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1.	Bylund, Annika, et al. (författare) Anticancer effects of a plant lignan 7-hydroxymatairesinol on a prostate cancer model in vivo. 2005 Ingår i: Experimental biology and medicine. - 1535-3702 .- 1535-3699. ; 230:3, s. 217-223 Tidskriftsartikel (refereegranskat)abstract Clinical intervention studies and experimental studies with lignan-rich diets suggest that lignans may have inhibitory effects on prostate cancer, but no clinical or experimental studies with purified lignans have been published. The purpose of this study was to investigate the effect of a plant lignan 7-hydroxymatairesinol (HMR) on LNCaP human prostate cancer xenografts in athymic mice. Athymic nude male mice were injected subcutaneously with LNCaP cells. Starting 3 days after tumor cell injections, a control diet or a control diet supplemented with 0.15% or 0.30% of HMR was administered to mice and the tumor take rate and growth was observed for 9 weeks. HMR diet inhibited the growth of LNCaP tumors. Mice treated with HMR had smaller tumor volume, lower tumor take rate, increased proportion of nongrowing tumors, and higher tumor cell apoptotic index compared with controls. Furthermore, the cell proliferation index was reduced in mice receiving the 0.30% HMR diet compared with mice receiving the control diet. Our results suggest that dietary HMR started at the early phase of the tumor development inhibits the growth of the LNCaP human prostate cancer xenografts in athymic male mice.
2.	Bylund, Annika, et al. (författare) Rye bran and soy protein delay growth and increase apoptosis of human LNCaP prostate adenocarcinoma in nude mice 2000 Ingår i: The Prostate. - 0270-4137 .- 1097-0045. ; 42:4, s. 304-314 Tidskriftsartikel (refereegranskat)
3.	Iglesias-Gato, Diego, et al. (författare) The Proteome of Primary Prostate Cancer 2016 Ingår i: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 69:5, s. 942-952 Tidskriftsartikel (refereegranskat)abstract Background: Clinical management of the prostate needs improved prognostic tests and treatment strategies. Because proteins are the ultimate effectors of most cellular reactions, are targets for drug actions and constitute potential biomarkers; a quantitative systemic overview of the proteome changes occurring during prostate cancer (PCa) initiation and progression can result in clinically relevant discoveries.Objectives: To study cellular processes altered in PCa using system-wide quantitative analysis of changes in protein expression in clinical samples and to identify prognostic biomarkers for disease aggressiveness.Design, setting, and participants: Mass spectrometry was used for genome-scale quantitative proteomic profiling of 28 prostate tumors (Gleason score 6-9) and neighboring nonmalignant tissue in eight cases, obtained from formalin-fixed paraffin-embedded prostatectomy samples. Two independent cohorts of PCa patients (summing 752 cases) managed by expectancy were used for immunohistochemical evaluation of proneuropeptide-Y (pro-NPY) as a prognostic biomarker.Results and limitations: Over 9000 proteins were identified as expressed in the human prostate. Tumor tissue exhibited elevated expression of proteins involved in multiple anabolic processes including fatty acid and protein synthesis, ribosomal biogenesis and protein secretion but no overt evidence of increased proliferation was observed. Tumors also showed increased levels of mitochondrial proteins, which was associated with elevated oxidative phosphorylation capacity measured in situ. Molecular analysis indicated that some of the proteins overexpressed in tumors, such as carnitine palmitoyltransferase 2 (CPT2, fatty acid transporter), coatomer protein complex, subunit alpha (COPA, vesicle secretion), and mitogen-and stress-activated protein kinase 1 and 2 (MSK1/2, protein kinase) regulate the proliferation of PCa cells. Additionally, pro-NPY was found overexpressed in PCa (5-fold, p < 0.05), but largely absent in other solid tumor types. Pro-NPY expression, alone or in combination with the ERG status of the tumor, was associated with an increased risk of PCa specific mortality, especially in patients with Gleason score <= 7 tumors.Conclusions: This study represents the first system-wide quantitative analysis of proteome changes associated to localized prostate cancer and as such constitutes a valuable resource for understanding the complex metabolic changes occurring in this disease. We also demonstrated that pro-NPY, a protein that showed differential expression between high and low risk tumors in our proteomic analysis, is also a PCa specific prognostic biomarker associated with increased risk for disease specific death in patients carrying low risk tumors.Patient summary: The identification of proteins whose expression change in prostate cancer provides novel mechanistic information related to the disease etiology. We hope that future studies will prove the value of this proteome dataset for development of novel therapies and biomarkers. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
4.	Rydh, Anders, et al. (författare) Radioimmunoscintigraphy with a novel monoclonal antiprostate antibody (E4) : an experimental study in nude mice. 1997 Ingår i: Cancer. - 0008-543X .- 1097-0142. ; 80:12 Suppl, s. 2398-2403 Tidskriftsartikel (refereegranskat)abstract The MoAb E4 is a promising radiotracer for prostate cancer and may be used in radioimmunotherapy. As in earlier studies, TS1 shows significant radioimmunolocalization into necrotic tumor tissue, which also exists in prostate cancer.
5.	Rydh, Anders, et al. (författare) Radioimmunotherapy of DU-145 tumours in nude mice--a pilot study with E4, a novel monoclonal antibody against prostate cancer. 1999 Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 38:8, s. 1075-1079 Tidskriftsartikel (refereegranskat)abstract The anti-tumour effect of the 131I-labelled antiprostate monoclonal antibody (MAb) E4 was studied in an experimental model with 41 nude mice, subcutaneously xenografted with a human prostate cancer cell line (DU-145). The mice were divided into four study groups, i.e. one receiving single and another repeated injections of the radiolabelled MAb. A third group was injected with non-labelled MAb, and the fourth served as an untreated control group. The tumour volumes increased similarly in all groups during the 27-day observation period. The tumour tissue was morphologically disintegrated in the group that received repeated radioimmunotherapy (RIT). The tumours from this group contained large fluid-filled cystic parts and demonstrated pronounced cellular and subcellular polymorphism in the remaining viable tumour tissue. The untreated control tumours and single therapy tumours remained solid. The proportion of the total tumour volume that consisted of viable tumour cells, as determined by morphometric techniques, was significantly lower in the 131I-E4-treated groups. The use of 131I-labelled E4 MAb has thus demonstrated a promising therapeutic potential.
6.	Solberg, Arne, et al. (författare) Residual Prostate Cancer in Patients Treated with Endocrine Therapy with or Without Radical Radiotherapy : A Side Study of the SPCG-7 Randomized Trial. 2011 Ingår i: International journal of radiation oncology, biology, physics. - : Elsevier. - 1879-355X .- 0360-3016. ; 80:1, s. 55-61 Tidskriftsartikel (refereegranskat)abstract PURPOSE: The Scandinavian Prostate Cancer Group-7 randomized trial demonstrated a survival benefit of combined endocrine therapy and external-beam radiotherapy over endocrine therapy alone in patients with high-risk prostate cancer. In a subset of the study population, the incidence and clinical implications of residual prostate cancer in posttreatment prostate biopsy specimens was evaluated. METHODS AND MATERIALS: Biopsy specimens were obtained from 120 of 875 men in the Scandinavian Prostate Cancer Group-7 study. RESULTS: Biopsies were performed at median of 45 months follow-up. In 63 patients receiving endocrine treatment only and 57 patients receiving combined treatment, residual cancer was found in 66% (n = 41) and 22% (n = 12), respectively (p < 0.0001). The vast majority of residual tumors were poorly differentiated (Gleason score >/=8). Endocrine therapy alone was predictive of residual prostate cancer: odds ratio 7.49 (3.18-17.7), p < 0.0001. In patients with positive vs. negative biopsy the incidences of clinical events were as follows: biochemical recurrence 74% vs. 27% (p < 0.0001), local progression 26% vs. 4.7% (p = 0.002), distant recurrence 17% vs. 9.4% (p = 0.27), clinical recurrence 36% vs. 13% (p = 0.006), cancer-specific death 19% vs. 9.7% (p = 0.025). In multivariable analysis, biochemical recurrence was significantly associated with residual cancer: hazard ratio 2.69 (1.45-4.99), p = 0.002, and endocrine therapy alone hazard ratio 3.45 (1.80-6.62), p < 0.0001. CONCLUSIONS: Radiotherapy combined with hormones improved local tumor control in comparison with endocrine therapy alone. Residual prostate cancer was significantly associated with serum prostate-specific antigen recurrence, local tumor progression, clinical recurrence, and cancer-specific death in univariable analysis. Residual cancer was predictive of prostate-specific antigen recurrence in multivariable analysis.
