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Defining the transition from benign to malignant tissue is fundamental to improving early diagnosis of cancer 1 . Here we use a systematic approach to study spatial genome integrity in situ and describe previously unidentified clonal relationships. We used spatially resolved transcriptomics 2 to infer spatial copy number variations in >120,000 regions across multiple organs, in benign and malignant tissues. We demonstrate that genome-wide copy number variation reveals distinct clonal patterns within tumours and in nearby benign tissue using an organ-wide approach focused on the prostate. Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution. We highlight the power of capturing the molecular and spatial continuums in a tissue context and challenge the rationale for treatment paradigms, including focal therapy., (© 2022. The Author(s).)

Background: Active surveillance (AS) is the preferred option for initial management for low-risk prostate cancer (PC). Although many AS protocols exist, there is little evidence to support one over another., Objective: To assess whether there is difference in overall (OS), prostate cancer-specific (CSS), metastasis-free (MFS), or treatment-free (TFS) survival between a strict (Prostate cancer Research International: Active Surveillance [PRIAS]) and a loose (European Randomized study of Screening for Prostate Cancer [ERSPC]) AS protocol., Design Setting and Participants: This study included two cohorts of men ( n = 518) with low-risk, localized, Gleason score ≤7 PC. The ERSPC cohort included 241 men followed for 9.5 yr (median) with a non-protocol-based follow-up. The PRIAS cohort included 277 men followed for 5 yr (median) with a strict protocol., Outcome Measurements and Statistical Analysis: OS, CSS, MFS, and TFS were compared by the Kaplan-Meier method, competing risk analysis, and Cox proportional hazard regression., Results and Limitations: As expected, due to the difference in median follow-up time between the cohorts, a difference in the absolute number of events was seen. However, no difference in any of the survival outcomes was evident in the Kaplan-Meier or competing risks analysis. Furthermore, in Cox proportional hazard regression analysis, cohort (ERSPC vs PRIAS) was not associated with any of the outcomes. Results are limited by the retrospective study design, limited statistical power, and inability to match the cohorts for predictive factors., Conclusions: There was no difference in survival outcomes between a non-protocol-based follow-up and a protocol-based contemporary AS follow-up of patients with low-risk PC. However, a longer follow-up is needed., Patient Summary: We compared survival outcomes of two cohorts of patients with low-risk prostate cancer: a strict and a loose follow-up protocol. We found no differences in survival measures between the cohorts., (© 2021 The Author(s).)

Robotic-assisted laparoscopic radical prostatectomy (RALP) has become the most widespread treatment for organ-confined prostate cancer. Here, we describe a fast specimen retrieval technique for RALP to obtain high-quality tissue specimen with minimal warm ischemia time for next-generation biobanking. Here, we show that using fast retrieval technique, short warm ischemia times can be achieved while not increasing the surgical time. Patients undergoing RALP with written informed consent participated in Helsinki Urological Bank study. Previously operated RALP patients and those, who were not willing to participate in the study, served as a control group. The study consisted of 1685 patients, 684 in fast retrieval and 1001 in control group. We developed a novel fast retrieval technique in which fascia is opened for camera port according to the prostate size and a running suture is placed and tightened against the camera port in the beginning of the operation. Immediately after prostate is freed from attachments, suture is loosened and the prostate is extirpated inside the endoscopic bag through the camera port fascial opening, then the fascial suture is again tightened against the camera port and the RALP procedure is completed. The mean warm ischemia times in fast retrieval group were 20 min 18 s and 22 min 30 s, respectively, in patients without and with lymphadenectomy. The mean console and surgery times with and without lymphadenectomy were similar in both groups. There were no technique-related complications associated with Fast Retrieval procedure. Tissue integrity test results for the RNA and DNA quality showed good quality for the specimen. Fast retrieval technique can easily and safely be utilized to maximize usefulness of RALP tissue specimen in downstream biobank applications.

