| 1. |
- Carlsson, Jessica, 1984-, et al.
(author)
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Quantity and quality of nucleic acids extracted from archival formalin fixed paraffin embedded prostate biopsies
- 2018
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In: BMC Medical Research Methodology. - : BioMed Central. - 1471-2288. ; 18:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: In Sweden, human tissue samples obtained from diagnostic and surgical procedures have for decades been routinely stored in a formalin-fixed, paraffin-embedded, form. Through linkage with nationwide registers, these samples are available for molecular studies to identify biomarkers predicting mortality even in slow-progressing prostate cancer. However, tissue fixation causes modifications of nucleic acids, making it challenging to extract high-quality nucleic acids from formalin fixated tissues.METHODS: In this study, the efficiency of five commercial nucleic acid extraction kits was compared on 30 prostate biopsies with normal histology, and the quantity and quality of the products were compared using spectrophotometry and Agilent's BioAnalyzer. Student's t-test's and Bland-Altman analyses were performed in order to investigate differences in nucleic acid quantity and quality between the five kits. The best performing extraction kits were subsequently tested on an additional 84 prostate tumor tissues. A Spearman's correlation test and linear regression analyses were performed in order to investigate the impact of tissue age and amount of tissue on nucleic acid quantity and quality.RESULTS: Nucleic acids extracted with RNeasy® FFPE and QIAamp® DNA FFPE Tissue kit had the highest quantity and quality, and was used for extraction from 84 tumor tissues. Nucleic acids were successfully extracted from all biopsies, and the amount of tumor (in millimeter) was found to have the strongest association with quantity and quality of nucleic acids.CONCLUSIONS: To conclude, this study shows that the choice of nucleic acid extraction kit affects the quantity and quality of extracted products. Furthermore, we show that extraction of nucleic acids from archival formalin-fixed prostate biopsies is possible, allowing molecular studies to be performed on this valuable sample collection.
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| 2. |
- Zelic, Renata, et al.
(author)
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Estimation of Relative and Absolute Risks in a Competing-Risks Setting Using a Nested Case-Control Study Design : Example From the ProMort Study
- 2019
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In: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1165-1173
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Journal article (peer-reviewed)abstract
- In this paper, we describe the Prognostic Factors for Mortality in Prostate Cancer (ProMort) study and use it to demonstrate how the weighted likelihood method can be used in nested case-control studies to estimate both relative and absolute risks in the competing-risks setting. ProMort is a case-control study nested within the National Prostate Cancer Register (NPCR) of Sweden, comprising 1,710 men diagnosed with low- or intermediate-risk prostate cancer between 1998 and 2011 who died from prostate cancer (cases) and 1,710 matched controls. Cause-specific hazard ratios and cumulative incidence functions (CIFs) for prostate cancer death were estimated in ProMort using weighted flexible parametric models and compared with the corresponding estimates from the NPCR cohort. We further drew 1,500 random nested case-control subsamples of the NPCR cohort and quantified the bias in the hazard ratio and CIF estimates. Finally, we compared the ProMort estimates with those obtained by augmenting competing-risks cases and by augmenting both competing-risks cases and controls. The hazard ratios for prostate cancer death estimated in ProMort were comparable to those in the NPCR. The hazard ratios for dying from other causes were biased, which introduced bias in the CIFs estimated in the competing-risks setting. When augmenting both competing-risks cases and controls, the bias was reduced.
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| 3. |
- Zelic, Renata, et al.
(author)
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Interchangeability of light and virtual microscopy for histopathological evaluation of prostate cancer
- 2021
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 11:1
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Journal article (peer-reviewed)abstract
- Virtual microscopy (VM) holds promise to reduce subjectivity as well as intra- and inter-observer variability for the histopathological evaluation of prostate cancer. We evaluated (i) the repeatability (intra-observer agreement) and reproducibility (inter-observer agreement) of the 2014 Gleason grading system and other selected features using standard light microscopy (LM) and an internally developed VM system, and (ii) the interchangeability of LM and VM. Two uro-pathologists reviewed 413 cores from 60 Swedish men diagnosed with non-metastatic prostate cancer 1998-2014. Reviewer 1 performed two reviews using both LM and VM. Reviewer 2 performed one review using both methods. The intra- and inter-observer agreement within and between LM and VM were assessed using Cohen's kappa and Bland and Altman's limits of agreement. We found good repeatability and reproducibility for both LM and VM, as well as interchangeability between LM and VM, for primary and secondary Gleason pattern, Gleason Grade Groups, poorly formed glands, cribriform pattern and comedonecrosis but not for the percentage of Gleason pattern 4. Our findings confirm the non-inferiority of VM compared to LM. The repeatability and reproducibility of percentage of Gleason pattern 4 was poor regardless of method used warranting further investigation and improvement before it is used in clinical practice.
