| 1. |
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| 2. |
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| 3. |
- Chowdhury, S., et al.
(författare)
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Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer
- 2023
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534. ; 34:5, s. 477-485
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Tidskriftsartikel (refereegranskat)abstract
- Background: The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN. Patients and methods: Patients received apalutamide (240 mg/day) or placebo plus ADT (1: 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months’ follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months’ follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan–Meier method, and Cox proportional hazards model. Results: One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.25-0.48), rPFS (HR 0.44; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% CI 0.27-0.52) compared with no decline (P < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of apalutamide treatment. Conclusions: Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival.
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| 4. |
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| 5. |
- Bhatt, Nikita R., et al.
(författare)
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Contemporary use of phytotherapy in patients with lower urinary tract symptoms due to benign prostatic hyperplasia : results from the EVOLUTION European registry
- 2021
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Ingår i: World Journal of Urology. - : Springer Science and Business Media LLC. - 0724-4983 .- 1433-8726. ; 39:7, s. 2661-2667
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Tidskriftsartikel (refereegranskat)abstract
- Background: To use the European Association of Urology Research Foundation (EAURF) registry data to determine the proportion of contemporary Lower Urinary Tract Symptoms associated with Benign Prostatic Enlargement (LUTS/BPE) patients prescribed phytotherapy, and to determine their subjective quality of life and clinical progression responses. Methods: This was a prospective multicenter multinational observational registry study, conducted over 2 years. Men ≥ 50 years seeking LUTS/BPE were divided at baseline into two cohorts, presently/recently untreated patients (PUP) commencing pharmacotherapy at baseline and presently/recently treated patients (c-PTP) continuing previously received pharmacotherapy, with 24-month follow-up (FU). Results: Overall, 2175 patients were enrolled with 1838 analyzed. Of the PUP cohort (n = 575), 92 (16%) received phytotherapy and 65 (71%, n = 65/92) completed 24-month FU, with France prescribing 34% (n = 30/89) the highest proportion of phytotherapy among all LUTS/BPE medications. In the c-PTP group (n = 1263), only 69 (5%) patients were using phytotherapy, falling to n = 35/69 (51%) at 24-month FU (highest in France 20% (n = 43/210)). Though defined disease progression occurred in ≤ 20%, with only 1% proceeding to surgical intervention, in both groups, clinically meaningful improvement was lower and symptom persistence was higher in PUP but similar in the treated (c-PTP) patients on phytotherapy compared to the other LUTS/BPE medication. Conclusion: Low heterogeneous prescribing rates for phytotherapy were reported in both PUP and c-PTP cohorts over the 24-month FU. Although phytotherapy led to subjective improvements, healthcare practitioners should prescribe them with caution until higher quality evidence and guideline recommendations supporting its use are available.
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| 6. |
- Bhatt, Nikita R., et al.
(författare)
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Quality of life with pharmacological treatment in patients with benign prostatic enlargement : results from the Evolution European Prospective Multicenter Multi-National Registry Study
- 2021
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Ingår i: World Journal of Urology. - : Springer Science and Business Media LLC. - 0724-4983 .- 1433-8726. ; 39:2, s. 517-526
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lower urinary tract symptoms due to benign prostate enlargement (LUTS/BPE) can lead to significant disturbances to health-related quality of life (HRQoL) and psychological well-being. The aim of this study was to evaluate the effect of pharmacological treatment of LUTS/BPE on disease specific and generic QOL measures. Methods: Evolution was a European prospective, multicenter multi-national, observational registry collecting real-life clinical data over 2 years on the management of LUTS/BPE in primary and secondary care. This study investigated disease-specific QOL using questionnaires such as IPSS Q8, BPH Impact Index (BII) and generic QOL using questionnaires like EuroQOL Five Dimension (EQ5D) which encompassed EQ5D VAS and EQ5D health index. Results: The registry enrolled 1838 BPE patients and 1246 patients were evaluable at the end of 24 months. Nearly 70% of patients in the study were previously treated with medical therapy and 17% of these had already discontinued medical treatment previously for various reasons with lack of efficacy being the most common. The mean time since diagnosis of LUTS in the previously treated group was 4.7 years (0–26 years). Medical management produced statistically significant improvement in QOL (disease specific and generic) in previously untreated patients and an insignificant change in generic QOL in previously treated patients. Conclusions: After 5-years from the onset of symptoms, LUTS/BPE patients previously treated with medication had significantly impaired QOL in patients in a manner comparable to other chronic diseases. Earlier intervention with minimally invasive surgical techniques (MIT) should be considered in LUTS/BPE patients that do not show a significant improvement in QOL with medical therapy.
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| 7. |
- Dahlman, A., et al.
(författare)
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Effect of androgen deprivation therapy on the expression of prostate cancer biomarkers MSMB and MSMB-binding protein CRISP3
- 2010
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Ingår i: Prostate Cancer and Prostatic Diseases. - : Nature Publishing Group. - 1365-7852 .- 1476-5608. ; 13:4, s. 369-375
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated the effects of short-term neoadjuvant and long-term androgen deprivation therapies (ADTs) on β-microseminoprotein (MSMB) and cysteine-rich secretory protein-3 (CRISP3) expression in prostate cancer patients. We also studied if MSMB expression was related to genotype and epigenetic silencing. Using an Affymetrix cDNA microarray analysis, we investigated the expression of MSMB, CRISP3, androgen receptor (AR), KLK3 and Enhancer of Zeste Homologue-2 (EZH2) in tissue from prostate cancer patients receiving (n=17) or not receiving (n=23) ADT before radical prostatectomy. MSMB, CRISP3 and AR were studied in tissue from the same patients undergoing TURP before and during ADT (n=16). MSMB genotyping of these patients was performed by TaqMan PCR. MSMB and KLK3 expression levels decreased during ADT. Expression levels of AR and CRISP3 were not affected by short-term ADT but were high in castration-resistant prostate cancer (CRPC) and metastases. Levels of EZH2 were also high in metastases, where MSMB was low. Genotyping of the MSMB rs10993994 polymorphism showed that the TT genotype conveys poor MSMB expression. MSMB expression is influenced by androgens, but also by genotype and epigenetic silencing. AR and CRISP3 expression are not influenced by short-term ADT, and high levels were found in CRPC and metastases.
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| 8. |
- Davis, Niall F., et al.
