A Novel Risk Score (P-score) Based on a Three-Gene Signature, for Estimating the Risk of Prostate Cancer-Specific Mortality

Purpose: To develop and validate a risk score (P-score) algorithm which includes previously described three-gene signature and clinicopathological parameters to predict the risk of death from prostate cancer (PCa) in a retrospective cohort. Patients and Methods: A total of 591 PCa patients diagnosed between 2003 and 2008 in Stockholm, Sweden, with a median clinical follow-up time of 7.6 years (1– 11 years) were included in this study. Expression of a three-gene signature (IGFBP3, F3, VGLL3) was measured in formalin-fixed paraffin-embedded material from diagnostic core needle biopsies (CNB) of these patients. A point-based scoring system based on a Fine-Gray competing risk model was used to establish the P-score based on the three-gene signature combined with PSA value, Gleason score and tumor stage at diagnosis. The endpoint was PCa-specific mortality, while other causes of death were treated as a competing risk. Out of the 591 patients, 315 patients (estimation cohort) were selected to develop the P-score. The P-score was subsequently validated in an independent validation cohort of 276 patients. Results: The P-score was established ranging from the integers 0 to 15. Each one-unit increase was associated with a hazard ratio of 1.39 (95% confidence interval: 1.27– 1.51, p < 0.001). The P-score was validated and performed better in predicting PCa-specific mortality than both D’Amico (0.76 vs 0.70) and NCCN (0.76 vs 0.71) by using the concordance index for competing risk. Similar improvement patterns are shown by time-dependent area under the curve. As demonstrated by cumulative incidence function, both P-score and gene signature stratified PCa patients into significantly different risk groups. Conclusion: We developed the P-score, a risk stratification system for newly diagnosed PCa patients by integrating a three-gene signature measured in CNB tissue. The P-score could provide valuable decision support to distinguish PCa patients with favorable and unfavorable outcomes and hence improve treatment decisions

P-score in preoperative biopsies accurately predicts P-score in final pathology at radical prostatectomy in patients with localized prostate cancer

BACKGROUND: Prostate cancer (PCa) is a highly heterogeneous, multifocal disease, and identification of clinically significant lesions is challenging, which complicates the choice of adequate treatment. The Prostatype® score (P-score) is intended to guide treatment decisions for newly diagnosed PCa patients based on a three-gene signature (IGFBP3, F3, and VGLL3) and clinicopathological information obtained at diagnosis. This study evaluated association of the P-score measured in preoperative magnetic resonance imaging/transrectal ultrasound fusion-guided core needle biopsies (CNBs) and the P-score measured in radical prostatectomy (RP) specimens of PCa patients. We also evaluated the P-score association with the pathology of RP specimens. Furthermore, concordance of the P-score in paired CNB and RP specimens, as well as in index versus concomitant nonindex tumor foci from the same RP was investigated. METHODS: The study included 100 patients with localized PCa. All patients were diagnosed by CNB and underwent RP between 2015 and 2018. Gene expression was assessed with the Prostatype® real-time quantitative polymerase chain reaction kit and the P-score was calculated. Patients were categorized into three P-score risk groups according to previously defined cutoffs. RESULTS: For 71 patients, sufficient CNB tumor material was available for comparison with the RP specimens. The CNB-based P-score was associated with the pathological T-stage in RP specimens (p = 0.02). Moreover, the CNB-based P-score groups were in substantial agreement with the RP-based P-score groups (weighted κ score: 0.76 [95% confidence interval, 95% CI: 0.60-0.92]; Spearman's rank correlation coefficient r = 0.83 [95% CI: 0.74-0.89]; p < 0.0001). Similarly, the P-score groups based on paired index tumor and concomitant nonindex tumor foci (n = 64) were also in substantial agreement (weighted κ score: 0.74 [95% CI: 0.57-0.91]; r = 0.83 [95% CI: 0.73-0.89], p < 0.0001). CONCLUSIONS: Our findings suggest that the P-score based on preoperative CNB accurately reflects the pathology of the whole tumor, highlighting its value as a decision support tool for newly diagnosed PCa patients

Bi-parametric MRI/TRUS fusion targeted repeat biopsy after systematic 10-12 core TRUS-guided biopsy reveals more significant prostate cancer especially in anteriorly located tumors

