Disease-specific outcomes of Radical Prostatectomies in Northern Norway; A case for the impact of perineural infiltration and postoperative PSA-doubling time

Background Prostate cancer is the most common male malignancy and a mayor cause of mortality in the western world. The impact of clinicopathological variables on disease related outcomes have mainly been reported from a few large US series, most of them not reporting on perineural infiltration. We therefore wanted to investigate relevant cancer outcomes in patients undergoing radical prostatectomy in two Norwegian health regions with an emphasis on the impact of perineural infiltration (PNI) and prostate specific antigen- doubling time (PSA-DT). Methods We conducted a retrospective analysis of 535 prostatectomy patients at three hospitals between 1995 and 2005 estimating biochemical failure- (BFFS), clinical failure- (CFFS) and prostate cancer death-free survival (PCDFS) with the Kaplan-Meier method. We investigated clinicopathological factors influencing risk of events using cox proportional hazard regression. Results After a median follow-up of 89 months, 170 patients (32%) experienced biochemical failure (BF), 36 (7%) experienced clinical failure and 15 (3%) had died of prostate cancer. pT-Stage (p = 0.001), preoperative PSA (p = 0.047), Gleason Score (p = 0.032), non-apical positive surgical margins (PSM) (p = 0.003) and apical PSM (p = 0.031) were all independently associated to BFFS. Gleason score (p = 0.019), PNI (p = 0.012) and non-apical PSM (p = 0.002) were all independently associated to CFFS while only PNI (P = 0.047) and subgroups of Gleason score were independently associated to PCDFS. After BF, patients with a shorter PSA-DT had independent and significant worse event-free survivals than patients with PSA-DT > 15 months (PSA-DT = 3-9 months, CFFS HR = 6.44, p < 0.001, PCDFS HR = 13.7, p = 0.020; PSA-DT < 3 months, CFFS HR = 11.2, p < 0.001, PCDFS HR = 27.5, p = 0.006). Conclusions After prostatectomy, CFFS and PCDFS are variable, but both are strongly associated to Gleason score and PNI. In patients with BF, PSA-DT was most strongly associated to CF and PCD. Our study adds weight to the importance of PSA-DT and re-launches PNI as a strong prognosticator for clinically relevant endpoints

Towards Adaptive Technology in Routine Mental Healthcare

This paper summarizes the information technology-related research findings after 5 years with the INTROducing Mental health through Adaptive Technology project. The aim was to improve mental healthcare by introducing new technologies for adaptive interventions in mental healthcare through interdisciplinary research and development. We focus on the challenges related to internet-delivered psychological treatments, emphasising artificial intelligence, human-computer interaction, and software engineering. We present the main research findings, the developed artefacts, and lessons learned from the project before outlining directions for future research. The main findings from this project are encapsulated in a reference architecture that is used for establishing an infrastructure for adaptive internet-delivered psychological treatment systems in clinical contexts. The infrastructure is developed by introducing an interdisciplinary design and development process inspired by domain-driven design, user-centred design, and the person based approach for intervention design. The process aligns the software development with the intervention design and illustrates their mutual dependencies. Finally, we present software artefacts produced within the project and discuss how they are related to the proposed reference architecture. Our results indicate that the proposed development process, the reference architecture and the produced software can be practical means of designing adaptive mental health care treatments in correspondence with the patients’ needs and preferences. In summary, we have created the initial version of an information technology infrastructure to support the development and deployment of Internet-delivered mental health interventions with inherent support for data sharing, data analysis, reusability of treatment content, and adaptation of intervention based on user needs and preferences.publishedVersio

High miR-205 expression in normal epithelium is associated with biochemical failure - An argument for epithelial crosstalk in prostate cancer?

Due to insufficient prognostic tools, failure to predict aggressive prostate cancer (PC) has left patient selection for radical treatment an unsolved challenge. This has resulted in overtreatment with radical therapy. Better prognostic tools are urgently warranted. MicroRNAs (miRs) have emerged as important regulators of cellular pathways, resulting in altered gene expressions. miR-205 has previously been observed downregulated in PC, acting as tumor suppressor. Herein, the expression of miR-205 in prostate tissue was examined in a large, well-described cohort of 535 Norwegian prostatectomy patients. Using in situ hybridization, miR-205 expression was semiquantatively measured in normal and tumor tissues from radical prostatectomy specimens. Associations with clinicopathological data and PC relapse were calculated. Expression of miR-205 was lower in tumor epithelium compared to normal epithelium. No association was observed between miR-205 expression in primary tumor epithelium and cancer relapse. In contrast, high expression of miR-205 in normal epithelium was independently associated with biochemical relapse (HR = 1.64, p = 0.003). A prognostic importance of miR-205 expression was only found in the normal epithelium, raising the hypothesis of epithelial crosstalk between normal and tumor epithelium in PC. This finding supports the proposed novel hypothesis of an anti-cancerogenous function of normal epithelium in tumor tissue

Fibroblast miR-210 overexpression is independently associated with clinical failure in Prostate Cancer – a multicenter (in situ hybridization) study

