cells. IL-6, a cytokine which is elevated in prostate tumors, reduced the expression of PCAT29 in both DU145 and LNCaP cells by activating signal transducer and activator of transcription 3 (STAT3). One downstream target of STAT3 is microRNA (miR)-21, inhibition of which enhanced basal PCAT29 expression. In addition, we show that resveratrol is a potent stimulator of PCAT29 expression under basal condition and reversed the down regulation of this lncRNA by IL-6. Furthermore, we show that knock down of PCAT29 expression by siRNA in DU145 and LNCaP cells increased cell viability while increasing PCAT29 expression with resveratrol decreased cell viability. Immunohistochemistry studies showed increased levels of STAT3 and IL-6, but low levels of programmed cell death protein 4 (PDCD4), in prostate tumor epithelial cells compared to adjacent perinormal prostate epithelial cells. These data show that the IL-6/STAT3/miR-21 pathway mediates tonic suppression of PCAT29 expression and function. Inhibition of this signaling pathway by resveratrol induces PCAT29 expression and tumor suppressor function. [ABSTRACT FROM AUTHOR]

Anoctamin 1 (ANO1), a calcium-activated chloride channel, is highly amplified in prostate cancer, the most common form of cancer and leading causes of cancer death in men, and downregulation of ANO1 expression or its functional activity is known to inhibit cell proliferation, migration and invasion in prostate cancer cells. Here, we performed a cell-based screening for the identification of ANO1 inhibitors as potential anticancer therapeutic agents for prostate cancer. Screening of ~300 selected bioactive natural products revealed that luteolin is a novel potent inhibitor of ANO1. Electrophysiological studies indicated that luteolin potently inhibited ANO1 chloride channel activity in a dose-dependent manner with an IC50 value of 9.8 μM and luteolin did not alter intracellular calcium signaling in PC-3 prostate cancer cells. Luteolin inhibited cell proliferation and migration of PC-3 cells expressing high levels of ANO1 more potently than that of ANO1-deficient PC-3 cells. Notably, luteolin not only inhibited ANO1 channel activity, but also strongly decreased protein expression levels of ANO1. Our results suggest that downregulation of ANO1 by luteolin is a potential mechanism for the anticancer effect of luteolin. [ABSTRACT FROM AUTHOR]

Androgen receptor (AR) is a member of the steroid receptor family and a therapeutic target for all stages of prostate cancer. AR is activated by ligand binding within its C-terminus ligand-binding domain (LBD). Here we show that overexpression of the AR NTD to generate decoy molecules inhibited both the growth and progression of prostate cancer in castrated hosts. Specifically, it was shown that lentivirus delivery of decoys delayed hormonal progression in castrated hosts as indicated by increased doubling time of tumor volume, prolonged time to achieve pre-castrate levels of serum prostate-specific antigen (PSA) and PSA nadir. These clinical parameters are indicative of delayed hormonal progression and improved therapeutic response and prognosis. Decoys reduced the expression of androgen-regulated genes that correlated with reduced in situ interaction of the AR with androgen response elements. Decoys did not reduce levels of AR protein or prevent nuclear localization of the AR. Nor did decoys interact directly with the AR. Thus decoys did not inhibit AR transactivation by a dominant negative mechanism. This work provides evidence that the AR NTD plays an important role in the hormonal progression of prostate cancer and supports the development of AR antagonists that target the AR NTD. [ABSTRACT FROM AUTHOR]

