| 1. |
- Cornillet, Martin, et al.
(författare)
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The Swedish initiative for the study of Primary sclerosing cholangitis (SUPRIM)
- 2024
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Ingår i: eClinicalMedicine. - : Elsevier. - 2589-5370. ; 70
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDespite more than 50 years of research and parallel improvements in hepatology and oncology, there is still today neither a treatment to prevent disease progression in primary sclerosing cholangitis (PSC), nor reliable early diagnostic tools for the associated hepatobiliary cancers. Importantly, the limited understanding of the underlying biological mechanisms in PSC and its natural history not only affects the identification of new drug targets but implies a lack of surrogate markers that hampers the design of clinical trials and the evaluation of drug efficacy. The lack of easy access to large representative well-characterised prospective resources is an important contributing factor to the current situation.MethodsWe here present the SUPRIM cohort, a national multicentre prospective longitudinal study of unselected PSC patients capturing the representative diversity of PSC phenotypes. We describe the 10-year effort of inclusion and follow-up, an intermediate analysis report including original results, and the associated research resource. All included patients gave written informed consent (recruitment: November 2011–April 2016).FindingsOut of 512 included patients, 452 patients completed the five-year follow-up without endpoint outcomes. Liver transplantation was performed in 54 patients (10%) and hepatobiliary malignancy was diagnosed in 15 patients (3%). We draw a comprehensive landscape of the multidimensional clinical and biological heterogeneity of PSC illustrating the diversity of PSC phenotypes. Performances of available predictive scores are compared and perspectives on the continuation of the SUPRIM cohort are provided.InterpretationWe envision the SUPRIM cohort as an open-access collaborative resource to accelerate the generation of new knowledge and independent validations of promising ones with the aim to uncover reliable diagnostics, prognostic tools, surrogate markers, and new treatment targets by 2040.
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| 2. |
- Moro, Carlos Fernandez, et al.
(författare)
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An idiosyncratic zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- A perimetastatic capsule is a strong positive prognostic factor in liver metastases, but its origin remains unclear. Here, we systematically quantify the capsule's extent and cellular composition in 263 patients with colorectal cancer liver metastases to investigate its clinical significance and origin. We show that survival improves proportionally with increasing encapsulation and decreasing tumor-hepatocyte contact. Immunostaining reveals the gradual zonation of the capsule, transitioning from benign-like NGFR(high) stroma at the liver edge to FAP(high) stroma towards the tumor. Encapsulation correlates with decreased tumor viability and preoperative chemotherapy. In mice, chemotherapy and tumor cell ablation induce capsule formation. Our results suggest that encapsulation develops where tumor invasion into the liver plates stalls, representing a reparative process rather than tumor-induced desmoplasia. We propose a model of metastases growth, where the efficient tumor colonization of the liver parenchyma and a reparative liver injury reaction are opposing determinants of metastasis aggressiveness.