(författare)
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Medical therapy versus transurethral resection of the prostate (TURP) for the treatment of symptomatic benign prostatic enlargement (BPE) : a cost minimisation analysis
- 2019
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Ingår i: World Journal of Urology. - : Springer Science and Business Media LLC. - 0724-4983 .- 1433-8726. ; 37:5, s. 873-878
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: A cost minimisation analysis compares the costs of different interventions’ to ascertain the least expensive over time. We compared different prostate targeted drug treatments with TURP to identify the optimal cost saving duration of a medical therapy for symptomatic benign prostatic enlargement (BPE). Methods: The Evolution registry is a prospective, multicentre registry, conducted by the European Association of Urology Research Foundation (EAUrf) for 24 months in 5 European countries. Evolution was designed to register the management of symptomatic BPE in clinical practice settings in 5 European countries. Direct cost evaluation associated with prostate targeted medical therapies and TURP was also recorded and analysed. Results: In total, 1838 men were enrolled with 1246 evaluable at 24 months. Medical therapies were more cost saving than TURP for treatment durations ranging from 2.9 to 70.4 years. Cost saving depended on both medication class and individual country assessed. Daily tamsulosin monotherapy was more cost saving than TURP for ≤ 13.9 years in Germany compared to ≤ 32.7 years in Italy. Daily finasteride monotherapy was more cost saving for ≤ 5.9 years in France compared to ≤ 36.9 years in Spain. Combination therapy was more cost saving for ≤ 5.9 years for Italian patients versus ≤ 13.8 years in Germany. Conclusions: BPE medical management was more cost saving than TURP for different specific treatment durations. Information from this study will allow clinicians to convey medical and surgical costs over time, to both patients and payors alike, when considering BPE treatment.
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| 9. |
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| 10. |
- Rohrmann, S., et al.
(författare)
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Smoking and the risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition
- 2013
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 108:3, s. 708-714
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Tidskriftsartikel (refereegranskat)abstract
- Background: Smoking is not associated with prostate cancer incidence in most studies, but associations between smoking and fatal prostate cancer have been reported. Methods: During 1992 and 2000, lifestyle information was assessed via questionnaires and personal interview in a cohort of 145112 European men. Until 2009, 4623 incident cases of prostate cancer were identified, including 1517 cases of low-grade, 396 cases of high grade, 1516 cases of localised, 808 cases of advanced disease, and 432 fatal cases. Multivariable Cox proportional hazards regression models were used to examine the association of smoking status, smoking intensity, and smoking duration with the risk of incident and fatal prostate cancer. Results: Compared with never smokers, current smokers had a reduced risk of prostate cancer (RR = 0.90, 95% CI: 0.83-0.97), which was statistically significant for localised and low-grade disease, but not for advanced or high-grade disease. In contrast, heavy smokers (25+ cigarettes per day) and men who had smoked for a long time (40+ years) had a higher risk of prostate cancer death (RR = 1.81, 95% CI: 1.11-2.93; RR = 1.38, 95% CI: 1.01-1.87, respectively). Conclusion: The observation of an increased prostate cancer mortality among heavy smokers confirms the results of previous prospective studies.
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| 11. |
- Vertosick, Emily A., et al.
(författare)
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Individual Patient Data Meta-analysis of Discrimination of the Four Kallikrein Panel Associated With the Inclusion of Prostate Volume
- 2021
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Ingår i: Urology. - : Elsevier BV. - 0090-4295. ; 157, s. 102-106
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To assess whether adding prostate volume to the kallikrein panel improves discrimination for ISUP Grade Group 2 or higher (GG2+) disease, as some men may have volume measurements available at the time of blood draw. While prostate volume predicts biopsy outcome, it requires an imaging procedure for measurement. The four kallikrein panel - commercially available as the 4Kscore - predicts risk of GG2+ disease and requires only a blood draw. Materials and Methods: A total of 9131 patients with available prostate volume and total PSA ≤25 ng/ml from 5 historical (sextant biopsy, pre-ISUP 2005 grading) and 4 contemporary cohorts (10+ cores, ISUP 2005 grading). Previously published kallikrein panel models were used to predict risk of GG2+. Volume was added to the model in each cohort and change in discrimination was meta-analyzed. Results: Increased prostate volume was associated with decreased risk of GG2+ disease after controlling for the kallikrein panel in 7/9 cohorts. However, kallikrein panel discrimination (0.817, 95% CI 0.802, 0.831) was not improved after including volume (AUC difference 0.002, 95% CI -0.003, 0.006). Heterogeneity (P <.0001) was driven by an AUC increase in 1 cohort of academic cancer centers (0.044, 95% CI 0.025, 0.064), with no evidence of heterogeneity after excluding this cohort (P = .15). Conclusion: The kallikrein panel provides a non-invasive approach to assess the risk of high-grade prostate cancer. Our results do not justify the inclusion of prostate volume in the four kallikrein panel. There is some evidence that the predictive value of prostate volume is provider dependent: further research is needed to address this question. © 2021 Elsevier Inc.
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| 12. |
- Nilsson, Ola, 1957, et al.
(författare)
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Human pheochromocytoma cells studied in culture contain large amounts of DSIP-like material.
- 1991
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Ingår i: Peptides. - 0196-9781. ; 12:5, s. 1077-83
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Tidskriftsartikel (refereegranskat)abstract
- Delta sleep-inducing peptide (DSIP)-like immunoreactive (LI) material has been detected in nine different human pheochromocytoma tumors by immunocytochemistry. In primary tumors subjected to indirect immunofluorescence a variable number of tumor cells (25-75%) showed positive cytoplasmic labeling after incubation with DSIP antiserum. Tumor cells grown in culture were strongly labeled by the DSIP antiserum with DSIP-LI concentrated to cell bodies. Electron microscopic immunocytochemistry (immunogold labeling) of pheochromocytoma cells demonstrated DSIP-LI over the dense core of secretory granules. The presence of DSIP-LI in several HPLC fractions from conditioned culture media indicates secretion of DSIP-LI from cultured pheochromocytoma cells. The observations suggest that DSIP-LI is synthesized and stored in secretory granules before release. The different HPLC profiles from each of the tumors may reflect differences in processing or turnover of DSIP-LI in pheochromocytoma cells.
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| 13. |
- Tomlins, Scott A., et al.
(författare)
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ETS Gene Fusions in Prostate Cancer: From Discovery to Daily Clinical Practice
- 2009
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 56:2, s. 275-286
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Forskningsöversikt (refereegranskat)abstract
- Context. In 2005, fusions between the androgen-regulated transmembrane protease serine 2 gene, TMPRSS2, and E twenty-six (ETS) transcription factors were discovered in prostate cancer. Objective: To review advances in our understanding of ETS gene fusions, focusing on challenges affecting translation to clinical application. Evidence acquisition: The PubMed database was searched for reports on ETS fusions in prostate cancer. Evidence synthesis: Since the discovery of ETS fusions, novel 5' and 3' fusion partners and multiple splice isoforms have been reported. The most common fusion, TMPRSS2:ERG, is present in approximately 50% of prostate-specific antigen (PSA)-screened localized prostate cancers and in 15-35% of population-based cohorts. ETS fusions can be detected noninvasively in the urine of men with prostate cancer, with a specificity rate in PSA-screened cohorts of >90%. Reports from untreated population-based cohorts suggest an association between ETS fusions and cancer-specific death and metastatic spread. In retrospective prostatectomy cohorts, conflicting results have been published regarding associations between ETS fusions and cancer aggressiveness. In addition to serving as a potential biomarker, tissue and functional studies suggest a specific role for ETS fusions in the transition to carcinoma. Finally, recent results suggest that the 5' and 3' ends of ETS fusions as well as downstream targets may be targeted therapeutically. Conclusions: Recent studies suggest that the first clinical applications of ETS fusions are likely to be in noninvasive detection of prostate cancer and in aiding with difficult diagnostic cases. Additional studies are needed to clarify the association between gene fusions and cancer aggressiveness, particularly those studies that take into account the multifocal and heterogeneous nature of localized prostate cancer. Multiple promising strategies have been identified to potentially target ETS fusions. Together, these results suggest that ETS fusions will affect multiple aspects of prostate cancer diagnosis and management. (C) 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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| 14. |
- Tomlins, Scott A., et al.