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| 4. |
- Zelic, Renata, et al.
(author)
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Predicting Prostate Cancer Death with Different Pretreatment Risk Stratification Tools : A Head-to-head Comparison in a Nationwide Cohort Study
- 2020
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In: European Urology. - : ELSEVIER. - 0302-2838 .- 1873-7560. ; 77:2, s. 180-188
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Journal article (peer-reviewed)abstract
- Background: Numerous pretreatment risk classification tools are available for prostate cancer. Which tool is best in predicting prostate cancer death is unclear.Objective: To systematically compare the prognostic performance of the most commonly used pretreatment risk stratification tools for prostate cancer.Design, setting, and participants: A nationwide cohort study was conducted, including 154 811 men in Prostate Cancer data Base Sweden (PCBaSe) 4.0 diagnosed with nonmetastatic prostate cancer during 1998-2016 and followed through 2016.Outcome measurements and statistical analysis: We compared the D'Amico, National Institute for Health and Care Excellence (NICE), European Association of Urology (EAU), Genito-Urinary Radiation Oncologists of Canada (GUROC), American Urological Association (AUA), National Comprehensive Cancer Network (NCCN), and Cambridge Prognostic Groups (CPG) risk group systems; the Cancer of the Prostate Risk Assessment (CAPRA) score; and the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram in predicting prostate cancer death by estimating the concordance index (C-index) and the observed versus predicted cumulative incidences at different follow-up times.Results and limitations: A total of 139 515 men were included in the main analysis, of whom 15 961 died from prostate cancer during follow-up. The C-index at 10 yr of follow-up ranged from 0.73 (95% confidence interval [CI]: 0.72-0.73) to 0.81 (95% CI: 0.80-0.81) across the compared tools. The MSKCC nomogram (C-index: 0.81, 95% CI: 0.80-0.81), CAPRA score (C-index: 0.80, 95% CI: 0.79-0.81), and CPG system (C-index: 0.78, 95% CI: 0.78-0.79) performed the best. The order of performance between the tools remained in analyses stratified by primary treatment and year of diagnosis. The predicted cumulative incidences were close to the observed ones, with some underestimation at 5 yr. It is a limitation that the study was conducted solely in a Swedish setting (ie, case mix).Conclusions: The MSKCC nomogram, CAPRA score, and CPG risk grouping system performed better in discriminating prostate cancer death than the D'Amico and D'Amico-derived systems (NICE, GUROC, EAU, AUA, and NCCN). Use of these tools may improve clinical decision making.Patient summary: There are numerous pretreatment risk classification tools that can aid treatment decision for prostate cancer. We systematically compared the prognostic performance of the most commonly used tools in a large cohort of Swedish men with prostate cancer. The Memorial Sloan Kettering Cancer Center nomogram, Cancer of the Prostate Risk Assessment score, and Cambridge Prognostic Groups performed best in predicting prostate cancer death. The use of these tools may improve treatment decisions.
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| 5. |
- Zelic, Renata, et al.
(author)
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Prognostic Utility of the Gleason Grading System Revisions and Histopathological Factors Beyond Gleason Grade.
- 2022
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In: Clinical Epidemiology. - : Dove Medical Press Ltd.. - 1179-1349. ; 14, s. 59-70
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Journal article (peer-reviewed)abstract
- Background: The International Society of Urological Pathology (ISUP) revised the Gleason system in 2005 and 2014. The impact of these changes on prostate cancer (PCa) prognostication remains unclear.Objective: To evaluate if the ISUP 2014 Gleason score (GS) predicts PCa death better than the pre-2005 GS, and if additional histopathological information can further improve PCa death prediction.Patients and Methods: We conducted a case-control study nested among men in the National Prostate Cancer Register of Sweden diagnosed with non-metastatic PCa 1998-2015. We included 369 men who died from PCa (cases) and 369 men who did not (controls). Two uro-pathologists centrally re-reviewed biopsy ISUP 2014 Gleason grading, poorly formed glands, cribriform pattern, comedonecrosis, perineural invasion, intraductal, ductal and mucinous carcinoma, percentage Gleason 4, inflammation, high-grade prostatic intraepithelial neoplasia (HGPIN) and post-atrophic hyperplasia. Pre-2005 GS was back-transformed using i) information on cribriform pattern and/or poorly formed glands and ii) the diagnostic GS from the registry. Models were developed using Firth logistic regression and compared in terms of discrimination (AUC).Results: The ISUP 2014 GS (AUC = 0.808) performed better than the pre-2005 GS when back-transformed using only cribriform pattern (AUC = 0.785) or both cribriform and poorly formed glands (AUC = 0.792), but not when back-transformed using only poorly formed glands (AUC = 0.800). Similarly, the ISUP 2014 GS performed better than the diagnostic GS (AUC = 0.808 vs 0.781). Comedonecrosis (AUC = 0.811), HGPIN (AUC = 0.810) and number of cores with ≥50% cancer (AUC = 0.810) predicted PCa death independently of the ISUP 2014 GS.Conclusion: The Gleason Grading revisions have improved PCa death prediction, likely due to classifying cribriform patterns, rather than poorly formed glands, as Gleason 4. Comedonecrosis, HGPIN and number of cores with ≥50% cancer further improve PCa death discrimination slightly.