There is a need for better prognostication in prostate cancer (PC). “The micromanager of hypoxia”, microRNA-210 (miR-210) is directly linked to hypoxia, is overexpressed in PC and has been implied in tumor cell-fibroblast crosstalk. We investigated the prognostic impact of miR-210 in tumor cells and fibroblasts in PC. Tumor and stromal samples from a multicenter PC cohort of 535 prostatectomy patients were inserted into tissue microarrays. To investigate the expression of miR-210, we used in situ hybridization and two pathologists semiquantitatively scored its expression. Overexpression of miR-210 in tumor cells was not associated to biochemical failure-free survival (BFFS, p=0.85) or clinical failure-free survival (CFFS, p=0.09). However, overexpression of miR-210 in fibroblasts was significantly associated to a poor CFFS (p=0.001), but not BFFS (p=0.232). This feature was validated in both cohorts. Overexpression of miR-210 was independently associated with a reduced CFFS (HR=2.76, CI 95% 1.25–6.09, p=0.012). Overexpression of miR-210 in fibroblasts is independently associated with a poor CFFS. This highlights the importance of fibroblasts and cellular compartment crosstalk in PC. miR-210 is a candidate prognostic marker and potential therapeutic target in PC

High expression of PDGFR-β in prostate cancer stroma is independently associated with clinical and biochemical prostate cancer recurrence

Due to a lack of sufficient diagnostic tools to predict aggressive disease, there is a significant overtreatment of patients with prostate cancer. Platelet derived growth factors (PDGFs) and their receptors (PDGFRs) are key regulators of mesenchymal cells in the tumor microenvironment, and has been associated with unfavorable outcome in several other cancers. Herein, we aimed to investigate the prognostic impact of PDGFR-β and its ligands (PDGF-B and PDGF-D) in a multicenter prostatectomy cohort of 535 Norwegian patients. Using tissue microarrays and immunohistochemistry, the expression of ligands PDGF-B and PDGF-D and their corresponding receptor, PDGFR-β, was assessed in neoplastic tissue and tumor-associated stroma. PDGFR-β was expressed in benign and tumor associated stroma, but not in epithelium. High stromal expression of PDGFR-β was independently associated with clinical relapse (HR = 2.17, p = 0.010) and biochemical failure (HR = 1.58, p = 0.002). This large study highlights the prognostic importance of PDGFR-β expression, implicating its involvement in prostate cancer progression even in early stage disease. Hence, analyses of PDGFR-β may help distinguish which patients will benefit from radical treatment, and since PDGFR-β is associated with relapse and shorter survival, it mandates a focus as a therapeutic target

Disease-specific outcomes of Radical Prostatectomies in Northern Norway; A case for the impact of perineural infiltration and postoperative PSA-doubling time

Background: Prostate cancer is the most common male malignancy and a mayor cause of mortality in the western world. The impact of clinicopathological variables on disease related outcomes have mainly been reported from a few large US series, most of them not reporting on perineural infiltration. We therefore wanted to investigate relevant cancer outcomes in patients undergoing radical prostatectomy in two Norwegian health regions with an emphasis on the impact of perineural infiltration (PNI) and prostate specific antigen- doubling time (PSA-DT). Methods: We conducted a retrospective analysis of 535 prostatectomy patients at three hospitals between 1995 and 2005 estimating biochemical failure- (BFFS), clinical failure- (CFFS) and prostate cancer death-free survival (PCDFS) with the Kaplan-Meier method. We investigated clinicopathological factors influencing risk of events using cox proportional hazard regression. Results: After a median follow-up of 89 months, 170 patients (32%) experienced biochemical failure (BF), 36 (7%) experienced clinical failure and 15 (3%) had died of prostate cancer. pT-Stage (p = 0.001), preoperative PSA (p = 0.047), Gleason Score (p = 0.032), non-apical positive surgical margins (PSM) (p = 0.003) and apical PSM (p = 0.031) were all independently associated to BFFS. Gleason score (p = 0.019), PNI (p = 0.012) and non-apical PSM (p = 0.002) were all independently associated to CFFS while only PNI (P = 0.047) and subgroups of Gleason score were independently associated to PCDFS. After BF, patients with a shorter PSA-DT had independent and significant worse event-free survivals than patients with PSA-DT > 15 months (PSA-DT = 3-9 months, CFFS HR = 6.44, p < 0.001, PCDFS HR = 13.7, p = 0.020; PSA-DT < 3 months, CFFS HR = 11.2, p < 0.001, PCDFS HR = 27.5, p = 0.006). Conclusions: After prostatectomy, CFFS and PCDFS are variable, but both are strongly associated to Gleason score and PNI. In patients with BF, PSA-DT was most strongly associated to CF and PCD. Our study adds weight to the importance of PSA-DT and re-launches PNI as a strong prognosticator for clinically relevant endpoints

The prognostic role of immune checkpoint markers programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) in a large, multicenter prostate cancer cohort

