| 1. |
- Andersson, Nina, et al.
(författare)
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Lymphocyte antigen 6 superfamily member D is a marker of urothelial and squamous differentiation : Implications for risk stratification of bladder cancer
- 2020
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Ingår i: Biomarker research. - : Springer Science and Business Media LLC. - 2050-7771. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Screening across a multitude of normal and malignant tissues revealed an enhanced expression of lymphocyte antigen 6 superfamily member D (LY6D) in squamous epithelium and urothelium, as well as in malignancies derived therefrom. The aim of this study was to further delineate the protein expression of LY6D in urothelial bladder cancer, with particular attention to its relationship with clinicopathological characteristics and patient outcome. Methods: Immunohistochemical expression of LY6D was assessed in tissue microarrays with urothelial bladder cancer tumours from three independent patient cohorts; one with transurethral resection of the bladder (TURB) specimens of mixed tumour stages from 110 consecutive cases, one with tumours of mixed stages from 260 incident cases in a population-based cohort, and one with paired TURB specimens, resected tumours and a subset of lymph node metastases from 145 patients with muscle-invasive bladder cancer (MIBC). Chi-square and non-parametric tests were applied to examine associations of LY6D expression with clinicopathological characteristics. Kaplan-Meier and Cox regression analyses were applied to examine 5-year overall survival (OS) and recurrence free survival (RFS) in relation to LY6D expression. Results: In the two cohorts with mixed stages, positive LY6D expression was denoted in 63 and 64% of the cases, respectively, and found to be significantly higher in low-grade and less invasive tumours. Negative LY6D expression was significantly associated with a reduced 5-year OS, although not independently of established prognostic factors. In the population-based cohort, LY6D expression was higher in tumours with squamous differentiation and lower in other variant histologies compared to pure urothelial tumours, and the association of LY6D expression with survival was somewhat enhanced after exclusion of the former. LY6D expression was generally lower in the MIBC cohort, and even more reduced in resected tumours compared to TURB specimens in patients who had not received neoadjuvant chemotherapy. There were no significant associations between LY6D expression and RFS, neither allover nor in relation to neoadjuvant chemotherapy. Conclusion: LY6D is a marker of urothelial and squamous differentiation that may add useful diagnostic and prognostic information to better guide the clinical management of bladder cancer, given that the presence of variant histology is taken into account.
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| 2. |
- Björnfot, Cecilia, et al.
(författare)
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Assessing cerebral arterial pulse wave velocity using 4D flow MRI
- 2021
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : Sage Publications. - 0271-678X .- 1559-7016. ; 41:10, s. 2769-2777
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Tidskriftsartikel (refereegranskat)abstract
- Intracranial arterial stiffening is a potential early marker of emerging cerebrovascular dysfunction and could be mechanistically involved in disease processes detrimental to brain function via several pathways. A prominent consequence of arterial wall stiffening is the increased velocity at which the systolic pressure pulse wave propagates through the vasculature. Previous non-invasive measurements of the pulse wave propagation have been performed on the aorta or extracranial arteries with results linking increased pulse wave velocity to brain pathology. However, there is a lack of intracranial “target-organ” measurements. Here we present a 4D flow MRI method to estimate pulse wave velocity in the intracranial vascular tree. The method utilizes the full detectable branching structure of the cerebral vascular tree in an optimization framework that exploits small temporal shifts that exists between waveforms sampled at varying depths in the vasculature. The method is shown to be stable in an internal consistency test, and of sufficient sensitivity to robustly detect age-related increases in intracranial pulse wave velocity.
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| 3. |
- Korlen, Sara, et al.