Purpose: Androgen deprivation therapy (ADT) commonly leads to incomplete cell death and the fate of persistent cells involves, in part, a senescent phenotype. Senescence is terminal growth arrest in response to cell stress that is characterized by increased lysosomal-β-galactosidase (GLB1) the origin of senescence associated-β-gal activity (SA-β-gal). In the current study senescence is examined in vivo after ADT use in a neoadjuvant trial. Methods and materials: Tissue microarrays were generated from prostate cancer specimens (n = 126) from a multicenter neoadjuvant ADT trial. Arrays were subjected to multiplexed immunofluorescent staining for GLB1, Ki67, cleaved caspase 3 (CC3) and E-cadherin. Automated quantitative imaging was performed using Vectra™ and expression correlated with clinicopathologic features. Results: Tissue was analyzed from 59 patients treated with neoadjuvant ADT and 67 receiving no therapy preoperatively. Median follow-up was 85.3 mo and median ADT treatment was 5 mo. In PC treated with neoadjuvant ADT, GLB1 expression increased in intermediate Gleason score (GS 6–7; p = 0.001), but not high grade (GS 8–10) cancer. Significantly higher levels of GLB1 were seen in tissues undergoing neoadjuvant ADT longer than 5 months compared to untreated tissues (p = 0.002). In contrast, apoptosis significantly increased earlier (1–4 mo) after ADT treatment (p<0.5). Conclusions: Increased GLB1 after neoadjuvant ADT occurs primarily among more clinically favorable intermediate grade cancers and enrichment of the phenotype occurs in a temporally prolonged fashion. Senescence may explain the persistence of PCa cells after ADT. Given concerns for the detrimental longer term presence of senescent cells, targeting these cells for removal may improve outcomes. [ABSTRACT FROM AUTHOR]

Objective: To develop a method for estimating the future numbers of prostate cancer survivors requiring different levels of care. Design, setting and participants: Analysis of population-based cancer registry data for prostate cancer cases (aged 18–84 years) diagnosed in 1996–2007, and a linked dataset with hospital admission data for men with prostate cancer diagnosed during 2005–2007 in New South Wales (NSW), Australia. Methods: Cancer registry data (1996–2007) were used to project complete prostate cancer prevalence in NSW, Australia for 2008–2017, and treatment information from hospital records (2005–2007) was used to estimate the inpatient care needs during the first year after diagnosis. The projected complete prevalence was divided into care needs-based groups. We first divided the cohort into two groups based on patient’s age (<75 and 75–84 years). The younger cohort was further divided into initial care and monitoring phases. Cause of death data were used as a proxy for patients requiring last year of life prostate cancer care. Finally, episode data were used to estimate the future number of cases with metastatic progression. Results: Of the estimated total of 60,910 men with a previous diagnosis of prostate cancer in 2017, the largest groups will be older patients (52.0%) and younger men who require monitoring (42.5%). If current treatment patterns continue, in the first year post-diagnosis 41% (1380) of patients (<75 years) will have a radical prostatectomy, and 52.6% (1752) will be likely to have either active surveillance, external beam radiotherapy or androgen deprivation therapy. About 3% will require care for subsequent metastases, and 1288 men with prostate cancer are likely to die from the disease in 2017. Conclusions: This method extends the application of routinely collected population-based data, and can contribute much to the knowledge of the number of men with prostate cancer and their health care requirements. This could be of significant use in planning future cancer care services and facilities in Australia. [ABSTRACT FROM AUTHOR]

