| 1. |
- Thysell, Elin, et al.
(författare)
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Clinical and biological relevance of the transcriptomic-based prostate cancer metastasis subtypes MetA-C
- 2022
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 16:4, s. 846-859
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Tidskriftsartikel (refereegranskat)abstract
- To improve treatment of metastatic prostate cancer, the biology of metastases needs to be understood. We recently described three subtypes of prostate cancer bone metastases (MetA-C), based on differential gene expression. The aim of this study was to verify the clinical relevance of these subtypes and to explore their biology and relations to genetic drivers. Freshly-frozen metastasis samples were obtained as hormone-naive (n = 17), short-term castrated (n = 21), or castration-resistant (n = 65) from a total of 67 patients. Previously published sequencing data from 573 metastasis samples were also analyzed. Through transcriptome profiling and sample classification based on a set of predefined MetA-C-differentiating genes, we found that most metastases were heterogeneous for the MetA-C subtypes. Overall, MetA was the most common subtype, while MetB was significantly enriched in castration-resistant samples and in liver metastases, and consistently associated with poor prognosis. By gene set enrichment analysis, the phenotype of MetA was described by high androgen response, protein secretion and adipogenesis, MetB by high cell cycle activity and DNA repair, and MetC by epithelial-to-mesenchymal transition and inflammation. The MetB subtype demonstrated single nucleotide variants of RB transcriptional corepressor 1 (RB1) and loss of 21 genes at chromosome 13, including RB1, but provided independent prognostic value to those genetic aberrations. In conclusion, a distinct set of gene transcripts can be used to classify prostate cancer metastases into the subtypes MetA-C. The MetA-C subtypes show diverse biology, organ tropism, and prognosis. The MetA-C classification may be used independently, or in combination with genetic markers, primarily to identify MetB patients in need of complementary therapy to conventional androgen receptor-targeting treatments.
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| 2. |
- Anand, Aseem, et al.
(författare)
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Automated Bone Scan Index as a quantitative imaging biomarker in metastatic castration-resistant prostate cancer patients being treated with enzalutamide
- 2016
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Ingår i: EJNMMI Research. - : Springer. - 2191-219X. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Having performed analytical validation studies, we are now assessing the clinical utility of the upgraded automated Bone Scan Index (BSI) in metastatic castration-resistant prostate cancer (mCRPC). In the present study, we retrospectively evaluated the discriminatory strength of the automated BSI in predicting overall survival (OS) in mCRPC patients being treated with enzalutamide.METHODS: Retrospectively, we included patients who received enzalutamide as a clinically approved therapy for mCRPC and had undergone bone scan prior to starting therapy. Automated BSI, prostate-specific antigen (PSA), hemoglobin (HgB), and alkaline phosphatase (ALP) were obtained at baseline. Change in automated BSI and PSA were obtained from patients who have had bone scan at week 12 of treatment follow-up. Automated BSI was obtained using the analytically validated EXINI Bone(BSI) version 2. Kendall's tau (τ) was used to assess the correlation of BSI with other blood-based biomarkers. Concordance index (C-index) was used to evaluate the discriminating strength of automated BSI in predicting OS.RESULTS: Eighty mCRPC patients with baseline bone scans were included in the study. There was a weak correlation of automated BSI with PSA (τ = 0.30), with HgB (τ = -0.17), and with ALP (τ = 0.56). At baseline, the automated BSI was observed to be predictive of OS (C-index 0.72, standard error (SE) 0.03). Adding automated BSI to the blood-based model significantly improved the C-index from 0.67 to 0.72, p = 0.017. Treatment follow-up bone scans were available from 62 patients. Both change in BSI and percent change in PSA were predictive of OS. However, the combined predictive model of percent PSA change and change in automated BSI (C-index 0.77) was significantly higher than that of percent PSA change alone (C-index 0.73), p = 0.041.CONCLUSIONS: The upgraded and analytically validated automated BSI was found to be a strong predictor of OS in mCRPC patients. Additionally, the change in automated BSI demonstrated an additive clinical value to the change in PSA in mCRPC patients being treated with enzalutamide.
