| 1. |
- Fridriksson, Jon Örn, 1981-
(författare)
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Adverse effects of curative treatment of prostate cancer
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Screening for prostate cancer is debated, there is conflicting data on the net benefit of screening. Men who consider screening need to be informed on the pros and cons. Rehospitalization after surgery can be used as an indicator of general quality of care. For radical prostatectomy, little is known on the readmission rate after surgery. Men diagnosed with low- and intermediate-risk prostate cancer have low prostate-cancer specific mortality. However, adverse effects after curative treatment can be severe and decrease quality of life. Curative treatments for prostate cancer differ mainly in the pattern of adverse effects but detailed analysis of long-term adverse effects is lacking.The aim of this thesis was to assess the perioperative quality of radical prostatectomy and the risk of adverse effects after curative treatment for prostate cancer.Material and Methods In this thesis, data from the National Prostate Cancer Register (NPCR) and other nationwide Swedish registers were used. By use of the Swedish personal identity number, NPCR was cross-linked to other registers creating Prostate Cancer data Base Sweden (PCBaSe), a large dataset for research.Results The proportion of men who had received information on the pros and cons of screening for prostate cancer with PSA testing was low (14%) indicating that the majority of men who were screened did not make an informed decision. The risk of rehospitalization within 90 days after radical prostatectomy was approximately 10% and similar after retropubic and robot-assisted radical prostatectomy. Compared to controls, there was an increased risk of adverse effects after both radiotherapy and radical prostatectomy up to twelve years after treatment and the overall risk was quite similar after retropubic and robot-assisted radical prostatectomy.Conclusion Improved information to men on the pros and cons of PSA screening is warranted. The risk of adverse effects was elevated up to 12 years after curative treatment for prostate cancer. The pattern of adverse effects was different after radiotherapy and radical prostatectomy but quite similar after retropubic and robot-assisted radical prostatectomy.
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| 2. |
- Westerberg, Marcus
(författare)
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Modelling short and long term consequences of changes in diagnostic activity and treatment
- 2020
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Since the late 90’s the diagnostic activity for prostate cancer has increased in Sweden, primarily due to increased use of PSA testing, and this has led to a large increase in diagnoses. Simultaneously, there have been changes in treatment strategies, and more effective treatments have been introduced. This thesis aims to increase the understanding of short and long term consequences of these changes by use of high quality data on virtually all men diagnosed with prostate cancer in Sweden.In paper I, the survival of men with metastatic prostate cancer at diagnosis was investigatedby use of survival models, including Kaplan-Meier analyses and Cox proportional hazards regression.The median survival from diagnosis increased with 6 months when comparing mendiagnosed 1998-2001 with men diagnosed 2010-2015, and the risk of death decreased with 13%, while median levels of prostate specific antigen at diagnosis dropped with up to 50%.In paper II, the interplay between diagnostic activity, incidence and risk of death by prostate cancer was modelled using a discrete time model. Data on diagnostic activity, e.g. in termsof testing frequencies, was not available and therefore a proxy for the diagnostic activity wasused. The hazards were estimated within the framework of generalized additive models. Two simulations were performed, assuming low and high diagnostic activity respectively, to compare incidence and mortality from 2017-2060. Higher diagnostic activity, compared to lower, led to more men being diagnosed, primarily with lower risk prostate cancer, but in the long run it led to fewer men diagnosed with metastatic disease and fewer prostate cancer deaths.
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| 3. |
- Häggström, Christel, 1980-
(författare)
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Metabolic factors and risk of prostate, kidney, and bladder cancer
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Prostate cancer is the most common cancer in Sweden with around 10,000 new cases every year. Kidney and bladder cancer are less common with 1,000 and 2,000 new cases annually, respectively. The incidence of these cancer sites is higher in developed, than in developing countries, suggesting an association between lifestyle and cancer risk. The aims of this thesis were to investigate body mass index (BMI), blood pressure, and blood levels of glucose, total cholesterol, and triglycerides as risk factors for prostate, kidney, and bladder cancer. Furthermore, we aimed at assess probabilities of prostate cancer and competing events, all-cause death, for men with normal and high levels of metabolic factors.Material and methods: This thesis was conducted within the Metabolic Syndrome and Cancer project (Me-Can), a pooled cohort study with data from 578,700 participants from Norway, Sweden, and Austria. Data from metabolic factors were prospectively collected at health examinations and linked to the Cancer and Cause of Death registers in each country. Results: High levels of metabolic factors were not associated with increased risk of prostate cancer, but high levels of BMI and blood pressure were associated with risk of prostate cancer death. The probability of prostate cancer was higher for men with normal levels of metabolic factors compared to men with high levels, but the probability of all-cause death, was higher for men with high levels than for those with normal levels. For both men and women, high levels of metabolic factors were associated with increased risk of kidney cancer (renal cell carcinoma). Furthermore, blood pressure for men and BMI for women were found as independent risk factors of kidney cancer. High blood pressure was associated with an increased risk of bladder cancer for men.Conclusions: High levels of metabolic factors were associated to risk of kidney and bladder cancer and to death from kidney, bladder, and prostate cancer. Compared to men with normal levels, men with high levels of metabolic factors had a decreased probability of prostate cancer but an increased probability of all-cause death.
