The aim of this thesis was to investigate the involvement of the insulin-like growth factor- and the one-carbon metabolism pathways in prostate cancer aetiology, studying both circulating biomarkers and genetic variation. Papers included in the thesis were conducted within the case-control study CAncer Prostate in Sweden (CAPS), and the two prospective studies European Prospective Investigation into nutrition and Cancer (EPIC), and Northern Sweden Health and Disease Cohort (NSHDC). In paper I, we investigated the relation between genetic variants of the IGF1 gene and prostate cancer risk within the CAPS study. We found that a common haplotype within the 3’ region of the IGF1 gene is associated with increased prostate cancer risk. In paper II, we investigated if the variants of the IGF1 gene that were associated with prostate cancer risk in paper I, are also associated with circulating levels of IGF1. Circulating levels of IGF1 were analysed in controls from the CAPS study and three haplotype tagging SNPs (htSNPs) were genotyped in subjects from the NSHDC study in which circulating IGF1 had previously been analysed. The genetic variants previously associated with increased prostate cancer risk were now also found to be associated with elevated levels of circulating IGF1. We concluded that variation in the 3’ region of the IGF1 gene affects prostate cancer risk by influencing circulating levels of IGF1. In paper III, we investigated if variants of the IGFBP1, IGFBP3 and IGFALS genes are associated with i) prostate cancer risk, ii) circulating concentrations of total and intact IGFBP3, and iii) prostate cancer-specific survival probability. In addition, we investigated if circulating concentrations of total and intact IGFBP3 are associated with prostate cancer-specific survival probability. No association between genetic variation and overall prostate cancer risk or survival was observed, but we found a strong association between elevated levels of intact IGFBP3 and increased risk of prostate cancer-specific death. We could, however, not exclude that this association was confounded by treatment or by the tumour. In paper IV, we investigated if circulating levels of folate and vitamin B12 are associated with prostate cancer risk within the EPIC study. We observed no associations between levels of folate, vitamin B12 and overall prostate cancer risk, but elevated levels of vitamin B12 were associated with increased risk of advanced stage disease. In paper V, we investigated if circulating levels of ten B-vitamins and related metabolites within the one-carbon metabolism pathway are associated with prostate cancer risk within the NSHDC study. Overall positive associations with prostate cancer risk were observed for levels of choline, vitamin B2 and vitamin B12, and inverse associations were observed for levels of homocysteine and MMA. We also observed a biologically plausible risk modification by smoking status on the association between vitamin B12 and risk; in non-smokers vitamin B12 was positively associated with risk, whereas the association between vitamin B12 and risk was inverse or null in ever/current-smokers. In summary, our results suggest that genetic variation of the IGF1 gene affects prostate cancer risk by affecting circulating levels of IGF1. The association between circulating concentrations of intact IGFBP3 and prostate cancer-specific survival is intriguing, but further studies are needed to conclude if this association is caused by confounding. We also observed associations between several factors of one-carbon metabolism and risk, but these associations were statistically week and require confirmation in other prospective studies.

