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1.	Bancroft, EK, et al. (author) Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study 2014 In: European urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 66:3, s. 489-499 Journal article (peer-reviewed)
2.	Cremers, Ruben G., et al. (author) The role of the prostate cancer gene 3 urine test in addition to serum prostate-specific antigen level in prostate cancer screening among breast cancer, early-onset gene mutation carriers 2015 In: Urologic Oncology: Seminars and Original Investigations. - : Elsevier BV. - 1078-1439. ; 33:5, s. 19-202 Journal article (peer-reviewed)abstract Objective: To evaluate the additive value of the prostate cancer gene 3 (PCA3) urine test to serum prostate-specific antigen (PSA) in prostate cancer (PC) screening among breast cancer, early-onset gene (BRCA) mutation carriers. This study was performed among the Dutch participants of IMPACT, a large international study on the effectiveness of PSA screening among BRCA mutation carriers. Materials and methods: Urinary PCA3 was measured in 191 BRCA1 mutation carriers, 75 BRCA2 mutation carriers, and 308 noncarriers. The physicians and participants were blinded for the results. Serum PSA level≥3.0. ng/ml was used to indicate prostate biopsies. PCA3 was evaluated (1) as an independent indicator for prostate biopsies and (2) as an indicator for prostate biopsies among men with an elevated PSA level. PC detected up to the 2-year screening was used as gold standard as end-of-study biopsies were not performed. Results: Overall, 23 PCs were diagnosed, 20 of which were in men who had an elevated PSA level in the initial screening round. (1) PCA3, successfully determined in 552 participants, was elevated in 188 (cutoff≥25; 34%) or 134 (cutoff≥35; 24%) participants, including 2 of the 3 PCs missed by PSA. PCA3 would have added 157 (≥25; 28%) or 109 (≥35; 20%) biopsy sessions to screening with PSA only. (2) Elevated PCA3 as a requirement for biopsies in addition to PSA would have saved 37 (cutoff≥25) or 43 (cutoff≥35) of the 68 biopsy sessions, and 7 or 11 PCs would have been missed, respectively, including multiple high-risk PCs. So far, PCA3 performed best among BRCA2 mutation carriers, but the numbers are still small. Because PCA3 was not used to indicate prostate biopsies, its true diagnostic value cannot be calculated. Conclusions: The results do not provide evidence for PCA3 as a useful additional indicator of prostate biopsies in BRCA mutation carriers, as many participants had an elevated PCA3 in the absence of PC. This must be interpreted with caution because PCA3 was not used to indicate biopsies. Many participants diagnosed with PC had low PCA3, making it invalid as a restrictive marker for prostate biopsies in men with elevated PSA levels.
3.	Dankiewicz, Josef, et al. (author) Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest 2021 In: New England Journal of Medicine. - : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 384:24, s. 2283-2294 Journal article (peer-reviewed)abstract Hypothermia or Normothermia after Cardiac Arrest This trial randomly assigned patients with coma after out-of-hospital cardiac arrest to undergo targeted hypothermia at 33 degrees C or normothermia with treatment of fever. At 6 months, there were no significant between-group differences regarding death or functional outcomes. Background Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. Methods In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33 degrees C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, >= 37.8 degrees C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. Results A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P=0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score >= 4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. Conclusions In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, .)
4.	Assel, Melissa J., et al. (author) Kallikrein markers performance in pretreatment blood to predict early prostate cancer recurrence and metastasis after radical prostatectomy among very high-risk men 2019 In: Prostate. - : Wiley. - 0270-4137. Journal article (peer-reviewed)abstract Background: To assess whether a prespecified statistical model based on the four kallikrein markers measured in blood—total, free, and intact prostate-specific antigen (PSA), together with human kallikrein-related peptidase 2 (hK2)—or any individual marker measured in pretreatment serum were associated with biochemical recurrence-free (BCR) or metastasis-free survival after radical prostatectomy (RP) in a subgroup of men with very high-risk disease. Methods: We identified 106 men treated at Mayo Clinic from 2004 to 2008 with pathological Gleason grade group 4 to 5 or seminal vesicle invasion at RP. Univariable and multivariable Cox models were used to test the association between standard predictors (Kattan nomogram and GPSM [Gleason, PSA, seminal vesicle and margin status] score), kallikrein panel, and individual kallikrein markers with the outcomes. Results: BCR and metastasis occurred in 67 and 30 patients, respectively. The median follow-up for patients who did not develop a BCR was 10.3 years (interquartile range = 8.2-11.8). In this high-risk group, neither Kattan risk, GPSM score, or the kallikrein panel model was associated with either outcome. However, after adjusting for Kattan risk and GPSM score, separately, preoperative intact PSA was associated with both outcomes while hK2 was associated with metastasis-free survival. Conclusions: Conventional risk prediction tools were poor discriminators for risk of adverse outcomes after RP (Kattan risk and GPSM risk) in patients with very high-risk disease. Further studies are needed to define the role of individual kallikrein marker forms in the blood to predict adverse prostate cancer outcomes after RP in this high-risk setting.
5.	Cuzick, Jack, et al. (author) Prevention and early detection of prostate cancer. 2014 In: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 15:11, s. e484-92 Journal article (peer-reviewed)abstract Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-specific antigen (PSA) screening is controversial, but changes in the PSA threshold, frequency of screening, and the use of other biomarkers have the potential to minimise the overdiagnosis associated with PSA screening. Several new biomarkers for individuals with raised PSA concentrations or those diagnosed with prostate cancer are likely to identify individuals who can be spared aggressive treatment. Several pharmacological agents such as 5α-reductase inhibitors and aspirin could prevent development of prostate cancer. In this Review, we discuss the present evidence and research questions regarding prevention, early detection of prostate cancer, and management of men either at high risk of prostate cancer or diagnosed with low-grade prostate cancer.
6.	Dankiewicz, Josef, et al. (author) Targeted hypothermia versus targeted Normothermia after out-of-hospital cardiac arrest (TTM2): A randomized clinical trial - Rationale and design 2019 In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 217, s. 23-31 Journal article (peer-reviewed)abstract Background: Less than 500 participants have been included in randomized trials comparing hypothermia with regular care for out-of-hospital cardiac arrest patients, and many of these trials were small and at a high risk of bias. Consequently, the accrued data on this potentially beneficial intervention resembles that of a drug following small phase II trials. A large confirmatory trial is therefore warranted. Methods: The TTM2-trial is an international, multicenter, parallel group, investigator-initiated, randomized, superiority trial in which a target temperature of 33°C after cardiac arrest will be compared with a strategy to maintain normothermia and early treatment of fever (≥37.8°C). Participants will be randomized within 3 hours of return of spontaneous circulation with the intervention period lasting 40 hours in both groups. Sedation will be mandatory for all patients throughout the intervention period. The clinical team involved with direct patient care will not be blinded to allocation group due to the inherent difficulty in blinding the intervention. Prognosticators, outcome-assessors, the steering group, the trial coordinating team, and trial statistician will be blinded. The primary outcome will be all-cause mortality at 180 days after randomization. We estimate a 55% mortality in the control group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The main secondary neurological outcome will be poor functional outcome (modified Rankin Scale 4–6) at 180 days after arrest. Discussion: The TTM2-trial will compare hypothermia to 33°C with normothermia and early treatment of fever (≥37.8°C) after out-of-hospital cardiac arrest. © 2019
7.	Holgersson, Johan, et al. (author) Hypothermic versus Normothermic Temperature Control after Cardiac Arrest 2022 In: NEJM Evidence. - 2766-5526. ; 1:11, s. 1-13 Journal article (peer-reviewed)abstract BACKGROUNDThe evidence for temperature control for comatose survivors of cardiac arrest is inconclusive. Controversy exists as to whether the effects of hypothermia differ per the circumstances of the cardiac arrest or patient characteristics.METHODSAn individual patient data meta-analysis of the Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest (TTM) and Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trials was conducted. The intervention was hypothermia at 33°C and the comparator was normothermia. The primary outcome was all-cause mortality at 6 months. Secondary outcomes included poor functional outcome (modified Rankin scale score of 4 to 6) at 6 months. Predefined subgroups based on the design variables in the original trials were tested for interaction with the intervention as follows: age (older or younger than the median), sex (female or male), initial cardiac rhythm (shockable or nonshockable), time to return of spontaneous circulation (above or below the median), and circulatory shock on admission (presence or absence).RESULTSThe primary analyses included 2800 patients, with 1403 assigned to hypothermia and 1397 to normothermia. Death occurred for 691 of 1398 participants (49.4%) in the hypothermia group and 666 of 1391 participants (47.9%) in the normothermia group (relative risk with hypothermia, 1.03; 95% confidence interval [CI], 0.96 to 1.11; P=0.41). A poor functional outcome occurred for 733 of 1350 participants (54.3%) in the hypothermia group and 718 of 1330 participants (54.0%) in the normothermia group (relative risk with hypothermia, 1.01; 95% CI, 0.94 to 1.08; P=0.88). Outcomes were consistent in the predefined subgroups.CONCLUSIONSHypothermia at 33°C did not decrease 6-month mortality compared with normothermia after out-of-hospital cardiac arrest. (Funded by Vetenskapsrådet; ClinicalTrials.gov numbers NCT02908308 and NCT01020916.)