7.	Alexeyev, Oleg, et al. (författare) Association between the presence of bacterial 16S RNA in prostate specimens taken during transurethral resection of prostate and subsequent risk of prostate cancer (Sweden) 2006 Ingår i: Cancer Causes and Control. - Dordrecht : Kluwer Academic Publishers. - 0957-5243 .- 1573-7225. ; 17:9, s. 1127-1133 Tidskriftsartikel (refereegranskat)abstract Objective: To study bacterial 16S RNA in archival prostate samples from 352 patients with benign prostate hyperplasia (BPH) and evaluate whether the presence of bacterial DNA was different in those who later developed prostate cancer (n = 171) and in the matched controls that did not progress to cancer (n = 181).Methods: 16S DNA PCR followed by cloning and sequencing the positive samples.Results: In 96/352 (27%) of the prostate tissue specimens 16S RNA were detected. Sequence analysis revealed Propionibacterium acnes as the predominant microorganism (23% of 16S RNA positive patients). The second most frequent isolate—Escherichia coli was found in 12 (12%) patients. The other isolates included Pseudomonas sp. (3 patients), Actinomyces sp. (2), Streptococcus mutans (1), Corynebacterium sp. (2),Nocardioides sp. (1), Rhodococcus sp. (1) Veillonella sp. (2). In P. acnes positive samples 62% exhibited severe histological inflammation versus 50% in the bacteria-negative group (p = 0.602). The presence of P. acnes in the prostate was associated with prostate cancer development (OR 2.17, 95% CI 0.77–6.95).Conclusions: This study has revealed P. acnes as the most common bacteria in the prostate in BPH. Further studies are needed to clarify its role in contributing to the development of prostatic inflammation and prostate cancer.
8.	Assel, Melissa, et al. (författare) Association Between Lead Time and Prostate Cancer Grade : Evidence of Grade Progression from Long-term Follow-up of Large Population-based Cohorts Not Subject to Prostate-specific Antigen Screening 2018 Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 73:6, s. 961-967 Tidskriftsartikel (refereegranskat)abstract Background: Lead time (LT) is of key importance in early detection of cancer, but cannot be directly measured. We have previously provided LT estimates for prostate cancer (PCa) using archived blood samples from cohorts followed for many years without screening. Objective: To determine the association between LT and PCa grade at diagnosis to provide an insight into whether grade progresses or is stable over time. Design, setting, and participants: The setting was three long-term epidemiologic studies in Sweden including men not subject to prostate-specific antigen (PSA) screening. The cohort included 1041 men with PSA of 3–10 ng/ml at blood draw and subsequently diagnosed with PCa with grade data available. Outcome measurements and statistical analysis: Multivariable logistic regression was used to predict high-grade (Gleason grade group ≥2 or World Health Organization grade 3) versus low-grade PCa at diagnosis in terms of LT, defined as the time between the date of elevated PSA and the date of PCa diagnosis with adjustment for cohort and age. Results and limitations: The probability that PCa would be high grade at diagnosis increased with LT. Among all men combined, the risk of high-grade disease increased with LT (odds ratio 1.13, 95% confidence interval [CI] 1.10–1.16; p < 0.0001), with no evidence of differences in effect by age group or cohort. Higher PSA predicted shorter LT by 0.46 yr (95% CI 0.28–0.64; p < 0.0001) per 1 ng/ml increase in PSA. However, there was no interaction between PSA and grade, suggesting that the longer LT for high-grade tumors is not simply related to age. Limitations include the assumption that men with elevated PSA and subsequently diagnosed with PCa would have had biopsy-detectable PCa at the time of PSA elevation. Conclusions: Our data support grade progression, whereby following a prostate over time would reveal transitions from benign to low-grade and then high-grade PCa. Patient summary: Men with a longer lead time between elevated prostate-specific antigen and subsequent prostate cancer diagnosis were more likely to have high-grade cancers at diagnosis. The probability that a cancer will be of high grade at diagnosis increases with the lead time. Our findings provide evidence of grade progression, whereby a prostate followed over time would exhibit transitions from benign to low-grade to high-grade prostate cancer.
9.	Bergh, Anders, et al. (författare) Cobalt-mediated solid phase synthesis of 3-O-alkynylbenzyl galactosides and their evaluation as galectin inhibitors 2006 Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 62:35, s. 8309-8317 Tidskriftsartikel (refereegranskat)abstract Methyl beta-D-galactoside was converted to the corresponding 3,4-O-stannylene acetal, which was selectively benzylated with 3-iodobenzyl bromide and coupled to a polymer-bound propargylic ether via a Sonogashira reaction. The polymer-bound carbohydrate substrate was cleaved from the resin with different carbon nucleophiles in a cobalt-mediated Nicholas reaction. The product 3-O-alkynylbenzyl galactosides were screened towards galectin-1, -3, -7, -8N and -9N in a competitive fluorescence polarisation assay. Particularly potent inhibitors were identified against galectin-7 with affinity enhancements up to one order of magnitude due to the 3-O-alkynylbenzyl moiety. (c) 2006 Elsevier Ltd. All rights reserved.
10.	Bergh Drott, Johanna, et al. (författare) Propionibacterium acnes induces chronic inflammation and precancerous epithelial lesions in the dorso-lateral prostate in rats Annan publikation (övrigt vetenskapligt/konstnärligt)
11.	Berndes, Göran, 1966, et al. (författare) Forests and the climate: manage for maximum wood production or leave the forest as a carbon sink? 2018 Rapport (övrigt vetenskapligt/konstnärligt)
12.	Bovinder Ylitalo, Erik, et al. (författare) A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer 2021 Ingår i: Clinical Epigenetics. - : BioMed Central. - 1868-7083 .- 1868-7075. ; 13:1 Tidskriftsartikel (refereegranskat)abstract Background: Patients with metastatic prostate cancer (PC) are treated with androgen deprivation therapy (ADT) that initially reduces metastasis growth, but after some time lethal castration-resistant PC (CRPC) develops. A better understanding of the tumor biology in bone metastases is needed to guide further treatment developments. Subgroups of PC bone metastases based on transcriptome profiling have been previously identified by our research team, and specifically, heterogeneities related to androgen receptor (AR) activity have been described. Epigenetic alterations during PC progression remain elusive and this study aims to explore promoter gene methylation signatures in relation to gene expression and tumor AR activity.Materials and methods: Genome-wide promoter-associated CpG methylation signatures of a total of 94 tumor samples, including paired non-malignant and malignant primary tumor areas originating from radical prostatectomy samples (n = 12), and bone metastasis samples of separate patients with hormone-naive (n = 14), short-term castrated (n = 4) or CRPC (n = 52) disease were analyzed using the Infinium Methylation EPIC arrays, along with gene expression analysis by Illumina Bead Chip arrays (n = 90). AR activity was defined from expression levels of genes associated with canonical AR activity.Results: Integrated epigenome and transcriptome analysis identified pronounced hypermethylation in malignant compared to non-malignant areas of localized prostate tumors. Metastases showed an overall hypomethylation in relation to primary PC, including CpGs in the AR promoter accompanied with induction of AR mRNA levels. We identified a Methylation Classifier for Androgen receptor activity (MCA) signature, which separated metastases into two clusters (MCA positive/negative) related to tumor characteristics and patient prognosis. The MCA positive metastases showed low methylation levels of genes associated with canonical AR signaling and patients had a more favorable prognosis after ADT. In contrast, MCA negative patients had low AR activity associated with hypermethylation of AR-associated genes, and a worse prognosis after ADT.Conclusions: A promoter methylation signature classifies PC bone metastases into two groups and predicts tumor AR activity and patient prognosis after ADT. The explanation for the methylation diversities observed during PC progression and their biological and clinical relevance need further exploration.
