Abdominal aortic aneurysm in women : risk factor profile and aneurysm wall

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

Practice patterns in diagnostics, staging, and management strategies of gallbladder cancer among Nordic tertiary centers

Background and objective: Gallbladder cancer (GBC) is a rare malignancy in the Nordic countries and no common Nordic treatment guidelines exist. This study aimed to characterize the current diagnostic and treatment strategies in the Nordic countries and disclose differences in these strategies. Methods: This was a survey study with a cross-sectional questionnaire of all 19 university hospitals providing curative-intent surgery for GBC in Sweden, Norway, Denmark, and Finland. Results: In all Nordic countries except Sweden, neoadjuvant/downstaging chemotherapy was used in GBC patients. In T1b and T2, majority of the centers (15–18/19) performed extended cholecystectomy. In T3, majority of the centers (13/19) performed cholecystectomy with resection of segments 4b and 5. In T4, majority of the centers (12–14/19) chose palliative/oncological care. The centers in Sweden extended lymphadenectomy beyond the hepatoduodenal ligament, whereas all other Nordic centers usually limited lymphadenectomy to the hepatoduodenal ligament. All Nordic centers except those in Norway used adjuvant chemotherapy routinely for GBC. There were no major differences between the Nordic centers in diagnostics and follow-up. Conclusions: The surgical and oncological treatment strategies of GBC vary considerably between the Nordic centers and countries.publishedVersio

HelmCoP: An Online Resource for Helminth Functional Genomics and Drug and Vaccine Targets Prioritization

A vast majority of the burden from neglected tropical diseases result from helminth infections (nematodes and platyhelminthes). Parasitic helminthes infect over 2 billion, exerting a high collective burden that rivals high-mortality conditions such as AIDS or malaria, and cause devastation to crops and livestock. The challenges to improve control of parasitic helminth infections are multi-fold and no single category of approaches will meet them all. New information such as helminth genomics, functional genomics and proteomics coupled with innovative bioinformatic approaches provide fundamental molecular information about these parasites, accelerating both basic research as well as development of effective diagnostics, vaccines and new drugs. To facilitate such studies we have developed an online resource, HelmCoP (Helminth Control and Prevention), built by integrating functional, structural and comparative genomic data from plant, animal and human helminthes, to enable researchers to develop strategies for drug, vaccine and pesticide prioritization, while also providing a useful comparative genomics platform. HelmCoP encompasses genomic data from several hosts, including model organisms, along with a comprehensive suite of structural and functional annotations, to assist in comparative analyses and to study host-parasite interactions. The HelmCoP interface, with a sophisticated query engine as a backbone, allows users to search for multi-factorial combinations of properties and serves readily accessible information that will assist in the identification of various genes of interest. HelmCoP is publicly available at: http://www.nematode.net/helmcop.html

Prognostic influence of multiple hepatic lesions in resectable intrahepatic cholangiocarcinoma: A systematic review and meta-analysis

Background: Presence of multiple hepatic lesions in intrahepatic cholangiocarcinoma (iCCA) is included in staging as a negative prognostic factor, but both prognostic value and therapeutic implications remain debated. The aim of this study was to systematically review the prognostic influence of multiple lesions on survival after resection for iCCA, with stratification for distribution and number of lesions. Methods: Medline and Embase were systematically searched to identify records (2010–2021) reporting survival for patients undergoing primary resection for iCCA. Included were original articles reporting overall survival, with data on multiple lesions including tumour distribution (satellites/other multiple lesions) and/or number. For meta-analysis, the random effects model and inverse variance method were used. PRISMA 2020 guidelines were followed. Results: Thirty-one studies were included for review. For meta-analysis, nine studies reporting data on the prognostic influence of satellite lesions (2737 patients) and six studies reporting data on multiple lesions other than satellites (1589 patients) were included. Satellite lesions (hazard ratio 1.89, 95% confidence interval 1.67–2.13) and multiple lesions other than satellites (hazard ratio 2.41, 95% confidence interval 1.72–3.37) were significant negative prognostic factors. Data stratified for tumour number, while limited, indicated increased risk per additional lesion. Conclusion: Satellite lesions, as well as multiple lesions other than satellites, was a negative prognostic factor in resectable iCCA. Considering the prognostic impact, both tumour distribution and number of lesions should be evaluated together with other risk factors to allow risk stratification for iCCA patients with multiple lesions, rather than precluding resection for the entire patient group

Dipeptidyl peptidase-4 is increased in the abdominal aortic aneurysm vessel wall and is associated with aneurysm disease processes.

BACKGROUND:Abdominal aortic aneurysm (AAA) is a potentially life-threatening disease, and until today there is no other treatment available than surgical intervention. Dipeptidyl peptidase-4 (DPP4)-inhibitors, used clinically to treat type 2 diabetes, have in murine models been shown to attenuate aneurysm formation and decrease aortic wall matrix degradation, inflammation and apoptosis. Our aim was to investigate if DPP4 is present, active and differentially expressed in human AAA. METHODS AND RESULTS:DPP4 gene expression was elevated in both media and adventitia of AAA tissue compared with control tissue, as measured by microarrays and qPCR, with consistent findings in external data. The plasma activity of DPP4 was however lower in male patients with AAA compared with age- and gender-matched controls, independently of comorbidity or medication. Immunohistochemical double staining revealed co-localization of DPP4 with cells positive for CD68, CD4 and -8, CD20, and SMA. Gene set enrichment analysis demonstrated that expression of DPP4 in AAA tissue correlated with expression of biological processes related to B- and T-cells, extracellular matrix turnover, peptidase activity, oxidative stress and angiogenesis whereas it correlated negatively with muscle-/actin-related processes. CONCLUSION:DPP4 is upregulated in both media and adventitia of human AAA and correlates with aneurysm pathophysiological processes. These results support previous murine mechanistic studies and implicate DPP4 as a target in AAA disease