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| 3. |
- Villard, Christina
(författare)
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Abdominal aortic aneurysm in women : risk factor profile and aneurysm wall
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abdominal aortic aneurysm (AAA) in women is rare; the prevalence is approximately 0.5% in elderly women, to compare with 2-4% in aging men. The few women that suffer from AAA are older and have a higher rupture risk. A preventive effect of estrogen on AAA formation in animal models implies that the lower prevalence of AAA in women can depend on a protective effect of female sex hormones. The knowledge is scarce of how the aneurysm wall of women differs from that of men. Altogether, it is likely that biological gender differences could influence the risk of AAA development, growth rate and rupture risk. This thesis, based on five papers, focuses on risk factors for AAA in women and gender differences in the aneurysm wall. In the first paper, a case-control study, the reproductive history in women with AAA and a control group of women with peripheral artery disease was investigated. 280 women were invited to answer a questionnaire about their reproductive history and general health. The response rate was 70% and the results showed a lower mean menopausal age in women with larger AAA compared with women with smaller AAA and women with peripheral artery disease. The second paper, a case-control study, investigated previously reported, potential biomarkers for AAA. These had never been analysed in women with AAA and thus it was uncertain if they would apply to a female cohort. Men and women were in many aspects similar in biomarker profile, with the exception of matrix metalloproteinase 9 (MMP9). The levels of MMP9 were higher in women compared with men, with equally large AAA. In the third paper elastin content and elastolytic proteins in the aneurysm wall of men and women were analysed. 37 patients were included. The results suggest a more pronounced elastolysis and a lower elastin content in women compared with men. In the fourth paper collagen and its cross-linking were studied in 28 patients with AAA. The results showed no difference in the relative collagen content between men and women but a different collagen cross-linking in women compared with that in men. The findings might have implications for the biomechanical properties of the aneurysm wall in women, yet further analyses are required to clarify the mechanisms. The fifth paper was a study of the degree of apoptosis and inflammation, in relation to smooth muscle cells in the aneurysm wall of men and women. 40 patients with AAA were included. The findings suggest a more pronounced apoptosis in the aneurysm wall of women compared with men, which might be related to a greater infiltration of inflammatory cells. In conclusion, women with larger AAA have an altered reproductive history with a lower mean menopausal age, suggesting hormonal changes to be of importance for AAA development in women. The observed gender differences in the aortic wall described in this thesis, contribute to the presently poorly understood biological and morphological processes that trigger aneurysm development, progression and rupture.
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| 4. |
- Villard, Christina, et al.
(författare)
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Biomarkers for Abdominal Aortic Aneurysms From a Sex Perspective
- 2012
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Ingår i: Gender Medicine. - : Elsevier. - 1550-8579 .- 1878-7398. ; 9:4, s. 259-266
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Abdominal aortic aneurysms (AAAs) differ in men and women. Women are older at diagnosis, have a higher risk of rupture, and worse outcome after surgery compared with men. The higher occurrence of AAAs in men accounts for the dominance of men in biomarker analyses.OBJECTIVE:The primary aim of this study was to investigate levels of established biomarkers for AAA in men and women, and the secondary aim was to compare biomarker levels in women with and without AAAs.METHODS:In this prospective case-control study, blood samples were collected from 16 women and 18 men with AAAs ≥5.5 cm, from 20 women with AAAs <5.5 cm, and from 18 women with peripheral artery disease (PAD). Plasma concentrations of matrix metalloproteinase (MMP) -2, -9, and -13; tissue inhibitor of MMP-1 (TIMP-1); plasminogen activator inhibitor 1 (PAI-1); high-sensitivity C-reactive protein (hsCRP); and estradiol levels were analyzed by ELISA. An ultrasound examination was performed in women with PAD to exclude an AAA.RESULTS:Age and other comorbid conditions were similar between men and women with AAAs. Women with AAAs had higher levels of MMP-9 compared with men with equally large AAAs (42.8 ng/mL vs 36.2 ng/mL, P = 0.036) and lower levels of estradiol (30.0 pmoL vs 86.5 pmol/L, P < 0.001). Women with AAAs had lower levels of MMP-9 compared with women without (59.5 ng/mL vs 132.6 ng/mL, P = 0.010). There was no significant difference in the plasma levels of MMP-2, MMP-13, hsCRP, PAI-1, TIMP-1, and estradiol between women with and without AAAs.CONCLUSION:The higher levels of MMP-9 in women compared with men with equally large AAAs could suggest that MMP-9 is a biomarker related to the sex differences in aneurysm development. The lower levels of estradiol in women with AAAs compared with men suggest that the possible protective effect of endogenous estrogen cannot be explained by a difference in circulating levels of estradiol.
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| 5. |
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| 6. |
- Villard, Christina, et al.