13.	Bovinder Ylitalo, Erik, et al. (författare) Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases 2018 Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 78:16, s. 50-50 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
14.	Bovinder Ylitalo, Erik, et al. (författare) Excellent cabazitaxel response in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of resistance development by anti-androgens Annan publikation (övrigt vetenskapligt/konstnärligt)
15.	Bovinder Ylitalo, Erik, et al. (författare) Integrated DNA methylation and gene expression analysis of molecular heterogeneity in prostate cancer bone metastasis Annan publikation (övrigt vetenskapligt/konstnärligt)
16.	Bovinder Ylitalo, Erik, et al. (författare) Marked response to cabazitaxel in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of acquired resistance by anti-androgens 2020 Ingår i: Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 80:1, s. 214-224 Tidskriftsartikel (refereegranskat)abstract Background Taxane treatment may be a suitable therapeutic option for patients with castration-resistant prostate cancer and high expression of constitutively active androgen receptor variants (AR-Vs). The aim of the study was to compare the effects of cabazitaxel and androgen deprivation treatments in a prostate tumor xenograft model expressing high levels of constitutively active AR-V7. Furthermore, mechanisms behind acquired cabazitaxel resistance were explored. Methods Mice were subcutaneously inoculated with 22Rv1 cells and treated with surgical castration (n = 7), abiraterone (n = 9), cabazitaxel (n = 6), castration plus abiraterone (n = 8), castration plus cabazitaxel (n = 11), or vehicle and/or sham operation (n = 23). Tumor growth was followed for about 2 months or to a volume of approximately 1000 mm(3). Two cabazitaxel resistant cell lines; 22Rv1-CabR1 and 22Rv1-CabR2, were established from xenografts relapsing during cabazitaxel treatment. Differential gene expression between the cabazitaxel resistant and control 22Rv1 cells was examined by whole-genome expression array analysis followed by immunoblotting, immunohistochemistry, and functional pathway analysis. Results Abiraterone treatment alone or in combination with surgical castration had no major effect on 22Rv1 tumor growth, while cabazitaxel significantly delayed and in some cases totally abolished 22Rv1 tumor growth on its own and in combination with surgical castration. The cabazitaxel resistant cell lines; 22Rv1-CabR1 and 22Rv1-CabR2, both showed upregulation of the ATP-binding cassette sub-family B member 1 (ABCB1) efflux pump. Treatment with ABCB1 inhibitor elacridar completely restored susceptibility to cabazitaxel, while treatment with AR-antagonists bicalutamide and enzalutamide partly restored susceptibility to cabazitaxel in both cell lines. The cholesterol biosynthesis pathway was induced in the 22Rv1-CabR2 cell line, which was confirmed by reduced sensitivity to simvastatin treatment. Conclusions Cabazitaxel efficiently inhibits prostate cancer growth despite the high expression of constitutively active AR-V7. Acquired cabazitaxel resistance involving overexpression of efflux transporter ABCB1 can be reverted by bicalutamide or enzalutamide treatment, indicating the great clinical potential for combined treatment with cabazitaxel and anti-androgens.
17.	Bovinder Ylitalo, Erik, et al. (författare) Subgroups of castration-resistant prostate cancer bone metastases defined through an inverse relationship between androgen receptor activity and immune response 2017 Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 71:5, s. 776-787 Tidskriftsartikel (refereegranskat)abstract Background: Novel therapies for men with castration-resistant prostate cancer (CRPC) are needed, particularly for cancers not driven by androgen receptor (AR) activation. Objectives: To identify molecular subgroups of PC bone metastases of relevance for therapy.Design, setting, and participants: Fresh-frozen bone metastasis samples from men with CRPC (n = 40), treatment-naïve PC (n = 8), or other malignancies (n = 12) were characterized using whole-genome expression profiling, multivariate principal component analysis (PCA), and functional enrichment analysis. Expression profiles were verified by reverse transcription–polymerase chain reaction (RT-PCR) in an extended set of bone metastases (n = 77) and compared to levels in malignant and adjacent benign prostate tissue from patients with localized disease (n = 12). Selected proteins were evaluated using immunohistochemistry. A cohort of PC patients (n = 284) diagnosed at transurethral resection with long follow-up was used for prognostic evaluation.Results and limitations: The majority of CRPC bone metastases (80%) was defined as AR-driven based on PCA analysis and high expression of the AR, AR co-regulators (FOXA1, HOXB13), and AR-regulated genes (KLK2, KLK3, NKX3.1, STEAP2, TMPRSS2); 20% were non–AR-driven. Functional enrichment analysis indicated high metabolic activity and low immune responses in AR-driven metastases. Accordingly, infiltration of CD3+ and CD68+ cells was lower in AR-driven than in non–AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity. RT-PCR analysis showed low MHC class I expression (HLA-A, TAP1, and PSMB9 mRNA) in PC bone metastases compared to benign and malignant prostate tissue and bone metastases of other origins. In primary PC, low HLA class I ABC immunoreactivity was associated with high Gleason score, bone metastasis, and short cancer-specific survival. Limitations include the limited number of patients studied and the single metastasis sample studied per patient.Conclusions: Most CRPC bone metastases show high AR and metabolic activities and low immune responses. A subgroup instead shows low AR and metabolic activities, but high immune responses. Targeted therapy for these groups should be explored. Patient summary: We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possible importance for therapy selection in individual patients.
18.	Cahill, Nicola, et al. (författare) 450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments 2013 Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 27:1, s. 150-158 Tidskriftsartikel (refereegranskat)abstract In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n = 36) and patient-matched peripheral blood and lymph node samples (n = 20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-beta and NF-kappa B/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event. Leukemia (2013) 27, 150-158; doi:10.1038/leu.2012.245
19.	Cahill, Nicola, 1983-, et al. (författare) 450K DNA methylation analysis of chronic lymphocytic leukaemia reveals DNA methylation to be relatively stable over time and remarkably similar in cells derived from resting and proliferation compartments Annan publikation (övrigt vetenskapligt/konstnärligt)
20.	Crnalic, Sead, et al. (författare) Early diagnosis and treatment is crucial for neurological recovery after surgery for metastatic spinal cord compression in prostate cancer 2013 Ingår i: Acta Oncologica. - London : Informa Healthcare. - 0284-186X .- 1651-226X. ; 52:4, s. 809-815 Tidskriftsartikel (refereegranskat)abstract Background. Spinal cord compression is an oncological and surgical emergency. Delays in referral and diagnosis may influence functional outcome. It is therefore important to identify patients who will regain or maintain ability to walk after surgery. The aim of the present study was to examine current practice for referral and diagnosis of prostate cancer patients with spinal cord compression and to identify prognostic factors for neurological outcome after surgery.Patients and methods. The study includes 68 consecutive patients with prostate cancer who underwent surgery due to neurological compromise. Intervals from onset of neurological symptoms to referral, diagnosis, and treatment were analyzed in relation to functional outcome. The prognostic significance of preoperative clinical parameters on gait function one month after surgery was evaluated.Results. Patients who were referred from local hospitals had longer delay to surgery than those who directly presented to the cancer centre (p=0.004). The rate of diagnosis with MRI increased through the week and peaked on Friday, with few patients being diagnosed during weekends. Ability to walk before surgery, hormone-naive prostate cancer, and/or shorter time from loss of ambulation were associated with more favorable neurological outcome. In patients with hormone-refractory disease who were unable to walk before surgery regaining of ambulation was associated with: duration of paresis <48 hours (p=0.005), good preoperative performance status (p=0.04), preoperative PSA serum level <200 ng/ml (p=0.03), and surgery with posterior decompression and stabilization (p=0.03).Conclusion. Early diagnosis and rapid treatment of spinal cord compression in prostate cancer patients is crucial for neurological recovery. Rising of awareness for the condition among patients at risk and among physicians is mandatory as well as improvement of local and regional guidelines for treatment.