(författare)
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The development and validation of a scale to explore staff experience of governance of economic efficiency and quality (GOV-EQ) of health care
- 2018
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Ingår i: BMC Health Services Research. - : BMC. - 1472-6963. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn publicly funded health care systems, governance models are developed to push public service providers to use tax payers' money more efficiently and maintain a high quality of service. Although this implies change in staff behaviors, evaluation studies commonly focus on organizational outputs. Unintended consequences for staff have been observed in case studies, but theoretical and methodological development is necessary to enable studies of staff experience in larger populations across various settings. The aim of the study is to develop a self-assessment scale of staff experience of the governance of economic efficiency and quality of health care and to assess its psychometric properties.MethodsFactors relevant to staff members' experience of economic efficiency and quality requirements of health care were identified in the literature and through interviews with practitioners, and then compared to a theoretical model of behavior change. Relevant experiences were developed into sub-factors and items. The scale was tested in collaboration with the Department of Rehabilitation Medicine at a university hospital. 93 staff members participated. The scale's psychometric properties were assessed using exploratory factor analysis, analysis of internal consistency and criterion-related validity.ResultsThe analysis revealed an eight factor structure (including sub-factors knowledge and awareness, opportunity to influence, motivation, impact on professional autonomy and organizational alignment), and items showed strong factor loadings and high internal consistency within sub-factors. Sub-factors were interrelated and contributed to the prediction of impact on clinical behavior (criterion).ConclusionsThe scale clearly distinguishes between various experiences regarding economic efficiency and quality requirements among health care staff, and shows satisfactory psychometric quality. The scale has broad applications for research and practice, as it serves as a tool for capturing staff members' perspectives when evaluating and improving health care governance. The scale could also be useful for understanding the underlying processes of changes in provider performance and for adapting management strategies to engage staff in driving change that contributes to increased economic efficiency and quality, for the benefit of health care systems, patients and staff.
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| 4. |
- Marschall, Hanns-Ulrich, 1954, et al.
(författare)
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Incidence, prevalence, and outcome of primary biliary cholangitis in a nationwide Swedish population-based cohort
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Available epidemiological data on primary biliary cholangitis (PBC) in Sweden originate from regional studies in the 1980s and may not reflect modern day PBC. We aimed to estimate incidence and prevalence, survival and death causes, and gender differences in PBC. We used international classification of disease (ICD) codes to identify patients with PBC in inpatient and outpatient registries 1987-2014 who were then linked to the Swedish cause of death, cancer and prescribed drug registries. Each PBC patient was matched with 10 reference individuals from the general population. In sensitivity analyses, we examined PBC patients identified through clinical patient records from Karolinska, Sahlgrenska and Orebro University Hospitals. We identified 5,350 adults with PBC. Prevalence of PBC increased steadily from 5.0 (1987) to 34.6 (2014) per 100,000 inhabitants whereas the yearly incidence rate was relatively constant with a median of 2.6 per 100,000 person-years, with a female: male gender ratio of 4:1. Compared to reference individuals, PBC individuals aged 15-39 years at diagnosis had a substantially higher risk of death (Hazard Ratio [HR] 12.7, 95% Confidence Interval [CI] 8.3-19.5) than those diagnosed between 40-59 (HR 4.1, 95% CI 3.7-4.5) and > 60 (HR 3.7, 95% CI 3.5-3.9) years of age. Relative risks of mortality were highest in men. In conclusion, we found that recorded prevalence of PBC in Sweden has increased substantially during the last 30 years although incidence has been stable. Patients diagnosed in young adulthood were at a 12.7-fold increased risk of death, and male PBC patients had worse prognosis.
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| 5. |
- Merrien, Magali, et al.
(författare)
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Clinical and biological impact of SAMHD1 expression in mantle cell lymphoma
- 2022
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Ingår i: Virchows Archiv. - : Springer Science and Business Media LLC. - 0945-6317 .- 1432-2307. ; 480:3, s. 655-666
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Tidskriftsartikel (refereegranskat)abstract
- SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that restricts viral replication in infected cells and limits the sensitivity to cytarabine by hydrolysing its active metabolite, as recently shown in acute myeloid leukemia. Cytarabine is an essential component in the Nordic mantle cell lymphoma protocols (MCL2 and MCL3) for induction and high-dose chemotherapy treatment before autologous stem cell transplantation for younger patients with mantle cell lymphoma (MCL). We here investigated the expression of SAMHD1 in a population-based cohort of MCL (N = 150). SAMHD1 was highly variably expressed in MCL (range, 0.4% to 100% of positive tumor cells). Cases with blastoid/pleomorphic morphology had higher SAMHD1 expression (P = 0.028) and SAMHD1 was also correlated to tumor cell proliferation (P = 0.016). SAMHD1 expression showed moderate correlation to the expression of the transcriptional regulator SOX11 (P = 0.036) but genetic silencing of SOX11 and SAMHD1 by siRNA in MCL cell lines did not suggest mutual regulation. We hypothesized that expression of SAMHD1 could predict short time to progression in patients treated with Cytarabine as part of high-dose chemotherapy. Despite the correlation with known biological adverse prognostic factors, neither low or high SAMHD1 expression correlated to PFS or OS in patients treated according to the Nordic MCL2 or MCL3 protocols (N = 158).
