The epithelium of the human epididymis maintains an appropriate luminal environment for sperm maturation that is essential for male fertility. Regional expression of small noncoding RNAs such as ...microRNAs contributes to segment-specific gene expression and differentiated functions. MicroRNA profiles were reported in human epididymal tissues but not specifically in the epithelial cells derived from those regions. Here, we reveal miRNA signatures of primary cultures of caput, corpus, and cauda epididymis epithelial cells and of the tissues from which they were derived. We identify 324 epithelial cell-derived microRNAs and 259 tissue-derived microRNAs in the epididymis, some of which displayed regionalized expression patterns in cells and/or tissues. Caput cell-enriched miRNAs included miR-573 and miR-155. Cauda cell-enriched miRNAs included miR-1204 and miR-770. Next, we determined the gene ontology pathways associated with in silico predicted target genes of the differentially expressed miRNAs. The effect of androgen receptor stimulation on miRNA expression was also investigated. These data show novel epithelial cell-derived miRNAs that may regulate the expression of important gene networks that are responsible for the regionalized gene expression and function of the epididymis.
After an initial negative biopsy there is an ongoing need for strategies to improve patient selection for repeat biopsy as well as the diagnostic yield from repeat biopsies.
As a collaborative ...initiative of the AUA (American Urological Association) and SAR (Society of Abdominal Radiology) Prostate Cancer Disease Focused Panel, an expert panel of urologists and radiologists conducted a literature review and formed consensus statements regarding the role of prostate magnetic resonance imaging and magnetic resonance imaging targeted biopsy in patients with a negative biopsy, which are summarized in this review.
The panel recognizes that many options exist for men with a previously negative biopsy. If a biopsy is recommended, prostate magnetic resonance imaging and subsequent magnetic resonance imaging targeted cores appear to facilitate the detection of clinically significant disease over standardized repeat biopsy. Thus, when high quality prostate magnetic resonance imaging is available, it should be strongly considered for any patient with a prior negative biopsy who has persistent clinical suspicion for prostate cancer and who is under evaluation for a possible repeat biopsy. The decision of whether to perform magnetic resonance imaging in this setting must also take into account the results of any other biomarkers and the cost of the examination, as well as the availability of high quality prostate magnetic resonance imaging interpretation. If magnetic resonance imaging is done, it should be performed, interpreted and reported in accordance with PI-RADS version 2 (v2) guidelines. Experience of the reporting radiologist and biopsy operator are required to achieve optimal results and practices integrating prostate magnetic resonance imaging into patient care are advised to implement quality assurance programs to monitor targeted biopsy results.
Patients receiving a PI-RADS assessment category of 3 to 5 warrant repeat biopsy with image guided targeting. While transrectal ultrasound guided magnetic resonance imaging fusion or in-bore magnetic resonance imaging targeting may be valuable for more reliable targeting, especially for lesions that are small or in difficult locations, in the absence of such targeting technologies cognitive (visual) targeting remains a reasonable approach in skilled hands. At least 2 targeted cores should be obtained from each magnetic resonance imaging defined target. Given the number of studies showing a proportion of missed clinically significant cancers by magnetic resonance imaging targeted cores, a case specific decision must be made whether to also perform concurrent systematic sampling. However, performing solely targeted biopsy should only be considered once quality assurance efforts have validated the performance of prostate magnetic resonance imaging interpretations with results consistent with the published literature. In patients with negative or low suspicion magnetic resonance imaging (PI-RADS assessment category of 1 or 2, respectively), other ancillary markers (ie PSA, PSAD, PSAV, PCA3, PHI, 4K) may be of value in identifying patients warranting repeat systematic biopsy, although further data are needed on this topic. If a repeat biopsy is deferred on the basis of magnetic resonance imaging findings, then continued clinical and laboratory followup is advised and consideration should be given to incorporating repeat magnetic resonance imaging in this diagnostic surveillance regimen.