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| 4. |
- Josefsson, Andreas, 1979-
(författare)
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Prognostic markers in prostate cancer : studies of a watchful waiting cohort with long follow up
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Prostate Cancer (PC) is a common and highly variable disease. Using current diagnostic methods, the prostate specific antigen (PSA) blood test and histological grading of prostate tissue needle biopsies, it is often difficult to evaluate whether the patient has a PC that requires active treatment or not. The absolute majority of all 10,000 cases of PCs diagnosed annually in Sweden have tumours graded as Gleason score (GS) 6-7 and a PSA value in blood below 10. Many of these are harmless and can be left without active treatment and hence spared problematic post-therapy side-effects, others are highly malignant and require early diagnosis and treatment. Better prognostic markers are needed and the aim of this study was to evaluate prognostic markers and to test if these markers could identify patients with indolent tumours. Methods: We have studied tumour material from 419 men consecutively diagnosed with PC at transurethral resection (1975-1990). The majority of these patients (295) had no metastasis at diagnosis and was not given any curative treatment and only hormonal treatment upon symptoms from metastatic progression. Standard histological sections and tissue microarrays (TMA) from these tumours and surrounding normal prostate tissue were stained and evaluated for cell proliferation (Ki67), blood vessels (endoglin and von Willebrand factor, vWf) and the extracellular matrix component hyaluronan (HA). An orthotopic rat PC model was used to explore hyaluronan staining, hyaluronic acid synthase (HAS)-1 mRNA levels and the effect of local HA treatment on tumour growth. Results: Tumour cell proliferation (Ki67) and the density of intra-tumoural endoglin stained blood vessels were independent prognostic markers (i.e. they added prognostic information to the conventional prognostic markers; clinical stage and GS). None of the GS 6 patients with low staining for both Ki67 and endoglin died of PC within 15 years of follow-up. High HA staining in the tumour epithelium and stroma was a negative prognostic marker of cancer specific survival but they were not independent of GS. High HA staining and high vascular density in the stroma of the surrounding morphologically normal prostate were prognostic for short cancer specific survival. Implantation of tumour cells in the normal rat prostate resulted in an increase in HA and HAS-1 mRNA levels in the prostate tissue surrounding prostate tumours. Concurrently intra-prostatic injection of HA also stimulated tumour growth. Conclusions: By evaluating both tumour cell proliferation (Ki67) and vascular density, it is possible to identify patients with very low risk of cancer specific death in the absence of active treatment. Prostate tumours influence the surrounding non-malignant prostate tissue, for example they cause an increased angiogenesis and synthesis of hyaluronan. Such responses can possibly be used to diagnose PC and to evaluate PC aggressiveness.
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| 5. |
- Lundström, Karl-Johan, 1977-
(författare)
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Outcomes and complications in surgical and urological procedures
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 6. |
- Orrason, Andri Wilberg, 1988-
(författare)
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Trends in Prostate Cancer Mortality
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the early 20th century, cancer of the prostate was considered a rare and deadly disease with little to no possibility of cure. Since then, prostate cancer management has improved substantially with earlier detection, hormonal therapy, surgery and radiotherapy of the prostate. Nevertheless, prostate cancer remains the leading cause of cancer death in men in Western countries. The purpose of this thesis was to study trends in prostate cancer mortality including investigations of adjudication and measures of prostate cancer death. In paper I, we studied whether increased use of radical treatment in men with locally advanced prostate cancer diagnosed between 2000-2016 has affected prostate cancer mortality in the Swedish population. The use of radical treatment almost tripled and 5-year cumulative incidence of prostate cancer death declined from 17% to 10% for all men below age 80 with locally advanced prostate cancer. In paper II, we compared relative and cause-specific survival in all men with prostate cancer, according to age at death and risk category at diagnosis. Older men with low-risk prostate cancer at diagnosis had a substantially higher relative survival compared to cause-specific survival, 116% vs. 96% at five years after diagnosis. Despite efforts to increase comparability of expected survival, relative survival remained above 100% in these men due to healthy selection bias. In paper III, we assessed the amount of evidence in support of prostate cancer as the cause of death by review of health care records for 495 men who between 2011-2018 died of prostate cancer according to the Cause of Death Register. Older men and men with low-risk prostate cancer at diagnosis had considerably less evidence in support of prostate cancer death compared with younger men and men with high-risk disease. In paper IV, we applied a simulation model to estimate the lifetime risk of prostate cancer for different levels of diagnostic activity and life expectancy. Men exposed to high diagnostic activity had five-fold life-time risk of low or intermediate-risk prostate cancer and half the lifetime risk of high-risk or metastatic prostate cancer compared to men exposed to low diagnostic activity. Long life expectancy moderately increased the lifetime risk of prostate cancer in all risk categories, especially high-risk disease.