Objective: Androgen deprivation therapy (ADT) increases fracture risk in men with carcinoma of the prostate, but little is known about the fracture risk for different types of ADT. We studied the fracture risk amongst Chinese patients with carcinoma of the prostate prescribed different ADT regimens. Subjects and methods: This was a single-centered observational study that involved 741 patients with carcinoma of the prostate from January 2001 to December 2011. Results: After a median follow-up of 5 years, 71.7% of the study cohort received ADT and the incidence rate of fracture was 8.1%. Multivariable Cox regression analysis revealed that use of ADT was significantly associated with risk of incident fracture (Hazard Ratio [HR] 3.60; 95% Confidence Interval [95% CI] 1.41–9.23; p = 0.008), together with aged >75 years and type 2 diabetes. Compared with no ADT, all three types of ADT were independently associated with the risk of incident fracture: anti-androgen monotherapy (HR 4.47; 95% CI 1.47–13.7; p = 0.009), bilateral orchiectomy ± anti-androgens (HR 4.01; 95% CI 1.46–11.1; p = 0.007) and luteinizing hormone-releasing hormone agonists ± anti-androgens (HR 3.16; 95% CI 1.18–8.43; p = 0.022). However, there was no significant difference in the relative risks among the three types of ADT. Conclusions: Fracture risk increases among all types of ADT. Clinicians should take into account the risk-benefit ratio when prescribing ADT, especially in elderly patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Prognostic models in metastatic castrate resistant prostate cancer (mCRPC) may have clinical utility. Using data from PDS, we aimed to 1) validate a contemporary prognostic model (Templeton et al., 2014) 2) evaluate prognostic impact of concomitant medications and PSA decrease 3) evaluate factors associated with docetaxel toxicity. Methods: We accessed data on 2,449 mCRPC patients in PDS. The existing model was validated with a continuous risk score, time-dependent receiver operating characteristic (ROC) curves, and corresponding time-dependent Area under the Curve (tAUC). The prognostic effects of concomitant medications and PSA response were assessed by Cox proportional hazards models. One year tAUC was calculated for multivariable prognostic model optimized to our data. Conditional logistic regression models were used to assess associations with grade 3/4 adverse events (G3/4 AE) at baseline and after cycle 1 of treatment. Results: Despite limitations of the PDS data set, the existing model was validated; one year AUC, was 0.68 (95% CI 95% CI, .66 to .71) to 0.78 (95%CI, .74 to .81) depending on the subset of datasets used. A new model was constructed with an AUC of .74 (.72 to .77). Concomitant medications low molecular weight heparin and warfarin were associated with poorer survival, Metformin and Cox2 inhibitors were associated with better outcome. PSA response was associated with survival, the effect of which was greatest early in follow-up. Age was associated with baseline risk of G3/4 AE. The odds of experiencing G3/4 AE later on in treatment were significantly greater for subjects who experienced a G3/4 AE in their first cycle (OR 3.53, 95% CI 2.53–4.91, p < .0001). Conclusion: Despite heterogeneous data collection protocols, PDS provides access to large datasets for novel outcomes analysis. In this paper, we demonstrate its utility for validating existing models and novel model generation including the utility of concomitant medications in outcome analyses, as well as the effect of PSA response on survival and toxicity prediction. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is one of the most common cancers in elderly men. Mediator Complex Subunit 19 (Med19) is overexpressed and plays promotional roles in many cancers. However, the roles of Med19 in PCa are still obscure. In this study, by using immunohistochemical staining, we found higher expression level of Med19 in PCa tissues than in adjacent benign prostate tissues. We then knocked down the Med19 expression in PCa cell lines LNCaP and PC3 by using lentivirus siRNA. Cell proliferation, anchor-independent growth, migration, and invasion were suppressed in Med19 knockdown PCa cells. In nude mice xenograft model, we found that Med19 knockdown PCa cells formed smaller tumors with lower proliferation index than did control cells. In the mechanism study, we found that Med19 could regulate genes involved in cell proliferation, cell cycle, and epithelial-mesenchymal transition, including P27, pAKT, pPI3K, IGF1R, E-Cadherin, N-Cadherin, Vimentin, ZEB2, Snail-1 and Snail-2. Targeting Med19 in PCa cells could inhibit the PCa growth and metastasis, and might be a therapeutic option for PCa in the future. [ABSTRACT FROM AUTHOR]

Technological and methodological advances in multi-omics data generation and integration approaches help elucidate genetic features of complex biological traits and diseases such as prostate cancer. Due to its heterogeneity, the identification of key functional components involved in the regulation and progression of prostate cancer is a methodological challenge. In this study, we identified key regulatory interactions responsible for primary to metastasis transitions in prostate cancer using network inference approaches by integrating patient derived transcriptomic and miRomics data into gene/miRNA/transcription factor regulatory networks. One such network was derived for each of the clinical states of prostate cancer based on differentially expressed and significantly correlated gene, miRNA and TF pairs from the patient data. We identified key elements of each network using a network analysis approach and validated our results using patient survival analysis. We observed that HOXD10, BCL2 and PGR are the most important factors affected in primary prostate samples, whereas, in the metastatic state, STAT3, JUN and JUNB are playing a central role. Benefiting integrative networks our analysis suggests that some of these molecules were targeted by several overexpressed miRNAs which may have a major effect on the dysregulation of these molecules. For example, in the metastatic tumors five miRNAs (miR-671-5p, miR-665, miR-663, miR-512-3p and miR-371-5p) are mainly responsible for the dysregulation of STAT3 and hence can provide an opportunity for early detection of metastasis and development of alternative therapeutic approaches. Our findings deliver new details on key functional components in prostate cancer progression and provide opportunities for the development of alternative therapeutic approaches. [ABSTRACT FROM AUTHOR]