Colorectal cancer (CRC) remains a significant burden in contemporary society due to an aging population, unhealthy dietary choices and an increasingly sedentary lifestyle. While the underlying defects for many hereditary forms of CRC have been determined, many genetic and epigenetic changes promoting common sporadic CRCs have yet to be identified. The Mutated in Colorectal Cancer (MCC) gene, identified in 1991, was initially thought to be responsible for the hereditary form of CRC, familial adenomatous polyposis, before the discovery of the susceptibility gene Adenomatous Polyposis Coli (APC), which then became the focus of intense research. Recent data, however, suggests that MCC may also be important in the development of CRC. I have investigated the mechanism of MCC gene silencing, the putative structure, and multiple functions of MCC. MCC was frequently silenced by promoter hypermethylation in CRC cell lines and primary tumours. MCC methylation showed strong molecular and clinicopathological associations with hallmarks of the serrated neoplasia pathway. Furthermore, MCC methylation was more frequent in serrated precursor lesions compared with adenomas, thus occurring early during carcinogenesis. MCC is highly conserved in complex multicellular organisms. Re-introduction of MCC in CRC cell lines resulted in partial G1 to S phase, and G2/M phase cell cycle blocks, potentially by upregulating cell cycle inhibitor gene transcription and interfering with the process of mitotic checkpoints and division, respectively. Changes in MCC levels also modulated NF?B pathway signalling, the pathway required for maintaining cell viability and proliferation in colonic epithelial cells. In particular, MCC overexpression suppressed both TNF? and LPS-induced NF?B activation, decreasing both the magnitude and rate of cellular responses. Overexpression also resulted in downregulation of proteins involved in canonical NF?B pathway signalling, while increasing the transcription of non-canonical NF?B genes. Therefore, MCC may direct activation of this pathway to a specific subset of NF?B-regulated genes. These data provide a molecular basis for the role of MCC as a tumour suppressor gene in CRC. MCC may have multiple functions, regulating cell cycle progression and modulating NF?B pathway signalling, either through direct involvement in pathway signalling cascades, or by providing a scaffold on which signalling events can occur.

<p>The major advantage of position sensitive radiation detector systems lies in their ability to non invasively map the regional distribution of the emitted radiation in real-time. Three of such detector systems were studied in this thesis, gamma-cameras, positron cameras and CMOS image sensors. A number of physical factors associated to these detectors degrade the qualitative and quantitative properties of the obtained images. These blurring factors could be divided into two groups. The first group consists of the general degrading factors inherent to the physical interaction processes of radiation with matter, such as scatter and attenuation processes which are common to all three detectors The second group consists of specific factors inherent to the particular radiation detection properties of the used detector which have to be separately studied for each detector system. Therefore, the aim of this thesis was devoted to the development of computational methods to enable quantitative molecular imaging in PET, SPET and in vivo patient dosimetry with CMOS image sensors.</p><p>The first task was to develop a novel quantitative dual isotope method for simultaneous assessments of regional lung ventilation and perfusion using a SPET technique. This method included correction routines for photon scattering, non uniform attenuation at two different photon energies (140 and 392 keV) and organ outline. This quantitative method was validated both with phantom experiments and physiological studies on healthy subjects.</p><p>The second task was to develop and clinically apply a quantitative method for tumour to background activity uptake measurements using planar mammo-scintigraphy, with partial volume compensation.</p><p>The third stage was to produce several computational models to assess the spatial resolution limitations in PET from the positron range, the annihilation photon non-collineairy and the photon depth of interaction.</p><p>Finally, a quantitative image processing method for a CMOS image sensor for applications in ion beam therapy dosimetry was developed.</p><p>From the obtained phantom and physiological results it was concluded that the methodologies developed for the simultaneous measurement of the lung ventilation and perfusion and for the quantification of the tumour malignancy grade in breast carcinoma were both accurate. Further, the obtained models for the influence that the positron range in various human tissues, and the photon emission non-collinearity and depth of interaction have on PET image spatial resolution, could be used both to optimise future PET camera designs and spatial resolution recovery algorithms. Finally, it was shown that the proton fluence rate in a proton therapy beam could be monitored and visualised by using a simple and inexpensive CMOS image sensor.</p>