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| 3. |
- Huang, Junchi, et al.
(författare)
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Osteoclasts directly influence castration-resistant prostate cancer cells
- 2022
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Ingår i: Clinical and Experimental Metastasis. - : Springer Nature. - 0262-0898 .- 1573-7276. ; 39:5, s. 801-814
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Tidskriftsartikel (refereegranskat)abstract
- Metastasis to bone is the leading cause of death from prostate cancer. Interaction between tumor cells and bone cells can promote progression and influence tumor phenotype. It is known that prostate cancer cells support osteoclast differentiation, and degradation of bone matrix by osteoclasts releases growth factors stimulating tumor cell proliferation and invasion. In the present study osteolytic (PC-3) and osteoblastic (LNCaP-19) castration-resistant prostate cancer (CRPC) cells were co-cultured with mature osteoclasts or their precursor cells (RAW 264.7) to characterize direct effects of mature osteoclasts on CRPC cells. Osteoclasts increased proliferation and decrease apoptosis of CRPC cells as assessed with flow cytometry. RNA sequencing revealed that osteolytic CRPC cells were more responsive to osteoclast stimulation regarding gene expression, but the overall induced expression patterns were similar between the prostate cancer cell lines. Genes related to DNA repair were upregulated by osteoclasts, while genes related to endoplasmic reticulum stress-induced apoptosis and cholesterol synthesis were downregulated. The results of this study shows that osteoclasts directly influence CRPC cells, increasing proliferation, decreasing apoptosis, and affecting gene expression pathways that can affect sensitivity to DNA damage and endoplasmic reticulum function. This suggests targeting of osteoclasts to be a possible way to affect efficacy of other drugs by combination regimens in treating prostate cancer metastases.
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| 4. |
- Josefsson, Andreas, 1979, et al.
(författare)
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Gene expression alterations during development of castration-resistant prostate cancer are detected in circulating tumor cells
- 2020
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Development of castration-resistant prostate cancer (CRPC) is associated with alterations in gene expression involved in steroidogenesis and androgen signaling. This study investigates whether gene expression changes related to CRPC development can be identified in circulating tumor cells (CTCs). Gene expression in paired CTC samples from 29 patients, before androgen deprivation therapy (ADT) and at CRPC relapse, was compared using a panel including 47 genes related to prostate cancer progression on a qPCR platform. Fourteen genes displayed significantly changed gene expression in CTCs at CRPC relapse compared to before start of ADT. The genes with increased expression at CRPC relapse were related to steroidogenesis, AR-signaling, and anti-apoptosis. In contrast, expression of prostate markers was downregulated at CRPC. We also show that midkine (MDK) expression in CTCs from metastatic hormone-sensitive prostate cancer (mHSPC) was associated to short cancer-specific survival (CSS). In conclusion, this study shows that gene expression patterns in CTCs reflect the development of CRPC, and that MDK expression levels in CTCs are prognostic for cancer-specific survival in mHSPC. This study emphasizes the role of CTCs in exploring mechanisms of therapy resistance, as well as a promising biomarker for prognostic and treatment-predictive purposes in advanced mHSPC. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
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| 5. |
- Josefsson, Torbjörn, 1965-, et al.