8.	Hugosson, J, et al. (author) Population-based screening for prostate cancer by measuring free and total serum prostate-specific antigen in Sweden 2003 In: BJU International. - : Wiley. - 1464-4096 .- 1464-410X. ; 92, s. 39-43 Journal article (peer-reviewed)abstract Objectives To report the initial results from Sweden of a large population-based randomized study of screening using prostate-specific antigen (PSA) to detect prostate cancer, as the efficacy of such screening to decrease prostate cancer mortality has not yet been proven. Methods From the population registry men aged 50-66 years were randomized to screening (9973) and to future controls (9973). Men randomized to screening were invited to have their serum measured for free PSA (fPSA) and total PSA (tPSA) in serum using the Prostatus(R) f/tPSA assay (Perkin-Elmer, Turku, Finland). Men with a tPSA of <3.0 ng/mL were not further investigated, while those with a tPSA of &GE;3.0 ng/mL were investigated with a digital rectal examination (DRE), transrectal ultrasonography (TRUS) and sextant biopsies. Results Of those invited, 60% accepted PSA testing and 11.3% had a tPSA of &GE;3.0 ng/mL. Altogether 145 cancers were detected (positive predictive value, PPV, 24%); none were stage M1, two were stage N+ and 10 stage T3-4. Most (59%) cancers were impalpable and 39% were both impalpable and invisible on TRUS. At biopsy, 7% were Gleason score 2-4, 71% 5-6, 19% 7 and 2% Gleason score 8-10. A threshold tPSA of &GE;4.0 ng/mL would have detected 109 cancers in 366 biopsied men (PPV 30%) while cancer detection would have been 14% higher with a PPV of 36% using a threshold tPSA of &GE;3.0 ng/mL combined with a f/tPSA threshold of &LE;18%. Conclusion PSA screening detects early-stage low-grade prostate cancer. Both the sensitivity and specificity can be increased by incorporating f/tPSA with a tPSA threshold of <4 ng/mL.
9.	Hugosson, J, et al. (author) Would prostate cancer detected by screening with prostate-specific antigen develop into clinical cancer if left undiagnosed? A comparison of two population-based studies in Sweden 2000 In: BJU International. - : Wiley. - 1464-4096. ; 85:9, s. 1078-1084 Journal article (peer-reviewed)abstract OBJECTIVE: To assess the risk of over-diagnosing and over-treating prostate cancer if population-based screening with serum prostate-specific antigen (PSA) is instituted. PATIENTS AND METHODS: From a serum bank stored in 1980, PSA was analysed in 658 men with no previously known prostate cancer from a well-defined cohort from Goteborg, Sweden (men born in 1913); the incidence of clinical prostate cancer was registered until 1995. From the same area, and with the same selection criteria, another cohort of 710 men born in 1930-31, who in 1995 accepted an invitation for PSA screening, was also analysed. RESULTS: Of men born in 1913, 18 (2.7%) had died from prostate cancer and the cumulative probability of being diagnosed with clinical prostate cancer was 11.1% (5.0% in those with a PSA level of < 3 ng/mL vs 32.9% in those with a PSA level of > 3 ng/mL, P < 0.01). The mean lead-time from increased PSA (> 3 ng/mL) to clinical diagnosis was 7 years. The prostate cancer detection rate in men born in 1930-31 was 4.4% (22% among those with increased PSA levels) and 30 of 31 detected cancers were clinically localized. CONCLUSIONS: Screening and sextant biopsies resulted in a lower detection rate (22%) than the cumulative risk of having clinical prostate cancer (33%) in men with increased PSA levels, indicating that under-diagnosis rather than over-diagnosis is the case at least with 'one-time' screening. Even if the stage distribution in screening-detected cancers seems promising (and thus may result in reduced mortality) it is notable that screening 67-year-old men will result in treatment a mean of 7 years before clinical symptoms occur and only one in four men anticipated to develop prostate cancer will die from the disease within 15 years. Large randomized screening trials seem mandatory to further explore the benefits and hazards of PSA screening.
10.	Jakobsen, Janus Christian, et al. (author) Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest: a statistical analysis plan. 2020 In: Trials. - : Springer Science and Business Media LLC. - 1745-6215. ; 21:1 Journal article (peer-reviewed)abstract To date, targeted temperature management (TTM) is the only neuroprotective intervention after resuscitation from cardiac arrest that is recommended by guidelines. The evidence on the effects of TTM is unclear.The Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest (TTM2) trial is an international, multicentre, parallel group, investigator-initiated, randomised, superiority trial in which TTM with a target temperature of 33°C after cardiac arrest will be compared with a strategy to maintain normothermia and active treatment of fever (≥37.8°C). Prognosticators, outcome assessors, the steering group, the trial coordinating team, and trial statisticians will be blinded to treatment allocation. The primary outcome will be all-cause mortality at 180days after randomisation. We estimate a 55% mortality in the targeted normothermia group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The secondary neurological outcome will be poor functional outcome (modified Rankin scale 4-6) at 180days after cardiac arrest. In this paper, a detailed statistical analysis plan is presented, including a comprehensive description of the statistical analyses, handling of missing data, and assessments of underlying statistical assumptions. Final analyses will be conducted independently by two qualified statisticians following the present plan.This SAP, which was prepared before completion of enrolment, should increase the validity of the TTM trial by mitigation of analysis-bias.
11.	Kallio, Heini M.L., et al. (author) Constitutively active androgen receptor splice variants AR-V3, AR-V7 and AR-V9 are co-expressed in castration-resistant prostate cancer metastases 2018 In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 119:3, s. 347-356 Journal article (peer-reviewed)abstract Background: A significant subset of prostate cancer (PC) patients with a castration-resistant form of the disease (CRPC) show primary resistance to androgen receptor (AR)-targeting drugs developed against CRPC. As one explanation could be the expression of constitutively active androgen receptor splice variants (AR-Vs), our current objectives were to study AR-Vs and other AR aberrations to better understand the emergence of CRPC. Methods: We analysed specimens from different stages of prostate cancer by next-generation sequencing and immunohistochemistry. Results: AR mutations and copy number variations were detected only in CRPC specimens. Genomic structural rearrangements of AR were observed in 5/30 metastatic CRPC patients, but they were not associated with expression of previously known AR-Vs. The predominant AR-Vs detected were AR-V3, AR-V7 and AR-V9, with the expression levels being significantly higher in CRPC cases compared to prostatectomy samples. Out of 25 CRPC metastases that expressed any AR variant, 17 cases harboured expression of all three of these AR-Vs. AR-V7 protein expression was highly heterogeneous and higher in CRPC compared to hormone-naïve tumours. Conclusions: AR-V3, AR-V7 and AR-V9 are co-expressed in CRPC metastases highlighting the fact that inhibiting AR function via regions common to all AR-Vs is likely to provide additional benefit to patients with CRPC.
12.	Lilja, Gisela, et al. (author) Protocol for outcome reporting and follow-up in the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest trial (TTM2) 2020 In: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 150, s. 104-112 Journal article (peer-reviewed)abstract Aims: The TTM2-trial is a multi-centre randomised clinical trial where targeted temperature management (TTM) at 33 °C will be compared with normothermia and early treatment of fever (≥37.8 °C) after Out-of-Hospital Cardiac Arrest (OHCA). This paper presents the design and rationale of the TTM2-trial follow-up, where information on secondary and exploratory outcomes will be collected. We also present the explorative outcome analyses which will focus on neurocognitive function and societal participation in OHCA-survivors. Methods: Blinded outcome-assessors will perform follow-up at 30-days after the OHCA with a telephone interview, including the modified Rankin Scale (mRS) and the Glasgow Outcome Scale Extended (GOSE). Face-to-face meetings will be performed at 6 and 24-months, and include reports on outcome from several sources of information: clinician-reported: mRS, GOSE; patient-reported: EuroQol-5 Dimensions-5 Level responses version (EQ-5D-5L), Life satisfaction, Two Simple Questions; observer-reported: Informant Questionnaire on Cognitive Decline in the Elderly-Cardiac Arrest version (IQCODE-CA) and neurocognitive performance measures: Montreal Cognitive Assessment, (MoCA), Symbol Digit Modalities Test (SDMT). Exploratory analyses will be performed with an emphasis on brain injury in the survivors, where the two intervention groups will be compared for potential differences in neuro-cognitive function (MoCA, SDMT) and societal participation (GOSE). Strategies to increase inter-rater reliability and decrease missing data are described. Discussion: The TTM2-trial follow-up is a pragmatic yet detailed pre-planned and standardised assessment of patient's outcome designed to ensure data-quality, decrease missing data and provide optimal conditions to investigate clinically relevant effects of TTM, including OHCA-survivors’ neurocognitive function and societal participation.
13.	Robba, C., et al. (author) Ventilation management and outcomes in out-of-hospital cardiac arrest: a protocol for a preplanned secondary analysis of the TTM2 trial 2022 In: BMJ Open. - : BMJ. - 2044-6055. ; 12:3 Journal article (peer-reviewed)abstract Introduction Mechanical ventilation is a fundamental component in the management of patients post cardiac arrest. However, the ventilator settings and the gas-exchange targets used after cardiac arrest may not be optimal to minimise post-anoxic secondary brain injury. Therefore, questions remain regarding the best ventilator management in such patients. Methods and analysis This is a preplanned analysis of the international randomised controlled trial, targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (OHCA)-target temperature management 2 (TTM2). The primary objective is to describe ventilatory settings and gas exchange in patients who required invasive mechanical ventilation and included in the TTM2 trial. Secondary objectives include evaluating the association of ventilator settings and gas-exchange values with 6 months mortality and neurological outcome. Adult patients after an OHCA who were included in the TTM2 trial and who received invasive mechanical ventilation will be eligible for this analysis. Data collected in the TTM2 trial that will be analysed include patients' prehospital characteristics, clinical examination, ventilator settings and arterial blood gases recorded at hospital and intensive care unit (ICU) admission and daily during ICU stay. Ethics and dissemination The TTM2 study has been approved by the regional ethics committee at Lund University and by all relevant ethics boards in participating countries. No further ethical committee approval is required for this secondary analysis. Data will be disseminated to the scientific community by abstracts and by original articles submitted to peer-reviewed journals.