<p>Varje år diagnostiseras över 50 000 individer med cancer i Sverige. Ett cancerbesked väcker blandade känslor och associeras ofta med lidande och död. Ett svårt besked kan leda till en förändrad livssituation och kan även ses som början på en lång och mödosam resa. En vetenskaplig litteraturstudie baserad på 15 originalartiklar genomfördes med syftet att belysa patientens upplevelse av ett cancerbesked och därmed öka sjuksköterskans förståelse för patientens situation samt fördjupa kunskaperna inom ämnet. Genom litteraturgranskningen identifierades tre teman: information, emotionella reaktioner samt psykosocialt stöd. Patienten upplever att det är viktigt att informationen ges på ett öppet och ärligt sätt. Vidare framkom det betydelsefullt att uppmärksamma patientens emotionella reaktioner i samband med beskedet. Eftersom upplevelsen av ett cancerbesked påverkar patientens fortsatta upplevelse av sin sjukdom, har sjuksköterskan en viktig roll att fylla genom att erbjuda psykosocialt stöd i de olika tänkbara situationer som kan uppkomma i samband med ett livsavgörande besked. Fortsatt forskning behövs för att jämföra hur de rekommendationer som finns angående delgivandet av ett svårt besked överensstämmer med patienternas egna upplevelser och önskemål.</p> / <p>Every year, over 50 000 individuals in Sweden are diagnosed with cancer. The disclosure of the cancer diagnosis arouses emotions and is often associated with suffering and death. Receiving bad news may lead to changes in life and can also be seen as the beginning of a long and difficult journey. A scientific study based on 15 original articles was carried out with the purpose to identify the patient’s experience of receiving a cancer diagnosis and therefore increase the nurse’s understanding for the patient’s situation and deepen the knowledge of the subject. When examining the articles three themes were identified: information, emotional reactions and psychosocial support. The patient experience that it is important that the information is given in an open and honest manner. Patients also find it important that their emotional reaction is being observed as receiving the diagnosis. As the disclosure of the cancer diagnosis affects the patient’s further perception of the disease the nurse has an important role providing psychosocial support in various situations that may arise in connection with the disclosure. Continued research is needed to compare how guidelines for giving bad news to a patient correspond with the patient’s own experiences and preferences.</p>

<p>The positron emitting radionuclide ⁶⁸Ga (T_1/2 = 68 min) might become of practical interest for clinical positron emission tomography (PET). The metallic cation, ⁶⁸Ga(III), is suitable for complexation with chelators, either naked or conjugated with biological macromolecules. Such labelling procedures require pure and concentrated preparations of ⁶⁸Ga(III), which cannot be sufficiently fulfilled by the presently available ⁶⁸Ge/⁶⁸Ga generator eluate. This thesis presents methods to increase the concentration and purity of ⁶⁸Ga obtained from a commercial ⁶⁸Ge/⁶⁸Ga generator. The use of the preconcentrated and purified ⁶⁸Ga eluate along with microwave heating allowed quantitative ⁶⁸Ga-labelling of peptide conjugates within 15 min. The specific radioactivity of the radiolabelled peptides was improved considerably compared to previously applied techniques using non-treated generator eluate and conventional heating. A commercial ⁶⁸Ge/⁶⁸Ga generator in combination with the method for preconcentration/purification and microwave heated labelling might result in an automated device for ⁶⁸Ga-based radiopharmaceutical kit production with quantitative incorporation of ⁶⁸Ga(III).</p><p>Macromolecules were labelled with ⁶⁸Ga(III) either directly or via a chelator. The bifunctional chelator, DOTA, was conjugated in solution to peptides, an antibody and oligonucleotides. The peptides had varied pI values, constitution, and length ranging from 8 to 53 amino acid residues. The oligonucleotides were of various sequences and length with modifications in backbone, sugar moiety and both 3' and 5' ends with a molecular weight up to 9.8 kDa. The bioconjugates were labeled with ⁶⁸Ga(III), and the resulting tracers were characterised chemically and biologically. The identity of the ⁶⁸Ga-labelled bioconjugates was verified. The tracers were found to be stable and their biological activity maintained. Specific radioactivity was shown to be an important parameter influencing the feasibility of accurate imaging data quantification.</p><p>Furthermore, ⁶⁸Ga-labelled peptide imaging was shown to be a useful tool to study peptide adsorption to microstructures in a chemical analysis device.</p>

<p>Midgut carcinoid tumours are rare with an incidence of 0.5-2.1/100 000. The primary tumour is usually small and grows slowly but has almost always set metastases at diagnosis. When radically operated, most patients will eventually recur in their disease. </p><p>We evaluated different methods in detecting recurrent disease in 61 malignant midgut carcinoid tumours that had been radically operated. Thirty-eight patients have been diagnosed with a recurrence. In 32/38 of these patients P-Chromogranin A was the first method to indicate a recurrence. We therefore recommend using P-CgA in the work up in these patients.</p><p>We investigated characteristics, survival and independent factors that could be of bad prognostic value. We found that in our 284 malignant midgut carcinoid tumours, 208/284 (73%) had distant metastases and 30/284 (11%) had carcinoid heart disease. Median survival was 115.5 months and five-year survival was 77%. In a multivariate analysis liver metastases and carcinoid heart disease were poor prognostic factors.</p><p>We performed a phase II study with octreotide pamoate investigating the clinical effect in 12 malignant midgut carcinoid tumours in a progressive phase. We found that 9/12 (75%) were stabilised for a median duration of 12 months. We think that this is a good effect considering the advanced stage.</p><p>We investigated the frequency of four different tyrosine kinase receptors, platelet derived growth factor receptor (PDGR) α and β, epidermal growth factor receptor (EGFR) and c-kit, in 36 malignant midgut carcinoid tumours with immunohistochemistry. We found that 13/34 (38%) tumour samples expressed PDGFRα, 29/33 (88%) PDGFRβ, 24/33 (73%) EGFR, whereas none expressed c-kit. This implicates that midgut carcinoid tumours might be susceptible to treatment with tyrosine kinase receptor inhibitors. </p>