(författare)
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Effects of Mindfulness-Acceptance-Commitment (MAC) on Sport-Specific Dispositional Mindfulness, Emotion Regulation, and Self-Rated Athletic Performance in a Multiple-Sport Population : an RCT Study
- 2019
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Ingår i: Mindfulness. - New York, NY : Springer. - 1868-8527 .- 1868-8535. ; 10:8, s. 1518-1529
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesThe aim of the study was to examine mediating effects of emotion regulation and sport-specific dispositional mindfulness on self-rated athletic training performance, following the Mindfulness-Acceptance-Commitment (MAC) intervention, compared to a Psychological Skills Training (PST) control group.MethodsSixty-nine competitive elite athletes who did not have any prior experience with mindfulness- and acceptance-based exercises, were recruited and randomly assigned into either a MAC group or a traditional PST group. Latent growth curve analyses were performed to examine longitudinal relationships among the study variables. Mediation analyses were conducted to test if the growth trajectory of each of the proposed mediators mediated the relationship between the intervention and perceived performance (measured at T3).ResultsFindings showed that the MAC intervention had an indirect effect on self-rated athletic training performance through changes in dispositional mindfulness and emotion regulation respectively. Further, the MAC- group obtained greater post-test improvements in athletic mindfulness, emotion regulation abilities, and perceived performance compared to the PST group.ConclusionsOverall, findings suggest that dispositional athletic mindfulness and emotion regulation may function as important mechanisms in MAC, and that the MAC approach is a more effective intervention compared to the PST condition in reducing emotion regulation difficulties, as well as enhancing sport-relevant mindfulness skills and perceived athletic training performance in elite sport.
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| 6. |
- Magnusson, Cecilia, et al.
(författare)
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Acoustic Enrichment of Heterogeneous Circulating Tumor Cells and Clusters from Metastatic Prostate Cancer Patients
- 2024
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 1520-6882 .- 0003-2700. ; 96:18, s. 6914-6921
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There are important unmet clinical needs to develop cell enrichment technologies to enable unbiased label-free isolation of both single cell and clusters of circulating tumor cells (CTCs) manifesting heterogeneous lineage specificity. Here, we report a pilot study based on the microfluidic acoustophoresis enrichment of CTCs using the CellSearch CTC assay as a reference modality.METHODS: Acoustophoresis uses an ultrasonic standing wave field to separate cells based on biomechanical properties (size, density, and compressibility), resulting in inherently label-free and epitope-independent cell enrichment. Following red blood cell lysis and paraformaldehyde fixation, 6 mL of whole blood from 12 patients with metastatic prostate cancer and 20 healthy controls were processed with acoustophoresis and subsequent image cytometry.RESULTS: Acoustophoresis enabled enrichment and characterization of phenotypic CTCs (EpCAM +, Cytokeratin +, DAPI +, CD45 -/CD66b -) in all patients with metastatic prostate cancer and detected CTC-clusters composed of only CTCs or heterogeneous aggregates of CTCs clustered with various types of white blood cells in 9 out of 12 patients. By contrast, CellSearch did not detect any CTC clusters, but detected comparable numbers of phenotypic CTCs as acoustophoresis, with trends of finding a higher number of CTCs using acoustophoresis. CONCLUSION: Our preliminary data indicate that acoustophoresis provides excellent possibilities to detect and characterize CTC clusters as a putative marker of metastatic disease and outcomes. Moreover, acoustophoresis enables the sensitive label-free enrichment of cells with epithelial phenotypes in blood and offers opportunities to detect and characterize CTCs undergoing epithelial-to-mesenchymal transitioning and lineage plasticity.
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| 7. |
- Spyratou, Vasiliki, 1981, et al.