(författare)
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The role of SPINK1 in ETS rearrangement-negative prostate cancers
- 2008
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Ingår i: Cancer Cell. - Amsterdam : Elsevier. - 1535-6108 .- 1878-3686. ; 13:6, s. 519-28
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Tidskriftsartikel (refereegranskat)abstract
- ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers ( approximately 10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.
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| 15. |
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| 16. |
- Axén, Elin, et al.
(författare)
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Degree of Preservation of Neurovascular Bundles in Radical Prostatectomy and Recurrence of Prostate Cancer
- 2021
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Ingår i: European Urology Open Science. - : Elsevier BV. - 2666-1691 .- 2666-1683. ; 30, s. 25-33
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Tidskriftsartikel (refereegranskat)abstract
- Background: Reports on possible benefits for continence with nerve-sparing (NS) radical prostatectomy have expanded the indications beyond preservation of erectile function. It is unclear whether NS surgery affects oncological outcomes. Objective: To determine whether the degree of NS during radical prostatectomy influences oncological outcomes. Design, setting, and participants: Of 4003 patients enrolled in a prospective, controlled trial comparing open and robotic radical prostatectomy during 2008–2011, we evaluated 2401 patients who received robotic radical prostatectomy at seven Swedish centres. Patients were followed for 8 yr. Outcome measurements and statistical analysis: Data for recurrence and positive surgical margin status were assessed using validated patient questionnaires, patient interviews, and clinical record forms before and at 3, 12, and 24 mo and 6 and 8 yr after surgery. Cox and logistic regressions were used to model the effect on recurrence and positive surgical margins (PSM), respectively. Results and limitations: A total of 481 men had PSM and 467 experienced recurrence during follow-up. Median follow-up for men without recurrence was 6.6 yr. There were no statistically significant differences in recurrence rate between degrees of NS. The PSM rate was significantly higher with a higher degree of NS: interfascial NS, odds ratio (OR) 2.32 (95% confidence interval [CI] 1.69–3.16); intrafascial NS, OR 3.23 (95% CI 2.17–4.80). Recurrence rates were higher for patients with pT2 disease and PSM (hazard ratio [HR] 3.32, 95% CI 2.43–4.53) than for patients with pT3 disease without PSM (HR 2.08, 95% CI 1.66–2.62). The lack of central review of pathological specimens is a limitation. Conclusions: A higher degree of NS significantly increased the risk of PSM but did not significantly increase the risk of cancer recurrence. Combined with the known functional benefits of NS surgery, these results underscore the need to identify an individualised balance. Patient summary: In this report we looked at the effect of a nerve-sparing approach during removal of the prostate on cancer outcomes for patients having robot-assisted surgery at seven Swedish hospitals. We found that a high degree of nerve-sparing increased the rate of cancer positivity at the margins of surgical specimens and that positive surgical margins increased the risk of recurrence of prostate cancer. © 2021 The Authors
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| 17. |
- Bock, David, 1976, et al.
(författare)
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Do negative intrusive thoughts at diagnosis predict impaired quality of life, depressed mood and waking up with anxiety 3, 12 and 24 months after radical prostatectomy?–a longitudinal study
- 2020
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 54:3, s. 220-226
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate the effect of intrusive thoughts at diagnosis on quality of life, depressed mood and waking up with anxiety up to two years after radical prostatectomy. Method: The Laparoscopic Prostatectomy Robot Open (LAPPRO) trial was a prospective, longitudinal multicenter study of 4003 patients undergoing radical prostatectomy. Questionnaire data were collected preoperatively, at 3, 12 and 24 months after surgery. Results: The group of patients with intrusive thoughts at diagnosis had a statistically significant higher postoperative prevalence of impaired quality of life, depressed mood and waking up with anxiety as compared with the group of patients with no or minor intrusive thoughts. The highest risk increase for impaired QoL, depressed mood and waking up with anxiety ≥1/week was at 12, 3 and 3 months, respectively, where the three outcomes increased by 38% (RR: 1.38; 95%CI: 1.27–1.49)), 136% (RR: 2.36; 95%CI: 1.74–3.19)) and 165% (RR: 2.65; 95%CI: 2.22–3.17)), respectively. Conclusions: The demonstrated link between intrusive thoughts and quality of life, depressed mood and waking up with anxiety deliver is further evidence to the idea that intrusive thoughts has potential as an endpoint for assessing and predicting psychological distress among men with prostate cancer diagnosis. Trial registration number: ISRCTN06393679 (www.isrctn.com). Date of registration: 07/02/2008. Retrospectively registered. © 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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| 18. |
- Christensson, A, et al.
(författare)
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The significance of serpins in the regulation of proteases in the male genital tract
- 1997
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Ingår i: Advances in Experimental Medicine and Biology. - Boston, MA : Springer US. - 0065-2598. ; 425, s. 76-163
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Forskningsöversikt (refereegranskat)abstract
- The male genital tract is rich in proteases, delivered by the male accessory sex glands, that are delicately balanced in their action by serpins, non-serpin class protease inhibitors and other regulatory mechanisms. Still, the biological function of the serpins and their target enzymes in the male genital tract and possible involvement in the regulation of normal reproductive function mainly remains to be elucidated. However, it is important with careful control of the catalytic activity of serine proteases, in particular in the different extracellular compartments, where they may produce significant potential hazards for biological structures. Immunochemical measurements of the serine protease prostate-specific antigen (PSA) in serum have gained widespread use in the monitoring and detection of prostate cancer. Moreover, the rapidly growing body of data on the disease-related variations in the proportion of different forms of PSA in serum which relate to the covalent complex formation between the serpin α1-antichymotrypsin and PSA has significantly improved the diagnostic specificity in blood testing for early detection of prostate cancer.
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| 19. |
- Forsmark, A., et al.
