Enterochromaffin-like (ECL) and ghrelin cells, in the human gastric mucosa and in gastric endocrine tumours (GETs), were subclassified with respect to immunohistochemical reaction vs. vesicular monoamine transporter 2 (VMAT-2), ghrelin/obestatin, and histidine decarboxylase (HDC). The immunohistochemical expression of ghrelin/obestatin and HDC in GETs was related/correlated to plasma ghrelin/obestatin and urinary methyl imidazole acetic acid (U-MeImAA) excretion respectively, with the intention of identifying markers for these tumour types. ECL cells in the gastric mucosa appear either with VMAT-2 only, or with HDC immunoreactivity only, or they can express both proteins; but in GETs the transporter protein and the enzyme were almost always co-expressed in the same cells. Furthermore, ghrelin and obestatin were co-localized in the same cells in the gastric mucosa and in the tumours. In the gastric mucosa, occasional ghrelin/obestatin cells expressed VMAT-2, but in GETs these proteins were always co-localized. Ghrelin expressing cells were non-immunoreactive to HDC. Plasma ghrelin/obestatin concentrations remained low in patients with GETs, irrespective of the relative incidence of these cells in the mucosa and in tumours. The plasma values were not related/correlated to various clinico-pathological parameters. A malignant ghrelinoma was however an exception. The tumour released high total and active ghrelin concentrations into the blood circulation. The patient suffered from diarrhoea, hypothyroidism and diabetes mellitus, but it is not clear if these conditions were due to hyperghrelinaemia. The excretion U-MeImAA was increased in a few patients with GETs, but this increase was not always related to clinical symptoms. In conclusion, ECL cells are an heterogeneous group according to VMAT-2 and HDC immunoreactivity. Ghrelin and obestatin are expressed in the same cells in the gastric mucosa, and a few of these cells display VMAT-2 immunoreactivity. Ghrelinoma is a new gastric tumour entity.

Ovarian cancer is a fatal disease because of the lack of symptoms and markers for early detection. Most ovarian neoplasms resemble and are classified according to the complex characteristics of Mullerian duct epithelia. We tested the hypothesis that Mullerian epithelial characteristics influence early ovarian neoplastic progression. The most common type of ovarian cancer is the serous carcinoma which resembles Mullerian-derived oviductal epithelium. We discovered that oviduct-specific glycoprotein (OVGP1), a tubal differentiation marker, was present in inclusion cysts, which are the preferential sites for malignant transformation, and in most low grade serous tumors, but absent in ovarian surface epithelium and most high grade carcinomas. OVGP1 was almost entirely limited to ovarian neoplasms with the notable exception of endometrial hyperplasia and carcinoma. A new antibody against OVGP1 detected elevated serum levels from most women with low grade ovarian cancers compared to normal controls. OVGP1 also identified a subset of patients with high grade serous carcinomas who had a more favorable outcome. To examine whether the differentiated phenotype of early ovarian neoplasms alters invasiveness, we established the first permanent cell line for serous borderline ovarian tumors (SBOT), which are differentiated but noninvasive. The results revealed a striking phenotypic similarity between two lines regardless of their cytogenetic diversity. They retained Mullerian epithelial characteristics in vitro, as demonstrated by their morphologic appearance and the differentiation markers keratin, E-cadherin, CA125 and OVGP1. Neither disruption of the growth pattern nor manipulations of the cadherin profile induced invasivenesss. Induction of invasiveness by SV40 early genes was associated with a loss in morphologic differentiation and of differentiation markers but increased motility. MMP secretion was independent of the invasion status. Our findings indicate that OVGP1 is an indicator of early ovarian epithelial neoplasia. It can be detected in the sera from women with early ovarian cancer, and thus, may be a new promising diagnostic marker for the early detection of ovarian cancer. In addition, the results show that Mullerian differentiation does not directly prevent invasiveness, but it diminishes in parallel with invasion caused by other factors. The lack of invasiveness by SBOT cells may depend on factors that regulate motility.

