Showing papers by "John T. Wei published in 2018"

Analysis of the androgen receptor–regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression

Abstract: The androgen receptor (AR) plays a critical role in the development of the normal prostate as well as prostate cancer. Using an integrative transcriptomic analysis of prostate cancer cell lines and tissues, we identified ARLNC1 (AR-regulated long noncoding RNA 1) as an important long noncoding RNA that is strongly associated with AR signaling in prostate cancer progression. Not only was ARLNC1 induced by the AR protein, but ARLNC1 stabilized the AR transcript via RNA-RNA interaction. ARLNC1 knockdown suppressed AR expression, global AR signaling and prostate cancer growth in vitro and in vivo. Taken together, these data support a role for ARLNC1 in maintaining a positive feedback loop that potentiates AR signaling during prostate cancer progression and identify ARLNC1 as a novel therapeutic target.

Cost‐effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer

Abstract: OBJECTIVE To determine how best to use magnetic resonance imaging (MRI) and targeted MRI/ultrasonography fusion biopsy for early detection of prostate cancer (PCa) in men with elevated prostate-specific antigen (PSA) concentrations and whether it can be cost-effective METHODS A Markov model of PCa onset and progression was developed to estimate the health and economic consequences of PCa screening with MRI Patients underwent PSA screening from ages 55 to 69 years Patients with elevated PSA concentrations (>4 ng/mL) underwent MRI, followed by targeted fusion or combined (standard + targeted fusion) biopsy on positive MRI, and standard or no biopsy on negative MRI Prostate Imaging Reporting and Data System (PI-RADS) score on MRI was used to determine biopsy decisions Deaths averted, quality-adjusted life-years (QALYs), cost and incremental cost-effectiveness ratio (ICER) were estimated for each strategy RESULTS With a negative MRI, standard biopsy was more expensive and had lower QALYs than performing no biopsy The optimum screening strategy (ICER $23 483/QALY) recommended combined biopsy for patients with PI-RADS score ≥3 and no biopsy for patients with PI-RADS score <3, and reduced the number of screening biopsies by 15% Threshold analysis suggests MRI continues to be cost-effective when the sensitivity and specificity of MRI and combined biopsy are simultaneously reduced by 19 percentage points CONCLUSIONS Our analysis suggests MRI followed by targeted MRI/ultrasonography fusion biopsy can be a cost-effective approach to the early detection of PCa

A multi-institutional phase 2 trial of prostate stereotactic body radiation therapy (SBRT) using continuous real-time evaluation of prostate motion with patient-reported quality of life.

Abstract: Purpose The use of stereotactic body radiation therapy (SBRT) for prostate cancer has been reported predominantly from single institutional studies, although concerns for broader adoption exist. Methods and materials From 2011 through 2013, 66 men were accrued to a phase 2 trial at 5 centers. SBRT consisted of 5 fractions of 7.4 Gy to a total dose of 37 Gy using conventional linear accelerators. Electromagnetic transponders were used for motion management. Health-related quality of life (HRQOL) was evaluated via the Expanded Prostate Cancer Index Composite 26 questionnaire. Acute and late toxicities were collected according to Common Terminology Criteria for Adverse Events, version 4.0. Linear mixed modeling was performed to assess changes in HRQOL over time. Results Median follow-up was 36 months. All men had low- or intermediate-risk disease. There have been 0 biochemical recurrences. No grade 3 urinary or bowel toxicity was reported. Twenty-three percent of patients had acute grade 2 urinary toxicity, with 9% late grade 2 urinary toxicity. Four percent and 5% experienced acute or late grade 2+ bowel toxicity, respectively. Urinary bother and bowel HRQOL transiently decreased during the first 6 to 12 months post-SBRT, and then returned to baseline. In men with good erectile function at baseline, sexual HRQOL declined during the first 6 months and stabilized thereafter. On linear mixed modeling, the strongest predictor of sustained bowel and sexual HRQOL was baseline HRQOL. Conclusions In this multi-institutional phase 2 clinical trial using continuous real-time evaluation of prostate motion, prostate SBRT has excellent intermediate-term tumor control with mild and expected treatment-related side effects.