(författare)
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Health Economic Analysis of Open and Robot-assisted Laparoscopic Surgery for Prostate Cancer Within the Prospective Multicentre LAPPRO Trial
- 2018
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 74:6, s. 816-824
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Tidskriftsartikel (refereegranskat)abstract
- Background: The rapid adoption of robot-assisted laparoscopy in radical prostatectomy has preceded data regarding associated costs. Qualitative evidence regarding cost outcomes is lacking. Objective: This study assessed how costs were affected by robot-assisted laparoscopic prostatectomy (RALP) compared with open surgery. Design, setting, and participants: Cost analysis was based on the dataset of the LAPPRO (Laparoscopic Prostatectomy Robot Open) clinical trial, which is a prospective controlled, nonrandomised trial of patients who underwent prostatectomy at 14 centres in Sweden between September 2008 and November 2011. Currently, data are available from a follow-up period of 24 mo. Intervention: In the LAPPRO trial, RALP was compared with radical retropubic prostatectomy (RRP). Outcome measurements and statistical analysis: Costs per surgical technique were assessed based on resource variable data from the LAPPRO database. The calculation of average costs was based on mean values; Swedish currency was converted to purchasing power parity US dollar (PPP$). All tests were two-tailed and conducted at alpha = 0.05 significance level. Results and limitations: The cost analysis comprised 2638 men. Based on the LAPPRO trial data, RALP was associated with an increased cost/procedure of PPP$ 3837 (95% confidence interval: 2747-4928) compared with RRP. The result was sensitive to variations in caseload. Main drivers of overall cost were robotic system cost, operation time, length of stay, and sick leave. Limitations of the study include the uneven distribution between RALP and RRP regarding procedures in public/for-profit hospitals and surgeon/centre procedural volume. Conclusions: Based on the LAPPRO trial data, this study showed that RALP was associated with an increased cost compared with RRP in Swedish health care. There are many factors influencing the costs, making the absolute result dependent on the specific setting. However, by identifying the main cost drivers and/or most influential parameters, the study provides support for informed decisions and predictions. Patient summary: In this study, we looked at the cost outcome when performing prostatectomies by robot-assisted laparoscopic technique compared with open surgery in Sweden. We found that the robot-assisted procedure was associated with a higher mean cost. (C) 2018 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.
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| 20. |
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| 21. |
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| 22. |
- Hagman, A., et al.
(författare)
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Urinary continence recovery and oncological outcomes after surgery for prostate cancer analysed by risk category: results from the LAParoscopic prostatectomy robot and open trial
- 2021
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Ingår i: World Journal of Urology. - : Springer Science and Business Media LLC. - 0724-4983 .- 1433-8726. ; 39:9, s. 3239-3249
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To evaluate urinary continence (UC) recovery and oncological outcomes in different risk-groups after robot-assisted radical prostatectomy (RALP) and open retropubic radical prostatectomy (RRP). Patients and methods We analysed 2650 men with prostate cancer from seven open (n = 805) and seven robotic (n = 1845) Swedish centres between 2008 and 2011 in a prospective non-randomised trial, LAPPRO. UC recovery was defined as change of pads less than once in 24 h. Information was collected through validated questionnaires. Rate of positive surgical margins (PSM) and biochemical recurrence (BCR), defined as prostate-specific antigen (PSA) > 0.25 mg/ml, were recorded. We stratified patients into two risk groups (low-intermediate and high risk) based on the D'Amico risk classification system. Result Among men with high-risk prostate cancer, we found significantly higher rates of UC recovery up to 24 months after RRP compared to RALP (66.1% vs 60.5%) RR 0.85 (CI 95% 0.73-0.99) while PSM was more frequent after RRP compared to RALP (46.8% vs 23.5%) RR 1.56 (CI 95% 1.10-2.21). In the same group no significant difference was seen in BCR. Overall, however, BCR was significantly more common after RRP compared to RALP at 24 months (9.8% vs 6.6%) RR 1.43 (Cl 95% 1.08-1.89). The limitations of this study are its non-randomized design and the relatively short time of follow-up. Conclusions Our study indicates that men with high-risk tumour operated with open surgery had better urinary continence recovery but with a higher risk of PSM than after robotic-assisted laparoscopic surgery. No significant difference was seen in biochemical recurrence.
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| 23. |
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| 24. |
- Hotakainen, K, et al.
(författare)
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Differential expression of trypsinogen and tumor-associated trypsin inhibitor (TATI) in bladder cancer
- 2006
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Ingår i: International Journal of Oncology. - 1019-6439. ; 28:1, s. 95-101
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Tidskriftsartikel (refereegranskat)abstract
- Tumor-associated trypsin inhibitor (TATI) is a marker of mucinous ovarian carcinoma, but it is also widely expressed in other malignant tumors and normal human tissues. Elevated serum concentrations of TATI are of prognostic value in ovarian, kidney, and bladder cancer. Tumor-associated trypsin is co-expressed with TATI in many malignancies and is thought to be involved in tumor invasion. TATI mRNA has been shown to be overexpressed in bladder cancer. We therefore studied whether trypsinogen expression also can be detected in bladder cancer and how this and TATI expression are associated with the clinicopathological characteristics of the tumors. We used RT-PCR, in situ hybridization and immunohistochemistry to detect trypsinogen-and TATI mRNA and protein in tissue samples from 28 bladder cancer patients and ten benign urothelia. TATI expression was detected in all benign tissues and non-invasive tumors. However, the expression was lower in the muscle-invasive tumors (pT2; n=5), whereas trypsinogen expression was seen in all but one non-invasive tumor. We conclude that trypsinogen is expressed in both malignant and benign bladder epithelium, whereas TATI expression decreases with increasing stage and grade of the tumor. This may suggest that a balanced expression of TATI and trypsinogen is required in normal tissue and that this balance is disrupted during tumor progression.
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| 25. |
- Kasivisvanathan, Veeru, et al.
(författare)
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MRI-targeted or standard biopsy for prostate-cancer diagnosis
- 2018
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 378:19, s. 1767-1777
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited. METHODS: In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. RESULTS: A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P = 0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P<0.001). CONCLUSIONS: The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027.)
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| 26. |
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| 27. |
- Necchi, A., et al.
(författare)
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A phase III study of INCB054828 as adjuvant therapy in patients (pts) with high-risk urothelial carcinoma (UC) harboring fibroblast growth factor receptor 3 (FGFR3) genomic alterations
- 2018
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Ingår i: Annals of oncology : official journal of the European Society for Medical Oncology. - : Elsevier BV. - 1569-8041. ; 29:Suppl. 8, s. 328-328
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Tidskriftsartikel (refereegranskat)abstract
- Background: After neoadjuvant chemotherapy (NAC), about 20% of pts with muscle-invasive UC are found to have advanced pT-stage or lymph node involvement and 5-year overall survival (OS) of them is < 30%. Tumor samples from these pts may provide information about chemotherapy resistance, and may predict for the activity of new drugs given postoperatively. Alterations of FGFR3 gene represent a therapeutic target in UC and FGFR3 mutations/fusions are enriched in UC Luminal-1 subtype. The pan-FGFR inhibitor INCB054828 has shown promising results in chemotherapy-treated patients with genomic alterations of FGFR3 in tumor tissue and is currently being evaluated in an international phase 2 study (fight-201, NCT02872714). Our study aims to assess the safety and efficacy of adjuvant INCB054828 in pts with FGFR3 mutations/fusions. Trial design: This is an open-label, single-arm, phase 2 study. Subjects will receive INCB054828 at a once-daily (QD) dose of 13.5 mg on a 2-weeks-on and 1-week-off schedule. Treatment should start within 60 days of surgery and will continue until 12 months, or until the evidence of disease recurrence or unacceptable toxicity onset. Key inclusion criteria are predominant UC histology, FGFR3 mutations/fusions (FoundationOne), bladder or upper tract UC, previous radical cystectomy or nephroureterectomy, previous administration ≥3 cycles of CDDP-based NAC, pT3-4 and/or pN1-3 stage. Relapse-free survival (RFS) is the primary endpoint, assessed every 9 weeks until disease recurrence or death. No interim analyses are planned. It is expected that about 30% of the total screened pts will harbor FGFR3 aberrations. In a single-stage design, with 90% power and one-sided alpha at 0.10, the total enrolled pts will be 56 (H0: 2-y RFS: 30%; H1: 2-y RFS: 45%). Translational research on tissue samples will include associations of immune-inflamed phenotype with next-generation sequencing results and outcome of treatment, and response to any subsequent immunotherapy. The study is sponsored by the EAU-Research Foundation and will involve 15 centers in Europe (EudraCT number 2017-004426-15). Clinical trial identification: EudraCT: 2017-004426-15.