Phthalates are industrial plasticizers with a wide range of applications. Di-(2-ethylhexyl) phthalate (DEHP) is one of the most highly produced and frequently studied phthalates. Its metabolite, mono-(2-ethylhexyl) phthalate (MEHP) is known as a testicular toxicant. The objective of this study was to examine expression of the genes of interest in testicular germ cells exposed to MEHP in a dose- and time-dependent manner at concentrations of 1µM, 10µM, and 100µM at 24, 48, 72 and 96hr time points. The genes consisted of Testisin, GSPT1, and MGMT genes which are a tumor suppressors, phase II xenobiotic metabolizing enzyme and DNA repair gene respectively. These genes were analyzed by Quantitative Real Time PCR (RT-PCR). The results revealed an overall down-regulation for each gene as the concentration and/or time increased. Testisin was the focus of the gene expression analysis. Testisin is epigenetically silenced in testicular germ cell tumors (TGCT) by DNA methylation at the 5’CpG island of the gene. To investigate if MEHP is capable of DNA hypermethylation, a co-exposure with 5-azacytidine (demethylating agent) was conducted. Compared with the 5-azacytidine treatment alone, there was a significant down-regulation of the Testisin gene in the co-exposure. This suggests that MEHP may down-regulate Testisin gene expression by DNA methylation. These findings provide evidence that MEHP can alter the expression of Testisin, GSTP1 and MGMT, genes that are associated in the risk of developing testicular germ cell tumors. In addition, results indicated that MEHP may cause DNA methylation leading to the down-regulation/silencing of genes such as Testisin.

The use of complementary non-invasive imaging modalities has been proposed to track disease progression, particularly cancer, while simultaneously evaluating therapeutic efficacy. A major obstacle is a limited ability to compare parameters obtained from different modalities, especially those from exogenous contrast agents or tracers. We hypothesize that combining Magnetic Resonance Imaging (MRI) and Ultrasound (US) will improve characterization of the tumour microenvironment. In this study, we describe a co-registration apparatus that facilitates the acquisition of a priori co-registered MR and US images in vivo. This apparatus was validated using phantom data and it was found that the US slices can be selected to an accuracy of +/- 100µm translationally and +/- 2 degrees rotationally. Additionally, it was shown that MRI and US may provide complimentary information about the tumour microenvironment, but more work needs to be done to assess repeatability of dynamic contrast enhanced MRI and US.

Smärta i samband med intrakraniell kirurgi liknar smärta i samband med all annan form av kirurgi. Syftet var att granska hur barn med hjärntumör smärtbedömts och smärtbehandlats postoperativt efter tumörkirurgi. Metod: Totalt har journaler för 40 barn (20 barn på Akademiska barnsjukhuset i Uppsala och 20 barn på Astrid Lindgrens barnsjukhus vid Karolinska sjukhuset, Stockholm) som opererats för tumörer i hjärnan granskats, avseende smärtbedömning, användandet av smärtskalor, farmakologiska och ickefarmakologisk smärtbehandling de tre första postoperativa dygnen. Resultat: Studien visade att smärtskattning med smärtskalor användes på 12 av 40 barn. Den vanligaste formen av smärtbedömning som återfanns dokumenterad var en bedömning av sjuksköterskan. På Akademiska sjukhuset återfanns ingen dokumenterad smärtbedömning i 60 % av de granskade dygnen, på Astrid Lindgrens barnsjukhus var motsvarande siffra 20 %. De vanligaste läkemedlen som används på båda sjukhusen var paracetamol och opioider, framförallt morfin. Vid Astrid Lindgrens barnsjukhus används företrädelsevis stående ordinationer med paracetamol i kombination med opioidinfusioner. Vid Akademiska sjukhuset används framförallt paracetamol som stående ordination och opioidinjektioner som vid behovsordinationer. I dokumentationen återfanns ingen ickefarmakologisk behandling. För totalt 6 barn fanns omnämnt olika typer av distraktion eller tröst. Slutsats: Slutsatsen blir att utifrån journaldokumentation är systematisk smärtskattning av barn som opererats för tumörer i hjärnan, och utvärdering av given smärtbehandling bristfällig. / Pain in relation to intracranial surgery is similar to pain in relation to all other kind of surgery. Aim: The aim of this study was to review how children with brain tumour were assessed and treated for postoperative pain after tumour surgery. A total of 40 charts of children (20 children at Akademiska University Hospital and 20 children at Astrid Lindgren Children’s Hospital) who had gone through brain surgery have been reviewed with respect to pain assessment, use of assessment tools, pharmacological and nonpharmacological treatment the first tree days after surgery. Result: This study showed that pain assessment tools were used for 12 out of 40 children. The most used documented way of pain assessment was an assessment by the nurse. At the Akademiska University Hospital no documented pain assessment was performed in 60% of the reviewed days. At Astrid Lindgren Children’s Hospital the corresponding number was 20%. The most common drugs used at both hospitals were paracetamol and opioids, particularly morphine. At Astrid Lindgren Children’s Hospital they preferably used standing prescriptions of paracetamol in combination with morphine. At the Akademiska University Hospital they used paracetamol as a standing prescription and opioids as an on demand prescription. In the documentation no nonpharmacological treatment was found. For 6 children there was documentation of different types of distraction or consolation. Conclusion: The conclusion from the study of the documentation is that systematic pain assessment of children who had gone through brain surgery and evaluation of given pain treatment is insufficient.