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| 7. |
- Stocks, Tanja, 1977-
(författare)
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Metabolic factors and cancer risk : prospective studies on prostate cancer, colorectal cancer, and cancer overall
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 8. |
- Tomic, Katarina, 1978-
(författare)
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Data quality in the National Prostate Cancer Register (NPCR) of Sweden
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Data in quality registers are increasingly used for quality assurance of health care, benchmarking, and research. If valid conclusions are to be drawn from such studies, it is vital that register data have high quality. The aim of this thesis was to assess data quality in the National Prostate Cancer Register (NPCR) of Sweden, a nationwide register that since 1998 captures 98% of all cases of Prostate cancer (Pca) in Sweden. The proportion and characteristics of Pca cases not registered in NPCR was investigated in paper I. Four dimensions of data quality were evaluated for NPCR in paper II: completeness, timeliness, comparability, and validity. Proportion and characteristics of Pca cases registered in NPCR but with unknown risk category were investigated in paper III. Finally, the association between Socioeconomic Status (SES) and Pca diagnosis, treatment, and mortality was studied in paper IV. Material and methods: Data quality of NPCR was studied by cross-linkages between NPCR and other health care registers and demographical databases by use of the Swedish personal identity number. Validity was further studied by re-abstraction of patient health care records, followed by comparison of re-abstracted and original register data.Results: Men not registered in NPCR, who constituted around 2% of all cases in the Swedish Cancer Register, differed only modestly in characteristics from cases in NPCR, indicating that NPCR is generalizable for all men with Pca in Sweden. Data quality in NPCR was high overall, with high completeness compared to the Swedish Cancer Register with registration mandated by law and few Pca cases were detected by use of death certificates. There was timely registration, and good comparability with registration forms and coding routines that were compliant with international guidelines. Data validity was high with high agreement and correlation for key variables. Men with unknown risk category had, compared to men with known risk category, more often concomitant bladder cancer, higher comorbidity, and lower Pca mortality. Men with high SES had, compared to men with low SES, higher probability of Pca detected during health checkup, shorter waiting times for prostatectomy, and higher probability of curative treatment for intermediate and high-risk cancer. Pca mortality was lower in men with high SES than in men with low SES for high-risk cancer.Conclusion: These results indicate that data quality in NPCR is high and that NPCR is population-based. There were consistent differences in diagnostic and therapeutic activity according to SES despite an equal access tax-financed healthcare system in Sweden.
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| 9. |
- Ventimiglia, Eugenio, 1988-
(författare)
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How to model temporal changes in epidemiological data : Treatment trajectories in men with prostate cancer
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Owing to the improvements in detection, diagnostics, and treatment, many men currently diagnosed with prostate cancer (PCa) have a low risk of PCa death. For many men PCa has become a chronic disease with a small risk of progression that remains even decades after date of diag-nosis. In this thesis PCa was used as an example of a chronic disease, since it holds all the main characteristics required by the WHO definition of a chronic disease. Against this background, the aim of this PhD thesis was to create models that can be used to quantify the probability of dif-ferent treatment trajectories and to assess the duration of certain disease states, while accounting for patient characteristics, disease severity, and primary treatment.In Paper I a state transition model was developed for prediction of dis-ease trajectories. The developed state transition model showed good consistency with a follow-up spanning up to 30 years.In Paper II a state transition model was developed and validated using age, Charlson comorbidity index, and a drug comorbidity index (DCI) based on filled drug prescriptions collected at a population-based level to estimate life expectancy.In Paper III the state transition model proposed in Paper I was used to assess 30-year PCa trajectories in men managed with active surveillance, in order to identify the ideal candidates for this management strategy.In Paper IV the state transition model from Paper I was updated includ-ing the castration resistant PCa (CRPC) state as an additional state and estimating the duration of the CRPC state as well as its outcomes.In Paper V, the updated state transition model from Paper IV was used to model long term outcomes for men with PCa managed with watchful waiting (WW). Since WW is currently recommended for men with PCa and life expectancy less than 10 years, the state transition model from Paper II was used to estimate life expectancy.