Background: A large number of prospective studies have shown that overweight and diabetes are related to an increased risk of many cancers, including colorectal cancer. In contrast, diabetes has been related to a decreased risk of prostate cancer, and overweight has been related to an increased risk of fatal, but not of incident, prostate cancer. Data from studies on metabolic factors related to overweight and diabetes, and the association with cancer risk, are limited.  Aim: The aim of this thesis was to study metabolic factors in relation to risk of prostate cancer (paper I and III), colorectal cancer (paper II and V), and cancer overall (paper VI).  Methods: Study designs were i) case-control studies, nested within the Northern Sweden Health and Disease Cohort (paper I and II), and ii) cohort studies of the Swedish Construction Workers cohort (paper III), and the Metabolic syndrome and Cancer project (Me-Can) comprising seven European cohorts (paper V and VI). Paper IV was a descriptive paper of Me-Can.  Results, prostate cancer: In paper I, increasing levels of several factors related to insulin resistance (insulin, insulin resistance index, leptin, HbA1c, and glucose) were associated with a decreased risk of overall incident prostate cancer, and the associations were stronger for non-aggressive tumours. In paper III, increasing levels of blood pressure was associated with a significant decreased risk of overall incident prostate cancer and of non-aggressive tumours. Body mass index (BMI) was significantly positively related to fatal prostate cancer.   Results, colorectal cancer: In paper II, obesity, hypertension, and hyperglycaemia, were associated with an increased risk of colorectal cancer, and presence of two or three of these factors was associated with a higher risk than the presence of one single factor. In paper V, BMI was associated with a significant linear positive association with risk of colorectal cancer in men and women, and significant positive associations were also found in men for blood pressure and triglycerides. A high metabolic syndrome score, based on levels of BMI, blood pressure, glucose, cholesterol, and triglycerides, was associated with a significant increased risk of colorectal cancer in men and women. The association was stronger than for any of the factors in single, but there was no evidence of a positive interaction between these metabolic factors.  Results, cancer overall: Blood glucose was significantly positively associated with risk of incident and fatal cancer overall, and at several specific sites. The associations were stronger in women than in men, and for fatal than for incident cancer.  Conclusions: Results from these studies indicate that elevated blood glucose is related to an increased risk of cancer overall and at several specific sites, and further, that overweight and metabolic aberrations increase the risk of colorectal cancer in an additive way. The association with prostate cancer seems to be more complex; insulin resistance and high blood pressure were in our studies related to a decreased risk of overall incident prostate cancer and of non-aggressive tumours, whereas overweight increased the risk of fatal prostate cancer.

<p>När en man diagnostiseras med prostatacancer innebär det en psykisk påfrestning för mannen och hans kvinnliga partner. Reaktioner som chock, meningsförlust, ensamhet och ångest är vanligt förekommande. Syftet med denna litteraturstudie var att beskriva hur det vardagliga livet upplevs och påverkas hos par där mannen lever med diagnostiserad prostatacancer. Resultaten i studien baseras på tio vetenskapliga artiklar med fokus på parens erfarenheter av sjukdomen. Impotens, inkontinens och fatigue var symtom som drabbade mannen till följd av sjukdomen. Dessa förändringar inverkade på parets vardag och relation. Förändringarna var psykiskt påfrestande för parets hälsa och både mannens och kvinnans livskvalitet försämrades på grund av cancersjukdomen. Psykiska problem som depression, oro, ångest och skuld var dock mer förekommande hos kvinnan. Trots att paren var i stort behov av information upplevde de att hälso- och sjukvården inte uppmärksammade deras behov. Tydligare riktlinjer inom sjukvården för hur par som lever med prostatacancer ska bemötas efterlyses. På så sätt kan sjuksköterskan lättare tillgodose parets behov av information och stöd. Sjuksköterskan bör uppmärksamma och bemöta kvinnans individuella önskemål samt visa en öppenhet gentemot de sexuella problem som kan drabba paren. Mer forskning, speciellt i Skandinavien, efterlyses för att få en klarare bild över hur både en homosexuellt och heterosexuell relation påverkas av prostatacancer.  </p> / <p>When a man is diagnosed with prostate cancer it implies a psychological strain for the man and his female partner where reactions such as shock, loss of meaning, loneliness and anxiety are common. The purpose of this literature review was to describe how everyday life is perceived and influenced in couples where the man has been diagnosed with prostate cancer. The results of the study are based on ten scientific articles focused on exploring couple’s experiences of the disease and how they are affected by the situation. Symptoms such as impotence, incontinence and fatigue were changes that affected the couple’s everyday life and their relationship. These changes were psychologically trying for the couple’s health and their quality of life decreased because of the cancer.  Psychological problems like depression, anxiety and guilt were more common for the woman. Despite the fact that the couples were in great need of information, they felt that health care providers were not attentive to these needs. Clearer guidelines are needed within the health-care system for how couples living with prostate cancer should be treated. The nurse would thereafter be better equipped to meet the couple’s needs for information and support. The nurse should highlight and approach women’s individual needs and show openness towards the sexual problems that can befall couples. More research is needed, particularly in Scandinavia, in order to get a clearer picture of how a homosexual and heterosexual relationship is affected by prostate cancer.</p>

