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Background: Pancreatic ductal adenocarcinoma (pancreatic cancer) is often detected at late stages resulting in poor overall survival. To improve survival, more patients need to be diagnosed early when curative surgery is feasible. We aimed to identify circulating metabolites that could be used as early pancreatic cancer biomarkers. Methods: We performed metabolomics by liquid and gas chromatography-mass spectrometry in plasma samples from 82 future pancreatic cancer patients and 82 matched healthy controls within the Northern Sweden Health and Disease Study (NSHDS). Logistic regression was used to assess univariate associations between metabolites and pancreatic cancer risk. Least absolute shrinkage and selection operator (LASSO) logistic regression was used to design a metabolite-based risk score. We used receiver operating characteristic (ROC) analyses to assess the discriminative performance of the metabolite-based risk score. Results: Among twelve risk-associated metabolites with a nominal P value <0.05, we defined a risk score of three metabolites [indoleacetate, 3-hydroxydecanoate (10:0-OH), and retention index (RI): 2,745.4] using LASSO. A logistic regression model containing these three metabolites, age, sex, body mass index (BMI), smoking status, sample date, fasting status, and carbohydrate antigen 19-9 (CA 19-9) yielded an internal area under curve (AUC) of 0.784 [95% confidence interval (CI): 0.714–0.854] compared to 0.681 (95% CI: 0.597–0.764) for a model without these metabolites (P value =0.007). Seventeen metabolites were significantly associated with pancreatic cancer survival [false discovery rate (FDR) <0.1]. Conclusions: Indoleacetate, 3-hydroxydecanoate (10:0-OH), and RI: 2,745.4 were identified as the top candidate biomarkers for early detection. However, continued efforts are warranted to determine the usefulness of these metabolites as early pancreatic cancer biomarkers.

Studien syftar till att skapa en djupare förståelse över individers upplevelser av ett tidigare missbruk och dess inverkan på livet i efterhand och avsåg att besvara frågeställningen: Hur upplever individer som varit i missbruk att detta har influerat deras perspektiv på livet? Då upplevelsen av ett missbruk tenderar att vara en komplex upplevelse så valdes hermeneutiken som metodansats. Den hermeneutiska metodansatsen gjorde det möjligt att kunna få en bredare och djupare förståelse kring fenomenet. Tio dialogiska samtal genomfördes med före detta missbrukare som varit fria från sitt missbruk mellan 3-9 år. Den existentialistiska synen på människans sätt att vara-i-världen med begreppen varat, ångest, skuld, frihet, autenticitet och kriser användes som det teoretiska ramverket för att kunna förstå och tolka upplevelsen hos individer som tidigare missbrukat. Studiens resultat presenteras med en huvudtolkning som lyfter fram att erfarenheten av ett tidigare missbruk leder till ett perspektiv på livet som innefattar äkthet. Individerna som tidigare missbrukat ser och lever idag livet som äkta. De har omfamnat friheten och genom detta valt att möta de känslor som hör livet till, detta gör att de idag kan uppleva äkta känslor och följa sina egna värderingar vilket också genererat i en känsla av kontroll och att de är den personen de själva vill vara idag.

Studiens syfte är att bidra med kunskap om hur förskollärare resonerar kring arbetet med analog och digital barnlitteratur på förskolan. Forskningsfrågorna som studien besvarar är “hur resonerar förskollärare kring barns användande av analog barnlitteratur och digital barnlitteratur på förskolan?”, “vad anser förskollärare påverka barns intresse för användningen av analog och digital barnlitteratur?” och “hur resonerar förskollärare kring möjligheter och begränsningar med analog och digital barnlitteratur?”. En kvalitativ metod med semistrukturerade intervjuer har legat till grund för studien och sex förskollärare har intervjuats. Resultatet visar att förskollärare beskriver att de dagligen arbetar med barnlitteratur, både spontant och i planerade aktiviteter och att det främst är analog barnlitteratur som används och är tillgänglig i barnens miljö. Förskollärarna framhåller att det finns aspekter som påverkar barns intressen för de olika medierna och den största aspekten som uppdagas är att analog litteratur finns tillgänglig i lärmiljön för barnen att på eget initiativ använda och inspireras av vilket inte den digitala litteraturen gör. Förskollärarna beskriver analog och digital barnlitteratur som något positivt men nämner att digital litteratur kan vara mer krävande än analog litteratur.