(författare)
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Ki67 and prostate specific antigen are prognostic in metastatic hormone naïve prostate cancer
- 2023
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Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 62:12, s. 1698-1706
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Tidskriftsartikel (refereegranskat)abstract
- Background: For metastatic hormone naïve prostate cancer patients, androgen deprivation therapy (ADT) with escalation therapy including docetaxel and/or androgen targeting drugs is the standard therapy. However, de-escalation is preferable to avoid unnecessary side effects, especially from docetaxel, but markers to identify these patients are lacking. The purpose of the present study was to investigate the potential of PSA and Ki67 immunoreactive scores as prognostic and treatment-predictive markers. Material and methods: Prostate biopsies from 92 patients with metastatic hormone naïve PC (PSA > 80 ng/mL or clinical metastases) were immunohistochemically evaluated for PSA and Ki67. Gene expression analysis was performed with Clariom D microarrays to identify the phenotypic profile associated with the immunohistochemistry scores of biopsies. Cox regression analysis for progression free survival after ADT adjustment for age, ISUP, and serum PSA and Kaplan-Meier analyses were performed to assess prognostic values of Ki67, PSA, and the Ki67/PSA ratio. Results: The immunohistochemical score for PSA was the strongest prognostic factor for progression-free and overall survival after ADT. Consequently, the ratio between Ki67 and PSA displayed a stronger prognostic value than Ki67 itself. Further, mRNA expression data analysis showed an association between high Ki67/PSA ratio, cell-cycle regulation, and DNA damage repair. In an exploratory sub-analysis of 12 patients treated with early docetaxel as addition to ADT and matched controls, a high Ki67/PSA ratio showed potential to identify those who benefit from docetaxel. Conclusion: PSA and Ki67 immunoreactive scores are prognostic in the metastatic hormone-sensitive setting, with PSA being superior. The combination of Ki67 and PSA did not give additional prognostic value. The results suggest immunohistochemical scoring of PSA to have potential to improve identification of patients responding well to ADT alone.
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| 8. |
- Welen, Karin, et al.
(författare)
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COVIDENZA - A prospective, multicenter, randomized PHASE II clinical trial of enzalutamide treatment to decrease the morbidity in patients with Corona virus disease 2019 (COVID-19): a structured summary of a study protocol for a randomised controlled trial.
- 2021
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Ingår i: Trials. - : Springer Science and Business Media LLC. - 1745-6215. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- The main goal of the COVIDENZA trial is to evaluate if inhibition of testosterone signalling by enzalutamide can improve the outcome of patients hospitalised for COVID-19. The hypothesis is based on the observation that the majority of patients in need of intensive care are male, and the connection between androgen receptor signalling and expression of TMPRSS2, an enzyme important for SARS-CoV-2 host cell internalization.Hospitalised COVID-19 patients will be randomised (2:1) to enzalutamide plus standard of care vs. standard of care designed to identify superiority.Included participants, men or women above 50 years of age, must be hospitalised for PCR confirmed COVID-19 symptoms and not in need of immediate mechanical ventilation. Major exclusion criteria are breast-feeding or pregnant women, hormonal treatment for prostate or breast cancer, treatment with immunosuppressive drugs, current symptomatic unstable cardiovascular disease (see Additional file 1 for further details). The trial is registered at Umeå University Hospital, Region Västerbotten, Sweden and 8 hospitals are approved for inclusion in Sweden.Patients randomised to the treatment arm will be treated orally with 160 mg (4x40 mg) enzalutamide (Xtandi®) daily, for five consecutive days. The study is not placebo controlled. The comparator is standard of care treatment for patients hospitalised with COVID-19.The primary endpoints of the study are (time to) need of mechanical ventilation or discharge from hospital as assessed by a clinical 7-point ordinal scale (up to 30 days after inclusion).Randomisation was stratified by center and sex. Each strata was randomized separately with block size six with a 2:1 allocation ratio (enzalutamide + "standard of care": "standard of care"). The randomisation list, with consecutive subject numbers, was generated by an independent statistician using the PROC PLAN procedure of SAS version 9.4 software (SAS Institute, Inc, Cary, North Carolina) BLINDING (MASKING): This is an open-label trial.The trial is designed to have three phases. The first, an exploration phase of 45 participants (30 treatment and 15 control) will focus on safety and includes a more extensive laboratory assessment as well as more frequent safety evaluation. The second prolongation phase, includes the first 100 participants followed by an interim analysis to define the power of the study. The third phase is the continuation of the study up to maximum 600 participants included in total.The current protocol version is COVIDENZA v2.0 as of September 10, 2020. Recruitment started July 29, 2020 and is presently in safety pause after the first exploration phase. Recruitment is anticipated to be complete by 31 December 2021.Eudract number 2020-002027-10 ClinicalTrials.gov Identifier: NCT04475601 , registered June 8, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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