(författare)
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Prospective surveillance for cholangiocarcinoma in unselected individuals with primary sclerosing cholangitis
- 2023
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 78:3, s. 604-613
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The evidence for hepatobiliary tumour surveillance in patients with primary sclerosing cholangitis (PSC) is scarce. This study aimed to prospectively evaluate cholangiocarcinoma (CCA) surveillance with yearly magnetic resonance imaging including cholangiopancreatography (MRI/MRCP) in a nationwide cohort.METHODS: In total, 512 PS C patients from 11 Swedish hospitals were recruited. The study protocol included yearly clinical follow-ups, liver function tests and contrast-enhanced MRI/MRCP and carbohydrate antigen (CA) 19-9. Patients with severe/progressive bile duct changes on MRI/MRCP were further investigated with endoscopic retrograde cholangiopancreatography. Patients were followed for five years or until a diagnosis of CCA, liver transplantation (LT) and/or death. Risk factors associated with CCA were analysed with Cox regression.RESULTS: Eleven patients (2%) were diagnosed with CCA, and two (.5%) with high-grade bile duct dysplasia. Severe/progressive bile duct changes on MRI/MRCP were detected in 122 patients (24%), of whom 10% had an underlying malignancy. The primary indication for LT (n=54) was biliary dysplasia in nine patients (17%) and end-stage liver disease in 45 patients (83%), of whom three patients (7%) had unexpected malignancy in the explants. The median survival for CCA patients was 13 months (3-22 months). Time to diagnosis of high-grade dysplasia and/or hepatobiliary malignancy was significantly associated with MRI/MRCP with severe/progressive bile duct changes hazard ratio (HR) 10.50 (95%CI 2.49-44.31) and increased levels of CA19-9 H R 1.00 (95%CI 1.00-1.01).CONCLUSION: In an unselected cohort of PSC patients, yearly CA19-9 and MRI/MRCP surveillance followed by ERCP was ineffective in detecting cancer early enough to provide long-term survival. Given the low occurrence of CCA, studies on individualized strategies for follow-up and improved diagnostic methods for PSC-CCA are warranted.IMPACT AND IMPLICATIONS: A prospective nationwide 5-year study was conducted to evaluate yearly surveillance with magnetic resonance imaging (MRI) and CA19-9 in patients with primary sclerosing cholangitis. Only 2% of the patients were diagnosed with cholangiocarcinoma during follow-up with a poor prognosis. This surveillance strategy was ineffective to detect cancer early enough to provide long-term survival.
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| 7. |
- Vujasinovic, Miroslav, et al.
(författare)
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The Role of Immunoglobulin G4 in Outcomes of Primary Sclerosing Cholangitis
- 2024
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Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease that is characterized by an inflammatory and fibrotic process affecting bile ducts which eventually develops into liver cirrhosis and liver failure. The aim of this study was to investigate serum IgG subclass distribution in patients with PSC and its possible association with PSC outcomes.Patients and methods: We performed a retrospective analysis of 181 patients who had been diagnosed with PSC between January 1970 and December 2015 and followed at our outpatient clinic. Their demographic, immunological, and clinical characteristics were recorded and analyzed.Results: This study included 181 patients with PSC (120 males, 61 females). There was no association between IgGs and the development of autoimmune hepatitis, cirrhosis, cholangiocarcinoma, liver transplantation, inflammatory bowel disease, and colectomy. Patients with elevated IgG4 had statistically significant higher rates of cholangitis (p = 0.02) and endoscopic retrograde cholangiopancreatography (ERCP) (p = 0.009). High IgG4 values were observed in nine patients who underwent ERCP. In these nine patients, on average, IgG4 was evaluated 5 years after ERCP (min 3 days, max 11 years). Subanalysis considering only IgG4 values evaluated before ERCP showed no significant difference but remains significant if we consider IgG4 values after ERCP.Conclusion: Elevated IgG4 in our study showed a possible association with higher rates of cholangitis and ERCP among patients with primary sclerosing cholangitis. It seems that IgGs may be a useful tool for the prediction of outcomes in patients with PSC. A prospective study is necessary, especially to study the trends of IgGs values during disease as well as the role of possible seroconversion.
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