21.	Crnalic, Sead, 1960- (författare) Metastatic spinal cord compression in prostate cancer : clinical and morphological studies 2012 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Background: Bone metastases occur in most patients with advanced hormone-refractory prostate cancer causing pain, pathologic fractures, and spinal cord compression. Few studies specifically address surgical treatment of metastatic spinal cord compression (MSCC) in prostate cancer. Criteria for identifying patients who may benefit from surgery are poorly defined. Most of the current knowledge regarding tumor biology in prostate cancer is based on studies of primary tumors or soft tissue metastases. The mechanisms regulating growth of bone metastases are not fully established. Aims: a) to evaluate outcome after surgery for MSCC in prostate cancer and to identify prognostic factors for survival and functional recovery; b) to evaluate current practice for referral of prostate cancer patients with MSCC; c) to analyze expression of androgen receptor (AR), cell proliferation, apoptosis, and prostate-specific antigen (PSA) in bone metastases with regard to survival after surgery for complications of bone metastases. Patients and Methods: We retrospectively evaluated the hospital records of 68 consecutive patients operated for metastatic spinal cord compression. Tumor tissue from bone metastases was obtained on spinal surgery (54 patients), fracture surgery (4 patients) and biopsy (2 patients), and analyzed by immunohistochemistry. Results: Study I: Mortality and complication rate after surgery was high. Patients with hormone-naïve disease and those with hormone-refractory disease with good performance status and without visceral metastases had more favorable survival. The ability to walk after surgery was related to better survival. Study II: A new score for prognosis of survival after surgery for spinal cord compression includes: hormone status of prostate cancer, Karnofsky performance status, evidence of visceral metastasis, and preoperative serum PSA. The score is simple, tumor specific, and easy to apply in clinical practice. Study III: Our results suggest that delays in diagnosis and treatment may have negative impact on functional outcome. Pretreatment ability to walk, hormone status of prostate cancer, and time from loss of ambulation influenced neurological recovery after surgery for spinal cord compression. Study IV: High nuclear AR immunostaining in bone metastases and high preoperative serum PSA were associated with a poor outcome after metastasis surgery in patients with hormone-refractory prostate cancer. Short-term effect of castration therapy disclosed that nuclear AR immunostaining was decreased and apoptosis was increased, but cell proliferation remained largely unaffected. Conclusion: Prostate cancer patients with metastatic spinal cord compression represent a heterogeneous group. We identified prognostic factors for survival and functional outcome, which may help clinicians in making decisions about treatment. Our results also implicate the need for development of local and regional guidelines for treatment of patients with spinal cord compression, as well as the importance of information to patients at risk.
22.	Crnalic, Sead, et al. (författare) Nuclear androgen receptor staining in bone metastases is related to a poor outcome in prostate cancer patients 2010 Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 17:4, s. 885-895 Tidskriftsartikel (refereegranskat)abstract Androgen receptors (ARs) are probably of importance during all phases of prostate cancer (PC) growth, but their role in bone metastases is largely unexplored. Bone metastases were therefore collected from hormone-naive (n=11), short-term castrated (n=7) and castration-resistant PC (CRPC, n=44) patients by biopsy (n=4) or at surgery to alleviate symptoms from metastases complications (metastasis surgery, n=58), and immunostained for nuclear ARs, Ki67, active caspase-3, prostate-specific antigen (PSA) and chromogranin A, and results were related to serum PSA, treatments and outcome. Nuclear AR immunostaining was decreased and apoptosis was increased, but cell proliferation remained largely unaffected in metastases within a few days after surgical castration. In CRPC patients, nuclear AR staining of metastases was increased when compared to short-term castrated patients. The nuclear AR staining score was related to tumour cell proliferation, but it was not associated with other downstream effects of AR activation such as apoptosis and PSA staining, and it was only marginally related to the presence of neuroendocrine tumour cells. Serum PSA at metastasis surgery, although related to outcome, was not associated with AR staining, markers of metastasis growth or PSA staining in metastases. High nuclear AR immunostaining was associated with a particularly poor prognosis after metastasis surgery in CRPC patients, suggesting that such men may benefit from the potent AR blockers now tested in clinical trials.
23.	Crnalic, Sead, et al. (författare) Outcome after surgery for metastatic spinal cord compression in 54 patients with prostate cancer 2012 Ingår i: Acta Orthopaedica. - : Informa Healtcare. - 1745-3674 .- 1745-3682. ; 83:1, s. 80-86 Tidskriftsartikel (refereegranskat)abstract Background and purpose The criteria for selecting patients who may benefit from surgery of spinal cord compression in metastatic prostate cancer are poorly defined. We therefore studied patients operated for metastatic spinal cord compression in order to evaluate outcome of surgery and to find predictors of survival. Patients and methods We reviewed the records of 54 consecutive patients with metastatic prostate cancer who were operated for spinal cord compression at Umeå University Hospital. The indication for surgery was neurological deficit due to spinal cord compression. 41 patients had hormone-refractory cancer and 13 patients had previously untreated, hormone-naïve prostate cancer. 29 patients were operated with posterior decompression only, and in 25 patients posterior decompression and stabilization was performed. Results Preoperatively, 6/54 of patients were able to walk. 1 month after surgery, 33 patients were walking, 15 were non-ambulatory, and 6 had died. Mortality rate was 11% at 1 month, 41% at 6 months, and 59% at 1 year. In the hormone-naïve group, 8/13 patients were still alive with a median postoperative follow-up of 26 months. In the hormone-refractory group, median survival was 5 months. Patients with hormone-refractory disease and Karnofsky performance status (KPS) of ≤ 60% had median survival of 2.5 months, whereas those with KPS of 70% and KPS of ≥ 80% had a median survival of 7 months and 18 months, respectively (p < 0.001). Visceral metastases were present in 12/41 patients with hormone-refractory tumor at the time of spinal surgery, and their median survival was 4 months-as compared to 10 months in patients without visceral metastases (p = 0.003). Complications within 30 days of surgery occurred in 19/54 patients. Interpretation Our results indicate that patients with hormone-naive disease, and those with hormone-refractory disease with good performance status and lacking visceral metastases, may be helped by surgery for metastatic spinal cord compression.
24.	Crnalic, Sead, et al. (författare) Predicting survival for surgery of metastatic spinal cord compression in prostate cancer : a new score 2012 Ingår i: Spine. - 0362-2436 .- 1528-1159. ; 37:26, s. 2168-2176 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Study design. We retrospectively analyzed prognostic factors for survival in prostate cancer patients operated for metastatic spinal cord compression.Objective. The aim was to obtain a clinical score for prediction of survival after surgery.Summary of background data. Survival prognosis is important when deciding about treatment of patients with metastatic spinal cord compression. The criteria for identifying prostate cancer patients who may benefit from surgical treatment are unclear.Patients and methods The study comprised 68 consecutive patients with prostate cancer operated for metastatic spinal cord compression at Umeå University Hospital, Sweden. The indication for surgery was neurological deficit; 53 patients had hormone-refractory prostate cancer, and 15 patients had previously untreated, hormone-naïve prostate cancer. In 42 patients posterior decompression was performed and 26 patients were operated with posterior decompression and stabilization.Results A new score for prediction of survival was developed based on the results of survival analyses. The score includes: hormone status of prostate cancer, Karnofsky performance status, evidence of visceral metastasis, and preoperative serum PSA. The total scores ranged from 0 to 6. Three prognostic groups were formulated: group A (n = 32) with scores 0-1; group B (n = 23) with scores 2-4, and group C (n = 12) with scores 5-6. The median overall survival was 3 (0.3 - 20) months in group A, 16 (1.8 - 59) months in group B, and in group C more than half (7 of 12) of patients were still alive.Conclusion We present a new prognostic score for predicting survival of prostate cancer patients after surgery for metastatic spinal cord compression. The score is easy to apply in clinical practice and may be used as additional support when making decision about treatment.
