Serial Molecular Profiling of Low-grade Prostate Cancer to Assess Tumor Upgrading: A Longitudinal Cohort Study.

BACKGROUND: The potential for low-grade (grade group 1 [GG1]) prostate cancer (PCa) to progress to high-grade disease remains unclear. OBJECTIVE: To interrogate the molecular and biological features of low-grade PCa serially over time. DESIGN, SETTING, AND PARTICIPANTS: Nested longitudinal cohort study in an academic active surveillance (AS) program. Men were on AS for GG1 PCa from 2012 to 2017. INTERVENTION: Electronic tracking and resampling of PCa using magnetic resonance imaging/ultrasound fusion biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: ERG immunohistochemistry (IHC) and targeted DNA/RNA next-generation sequencing were performed on initial and repeat biopsies. Tumor clonality was assessed. Molecular data were compared between men who upgraded and those who did not upgrade to GG ≥ 2 cancer. RESULTS AND LIMITATIONS: Sixty-six men with median age 64 yr (interquartile range [IQR], 59-69) and prostate-specific antigen 4.9 ng/mL (IQR, 3.3-6.4) underwent repeat sampling of a tracked tumor focus (median interval, 11 mo; IQR, 6-13). IHC-based ERG fusion status was concordant at initial and repeat biopsies in 63 men (95% vs expected 50%, p < 0.001), and RNAseq-based fusion and isoform expression were concordant in nine of 13 (69%) ERG+ patients, supporting focal resampling. Among 15 men who upgraded with complete data at both time points, integrated DNA/RNAseq analysis provided evidence of shared clonality in at least five cases. Such cases could reflect initial undersampling, but also support the possibility of clonal temporal progression of low-grade cancer. Our assessment was limited by sample size and use of targeted sequencing. CONCLUSIONS: Repeat molecular assessment of low-grade tumors suggests that clonal progression could be one mechanism of upgrading. These data underscore the importance of serial tumor assessment in men pursuing AS of low-grade PCa. PATIENT SUMMARY: We performed targeted rebiopsy and molecular testing of low-grade tumors on active surveillance. Our findings highlight the importance of periodic biopsy as a component of monitoring for cancer upgrading during surveillance.

Utility of Multiparametric MRI for Predicting Residual Clinically Significant Prostate Cancer After Focal Laser Ablation.

OBJECTIVE. The purpose of this study was to compare in a multireader manner the diagnostic accuracies of 3-T multiparametric MRI interpretation and serial prostate-specific antigen (PSA) measurement in predicting the presence of residual clinically significant prostate cancer after focal laser ablation. MATERIALS AND METHODS. Eighteen men had undergone focal laser ablation for low- or intermediate-risk prostate cancer as part of two National Cancer Institute-funded phase 1 clinical trials. Multiparametric MRI was performed immediately after and 6 and 12 months after focal laser ablation. Serial PSA measurements after focal laser ablation were recorded, and MRI-ultrasound fusion biopsy was performed 6 and 12 months after ablation and served as the reference standard. Multiparametric MRI was performed at 3 T with pelvic phased-array coils. T2-weighted, DW, and dynamic contrast-enhanced MR images were retrospectively assessed by two blinded radiologists using a 3-point Likert scale (0-2). Inter-reader agreement was assessed with the Cohen kappa statistic. The diagnostic accuracies of multiparametric MRI and PSA measurement were compared. RESULTS. Residual clinically significant prostate cancer was identified in 11 of 18 (61%) men. Logistic regression analysis of serial PSA measurements yielded a correct classification rate of 61.1% (p > 0.05). Using a multiparametric MRI threshold score of 4 or greater, both radiologists made correct classifications for 16 of 18 men (89%) at 6 months and 15 of 17 men (88%) at 12 months. Interreader agreement was substantial to excellent for T2-weighted imaging, DWI, and dynamic contrast-enhanced MRI and improved uniformly from 6 to 12 months. Logistic regression analysis of the retrospectively reviewed multiparametric MR images yielded AUCs greater than 0.90 for each radiologist 6 and 12 months after focal laser ablation (p < 0.001). CONCLUSION. Multiparametric MRI 6 and 12 months after focal laser ablation significantly outperformed serial PSA measurements for predicting the presence of residual clinically significant prostate cancer.

Comparison of Targeted vs Systematic Prostate Biopsy in Men Who Are Biopsy Naive: The Prospective Assessment of Image Registration in the Diagnosis of Prostate Cancer (PAIREDCAP) Study.

