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.

digitalisering@umu

digitalisering@umu.se

<p>2022-03-23</p>

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2009. / Härtill 4 uppsatser.

Background: Minor procedures in surgery and urology such as groin hernia and hydrocele repair, as well as prostate biopsies are very frequently done in routine practice. Complications and insufficient outcomes thus affecting many patients and the cumulative effect of this are of major importance in a population perspective. Aim: To explore complications and outcomes of surgical or diagnostic procedures and possible risk factors or predictors for adverse effects. Methods: By using both national quality and administrative registers, and by complementing registers with patient reported outcome measures, examine outcomes such as complications, persistent pain and recurrences. Also, in the case of hydro and spermatoceles, report incidence numbers. Further, by using a randomized trial, explore minimally invasive procedure such as sclerotheraphy compared to conventional surgery in respect to cure and adverse events. Results: When comparing with the open anterior mesh repair, endoscopic technique is advantageous in respect to the patient reported outcome of persistent pain. The drawback was an increased risk of postoperative complications and reoperation for recurrence. Incidence numbers for hydro and spematocele were 100/100000 men. Aspiration (± sclerotherapy) had a significantly lower rate of complications as compared to conventional surgery. In the interim analysis of the randomized trial, comparing sclerotherapy to Lord´s procedure for hydroceles, the cure rate was similar between treatments. Definite conclusions cannot be made due to the risk of type 2 errors, and the study will thus continue. In the case of trans-rectal prostate biopsy, the rates increased every year during the study time frame, up to an approximate risk of two per cent in 2012 for hospital readmission within 30 days, without an increased mortality within 30 days. Conclusions: The open anterior mesh procedure is still the preferred method for groin hernia repair in routine surgical practice. Hydro and spermatocele surgery is associated with high rates of complications, and the indication for repair should be scrutinized. The rates of infection after prostate biopsy is increasing and methods to reduce unnecessary biopsies as well as improved prophylaxis should be investigated.

Colorectal cancer (CRC) is defined as a cancer appearing in the colon or in the rectum. In Sweden, ~ 6300 individuals were diagnosed with the disease in 2014 and ~ 2550 individuals diagnosed with CRC die each year due to their cancer. Surgery is the main treatment option of CRC and a survival rate of ~ 10 % is estimated if distant metastases have developed. It is therefore of importance to find factors that may be useful together with tumour, node, metastasis (TNM) stage to establish early CRC diagnosis, prognosis and follow-up of CRC patients. The aim of this thesis was to study the possible association of CD93, PLA2G4C, PDGF-D and inflammatory cytokines with CRC disease progression. In a prospective study approach CD93 and PLA2G4C single nucleotide polymorphisms (SNPs) were of potential importance in CRC prognosis. The T/T genotype of CD93 was associated with an increased CD93 expression in CRC tissue. Further, CRC patients carrying this genotype were associated with disseminated CRC at diagnosis and a lower recurrence-free survival after surgery. The A allele of a SNP of PLA2G4C was a stronger predictor for CRC-specific mortality than the conventional risk factors used in the clinic for selection of TNM stage II patients for adjuvant treatment. This indicates that the T/T genotype of CD93 and the A allele of PLA2G4C may be potential genetic factors related to disease severity and spread. Furthermore, they distinguish CRC patients that may benefit from a more comprehensive follow-up and adjuvant treatment. To study the putative involvement of PDGF-D in CRC the effects of PDGF-D signalling was studied in vitro. PDGF-D signalling altered the expression of genes of importance in CRC carcinogenesis and proliferation which was blocked by imatinib, a tyrosine kinase inhibitor. This indicates that PDGF-D signalling may be an important pathway in CRC progression and a potential target in CRC treatment. The analysis of various inflammatory cytokines in plasma at diagnosis showed an association between high levels and increased total- or CRC-specific mortality two years after surgery. High levels of CCL1 and CCL24 was the only cytokines strongly correlated with a worse CRC prognosis after statistical adjustments and may be of interest for further evaluation. In conclusion, this thesis presents circulating and genetic factors such as CD93, PLA2G4C, PDGF-D, CCL1 and CCL24 that may be of importance in CRC progression and may be of clinical value together with TNM stage in establishing prognosis. / Kolorektal cancer är en tumör i kolon eller rektum. I Sverige diagnosticerades år 2014 ca6300 individer med denna cancertyp och ca 2550 personer dör årligen till följd av kolorektalcancer. Operation är det huvudsakliga behandlingsalternativet för kolorektal cancer och vidfjärrmetastaser är överlevnaden &lt; 10 %. Det är därför viktigt att hitta markörer somtillsammans med TNM-stadium kan ge tidig information om sjukdomens prognos och lämpliguppföljning av patienter. Utveckling av kolorektal cancer sker genom ackumulering av genetiska mutationer ochepigenetisk nedreglering av tumörsuppressorgener. Därutöver spelar interaktionen mellantumören och dess närmaste omgivning, innehållande tillväxt- och inflammatoriska faktorer,en viktig roll i tumörens utveckling och metastasering. Syftet med avhandlingen var att studera associationen mellan CD93, PLA2G4C, PDGF-D samtinflammatoriska cytokiner och kolorektal cancer progression. En prospektiv studie visade att CD93 och PLA2G4C SNP var potentiellt viktiga förbedömningav kolorektal cancer prognos. T/T genotypen av SNP rs2749817 i CD93 var associerad medhögre uttryck av CD93 i kolorektal cancer vävnad, främst bland patienter i stadium IV.Därutöver observerades fler återfall efter operation hos patienter med T/T genotypen. Aallelen hos PLA2G4C SNP rs1549637 är en möjligtvis bättre markör för cancerspecifiköverlevnad vid stadium II än faktorer som idag används för att selektera patienter tilladjuvant behandling. Sammantaget antyder detta att T/T genotypen av CD93 och A allelenav PLA2G4C kan vara genetiska markörer relaterade till allvarlig tumörsjukdom ochspridning. Därutöver kan de eventuellt selektera patienter som kräver tätare uppföljning ochadjuvant behandling. För att studera den förmodade inblandningen av PDGF-D i kolorektal cancer undersöktesdess effekt på PDGF-D signalering in vitro. PDGF-D signaleringen förändradegenexpressionen av gener involverade i tumörutveckling och spridning, vilken kundeblockeras av tyrosinkinashämmaren imatinib. Det antyder att PDGF-D signalering kan vara enviktig faktor vid kolorektal cancer progression och ett potentiellt mål för behandling. Analysen av ett flertal inflammatoriska cytokiner visade en korrelation mellan högacytokinnivåer och ökad cancerspecifik och total dödlighet två år efter operation. Höga CCL1och CCL24 nivåer var de enda faktorerna som förblev signifikant associerade medcancerspecifik mortalitet vid fördjupad statistisk analys och bör studeras vidare. Sammanfattningsvis presenterar denna avhandling cirkulerande och genetiska faktorersåsom CD93, PLA2G4C, PDGF-D, CCL1 and CCL24 som eventuellt är viktiga vid bedömning avkolorektal cancer progression tillsammans med TNM stadium.

<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.