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| 6. |
- Olsson Hau, Sofie, et al.
(författare)
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PRR11 unveiled as a top candidate biomarker within the RBM3-regulated transcriptome in pancreatic cancer
- 2022
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Ingår i: Journal of Pathology: Clinical Research. - : Wiley. - 2056-4538. ; 8:1, s. 65-77
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Tidskriftsartikel (refereegranskat)abstract
- The outlook for patients with pancreatic cancer remains dismal. Treatment options are limited and chemotherapy remains standard of care, leading to only modest survival benefits. Hence, there is a great need to further explore the mechanistic basis for the intrinsic therapeutic resistance of this disease, and to identify novel predictive biomarkers. RNA-binding motif protein 3 (RBM3) has emerged as a promising biomarker of disease severity and chemotherapy response in several types of cancer, including pancreatic cancer. The aim of this study was to unearth RBM3-regulated genes and proteins in pancreatic cancer cells in vitro, and to examine their expression and prognostic significance in human tumours. Next-generation RNA sequencing was applied to compare transcriptomes of MIAPaCa-2 cells with and without RBM3 knockdown. The prognostic value of differentially expressed genes (DEGs) was examined in The Cancer Genome Atlas (TCGA). Top deregulated genes were selected for further studies in vitro and for immunohistochemical analysis of corresponding protein expression in tumours from a clinically well-annotated consecutive cohort of 46 patients with resected pancreatic cancer. In total, 19 DEGs (p < 0.01) were revealed, among which some with functions in cell cycle and cell division stood out; PDS5A (PDS cohesin associated factor A) as the top downregulated gene, CCND3 (cyclin D3) as the top upregulated gene, and PRR11 (proline rich 11) as being highly prognostic in TCGA. Silencing of RBM3 in MiaPaCa-2 cells led to congruent alterations of PDS5A, cyclin D3, and PRR11 levels. High protein expression of PRR11 was associated with adverse clinicopathological features and shorter overall survival. Neither PDS5A nor cyclin D3 protein expression was prognostic. This study unveils several RBM3-regulated genes with potential clinical relevance in pancreatic cancer, among which PRR11 shows the most consistent association with disease severity, at both transcriptome and protein levels.
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| 7. |
- Wahlin, Sara, et al.
(författare)
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Clinical impact of T cells, B cells and the PD-1/PD-L1 pathway in muscle invasive bladder cancer : a comparative study of transurethral resection and cystectomy specimens
- 2019
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Ingår i: OncoImmunology. - 2162-4011. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- In patients with muscle invasive bladder cancer (MIBC), neoadjuvant chemotherapy (NAC) prior to radical cystectomy has improved survival but there is an urgent unmet need to identify prognostic and predictive biomarkers to stratify patients who will benefit from treatment. This study aimed to examine the composition of tumor-infiltrating immune cells in MIBC, with particular reference to the clinical outcome and the potential modifying effect of NAC. To this end, the expression of CD8+ and FoxP3+ T cells, CD20+ B cells, PD-1+ and PD-L1+ immune cells and PD-L1+ tumor cells was evaluated by immunohistochemistry on tissue microarrays with paired transurethral resection (TURB) specimens, cystectomy specimens and lymph node metastases from 145 patients, 65 of whom had received NAC. Kaplan–Meier and Cox regression analyses were applied to assess the impact of investigated cell subsets on time to recurrence (TTR). In cystectomy specimens, high infiltration of the investigated immune cell populations, but not PD-L1+ tumor cells, were independently associated with a prolonged TTR, whereas in TURB specimens, this association was only seen for CD8+ lymphocytes. An additive beneficial prognostic effect of NAC was seen for the majority of the cell subsets but there was no significant interaction between any immune marker and NAC in relation to TTR. Furthermore, no differences in cell densities prior to NAC treatment were observed between complete and non-complete responders, or pre- and posttreatment in non-complete responders. In conclusion, immune cell infiltration provides important prognostic information in both pre- and postsurgical samples of MIBC, independently of NAC.