Interstitial assessment of aggressive prostate cancer by physio-chemical photoacoustics: An ex vivo study with intact human prostates.

Abstract: PURPOSE Transrectal ultrasound (TRUS)-guided biopsy is the standard procedure for evaluating the presence and aggressiveness of prostate cancer. TRUS biopsy involves tissue removal, and suffers from low core yield as well as high false negative rate. A less invasive and more accurate diagnostic procedure for prostate cancer is therefore highly desired. Combining the optical sensitivity and ultrasonic resolution to resolve the spatial distribution of the major molecular components in tissue, photoacoustic (PA) technology could be an alternative approach for the diagnosis of prostate cancer. The purpose of this study was to examine the feasibility of identifying aggressive prostate cancer using interstitial PA measurements. METHODS Seventeen patients with prebiopsy magnetic resonance imaging (MRI), TRUS biopsies, and planned prostatectomies were enrolled in this study. The interstitial PA measurements were achieved using our recently developed needle PA probe, which was inserted into the ex vivo prostates in the fashion of a biopsy needle. A total of 70 interstitial PA measurements were acquired. The PA measurements were quantified by a previously established PA physio-chemical analysis (PAPCA) method. The histology has confirmed the nonaggressive and aggressive cancerous conditions at the insertion locations. The diagnostic accuracy was also compared to that provided by the prebiopsy MRI. RESULTS The quantitative study shows significant differences between the individual parameters of the nonaggressive and the aggressive cancerous regions (P < 0.005). Multivariate analysis of the quantitative features achieved a diagnostic accuracy of 78.6% for differentiating nonaggressive and aggressive prostate cancer tissues. CONCLUSIONS The proposed procedure has shown promises in the diagnosis of aggressive prostate cancer.

Incorporation of Urinary Prostate Cancer Antigen 3 and TMPRSS2:ERG into Prostate Cancer Prevention Trial Risk Calculator

Abstract: Background The Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) is a commonly used risk tool for predicting the outcome on biopsy based on the established risk factors Objective To determine whether incorporation of the novel urinary markers prostate cancer antigen 3 (PCA3) and TMPRSS2:ERG (T2:ERG) into the PCPTRC improves its discrimination, accuracy, and clinical net benefit Design, setting, and participants Since PCA3 and T2:ERG were not measured as part of the PCPTRC, a Bayesian modeling approach was used to combine data where the markers were measured in a Michigan cohort with the PCPTRC as prior probabilities to form an updated PCPTRC This update was compared to the existing PCPTRC on an independent Early Detection Research Network cohort in terms of discrimination, calibration, and decision curve analysis Results and limitations Among the 1225 Michigan biopsies, 577%, 240%, and 183% were negative, with low- and high-grade (Gleason grade ≥ 7) prostate cancer, respectively Evaluated on the Early Detection Research Network validation set comprising 854 biopsies, areas under the curve (95% confidence interval) for predicting high-grade cancer in the 854 biopsies comprising the validation set were 700% (660–740%), 764% (728–800%), and 771% (736–806%) for the PCPTRC alone, with PCA3 added, and PCA3 and T2:ERG added, respectively Net benefit was improved for the updated PCPTRC, while calibration was not Limitations are that the updated PCPTRC is based on two different cohorts, the PCPT and Michigan, and that 20% of the validation set came from the Michigan center More validation is required; hence, the updated risk tool is posted online Conclusions Incorporation of PCA3 into the PCPTRC improved validation on an independent cohort, whereas T2:ERG offered negligible utility in addition to PCA3 Patient summary After passing external validation, prostate cancer antigen 3 has been added to the online Prostate Cancer Prevention Trial Risk Calculator for use by patients in deciding whether to proceed to biopsy TMPRSS2:ERG did not improve prediction on the external validation set, but is included for further validation