<p>In this study, metastasizing serotonin-producing ileocaecal carcinoid tumours (MSPCs) were examined for biological characteristics that could be used to define clinically relevant subgroups within this patient population. Possible targets for new treatment options were also explored.</p><p>It was found that MSPCs share several biological characteristics such as expression of serotonin, tachykinins (TKs), chromogranin A, islet autoantigen-2 and connective tissue growth factor (CTGF). TKs and serotonin were demonstrated in the same endocrine tumours in the gut and lung. IA-2 expression was shown to be up-regulated in MSPCs, possibly in connection with active hormone secretion. CTGF expression was high in tumour areas adjacent to extensive stroma expressing alpha-smooth muscle actin. This indicated myofibroblast differentiation, which may be associated with fibrosis-related complications prevalent in patients with MSPCs. When compared with other endocrine tumours, MSPCs behaved as a relatively homogeneous group, though within the MSPC population several subgroups could be defined. Patients with tumours displaying either a solid growth pattern and/or a Ki67 index ≥1% had a less favourable prognosis than those who did not. Another group of patients, who had increased plasma TK concentrations, were more likely to suffer from severe diarrhea. This information should be considered when discussing clinical treatment and when undertaking tumour biological studies. New treatment possibilities, such as drugs that specifically target TK receptors and antibodies to CTGF, are also discussed.</p><p>In conclusion, MSPCs comprise a clinically relevant tumour group with similar biological features that are distinct from other endocrine tumours. Subgroups of patients within this patient category can be defined which may be relevant when establishing prognosis and when selecting future treatment modalities.</p>

The positron emitting radionuclide 68Ga (T1/2 = 68 min) might become of practical interest for clinical positron emission tomography (PET). The metallic cation, 68Ga(III), is suitable for complexation with chelators, either naked or conjugated with biological macromolecules. Such labelling procedures require pure and concentrated preparations of 68Ga(III), which cannot be sufficiently fulfilled by the presently available 68Ge/68Ga generator eluate. This thesis presents methods to increase the concentration and purity of 68Ga obtained from a commercial 68Ge/68Ga generator. The use of the preconcentrated and purified 68Ga eluate along with microwave heating allowed quantitative 68Ga-labelling of peptide conjugates within 15 min. The specific radioactivity of the radiolabelled peptides was improved considerably compared to previously applied techniques using non-treated generator eluate and conventional heating. A commercial 68Ge/68Ga generator in combination with the method for preconcentration/purification and microwave heated labelling might result in an automated device for 68Ga-based radiopharmaceutical kit production with quantitative incorporation of 68Ga(III). Macromolecules were labelled with 68Ga(III) either directly or via a chelator. The bifunctional chelator, DOTA, was conjugated in solution to peptides, an antibody and oligonucleotides. The peptides had varied pI values, constitution, and length ranging from 8 to 53 amino acid residues. The oligonucleotides were of various sequences and length with modifications in backbone, sugar moiety and both 3' and 5' ends with a molecular weight up to 9.8 kDa. The bioconjugates were labeled with 68Ga(III), and the resulting tracers were characterised chemically and biologically. The identity of the 68Ga-labelled bioconjugates was verified. The tracers were found to be stable and their biological activity maintained. Specific radioactivity was shown to be an important parameter influencing the feasibility of accurate imaging data quantification. Furthermore, 68Ga-labelled peptide imaging was shown to be a useful tool to study peptide adsorption to microstructures in a chemical analysis device.