14.	Stenman, U H, et al. (author) Summary report of the TD-3 workshop: characterization of 83 antibodies against prostate-specific antigen 1999 In: Tumor Biology. - : Springer Science and Business Media LLC. - 1423-0380 .- 1010-4283. ; 20:Suppl. 1, s. 1-12 Journal article (peer-reviewed)abstract Twelve research groups participated in the ISOBM TD-3 Workshop in which the reactivity and specificity of 83 antibodies against prostate-specific antigen (PSA) were investigated. Using a variety of techniques including cross-inhibition assays, Western blotting, BIAcore, immunoradiometric assays and immunohistochemistry, the antibodies were categorized into six major groups which formed the basis for mapping onto two- and three-dimensional (2-D and 3-D) models of PSA. The overall findings of the TD-3 Workshop are summarized in this report. In agreement with all participating groups, three main antigenic domains were identified: free PSA-specific epitopes located in or close to amino acids 86-91; discontinuous epitopes specific for PSA without human kallikrein (hK2) cross-reactivity located at or close to amino acids 158-163; and continuous or linear epitopes shared between PSA and hK2 located close to amino acids 3-11. In addition, several minor and partly overlapping domains were also identified. Clearly, the characterization of antibodies from this workshop and the location of their epitopes on the 3-D model of PSA illustrate the importance of selecting appropriate antibody pairs for use in immunoassays. It is hoped that these findings and the epitope nomenclature described in this TD-3 Workshop are used as a standard for future evaluation of anti-PSA antibodies.
15.	Wu, X. N., et al. (author) Increased EZH2 expression in prostate cancer is associated with metastatic recurrence following external beam radiotherapy 2019 In: Prostate. - : Wiley. - 0270-4137. ; 79:10, s. 1079-1089 Journal article (peer-reviewed)abstract Background Enhancer of zeste 2 (EZH2) promotes prostate cancer progression. We hypothesized that increased EZH2 expression is associated with postradiotherapy metastatic disease recurrence, and may promote radioresistance. Methods EZH2 expression was investigated using immunohistochemistry in diagnostic prostate biopsies of 113 prostate cancer patients treated with radiotherapy with curative intent. Associations between EZH2 expression in malignant and benign tissue in prostate biopsy cores and outcomes were investigated using univariate and multivariate Cox regression analyses. LNCaP and PC3 cell radiosensitivity was investigated using colony formation and gamma H2AX assays following UNC1999 chemical probe-mediated EZH2 inhibition. Results While there was no significant association between EZH2 expression and biochemical recurrence following radiotherapy, univariate analysis revealed that prostate cancer cytoplasmic and total EZH2 expression were significantly associated with metastasis development postradiotherapy (P = 0.034 and P = 0.003, respectively). On multivariate analysis, the prostate cancer total EZH2 expression score remained statistically significant (P = 0.003), while cytoplasmic EZH2 expression did not reach statistical significance (P = 0.053). No association was observed between normal adjacent prostate EZH2 expression and biochemical recurrence or metastasis. LNCaP and PC3 cell treatment with UNC1999 reduced histone H3 lysine 27 tri-methylation levels. Irradiation of LNCaP or PC3 cells with a single 2 Gy fraction with UNC1999-mediated EZH2 inhibition resulted in a statistically significant, though modest, reduction in cell colony number for both cell lines. Increased gamma H2AX foci were observed 24 hours after ionizing irradiation in LNCaP cells, but not in PC3, following UNC1999-mediated EZH2 inhibition vs controls. Conclusions Taken together, these results reveal that high pretreatment EZH2 expression in prostate cancer in diagnostic biopsies is associated with an increased risk of postradiotherapy metastatic disease recurrence, but EZH2 function may only at most play a modest role in promoting prostate cancer cell radioresistance.
16.	Aus, G, et al. (author) Cumulative prostate cancer risk assessment with the aid of the free-to-total prostate specific antigen ratio 2004 In: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 45:2, s. 160-165 Journal article (peer-reviewed)abstract Objective: To evaluate the cumulative risk of having a prostate cancer diagnosis in a repeated screening situation in relation to the free-to-total prostate specific antigen ratio (F/T-PSA). Patients and Methods: The present study includes 1385 men (aged 50-70 years) who underwent prostate biopsy for the first time in the screening program that started in 1995. In case of a benign finding, the men have been followed biennially and new biopsies performed in case of persistently elevated PSA. The cumulative risk to be diagnosed with prostate cancer until July 1, 2002 was calculated by the Kaplan-Meier method and comparison was made between different levels of T-PSA and F/T-PSA ratios. Results: Of 2129 biopsies 469 showed cancer. The cumulative 5-year risk to be diagnosed with prostate cancer was significantly dependent of the F/T-ratio. The risk for men with a T-PSA of 3-5.99 ng/ml was 16% [6-25%] for those who had a ratio of >30% and 44% [34-60%] for those with a ratio of <10%. The corresponding difference for patients with a T-PSA of 6-9.99 ng/ml was even more pronounced: 21% [0-42%] vs. 80% [64-96%]. Conclusion: By completing the T-PSA measurement with the F/T-PSA ratio it is possible to significantly better assess the cumulative prostate cancer risk within the next five years (without the aid of further urological work-up).
17.	Aus, G, et al. (author) Free-to-total prostate-specific antigen ratio as a predictor of non-organ-confined prostate cancer (stage pT3) 2003 In: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 37:6, s. 466-470 Journal article (peer-reviewed)abstract Objective: To evaluate whether the free-to-total prostate-specific antigen (F/T-PSA) ratio can be used to differentiate between stage pT2 and pT3 prostate cancer. Material and Methods: A total of 176 consecutive patients from the Goteborg Screening Study (median T-PSA 4.2 ng/ml) who underwent radical prostatectomy (without neoadjuvant hormonal therapy) were included in the study. The pT stage was correlated with classical risk factors such as T-PSA and Gleason sum and the impact of the F/T-PSA ratio was evaluated. Results: A total of 42/176 patients (23.9%) had stage pT3 prostate cancer. Patients with an F/T-PSA ratio in the lowest quartile (<10.7%) had extracapsular tumor growth in 46.5% of cases, compared to 16.7% for those with an F/T-PSA ratio >10.7% ( p = 0.0002). Patients with high-risk features (T-PSA >10 ng/ml or Gleason sum greater than or equal to7) had a high risk (54-60%) for stage pT3 prostate cancer. In low-risk patients, the subgroup with an F/T-PSA ratio <10.7% had a risk of 37.0%, compared to only 13.3% for those with a ratio of >10.7% (p = 0.0092). Conclusions: In patients with low-risk early-stage prostate cancer, the F/T-PSA ratio provides statistically significant, independent and clinically relevant preoperative information about the risk of extracapsular tumor growth.
18.	Aus, G, et al. (author) Individualized screening interval for prostate cancer based on prostate-specific antigen level - Results of a prospective, randomized, population-based study 2005 In: Archives of Internal Medicine. - 0003-9926. ; 165:16, s. 1857-1861 Journal article (peer-reviewed)abstract Background: The aim of the present study was to evaluate the future cumulative risk of prostate cancer in relation to levels of prostate-specific antigen (PSA) in blood and to determine whether this information could be used to individualize the PSA testing interval. Methods: The study included 5855 of 9972 men (aged 50-66 years) who accepted an invitation to participate in a prospective, randomized study of early detection for prostate cancer. We used a protocol based on biennial PSA measurements starting from 1995 and 1996. Men with serum PSA levels of 3.0 ng/mL or more were offered prostate biopsies. Results: Among the 5855 men, 539 cases of prostate cancer (9.2%) were detected after a median follow-up of 7.6 years (up to July 1, 2003). Cancer detection rates during the follow-up period in relation to PSA levels were as follows: 0 to 0.49 ng/mL, 0% (0/958); 0.50 to 0.99 ng/ mL, 0.9% (17/1992); 1.00 to 1.49 ng/mL, 4.7% (54/ 1138); 1.50 to 1.99 ng/mL, 12.3% (70/571); 2.00 to 2.49 ng/mL, 21.4% (67/313); 2.50 to 2.99 ng/mL, 25.2% (56/222); 3.00 to 3.99 ng/mL, 33.3% (89/267); 4.00 to 6.99 ng/mL, 38.9% (103/265); 7.00 to 9.99 ng/mL, 50.0% (30/60); and for men with an initial PSA of 10.00 ng/mL or higher, 76.8% (53/69). Not a single case of prostate cancer was detected within 3 years in 2950 men (50.4% of the screened population) with an initial PSA level less than 1 ng/mL. Conclusions: Retesting intervals should be individualized on the basis of the PSA level, and the large group of men with PSA levels of less than 1 ng/mL can safely be scheduled for a 3-year testing interval.