Intravesical electrical stimulation (IVES) has been used in treatment of patients with urinary bladder dysfunctions for more than four decades. While some investigators have reported excellent results others have observed less convincing effects or outright failures. The discrepancies may reflect differences in patient selection or stimulation procedure. A better theoretical understanding of the IVES working mechanism might help to improve the success rate of the treatment. The aims of the present study were to provide such information. Experiments were performed on adult female cats and rats under /alpha/-chloralose anesthesia. IVES was delivered by a catheter electrode in the bladder. At proper intensity and frequency, IVES evoked reflex detrusor contractions that were abolished by bilateral rhizotomy of sacral dorsal roots. Stimulation parameters and response characteristics revealed that bladder mechanoreceptor A/delta/ afferents were activated by the IVES, the same afferents that drive the normal micturition reflex. Five minutes of continues IVES at 20 Hz induced a prolonged, significant decrease in the micturition threshold volume of anesthetized rats. Similarly, selective bladder A/delta/ afferent stimulation induced a long-lasting enhancement of micturition reflex discharges in cats. A comparable prolonged inhibitory effect on the micturition reflex was demonstrated after ano-genital afferent stimulation. Both modulatory effects occurred without changes in response sensitivity of stimulated afferents. The IVES induced modulation was prevented by transient exposure of the bladder to a local anesthetic and by systemic administration of a glutamate NMDA receptor antagonist. In conclusion, IVES induces a prolonged modulation of the micturition reflex by an LTP like enhancement of excitatory synaptic transmission in the central micturition reflex pathway. The findings provide an experimental explanation for the neuronal mechanisms underlying the curative effect of IVES in patients with bladder evacuation problems. / On the day of the public defence the status of article V was: Accepted.

När en man diagnostiseras med prostatacancer innebär det en psykisk påfrestning för mannen och hans kvinnliga partner. Reaktioner som chock, meningsförlust, ensamhet och ångest är vanligt förekommande. Syftet med denna litteraturstudie var att beskriva hur det vardagliga livet upplevs och påverkas hos par där mannen lever med diagnostiserad prostatacancer. Resultaten i studien baseras på tio vetenskapliga artiklar med fokus på parens erfarenheter av sjukdomen. Impotens, inkontinens och fatigue var symtom som drabbade mannen till följd av sjukdomen. Dessa förändringar inverkade på parets vardag och relation. Förändringarna var psykiskt påfrestande för parets hälsa och både mannens och kvinnans livskvalitet försämrades på grund av cancersjukdomen. Psykiska problem som depression, oro, ångest och skuld var dock mer förekommande hos kvinnan. Trots att paren var i stort behov av information upplevde de att hälso- och sjukvården inte uppmärksammade deras behov. Tydligare riktlinjer inom sjukvården för hur par som lever med prostatacancer ska bemötas efterlyses. På så sätt kan sjuksköterskan lättare tillgodose parets behov av information och stöd. Sjuksköterskan bör uppmärksamma och bemöta kvinnans individuella önskemål samt visa en öppenhet gentemot de sexuella problem som kan drabba paren. Mer forskning, speciellt i Skandinavien, efterlyses för att få en klarare bild över hur både en homosexuellt och heterosexuell relation påverkas av prostatacancer. / When a man is diagnosed with prostate cancer it implies a psychological strain for the man and his female partner where reactions such as shock, loss of meaning, loneliness and anxiety are common. The purpose of this literature review was to describe how everyday life is perceived and influenced in couples where the man has been diagnosed with prostate cancer. The results of the study are based on ten scientific articles focused on exploring couple’s experiences of the disease and how they are affected by the situation. Symptoms such as impotence, incontinence and fatigue were changes that affected the couple’s everyday life and their relationship. These changes were psychologically trying for the couple’s health and their quality of life decreased because of the cancer.  Psychological problems like depression, anxiety and guilt were more common for the woman. Despite the fact that the couples were in great need of information, they felt that health care providers were not attentive to these needs. Clearer guidelines are needed within the health-care system for how couples living with prostate cancer should be treated. The nurse would thereafter be better equipped to meet the couple’s needs for information and support. The nurse should highlight and approach women’s individual needs and show openness towards the sexual problems that can befall couples. More research is needed, particularly in Scandinavia, in order to get a clearer picture of how a homosexual and heterosexual relationship is affected by prostate cancer.