Background: MRI and fusion guided biopsy have an increased role in the diagnosis of prostate cancer. Purpose: To demonstrate the possible advantages with Bi-parametric MRI fusion-guided repeat biopsy over systematic 10-12-core biopsy for the diagnosis of prostate cancer. Material and Methods: Four hundred and twenty-three consecutive men, with previous systematic 10-12-core TRUS-guided biopsy, and with suspicion of, or diagnosis of, low-risk prostate cancer underwent fusion-guided prostate biopsy between February 2015 and February 2017. The material was retrospectively assessed. In 220 cases no previous cancer was diagnosed, and in 203 cases confirmatory fusion guided biopsy was performed prior to active monitoring. MRI was classified according to PI-RADS. Systematic biopsy was compared to fusion guided biopsy for the detection of cancer, and PI-RADS was compared to the Gleason score. Results: Fusion guided biopsy detected significantly more cancers than systematic (p < .001). Gleason scores were higher in the fusion biopsy group (p < .001). Anterior tumors were present in 54% of patients. Fusion biopsy from these lesions showed cancer in 53% with previously negative biopsy in systematic biopsies and 66% of them were upgraded from low risk to intermediate or high-risk cancers. Conclusion: These results show superior detection rate and grading of bi-parametric MRI/TRUS fusion targeted repeat biopsy over systematic 10-12 core biopsies. Fusion guided biopsy detects more significant cancers despite using fewer cores. The risk group was changed for many patients initially selected for active surveillance due to upgrading of tumors. Bi-parametric MRI shows promising results in detecting anterior tumors in patients with suspected prostate cancer

Prostate biopsy sampling causes hematogenous dissemination of epithelial cellular material

The extent of epithelial cellular material (ECM) occurring in venous blood samples after diagnostic core needle biopsy (CNB) was studied in 23 patients with CNB diagnosed prostate cancer without provable metastases and 15 patients without cancer. The data show a significant increase of ECM in the peripheral blood sampled 20 seconds or 30 minutes after the last of 10 CNB procedures compared to the number of ECM detectable in the blood samples taken before the performance of CNB. The data indicate that diagnostic CNB of prostate cancer causes an extensive tissue trauma with a potential risk of cancer cell dissemination

Prostate Biopsy Sampling Causes Hematogenous Dissemination of Epithelial Cellular Material

The extent of epithelial cellular material (ECM) occurring in venous blood samples after diagnostic core needle biopsy (CNB) was studied in 23 patients with CNB diagnosed prostate cancer without provable metastases and 15 patients without cancer. The data show a significant increase of ECM in the peripheral blood sampled 20 seconds or 30 minutes after the last of 10 CNB procedures compared to the number of ECM detectable in the blood samples taken before the performance of CNB. The data indicate that diagnostic CNB of prostate cancer causes an extensive tissue trauma with a potential risk of cancer cell dissemination

The socio – emotional skills of children of childhood age, self – driving development opportunities in games

Darba autors: Sintija Puriņa Kvalifikācijas darba temats: “Pirmsskolas vecuma bērnu sociāli emocionālās kompetences, pašvadības attīstības iespējas rotaļās”. Mērķis: teorētiski un praktiski izpētīt pirmsskolas vecuma bērnu pašvadītas attīstības iespējas rotaļās. Pirmajā nodaļā tiek skaidrots sociāli emocionālās kompetences jēdziens, kā tas attiecas uz bērnu attīstību un apskatīts dažādu autoru skatījums uz to. Otrajā nodaļā ir apskatīts un skaidrots kas ir pašvadīta mācīšanās, tās jēdziens un dažādu autoru viedoklis un skatījums par pašvadītu mācīšanos. Kā arī tiek aprakstīti zinātniskie kritēriji pašvadītas mācīšanās vērtēšanai. Trešajā nodaļā ir aprakstīts dažādu autoru skaidrojums par 2-3 gadus vecu bērnu vecumposma īpatnību saistība ar pašvadītu prasmju attīstības aktualitāti. Ceturtajā nodaļā tikai veikta praktiskā izpēte pirmskolas vecuma bērnu sociāli emocionālās kompetences, pašvadības attīstības iespējas rotaļās, iesaistot bērnus rotaļās. Tika izvirzīti kritēriji pēc kuriem vadoties notika bērnu sociāli emocionālo un pašvadības prasmju izvērtēšanā pētījuma sākumā un beigās. Izmantojot pašvadības kā sociāli emocionālās mācīšanās daļas kritēriju, paaugstinājās bērnu pašvadības kompetence sociāli emocionālās mācīšanās nodarbībās. Kā arī izmainījās bērnu rādītāji pedagoģiskā eksperimenta procesā, tie uzlabojās. Kvalifikācijas darbs sastāv no 4 nodaļām un 5 apakšnodaļām, secinājumiem, priekšlikumiem, literatūras un avotu saraksta, pielikumiem. Kvalifikācijas darba struktūra: no 44. lpp, ievietoti 2 attēli, 4 tabulas un 3 diagrammas, 1 pielikums. Kvalifikācijas darbam izmantoti 47 informācijas avoti. Atslēgvārdi: sociāls, emocionāls, pašvadīts, bērns, pirmsskola, rotaļas.Author of the job: Sintija Purina. Subject of the qualification work: “The socio – emotional skills of children of childhood age, self – driving development opportunities in games”. Objective: Theoretically and practically explore the possibilities for self- directed development of children of pre- school age in games. The first chapter clarifies the concept of socio-emotional competence, as it relates to the development of children and looks at the views of the various authors. The second chapter deals with and clarifies what is self-directed learning, its concept and the views of different authors and the view of self-directed learning. The scientific criteria for evaluating self-directed learning are also described. The third chapter describes the interpretation of the characteristics of the 2-3-year-old child age with regard to the ongoing development of self-directed skills. In Chapter four, only practical studies have been carried out in the games of the socio-emotional competence of children of pre-school age, self-management development opportunities involving children in games. Criteria were identified for evaluating children's socio-emotional and self-management skills at the beginning and end of the study. Using self-driving as a criterion for socio-emotional learning increased the competence of child self-driving in socio-emotional learning. As well as changes in child indicators in the pedagogical experiment process, they improved. The qualification work consists of 4 chapters and 5 sub-chapters, conclusions, proposals, lists of literature and sources, annexes. Structure of the qualification work: from page 44, 2 pictures, 4 tables and 3 charts, Annex 1. 47 sources of information have been used for qualification work. Keywords: social, emotional, self-driving, child, preschool, playing