19.	Bancroft, EK, et al. (author) A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study 2021 In: The Lancet. Oncology. - 1474-5488. ; 22:11, s. 1618-1631 Journal article (peer-reviewed)
20.	Bicak, Mesude, et al. (author) Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy 2020 In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 117:26, s. 15172-15181 Journal article (peer-reviewed)abstract Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate-specific enzyme human kallikrein-related peptidase 2 (hK2; KLK2). In multiple rodent models, Actinium-225-labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [225Ac]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG3, the IgG subclass with superior activation of complement and ability to mediate FC-γ-receptor binding, for immunotherapeutically enhanced hK2 targeted α-radioimmunotherapy. Second, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted α-therapy. [225Ac]hu11B6-IgG3 was a functionally enhanced alternative to [225Ac]hu11B6-IgG1 but offered no improvement of therapeutic efficacy. Progression-free survival was slightly increased with a single high activity compared to fractionated activity. Tumor-free animals succumbing after treatment revealed no evidence of treatment-associated toxicity. In addition to up-regulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS, and SCHLAP1, we also noted a significant decrease in both KLK3 (prostate-specific antigen ) and FOLH1 (prostate-specific membrane antigen) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.
21.	Bjartell, Anders, et al. (author) Studies on phenotypic expression patterns of proteases and protease inhibitors in benign compared to malignant prostate tissues 2000 In: Prostate Cancer and Prostatic Diseases. - : Springer Science and Business Media LLC. - 1476-5608 .- 1365-7852. ; 3:Suppl 1, s. 7-7 Journal article (peer-reviewed)
22.	Carlsson, Sigrid, 1982, et al. (author) Young Age on Starting Prostate-specific Antigen Testing Is Associated with a Greater Reduction in Prostate Cancer Mortality: 24-Year Follow-up of the Goteborg Randomized Population-based Prostate Cancer Screening Trial 2023 In: European Urology. - : Elsevier BV. - 0302-2838. ; 83:2, s. 103-109 Journal article (peer-reviewed)abstract Background: The risk of death from prostate cancer (PC) depends on age, but the age at which to start prostate-specific antigen (PSA) screening remains uncertain. Objective: To study the relationship between risk reduction for PC mortality and age at first PSA screening. Design, setting, and participants: The randomized Goteborg-1 trial invited men for bien-nial PSA screening between the ages of 50 and 70 yr (screening, n = 10 000) or no invi-tation but exposure to opportunistic PSA testing (control, n = 10 000). Intervention: Regular versus opportunistic PSA screening or no PSA. Outcome measurements and statistical analysis: We modeled the nonlinear association between starting age and the absolute risk reduction in PC mortality in three settings: (1) intention-to-screen (randomized arms); (2) historical control (screening group and 1990-1994 registry data); and (3) attendees only (screening attendees and matched controls). We tested whether the effect of screening on PC mortality depends on the age at starting screening by comparing survival models with and without an interaction between trial arm and age (intention-to-screen and attendees only). Results and limitations: Younger age on starting PSA testing was associated with a greater reduction in PC mortality. Starting screening at age 55 yr approximately halved the risk of PC death compared to first PSA at age 60 yr. The test of association between starting age and the effect of screening on PC mortality was slightly greater than the con-ventional level of statistical significance (p = 0.052) for the entire cohort, and statistically significant among attendees (p = 0.002). This study is limited by the low number of disease-specific deaths for men starting screening before age 55 yr and the difficulty in discriminating between the effect of starting age and screening duration. Conclusions: Given that prior screening trials included men aged up to 70 yr on starting screening, our results suggest that the effect size reported in prior trials underestimates that of currently recommended programs starting at age 50-55 yr. Patient summary: In this study from the Goteborg-1 trial, we looked at the effect of prostate-specific antigen (PSA) screening in reducing men's risk of dying from prostate cancer given the age at which they begin testing. Starting at a younger age reduced the risk of prostate cancer death by a greater amount. We recommend that PSA screen-ing should start no later than at age 55 yr. (c) 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.
23.	Danila, DC, et al. (author) Circulating Tumor Cell Number and Prognosis in Progressive Castration-Resistant Prostate Cancer 2007 In: Clinical Cancer Research. - 1078-0432. ; 13:23, s. 7053-7058 Journal article (peer-reviewed)abstract PURPOSE: The development of tumor-specific markers to select targeted therapies and to assess clinical outcome remains a significant area of unmet need. We evaluated the association of baseline circulating tumor cell (CTC) number with clinical characteristics and survival in patients with castrate metastatic disease considered for different hormonal and cytotoxic therapies. EXPERIMENTAL DESIGN: CTC were isolated by immunomagnetic capture from 7.5-mL samples of blood from 120 patients with progressive clinical castrate metastatic disease. We estimated the probability of survival over time by the Kaplan-Meier method. The concordance probability estimate was used to gauge the discriminatory strength of the informative prognostic factors. RESULTS: Sixty-nine (57%) patients had five or more CTC whereas 30 (25%) had two cells or less. Higher CTC numbers were observed in patients with bone metastases relative to those with soft tissue disease and in patients who had received prior cytotoxic chemotherapy relative to those who had not. CTC counts were modestly correlated to measurements of tumor burden such as prostate-specific antigen and bone scan index, reflecting the percentage of boney skeleton involved with tumor. Baseline CTC number was strongly associated with survival, without a threshold effect, which increased further when baseline prostate-specific antigen and albumin were included. CONCLUSIONS: Baseline CTC was predictive of survival, with no threshold effect. The shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease, and provides unique information relative to prognosis.
24.	Darst, Burcu F., et al. (author) The Four-Kallikrein Panel Is Effective in Identifying Aggressive Prostate Cancer in a Multiethnic Population 2020 In: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 29:7, s. 1381-1388 Journal article (peer-reviewed)abstract BACKGROUND: The four-kallikrein (4K) panel has been demonstrated to improve prediction of aggressive prostate cancer compared with prostate-specific antigen (PSA) among men with moderately elevated PSA levels. However, the development and testing of the 4K panel has been conducted primarily in White men, with limited data in African Americans and no studies in other racial and ethnic groups. METHODS: We evaluated the 4K panel in a nested case-control study among African American, Latino, Japanese, Native Hawaiian, and White men in the Multiethnic Cohort. Prediagnostic blood levels of free, intact, and total PSA and human kallikrein-related peptidase 2 were measured among 1,667 incident prostate cancer cases and 691 controls with PSA ≥2 ng/mL. We evaluated the discriminative ability of the 4K panel within and across all racial/ethnic groups. RESULTS: The 4K panel enhanced discrimination of overall prostate cancer compared with free plus total PSA and total PSA alone (AUC 0.748 vs. 0.711 and 0.669, respectively). Discrimination was further enhanced for Gleason 8+ prostate cancer, aggressive prostate cancer, and death due to prostate cancer, and to a lesser degree for nonaggressive prostate cancer. Improvement of the 4K panel over PSA was observed in each population. Adding a prostate cancer polygenic risk score slightly improved upon the discriminative ability of the 4K panel. CONCLUSIONS: The superior discriminative ability of the 4K panel over PSA for overall and aggressive prostate cancer across multiethnic populations indicates the broad clinical applicability of the 4K panel. IMPACT: Our multiethnic investigation suggests potential for the 4K panel to improve current prostate cancer screening practices.
25.	Ek, P, et al. (author) Exogenous protein kinases A and C, but not endogenous prostasome-associated protein kinase, phosphorylate semenogelins I and II from human semen 2002 In: Journal of Andrology. - 0196-3635. ; 23:6, s. 806-814 Journal article (peer-reviewed)abstract Semenogelins I and II are the quantitatively dominating proteins in human semen. They comprise the major part of the sperm-entrapping gel formed at ejaculation, which subsequently liquefies due to proteolysis of the gel-forming proteins by prostate-specific antigen (PSA). The mechanism behind gel formation and its physiological significance is not known. We have studied phosphorylation and dephosphorylation of human semenogelins. Both were phosphorylated by protein kinases A and C (PKA and PKC, respectively) at a rate about 5 times less than that of histone. For PKA, incorporated ( P)phosphate into semenogelin approached a maximum above 1 mol/mol. Corresponding values for phosphorylation of the semenogelins with PKC were greater than 10. There was no change in the sensitivity of phosphosemenogelins to proteolysis by PSA. Serine (PKA) and serine and threonine (PKC) were the phosphate-accepting amino acid residues, and all incorporated (P-32)phosphate could be removed from the semenogelins with human acid phosphatase. Nil or very little phosphate could be detected in purified semenogelins isolated from seminal plasma. In vivo, about half the protein kinase activity in seminal plasma was bound to prostasomes. PKA but not PKC purified from prostasomes could phosphorylate specific substrates, but they could phosphorylate either of the semenogelins.