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| 28. |
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| 29. |
- Nilsson, Hanna, et al.
(författare)
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Risk of hernia formation after radical prostatectomy : a comparison between open and robot-assisted laparoscopic radical prostatectomy within the prospectively controlled LAPPRO trial
- 2022
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Ingår i: Hernia. - : Springer Science and Business Media LLC. - 1265-4906 .- 1248-9204. ; 26, s. 157-164
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: In addition to incisional hernia, inguinal hernia is a recognized complication to radical retropubic prostatectomy. To compare the risk of developing inguinal and incisional hernias after open radical prostatectomy compared to robot-assisted laparoscopic prostatectomy. Method: Patients planned for prostatectomy were enrolled in the prospective, controlled LAPPRO trial between September 2008 and November 2011 at 14 hospitals in Sweden. Information regarding patient characteristics, operative techniques and occurrence of postoperative inguinal and incisional hernia were retrieved using six clinical record forms and four validated questionnaires. Results: 3447 patients operated with radical prostatectomy were analyzed. Within 24 months, 262 patients developed an inguinal hernia, 189 (7.3%) after robot-assisted laparoscopic prostatectomy and 73 (8.4%) after open radical prostatectomy. The relative risk of having an inguinal hernia after robot-assisted laparoscopic prostatectomy was 18% lower compared to open radical retropubic prostatectomy, a non-significant difference. Risk factors for developing an inguinal hernia after prostatectomy were increased age, low BMI and previous hernia repair. The incidence of incisional hernia was low regardless of surgical technique. Limitations are the non-randomised setting. Conclusions: We found no difference in incidence of inguinal hernia after open retropubic and robot-assisted laparoscopic radical prostatectomy. The low incidence of incisional hernia after both procedures did not allow for statistical analysis. Risk factors for developing an inguinal hernia after prostatectomy were increased age and BMI.
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| 30. |
- Pérez, Moisés, et al.
(författare)
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The fungal metabolite galiellalactone interferes with the nuclear import of NF-κB and inhibits HIV-1 replication.
- 2014
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Ingår i: Chemico-Biological Interactions. - : Elsevier BV. - 1872-7786 .- 0009-2797. ; 214:Mar 11, s. 69-76
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Tidskriftsartikel (refereegranskat)abstract
- Galiellalactone (GL) is a metabolite produced by the fungus Galiella rufa that presents antitumor and immunomodulatory activities. GL interferes with the binding to DNA of signal transducer and activator of transcription (STAT)-3 and also inhibits other signal pathways such as NF-κB, but the mechanism of action in this pathway remains unknown. In this study we report that GL inhibits vesicular stomatitis virus-recombinant HIV-1 infection and the NF-κB-dependent transcriptional activity of the HIV-LTR promoter. We found that GL prevents the binding of NF-κB to DNA but neither affects the phosphorylation and degradation of NF-κB inhibitory protein, IκBα, nor the phosphorylation and acetylation of the NF-κB p65 subunit. However, GL prevents the association of p65 with the importin α3 impairing the nuclear translocation of this transcription factor. Using a biotinylated probe we found that GL binds to p65 but not to importin α3. Therefore, GL is a dual NF-κB/STAT3 inhibitor that could serve as a lead compound for the development of novel drugs against HIV-1, cancer and inflammatory diseases.
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| 31. |
- Scorilas, A., et al.
(författare)
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Streptavidin-polyvinylamine conjugates labeled with a europium chelate : Applications in immunoassay, immunohistochemistry, and microarrays
- 2000
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 46:9, s. 1450-1455
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Tidskriftsartikel (refereegranskat)abstract
- Background: The favorable properties of lanthanide chelates compared with conventional fluorescent probes have attracted considerable interest. A Eu3+ chelator, 4,7-bis(chlorosulfophenyl)-1,10-phenanthroline-2,9-dicarboxylic acid (BCPDA), has been synthesized previously. Methods: We here describe immunoassay, immunohistochemistry, and microarray applications of a new streptavidin-based universal polyvinylamine (PVA) detection reagent that is multiply labeled with the europium chelate of BCPDA. Solid-phase time-resolved immunofluorometric assays for biotinylated mouse IgG and prostate-specific antigen (PSA) were developed using the new conjugate as a detection reagent. The new conjugate was also used for the immunohistochemical localization of PSA expression in paraffin-embedded prostatic tissues. A model microarray with spotted biotinylated antibody as target was also performed. Results: Approximately 50-100 BCPDA moieties were covalently bound to PVA, which was then linked to streptavidin via biotin interaction. The macromolecular complex successfully recognized and bound biotinylated detection reagents, e.g., antibodies. The new reagent enabled measurement of solid phase-immobilized biotinylated mouse IgG with a detection limit of ~1 pg/assay and demonstrated excellent linearity. In an ELISA-type sandwich PSA assay that included two PSA monoclonal antibodies using the new conjugate as detection reagent, we detected 0.001 μg/L PSA (~100 fg or ~3 amol/assay). Serum samples analyzed for PSA by this method and a commercial assay gave highly correlated results. The new reagent enabled excellent immunohistochemical localization of PSA expression in prostate tissues. Using the new reagent in a model microarray experiment with biotinylated mouse IgG as target, we demonstrated excellent spatial resolution of 5-to 10-nL microspots. Conclusions: The new detection reagent may find important applications in biotechnology. (C) 2000 American Association for Clinical Chemistry.
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| 32. |
- Secin, Fernando P, et al.