Importance: Magnetic resonance imaging (MRI) guidance improves the accuracy of prostate biopsy for the detection of clinically significant prostate cancer, but the optimal use of such guidance is not yet clear. Objective: To determine the cancer detection rate (CDR) of targeting MRI-visible lesions vs systematic prostate sampling in the diagnosis of clinically significant prostate cancer in men who were biopsy naive. Design, Setting, and Participants: This paired cohort trial, known as the Prospective Assessment of Image Registration in the Diagnosis of Prostate Cancer (PAIREDCAP) study, was conducted in an academic medical center from January 2015 to April 2018. Men undergoing first-time prostate biopsy were enrolled. Paired-cohort participants were a consecutive series of men with MRI-visible lesions (defined by a Prostate Imaging Reporting & Data System version 2 score ≥ 3), who each underwent 3 biopsy methods at the same sitting: first, a systematic biopsy; second, an MRI-lesion biopsy targeted by cognitive fusion; and third, an MRI-lesion targeted by software fusion. Another consecutive series of men without MRI-visible lesions underwent systematic biopsies to help determine the false-negative rate of MRI during the trial period. Main Outcomes and Measures: The primary end point was the detection rate of clinically significant prostate cancer (Gleason grade group ≥2) overall and by each biopsy method separately. The secondary end points were the effects of the Prostate Imaging Reporting & Data System version 2 grade, prostate-specific antigen density, and prostate volume on the primary end point. Tertiary end points were the false-negative rate of MRI and concordance of biopsy-method results by location of detected cancers within the prostate. Results: A total of 300 men participated; 248 had MRI-visible lesions (mean [SD] age, 65.5 [7.7] years; 197 were white [79.4%]), and 52 were control participants (mean [SD] age, 63.6 [5.9] years; 39 were white [75%]). The overall CDR was 70% in the paired cohort group, achieved by combining systematic and targeted biopsy results. The CDR by systematic sampling was 15% in the group without MRI-visible lesions. In the paired-cohort group, CDRs varied from 47% (116 of 248 men) when using cognitive fusion biopsy alone, to approximately 60% when using systematic biopsy (149 of 248 men) or either fusion method alone (154 of 248 men), to 70% (174 of 248 men) when combining systematic and targeted biopsy. Discordance of tumor locations suggests that the different biopsy methods detect different tumors. Thus, combining targeting and systematic sampling provide greatest sensitivity for detection of clinically significant prostate cancer. For all biopsy methods, the Prostate Imaging Reporting & Data System version 2 grade and prostate-specific antigen density were directly associated with CDRs, and prostate volume was inversely associated. Conclusions and Relevance: An MRI-visible lesion in men undergoing first-time prostate biopsy identifies those with a heightened risk of clinically significant prostate cancer. Combining targeted and systematic biopsy offers the best chances of detecting the cancer.

Utility of Restriction Spectrum Imaging Among Men Undergoing First-Time Biopsy for Suspected Prostate Cancer.

OBJECTIVE. The purpose of this article is to evaluate restriction spectrum imaging (RSI) in men undergoing MRI-ultrasound fusion biopsy for suspected prostate cancer (PCa) and to compare the performance of RSI with that of conventional DWI. MATERIALS AND METHODS. One hundred ninety-eight biopsy-naïve men enrolled in a concurrent prospective clinical trial evaluating MRI-targeted prostate biopsy underwent multiparametric MRI with RSI. Clinical and imaging features were compared between men with and without clinically significant (CS) PCa (MRI-ultrasound fusion biopsy Gleason score ≥ 3 + 4). RSI z score and apparent diffusion coefficient (ADC) were correlated, and their diagnostic performances were compared. RESULTS. CS PCa was detected in 109 of 198 men (55%). Using predefined thresholds of ADC less than or equal to 1000 µm2/s and RSI z score greater than or equal to 3, sensitivity and specificity for CS PCa were 86% and 38%, respectively, for ADC and 61% and 70%, respectively, for RSI. In the transition zone (n = 69), the sensitivity and specificity were 94% and 17%, respectively, for ADC and 59% and 69%, respectively, for RSI. Among lesions with CS PCa, RSI z score and ADC were significantly inversely correlated in the peripheral zone (ρ = -0.4852; p < 0.01) but not the transition zone (ρ = -0.2412; p = 0.17). Overall diagnostic accuracies of RSI and DWI were 0.70 and 0.68, respectively (p = 0.74). CONCLUSION. RSI and DWI achieved equivalent diagnostic performance for PCa detection in a large population of men undergoing first-time prostate biopsy for suspected PCa, but RSI had superior specificity for transition zone lesions.

MR-guided biopsy and focal therapy: new options for prostate cancer management.