<p>Radio frequency ablation (RFA) is a commonly used minimally invasive method of treating liver cancer tumours which utilises RF current for heating tumour tissue up to a lethal temperature. RF current is generated by a power generator and applied to the tumour by an electrode which is inserted into the tumour either during percutaneous or open surgery. </p><p>RFA is a method that has great advantages compared to traditional surgical resection of tumours due to minimal invasiveness, it can be used for a greater number of patients and enables repeated treatments. Even though there are many advantages coupled to RFA there are still some problems and difficulties associated with the method. One of these problems is the cooling effect from large vessel blood flow within the liver, the so called heat sink effect.</p><p>The aim of this master thesis work has been to develop a theoretical finite element model of RFA within Comsol Multiphysics software. This theoretical model has been used to simulate blood perfusion effects on resulting ablation volume. The effects from different large vessel blood flow parameters has been investigated, these parameters are: blood flow velocity, blood vessel diameter and distance between blood vessel and RF electrode. A factorial design has been utilised to setup parameter levels for the different simulations. A linear- and a second degree regression model has been calculated based on simulation results. The parameter with largest impact on simulative ablation volume and the interaction effects between the parameters were determined from the regression model coefficients. In addition to this has two simulations been performed, modelling perfused- and unperfused liver tissue, in order to investigate the effects resulting from microvascular perfusion.</p><p>The result shows that the parameter with largest impact on simulative ablation volume are the distance, it was also shown that there are a small interactional effects between diameter and distance, where a small distance increases the effect from a varying diameter. Modelled microvascular perfusion was shown to give a decrease in simulative ablation volume. A shortage of this master thesis work is the lack of experimental verification of the developed model. </p>

Within solid tumours, a microenvironment exists that causes resistance to chemotherapy. New drugs that target cells within this microenvironment are required, the first step in this process being the identification of new targets. The aim of this thesis was to characterise changes in the transcriptome and proteome within specific regions of multicell-tumour spheroids (MCTS), an experimental model that mimics many of the features of the tumour microenvironment. HT29 MCTS were separated by sequential trypsinisation into 3 main regions; the outer surface layer (SL) the peri-necroric region (PN) and the necrotic core (NC). Using an iTRAQ quantitative proteomics approach, the proteome of the different MCTS regions was investigated. A 2 dimensional separation approach using Agilent's OffGel system and RP-nano HPLC was incorporated prior to MS analysis. MS analysis was done using both MALDI-TOF-TOF (Bruker Ultraflex II) and ESI-Q-TOF (Agilent 6530 QTOF LC/MS) instruments. Gene expression profiles of the different MCTS were investigated and compared using Agilent's one-color oligonucleotide based microarrays. Transcriptomic and proteomic analysis identified several key differences in the proteins involved in cell metabolism between the SL and PN/NC regions. Similar metabolic changes were also noted between autophagic and normal monolayer cells. Many highlighted proteins represented established cancer associated proteins. Interestingly, a number of proteins were highlighted which have no previous association with cancer and may upon further validation, provide attractive leads for therapeutic intervention.