(författare)
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Multi-institutional Study of Symptomatic Deep Venous Thrombosis and Pulmonary Embolism in Prostate Cancer Patients Undergoing Laparoscopic or Robot-Assisted Laparoscopic Radical Prostatectomy
- 2008
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 53:1, s. 134-145
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The true incidence of symptomatic deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing laparoscopic radical prostatectomy is unknown. Our aim was to determine the incidence of symptomatic DVT and PE and the risk factors for these complications. METHODS: Fourteen surgeons from 13 referral institutions from both Europe and the United States provided retrospective data for all 5951 patients treated with laparoscopic radical prostatectomy (LRP), with or without robotic assistance, since the start of their institution's experience. Symptomatic DVT and PE within 90 d of surgery were regarded as venous thromboembolism (VTE). DVT was diagnosed mostly by Doppler ultrasound or contrast venography and PE by lung ventilation/perfusion scan or chest computed tomography or both. Statistical analysis included evaluation of incidence of symptomatic DVT and PE and risk factors as determined by exact methods and logistic regression. RESULTS: Of 5951 patients in the study, 31 developed symptomatic VTE (0.5%; 95% confidence interval [CI], 0.4%, 0.7%). Among patients with an event, 22 (71%) had DVT only, 4 had PE without identified DVT, and 5 had both. Two patients died of PE. Prior DVT (odds ratio [OR]=13.5; 95%CI, 1.4, 61.3), current tobacco smoking (OR=2.8; 95%CI, 1.0, 7.3), larger prostate volume (OR=1.18; 95%CI, 1.09, 1.28), patient re-exploration (OR=20.6; 95%CI, 6.6, 54.0), longer operative time (OR=1.05; 95%CI, 1.02, 1.09), and longer hospital stay (OR=1.05; 95%CI, 1.01, 1.09) were associated with VTE in univariate analysis. Neoadjuvant therapy, body mass index, surgical experience, surgical approach, pathologic stage, perioperative transfusion, and heparin administration were not significant predictors. CONCLUSIONS: The incidence of symptomatic VTE after LRP is low. These data do not support the administration of prophylactic heparin to all patients undergoing LRP, especially those without risk factors for VTE.
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| 33. |
- Siltari, A., et al.
(författare)
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How Well do Polygenic Risk Scores Identify Men at High Risk for Prostate Cancer? Systematic Review and Meta-Analysis
- 2023
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Ingår i: Clinical Genitourinary Cancer. - : Elsevier BV. - 1558-7673. ; 21:2, s. 1-316
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Genome-wide association studies have revealed over 200 genetic susceptibility loci for prostate cancer (PCa). By combining them, polygenic risk scores (PRS) can be generated to predict risk of PCa. We summarize the published evidence and conduct meta-analyses of PRS as a predictor of PCa risk in Caucasian men. Patients and methods: Data were extracted from 59 studies, with 16 studies including 17 separate analyses used in the main meta-analysis with a total of 20,786 cases and 69,106 controls identified through a systematic search of ten databases. Random effects meta-analysis was used to obtain pooled estimates of area under the receiver-operating characteristic curve (AUC). Meta-regression was used to assess the impact of number of single-nucleotide polymorphisms (SNPs) incorporated in PRS on AUC. Heterogeneity is expressed as I2 scores. Publication bias was evaluated using funnel plots and Egger tests. Results: The ability of PRS to identify men with PCa was modest (pooled AUC 0.63, 95% CI 0.62-0.64) with moderate consistency (I2 64%). Combining PRS with clinical variables increased the pooled AUC to 0.74 (0.68-0.81). Meta-regression showed only negligible increase in AUC for adding incremental SNPs. Despite moderate heterogeneity, publication bias was not evident. Conclusion: Typically, PRS accuracy is comparable to PSA or family history with a pooled AUC value 0.63 indicating mediocre performance for PRS alone. © 2022
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| 34. |
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| 35. |
- van Gils, M P M Q, et al.
(författare)
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Innovations in serum and urine markers in prostate cancer current European research in the P-Mark project
- 2005
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 48:6, s. 1031-1041
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Tidskriftsartikel (refereegranskat)abstract
- An overview is given of serum and urine prostate cancer markers that are currently under investigation and subsequently the P-Mark project is introduced. There are many markers showing promise to overcome the limitations of prostate specific antigen (PSA). Eventually, these markers should be able to increase the specificity in diagnosis, differentiate between harmless and aggressive disease and identify progression towards androgen independence at an early stage. In the P-Mark project, several recently developed, promising markers will be evaluated using clinically well-defined biorepositories. Following successful evaluation, these markers will be validated on a sample set derived from two large, European, prostate cancer studies and used for the identification of special risk groups in the general population. In addition, novel markers will be identified in the same biorepositories by different mass spectrometry techniques.
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| 36. |
- Ahlqvist, Kristofer, et al.
(författare)
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Expression of Id proteins is regulated by the Bcl-3 proto-oncogene in prostate cancer.
- 2013
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 32:12, s. 1601-1608
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Tidskriftsartikel (refereegranskat)abstract
- B-cell leukemia 3 (Bcl-3) is a member of the inhibitor of κB family, which regulates a wide range of biological processes by functioning as a transcriptional activator or as a repressor of target genes. As high levels of Bcl-3 expression and activation have been detected in different types of human cancer, Bcl-3 has been labeled a proto-oncogene. Our study uncovered a markedly upregulated Bcl-3 expression in human prostate cancer (PCa), where inflammatory cell infiltration was observed. Elevated Bcl-3 expression in PCa was dependent on the proinflammatory cytokine interleukin-6-mediated STAT3 activation. Microarray analyses, using Bcl-3 knockdown in PCa cells, identified the inhibitor of DNA-binding (Id) family of helix-loop-helix proteins as potential Bcl-3-regulated genes. Bcl-3 knockdown reduced the abundance of Id-1 and Id-2 proteins and boosted PCa cells to be more receptive to undergoing apoptosis following treatment with anticancer drug. Our data imply that inactivation of Bcl-3 may lead to sensitization of cancer cells to chemotherapeutic drug-induced apoptosis, thus suggesting a potential therapeutic strategy in PCa treatment.Oncogene advance online publication, 14 May 2012; doi:10.1038/onc.2012.175.
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| 37. |
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| 38. |
- Armstrong, Andrew J., et al.