PURPOSE OF REVIEW: Options for prostate cancer management are rapidly expanding. The recent advent of MRI technology has led to guided prostate biopsies by radiologists working in-bore or by urologists using MR/US fusion technology. The resulting tumor visualization now provides the option of focal therapy. Currently available are highly directed energies - focused ultrasound (HIFU), cryotherapy, and laser - all offering the hope of curing prostate cancer with few side effects. RECENT FINDINGS: MRI now enables visualization of many prostate cancers. MR/US fusion biopsy makes possible the targeted biopsy of suspicious lesions efficiently in the urology clinic. Several fusion devices are now commercially available. Focal therapy, a derivative of targeted biopsy, is reshaping the approach to treatment of some prostate cancers. Focal laser ablation, originally done in the MRI gantry (in-bore), promises to soon become feasible in a clinic setting (out-of-bore) under local anesthesia. Other focal therapy options, including HIFU and cryotherapy, are currently available. Herein are summarized outcomes data on focal therapy modalities. SUMMARY: MRI-guided biopsy is optimizing prostate cancer diagnosis. Focal therapy, an outgrowth of guided biopsy, promises to become a well tolerated and effective approach to treating many men with prostate cancer while minimizing the risks of incontinence and impotence from radical treatment.

Targeted Prostate Biopsy in the Era of Active Surveillance.

Targeted prostate biopsy using magnetic resonance imaging (MRI) guidance is improving the accuracy of prostate cancer (CaP) diagnosis. This new biopsy technology is especially important for men undergoing active surveillance, improving patient selection for enrollment and enabling precise longitudinal monitoring. Magnetic resonance imaging/ultrasound fusion biopsy allows for 3 functions not previously possible with US-guided biopsy: targeting of suspicious regions, template-mapping for systematic sampling, and tracking of cancer foci over time. This article reviews the evolving role of the new biopsy methods in active surveillance, including the UCLA Active Surveillance pathway, which has incorporated magnetic resonance imaging/ultrasound fusion biopsy from program inception as a possible model.

Optimization of urinary dipstick pH: Are multiple dipstick pH readings reliably comparable to commercial 24-hour urinary pH?

PURPOSE: Accurate measurement of pH is necessary to guide medical management of nephrolithiasis. Urinary dipsticks offer a convenient method to measure pH, but prior studies have only assessed the accuracy of a single, spot dipstick. Given the known diurnal variation in pH, a single dipstick pH is unlikely to reflect the average daily urinary pH. Our goal was to determine whether multiple dipstick pH readings would be reliably comparable to pH from a 24-hour urine analysis. MATERIALS AND METHODS: Kidney stone patients undergoing a 24-hour urine collection were enrolled and took images of dipsticks from their first 3 voids concurrently with the 24-hour collection. Images were sent to and read by a study investigator. The individual and mean pH from the dipsticks were compared to the 24-hour urine pH and considered to be accurate if the dipstick readings were within 0.5 of the 24-hour urine pH. The Bland-Altman test of agreement was used to further compare dipstick pH relative to 24-hour urine pH. RESULTS: Fifty-nine percent of patients had mean urinary pH values within 0.5 pH units of their 24-hour urine pH. Bland-Altman analysis showed a mean difference between dipstick pH and 24-hour urine pH of -0.22, with an upper limit of agreement of 1.02 (95% confidence interval [CI], 0.45-1.59) and a lower limit of agreement of -1.47 (95% CI, -2.04 to -0.90). CONCLUSIONS: We concluded that urinary dipstick based pH measurement lacks the precision required to guide medical management of nephrolithiasis and physicians should use 24-hour urine analysis to base their metabolic therapy.

Cardiovascular Health, Erectile Dysfunction, and Testosterone Replacement: Controversies and Correlations.

Erectile dysfunction and cardiovascular disease share a similar underlying pathophysiology, and low serum testosterone, known as hypogonadism, is a significant player in both conditions. Hypogonadism is a known risk factor for cardiovascular events and worsened mortality, thus influencing physicians to recommend testosterone replacement in hypogonadal men. However, at least 4 recent reports suggest that testosterone replacement may worsen cardiovascular risk, heightening hesitancy in the medical community to treat patients with hypogonadism with testosterone. This review highlights the triad of cardiovascular disease, erectile dysfunction, and testosterone therapy and provides the physician with some guiding principles for navigating these recent concerns.

Survival outcomes after radical and partial nephrectomy for clinical T2 renal tumours categorised by R.E.N.A.L. nephrometry score.