26.	Haese, A., et al. (author) A pre-specified model based on four kallikrein markers in blood improves predictions of adverse pathology and biochemical recurrence after radical prostatectomy 2020 In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 123:4, s. 604-609 Journal article (peer-reviewed)abstract Background A pre-specified model based on four kallikrein markers in blood, commercially available as 4Kscore, predicts Gleason Grade (GG) 3 + 4 or higher prostate cancer on biopsy. However, sampling error and variation in pathology reporting may miss aggressive disease. Methods The 4Kscore was measured in cryopreserved blood from 2330 men obtained before prostatectomy at a single institution between 2002 and 2010. Adverse surgical pathology and biochemical recurrence (BCR) were pre-specified to be assessed in all men, biopsy GG 3 + 3, and 3 + 4. Results Adjusted for established clinical predictors, the 4Kscore was significantly associated with adverse pathology (OR 1.49; 95% CI 1.32, 1.67;p < 0.0001). Adding 4Kscore increased discrimination from (AUC) 0.672 to 0.718 and 0.644 to 0.659 within biopsy GG 3 + 3 and 3 + 4, respectively. Higher 4Kscore was associated with higher risk of BCR (HR 1.16, 95% CI 1.06, 1.26;p = 0.001). Adding 4Kscore improved the prediction of BCR (C-index 0.630-0.660) within GG 3 + 3, but not GG 3 + 4. Conclusions The 4Kscore can help guide the clinical decision whether additional risk assessment-such as confirmatory biopsy-is needed to decide between active surveillance versus curative therapy. Evidence that the panel could influence management in biopsy GG 3 + 4 is less strong and requires further investigation.
27.	Haese, A, et al. (author) Comparison of predictive accuracy for pathologically organ confined clinical stage T1c prostate cancer using human glandular kallikrein 2 and prostate specific antigen combined with clinical stage and Gleason grade 2005 In: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3792 .- 0022-5347. ; 173:3, s. 752-756 Journal article (peer-reviewed)abstract Purpose: Previously human glandular kallikrein 2 (hK2) has been implicated to predict pathologically organ confined prostate cancer (PCa) in patients with stage T2 disease. Now we evaluated the usefulness of hK2, as measured by 2 entirely different immunoassay designs, to enhance the discrimination of pathologically organ from nonorgan confined clinical stage T1c PCa. Materials and Methods: A consecutive series of pretreatment serum from 148 men with clinical stage T1c PCa was used in 2 equally sensitive and specific methods to measure total hK2 with independent reagents and entirely different assay designs. Total prostate specific antigen (tPSA) and free PSA (fPSA) were measured and percent fPSA was calculated. We determined the algorithm, hK2tPSA/fPSA, from data generated by each hK2 assay, calculated means, medians and ranges for each analyte and algorithm, and calculated the significance of differences on univariate analysis. Using pretreatment PSA, clinical stage and biopsy Gleason grade we then developed a multivariate logistic regression base model to predict organ confined cancer and we compared predictions of the base model supplemented by the different hK2 measurements. Results: hK2 and hK2 based algorithms obtained by each hK2 assay were significantly different for pT2a/b vs pT3a or greater PCa (p = 0.034 to 0.0001) compared to tPSA (p = 0.06), fPSA (p = 0.90) or percent fPSA (p = 0.059). However, AUC (0.67 to 0.70) calculated by ROC analysis of the 4 models containing hK2 derived information was not significantly larger than that of the base model (AUC = 0.64, p = 0.52). Conclusions: The current data confirm that hK2 alone or hK2tPSA/fPSA measured by 2 immunoassays is significantly lower in men with pT2a/b vs pT3a or greater PCa compared to tPSA, fPSA or percent fPSA on univariate analysis of a validation set of clinical stage T1c prostate cancer treated at an American center of excellence for prostate cancer surgery. However, the incorporation of preoperative hK2 into multiparameter predictive models for pT2 cancers did not increase predictive accuracy in this cohort of men.
28.	Heimburg, Katarina, et al. (author) Physical activity after cardiac arrest; protocol of a sub-study in the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest trial (TTM2) 2021 In: Resuscitation Plus. - : Elsevier BV. - 2666-5204. ; 5 Journal article (peer-reviewed)abstract Aims: The primary aim of this study is to investigate whether out-of-hospital cardiac arrest (OHCA) survivors have lower levels of self-reported physical activity compared to a non-cardiac arrest (CA) control group who had acute myocardial infarction (MI). Additional aims are to explore potential predictors of physical inactivity (older age, female gender, problems with general physical function, global cognition, mental processing speed/attention, anxiety symptoms, depression symptoms, kinesiophobia, fatigue), and to investigate the relationship between self-reported and objectively measured physical activity among OHCA-survivors. Methods: The Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest trial (TTM2-trial) collects information regarding age, gender, self-reported physical activity, general physical function, global cognition and mental processing speed/attention at 6 months after OHCA. In this TTM2-trial cross-sectional prospective sub-study, participants at selected sites are invited to an additional follow-up meeting within 4 weeks from the main study follow-up. At this meeting, information regarding anxiety symptoms, depression symptoms, kinesiophobia and fatigue is collected. The OHCA-survivors are then provided with an objective measure of physical activity, a hip-placed accelerometer, to wear for one week, together with a training diary. At the end of the week, participants are asked to once again answer two self-reported questions regarding physical activity for that specific week. MI-controls attend a single follow-up meeting and perform the same assessments as the OHCA-survivors, except from wearing the accelerometer. We aim to include 110 OHCA-survivors and 110 MI-controls in Sweden, Denmark and the United Kingdom. Conclusion: The results from this sub-study will provide novel information about physical activity among OHCA-survivors.
29.	Holten-Andersen, MN, et al. (author) Measurement of the noncomplexed free fraction of tissue inhibitor of metalloproteinases I in plasma by immunoassay 2002 In: Clinical Chemistry. - 0009-9147. ; 48:8, s. 1305-1313 Journal article (peer-reviewed)abstract Background: We previously found differences in total concentrations of tissue inhibitor of metalloproteinases 1 (TIMP-1) in plasma from donors and cancer patients. Because TIMP-1 can exist in more than one molecular form, a new immunoassay to specifically detect free TIMP-1 was developed and concentrations were determined in plasma from healthy donors and colorectal cancer (CRC) patients. Methods: We established and validated an immunoassay for the specific measurement of free TIMP-1 that uses a polyclonal anti-TIMP-1 antibody for capture and a monoclonal anti-TIMP-1 antibody that binds only free TIMP-1 for detection of antigen. Plasma samples from healthy donors and CRC patients were assayed for free TIMP-1. Total TIMP-1 was measured by our previously published assay. Results: The mean (SD) concentrations of free TIMP-1 were similar in citrate [55.5 (11.5) mug/L] and EDTA plasma [58.9 (13.3) mug/L] from 76 donors (r(2) = 0.82). In 154 donors, the ratio of free TIMP-1 [mean (SD), 64.5 (18.0) mug/L] to total TIMP-1 [83.8 (19.8) mug/L] in EDTA plasma was 0.77. Plasma concentrations of free and total TIMP-1 correlated significantly to age (free, r(2) = 0.19; total, r(2) = .0.27; P < 0.0001), increasing 50% over an age span of 45 years. Free and total TIMP-1 were significantly increased in CRC patients (P < 0.0001), whereas the ratio of free to total TIMP-1 (mean, 0.58) was significantly lower than in donors. Conclusions: Most of the TIMP-1 in donor plasma is present in its free form, and free TIMP-1 increases with age. Free and total TIMP-1 are increased in CRC patient plasma, but the ratio of free to total TIMP-1 is significantly lower in these patients than in donors. (C) 2002 American Association for Clinical Chemistry.
30.	Holten-Andersen, MN, et al. (author) Total levels of tissue inhibitor of metalloproteinases 1 in plasma yield high diagnostic sensitivity and specificity in patients with colon cancer 2002 In: Clinical Cancer Research. - 1078-0432. ; 8:1, s. 156-164 Journal article (peer-reviewed)abstract Purpose: The purpose of this study was to measure total levels of tissue inhibitor of metalloproteinases (TIMP-1) by ELISA in plasma from blood donors, patients with inflammatory bowel disease (IBD), and patients with cancer and to correlate the results to patient diagnosis. Experimental Design: Total TIMP-1 plasma levels were measured by ELISA in blood samples from two different blood donor populations from IBD patients, and preoperative samples from patients with primary colon cancer (CC), rectal cancer (RC), or breast cancer. Results: There were no significant differences in plasma TIMP-1 levels between healthy donors and 1131) or breast cancer patients, whereas patients with CC or RC had significantly elevated TIMP-1 levels. Total TIMP-1 levels identified patients with CC with a sensitivity of 63% at 98% specificity, patients with early CC (Dukes' A+B) with a sensitivity of 56% at 98% specificity, and patients with right-sided CC with a sensitivity of 72% at 98% specificity. Combining carcinoembryonic antigen and TIMP-1 measurements increased the sensitivities obtained from TIMP-1 measurements alone. Conclusions: TIMP-1 was significantly elevated in plasma from CC and RC patients, including those with early-stage disease. Sensitivity and specificity were both sufficiently high to consider TIMP-1 as a marker for the early identification of CC patients, in particular, those with right-sided CC.