The second-generation antiandrogen, enzalutamide, is approved for castrate-resistant prostate cancer (CRPC) and targets androgen receptor (AR) activity in CRPC. Despite initial clinical activity, acquired resistance to enzalutamide arises rapidly and most patients develop terminal disease. Previous work has established Stat5 as a potent inducer of prostate cancer growth. Here, we investigated the significance of Jak2-Stat5 signaling in resistance of prostate cancer to enzalutamide. The levels of Jak2 and Stat5 mRNA, proteins and activation were evaluated in prostate cancer cells, xenograft tumors, and clinical prostate cancers before and after enzalutamide therapy. Jak2 and Stat5 were suppressed by genetic knockdown using lentiviral shRNA or pharmacologic inhibitors. Responsiveness of primary and enzalutamide-resistant prostate cancer to pharmacologic inhibitors of Jak2-Stat5 signaling was assessed in vivo in mice bearing prostate cancer xenograft tumors. Patient-derived prostate cancers were tested for responsiveness to Stat5 blockade as second-line treatment after enzalutamide ex vivo in tumor explant cultures. Enzalutamide-liganded AR induces sustained Jak2-Stat5 phosphorylation in prostate cancer leading to the formation of a positive feed-forward loop, where activated Stat5, in turn, induces Jak2 mRNA and protein levels contributing to further Jak2 activation. Mechanistically, enzalutamide-liganded AR induced Jak2 phosphorylation through a process involving Jak2-specific phosphatases. Stat5 promoted prostate cancer growth during enzalutamide treatment. Jak2-Stat5 inhibition induced death of prostate cancer cells and patient-derived prostate cancers surviving enzalutamide treatment and blocked enzalutamide-resistant tumor growth in mice. This work introduces a novel concept of a pivotal role of hyperactivated Jak2-Stat5 signaling in enzalutamide-resistant prostate cancer, which is readily targetable by Jak2 inhibitors in clinical development., (©2019 American Association for Cancer Research.)

Background: Active surveillance (AS) is an option for men with low-risk prostate cancer (PCa). PTEN and ERG have been considered as potential biomarkers of PCa progression and survival., Objective: To study the role of ERG and PTEN status in the Prostate Cancer Research International: Active Surveillance (PRIAS) trial diagnostic biopsies (DBxs) in predicting surveillance discontinuation and adverse surgical findings in subsequent radical prostatectomy (RP)., Design, Setting, and Participants: A total of 231 patients were recruited to the PRIAS between 2007 and 2013 in Helsinki. DBx tissue for immunohistochemistry (IHC) was available from 190 patients. Tissue microarrays (TMAs) were constructed from 57 specimens of subsequent RPs. DBxs containing grade group (GG) 1 PCa and RP TMA sections were stained with ERG and PTEN antibodies, and scored as either negative or positive., Outcome Measurements and Statistical Analyses: Outcomes were followed up by biopsy GG upgrade (GG ≥ 2) and protocol-based treatment change, as well as adverse findings in RP (GG ≥ 3 or pathological stage≥3). Clinical variables and biomarker status in DBx were correlated in Cox regression analysis and cumulative survival in Kaplan-Meier analysis, and finally, Gray's competing risk analysis was performed and nonprotocol-based discontinuation was considered as a competing event., Results and Limitations: In both uni- and multivariate Cox regression analyses, only the number of positive cores in the DBx, the number of rebiopsy sessions, and PTEN status at diagnosis were significantly associated with rebiopsy GG upgrade, treatment change, and adverse histopathology in RP. In Kaplan-Meier analysis, PTEN loss was associated with a shorter time to GG upgrade and treatment change. Patients with PTEN loss had a higher probability for protocol-based discontinuation but not for competing risk factors compared with patients with intact PTEN. Biopsy ERG status was concordant with RP TMA ERG status, while PTEN was not. Limitations include a retrospective analysis of prospective cohort data., Conclusions: PTEN status at diagnosis is a potential biomarker for identifying patients with PCa on AS with a high risk for progression or adverse findings on subsequent RP., Patient Summary: A simple diagnostic biopsy-based analysis of PTEN status may help identify patients with high risk for prostate cancer progression., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Active surveillance (AS) of prostate cancer (PC) has increased in popularity to address overtreatment., Objective: To determine whether a novel metric, cumulative cancer locations (CCLO), can predict AS outcomes in a group of AS patients with low and very low risk., Design, Setting, and Participants: CCLO is obtained by summing the total number of histological cancer-positive locations in both diagnostic and confirmatory biopsies (Bx). The retrospective study cohort comprised three prospective AS cohorts (Helsinki University Hospital: n=316; European Institute of Oncology: n=204; and University of Münster: n=89)., Outcome Measurements and Statistical Analysis: We analyzed whether risk stratification based on CCLO predicts different AS outcomes: protocol-based discontinuation (PBD), Gleason upgrading (GU) during AS, and adverse findings in radical prostatectomy (RP) specimens., Results: In Kaplan Meier analyses, patients in the CCLO high-risk group experienced significantly shorter event-free survival for all outcomes (PBD, GU, and adverse RP findings; all p<0.002). In multivariable Cox regression analysis, patients in the CCLO high-risk group had a significantly higher risk of experiencing PBD (hazard ratio [HR] 12.15, 95% confidence interval [CI] 6.18-23.9; p<0.001), GU (HR 6.01, 95% CI 2.16-16.8; p=0.002), and adverse RP findings (HR 9.144, 95% CI 2.27-36.9; p=0.006). In receiver operating characteristic analyses, the area under the curve for CCLO outperformed the number of cancer-positive Bxs in confirmatory Bx in predicting PBD (0.734 vs 0.682), GU (0.655 vs 0.576) and adverse RP findings (0.662 vs 0.561) and the added value was supported by decision curve analysis., Conclusions: CCLO is distinct from the number of positive Bx cores. Higher CCLO predicts AS outcomes and may aid in selection of patients for AS., Patient Summary: For patients on active surveillance for prostate cancer, the cumulative number of cancer-positive locations in diagnostic and confirmatory biopsies is a predictor of active surveillance outcomes., (Copyright © 2018. Published by Elsevier B.V.)