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| 8. |
- Wahlin, Sara, et al.
(författare)
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Pre-clinical and clinical studies on the role of RBM3 in muscle-invasive bladder cancer : longitudinal expression, transcriptome-level effects and modulation of chemosensitivity
- 2022
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The response to neoadjuvant cisplatin-based chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) is impaired in up to 50% of patients due to chemoresistance, with no predictive biomarkers in clinical use. The proto-oncogene RNA-binding motif protein 3 (RBM3) has emerged as a putative modulator of chemotherapy response in several solid tumours but has a hitherto unrecognized role in MIBC. Methods: RBM3 protein expression level in tumour cells was assessed via immunohistochemistry in paired transurethral resection of the bladder (TURB) specimens, cystectomy specimens and lymph node metastases from a consecutive cohort of 145 patients, 65 of whom were treated with NAC. Kaplan-Meier and Cox regression analyses were applied to estimate the impact of RBM3 expression on time to recurrence (TTR), cancer-specific survival (CSS), and overall survival (OS) in strata according to NAC treatment. The effect of siRNA-mediated silencing of RBM3 on chemosensitivity was examined in RT4 and T24 human bladder carcinoma cells in vitro. Cellular functions of RBM3 were assessed using RNA-sequencing and gene ontology analysis, followed by investigation of cell cycle distribution using flow cytometry. Results: RBM3 protein expression was significantly higher in TURB compared to cystectomy specimens but showed consistency between primary tumours and lymph node metastases. Patients with high-tumour specific RBM3 expression treated with NAC had a significantly reduced risk of recurrence and a prolonged CSS and OS compared to NAC-untreated patients. In high-grade T24 carcinoma cells, which expressed higher RBM3 mRNA levels compared to RT4 cells, RBM3 silencing conferred a decreased sensitivity to cisplatin and gemcitabine. Transcriptomic analysis revealed potential involvement of RBM3 in facilitating cell cycle progression, in particular G1/S-phase transition, and initiation of DNA replication. Furthermore, siRBM3-transfected T24 cells displayed an accumulation of cells residing in the G1-phase as well as altered levels of recognised regulators of G1-phase progression, including Cyclin D1/CDK4 and CDK2. Conclusions: The presented data highlight the potential value of RBM3 as a predictive biomarker of chemotherapy response in MIBC, which could, if prospectively validated, improve treatment stratification of patients with this aggressive disease.
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| 9. |
- Weibull, Caroline E., et al.
(författare)
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Survival by First-line Treatment Type and Timing of Progression Among Follicular Lymphoma Patients : A National Population-based Study in Sweden
- 2023
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Ingår i: HemaSphere. - : Wolters Kluwer. - 2572-9241. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- In follicular lymphoma (FL), progression of disease <= 24 months (POD24) has emerged as an important prognostic marker for overall survival (OS). We aimed to investigate survival more broadly by timing of progression and treatment in a national population-based setting. We identified 948 stage II-IV indolent FL patients in the Swedish Lymphoma Register diagnosed 2007-2014 who received first-line systemic therapy, followed through 2020. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by first POD at any time during follow-up using Cox regression. OS was predicted by POD using an illness-death model. During a median follow-up of 6.1 years (IQR: 3.5-8.4), 414 patients experienced POD (44%), of which 270 (65%) occurred <= 24 months. POD was represented by a transformation in 15% of cases. Compared to progression-free patients, POD increased all-cause mortality across treatments, but less so among patients treated with rituximab(R)-single (HR = 4.54, 95% CI: 2.76-7.47) than R-chemotherapy (HR = 8.17, 95% CI: 6.09-10.94). The effect of POD was similar following R-CHOP (HR = 8.97, 95% CI: 6.14-13.10) and BR (HR = 10.29, 95% CI: 5.60-18.91). The negative impact of POD on survival remained for progressions up to 5 years after R-chemotherapy, but was restricted to 2 years after R-single. After R-chemotherapy, the 5-year OS conditional on POD occurring at 12, 24, and 60 months was 34%, 46%, and 57% respectively, versus 78%, 82%, and 83% if progression-free. To conclude, POD before but also beyond 24 months is associated with worse survival, illustrating the need for individualized management for optimal care of FL patients.
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