The Swedish initiative for the study of Primary sclerosing cholangitis (SUPRIM)Research in context

Summary: Background: Despite 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. Methods: We 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). Findings: Out 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. Interpretation: We 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. Funding: This work was supported by the Swedish Cancer Society, Stockholm County Council, and the Cancer Research Funds of Radiumhemmet

Gallbladder cancer mimicking perihilar cholangiocarcinoma—considerable rate of postoperative reclassification with implications for prognosis

Abstract Background For some patients undergoing resection under the suspicion of a perihilar cholangiocarcinoma (pCCA), postoperative diagnosis may differ from the preoperative diagnosis. While a postoperative finding of benign bile duct stricture is known to affect 3–15% of patients, less has been described about the consequences of finding other biliary tract cancers postoperatively. This study compared pre- and postoperative diagnoses, risk characteristics, and outcomes after surgery for suspected pCCA. Methods Retrospective single-center study, Karolinska University Hospital, Stockholm, Sweden (January 2009–May 2017). The primary postoperative outcome was overall survival. Secondary outcomes were disease-free survival and postoperative complications. Survival analysis was performed by the Kaplan–Meier method. Results Seventy-one patients underwent resection for suspected pCCA. pCCA was confirmed in 48 patients (68%). Ten patients had benign lesions (14%), 2 (3%) were diagnosed with other types of cholangiocarcinoma (CCA, distal n = 1, intrahepatic n = 1), while 11 (15%) were diagnosed with gallbladder cancer (GBC). GBC patients were older than patients with pCCA (median age 71 versus 58 years, p = 0.015), with a large proportion of patients with a high tumor extension stage (≥ T3, 91%). Median overall survival was 20 months (95% CI 15–25 months) for patients with pCCA and 17 months (95% CI 11–23 months) for patients with GBC (p = 0.135). Patients with GBC had significantly shorter median disease-free survival (DFS), 10 months (95% CI 3–17 months) compared 17 months (95% CI 15–19 months) for patients with pCCA (p = 0.010). Conclusions At a large tertiary referral center, 15% of patients resected for suspected pCCA were postoperatively diagnosed with GBC. Compared to patients with pCCA, GBC patients were older, with advanced tumors and shorter DFS. The considerable rate of re-classification stresses the need for improved preoperative staging, as these prognostic differences could have implications for treatment strategies

Immunohistochemical profiling of liver metastases and matched-pair analysis in patients with metastatic pancreatic ductal adenocarcinoma

Background The purpose of the current study was to investigate the immunohistochemical (IHC) profile of liver metastases (LM) in patients with pancreatic ductal adenocarcinoma (PDAC). Methods Expression of 15 IHC markers in liver biopsies from 77 patients with PDAC, who were diagnosed between 2010 and 2014, were evaluated. In a separate subgroup analysis (n = 12), paired samples (LM and primary tumor) from the same patient were investigated for IHC profile differences. Results LM samples were classified as pancreatobiliary-type (PB-type) in 72 patients (93.5%), intestinal-type (INT-type) in four patients (5.2%), and squamous in one patient (1.3%). There was no significant difference in overall survival (OS) between LM of the PB-type or INT-type (p = 0.097). In a multivariate analysis, age <70 years (p = 0.047), absence of SMAD4 mutation (p = 0.026), absence of CDX2 expression (p = 0.003), and well to moderate differentiation were significant prognostic factors for better OS in patients with LM (p = 0.031). Analysis of paired tissue samples from LM and the primary tumor revealed a difference in CDX2 (50% increase, p = 0.125) and SMAD4 (33% loss of SMAD4, p = 0.375). Conclusions CDX2 expression and SMAD4 mutation indicate a poor outcome in patients with LM of PDAC. Matched-pair analysis revealed differences in distinct IHC marker expression

Prospective surveillance for cholangiocarcinoma in unselected individuals with primary sclerosing cholangitis

Background &amp; Aims: The evidence for hepatobiliary tumour surveillance in patients with primary sclerosing cholangitis (PSC) is scarce. In this study, we aimed to prospectively evaluate cholangiocarcinoma (CCA) surveillance with yearly MRI with cholangiopancreatography (MRI/MRCP) in a nationwide cohort. Methods: In total, 512 patients with PSC 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 5 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 (0.5%) 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 patients with CCA was 13 months (3-22 months). Time to diagnosis of high-grade dysplasia and/or hepatobiliary malignancy was significantly associated with severe/progressive bile duct changes on MRI/MRCP (hazard ratio 10.50; 95% CI 2.49-44.31) and increased levels of CA19-9 (hazard ratio 1.00; 95% CI 1.00-1.01). Conclusion: In an unselected cohort of patients with PSC, yearly CA19-9 and MRI/MRCP surveillance followed by ERCP was ineffective in detecting cancer early enough to support long-term survival. Given the low occurrence of CCA, studies on individualised strategies for follow-up and improved diagnostic methods for PSC-related CCA are warranted. Impact and implications: A prospective nationwide 5-year study was conducted to evaluate yearly cholangiocarcinoma surveillance using MRI and CA19-9 in patients with primary sclerosing cholangitis. Only 2% of the patients were diagnosed with cholangiocarcinoma during follow-up and their prognosis remained poor despite surveillance. This surveillance strategy failed to detect cancer early enough to support long-term survival. Therefore, individualised strategies and improved diagnostic methods will be required to improve the early detection of cholangiocarcinoma in patients with primary sclerosing cholangitis