Circulating type IV collagen (cCOL IV) is a potential biomarker for patients with colorectal liver metastases (CLM) who present with elevated levels of COL IV in both CLM tissue and circulation. This study aimed to establish the cellular origin of elevated levels of COL IV and analyze circulating COL IV in CLM patients. The cellular source was established through in situ hybridization, immunohistochemical staining, and morphological evaluation. Cellular expression in vitro was assessed by immunofluorescence. Tissue expression of COL IV-degrading matrix metalloproteinases (MMPs)-2, -7, -9, and -13 was studied with immunohistochemical staining. Plasma levels of COL IV in CLM patients and healthy controls were analyzed with ELISA. This study shows that cancer-associated fibroblasts (CAFs) express COL IV in the stroma of CLM and that COL IV is expressed in vitro by fibroblasts but not by tumor cells. MMP-2, -7, -9, and -13 are expressed in CLM tissue, mainly by hepatocytes and immune cells, and circulating COL IV is significantly elevated in CLM patients compared with healthy controls. Our study shows that stromal cells, not tumor cells, produce COL IV in CLM, and that circulating COL IV is elevated in patients with CLM.

Colorectal cancer (CRC) remains one of the most common cancers worldwide. Metastatic disease is ultimately fatal when incurable. Cancer research has evolved to take the importance of the tumour microenvironment (TME) into account. The extracellular matrix (ECM) has been viewed merely as a structural scaffold, but it is now evident that the ECM is a highly active part of the TME and affects tumour cell behaviour and metastatic capability. The ECM context and composition are linked to patient outcome and the response to surgical and oncological therapy in CRC patients and may be an area for developing novel biomarkers and targeted therapy. In this review we focus on the components of the ECM in human primary and metastatic CRC. We discuss future aspects of the ECM for targeted therapy, as a source of novel biomarkers, current knowledge of the area and important considerations when studying the ECM in human CRC.

PURPOSE: Resectability assessment of patients with colorectal liver metastases is based on computed tomography and liver magnetic resonance imaging. Addition of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography has been recommended, but the impact of the added information remains unclear. The primary aim of this study was to determine how preoperative positron emission tomography/computed tomography changed management in patients with potentially resectable colorectal liver metastases. The secondary aim was to investigate whether findings on positron emission tomography/computed tomography correlated to metastatic disease in cases with extended surgery and influenced oncological outcomes. METHODS: A retrospective observational study of the impact of adding positron emission tomography/computed tomography to conventional imaging in the surgical decision-making of colorectal liver metastases. All patients with colorectal liver metastases diagnosed by conventional imaging were included and assessed by a multidisciplinary team conference at Umeå University Hospital between June 2013 and December 2017. Eligibility criteria were all patients with potentially resectable colorectal liver metastases. Patients who underwent preoperative positron emission tomography/computed tomography in addition to conventional radiology were compared with those who underwent conventional imaging only. RESULTS: 151/220 patients underwent preoperative positron emission tomography/computed tomography. Findings on positron emission tomography/computed tomography changed the management in 10.6% of the patients. Eight patients were excluded from surgery after detection by positron emission tomography/computed tomography of extrahepatic disease. Eight patients underwent more extended surgery than initially planned due to positron emission tomography/computed tomography. Five of these positron emission tomography-positive resected sites were verified by pathology as me

Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.