25.	Djusberg, Erik, et al. (författare) High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases 2017 Ingår i: The Prostate. - : Wiley-Blackwell Publishing Inc.. - 0270-4137 .- 1097-0045. ; 77:6, s. 625-638 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. RESULTS: AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6 overproducing 22Rv1 cells were enriched for proteins involved in blood coagulation and, accordingly, decreased the APTT in a dose-dependent fashion. CONCLUSIONS: AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs. Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients.
26.	Eklund, Anders, 1965-, et al. (författare) A catheter tactile sensor for measuring hardness of soft tissue : measurement in a silicone model and in an in vitro human prostate model 1999 Ingår i: Medical and Biological Engineering and Computing. - 0140-0118 .- 1741-0444. ; 37:5, s. 618-624 Tidskriftsartikel (refereegranskat)abstract Tissue hardness is related to tissue composition, and this is often changed by disease. It is therefore of interest to measure the hardness in an objective and non-invasive way. A tactile sensor based on a vibrating piezoelectric ceramic element in a feedback loop is described. When the sensor touches an object it produces a frequency shift related to the hardness of the object. The aim of this study was to develop an in vitro hardness measurement method using a catheter type version of the sensor. The method was evaluated in an established silicone tissue model and on human prostate tissue in vitro. A linear relationship was found with a high degree of explanation (R2 = 0.98) between a cone penetration hardness standard (DIN ISO 2137) applied to the silicone model and the corresponding frequency shift. The results from measurements on a human prostate tissue sample, fixed with formalin, showed that the relative hardness measured with the tactile sensor correlated (R = -0.96, p < 0.001, N = 60) with the proposed hardness related to the histological composition of the prostate tissue. The results indicated that hardness of prostate tissue, and maybe hardness of human tissue in general, can be expressed according to the cone penetration standard and that the hardness can be measured with this tactile sensory system. These findings hold the promise of further development of a non-invasive tool for hardness measurement in a clinical situation
27.	Eklund, Anders, et al. (författare) A resonator sensor for evaluation of prostate tissue composition and hardness 1999 Ingår i: Proceedings of the 11th Nordic-Baltic conference on biomedical engineering.. ; , s. 181-182 Konferensbidrag (övrigt vetenskapligt/konstnärligt)
28.	Eklund, Anders, et al. (författare) Vibrationssensor för värdering av vävnadsmjukhet 1998 Ingår i: Program & sammanfattningar. [55]. - Stockholm : Svenska läkaresällskapet. ; , s. 259- Konferensbidrag (övrigt vetenskapligt/konstnärligt)
29.	Gudey, Shyam Kumar, et al. (författare) TRAF6 stimulates the tumor-promoting effects of TGF beta type I receptor through polyubiquitination and activation of Presenilin 1 2014 Ingår i: Science Signaling. - : American Association for the Advancement of Science. - 1945-0877 .- 1937-9145. ; 7:307 Tidskriftsartikel (refereegranskat)abstract Transforming growth factor-beta (TGF beta) can be both a tumor promoter and suppressor, although the mechanisms behind the protumorigenic switch remain to be fully elucidated. The TGF beta type I receptor (T beta RI) is proteolytically cleaved in the ectodomain region. Cleavage requires the combined activities of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF-alpha-converting enzyme (TACE). The cleavage event occurs selectively in cancer cells and generates an intracellular domain (ICD) of T beta RI, which enters the nucleus to mediate gene transcription. Presenilin 1 (PS1), a gamma-secretase catalytic core component, mediates intramembrane proteolysis of transmembrane receptors, such as Notch. We showed that TGF beta increased both the abundance and activity of PS1. TRAF6 recruited PS1 to the T beta RI complex and promoted lysine-63-linked polyubiquitination of PS1, which activated PS1. Furthermore, PS1 cleaved T beta RI in the transmembrane domain between valine-129 and isoleucine-130, and ICD generation was inhibited when these residues were mutated to alanine. We also showed that, after entering the nucleus, T beta RI-ICD bound to the promoter and increased the transcription of the gene encoding T beta RI. The TRAF6- and PS1-induced intramembrane proteolysis of T beta RI promoted TGF beta-induced invasion of various cancer cells in vitro. Furthermore, when a mouse xenograft model of prostate cancer was treated with the gamma-secretase inhibitor DBZ {(2S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b, d]azepin-7-yl)-propionamide}, generation of T beta RI-ICD was prevented, transcription of the gene encoding the proinvasive transcription factor Snail1 was reduced, and tumor growth was inhibited. These results suggest that gamma-secretase inhibitors may be useful for treating aggressive prostate cancer.
30.	Gudey, Shyam Kumar, et al. (författare) TRAF6 Stimulates the Tumor-Promoting Effects of TGFβ Type I Receptor Through Polyubiquitination and Activation of Presenilin 1 2014 Ingår i: Science signaling. - : American Association for the Advancement of Science (AAAS). - 1937-9145 .- 1945-0877. ; 7:307, s. ra2- Tidskriftsartikel (refereegranskat)abstract Transforming growth factor-β (TGFβ) can be both a tumor promoter and suppressor, although the mechanisms behind the protumorigenic switch remain to be fully elucidated. The TGFβ type I receptor (TβRI) is proteolytically cleaved in the ectodomain region. Cleavage requires the combined activities of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF-α-converting enzyme (TACE). The cleavage event occurs selectively in cancer cells and generates an intracellular domain (ICD) of TβRI, which enters the nucleus to mediate gene transcription. Presenilin 1 (PS1), a γ-secretase catalytic core component, mediates intramembrane proteolysis of transmembrane receptors, such as Notch. We showed that TGFβ increased both the abundance and activity of PS1. TRAF6 recruited PS1 to the TβRI complex and promoted lysine-63-linked polyubiquitination of PS1, which activated PS1. Furthermore, PS1 cleaved TβRI in the transmembrane domain between valine-129 and isoleucine-130, and ICD generation was inhibited when these residues were mutated to alanine. We also showed that, after entering the nucleus, TβRI-ICD bound to the promoter and increased the transcription of the gene encoding TβRI. The TRAF6- and PS1-induced intramembrane proteolysis of TβRI promoted TGFβ-induced invasion of various cancer cells in vitro. Furthermore, when a mouse xenograft model of prostate cancer was treated with the γ-secretase inhibitor DBZ {(2S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-propionamide}, generation of TβRI-ICD was prevented, transcription of the gene encoding the proinvasive transcription factor Snail1 was reduced, and tumor growth was inhibited. These results suggest that γ-secretase inhibitors may be useful for treating aggressive prostate cancer.