Prostate-specific antigen (PSA) testing has caused a steep increase in the incidence of prostate cancer, especially the incidence of localised low risk disease. In order to decrease the overdiagnosis accompanied by PSA testing, analysis of inherited genetic variants have been suggested as potential tools for clinical assessment of disease risk. With the aim of minimizing overtreatment and postpone side-effects of curative treatment for low risk prostate cancer, active surveillance, a treatment strategy with initial surveillance and deferred radical prostatectomy at the time of progression has evolved.  The aim of this thesis was to study the validity of PSA (paper I) and inherited genetic variants (paper II) for early diagnosis of prostate cancer, to assess the extent of PSA testing in Sweden (paper III), and to study the safety of deferred radical prostatectomy in localised low to intermediate risk prostate cancer (paper IV). The study designs were i) case-control studies nested within the Västerbotten intervention project (paper I and II), ii) observational study in the Cancer Register of Sweden (paper III), and iii) observational study in the NPCR Follow-up study (paper IV). PSA had a high validity in predicting a prostate cancer diagnosis with an area under the receiver operating characteristics (ROC) curve of 0.86 (95% CI, 0.84 to 0.88). A combined test, including PSA, the ratio of free to total PSA, and 33 single nucleotide polymorphisms (SNPs) in a genetic risk score, increased the area under curve to 0.87 (95% CI, 0.85 to 0.89). The estimated uptake of PSA testing among men aged 55 to 69 years increased from zero to 56% between 1997 and 2007 and there were large variations in the uptake of PSA testing between counties in Sweden. After a median follow-up time of eight years there was no significant difference in presence of any one or more adverse pathology features or prostate cancer specific mortality after primary compared to deferred radical prostatectomy in localised low to intermediate risk prostate cancer. Results from these studies indicate that PSA and the hitherto identified SNPs are not suitable biomarkers in single-test prostate cancer screening. It is possible to estimate the uptake of PSA testing on a population level. Initial surveillance and deferred radical prostatectomy represent a feasible treatment strategy in localised low to intermediate risk prostate cancer.

Background. Angiogenesis is essential for tumour growth. Vascular endothelial growth factor (VEGF) and its isoforms were investigated in relation to the clinical course in a large number of patients with renal cell carcinoma (RCC). Methods. RCC subtypes and behaviour were established by clinicopathological criteria and surveillance. VEGF expression was analysed in serum by enzyme-linked immuno-sorbent assay (ELISA) and in tumour tissue by reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and Western blot (WB). Results. Serum VEGF (S-VEGF) was increased in RCC compared to control group. S-VEGF correlated with tumour stage and grade and was associated with survival in men but not in women. S-VEGF correlated with blood platelet counts, which were inversely correlated to increasing age in women, and they were decreased in chronically medicated patients, particularly in men. In contrast to S-VEGF, platelet counts associated with survival only in patients free of medication and chronic diseases. RT-PCR showed a correlation between VEGF121/VEGF165 mRNA and between VEGF165/VEGF-R1 mRNA. There was no association between different VEGF mRNA isoforms and S-VEGF. Conventional renal cell carcinoma (CRCC) had higher VEGF165, VEGF121, and VEGF-R1 mRNA levels compared with papillary renal cell carcinoma (PRCC). IHC VEGF staining was strong in kidney cortex. Kidney tumour showed a considerable variation in cytoplasmatic VEGF expression, which correlated with tumour size. Although, there was no difference in VEGF expression between the RCC types, VEGF expression was associated with survival only in CRCC. WB