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| 10. |
- Holmström, Benny, 1974-
(författare)
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Early diagnosis and treatment of prostate cancer : observational studies in the National Prostate Cancer Register of Sweden and the Västerbotten Intervention Project
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 11. |
- Johansson, Mattias, 1977-
(författare)
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Prostate cancer aetiology : epidemiological studies of the IGF- and one-carbon metabolism pathways
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 12. |
- Lukanova, Annekatrin, 1966-
(författare)
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Endogenous hormones in the etiology of ovarian and endometrial cancers
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The main purpose of this thesis was to examine the relationship of pre-diagnostic circulating levels of sex-steroids (androgens and estrogens), sex hormone binding globuline (SHBG), insulin-like growth factor-I (IGF-I), IGF binding proteins (BP) and C-peptide (as a marker of pancreatic insulin secretion) with risk of ovarian and endometrial cancer. Additionally, the interrelationships of body mass index (BMI), sex-steroids, IGF-I and IGFBP-3 were examined. Two case-control studies were nested within 3 prospective cohort studies centered in New York (USA), Umeå (Sweden) and Milan (Italy). The ovarian study included 132 cancer cases. The endometrial study included 166 cancer cases in the IGF-I and C-peptide component and 124 postmenopausal cases in the sex-steroids component. For each case, two controls matching the case for cohort, age, menopausal status and date at recruitment were selected. In total 286 and 315 controls were included in the ovarian and endometrial cancer studies, respectively. Odds ratios (OR) and their 95% confidence intervals (CI) for cancer risk associated with increasing hormone concentrations were estimated by conditional logistic regression. The cross-sectional analysis was based on anthropometric and hormonal data from 620 controls selected for the two nested case-control studies. There was no association of prediagnostic androstenedione, testosterone, DHEAS, SHBG or estrone with ovarian cancer risk in the whole study population or in women who were pre- or postmenopausal at blood donation. In the premenopausal group, risk appeared to increase with increasing androstenedione (OR (95% CI) for the highest tertile: 2.35 (0.81-6.82), p=0.12). There was no association of IGF-I, IGFBP-1, 2, 3 or C-peptide concentrations with risk of ovarian cancer risk in the study group as a whole. In analyses restricted to subjects who had developed ovarian cancer at an early age (<55), circulating IGF-I was directly and strongly associated with risk (OR (95% CI): 4.74 (1.20-18.7), p<0.05 for the highest IGF-I tertile). In the endometrial study, previous observations were confimed that elevated circulating estrogens and androgens and decreased SHBG increase risk of developing endometrial malignancy after menopause. Multivariate ORs (95% CI) for endometrial cancer for quartiles with the highest hormone levels were: 4.13 (1.76-9.72), p<0.001 for estradiol; 3.67 (1.71-7.88), p=0.001 for estrone; 2.15 (1.05-4.40), p<0.04 for androstenedione; 1.74 (0.88-3.46), p=0.06 for testosterone; 2.90 (1.42-5.90), p<0.01 for DHEAS and 0.46 (0.20-1.05), p<0.01 for SHBG. Prediagnostic IGF-I, IGFBP-1, -2 and –3 were not related to risk of endometrial cancer in the whole study population. In postmenopausal women, levels of IGFBP-1 were inversely related to risk with an OR for the highest quartile of 0.36 (0.13-0.95), p<0.05. Endometrial cancer risk increased with increasing levels of C-peptide (p<0.01), up to an OR of 4.40 (1.65-11.7) for the highest quintile after adjustment for BMI and other confounders. The cross-sectional analyses showed that in both pre- and postmenopausal women SHBG decreased with increasing BMI. In the postmenopausal group, estrogens, testosterone and androstenedione increased with BMI, while the association with IGF-I was non-linear, the highest mean IGF-I concentration being observed in women with BMI between 24 and 25. In postmenopausal women, IGF-I was positively related to androgens, inversely correlated with SHBG, and was not correlated with estrogens. In conclusion, elevated pre-diagnostic sex-steroids, IGF-I or C-peptide increase risk of developing ovarian and endometrial cancer. BMI influences the circulating levels of these hormones, especially after menopause.