31.	Hugosson, Jonas, 1955, et al. (author) Results of a randomized, population-based study of biennial screening using serum prostate-specific antigen measurement to detect prostate carcinoma 2004 In: Cancer. - : Wiley. - 1097-0142 .- 0008-543X. ; 100:7, s. 1397-1405 Journal article (peer-reviewed)abstract BACKGROUND. The purpose of the current study was to evaluate the effectiveness of a prostate carcinoma screening program in which serum prostate-specific antigen (PSA) levels were measured. METHODS. From a group of 20,000 men born between January 1, 1930, and December 31, 1944, 10,000 men were randomized into a screening group and 10,000 were randomized into a control group. Patients in the screening group were invited to undergo initial PSA testing between 1995 and 1996 and then were invited to receive testing every second year thereafter for 8 years (for a total of 4 PSA tests). 2 Men with PSA levels greater than or equal to 3 ng/mL (or greater than or equal to 2.54 ng/mL, in the third and fourth screening rounds) were invited to undergo clinical investigation, which included sextant 3 biopsy of the prostate. By linking to the regional cancer registry, the authors were able to obtain the true and expected incidence rates for the screening and control groups. RESULTS. The screening participation rate was high (73%). A total of 884 malignancies have been detected to date, with 640 having been detected in the screening group. There was an early and marked shift toward more favorable disease stage and grade for malignancies detected on repeat screening. In the fourth screening round, only 2 of 82 detected malignancies were classified as advanced disease. Of the 227 screen-detected tumors on which surgery was performed, only 20 (8.8%) had small volume (< 0.2 cm(3)). Forty-three interval malignancies were detected, but only five were accompanied by symptoms. At 8 years, the cumulative disease incidence rate among screening participants was 7.3%, compared with 2.4% in the control arm. The incidence rate observed in the screening population corresponds to the cumulative incidence rate observed in the Swedish male population at age 72 years. CONCLUSIONS. Biennial PSA screening was very successful in diagnosing prostate carcinoma at an early stage, when curative treatment typically is effective. In addition, the results regarding interval malignancies were favorable. Thus, decreased mortality should be observed on long-term follow-up. The lead time associated with screening appears to fall within the range described in earlier studies involving frozen sera (i.e., 5-9 years).
32.	Jacobsen, Steven J., et al. (author) Comparability of the tandem-R andIMx assays for the measurement of serum prostate-specific antigen 1994 In: Urology. - 0090-4295. ; 44:4, s. 512-518 Journal article (peer-reviewed)abstract Objectives.: To assess the comparability of the Tandem-R and IMx serumprostate-specific antigen (PSA) assays across levels of the ratio of free-to-total serum PSA found in a community-based population of healthy men. Methods.: Banked serum samples from the baseline component of the Olmsted CountyStudy of Urinary Symptoms and Health Status Among Men were thawed and analyzed using the Tandem-R and IMx PSA assays. Serum levels also were determined for the free, noncomplexed form of PSA, PSA complexed to alpha-1 antichymotrypsin, and total PSA with a research-based immunofluorometric assay. Results.: The results of the Tandem-R and IMx assays were strongly correlated at alllevels of the ratio of free-to-total serum PSA. The Spearman correlation coefficients ranged from 0.87 to 0.98 (all p < 0.001). The relationship between the Tandem-R and IMx assays, however, differed at low levels of free-to-total serum PSA compared with high levels. In the lowest 10th percentile of the ratio of free-to-total serum PSA (0.04 to 0.18), the IMx assay read lower than the Tandem-R (slope ± standard error = 0.92±0.04, intercept ± standard error = 0.21 ± 0.14); whereas in the upper 10th percentile of free-to-total ratio (0.46 to 0.65) the IMx assay yielded values higher than the Tandem-R assay (slope = 1.21 ± 0.07, intercept = 0.14 ± 0.05). In the middle 90%, the slope did not statistically differ from 1.0. Conclusions.: For the majority of men, results of the Tandem-R and IMx PSA assays were virtually identical. The small differences found would not be of clinical significance for most men but should be considered when comparing results of different assays in sequential determinations for a specific man.
33.	Jacobsen, Steven J., et al. (author) Stability of serum prostate-specific antigen determination across laboratory, assay, and storage time 1995 In: Urology. - 0090-4295. ; 45:3, s. 447-453 Journal article (peer-reviewed)abstract Objectives: To understand the comparability of serum prostate-specific antigen (PSA) determinations across assays and storage time. Methods: Serum PSA levels were determined for men aged 40 to 79 years from the clinical subset of the Olmsted County Study of Urinary Symptoms and Health Status Among Men on fresh samples and after a median of 32 months on banked samples, frozen at -70 °C. Baseline serum PSA levels were determined by Tandem-R PSA assay. Follow-up levels on the banked samples were determined by the IMx PSA assay and a repeat Tandem-R PSA assay in a different laboratory and by an immunofluorometric PSA assay at another site. Results: The median serum PSA level determined by Tandem-R assay at baseline was 1.0 ng/mL (25th percentile, 0.6; 75th percentile, 1.7). The distributions of determination made by follow-up Tandem-R, IMx, and immunofluorometric analyses were essentially identical. Overall, the assays were highly correlated. The correlations between the baseline serum PSA determination and repeated Tandem-R, IMx, and immunofluorometric determinations were 0.96, 0.96, and 0.97, respectively (all P < 0.001). The median duration of frozen storage was 32 months (range, 26 to 39 months), and the correlations between baseline and follow-up determinations did not change when stratified by duration of storage. Conclusions: These data provide important reassurance about the use of serum PSA determinations obtained by different assays, in different laboratories, and in properly tored samples across time.
34.	Kurek, R, et al. (author) Quantitative PSA RT-PCR for preoperative staging of prostate cancer 2003 In: The Prostate. - : Wiley. - 0270-4137. ; 56:4, s. 263-269 Journal article (peer-reviewed)abstract BACKGROUND. The clinical value of detecting prostate specific antigen (PSA) mRNA in the peripheral blood mononuclear cell fraction of patients (pts) by standard RT-PCR assays with localized prostate cancer remains controversial. We used a quantitative RT-PCR assay to measure the PSA mRNA copy number in addition to the qualitative PSA RT-PCR and correlated the results with clinical parameters. METHODS. Total RNA was extracted from the peripheral blood mononuclear cell fraction of 115 prostate cancer pts prior to radical retropubic prostatectomy (RP) who received 3 months of neoadjuvant androgen deprivation. For quantitative RT-PCR, a PSA-like internal standard (IS) was added to each sample prior to reverse transcription and the PCR products for PSA and IS were selectively detected with fluorescent europium chelates; after hybridization. Corresponding qualitative PSA-RT-PCR was performed for all samples. RESULTS. The median PSA copy number was 126 (range: 0-37988). There were no significant correlations established between qualitative or quantitative RT-PCR results and given clinical parameters. Corresponding quantitative and qualitative RT-PCR results were significantly associated (P = 0.01). CONCLUSIONS. We were unable to show any additional value of quantitative as well as qualitative PSA RT-PCR for preoperative staging of prostate cancer so far. Nevertheless, the long-term follow up of the patients has to be awaited. Prostate 56:263-269,2003. (C) 2003 Wiley-Liss, Inc.
35.	Lilja, Gisela, et al. (author) Anxiety and depression among out-of-hospital cardiac arrest survivors. 2015 In: Resuscitation. - : Elsevier BV. - 1873-1570 .- 0300-9572. ; 97, s. 68-75 Journal article (peer-reviewed)abstract Survivors of out-of-hospital cardiac arrest (OHCA) may experience psychological distress but the actual prevalence is unknown. The aim of this study was to investigate anxiety and depression within a large cohort of OHCA-survivors.
36.	Lilja, Gisela, et al. (author) Effects of Hypothermia vs Normothermia on Societal Participation and Cognitive Function at 6 Months in Survivors After Out-of-Hospital Cardiac Arrest A Predefined Analysis of the TTM2 Randomized Clinical Trial 2023 In: Jama Neurology. - 2168-6149 .- 2168-6157. ; 80:10, s. 1070-1079 Journal article (peer-reviewed)abstract IMPORTANCE The Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens. OBJECTIVES To investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA. DESIGN, SETTING, AND PARTICIPANTS This study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing. INTERVENTIONS Randomization 1:1 to temperature control with targeted hypothermia at 33 degrees C or targeted normothermia and early treatment of fever (37.8 degrees C or higher). MAIN OUTCOMES AND MEASURES Functional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes. RESULTS At 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P =.46) or in cognitive function by MoCA (mean difference, 0.36; 95% CI,-0.33 to 1.05; P =.37) and SDMT (mean difference, 0.06; 95% CI,-0.16 to 0.27; P =.62). Limitations in societal participation (GOSE score less than 7) were common regardless of intervention (hypothermia, 178 of 415 [43%]; normothermia, 168 of 419 [40%]). Cognitive impairment was identified in 353 of 599 survivors (59%). CONCLUSIONS In this predefined analysis of comatose patients after OHCA, hypothermia did not lead to better functional outcome assessed with a focus on societal participation and cognitive function than management with normothermia. At 6 months, many survivors had not regained their pre-arrest activities and roles, and mild cognitive dysfunction was common.