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| 6. |
- Zelić, Renata
(author)
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Prostate cancer prognostication based on clinical and histopathological tumor features
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Prostate cancer is the second most common cancer in men worldwide. Of almost 1.3 million newly diagnosed men per year, up to 80% will have localized disease with a characteristically prolonged natural history. Risk stratification and treatment decision-making for these men is currently based on the combination of standard clinical and histopathological predictors, such as the Gleason score, prostate specific antigen (PSA) level and clinical tumor stage at diagnosis. However, these standard predictors are not sufficient to capture the heterogeneity in prognosis for men with localized prostate cancer. As a consequence, these men are often overtreated and may suffer from treatment-related side effects. In this thesis we aimed to improve prognostication for men with localized prostate cancer through validation of existing risk stratification tools based on standard clinical and histopathological factors, and through validation of existing, and identification of novel, prognostic markers. In Study I, we evaluated if the nested case-control study design is appropriate for estimating relative and absolute risks of dying from prostate cancer in the presence of competing risks. We used a case-control study (ProMort I) nested in the National Prostate Cancer Register of Sweden (NPCR). We found that the relative risks of dying from prostate cancer estimated in ProMort I were comparable to the relative risks estimated in the NPCR. The relative risks of dying from other causes estimated in ProMort I were biased, which led to biased estimates of the absolute risks of dying from prostate cancer. The bias in both the relative and absolute risks was reduced by augmenting competing-risks cases, and especially by augmenting both the competing-risks cases and the controls. Our results indicate that, without the additional extensions to the design, the nested-case control studies are not suitable for the development of models predicting death from prostate cancer in the presence of competing risks. In Study II, we systematically compared the prognostic performance of the most commonly used pretreatment risk stratification tools in predicting death from prostate cancer using data from the Prostate Cancer data Base of Sweden. The Memorial Sloan Kettering Cancer Center nomogram, Cancer of the Prostate Risk Assessment score and Cambridge Prognostic Groups discriminated death from prostate cancer better than the D’Amico and D’Amico-derived risk grouping systems. The order of performance remained after stratifying by primary treatment and year of diagnosis. Using these tools could improve clinical decision-making. In Study III, we evaluated if a virtual microscopy system which we developed for central rereview in ProMort I and Study IV can be used interchangeably with standard light microscopy for the histopathological evaluation of prostate cancer. We found good repeatability (i.e., intra-observer agreement) and reproducibility (i.e., inter-observer agreement) for several key prostate cancer histopathological features (i.e., core length, tumor length, primary and secondary Gleason pattern, the Gleason score and the Gleason Grade Groups (GGs)) both within and between light and virtual microscopy. The repeatability and/or reproducibility for some of the rare, or less commonly reported, features and for the percentage of Gleason pattern 4 was poor. The repeatability and/or reproducibility for these features should be improved before they are used in prognostic models. For all evaluated features, the agreement was similar within and between light and virtual microscopy indicating that light microscopy and our internally developed virtual microscopy system can be used interchangeably for the histopathological evaluation of prostate cancer. In Study IV, we evaluated if the International Society of Urological Pathology (ISUP) revisions of the Gleason grading systems have improved prostate cancer prognostication. We used a nested case-control study (ProMort II) to compare the prognostic performance of the pre-2005 Gleason score and the ISUP 2014 Gleason score. In our study, the ISUP 2014 Gleason score discriminated death from prostate cancer better than the pre-2005 Gleason score. Our results also indicate that this improvement may be due to classifying all cribriform patterns, rather than poorly formed glands, as Gleason pattern 4. We then evaluated if other histopathological features can further improve the prediction of death from prostate cancer. The number of cores with ≥50% cancer involvement, comedonecrosis and high-grade prostatic intraepithelial neoplasia (HGPIN) predicted death from prostate cancer independently of the GGs. Only comedonecrosis and HGPIN remained independent predictors when added to the model with all the standard predictors (the GGs, age, PSA and clinical tumor stage at diagnosis). Adding these features had minimal impact on the model discrimination.
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