Prostate cancer is a highly heterogeneous disease and the clinical outcome is varying. While current prognostic tools are regarded insufficient, there is a critical need for markers that would aid prognostication and patient risk-stratification. Heat shock transcription factor 1 (HSF1) is crucial for cellular homeostasis, but also a driver of oncogenesis. The clinical relevance of HSF1 in prostate cancer is, however, unknown. Here, we identified HSF1 as a potential biomarker in mRNA expression datasets on prostate cancer. Clinical validation was performed on tissue microarrays from independent cohorts: one constructed from radical prostatectomies from 478 patients with long term follow-up, and another comprising of regionally advanced to distant metastatic samples. Associations with clinical variables and disease outcomes were investigated. Increased nuclear HSF1 expression correlated with disease advancement and aggressiveness and was, independently from established clinicopathological variables, predictive of both early initiation of secondary therapy and poor disease-specific survival. In a joint model with the clinical Cancer of the Prostate Risk Assessment post-Surgical (CAPRA-S) score, nuclear HSF1 remained a predictive factor of shortened disease-specific survival. The results suggest that nuclear HSF1 expression could serve as a novel prognostic marker for patient risk-stratification on disease progression and survival after radical prostatectomy., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Introduction: This study was conducted to describe the changes in repeat multiparametric MRI (mpMRI) occurring in prostate cancer (PCa) patients during active surveillance (AS), and to study possible associations between mpMRI-related parameters in predicting prostate biopsy (Bx) Gleason score (GS) upgrading >3+3 and protocol-based treatment change (TC)., Materials and Methods: The study cohort consisted of 76 AS patients with GS 3+3 PCa and at least two consecutive mpMRIs of the prostate performed between 2006-2015. Patients were followed according to the Prostate Cancer Research International Active Surveillance (PRIAS) protocol and an additional mpMRI. The primary end points were GS upgrading (GU) (>3+3) in protocol-based Bxs and protocol-based TC., Results: Out of 76 patients, 53 (69%) had progression (PIRADS upgrade, size increase or new lesion[s]), while 18 (24%) had radiologically stable disease, and 5 (7%) had regression (PIRADS or size decrease, disappearance of lesion[s]) in repeat mpMRIs during AS. PIRADS scores of 4-5 in the initial mpMRI were associated with GU (p = 0.008) and protocol-based TC (p = 0.009). Tumour progression on repeat mpMRIs was associated with TC (p = 0.045) but not with GU (p = 1.00). PIRADS scores of 4-5 predict GU (sensitivity 0.80 [95% confidence interval (CI); 0.51-0.95, specificity 0.62 [95% CI; 0.52-0.77]) with PPV and NPV values of 0.34 (95% CI; 0.21-0.55) and 0.93 (95% CI; 0.80-0.98), respectively., Conclusion: mpMRI is a useful tool not only to select but also to monitor PCa patients on AS.