31.	Gustavsson, Anders, et al. (författare) Cost of disorders of the brain in Europe 2010. 2011 Ingår i: European Neuropsychopharmacology. - Amsterdam : Elsevier BV. - 0924-977X .- 1873-7862. ; 21:10, s. 718-79 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of €386 billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514 million people.AIMS: To estimate the number of persons with defined disorders of the brain in Europe in 2010, the total cost per person related to each disease in terms of direct and indirect costs, and an estimate of the total cost per disorder and country.METHODS: The best available estimates of the prevalence and cost per person for 19 groups of disorders of the brain (covering well over 100 specific disorders) were identified via a systematic review of the published literature. Together with the twelve disorders included in 2004, the following range of mental and neurologic groups of disorders is covered: addictive disorders, affective disorders, anxiety disorders, brain tumor, childhood and adolescent disorders (developmental disorders), dementia, eating disorders, epilepsy, mental retardation, migraine, multiple sclerosis, neuromuscular disorders, Parkinson's disease, personality disorders, psychotic disorders, sleep disorders, somatoform disorders, stroke, and traumatic brain injury. Epidemiologic panels were charged to complete the literature review for each disorder in order to estimate the 12-month prevalence, and health economic panels were charged to estimate best cost-estimates. A cost model was developed to combine the epidemiologic and economic data and estimate the total cost of each disorder in each of 30 European countries (EU27+Iceland, Norway and Switzerland). The cost model was populated with national statistics from Eurostat to adjust all costs to 2010 values, converting all local currencies to Euro, imputing costs for countries where no data were available, and aggregating country estimates to purchasing power parity adjusted estimates for the total cost of disorders of the brain in Europe 2010.RESULTS: The total cost of disorders of the brain was estimated at €798 billion in 2010. Direct costs constitute the majority of costs (37% direct healthcare costs and 23% direct non-medical costs) whereas the remaining 40% were indirect costs associated with patients' production losses. On average, the estimated cost per person with a disorder of the brain in Europe ranged between €285 for headache and €30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was €1550 on average but varied by country. The cost (in billion €PPP 2010) of the disorders of the brain included in this study was as follows: addiction: €65.7; anxiety disorders: €74.4; brain tumor: €5.2; child/adolescent disorders: €21.3; dementia: €105.2; eating disorders: €0.8; epilepsy: €13.8; headache: €43.5; mental retardation: €43.3; mood disorders: €113.4; multiple sclerosis: €14.6; neuromuscular disorders: €7.7; Parkinson's disease: €13.9; personality disorders: €27.3; psychotic disorders: €93.9; sleep disorders: €35.4; somatoform disorder: €21.2; stroke: €64.1; traumatic brain injury: €33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted €477 billion, by and large confirming our previous study results after considering the inflation and population increase since 2004. Further, our results were consistent with administrative data on the health care expenditure in Europe, and comparable to previous studies on the cost of specific disorders in Europe. Our estimates were lower than comparable estimates from the US.DISCUSSION: This study was based on the best currently available data in Europe and our model enabled extrapolation to countries where no data could be found. Still, the scarcity of data is an important source of uncertainty in our estimates and may imply over- or underestimations in some disorders and countries. Even though this review included many disorders, diagnoses, age groups and cost items that were omitted in 2004, there are still remaining disorders that could not be included due to limitations in the available data. We therefore consider our estimate of the total cost of the disorders of the brain in Europe to be conservative. In terms of the health economic burden outlined in this report, disorders of the brain likely constitute the number one economic challenge for European health care, now and in the future. Data presented in this report should be considered by all stakeholder groups, including policy makers, industry and patient advocacy groups, to reconsider the current science, research and public health agenda and define a coordinated plan of action of various levels to address the associated challenges.RECOMMENDATIONS: Political action is required in light of the present high cost of disorders of the brain. Funding of brain research must be increased; care for patients with brain disorders as well as teaching at medical schools and other health related educations must be quantitatively and qualitatively improved, including psychological treatments. The current move of the pharmaceutical industry away from brain related indications must be halted and reversed. Continued research into the cost of the many disorders not included in the present study is warranted. It is essential that not only the EU but also the national governments forcefully support these initiatives.
32.	Halin Bergström, Sofia, et al. (författare) Extratumoral Heme Oxygenase-1 (HO-1) Expressing Macrophages Likely Promote Primary and Metastatic Prostate Tumor Growth. 2016 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:6 Tidskriftsartikel (refereegranskat)abstract Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1). To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RT-PCR showed that the main site of HO-1 synthesis was HO-1+ macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1+ macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1+ macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1+ macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1+ macrophages may have an important role in prostate cancer.
33.	Hamidi, Anahita, et al. (författare) TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α 2017 Ingår i: Science Signaling. - : American Association for the Advancement of Science. - 1945-0877 .- 1937-9145. ; 10:486 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract TGF-β signaling stimulates various intracellular pathways that can promote migration in tumor cells. These pathways are generally thought to be either dependent or independent of transcription factors called SMADs. One of the SMAD-independent pathways (PI3K-AKT) is mediated by a direct interaction between PI3K and the TGF-β type I receptor. However, Hamidi et al. found that the TGF-β–induced activation of PI3K depends on another ubiquitin ligase–mediated mechanism and a SMAD protein but is independent of the kinase function of TβRI. The binding of TGF-β to its receptor triggered the recruitment of PI3K and the ubiquitin ligase TRAF6, which polyubiquitylated the regulatory PI3K subunit p85α, thus enabling phosphorylation of the catalytic PI3K subunit p110, but only in the presence of SMAD7. The abundance of ubiquitylated p85α correlated with migration in cultured cells and prostate tumor grade in patient samples. TRAF6 mediates activation of the other “SMAD-independent” (JNK) pathway. These data suggest that, although distinct, the TGF-β signaling pathways are not as insulated from each other as was once thought.
34.	Hörnberg, Emma, et al. (författare) Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival 2011 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:4, s. e19059- Tidskriftsartikel (refereegranskat)abstract Background: Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival.Methodology/Principal Findings: Hormone-naı¨ve (n = 10) and CRPC bone metastases samples (n = 30) were obtained from 40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl) and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival.Conclusions/Significance: Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.
35.	Iglesias-Gato, Diego, et al. (författare) The proteome of prostate cancer bone metastases 2018 Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 78:16, s. 91-92 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
36.	Iglesias-Gato, Diego, et al. (författare) The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications 2018 Ingår i: Clinical Cancer Research. - : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 24:21, s. 5433-5444 Tidskriftsartikel (refereegranskat)abstract Purpose: Bone is the most predominant site of distant metastasis in prostate cancer, and patients have limited therapeutic options at this stage.Experimental Design: We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relieve spinal cord compression. At the time of surgery, most patients had relapsed after androgen-deprivation therapy, while 5 were previously untreated. An extended cohort of prostate cancer bone metastases (n = 65) was used for immunohistochemical validation.Results: On average, 5,067 proteins were identified and quantified per tumor. Compared with primary tumors (n = 26), bone metastases were more heterogeneous and showed increased levels of proteins involved in cell-cycle progression, DNA damage response, RNA processing, and fatty acid b-oxidation; and reduced levels of proteins were related to cell adhesion and carbohydrate metabolism. Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of AR canonical targets, and mitochondrial and Golgi apparatus resident proteins; and BM2, with increased expression of proliferation and DNA repair-related proteins. The two subgroups, validated by the inverse correlation between MCM3 and prostate specific antigen immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies.Conclusions: This work is the first system-wide quantitative characterization of the proteome of prostate cancer bone metastases and a valuable resource for understanding the etiology of prostate cancer progression. (C) 2018 AACR.
37.	Jalkanen, Ville, et al. (författare) Detektering av förändringar i prostatavävnad mha resonanssensor 2002 Ingår i: Program & sammanfattningar. [59]. - Stockholm : Svenska läkaresällskapet. ; , s. 231- Konferensbidrag (övrigt vetenskapligt/konstnärligt)
38.	Jernberg, Emma, et al. (författare) Characterization of prostate cancer bone metastases according to expression levels of steroidogenic enzymes and androgen receptor splice variants 2013 Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:11, s. e77407- Tidskriftsartikel (refereegranskat)abstract Background: Intra-tumoral steroidogenesis and constitutive androgen receptor (AR) activity have been associated withcastration-resistant prostate cancer (CRPC). This study aimed to examine if CRPC bone metastases expressed higher levels ofsteroid-converting enzymes than untreated bone metastases. Steroidogenic enzyme levels were also analyzed in relation toexpression of constitutively active AR variants (AR-Vs) and to clinical and pathological variables.Methodology/Principal Findings: Untreated, hormone-naıve (HN, n = 9) and CRPC bone metastases samples (n = 45) wereobtained from 54 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13prostatectomy specimens. Transcript and protein levels were analyzed by real-time RT-PCR, immunohistochemistry andimmunoblotting. No differences in steroidogenic enzyme levels were detected between CRPC and HN bone metastases.Significantly higher levels of SRD5A1, AKR1C2, AKR1C3, and HSD17B10 mRNA were however found in bone metastases thanin non-malignant and/or malignant prostate tissue, while the CYP11A1, CYP17A1, HSD3B2, SRD5A2, and HSD17B6 mRNAlevels in metastases were significantly lower. A sub-group of metastases expressed very high levels of AKR1C3, which wasnot due to gene amplification as examined by copy number variation assay. No association was found between AKR1C3expression and nuclear AR staining, tumor cell proliferation or patient outcome after metastases surgery. With only oneexception, high AR-V protein levels were found in bone metastases with low AKR1C3 levels, while metastases with highAKR1C3 levels primarily contained low AR-V levels, indicating distinct mechanisms behind castration-resistance in individualbone metastases.Conclusions/Significance: Induced capacity of converting adrenal-gland derived steroids into more potent androgens wasindicated in a sub-group of PC bone metastases. This was not associated with CRPC but merely with the advanced stage ofmetastasis. Sub-groups of bone metastases could be identified according to their expression levels of AKR1C3 and AR-Vs,which might be of relevance for patient response to 2nd line androgen-deprivation therapy.