Abstract Context The role of robot-assisted radical prostatectomy (RARP) for men with high-risk (HR) prostate cancer (PCa) has not been well studied. Objective To evaluate the indications for ...surgical treatment, technical aspects such as nerve sparing (NS) and lymph node dissection (LND), and perioperative outcomes of men with HR PCa treated with RARP. Evidence acquisition A systematic expert review of the literature was performed in October 2012, searching the Medline, Web of Science, and Scopus databases. Studies with a precise HR definition, robotic focus, and reporting of perioperative and pathologic outcomes were included. Evidence synthesis A total of 12 papers (1360 patients) evaluating RARP in HR PCa were retrieved. Most studies (67%) used the D’Amico classification for defining HR. Biopsy Gleason grade 8–10 was the most frequent HR identifier (61%). Length of follow-up ranged from 9.7 to 37.7 mo. Incidence of NS varied, although when performed did not appear to compromise oncologic outcomes. Extended LND (ELND) revealed positive nodes in up to a third of patients. The rate of symptomatic lymphocele after ELND was 3%. Overall mean operative time was 168 min, estimated blood loss was 189 ml, length of hospital stay was 3.2 d, and catheterization time was 7.8 d. The 12-mo continence rates using a no-pad definition ranged from 51% to 95% with potency recovery ranging from 52% to 60%. The rate of organ-confined disease was 35%, and the positive margin rate was 35%. Three-year biochemical recurrence–free survival ranged from 45% to 86%. Conclusions Although the use of RARP for HR PCa has been relatively limited, it appears safe and effective for select patients. Short-term results are similar to the literature on open radical prostatectomy. Variability exists for NS and the template of LND, although ELND improves staging and removes a higher number of metastatic nodes. Further study is required to assess long-term outcomes.
While active surveillance is the preferred management for most men with low-risk prostate cancer, a subset may harbor more aggressive disease. In this review we examine the evidence underlying an ...accurate and nuanced assessment of oncologic risk in these men.
We performed a nonsystematic literature review current to January 2023 on PubMed for articles relating to clinical, pathological, molecular, and imaging-based modalities available for risk assessment in men with low-risk prostate cancer. Relevant articles were reviewed by the authors and evidence was summarized.
Many tools are available to personalize clinical decision-making for men with low-risk prostate cancer. Total volume of cancer, PSA density, and presence of ductal components have been consistently and strongly associated with current or future evidence of higher-grade disease. PSA kinetics, Prostate Imaging Reporting & Data System 4/5 lesions on MRI, perineural invasion, germline mutations, and genomic classifiers all appear to be associated with an increased risk, although are not as extensively validated. Race, percent free PSA, and other serum biomarkers such as Prostate Health Index and 4Kscore do not appear to be associated with long-term elevated risk.
Long-term prognosis for men diagnosed with low-risk prostate cancer is excellent. There are many factors which should be routinely integrated into the initial management decision as well as determining intensity and frequency of active surveillance. Development of comprehensive multivariable instruments to guide clinical decisions is encouraged.
Hypoxic stress and hypoxia-inducible factors (HIFs) play important roles in a wide range of tumors. We demonstrate that SPOP, which encodes an E3 ubiquitin ligase component, is a direct ...transcriptional target of HIFs in clear cell renal cell carcinoma (ccRCC). Furthermore, hypoxia results in cytoplasmic accumulation of SPOP, which is sufficient to induce tumorigenesis. This tumorigenic activity occurs through the ubiquitination and degradation of multiple regulators of cellular proliferation and apoptosis, including the tumor suppressor PTEN, ERK phosphatases, the proapoptotic molecule Daxx, and the Hedgehog pathway transcription factor Gli2. Knockdown of SPOP specifically kills ccRCC cells, indicating that it may be a promising therapeutic target. Collectively, our results indicate that SPOP serves as a regulatory hub to promote ccRCC tumorigenesis.