37.	Lilja, Hans, et al. (author) Significance and metabolism of complexed and noncomplexed prostate specific antigen forms, and human glandular kallikrein 2 in clinically localized prostate cancer before and after radical prostatectomy 1999 In: Journal of Urology. - 1527-3792. ; 162:6, s. 2029-2035 Journal article (peer-reviewed)abstract PURPOSE: We studied plasma concentrations and elimination rates of prostate specific antigen (PSA) complexed to alpha1-antichymotrypsin and alpha2-macroglobulin, free PSA, total PSA (free PSA plus PSA alpha1-antichymotrypsin) and human glandular kallikrein 2 before, during and after radical retropubic prostatectomy for clinically localized prostate cancer. MATERIALS AND METHODS: Plasma was collected and frozen within 10 minutes after sampling from 18 patients undergoing radical retropubic prostatectomy for prostate cancer. One sample was drawn preoperatively. Subsequent sampling intervals were 5 to 20 minutes perioperatively, 2 to 4 hours during the first 12 postoperative hours and 24 to 48 hours until postoperative day 14. Free PSA, PSA alpha1-antichymotrypsin, total PSA, PSA alpha2-macroglobulin and human glandular kallikrein 2 were measured with time resolved immunofluorometric assays. RESULTS: Preoperatively PSA alpha2-macroglobulin was undetectable (less than 2 ng./ml.) in 17 of 18 patients. Human glandular kallikrein 2, free PSA and total PSA but not PSA alpha1-antichymotrypsin were significantly higher in patients with extraprostatic cancer (pT3a-pT4a, pN1) compared to those with organ confined cancer (pT2a/b). Surgical manipulation of the prostate caused no detectable elevation of human glandular kallikrein 2, PSA alpha1-antichymotrypsin or PSA alpha2-macroglobulin. In contrast, a mean 9.6-fold increase (range 3.4 to 22) in free PSA was noted 5 minutes after prostatectomy. Free PSA was eliminated from plasma in a biphasic exponential pattern with an early plasma half-life of 55 minutes and a late plasma half-life of 18 hours. PSA alpha1-antichymotrypsin decreased slowly, whereas human glandular kallikrein 2 was detectable only 12 hours after prostatectomy. PSA alpha2-macroglobulin remained at insignificant, nondetectable concentrations during the entire perioperative and postoperative period. CONCLUSIONS: Release of free PSA contributes to the elevation of plasma total PSA after prostatectomy. Free PSA is enzymatically inactive as the release does not result in subsequent elevation of PSA alpha1-antichymotrypsin or PSA alpha2-macroglobulin. Biphasic exponential elimination of free PSA may be explained by rapid extracellular redistribution (early half-life) and glomerular filtration in the kidneys (late half-life). Our data suggest rapid metabolism of human glandular kallikrein 2 but do not support suggestions of the significance in vivo of complex formations with alpha2-macroglobulin as a major means to eliminate PSA from plasma in patients with clinically localized prostate cancer.
38.	Lonergan, Peter E., et al. (author) Prospective validation of microseminoprotein-β added to the 4Kscore in predicting high-grade prostate cancer in an international multicentre cohort 2021 In: BJU International. - : Wiley. - 1464-4096 .- 1464-410X. ; 128:2, s. 218-224 Journal article (peer-reviewed)abstract Objectives: To prospectively evaluate the performance of a pre-specified statistical model based on four kallikrein markers in blood (total prostate-specific antigen [PSA], free PSA, intact PSA, and human kallikrein-related peptidase 2), commercially available as the 4Kscore, in predicting Gleason Grade Group (GG) ≥2 prostate cancer at biopsy in an international multicentre study at three academic medical centres, and whether microseminoprotein-β (MSP) adds predictive value. Patients and Methods: A total of 984 men were prospectively enrolled at three academic centres. The primary outcome was GG ≥2 on prostate biopsy. Three pre-specified statistical models were used: a base model including PSA, age, digital rectal examination and prior negative biopsy; a model that added free PSA to the base model; and the 4Kscore. Results: A total of 947 men were included in the final analysis and 273 (29%) had GG ≥2 on prostate biopsy. The base model area under the receiver operating characteristic curve of 0.775 increased to 0.802 with the addition of free PSA, and to 0.824 for the 4Kscore. Adding MSP to the 4Kscore model yielded an increase (0.014–0.019) in discrimination. In decision-curve analysis of clinical utility, the 4Kscore showed a benefit starting at a 7.5% threshold. Conclusion: A prospective multicentre evaluation of a pre-specified model based on four kallikrein markers (4Kscore) with the addition of MSP improves the predictive discrimination for GG ≥2 prostate cancer on biopsy and could be used to inform biopsy decision-making.
39.	Marsden, G. L., et al. (author) THE P-MARK BIOBANK: A EUROPEAN MULTICENTER BIOREPOSITORY FOR PROSTATE CANCER RESEARCH 2009 In: European Urology Supplements. - 1569-9056. ; 8:4, s. 165-165 Conference paper (peer-reviewed)
40.	McCormack, Robert T., et al. (author) Molecular forms of prostate-specific antigen and the human kallikrein gene family : A new era 1995 In: Urology. - 0090-4295. ; 45:5, s. 729-744 Research review (peer-reviewed)
41.	Oesterling, Joseph E., et al. (author) Free, Complexed and Total Serum Prostate Specific Antigen : The Establishment of Appropriate Reference Ranges for their Concentrations and Ratios 1995 In: The Journal of urology. - 0022-5347. ; 154:3, s. 1090-1095 Journal article (peer-reviewed)abstract Purpose: Prostate specific antigen (PSA) exists in the serum in several molecular forms that can be measured by immunodetectable assays: free PSA, PSA complexed to alpha 1-antichymotrypsin (complexed PSA) and total PSA, which represents the sum of the free and complexed forms. We determined the normal distribution of values and established the appropriate reference ranges for these 3 molecular forms of PSA and their ratios (free-to-total, complexed-to-total and free-to-complexed PSA). Knowing the amount and ratio of these molecular forms appears to be useful in enhancing the ability of PSA to distinguish potentially curable prostate cancer from benign prostatic hyperplasia and in decreasing the number of unnecessary prostate biopsies. Materials and Methods: A total of 422 healthy men 40 to 79 years old was randomly chosen from the male population of Olmsted County Minnesota and underwent a detailed clinical examination that included digital rectal examination, serum PSA determination and transrectal ultrasound to exclude the presence of prostate cancer. Using newly developed, monoclonal-monoclonal immunofluorometric assays for each molecular form, the free, complexed and total PSA, and the ratios of these 3 forms were determined for each study participant. Results: All 3 molecular forms correlated directly with patient age (r = 0.45, r = 0.43 and r = 0.45, respectively). Using the 95th percentile, the recommended age-specific reference ranges for the free, complexed and total PSA forms, respectively, are 0.5, 1.0 and 2.0 ng./ml. for men 40 to 49 years old; 0.7, 1.5 and 3.0 ng./ml. for men 50 to 59 years old; 1.0, 2.0 and 4.0 ng./ml. for men 60 to 69 years old, and 1.2, 3.0 and 5.5 ng./ml. for men 70 to 79 years old. With regard to each of the ratios (free-to-total, complexed-to-total and free-to-complexed PSA) none correlated with patient age. As a result, the appropriate upper limit of normal (95th percentile) for all 3 ratios is constant for men of all ages. These reference ranges are greater than 0.15 for free-to-total PSA ratio, less than 0.70 for complexed-to-total PSA ratio and greater than 0.25 for free-to-complexed PSA ratio. The free-to-total PSA ratio will have its greatest value for men with a serum PSA value between 2 and 10 ng./ml. Conclusions: The establishment of appropriate reference ranges for free, complexed and total PSA as well as the ratios will allow the practicing urologist to incorporate these new parameters into the diagnostic evaluation of men at risk for early, potentially curable prostate cancer.
42.	Page, EC, et al. (author) Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers 2019 In: European urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 76:6, s. 831-842 Journal article (peer-reviewed)
43.	Phronen, T, et al. (author) Enhanced discrimination of benign from malignant prostatic disease by selective measurements of cleaved forms of urokinase receptor in serum 2006 In: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 52:5, s. 838-844 Journal article (peer-reviewed)abstract Background: Early detection of prostate cancer (PCa) centers on measurements of prostate-specific antigen (PSA), but current testing practices suffer from lack of specificity and generate many unnecessary prostate biopsies. Soluble urokinase plasminogen activator receptor (uPAR) is present in blood in both intact and cleaved forms. Increased uPAR in blood is correlated with poor prognosis in various cancers, but uPAR has not been shown to be useful in PCa diagnostics. We assessed the ability of immunoassays for specific uPAR forms to discriminate PCa from benign conditions. Methods: We measured total PSA (tPSA), free PSA (fPSA), intact uPAR [uPAR(I-III)], intact uPAR + cleaved uPAR domains II+III [uPAR(I-III) + uPAR(II-III)], and cleaved uPAR domain I [uPAR(I)] in sera from 224 men with and 166 men without PCa. We assessed differences in serum concentrations between the PCa and noncancer groups within the entire cohort and in men with tPSA concentrations of 2-10 mu g/L. The diagnostic accuracy of individual analytes and analyte combinations was explored by logistic regression and ROC analyses and evaluations of sensitivity and specificity pairs. Results: Serum uPAR(I) and uPAR(II-III) were higher in PCa than in benign disease. In men with tPSA between 2 and 10 mu g/L, the combination of %fPSA with the ratio uPAR(I)/uPAR(I-III) had a greater area under the ROC curve (0.73) than did %fPSA (0.68). Conclusions: Specific measurements of different uPAR forms in serum improve the specificity of PCa detection. The uPAR forms may therefore be complementary to PSA for PCa detection, most importantly in men with moderately increased PSA. (c) 2006 American Association for Clinical Chemistry.