showed a strong protein expression of both VEGF189 and VEGF165 in kidney cortex. In kidney tumour, expression of VEGF189 varied the most, VEGF165 less so, and VEGF121 was rarely detected. Both CRCC and PRCC expressed low levels of VEGF189 and VEGF165 compared with kidney cortex. Chromophobe renal cell carcinoma (ChRCC) expressed VEGF189 levels comparable to those from kidney cortex, while VEGF165 was lower. In PRCC and ChRCC, VEGF189 levels correlated inversely with advancing tumour stage, and in PRCC, VEGF165 levels correlated inversely with increasing tumour size. VEGF189 was an independent prognostic factor for survival in patients with PRCC. Conclusions. S-VEGF has a stronger association to progression in RCC than platelet count. CRCC showed high levels of VEGF mRNA isoforms and VEGF-R1 mRNA compared to PRCC. VEGF mRNA isoforms expression decreased with advancing stage. IHC demonstrated VEGF expression in cell cytoplasm related to tumour growth, particular in CRCC. Different VEGF isoform patterns were found in different RCC types. Protein VEGF189 expression was associated with tumour stage and was an independent prognostic factor in PRCC. Protein VEGF165 expression was generally low and had no prognostic value. The trend for decreasing levels of VEGF isoforms in advanced tumour stages may indicate that angiogenic activity is an early event in tumour growth induced by VEGF, but that during later tumour progression the role of VEGF is less clear.

<p>This thesis deals with problem solving of general practitioners (GPs), which is explored with different methods and from different perspectives. The general aim was to explore and describe rules of thumb and to analyse the management of respiratory and urinary tract infections (RTI and UTI) in general practice in Sweden. The results are based upon focus group interviews concerning rules of thumb and a prospective diagnosis-prescription study concerning the management of patients allocated a diagnosis of RTI or UTI. In addition unpublished data are given from structured telephone interviews concerning specific rules of thumb in acute sinusitis and prevailing cough.</p><p>GPs were able to verbalize their rules of thumb, which could be called tacit knowledge. A specific set of rules of thumb was used for rapid assessment when emergency and psychosocial problems were identified. Somatic problems seemed to be the expected, normal state. In the further consultation the rules of thumb seemed to be used in an act of balance between the individual and the general perspective. There was considerable variation between the rules of thumb of different GPs for patients with acute sinusitis and prevailing cough. In their rules of thumb the GPs seemed to integrate their medical knowledge and practical experience of the consultation. A high number of near-patient antigen tests to probe Streptococcus pyogenes (Strep A tests) and C-reactive protein (CRP) tests were performed in patients, where testing was not recommended. There was only a slight decrease in antibiotic prescribing in patients allocated a diagnosis of RTI examined with CRP in comparison with patients not tested. In general, the GPs in Sweden adhered to current guidelines for antibiotic prescribing. Phenoxymethylpenicillin (PcV) was the preferred antibiotic for most patients allocated a diagnosis of respiratory tract infection.</p><p>In conclusion, the use of rules of thumb might explain why current practices prevail in spite of educational efforts. One way to change practice could be to identify and evaluate rules of thumb used by GPs and disseminate well adapted rules. The use of diagnostic tests in patients with infectious illnesses in general practice needs critical appraisal before introduction as well as continuing surveillance. The use of rules of thumb by GPs might be one explanation for variation in practice and irrational prescribing of antibiotics in patients with infectious conditions.</p> / On the day of the public defence the status of the articles IV and V was: Accepted.