A New Instrument for Assessing Work-Related Body Mechanics and Strain in the General Population

Clinical pain is often linked to poor body mechanics, with individuals sometimes presenting multiple painful disorders. Such disorders may be influenced by behaviors that affect the general resiliency and health of the musculoskeletal system. We aimed to develop a self-reported scale using the Malmö Diet and Cancer Study questions on work-related body mechanical exposures. An expert panel identified 41 variables having content validity for musculoskeletal problems. Exploratory factor analysis was conducted on a random selection of 50% of the cohort (n = 6,789 adults); the remaining was reserved for confirmatory factor analyses (CFA), item response theory (IRT) item calibration, and differential item functioning investigations. Supported by standard measure development methods and fit criteria, the final unidimensional item bank contains 13 items. Overall CFA statistics (root mean square error of approximation = .09; comparative fit index = .96; Tucker-Lewis index = .96; standardized root mean residuals = .05) indicated excellent single-factor model fit and appropriateness of IRT modeling and calibration. Expert review and item information values (score-precision) guided selection of an 8-item short form with acceptable score-level reliabilities (≥.70) for T-scores = 39–80+. This measure provides reliable assessment of body mechanics strain in adults and can be useful when evaluating different contributions to musculoskeletal problems affecting pain-treatment success in future clinical research. Perspective: This article presents the development and psychometric properties of a new measure, “Work-related Body Mechanics and Strain Scale (WR-BMSS).” The scale has 13-items or alternatively an 8-item short form. This measure could potentially help clinicians who seek to assess how musculoskeletal problems may contribute to patient pain and disability

An Intraprostatic Modified Release Formulation of Antiandrogen 2-Hydroxyflutamide for Localized Prostate Cancer

Purpose: We investigated the tolerability, safety and antitumor effects of a novel intraprostatic depot formulation of antiandrogen 2-hydroxyflutamide (in Nano-Zolid (R)) in men with localized prostate cancer. Materials and Methods: Two clinical trials, LPC-002 and LPC-003, were performed in a total of 47 men. The formulation was injected transrectally into the prostate under ultrasound guidance. In LPC-002 the effects on prostate specific antigen and prostate volume were measured for 6 months in 24 patients. In LPC-003 antitumor effects were evaluated by histopathology and magnetic resonance imaging including spectroscopy during 6 or 8 weeks in 23 patients. In each study testosterone and 2-hydroxyflutamide in plasma were measured as well as quality of life parameters. Results: In LPC-002 (mean dose 690 mg) a reduction was observed in prostate specific antigen and prostate volume. Average nadir prostate specific antigen and prostate volume were 24.9% and 14.0% below baseline, respectively. When increasing the dose in LPC-003 to 920 and 1,740 mg, average prostate specific antigen decreased 16% and 23% after 6 and 8 weeks, respectively. Magnetic resonance imaging and magnetic resonance spectroscopy showed morphological changes and a global reduction in metabolite concentrations following treatment, indicating an antitumor response. Injections did not result in hormone related side effects. Three serious adverse events were reported and all resolved with oral antibiotic treatment. Conclusions: Intraprostatic injections of 2-hydroxyflutamide depot formulations showed antitumor effects, and proved to be safe and tolerable. However, for better anticancer effects higher doses and better dose distribution are suggested.Peer reviewe