The clinical course of prostate cancer is highly variable. Current prognostic variables, stage, and Gleason score have limitations in assessing treatment regimens for individual patients, especially in the intermediate-risk group of Gleason score 7. ERG:TMPRSS2 fusion and loss of PTEN are some of the most common genetic alterations in prostate cancer. Immunohistochemistry of PTEN and ERG has generated interest as a promising method for more precise outcome prediction but requires further validation in population-based cohorts. We studied the predictive value of ERG and PTEN expression by immunohistochemistry in two large radical prostatectomy cohorts comprising 815 patients with extensive follow-up information. Clinical end points were initiation of secondary therapy, overall survival, and disease-specific survival. Predictions of clinical outcomes were also assessed according to androgen receptor (AR) activity. PTEN loss, especially in ERG-negative cancers, predicted initiation of secondary treatments and shortened disease-specific survival time, as well as stratifying Gleason score 7 patients into different prognostic groups with regard to secondary treatments and disease-specific survival. High AR immunoreactivity in ERG-negative cancers with PTEN loss predicted worse disease-specific survival. We also observed that in Gleason score 7 ERG-negative cases with PTEN loss and high AR expression have significantly shorter disease-specific survival time compared with ERG-positive cases. Our conclusion is that loss of PTEN is a strong determining factor for shorter disease-specific survival time and initiation of secondary therapies after radical prostatectomy. The predictive value of PTEN immunoreactivity is further accentuated in ERG-negative cancers with high AR expression. Negative PTEN expression, accompanied by ERG status, can be used to stratify patients with Gleason score 7 into different survival groups. Assessment of PTEN and ERG status could provide an additional tool for initial diagnostics when determining the prognosis and subsequent follow-up regimen for patients treated by radical prostatectomy.

Most treatment practices for urban runoff capture pollutants such as phosphorus by either settling or filtration while dissolved phosphorus, typically as phosphates, is untreated. Dissolved phosphorus, however, represents an average 45% of total phosphorus in stormwater runoff and can be more than 95%. In this study, a new stormwater treatment technology to capture phosphate, called the Minnesota Filter, is introduced. The filter comprises iron filings mixed with sand and is tested for phosphate removal from synthetic stormwater. Results indicate that sand mixed with 5% iron filings captures an average of 88% phosphate for at least 200 m of treated depth, which is significantly greater than a sand filter without iron filings. Neither incorporation of iron filings into a sand filter nor capture of phosphates onto iron filings in column experiments had a significant effect on the hydraulic conductivity of the filter at mixtures of 5% or less iron by weight. Field applications with up to 10.7% iron were operated over 1 year without detrimental effects upon hydraulic conductivity. A model is applied and fit to column studies to predict the field performance of iron-enhanced sand filters. The model predictions are verified through the predicted performance of the filters in removing phosphates in field applications. Practical applications of the technology, both existing and proposed, are presented so stormwater managers can begin implementation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Suspended solids either as total suspended solids (TSS) or suspended sediment concentration (SSC) is an integral particulate water quality parameter that is important in assessing particle-bound contaminants. At present, nearly all stormwater runoff quality monitoring is performed with automatic samplers in which the sampling intake is typically installed at the bottom of a storm sewer or channel. This method of sampling often results in a less accurate measurement of suspended sediment and associated pollutants due to the vertical variation in particle concentration caused by particle settling. In this study, the inaccuracies associated with sampling by conventional intakes for automatic samplers have been verified by testing with known suspended sediment concentrations and known particle sizes ranging from approximately 20 μm to 355 μm under various flow rates. Experimental results show that, for samples collected at a typical automatic sampler intake position, the ratio of sampled to feed suspended sediment concentration is up to 6600% without an intake strainer and up to 300% with a strainer. When the sampling intake is modified with multiple sampling tubes and fitted with a wing to provide lift (winged arm sampler intake), the accuracy of sampling improves substantially. With this modification, the differences between sampled and feed suspended sediment concentration were more consistent and the sampled to feed concentration ratio was accurate to within 10% for particle sizes up to 250 μm.

Previous work from our laboratory indicates that interhemispheric interaction (IHI) functionally increases the attentional capacity available to support performance on visual tasks (Banich in The asymmetrical brain, pp 261-302, 2003). Because manipulations of both computational complexity and selection demand alter the benefits of IHI to task performance, we argue that IHI may be a general strategy for meeting increases in attentional demand. Other researchers, however, have suggested that the apparent benefits of IHI to attentional capacity are an epiphenomenon of the organization of the visual system (Fecteau and Enns in Neuropsychologia 43:1412-1428, 2005; Marsolek et al. in Neuropsychologia 40:1983-1999, 2002). In the current experiment, we investigate whether IHI increases attentional capacity outside the visual system by manipulating the selection demands of an auditory temporal pattern-matching task. We find that IHI expands attentional capacity in the auditory system. This suggests that the benefits of requiring IHI derive from a functional increase in attentional capacity rather than the organization of a specific sensory modality.

5alpha-Androst-1-ene-3beta,17beta-diol (1) was detected in extracts from fat of Sus scrofa L. (pig) by comparison with the commercially available synthetic compound, using gas chromatography-mass spectrometry. This observation is unprecedented because 1 is currently sold as a nutritional supplement, yet has not been previously reported as naturally occurring in the food supply.