OBJECTIVE: We evaluated survival outcomes of partial nephrectomy (PN) and radical nephrectomy (RN) for clinical T2 renal masses (cT2RM) controlling for R.E.N.A.L. nephrometry score. PATIENTS AND METHODS: A two-centre study comprised of 202 patients with cT2RM who underwent RN (122) or PN (80) between July 2002 and June 2012 (median follow-up 41.5 months). Kaplan-Meier analysis compared overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS) among the entire cohort and within categories of R.E.N.A.L. nephrometry score of ≥10 and <10. Association between procedure and PFS and OS was analysed using Cox-proportional hazard. RESULTS: There were no significant differences between PN and RN in clinical T stage and R.E.N.A.L. nephrometry scores. For RN and PN, the 5-year PFS was 69.8% and 79.9% (P = 0.115), CSS was 82.5% and 86.7% (P = 0.407), and OS was 80% and 83.3% (P = 0.291). Cox regression showed no association between RN vs PN and PFS; a R.E.N.A.L. nephrometry score of ≥10 was associated with a shorter PFS (hazard ratio 6.69, P = 0.002). Kaplan-Meier analysis for RN vs PN showed no difference in PFS for entire cohort or within the R.E.N.A.L. nephrometry score categories of ≥10 and <10. The PFS was better for those with R.E.N.A.L nephrometry scores of <10 vs ≥10 (P < 0.001) and for cT2a vs cT2b tumours (P = 0.012). OS was no different between cT2a and cT2b tumours; patients with R.E.N.A.L. nephrometry scores of ≥10 were more likely to die from disease (P < 0.001) or any cause (P < 0.001) vs those with R.E.N.A.L. nephrometry scores of <10. CONCLUSIONS: PN may be oncologically effective for cT2RM. A R.E.N.A.L nephrometry score of ≥10 is negatively associated with OS among cT2RM compared with a score of <10 and provides additional risk assessment beyond clinical T stage. Further follow-up and prospective randomised investigation is requisite to confirm efficacy of PN for cT2RM.

Long-lasting changes in DNA methylation following short-term hypoxic exposure in primary hippocampal neuronal cultures.

While the effects of hypoxia on gene expression have been investigated in the CNS to some extent, we currently do not know what role epigenetics plays in the transcription of many genes during such hypoxic stress. To start understanding the role of epigenetic changes during hypoxia, we investigated the long-term effect of hypoxia on gene expression and DNA methylation in hippocampal neuronal cells. Primary murine hippocampal neuronal cells were cultured for 7 days. Hypoxic stress of 1% O2, 5% CO2 for 24 hours was applied on Day 3, conditions we found to maximize cellular hypoxic stress response without inducing cell death. Cells were returned to normoxia for 4 days following the period of hypoxic stress. On Day 7, Methyl-Sensitive Cut Counting (MSCC) was used to identify a genome-wide methylation profile of the hippocampal cell lines to assess methylation changes resulting from hypoxia. RNA-Seq was also done on Day 7 to analyze changes in gene transcription. Phenotypic analysis showed that neuronal processes were significantly shorter after 1 day of hypoxia, but there was a catch-up growth of these processes after return to normoxia. Transcriptome profiling using RNA-Seq revealed 369 differentially expressed genes with 225 being upregulated, many of which form networks shown to affect CNS development and function. Importantly, the expression level of 59 genes could be correlated to the changes in DNA methylation in their promoter regions. CpG islands, in particular, had a strong tendency to remain hypomethylated long after hypoxic stress was removed. From this study, we conclude that short-term, sub-lethal hypoxia results in long-lasting changes to genome wide DNA methylation status and that some of these changes can be highly correlated with transcriptional modulation in a number of genes involved in functional pathways that have been previously implicated in neural growth and development.

Smad7 regulates terminal maturation of chondrocytes in the growth plate.

Members of the bone morphogenetic protein (BMP) superfamily, including transforming growth factor-betas (TGFß), regulate multiple aspects of chondrogenesis. Smad7 is an intracellular inhibitor of BMP and TGFß signaling. Studies in which Smad7 was overexpressed in chondrocytes demonstrated that Smad7 can impact chondrogenesis by inhibiting BMP signaling. However, whether Smad7 is actually required for endochondral ossification in vivo is unclear. Moreover, whether Smad7 regulates TGFß in addition to BMP signaling in developing cartilage is unknown. In this study, we found that Smad7 is required for both axial and appendicular skeletal development. Loss of Smad7 led to impairment of the cell cycle in chondrocytes and to defects in terminal maturation. This phenotype was attributed to upregulation of both BMP and TGFß signaling in Smad7 mutant growth plates. Moreover, Smad7-/- mice develop hypocellular cores in the medial growth plates, associated with elevated HIF1α levels, cell death, and intracellular retention of types II and X collagen. Thus, Smad7 may be required to mediate cell stress responses in the growth plate during development.