The major advantage of position sensitive radiation detector systems lies in their ability to non invasively map the regional distribution of the emitted radiation in real-time. Three of such detector systems were studied in this thesis, gamma-cameras, positron cameras and CMOS image sensors. A number of physical factors associated to these detectors degrade the qualitative and quantitative properties of the obtained images. These blurring factors could be divided into two groups. The first group consists of the general degrading factors inherent to the physical interaction processes of radiation with matter, such as scatter and attenuation processes which are common to all three detectors The second group consists of specific factors inherent to the particular radiation detection properties of the used detector which have to be separately studied for each detector system. Therefore, the aim of this thesis was devoted to the development of computational methods to enable quantitative molecular imaging in PET, SPET and in vivo patient dosimetry with CMOS image sensors. The first task was to develop a novel quantitative dual isotope method for simultaneous assessments of regional lung ventilation and perfusion using a SPET technique. This method included correction routines for photon scattering, non uniform attenuation at two different photon energies (140 and 392 keV) and organ outline. This quantitative method was validated both with phantom experiments and physiological studies on healthy subjects. The second task was to develop and clinically apply a quantitative method for tumour to background activity uptake measurements using planar mammo-scintigraphy, with partial volume compensation. The third stage was to produce several computational models to assess the spatial resolution limitations in PET from the positron range, the annihilation photon non-collineairy and the photon depth of interaction. Finally, a quantitative image processing method for a CMOS image sensor for applications in ion beam therapy dosimetry was developed. From the obtained phantom and physiological results it was concluded that the methodologies developed for the simultaneous measurement of the lung ventilation and perfusion and for the quantification of the tumour malignancy grade in breast carcinoma were both accurate. Further, the obtained models for the influence that the positron range in various human tissues, and the photon emission non-collinearity and depth of interaction have on PET image spatial resolution, could be used both to optimise future PET camera designs and spatial resolution recovery algorithms. Finally, it was shown that the proton fluence rate in a proton therapy beam could be monitored and visualised by using a simple and inexpensive CMOS image sensor.

Midgut carcinoid tumours are rare with an incidence of 0.5-2.1/100 000. The primary tumour is usually small and grows slowly but has almost always set metastases at diagnosis. When radically operated, most patients will eventually recur in their disease. We evaluated different methods in detecting recurrent disease in 61 malignant midgut carcinoid tumours that had been radically operated. Thirty-eight patients have been diagnosed with a recurrence. In 32/38 of these patients P-Chromogranin A was the first method to indicate a recurrence. We therefore recommend using P-CgA in the work up in these patients. We investigated characteristics, survival and independent factors that could be of bad prognostic value. We found that in our 284 malignant midgut carcinoid tumours, 208/284 (73%) had distant metastases and 30/284 (11%) had carcinoid heart disease. Median survival was 115.5 months and five-year survival was 77%. In a multivariate analysis liver metastases and carcinoid heart disease were poor prognostic factors. We performed a phase II study with octreotide pamoate investigating the clinical effect in 12 malignant midgut carcinoid tumours in a progressive phase. We found that 9/12 (75%) were stabilised for a median duration of 12 months. We think that this is a good effect considering the advanced stage. We investigated the frequency of four different tyrosine kinase receptors, platelet derived growth factor receptor (PDGR) α and β, epidermal growth factor receptor (EGFR) and c-kit, in 36 malignant midgut carcinoid tumours with immunohistochemistry. We found that 13/34 (38%) tumour samples expressed PDGFRα, 29/33 (88%) PDGFRβ, 24/33 (73%) EGFR, whereas none expressed c-kit. This implicates that midgut carcinoid tumours might be susceptible to treatment with tyrosine kinase receptor inhibitors.

In this study, metastasizing serotonin-producing ileocaecal carcinoid tumours (MSPCs) were examined for biological characteristics that could be used to define clinically relevant subgroups within this patient population. Possible targets for new treatment options were also explored. It was found that MSPCs share several biological characteristics such as expression of serotonin, tachykinins (TKs), chromogranin A, islet autoantigen-2 and connective tissue growth factor (CTGF). TKs and serotonin were demonstrated in the same endocrine tumours in the gut and lung. IA-2 expression was shown to be up-regulated in MSPCs, possibly in connection with active hormone secretion. CTGF expression was high in tumour areas adjacent to extensive stroma expressing alpha-smooth muscle actin. This indicated myofibroblast differentiation, which may be associated with fibrosis-related complications prevalent in patients with MSPCs. When compared with other endocrine tumours, MSPCs behaved as a relatively homogeneous group, though within the MSPC population several subgroups could be defined. Patients with tumours displaying either a solid growth pattern and/or a Ki67 index ≥1% had a less favourable prognosis than those who did not. Another group of patients, who had increased plasma TK concentrations, were more likely to suffer from severe diarrhea. This information should be considered when discussing clinical treatment and when undertaking tumour biological studies. New treatment possibilities, such as drugs that specifically target TK receptors and antibodies to CTGF, are also discussed. In conclusion, MSPCs comprise a clinically relevant tumour group with similar biological features that are distinct from other endocrine tumours. Subgroups of patients within this patient category can be defined which may be relevant when establishing prognosis and when selecting future treatment modalities.