Τα τελευταία χρόνια, γίνεται πολύς λόγος για τους καρκινικούς όγκους, καθώς η νόσος αυτή προσβάλλει ολοένα και περισσότερα άτομα κάθε χρόνο. Ιδιαίτερη βαρύτητα έχει δοθεί τόσο ερευνητικά όσο και ιατρικά στην αντιμετώπιση του καρκίνου μέσω θεραπευτικών τεχνικών (χημειοθεραπείες, χειρουργικές επεμβάσεις κλπ) καθώς και στην βελτίωση των συνθηκών διαβίωσης των καρκινοπαθών. Επίσης, αρκετή έμφαση στην έρευνα σχετικά με την ανάπτυξη του καρκίνου σε βιοχημικό επίπεδο και για την βαθύτερη κατανόηση της νόσου. Η έρευνα αφορά ερευνητές πολλών διαφορετικών ειδικοτήτων μεταξύ των οποίων και των μαθηματικών. Από το 1954 με την πρόταση των Armitage και Doll σχετικά με την μαθηματική μοντελοποίηση της γένεσης των καρκινικών όγκων, αρκετοί έχουν ασχοληθεί με την μαθηματική προτυποποίηση των διαφόρων φάσεων του καρκίνου, από την δημιουργία του μέχρι και την αντίσταση του σε φαρμακευτική αγωγή. Η εργασία αυτή πραγματεύεται την μαθηματική θεμελίωση και προτυποποίηση των καρκινικών όγκων όσον αφορά την γεωμετρική τους ανάπτυξη. Με βάση το θεμελιώδες μαθηματικό μοντέλο που προτάθηκε το 1976 από τον H. P. Greenspan, μελετάται η επίπτωση επιφανειακών διαταραχών στην ανάπτυξη σφαιρικών καθώς και ελλειψοειδών όγκων. Στην πρωτότυπη εργασία, η μελέτη περιορίστηκε στην ανάλυση των διαταραχών με μεταβλητή την πολική γωνία των σφαιρικών συντεταγμένων. Στην εργασία αυτή αρχικά μελετάται η γενίκευση του μοντέλου διαταραχών και στις δυο γωνίες του σφαιρικού συστήματος συντεταγμένων (πολική θ και αζιμουθιακή φ). Στην συνέχεια επεκτείνεται η μέθοδος σε τρία μοντέλα που γενικεύουν τις παραδοχές του αρχικού μοντέλου διατηρώντας την παραδοχή της σφαιρικής γεωμετρίας και μελετάται η ευστάθεια των αντίστοιχων επιφανειακών διαταραχών. Τέλος, μελετάται και η ευστάθεια του ίδιου προβλήματος στην ελλειψοειδή γεωμετρία επειδή η ανισοτροπία του ελλειψοειδούς σχήματος καθιστά πιο ρεαλιστική την προσέγγιση του πραγματικού σχήματος του καρκινικού όγκου. / The mathematical analysis of the tumour growth attracted a lot of interest in the last two decades. However, as of today no generally accepted model for tumour growth exists. This is due partially to the incomplete understanding of the related pathology as well as the extremely complicated procedure that guides the evolution of a tumour. Moreover, the growth of a tumour does depend on the available tissue surrounding the tumour and therefore it represents a physical case that is realistically modelled by ellipsoidal geometry. The remarkable aspect of the ellipsoidal shape is that it represents the sphere of the anisotropic space. It provides the appropriate geometrical model for any direction dependent physical quantity. In the present work we analyze the stability of a spherical tumour for four continuous models of an avascular tumour and the stability study of an ellipsoidal tumour. For all five models, conditions for the stability are stated and the results are implemented numerically. For the spherical cases, it is observed that the steady state radii that secure the stability of the tumour are different for each of the four models, and that results to differences in the stable and unstable modes. As for the ellipsoidal model, it is shown that, in contrast to the highly symmetric spherical case, where stability is possible to be achieved, there are no conditions that secure the stability of an ellipsoidal tumour. Hence, as in many physical cases, the observed instability is a consequence of the lack of symmetry.