<p>The natural history of localized prostate cancer is not fully understood. In most patients the tumor will never progress to a lethal disease, while a subset of patients will ultimately die of the disease. Efficient tools to separate indolent from lethal disease is currently lacking which means that many patients will be offered treatment without any benefit, but still be at risk of experiencing treatment related side effects.</p><p>The aims of these studies were to get more insight into the natural history of untreated localized prostate cancer, to assess the prognostic value of established clinical parameters such as Gleason score, nuclear grade and tumor volume and, moreover, some new prognostic markers Ki-67, AMACR and MUC-1. We also aimed to study time trends in the detection of incidental tumors in Sweden.</p><p>Patients with localized disease (n=223) and no initial treatment were followed for 21 years. Most patients had a favorable outcome. However, a subset of patients developed lethal disease even beyond 15 years of follow-up and these patients define the group that may benefit most from treatment with curative intent. Patients with poorly differentiated tumors experienced a 9 time higher risk of dying in prostate cancer.</p><p>The studies on prognostic markers are based on a cohort of patients (n=253) with incidental prostate cancer detected by transurethral resection for presumed benign hyperplasia. All patients were left without initial treatment. Gleason grade, nuclear grade and tumor volume turned all out to be independent prognostic factors. MUC-1, AMACR and Ki-67 also carried prognostic information. However, after adjustment for Gleason grade, nuclear grade and tumor volume only MUC-1 and AMACR remained as statistically significant prognostic factors. When tested for sensitivity and specificity they all failed and, consequently, they seem to be of less value in daily practice for cancelling an individual patient regarding the choice of treatment.</p><p>Time trends in incidental prostate tumors in Sweden were analyzed in a cohort of patients with prostate tumors detected by transurethral resection (TUR-P). Through linkage of the national registration number (NRN) with several registers, e.g. the Swedish Cancer Registry, the National Inpatient registry and the Cause of Death Registry we identified, during the period 1970 through 2003, in total 23288 patients with incidental prostate cancer, who constituted the study group. As comparison group we choose all patients diagnosed with prostate cancer between 1970-2003 excluding those with incidental cancer, in total 112204 patients. Our result confirms earlier findings that there has been a dramatic change over time in incidence of incidental prostate cancers in Sweden, which parallels the introduction of prostate specific antigen. We also found that the cumulative incidence of prostate cancer death is high in the incidental group, opposing earlier findings that incidental tumours are a non-lethal disease.</p> / issn 1642-4063

This thesis deals with problem solving of general practitioners (GPs), which is explored with different methods and from different perspectives. The general aim was to explore and describe rules of thumb and to analyse the management of respiratory and urinary tract infections (RTI and UTI) in general practice in Sweden. The results are based upon focus group interviews concerning rules of thumb and a prospective diagnosis-prescription study concerning the management of patients allocated a diagnosis of RTI or UTI. In addition unpublished data are given from structured telephone interviews concerning specific rules of thumb in acute sinusitis and prevailing cough. GPs were able to verbalize their rules of thumb, which could be called tacit knowledge. A specific set of rules of thumb was used for rapid assessment when emergency and psychosocial problems were identified. Somatic problems seemed to be the expected, normal state. In the further consultation the rules of thumb seemed to be used in an act of balance between the individual and the general perspective. There was considerable variation between the rules of thumb of different GPs for patients with acute sinusitis and prevailing cough. In their rules of thumb the GPs seemed to integrate their medical knowledge and practical experience of the consultation. A high number of near-patient antigen tests to probe Streptococcus pyogenes (Strep A tests) and C-reactive protein (CRP) tests were performed in patients, where testing was not recommended. There was only a slight decrease in antibiotic prescribing in patients allocated a diagnosis of RTI examined with CRP in comparison with patients not tested. In general, the GPs in Sweden adhered to current guidelines for antibiotic prescribing. Phenoxymethylpenicillin (PcV) was the preferred antibiotic for most patients allocated a diagnosis of respiratory tract infection. In conclusion, the use of rules of thumb might explain why current practices prevail in spite of educational efforts. One way to change practice could be to identify and evaluate rules of thumb used by GPs and disseminate well adapted rules. The use of diagnostic tests in patients with infectious illnesses in general practice needs critical appraisal before introduction as well as continuing surveillance. The use of rules of thumb by GPs might be one explanation for variation in practice and irrational prescribing of antibiotics in patients with infectious conditions. / On the day of the public defence the status of the articles IV and V was: Accepted.