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•Transcriptional factor HIF can regulate the expression of SPOP in ccRCC•Hypoxia drives SPOP accumulation in ccRCC cell cytoplasm which promotes tumorigenesis•SPOP mediates the ubiquitination and degradation of PTEN and DUSP7•SPOP targets PTEN, DUSP7, DAXX, and Gli2, are downregulated in all primary ccRCC
Li et al. demonstrate that hypoxia drives the cytoplasmic accumulation of SPOP, an E3 ubiquitin ligase component, in clear cell renal cell carcinoma (ccRCC). Cytoplasmic SPOP promotes tumorigenesis by targeting tumor suppressors, including PTEN, for degradation and could be a promising therapeutic target in ccRCC.
Region-specific transcriptional profiling of tissues and cultured epithelial cells from the human epididymis will predict functional specialization along the duct.
We identified the molecular ...signature driving functions of the caput, corpus and cauda epithelium, and determined how these differ to establish the regional differentiation of the organ.
The epithelium lining the human male genital ducts has a critical role in fertility. In particular, it controls the luminal environment in the epididymis, which is required for normal sperm maturation and reproductive competence. Studies in many animal species have largely informed our understanding of the molecular basis of epididymis function. However, there are substantial differences between species.
Using RNA sequencing on biological replicates, we described gene expression profiles for tissue from each region of the epididymis and cultured epithelial cells derived from these regions. Bioinformatic tools were then utilized to identify differentially expressed genes (DEGs) between tissues and cells from the caput, corpus and cauda.
The data showed that the caput is functionally divergent from the corpus and cauda, which have very similar transcriptomes. Interrogation of DEGs using gene ontology process enrichment analyses showed that processes of ion transport, response to hormone stimulus and urogenital tract development are more evident in the caput, while defense response processes are more important in the corpus/cauda. Consistent with these regional differences in epididymis function, we observed differential expression of transcription factors in the caput and corpus/cauda.
Cultured caput, corpus and cauda cells may not faithfully represent the same cells in the intact organ, due to loss of hormonal signals from the testis and communication from other cell types.
Our data provide a molecular characterization that will facilitate advances in understanding human epididymis epithelium biology in health and disease. They may also reveal the mechanisms coordinating epididymis luminal environment and sperm maturation.
Data deposited at http://www.ncbi.nlm.nih.gov/geo/GSE72986.
This work was supported by the National Institutes of Health: R01HD068901 (PI: A.H.). The authors declare no conflict of interest.
Abstract Background Focal therapy has been introduced for the treatment of localised prostate cancer (PCa). To provide the necessary data for consistent assessment, all focal therapy trials should be ...performed according to uniform, systematic pre- and post-treatment evaluation with well-defined end points and strict inclusion and exclusion criteria. Objective To obtain consensus on trial design for focal therapy in PCa. Design, setting, and participants A four-staged consensus project based on a modified Delphi process was conducted in which 48 experts in focal therapy of PCa participated. According to this formal consensus-building method, participants were asked to fill out an iterative sequence of questionnaires to collect data on trial design. Subsequently, a consensus meeting was held in which 13 panellists discussed acquired data, clarified the results, and defined the conclusions. Outcome measurements and statistical analysis A multidisciplinary board from oncologic centres worldwide reached consensus on patient selection, pretreatment assessment, evaluation of outcome, and follow-up. Results and limitations Inclusion criteria for candidates in focal therapy trials are patients with prostate-specific antigen <15 ng/ml, clinical stage T1c–T2a, Gleason score 3 + 3 or 3 + 4, life expectancy of >10 yr, and any prostate volume. The optimal biopsy strategy includes transrectal ultrasound-guided biopsies to be taken between 6 mo and 12 mo after treatment. The primary objective should be focal ablation of clinically significant disease with negative biopsies at 12 mo after treatment as the primary end point. Conclusions This consensus report provides a standard for designing a feasible focal therapy trial. Patient summary A variety of ablative technologies have been introduced and applied in a focal manner for the treatment of prostate cancer (PCa). In this consensus report, an international panel of experts in the field of PCa determined pre- and post-treatment work-up for focal therapy research.
Limited long-term data characterize patient-reported quality of life (QOL) following postprostatectomy intensity-modulated radiation therapy (PPRT), and predictors of decline are poorly defined.