Programmed cell death protein 1 (PD-1) and its ligand Programmed death ligand 1 (PD-L1) have gained massive attention in cancer research due to recent availability and their targeted antitumor effects. Their role in prostate cancer is still undetermined. We constructed tissue microarrays from prostatectomy specimens from 535 prostate cancer patients. Following validation of antibodies, immunohistochemistry was used to evaluate the expression of PD-1 in lymphocytes and PD-L1 in epithelial and stromal cells of primary tumors. PD-L1 expression was commonly seen in tumor epithelial cells (92% of cases). Univariate survival analysis revealed a positive association between a high density of PD-1+ lymphocytes and worse clinical failure-free survival, limited to a trend (p = 0.084). In subgroups known to indicate unfavorable prostate cancer prognosis (Gleason grade 9, age 10, pT3) patients with high density of PD-1+ lymphocytes had a significantly higher risk of clinical failure (p = < 0.001, p = 0.025, p = 0.039 and p = 0.011, respectively). In the multivariate analysis, high density of PD-1+ lymphocytes was a significant negative independent prognostic factor for clinical failure-free survival (HR = 2.48, CI 95% 1.12–5.48, p = 0.025)

Progesterone receptors in prostate cancer: Progesterone receptor B is the isoform associated with disease progression

The role of steroid hormones in carcinogenesis of the prostate is to some extent unraveled thorough the effect of androgen deprivation therapy on prostate cancer (PCa) progression. Other members of the steroid hormone family, such as progesterone, are also implicated in PCa, but progesterone’s role remains undefined. This study aimed to examine the distribution of progesterone receptor isoforms (PGRA, PGRB) in PCa tissue and their association with clinical endpoints. This was conducted retrospectively by collecting radical prostatectomy specimens from 535 patients. Tissue was analyzed using tissue microarray, where representative tumor areas were carefully selected. Protein expression was evaluated through immunohistochemistry, in stromal and epithelial tissue. Associations between receptor expression and clinical data were considered using statistical survival analyses. Herein, we discovered a solely stromal PGRA- and a stromal and epithelial PGRB expression. Further, a high PGRB expression in tumor tissue was associated with an unfavorable prognosis in both univariate and multivariate analyses: Biochemical failure (HR: 2.0, 95% CI: 1.45–2.76, p < 0.001) and clinical failure (HR: 2.5, 95% CI: 1.29–4.85, p = 0.006). These findings are in agreement with our previous investigation on pan-PGR, indicating that the observed negative effect of PGR is represented by PGRB

Estrogen receptors α and β and aromatase as independent predictors for prostate cancer outcome

Androgens are considered important in normal prostate physiology and prostate cancer (PCa) pathogenesis. However, androgen-targeted treatment preventing PCa recurrence is still lacking. This indicates additional mediators contributing to cancer development. We sought to determine the prognostic significance of estrogen receptors, ERα and -β, and the aromatase enzyme in PCa. Tissue microarrays were created from 535 PCa patients treated with radical prostatectomy. Expression of ERα, ERβ and aromatase were evaluated using immunohistochemistry. Representative tumor epithelial (TE) and tumor stromal (TS) areas were investigated separately. Survival analyses were used to evaluate the markers correlation to PCa outcome. In univariate analyses, ERα in TS was associated with delayed time to clinical failure (CF) (p = 0.042) and PCa death (p = 0.019), while ERβ was associated with reduced time to biochemical failure (BF) (p = 0.002). Aromatase in TS and TE was associated with increased time to BF and CF respectively (p = 0.016, p = 0.046). Multivariate analyses supported these observations, indicating an independent prognostic impact of all markers. When stratifying the analysis according to different surgical centers the results were unchanged. In conclusion, significant prognostic roles of ERα, ERβ and aromatase were discovered in the in PCa specimens of our large multicenter cohort

MicroRNA 141 is associated to outcome and aggressive tumor characteristics in prostate cancer

A large number of miRNAs influence key cellular processes involved in prostate tumorigenesis. Previous studies have demonstrated high expression of miRNAs in human prostate cancer (PC) tissues and cell lines. In previous microarray data, we found miR-141 to be upregulated and miR-145 to be downregulated in PC. In this large PC cohort (n = 535), we explored the prognostic role of miR-141 and miR-145 in PC. Tumor epithelial (TE) and tumor stromal (TS) areas were evaluated separately and combined (TE + TS). In situ hybridization was used to evaluate the expression of the miRNAs. We found that miR-141 (TE) correlated significantly to Gleason score ≥8 (p = 0.040) and large tumor size (≥20 mm, p = 0.025) and miR-141 (TE + TS) to Gleason grade (p = 0.001). MiR-145 correlated to pT-stage (p = 0.038), tumor size (p = 0.025), Gleason grade (p = 0.051) and PSA (p = 0.032). In univariate analysis miR-141 (TE + TS) was significantly associated with biochemical failure-free survival (BFFS, p = 0.007) and clinical failure-free survival (CFFS, p = 0.021). For miR-145, there were no differences between patients with high versus low expression. In multivariate analysis overexpression of miR-141 in tumor epithelium and tumor stroma was significantly associated with BFFS (HR = 1.07 CI95% 1.00–1.14, p = 0.007). To conclude, high expression of miR-141 appears associated with increased risk of biochemical PC recurrence