Association of ERG/PTEN status with biochemical recurrence after radical prostatectomy for clinically localized prostate cancer

Abstract: We have previously demonstrated a significant correlative relationship between PTEN deletion and ERG rearrangement, both in the development of clinically localized prostate cancers and metastases. Herein, we evaluate the cooperative role of ERG and PTEN in oncological outcomes after radical prostatectomy for clinically localized prostate cancer. We evaluated ERG and PTEN status using three previously described cohorts. The first cohort included 235 clinically localized prostate cancer cases represented on tissue microarrays (TMA), evaluated using previously validated FISH assays for ERG and PTEN. The second cohort included 167 cases of clinically localized prostate cancer on TMAs evaluated for PTEN by FISH, and for PTEN and ERG by dual IHC. The third cohort comprised 59 clinically localized prostate cancer cases assessed by array comparative genomic hybridization (aCGH). Kaplan–Meir plots and long rank tests were used to assess the association of ERG and PTEN status with biochemical recurrence after radical prostatectomy for clinically localized prostate cancer. Of the 317 cases eligible for analyses with evaluable ERG and PTEN status, 88 (27.8%) patients developed biochemical recurrence over a median follow-up of 5.7 years. Overall, 45% (142/317) of cases demonstrated ERG rearrangement and 20% (62/317) of cases demonstrated PTEN loss. Hemizygous and homozygous deletion of PTEN was seen in 10% (18/175) and 3% (5/175) of ERG-negative cases, respectively. In contrast, hemizygous and homozygous deletion of PTEN was seen in 11% (15/142) and 17% (24/123) of ERG-positive cases, respectively. PTEN loss (heterozygous or homozygous) was significantly associated with shorter time to biochemical recurrence compared to no PTEN loss (p < 0.001). However, ERG rearrangement versus no rearrangement was not associated with time to PSA recurrence (p = 0.15). Patients who exhibited ERG rearrangement and loss of PTEN had no significant difference in time to recurrence compared to patients with wild-type ERG and loss of PTEN (p = 0.30). Our findings confirm a mutual cooperative role of ERG and PTEN in the pathogenesis of prostate cancer, particularly for homozygous PTEN deletion. ERG did not stratify outcome either alone or in combination with PTEN in this cohort.

Optimizing active surveillance strategies to balance the competing goals of early detection of grade progression and minimizing harm from biopsies

Abstract: BACKGROUND Active surveillance (AS) for prostate cancer includes follow-up with serial prostate biopsies. The optimal biopsy frequency during follow-up has not been determined. The goal of this investigation was to use longitudinal AS biopsy data to assess whether the frequency of biopsy could be reduced without substantially prolonging the time to the detection of disease with a Gleason score ≥ 7. METHODS With data from 1375 men with low-risk prostate cancer enrolled in AS at Johns Hopkins, a hidden Markov model was developed to estimate the probability of undersampling at diagnosis, the annual probability of grade progression, and the 10-year cumulative probability of reclassification or progression to Gleason score ≥ 7. It simulated 1024 potential AS biopsy strategies for the 10 years after diagnosis. For each of these strategies, the model predicted the mean delay in the detection of disease with a Gleason score ≥ 7. RESULTS The model estimated the 10-year cumulative probability of reclassification from a Gleason score of 6 to a Gleason score ≥ 7 to be 40.0%. The probability of undersampling at diagnosis was 9.8%, and the annual progression probability for men with a Gleason score of 6 was 4.0%. On the basis of these estimates, a simulation of an annual biopsy strategy estimated the mean time to the detection of disease with a Gleason score ≥ 7 to be 14.1 months; however, several strategies eliminated biopsies with only small delays (<12 months) in detecting grade progression. CONCLUSIONS Although annual biopsy for low-risk men on AS is associated with the shortest time to the detection of disease with a Gleason score ≥ 7, several alternative strategies may allow less frequent biopsying without sizable delays in detecting grade progression. Cancer 2018;124:698-705. © 2017 American Cancer Society.