44.	Ressine, Anton, et al. (author) Macro/Nano-Structured Silicon as Solid Support for Antibody Arrays: Surface Design, Reproducibility, and Assay Characteristics Enabling Discovery of Kallikrein Gene Products for Prostate Disease Diagnostics 2005 In: Nanobiotechnology. - 1551-1286. ; 1:1, s. 93-104 Journal article (peer-reviewed)abstract To facilitate high-throughput biomarker discovery and high-density protein-chip array analyses of complex biological samples, a novel macro- and nanoporous silicon surface for protein microarrays was developed. The surface offers three-dimensional surface enlarging properties and spot confinement, enabling both high sensitivity bioassays and design of high density arrays. Reproducible manufacturing of the protein chip surface was accomplished as demonstrated by the low imprecision when standard IgG bioassays were performed at 100 pM antigen level on a series of protein chips scanned at widely different locations within a silicon wafer, as well as between different wafers from two different manufacturers. The relative standard deviation (RSD) of fluorescence spot intensity within an array on a chip was less than 20%. Mean spot intensity RSD was 19% for all 25 microarray chips in the study. Within-manufacturer-lot RSDs in chips from either manufacturer were <15% of mean spot intensity. The detection limit and dynamic range of the novel protein chip surface were examined to evaluate whether they match criteria required in a search for novel biomarkers such as for prostate cancer. Monoclonal IgG against prostate-specific antigen (PSA) was arrayed on the porous silicon chips. These were subsequently incubated in serum samples containing widely different levels of fluorescence-labeled PSA. Detection of PSA in serum at concentrations from 0.7 ng/mL (26 pM) up to 104-fold higher levels verified assay characteristics required in the search for prostate biomarkers (e.g., kallikrein gene products) at clinically relevant levels.
45.	Schröder, Fritz H, et al. (author) Prostate-cancer mortality at 11 years of follow-up. 2012 In: The New England journal of medicine. - 1533-4406 .- 0028-4793. ; 366:11, s. 981-90 Journal article (peer-reviewed)abstract Several trials evaluating the effect of prostate-specific antigen (PSA) testing on prostate-cancer mortality have shown conflicting results. We updated prostate-cancer mortality in the European Randomized Study of Screening for Prostate Cancer with 2 additional years of follow-up.
46.	Schröder, Fritz H, et al. (author) Screening and prostate-cancer mortality in a randomized European study. 2009 In: The New England journal of medicine. - 1533-4406 .- 0028-4793. ; 360:13, s. 1320-8 Journal article (other academic/artistic)abstract The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific-antigen (PSA) testing on death rates from prostate cancer.
47.	Simpson, Rupert F.G., et al. (author) Speed of cooling after cardiac arrest in relation to the intervention effect : a sub-study from the TTM2-trial 2022 In: Critical Care. - : Springer Science and Business Media LLC. - 1364-8535 .- 1466-609X. ; 26:1 Journal article (peer-reviewed)abstract Background: Targeted temperature management (TTM) is recommended following cardiac arrest; however, time to target temperature varies in clinical practice. We hypothesised the effects of a target temperature of 33 °C when compared to normothermia would differ based on average time to hypothermia and those patients achieving hypothermia fastest would have more favorable outcomes. Methods: In this post-hoc analysis of the TTM-2 trial, patients after out of hospital cardiac arrest were randomized to targeted hypothermia (33 °C), followed by controlled re-warming, or normothermia with early treatment of fever (body temperature, ≥ 37.8 °C). The average temperature at 4 h (240 min) after return of spontaneous circulation (ROSC) was calculated for participating sites. Primary outcome was death from any cause at 6 months. Secondary outcome was poor functional outcome at 6 months (score of 4–6 on modified Rankin scale). Results: A total of 1592 participants were evaluated for the primary outcome. We found no evidence of heterogeneity of intervention effect based on the average time to target temperature on mortality (p = 0.17). Of patients allocated to hypothermia at the fastest sites, 71 of 145 (49%) had died compared to 68 of 148 (46%) of the normothermia group (relative risk with hypothermia, 1.07; 95% confidence interval 0.84–1.36). Poor functional outcome was reported in 74/144 (51%) patients in the hypothermia group, and 75/147 (51%) patients in the normothermia group (relative risk with hypothermia 1.01 (95% CI 0.80–1.26). Conclusions: Using a hospital’s average time to hypothermia did not significantly alter the effect of TTM of 33 °C compared to normothermia and early treatment of fever.
48.	Sjöblom, Liisa, et al. (author) Microseminoprotein-Beta Expression in Different Stages of Prostate Cancer. 2016 In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:3 Journal article (peer-reviewed)abstract Microseminoprotein-beta (MSMB, MSMB) is an abundant secretory protein contributed by the prostate, and is implicated as a prostate cancer (PC) biomarker based on observations of its lower expression in cancerous cells compared with benign prostate epithelium. However, as the current literature on MSMB is inconsistent, we assessed the expression of MSMB at the protein and mRNA levels in a comprehensive set of different clinical stages of PC. Immunohistochemistry using monoclonal and polyclonal antibodies against MSMB was used to study protein expression in tissue specimens representing prostatectomies (n = 261) and in diagnostic needle biopsies from patients treated with androgen deprivation therapy (ADT) (n = 100), and in locally recurrent castration-resistant PC (CRPC) (n = 105) and CRPC metastases (n = 113). The transcript levels of MSMB, nuclear receptor co-activator 4 (NCOA4) and MSMB-NCOA4 fusion were examined by qRT-PCR in prostatectomy samples and by RNA-sequencing in benign prostatic hyperplasia, PC, and CRPC samples. We also measured serum MSMB levels and genotyped the single nucleotide polymorphism rs10993994 using DNA from the blood of 369 PC patients and 903 controls. MSMB expression in PC (29% of prostatectomies and 21% of needle biopsies) was more frequent than in CRPC (9% of locally recurrent CRPCs and 9% of CRPC metastases) (p<0.0001). Detection of MSMB protein was inversely correlated with the Gleason score in prostatectomy specimens (p = 0.024). The read-through MSMB-NCOA4 transcript was detected at very low levels in PC. MSMB levels in serum were similar in cases of PC and controls but were significantly associated with PC risk when adjusted for age at diagnosis and levels of free or total PSA (p<0.001). Serum levels of MSMB in both PC patients and controls were significantly associated with the rs10993994 genotype (p<0.0001). In conclusion, decreased expression of MSMB parallels the clinical progression of PC and adjusted serum MSMB levels are associated with PC risk.
49.	Steiner, H, et al. (author) An autocrine loop for vascular endothelial growth factor is established in prostate cancer cells generated after prolonged treatment with interleukin 6 2004 In: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 40:7, s. 1066-1072 Journal article (peer-reviewed)abstract Concentrations of interleukin 6 (IL-6) and its receptor are increased in human prostate cancer. Prostate cancer LNCaP-IL-6+ cells, established after prolonged treatment with IL-6, have been found to acquire a growth advantage. Vascular endothelial growth factor (VEGF) may accelerate the growth of various tumours by stimulation of VEGF receptor 2 (VEGFR-2). To understand better the regulation of proliferation of LNCaP-IL-6+ cells, the expression of VEGF and VEGFR-2 was here investigated in the LNCaP-IL-6+ subline. VEGF was measured in cellular supernatants by enzyme-linked immunoassay. The expression of VEGFR-2 was assessed by Western blot. LNCaP-IL-6+ and control LNCaP-IL-6- cells were treated with a neutralising antibody against VEGFR-2. VEGF concentrations were 20-fold higher in LNCaP-IL-6+ than in LNCaP-IL-6- cells. The stimulatory effect of IL-6 on VEGF production was abolished by an inhibitor of the signalling pathway for phosphoinositol 3 kinase in LNCaP-IL-6+ and LNCaP-IL-6- cells. Exogenous VEGF did not stimulate proliferation in either LNCaP-IL-6+ cells or controls. VEGFR-2 was detected only in LNCaP-IL-6+ cells, in which the neutralising antibody caused a partial inhibition of cell proliferation. It was concluded that a VEGF autocrine loop is established in prostate cancer cells generated after chronic treatment with IL-6. Because of the upregulation of IL-6 in patients with prostate cancer, these findings might be clinically relevant.
50.	Thorek, Daniel L.J., et al. (author) Harnessing androgen receptor pathway activation for targeted alpha particle radioimmunotherapy of breast cancer 2019 In: Clinical Cancer Research. - 1078-0432. ; 25:2, s. 881-891 Journal article (peer-reviewed)abstract Purpose: The impact of androgen receptor (AR) activity Results: D-Norgestrel and DHT activated the AR pathway, in breast cancer biology is unclear. We characterized and while 17b-Estradiol did not. Competitive binding for AR tested a novel therapy to an AR-governed target in breast protein showed similar affinity between DHT and D-Norges-cancer. trel, indicating direct AR–ligand interaction. In vivo production Experimental Design: We evaluated the expression of of hK2 was sufficient to achieve site-specific delivery of ther-prototypical AR gene products human kallikrein 2 (hK2) apeutic radionuclide to tumor tissue at >20-fold over back- and PSA in breast cancer models. We screened 13 well-ground muscle uptake; effecting long-term local tumor characterized breast cancer cell lines for hK2 and PSA control. production upon in vitro hormone stimulation by testoster-Conclusions: [225Ac]hu11B6 targeted radiotherapy one [dihydrotestosterone (DHT)]. AR-positive lines were was potentiated by DHT and by D-Norgestrel in murine further evaluated by exposure to estrogen (17b-Estradiol) xenograft models of breast cancer. AR activity in and the synthetic progestin D-Norgestrel. We then evaluated breast cancer correlates with kallikrein-related peptidase-2 an anti-hK2–targeted radiotherapy platform (hu11B6), and can be activated by D-Norgestrel, a common con-labeled with alpha (a)-particle emitting Actinium-225, to traceptive, and AR induction can be harnessed for hK2-specifically treat AR-expressing breast cancer xenografts targeted breast cancer a-emitter radiotherapy. under hormone stimulation.

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