39.	Jernberg, Emma, et al. (författare) Molecular features of prostate cancer bone metastases harboring androgen receptor gene amplification Annan publikation (övrigt vetenskapligt/konstnärligt)abstract The relation between AR amplification and other mechanisms behind castration-resistance in prostate cancer, such as increased expression of AR splice variants and steroid-converting enzymes in CRPC metastases, has been poorly examined. Specific aims of this study were therefore to examine AR amplification in hormone-naïve and castration-resistant prostate cancer (CRPC) bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying molecular targets for treatment of CRPC bone metastases. AR amplification was assessed by fluorescence in situ hybridization and verified in 16 (53 %) of the CRPC bone metastases (n=30), and in none of the untreated bone metastases (n=10). AR amplification was associated with increased expression of AR and its constitutively active AR-V7 splice variant as well as with co-amplification of genes in the AR proximity at Xq12, such as of YIPF6. Furthermore, gene expression pattern pointed at decreased osteoclast activity, and consequently decreased bone resorption and increased bone mineral density in AR amplified metastases. In conclusion, our results indicated a sclerotic phenotype in CRPC bone metastases with AR amplification that may be of both biological and clinical relevance. This is a novel hypothesis that requires to be thoroughly examined.
40.	Jonsson, Björn-Anders, et al. (författare) -160C/A polymorphism in the E-cadherin gene promoter and risk of hereditary, familial and sporadic prostate cancer 2004 Ingår i: Int J Cancer. - : Wiley. - 0020-7136. ; 109:3, s. 348-352 Tidskriftsartikel (refereegranskat)
41.	Josefsson, Andreas, 1979- (författare) Prognostic markers in prostate cancer : studies of a watchful waiting cohort with long follow up 2011 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Background: Prostate Cancer (PC) is a common and highly variable disease. Using current diagnostic methods, the prostate specific antigen (PSA) blood test and histological grading of prostate tissue needle biopsies, it is often difficult to evaluate whether the patient has a PC that requires active treatment or not. The absolute majority of all 10,000 cases of PCs diagnosed annually in Sweden have tumours graded as Gleason score (GS) 6-7 and a PSA value in blood below 10. Many of these are harmless and can be left without active treatment and hence spared problematic post-therapy side-effects, others are highly malignant and require early diagnosis and treatment. Better prognostic markers are needed and the aim of this study was to evaluate prognostic markers and to test if these markers could identify patients with indolent tumours. Methods: We have studied tumour material from 419 men consecutively diagnosed with PC at transurethral resection (1975-1990). The majority of these patients (295) had no metastasis at diagnosis and was not given any curative treatment and only hormonal treatment upon symptoms from metastatic progression. Standard histological sections and tissue microarrays (TMA) from these tumours and surrounding normal prostate tissue were stained and evaluated for cell proliferation (Ki67), blood vessels (endoglin and von Willebrand factor, vWf) and the extracellular matrix component hyaluronan (HA). An orthotopic rat PC model was used to explore hyaluronan staining, hyaluronic acid synthase (HAS)-1 mRNA levels and the effect of local HA treatment on tumour growth. Results: Tumour cell proliferation (Ki67) and the density of intra-tumoural endoglin stained blood vessels were independent prognostic markers (i.e. they added prognostic information to the conventional prognostic markers; clinical stage and GS). None of the GS 6 patients with low staining for both Ki67 and endoglin died of PC within 15 years of follow-up. High HA staining in the tumour epithelium and stroma was a negative prognostic marker of cancer specific survival but they were not independent of GS. High HA staining and high vascular density in the stroma of the surrounding morphologically normal prostate were prognostic for short cancer specific survival. Implantation of tumour cells in the normal rat prostate resulted in an increase in HA and HAS-1 mRNA levels in the prostate tissue surrounding prostate tumours. Concurrently intra-prostatic injection of HA also stimulated tumour growth. Conclusions: By evaluating both tumour cell proliferation (Ki67) and vascular density, it is possible to identify patients with very low risk of cancer specific death in the absence of active treatment. Prostate tumours influence the surrounding non-malignant prostate tissue, for example they cause an increased angiogenesis and synthesis of hyaluronan. Such responses can possibly be used to diagnose PC and to evaluate PC aggressiveness.
42.	Järemo, Helena, et al. (författare) Investigating microRNA Profiles in Prostate Cancer Bone Metastases and Functional Effects of microRNA-23c and microRNA-4328 2023 Ingår i: Cancers. - : MDPI. - 2072-6694. ; 15:9 Tidskriftsartikel (refereegranskat)abstract MicroRNAs (miRNAs) are aberrantly expressed in prostate cancer (PC), but comprehensive knowledge about their levels and function in metastatic PC is lacking. Here, we explored the differential expression of miRNA profiles during PC progression to bone metastasis, and further focused on the downregulation of miRNA-23c and -4328 and their impact on PC growth in experimental models. Using microarray screening, the levels of 1510 miRNAs were compared between bone metastases (n = 14), localized PC (n = 7) and benign prostate tissue (n = 7). Differentially expressed miRNAs (n = 4 increased and n = 75 decreased, p < 0.05) were identified, of which miRNA-1, -23c, -143-3p, -143-5p, -145-3p, -205-5p, -221-3p, -222-3p and -4328 showed consistent downregulation during disease progression (benign > localized PC > bone metastases). The downregulation of miRNA-23c and -4328 was confirmed by reverse transcription and quantitative polymerase chain reaction analysis of 67 metastasis, 12 localized PC and 12 benign prostate tissue samples. The stable overexpression of miRNA-23c and -4328 in the 22Rv1 and PC-3 cell lines resulted in reduced PC cell growth in vitro, and in the secretion of high levels of miRNA-23c (but not -4328) in extracellular vesicles. However, no tumor suppressive effects were observed from miRNA-23c overexpression in PC-3 cells subcutaneously grown in mice. In conclusion, bone metastases display a profound reduction of miRNA levels compared to localized PC and benign disease. The downregulation of those miRNAs, including miRNA-23c and -4328, may lead to a loss of tumor suppressive effects and provide biomarker and therapeutic possibilities that deserve to be further explored.
43.	Källberg, Eva, et al. (författare) S100A9 Interaction with TLR4 Promotes Tumor Growth 2012 Ingår i: PLOS ONE. - San Francisco : Public Library of Science. - 1932-6203. ; 7:3, s. e34207- Tidskriftsartikel (refereegranskat)abstract By breeding TRAMP mice with S100A9 knock-out (S100A9(-/-)) animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b(+) S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68(+) macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9(-/-) and TLR4(-/-), but not in RAGE(-/-) animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGF beta expression in splenic CD11b(+) cells. Lastly, treatment of mice with a small molecule (ABR-215050) that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies.