Radio frequency ablation (RFA) is a commonly used minimally invasive method of treating liver cancer tumours which utilises RF current for heating tumour tissue up to a lethal temperature. RF current is generated by a power generator and applied to the tumour by an electrode which is inserted into the tumour either during percutaneous or open surgery. RFA is a method that has great advantages compared to traditional surgical resection of tumours due to minimal invasiveness, it can be used for a greater number of patients and enables repeated treatments. Even though there are many advantages coupled to RFA there are still some problems and difficulties associated with the method. One of these problems is the cooling effect from large vessel blood flow within the liver, the so called heat sink effect. The aim of this master thesis work has been to develop a theoretical finite element model of RFA within Comsol Multiphysics software. This theoretical model has been used to simulate blood perfusion effects on resulting ablation volume. The effects from different large vessel blood flow parameters has been investigated, these parameters are: blood flow velocity, blood vessel diameter and distance between blood vessel and RF electrode. A factorial design has been utilised to setup parameter levels for the different simulations. A linear- and a second degree regression model has been calculated based on simulation results. The parameter with largest impact on simulative ablation volume and the interaction effects between the parameters were determined from the regression model coefficients. In addition to this has two simulations been performed, modelling perfused- and unperfused liver tissue, in order to investigate the effects resulting from microvascular perfusion. The result shows that the parameter with largest impact on simulative ablation volume are the distance, it was also shown that there are a small interactional effects between diameter and distance, where a small distance increases the effect from a varying diameter. Modelled microvascular perfusion was shown to give a decrease in simulative ablation volume. A shortage of this master thesis work is the lack of experimental verification of the developed model.

Ovarian cancer is a fatal disease because of the lack of symptoms and markers for early detection. Most ovarian neoplasms resemble and are classified according to the complex characteristics of Mullerian duct epithelia. We tested the hypothesis that Mullerian epithelial characteristics influence early ovarian neoplastic progression. The most common type of ovarian cancer is the serous carcinoma which resembles Mullerian-derived oviductal epithelium. We discovered that oviduct-specific glycoprotein (OVGP1), a tubal differentiation marker, was present in inclusion cysts, which are the preferential sites for malignant transformation, and in most low grade serous tumors, but absent in ovarian surface epithelium and most high grade carcinomas. OVGP1 was almost entirely limited to ovarian neoplasms with the notable exception of endometrial hyperplasia and carcinoma. A new antibody against OVGP1 detected elevated serum levels from most women with low grade ovarian cancers compared to normal controls. OVGP1 also identified a subset of patients with high grade serous carcinomas who had a more favorable outcome. To examine whether the differentiated phenotype of early ovarian neoplasms alters invasiveness, we established the first permanent cell line for serous borderline ovarian tumors (SBOT), which are differentiated but noninvasive. The results revealed a striking phenotypic similarity between two lines regardless of their cytogenetic diversity. They retained Mullerian epithelial characteristics in vitro, as demonstrated by their morphologic appearance and the differentiation markers keratin, E-cadherin, CA125 and OVGP1. Neither disruption of the growth pattern nor manipulations of the cadherin profile induced invasivenesss. Induction of invasiveness by SV40 early genes was associated with a loss in morphologic differentiation and of differentiation markers but increased motility. MMP secretion was independent of the invasion status. Our findings indicate that OVGP1 is an indicator of early ovarian epithelial neoplasia. It can be detected in the sera from women with early ovarian cancer, and thus, may be a new promising diagnostic marker for the early detection of ovarian cancer. In addition, the results show that Mullerian differentiation does not directly prevent invasiveness, but it diminishes in parallel with invasion caused by other factors. The lack of invasiveness by SBOT cells may depend on factors that regulate motility.