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| 13. |
- Westerberg, Marcus, 1990-
(författare)
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Prostate cancer incidence, treatment and mortality : Empirical longitudinal register-based studies and methods for handling missing data
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The diagnostic activity for prostate cancer has increased substantially in Sweden, primarily due to increased use of prostate-specific antigen (PSA) testing in asymptomatic men, and this has led to a large increase in diagnoses. There have also been changes in the diagnostic workup, guidelines, treatment strategies, and more effective treatments have been introduced in different phases of the disease. This thesis aims to increase the understanding of consequences of changes in diagnostic activity and treatment, with a focus on empirical studies, methodological development, and handling of missing data.In paper I, the survival of men with metastatic prostate cancer was investigated across calendar time periods by use of Kaplan-Meier analyses and Cox regression. The median survival from diagnosis increased with six months comparing men diagnosed 1998-2001 with men diagnosed 2010-2015, while median PSA decreased.In paper II, a discrete time multivariate longitudinal model was combined with a proxy for the unobserved level of diagnostic activity to produce prognoses of incidence and mortality. Simulations indicated that a higher diagnostic activity was associated with fewer men diagnosed with metastatic disease and fewer prostate cancer deaths.In paper III, we looked for clinical variables predictive of the survival of men with castration-resistant prostate cancer (CRPC). A new data base was created including longitudinal data on prescriptions of hormonal treatment, PSA, and cause of death. We found that PSA doubling time and PSA at time of CRCP were highly predictive and could be used for treatment decision.In paper IV, we estimated annual incidence of metastatic prostate cancer using different methods for handling missing data in metastatic status (M stage). Missing data in M stage was high and varied over calendar time and risk groups, yet each method indicated a downward trend in incidence. Although men with unknown metastatic status cannot be assumed to have nonmetastatic disease in general, this may be reasonable among those with tumour characteristics that indicate a low risk of metastases.In paper V, the estimation of multivariate longitudinal models was considered in a context where some events are observed on a coarser level (e.g. grouped) at some time points, causing gaps in the data. The likelihood function, score and observed information were derived under an independent coarsening mechanism. A simulation study was conducted comparing properties of several estimators including direct maximum likelihood and Monte Carlo Expectation Maximisation.
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| 14. |
- Wirén, Sara, 1981-
(författare)
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Prospective studies of hormonal and life-style related factors and risk of cancer
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Androgens are important in prostate cancer development but how circulating levels of androgens affect risk of prostate cancer of different aggressiveness is not clear. Being childless has been associated with a lower risk of prostate cancer, but it is not clear if this association is causal or a result of residual confounding. Fathering of dizygotic twins, a marker of high fertility, has not been studied in relation to risk of prostate cancer.Another marker of life-long hormonal exposure is height, which has been associated with increased risk of cancer and cancer death. However, the association to separate cancer sites has not been consistent.The aims of this thesis were to study hormonal factors (paper I), and proxies of hormonal factors (paper II and III), and risk of prostate cancer; as well as height and risk of cancer and cancer death by separate sites (paper IV).Methods: Study designs were i) case-control studies, nested within the Västerbotten Intervention Project (paper I), and in Prostate Cancer database Sweden 2.0 (PCBaSe 2.0) (paper II and III), and ii) cohort study, in the Metabolic Syndrome and Cancer project (Me-Can) (paper IV).Results, prostate cancer: In paper I, increasing levels of serum androgens were not associated with risk of prostate cancer overall or in tumor risk categories. In paper II, childless men had a lower risk of prostate cancer, overall and in all risk categories, compared to fathers, an association which was in part explained by differences in marital status and educational level. In paper III, fathers of dizygotic twins did not have an increased risk of prostate cancer, either overall or in risk categories, when compared to fathers of singletons.Results, cancer overall: In paper IV, height was associated with an increased risk of cancer and cancer death overall in both women and men. The strongest association for cancer was to malignant melanoma in both women and men, and for cancer death to post-menopausal breast cancer in women and renal cell carcinoma in men.Conclusions: These studies indicate that hormonal factors, when studied as serum levels or when studied using proxies of fertility, do not have a major impact on the risk of prostate cancer. The association between height and an increased risk of cancer appears robust for total cancer and cancer death, as well as for several separate cancer sites.
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