44.	Lidgren, Anders, et al. (författare) Glucose transporter-1 expression in renal cell carcinoma and its correlation with hypoxia inducible factor-1 alpha 2008 Ingår i: BJU International. - : Wiley-Blackwell. - 1464-4096 .- 1464-410X. ; 101:4, s. 480-484 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: To evaluate transcription factor hypoxia inducible factor-1 alpha (HIF-1 alpha) activity, by analysing a target gene for HIF-1 alpha, glucose transporter-1 (GLUT-1), using a tissue microarray (TMA) in different types of renal cell carcinoma (RCC, a tumour with a variable clinical course, partly due to angiogenic activity), as angiogenesis is important for tumour progression and metastatic spread, and is activated by hypoxia.PATIENTS AND METHODS: GLUT-1 and HIF-1 alpha expressions were semiquantitatively analysed using immunohistological staining of a prepared TMA, using samples from 187 patients, including 148 with conventional, 26 with papillary and 13 with chromophobe RCC.RESULTS: GLUT-1 staining was found mainly in the cytoplasm. The tumours were subdivided into GLUT -1(LOW) and GLUT-1(HIGH), based on staining intensity. There was a significant difference in GLUT-1 expression between RCC types (P < 0.05). In conventional RCC, GLUT-1 had no correlation with clinicopathological variables. By contrast there was a correlation with tumour stage in papillary RCC. There was an insignificant trend to better survival of patients with GLUT-1(LOW) expression in both conventional and papillary RCC. GLUT-1 correlated significantly (P = 0.008) with HIF-1 alpha.CONCLUSIONS: Most patients with conventional RCC had GLUT-1(HIGH) staining and there was a significant correlation with HIF-1 alpha. In papillary RCC, GLUT-1 expression was associated with stage; GLUT-1 expression was significantly higher in conventional RCC than in papillary and chromophobe RCC. GLUT-1(LOW) in both papillary and conventional RCC appeared to correspond with a better prognosis.
45.	Lidgren, Anders, 1975-, et al. (författare) Hypoxia-inducible factor-1alfa mRNA and protein levels in renal cell carcinoma 2008 Ingår i: Journal of Cancer Molecules. - : MedUnion Press. - 1816-0735 .- 1817-4256. ; 4:5, s. 153-157 Tidskriftsartikel (refereegranskat)
46.	Lidgren, Anders, et al. (författare) Hypoxia-inducible factor 1alpha expression in renal cell carcinoma analyzed by tissue microarray 2006 Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 50:6, s. 1272-1277 Tidskriftsartikel (refereegranskat)
47.	Lidgren, Anders, 1975- (författare) Hypoxia inducible factor-1α in renal cell carcinoma 2007 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Hypoxia Inducible Factor-1α in Renal Cell Carcinoma Departments of Surgical and Perioperative Sciences, Urology and Andrology; Radiation Sciences, Oncology; Medical Biosciences, Pathology; and Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden Background: Renal cell carcinoma (RCC) accounts for approximately 2-3% of all human cancers. A distinguished feature of RCC is vascularisation and among the three dominating RCC types conventional RCC (cRCC) generally is more vascularised than papillary RCC (pRCC) and chromophobe RCC (chRCC). Angiogenesis is a critical step in tumour progression controlled by a balance involving molecules that have positive and negative regulatory activity. A balance distorted by metabolic stress such as hypoxia, acidosis, and inflammation. Hypoxia-Inducible Factor 1α (HIF-1α) is a key transcription factor in angiogenesis and tumour progression, targeting more than a 100 genes involved in vascular growth and regulation, iron metabolism and erythropoesis, collagen matrix formation, regulation of extracellular pH, glucose uptake and metabolism, proliferation, apoptosis, differentiation, and cell viability. Methods: Tumour tissue and corresponding kidney cortex from nephrectomised RCC patients was used in order to characterize HIF-1α expression and one of its target genes, Glucose Transporter 1 (GLUT-1). All tumour samples were thoroughly described regarding tumour type, TNM stage, nuclear grade, tumour size, vein invasion, and patient survival. Utilizing RT-PCR, Westen Blot and Tissue micro array (TMA) we studied HIF-1α mRNA and protein expression as well as GLUT-1 protein expression, correlating them to each other and clinicopathological parameters. Results: Using Western Blot, HIF-1α protein expression differed significantly between the different RCC types and kidney cortex. In cRCC, high expression of HIF-1α was an independent prognostic factor for favourable prognosis. TMA is a useful method to analyze HIF-1α protein expression in RCC. HIF-1α levels were significantly lower in locally aggressive cRCC and patients with high levels of HIF-1 tended to have a better prognosis. GLUT-1 levels were higher in cRCC than in other RCC types and for cRCC a correlation to HIF-1α was seen. HIF-1α mRNA levels were significantly lower in cRCC compared to other RCC types and kidney cortex. An inverse correlation between HIF-1α protein expression and mRNA levels was observed. Summary: These results demonstrate a discrepancy between RCC types, highlighting the need to separately evaluate biological events in different RCC types. Overexpression of HIF-1α protein is not necessarily all bad and translational regulation appears more critical than anticipated. Further studies are encouraged to clarify angiogenic pathways in RCC.
48.	Lidgren, Anders, et al. (författare) Hypoxia-inducible factor-1α mRNA and protein levels in renal cell carcinoma and in relation to kidney cortex tissue Annan publikation (övrigt vetenskapligt/konstnärligt)
49.	Lindmark, Fredrik, et al. (författare) Analysis of the macrophage scavenger receptor 1 gene in Swedish hereditary and sporadic prostate cancer. 2004 Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 59:2, s. 132-140 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The macrophage scavenger receptor 1 (MSR1) gene on chromosome 8p22 was recently reported as a candidate gene for hereditary prostate cancer (HPC). Here, we further elucidate the role of MSR1 in both Swedish families with HPC and in a cohort of unselected prostate cancer. METHODS: DNA samples from 83 Swedish HPC families and 215 unselected population based cases of prostate cancer as well as 425 age-matched controls were genotyped. RESULTS: A total of 18 variants were identified, including 2 exonic, 7 intronic changes, and 9 changes in the 5'- or 3'-uncoding region. Of the two exonic changes, one previously reported truncation mutation was identified, a R293X nonsense mutation. This mutation was found in 2 of the 83 (2.4%) HPC families. The R293X mutation was found more frequently in men with PC (4.9%) than in unaffected men (2.7%), consistent with previous published results, however our results were not significant (P = 0.16). To additionally test for potential association of common sequence variants and increased risk for the disease, five common polymorphisms (PRO3, INDEL1, IVS5-57, P275A, INDEL7) were genotyped in the group of 215 prostate cancer cases and 425 age-matched controls. No association between any of the five common sequence variants and prostate cancer were found. CONCLUSION: Our results suggest that mutations in MSR1 gene might play a role in prostate cancer susceptibility, particularly the R293X mutation. This study warrants further investigations of the role of MSR1 in prostate cancer etiology.
50.	Nilsson, Erik, et al. (författare) The grade of individual prostate cancer lesions predicted by magnetic resonance imaging and positron emission tomography 2023 Ingår i: Communications Medicine. - : Springer Nature. - 2730-664X. ; 3:1 Tidskriftsartikel (refereegranskat)abstract Background: Multiparametric magnetic resonance imaging (mpMRI) and positron emission tomography (PET) are widely used for the management of prostate cancer (PCa). However, how these modalities complement each other in PCa risk stratification is still largely unknown. We aim to provide insights into the potential of mpMRI and PET for PCa risk stratification.Methods: We analyzed data from 55 consecutive patients with elevated prostate-specific antigen and biopsy-proven PCa enrolled in a prospective study between December 2016 and December 2019. [68Ga]PSMA-11 PET (PSMA-PET), [11C]Acetate PET (Acetate-PET) and mpMRI were co-registered with whole-mount histopathology. Lower- and higher-grade lesions were defined by International Society of Urological Pathology (ISUP) grade groups (IGG). We used PET and mpMRI data to differentiate between grades in two cases: IGG 3 vs. IGG 2 (case 1) and IGG ≥ 3 vs. IGG ≤ 2 (case 2). The performance was evaluated by receiver operating characteristic (ROC) analysis.Results: We find that the maximum standardized uptake value (SUVmax) for PSMA-PET achieves the highest area under the ROC curve (AUC), with AUCs of 0.72 (case 1) and 0.79 (case 2). Combining the volume transfer constant, apparent diffusion coefficient and T2-weighted images (each normalized to non-malignant prostatic tissue) results in AUCs of 0.70 (case 1) and 0.70 (case 2). Adding PSMA-SUVmax increases the AUCs by 0.09 (p < 0.01) and 0.12 (p < 0.01), respectively.Conclusions: By co-registering whole-mount histopathology and in-vivo imaging we show that mpMRI and PET can distinguish between lower- and higher-grade prostate cancer, using partially discriminative cut-off values.

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