Barn som växer upp med psykiskt sjuka föräldrar är en målgrupp som sällan synliggörs i samhället. Psykisk ohälsa är idag ett omtalat forskningsområde, då det sedan länge är ett stort folkhälsoproblem i Sverige. När en person blir psykiskt sjuk, riskerar den att tappa sin förmåga att ta ansvar, och när en förälder blir psykiskt sjuk kan det ansvaret ofta landa på barnet, att de blir unga vårdare. Ett sådant ansvar på barnet är skadligt då det kan påverka anknytningen till sina föräldrar negativt, samt skapar en sämre förutsättning för att knyta hälsosamma relationer i framtiden. Ytterligare konsekvenser är att de utsatta barnen själva kan utveckla en psykisk ohälsa när de inte har någon möjlighet att få sina behov tillgodosedda från sina föräldrar. I samband med detta finns det också en risk att barnen utvecklar ett medberoende gentemot sin sjuke förälder, i hopp om att underlätta för den. Detta kan ske genom att barnen dämpar sina egna problem eller behov för att föräldern ska kunna fokusera helt på sin egen sjukdom. Genom detta kan unga vårdare ses som mogna eller ansvarsfulla för sin ålder, trots att detta egentligen grundar sig i att de fråntas rätten att vara barn. Trots att många professioner; exempelvis lärare, kuratorer, läkare eller socialarbetare, har anmälningsskyldighet kring misstanke om barn som far illa upptäcks ofta deras situation för sent. Baserat på detta syftar den här uppsatsen till att undersöka hur samhällsvetenskaplig forskning problematiserat situationen för hur barn påverkas av att växa upp med en förälder som lider av psykisk ohälsa. För att besvara syfte och frågeställningarna har en litteraturöversikt med systematisk litteraturgenomgång genomförts. Vidare baseras uppsatsen på anknytningsteorin för att belysa hur viktig relationen mellan förälder och barn är.

Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death that typically presents at an advanced stage. No reliable markers for early detection presently exist. The prominent tumor stroma represents a source of circulating biomarkers for use together with cancer cell-derived biomarkers for earlier PDAC diagnosis. CA19-9 and CEA (cancer cell-derived biomarkers), together with endostatin and collagen IV (stroma-derived) were examined alone, or together, by multivariable modelling, using pre-diagnostic plasma samples (n = 259 samples) from the Northern Sweden Health and Disease Study biobank. Serial samples were available for a subgroup of future patients. Marker efficacy for future PDAC case prediction (n = 154 future cases) was examined by both cross-sectional (ROC analysis) and longitudinal analyses. CA19-9 performed well at, and within, six months to diagnosis and multivariable modelling was not superior to CA19-9 alone in cross-sectional analysis. Within six months to diagnosis, CA19-9 (AUC = 0.92) outperformed the multivariable model (AUC = 0.81) at a cross-sectional level. At diagnosis, CA19-9 (AUC = 0.995) and the model (AUC = 0.977) performed similarly. Longitudinal analysis revealed increases in CA19-9 up to two years to diagnosis which indicates a window of opportunity for early detection of PDAC.

The liver has evolved to maintain tissue homeostasis and a state of immune-unresponsiveness in the face of constant exposure to food-derived and commensal microbial products entering through the portal circulation. This is achieved by the unique properties of cells residing in the liver that function to dampen adaptive immune responses. Here we will survey the unique features of the liver microenvironment that contribute to this general state of immune-tolerance and render the liver particularly “hospitable” to incoming metastatic cancer cells. The diverse cell types and unique liver ECM, which collectively control the progression of metastasis and can act to curtail or promote the process, will be described and recent insight into their respective roles highlighted.

Early detection of pancreatic ductal adenocarcinoma (PDAC) is challenging, and late diagnosis partly explains the low 5-year survival. Novel and sensitive biomarkers are needed to enable early PDAC detection and improve patient outcomes. Tissue polypeptide specific antigen (TPS) has been studied as a biomarker in PDAC diagnostics, and it has previously been shown to reflect clinical status better than the ‘golden standard’ biomarker carbohydrate antigen 19-9 (CA 19-9) that is most widely used in the clinical setting. In this cross-sectional case-control study using pre-diagnostic plasma samples, we aim to evaluate the potential of TPS as a biomarker for early PDAC detection. Furthermore, in a subset of individuals with multiple samples available at different time points before diagnosis, a longitudinal analysis was used. We assessed plasma TPS levels using enzyme-linked immunosorbent assay (ELISA) in 267 pre-diagnostic PDAC plasma samples taken up to 18.8 years before clinical PDAC diagnosis and in 320 matched healthy controls. TPS levels were also assessed in 25 samples at PDAC diagnosis. Circulating TPS levels were low both in pre-diagnostic samples of future PDAC patients and in healthy controls, whereas TPS levels at PDAC diagnosis were significantly increased (odds ratio 1.03; 95% confidence interval: 1.01–1.05) in a logistic regression model adjusted for age. In conclusion, TPS levels increase late in PDAC progression and hold no potential as a biomarker for early detection.