(författare)
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Phase 3 Assessment of the Automated Bone Scan Index as a Prognostic Imaging Biomarker of Overall Survival in Men With Metastatic Castration-Resistant Prostate Cancer : A Secondary Analysis of a Randomized Clinical Trial
- 2018
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Ingår i: JAMA Oncology. - : American Medical Association (AMA). - 2374-2437 .- 2374-2445. ; 4:7, s. 944-951
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Prostate cancer commonly metastasizes to bone, and bone metastases are associated with pathologic fractures, pain, and reduced survival. Bone disease is routinely visualized using the technetium Tc 99m(Tc-99m) bone scan; however, the standard interpretation of bone scan data relies on subjective manual assessment of counting metastatic lesion numbers. There is an unmet need for an objective and fully quantitative assessment of bone scan data.Objective: To clinically assess in a prospectively defined analysis plan of a clinical trial the automated Bone Scan Index (aBSI) as an independent prognostic determinant of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC).Design, Setting, and Participants: This investigationwas a prospectively planned analysis of the aBSI in a phase 3 multicenter randomized, double-blind, placebo-controlled clinical trial of tasquinimod (10TASQ10). Men with bone metastatic chemotherapy-naive CRPC were recruited at 241 sites in 37 countries between March 2011 and August 2015. The statistical analysis plan to clinically evaluate the aBSI was prospectively defined and locked before unmasking of the 10TASQ10 study. The analysis of aBSI was conducted between May 25, 2016, and June 3, 2017.Main Outcomes and Measures: The associations of baseline aBSI with OS, radiographic progression-free survival (rPFS), time to symptomatic progression, and time to opiate use for cancer pain.Results: Of the total 1245 men enrolled, 721 were evaluable for the aBSI. The mean (SD) age (available for 719 men) was 70.6 (8.0) years (age range, 47-90 years). The aBSI population was representative of the total study population based on baseline characteristics. The aBSI (median, 1.07; range, 0-32.60) was significantly associated with OS (hazard ratio [HR], 1.20; 95% CI, 1.14-1.26; P < .001). The median OS by aBSI quartile (lowest to highest) was 34.7, 27.3, 21.7, and 13.3 months, respectively. The discriminative ability of the aBSI (C index, 0.63) in prognosticating OS was significantly higher than that of the manual lesion counting (C index, 0.60) (P = .03). In a multivariable survival model, a higher aBSI remained independently associated with OS (HR, 1.06; 95% CI, 1.01-1.11; P = .03). A higher aBSI was also independently associated with time to symptomatic progression (HR, 1.18; 95% CI, 1.13-1.23; P < .001) and time to opiate use for cancer pain (HR, 1.21; 95% CI, 1.14-1.30; P < .001).Conclusions and Relevance: To date, this investigation is the largest prospectively analyzed study to validate the aBSI as an independent prognostic imaging biomarker of survival in mCRPC. These data support the prognostic utility of the aBSI as an objective imaging biomarker in the design and eligibility of clinical trials of systemic therapies for patients with mCRPC.
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| 39. |
- Barbieri, Christopher E., et al.
(författare)
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The Mutational Landscape of Prostate Cancer
- 2013
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 64:4, s. 567-576
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Forskningsöversikt (refereegranskat)abstract
- Context: Prostate cancer (PCa) is a clinically heterogeneous disease with marked variability in patient outcomes. Molecular characterization has revealed striking mutational heterogeneity that may underlie the variable clinical course of the disease. Objective: In this review, we discuss the common genomic alterations that form the molecular basis of PCa, their functional significance, and the potential to translate this knowledge into patient care. Evidence acquisition: We reviewed the relevant literature, with a particular focus on recent studies on somatic alterations in PCa. Evidence synthesis: Advances in sequencing technology have resulted in an explosion of data regarding the mutational events underlying the development and progression of PCa. Heterogeneity is the norm; few abnormalities in specific genes are highly recurrent, but alterations in certain signaling pathways do predominate. These alterations include those in pathways known to affect tumorigenesis in a wide spectrum of tissues, such as the phosphoinositide 3-kinase/phosphatase and tensin homolog/Akt pathway, cell cycle regulation, and chromatin regulation. Alterations more specific to PCa are also observed, particularly gene fusions of ETS transcription factors and alterations in androgen signaling. Mounting data suggest that PCa can be subdivided based on a molecular profile of genetic alterations. Conclusions: Major advances have been made in cataloging the genomic alterations in PCa and understanding the molecular mechanisms underlying the disease. These findings raise the possibility that PCa could soon transition from being a poorly understood, heterogeneous disease with a variable clinical course to being a collection of homogenous subtypes identifiable by molecular criteria, associated with distinct risk profiles, and perhaps amenable to specific management strategies or targeted therapies. (C) 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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| 40. |
- Bjartell, Anders, et al.
(författare)
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Association of cysteine-rich secretory protein 3 and beta-microseminoprotein with outcome after radical prostatectomy
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 13:14, s. 4130-4138
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: It has been suggested that cysteine-rich secretory protein 3 (CRISP-3) and p-microseminoprotein (MSP) are associated with outcome in prostate cancer. We investigated whether these markers are related to biochemical recurrence and whether addition of the markers improves prediction of recurring disease. Experimental Design: Tissue microarrays of radical prostatectomy specimens were analyzed for CRISP-3 and MSP by immunohistochemistry. Associations between marker positivity and postprostatectomy biochemical recurrence [prostate-specific antigen (PSA) > 0.2 ng/mL with a confirmatory level] were evaluated by univariate and multivariable Cox proportional hazards regression. Multivariable analyses controlled for preoperative PSA and pathologic stage and grade. Results: Among 945 patients, 224 had recurrence. Median follow-up for survivors was 6.0 years. Patients positive for CRISP-3 had smaller recurrence-free probabilities, whereas MSP-positive patients had larger recurrence-free probabilities. On univariate analysis, the hazard ratio for patients positive versus negative for CRISP-3 was 1.53 (P =0.010) and for MSP was 0.63 (P = 0.004). On multivariable analysis, both CRISP-3 (P = 0.007) and MSP (P = 0.002) were associated with recurrence. The hazard ratio among CRISP-3-positive/MSP-negative patients compared with CRISP-3-negative/MSP-positive patients was 2.38. Adding CRISP-3 to a base model that included PSA and pathologic stage and grade did not enhance the prediction of recurrence, but adding MSP increased the concordance index minimally from 0.778 to 0.781. Conclusion: We report evidence that CRISP-3 and MSP are independent predictors of recurrence after radical prostatectomy for localized prostate cancer. However, addition of the markers does not importantly improve the performance of existing predictive models. Further research should aim to elucidate the functions of CRISP-3 and MSP in prostate cancer cells.
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| 41. |
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| 42. |
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| 43. |
- Bjartell, A., et al.
(författare)
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Time-resolved fluorescence imaging (TRFI) for direct immunofluorescence of PSA and alpha-1-antichymotrypsin in prostatic tissue sections
- 1999
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Ingår i: Prostate Cancer and Prostatic Diseases. - : Springer Science and Business Media LLC. - 1365-7852 .- 1476-5608. ; 2:3, s. 140-147
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Tidskriftsartikel (refereegranskat)abstract
- We have developed a direct immunofluorescence technique utilising chelates of the lanthanide ions europium and terbium conjugated to monoclonal IgGs (Mabs) against prostate-specific antigen (PSA) and alpha-1- antichymotrypsin (ACT) for the detection and quantification on the same tissue section. Strong signals without disturbance from tissue autofluorescence were demonstrated in paraffin sections of ten benign and six malignant prostate tissue specimens. The signal intensity increased linearly with the amount of labelled Mab until epitope saturation began. The highest concentrations of bound IgG in tissue sections were 27.3 fmol/pixel for ACT and 7.2 for PSA. Time-resolved fluorescence imaging (TRFI) offers an attractive method for histochemical studies based on specific and quantitative detection of fluorescent lanthanide chelates.
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| 44. |
- Bock, David, 1976, et al.