To ...identify modifiable dosimetric and clinical risk factors impacting QOL and late toxicity following PPRT.
A prospective cohort study of consecutive men with prostate cancer who received PPRT between 2007 and 2015 at a single academic institution.
Patients were prospectively evaluated using the Expanded Prostate Cancer Index Composite (EPIC-26) QOL instrument. Radiation Therapy Oncology Group/Common Toxicity Criteria for Adverse Events toxicity grades were assigned at every follow-up visit. Treatment was delivered to the prostate bed (median 68Gy)±pelvic lymphatics (65%, median 50.4Gy) with daily image guidance. Androgen deprivation therapy was concomitantly administered to 132 (66%) men for a median of 4mo.
Changes were deemed relevant if they exceeded the minimally clinically important difference (MCID), as calculated by a distribution-based method. Generalized estimating equation models and Cox regression were used for QOL and late toxicity univariate and multivariable analysis.
Overall, 199 men were identified with a median follow-up of 33mo. Overall urinary function (UF), bowel function (BF), sexual function (SF), and urinary irritation/obstruction (UI/UO) scores were never lower than the MCID. Between 8% and 18% of men experienced a small multidomain (1× MCID) decline, and 0–8% experienced a moderate multidomain decline (2× MCID) at a given time point up to 84mo after PPRT. The rates of freedom from grade 2 or higher (Gr2+) genitourinary (GU) and gastrointestinal (GI) toxicity were 94% and 95%, respectively, at 4yr. Factors associated with worse QOL or toxicity included longer time to PPRT (UC and UF), higher BMI (UF, BF, and late GI toxicity), older age (BF, SF, and late GU toxicity); hormone therapy (SF), total dose (late GI toxicity), tobacco history (BF), and higher bladder V70Gy (UC, UF, and late GU toxicity).
Long-term QOL and late toxicity are favorable following postprostatectomy radiation therapy. Identifiable clinical and dosimetric risk factors may guide decision making to optimize urinary, sexual, and bowel function.
The following study provides a detailed report of favorable patient-reported quality of life and late side-effect profiles of radiation therapy following surgery for localized prostate cancer. Our findings provide patients guidance on what symptoms to expect if they are planning to undergo radiation therapy in this setting. It also allows physicians to counsel patients appropriately, and modify certain clinical and radiation-related risk factors to optimize quality of life.
Patient-reported long-term quality of life (QOL) and physician-assigned late toxicity remain favorable following postprostatectomy intensity-modulated radiation therapy. Certain clinical and dosimetric risk factors may help guide decision making in consideration of preserving QOL and limiting late toxicity.
Purpose To our knowledge factors affecting the adoption of noncurative initial management in the United States for low risk prostate cancer on a population based level are unknown. We measured ...temporal trends in the proportion of patients with low and intermediate risk prostate cancer who elected noncurative initial treatment in the United States and analyzed the association of factors affecting management choice. Materials and Methods We identified 465,591 and 237,257 men diagnosed with low or intermediate risk prostate cancer using NCDB and SEER (2004 to 2010), respectively. We measured the proportion of men who elected noncurative initial treatment and used multivariate logistic regression analysis to evaluate factors affecting the treatment choice. Results During the study period noncurative initial management increased in patients at low risk from 21% to 32% in SEER and from 13% to 20% in NCDB (each p <0.001). This increase was not reflected in our overall study population (SEER 20% to 22% and NCDB 11% to 13%) since the proportion of patients with Gleason score 6 or less decreased with time (61% to 49% and 61% to 45%, respectively). From 2004 to 2010 older age, lower prostate specific antigen, earlier clinical stage, increased comorbidity index and not being married were associated with a higher likelihood of noncurative initial management (each p <0.05). Conclusions Two independently managed, population based data sets confirmed a temporal increase in noncurative initial management in patients with low risk PCa that did not translate into greater use overall in those at low and intermediate risk combined. These contrasting results are likely due to grade migration resulting in fewer men being classified as with low risk PCa based on Gleason score.
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