The rising evidence of the tumor microenvironment (TME) and its role in cancer have made this an area of increased research efforts. The focus is both on the primary tumor but also on the metastatic setting. The TME though, does not only consist of the non-malignant cells of a tumor, but also of the acellular compartment: The Extracellular Matrix (ECM). The liver is a common organ for metastasis of many cancers and for some of these cancers' liver surgery is a standard treatment with long-term cure, whereas for other cancers not considered meaningful. Blood supply and anatomical reasons plays one part for the establishment of liver metastasis. It is however a well-known fact that the "soil" of a metastatic organ is of utter importance in the process of metastasis. The "soil" consists of the TME where the ECM is a critical and active part. This review focuses what is known about the normal ECM of the human liver, what is known about ECM proteins in human liver metastasis, challenges of studying the ECM in liver metastases and lastly, potential applications of this field of knowledge.

Gallstones, a common gastrointestinal condition, can lead to several digestive complications and can result in inflammation. Risk factors for gallstones include obesity, diabetes, smoking and physical inactivity, all of which are known risk factors for colorectal cancer (CRC), as is inflammation. However, it is unclear whether gallstones are a risk factor for CRC. We examined the association between history of gallstones and CRC in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a prospective cohort of over half a million participants from ten European countries. History of gallstones was assessed at baseline using a self-reported questionnaire. The analytic cohort included 334,986 participants; a history of gallstones was reported by 3,917 men and 19,836 women, and incident CRC was diagnosed among 1,832 men and 2,178 women (mean follow-up: 13.6 years). Hazard ratios (HR) and 95% confidence intervals (CI) for the association between gallstones and CRC were estimated using Cox proportional hazards regression models, stratified by sex, study centre and age at recruitment. The models were adjusted for body mass index, diabetes, alcohol intake and physical activity. A positive, marginally significant association was detected between gallstones and CRC among women in multivariable analyses (HR = 1.14, 95%CI 0.99-1.31, p = 0.077). The relationship between gallstones and CRC among men was inverse but not significant (HR = 0.81, 95%CI 0.63-1.04, p = 0.10). Additional adjustment for details of reproductive history or waist circumference yielded minimal changes to the observed associations. Further research is required to confirm the nature of the association between gallstones and CRC by sex.

Objectives: The aim of this research was to study whether plasma microRNAs (miRNA) can be used for early detection of pancreatic cancer (PC) by analyzing prediagnostic plasma samples collected before a PC diagnosis. Background: PC has a poor prognosis due to late presenting symptoms and early metastasis. Circulating miRNAs are altered in PC at diagnosis but have not been evaluated in a prediagnostic setting. Methods: We first performed an initial screen using a panel of 372 miRNAs in a retrospective case-control cohort that included early-stage PC patients and healthy controls. Significantly altered miRNAs at diagnosis were then measured in an early detection case-control cohort wherein plasma samples in the cases are collected before a PC diagnosis. Carbohydrate antigen 19–9 (Ca 19–9) levels were measured in all samples for comparison. Results: Our initial screen, including 23 stage I-II PC cases and 22 controls, revealed 15 candidate miRNAs that were differentially expressed in plasma samples at PC diagnosis. We combined all 15 miRNAs into a multivariate statistical model, which outperformed Ca 19–9 in receiver-operating characteristics analysis. However, none of the candidate miRNAs, individually or in combination, were significantly altered in prediagnostic plasma samples from 67 future PC patients compared with 132 matched controls. In comparison, Ca 19–9 levels were significantly higher in the cases at <5 years before diagnosis. Conclusion: Plasma miRNAs are altered in PC patients at diagnosis, but the candidate miRNAs found in this study appear late in the course of the disease and cannot be used for early detection of the disease., Originally included in thesis in manuscript form.

Background: Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs. Methods: Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined. Results: Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006). Conclusions: The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.

Background:Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs.Methods:Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined.Results:Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006).Conclusions:The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.