(författare)
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Learning curve for robot-assisted laparoscopic radical prostatectomy in a large prospective multicentre study
- 2022
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 56:3, s. 182-190
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Tidskriftsartikel (refereegranskat)abstract
- Objective Differences in outcome after radical prostatectomy for prostate cancer can partly be explained by intersurgeon differences, where degree of experience is one important aspect. This study aims to define the learning curve of robot-assisted laparoscopic prostatectomy (RALP) regarding oncological and functional outcomes. Materials and methods Out of 4003 enrolled patients in the LAPPRO trial, 3583 met the inclusion criteria, of whom 885 were operated on by an open technique. In total, 2672 patients with clinically localized prostate cancer from seven Swedish centres were operated on by RALP and followed for 8 years (LAPPRO trial). Oncological outcomes were pathology-reported surgical margins and biochemical recurrence at 8 years. Functional outcomes included patient-reported urinary incontinence and erectile dysfunction at 3, 12 and 24 months. Experience was surgeon-reported experience before and during the study. The relationship between surgeon experience and functional outcomes and surgical margin status was analysed by mixed-effects logistic regression. Biochemical recurrence was analysed by Cox regression, with robust standard errors. Results The learning curve for positive surgical margins was relatively flat, with rates of 21% for surgeons who had performed 0-74 cases and 24% for surgeons with > 300 cases. Biochemical recurrence at 4 years was 11% (0-74 cases) and 13% (> 300 cases). Incontinence was stable over the learning curve, but erectile function improved at 2 years, from 38% (0-74 cases) to 53% (> 300 cases). Conclusions Analysis of the learning curve for surgeons performing RALP showed that erectile function improved with increasing number of procedures, which was not the case for oncological outcomes.
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| 45. |
- Canesin, Giacomo, et al.
(författare)
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Scavenging of Labile Heme by Hemopexin Is a Key Checkpoint in Cancer Growth and Metastases
- 2020
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 32:12
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Tidskriftsartikel (refereegranskat)abstract
- Canesin et al. describe a role and mechanism for labile heme as a key player in regulating gene expression to promote carcinogenesis via binding to G-quadruplex in the c-MYC promoter. Hemopexin, a heme scavenger, may be used as a strategy to block progression of cancer.
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| 46. |
- Canesin, Giacomo, et al.
(författare)
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STAT3 inhibition with galiellalactone effectively targets the prostate cancer stem-like cell population
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Cancer stem cells (CSCs) are a small subpopulation of quiescent cells with the potential to differentiate into tumor cells. CSCs are involved in tumor initiation and progression and contribute to treatment failure through their intrinsic resistance to chemo- or radiotherapy, thus representing a substantial concern for cancer treatment. Prostate CSCs’ activity has been shown to be regulated by the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3). Here we investigated the effect of galiellalactone (GL), a direct STAT3 inhibitor, on CSCs derived from prostate cancer patients, on docetaxel-resistant spheres with stem cell characteristics, on CSCs obtained from the DU145 cell line in vitro and on DU145 tumors in vivo. We found that GL significantly reduced the viability of docetaxel-resistant and patient-derived spheres. Moreover, CSCs isolated from DU145 cells were sensitive to low concentrations of GL, and the treatment with GL suppressed their viability and their ability to form colonies and spheres. STAT3 inhibition down regulated transcriptional targets of STAT3 in these cells, indicating STAT3 activity in CSCs. Our results indicate that GL can target the prostate stem cell niche in patient-derived cells, in docetaxel-resistant spheres and in an in vitro model. We conclude that GL represents a promising therapeutic approach for prostate cancer patients, as it reduces the viability of prostate cancer-therapy-resistant cells in both CSCs and non-CSC populations.
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| 47. |
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| 48. |
- Ceder, Yvonne, et al.
(författare)
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The Molecular Evolution of Castration-resistant Prostate Cancer
- 2016
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Ingår i: European Urology Focus. - : Elsevier BV. - 2405-4569. ; 2:5, s. 506-513
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Forskningsöversikt (refereegranskat)abstract
- CONTEXT: Androgen deprivation therapy (ADT) is the backbone of treatment for advanced prostate cancer. However, castration-resistant prostate cancer (CRPC) nearly invariably develops through a range of different molecular mechanisms accompanied by progression to a more aggressive phenotype.OBJECTIVE: To understand the key molecular mechanisms leading to CRPC and the functional implications of this progression. Understanding molecular evolutionary mechanisms in CRPC is essential for the development of novel curative therapeutic approaches.EVIDENCE ACQUISITION: A systematic literature search to identify relevant original articles was conducted using PubMed. Findings verified in independent studies and supported by in vivo data were prioritised. From the eligible collection, 50 papers were selected.EVIDENCE SYNTHESIS: The majority of CRPC tumours harbour alterations in the androgen receptor (AR) at the DNA, RNA, and/or protein level, and/or other alterations involving the AR signalling pathway, so this central molecule is the focus of this review. To survive and resume growth despite low levels of circulating androgens, prostate cancer cells can also adapt androgen synthesis or induce alternative pathways.CONCLUSIONS: Despite more efficient ADT strategies, most evidence points to persistent AR signalling as a major mechanism of progression to CRPC. Resistance due to transdifferentiation or AR independence is also emerging as a mechanism of resistance. The diversity of potential resistance mechanisms supports the need for combination treatment and serial monitoring for adaptive treatment strategies.PATIENT SUMMARY: In this review, we summarise how prostate cancer cells evade androgen deprivation therapy and become more aggressive. Defining the molecular mechanisms will be critical for the development of new treatment approaches and hence improved survival.
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| 49. |
- Chi, Kim N., et al.
(författare)
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Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer : Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study
- 2021
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 0732-183X. ; 39:20, s. 2294-2303
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The first interim analysis of the phase III, randomized, placebo-controlled TITAN study showed that apalutamide significantly improved overall survival (OS) and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving ongoing androgen deprivation therapy (ADT). Herein, we report final efficacy and safety results after unblinding and placebo-to-apalutamide crossover. METHODS: Patients with mCSPC (N = 1,052) were randomly assigned 1:1 to receive apalutamide (240 mg QD) or placebo plus ADT. After unblinding in January 2019, placebo-treated patients were allowed to receive apalutamide. Efficacy end points were updated using the Kaplan-Meier method and Cox proportional-hazards model without formal statistical retesting and adjustment for multiplicity. Change from baseline in Functional Assessment of Cancer Therapy-Prostate total score was assessed. RESULTS: With a median follow-up of 44.0 months, 405 OS events had occurred and 208 placebo-treated patients (39.5%) had crossed over to apalutamide. The median treatment duration was 39.3 (apalutamide), 20.2 (placebo), and 15.4 months (crossover). Compared with placebo, apalutamide plus ADT significantly reduced the risk of death by 35% (median OS not reached v 52.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P < .0001) and by 48% after adjustment for crossover (hazard ratio, 0.52; 95% CI, 0.42 to 0.64; P < .0001). Apalutamide plus ADT delayed second progression-free survival and castration resistance (P < .0001 for both). Health-related quality of life, per total Functional Assessment of Cancer Therapy-Prostate, in both groups was maintained through the study. Safety was consistent with previous reports. CONCLUSION: The final analysis of TITAN confirmed that, despite crossover, apalutamide plus ADT improved OS, delayed castration resistance, maintained health-related quality of life, and had a consistent safety profile in a broad population of patients with mCSPC.
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