Changes of arterial pressure following relief of obstruction in adults with hydronephrosis

Background: As much as 20% of all cases of hypertension are associated with kidney malfunctions. We have previously demonstrated in animals and in pediatric patients that hydronephrosis causes hypertension, which was attenuated by surgical relief of the ureteropelvic junction (UPJ) obstruction. This retrospective cohort study aimed to investigate: (1) the proposed link between hydronephrosis, due to UPJ obstruction, and elevated arterial pressure in adults; and (2) if elevated blood pressure in patients with hydronephrosis might be another indication for surgery. Materials and methods: Medical records of 212 patients undergoing surgical management of hydronephrosis, due to UPJ obstruction, between 2000 and 2016 were assessed. After excluding patients with confounding conditions and treatments, paired arterial pressures (i.e. before/after surgery) were compared in 49 patients (35 years old; 95% CI 29–39). Split renal function was evaluated by using mercaptoacetyltriglycine (MAG3) renography before surgical management of the hydronephrotic kidney. Results: Systolic (−11 mmHg; 95% CI 6–15 mmHg), diastolic (−8 mmHg; 95% CI 4–11 mmHg), and mean arterial (-9 mmHg; 95% CI 6–12) pressures were significantly reduced after relief of the obstruction (p < 0.001). Split renal function of the hydronephrotic kidney was 39% (95% CI 37–41). No correlations were found between MAG3 and blood pressure level before surgery or between MAG3 and the reduction of blood pressure after surgical management of the UPJ obstruction. Conclusions: In adults with hydronephrosis, blood pressure was reduced following relief of the obstruction. Our findings suggest that elevated arterial pressure should be taken into account as an indication to surgically correct hydronephrosis

Carbon Flux as a Measure of Prostate Cancer Aggressiveness : [11C]-Acetate PET/CT

Purpose: Dynamic [11C]-acetate positron emission tomography (PET) can be used to study tissue perfusion and carbon flux simultaneously. In this study, the feasibility of the quantification of prostate cancer aggressiveness using parametric methods assessing [11C]-acetate kinetics was investigated in prostate cancer subjects. The underlying uptake mechanism correlated with [11C]-acetate influx and efflux measured in real-time in vitro in cell culture. Methods: Twenty-one patients with newly diagnosed low-to-moderate risk prostate cancer underwent magnetic resonance imaging (MRI) and dynamic [11C]-acetate PET/CT examinations of the pelvis. Parametric images of K1 (extraction × perfusion), k2 (oxidative metabolism) and VT (=K1/k2, anabolic metabolism defined as carbon retention) were constructed using a one-tissue compartment model with an arterial input function derived from pelvic arteries. Regions of interest (ROIs) of the largest cancer lesion in each patient and normal prostate tissue were drawn using information from MRI (T2 and DWI images), biopsy results, and post-surgical histopathology of whole prostate sections (n=7). In vitro kinetics of [11C]-acetate were studied on DU145 andPC3 cell lines using LigandTracer® White equipment for the measurement of the radioactivity uptake in real-time at 37°C. Results: Mean prostate specific antigen (PSA) was 8.33±3.92 ng/mL and median Gleason Sum 6 (range 5-7). K1,VT and standardized uptake values (SUVs) were significantly higher in cancerous prostate tissues compared to normal ones for all patients (p<0.001), while k2 was not (p=0.26). PSA values correlated to early SUVs (r=0.50,p=0.02) and K1 (r=0.48, p=0.03). Early and late SUVs correlated to VT (r>0.76, p<0.001) and K1 (r>0.64,p<0.005). In vitro studies demonstrated higher extraction and retention (p<0.01) of [11C]-acetate in the more aggressive PC3 cells. Conclusion: Parametric images could be used to visualize the [11C]-acetate kinetics of the prostate cancer exhibiting elevated extraction associated with the cancer aggressiveness. The influx rate of [11C]-acetate studied in cell culture also showed dependence on the cancer aggressiveness associated with elevated lipogenesis. Dynamic [11C]-acetate/PET demonstrated potential for prostate cancer aggressiveness estimation using parametric-based K1 and VT values