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1.  Patterns of Survival Among Patients With Myeloproliferative Neoplasms Diagnosed in Sweden From 1973 to 2008: A Population-Based Study 
Journal of Clinical Oncology  2012;30(24):2995-3001.
Reported survival in patients with myeloproliferative neoplasms (MPNs) shows great variation. Patients with primary myelofibrosis (PMF) have substantially reduced life expectancy, whereas patients with polycythemia vera (PV) and essential thrombocythemia (ET) have moderately reduced survival in most, but not all, studies. We conducted a large population-based study to establish patterns of survival in more than 9,000 patients with MPNs.
Patients and Methods
We identified 9,384 patients with MPNs (from the Swedish Cancer Register) diagnosed from 1973 to 2008 (divided into four calendar periods) with follow-up to 2009. Relative survival ratios (RSRs) and excess mortality rate ratios were computed as measures of survival.
Patient survival was considerably lower in all MPN subtypes compared with expected survival in the general population, reflected in 10-year RSRs of 0.64 (95% CI, 0.62 to 0.67) in patients with PV, 0.68 (95% CI, 0.64 to 0.71) in those with ET, and 0.21 (95% CI, 0.18 to 0.25) in those with PMF. Excess mortality was observed in patients with any MPN subtype during all four calendar periods (P < .001). Survival improved significantly over time (P < .001); however, the improvement was less pronounced after the year 2000 and was confined to patients with PV and ET.
We found patients with any MPN subtype to have significantly reduced life expectancy compared with the general population. The improvement over time is most likely explained by better overall clinical management of patients with MPN. The decreased life expectancy even in the most recent calendar period emphasizes the need for new treatment options for these patients.
PMCID: PMC3417050  PMID: 22802311
2.  Success Story of Targeted Therapy in Chronic Myeloid Leukemia: A Population-Based Study of Patients Diagnosed in Sweden From 1973 to 2008  
Journal of Clinical Oncology  2011;29(18):2514-2520.
Chronic myeloid leukemia (CML) management changed dramatically with the development of imatinib mesylate (IM), the first tyrosine kinase inhibitor targeting the BCR-ABL1 oncoprotein. In Sweden, the drug was approved in November 2001. We report relative survival (RS) of patients with CML diagnosed during a 36-year period.
Patients and Methods
Using data from the population-based Swedish Cancer Registry and population life tables, we estimated RS for all patients diagnosed with CML from 1973 to 2008 (n = 3,173; 1,796 males and 1,377 females; median age, 62 years). Patients were categorized into five age groups and five calendar periods, the last being 2001 to 2008. Information on use of upfront IM was collected from the Swedish CML registry.
Relative survival improved with each calendar period, with the greatest improvement between 1994-2000 and 2001-2008. Five-year cumulative relative survival ratios (95% Cls) were 0.21 (0.17 to 0.24) for patients diagnosed 1973-1979, 0.54 (0.50 to 0.58) for 1994-2000, and 0.80 (0.75 to 0.83) for 2001-2008. This improvement was confined to patients younger than 79 years of age. Five-year RSRs for patients diagnosed from 2001 to 2008 were 0.91 (95% CI, 0.85 to 0.94) and 0.25 (95% CI, 0.10 to 0.47) for patients younger than 50 and older than 79 years, respectively. Men had inferior outcome. Upfront overall use of IM increased from 40% (2002) to 84% (2006). Only 18% of patients older than 80 years of age received IM as first-line therapy.
This large population-based study shows a major improvement in outcome of patients with CML up to 79 years of age diagnosed from 2001 to 2008, mainly caused by an increasing use of IM. The elderly still have poorer outcome, partly because of a limited use of IM.
PMCID: PMC3138632  PMID: 21576640
3.  Partitioning of excess mortality in population-based cancer patient survival studies using flexible parametric survival models 
Relative survival is commonly used for studying survival of cancer patients as it captures both the direct and indirect contribution of a cancer diagnosis on mortality by comparing the observed survival of the patients to the expected survival in a comparable cancer-free population. However, existing methods do not allow estimation of the impact of isolated conditions (e.g., excess cardiovascular mortality) on the total excess mortality. For this purpose we extend flexible parametric survival models for relative survival, which use restricted cubic splines for the baseline cumulative excess hazard and for any time-dependent effects.
In the extended model we partition the excess mortality associated with a diagnosis of cancer through estimating a separate baseline excess hazard function for the outcomes under investigation. This is done by incorporating mutually exclusive background mortality rates, stratified by the underlying causes of death reported in the Swedish population, and by introducing cause of death as a time-dependent effect in the extended model. This approach thereby enables modeling of temporal trends in e.g., excess cardiovascular mortality and remaining cancer excess mortality simultaneously. Furthermore, we illustrate how the results from the proposed model can be used to derive crude probabilities of death due to the component parts, i.e., probabilities estimated in the presence of competing causes of death.
The method is illustrated with examples where the total excess mortality experienced by patients diagnosed with breast cancer is partitioned into excess cardiovascular mortality and remaining cancer excess mortality.
The proposed method can be used to simultaneously study disease patterns and temporal trends for various causes of cancer-consequent deaths. Such information should be of interest for patients and clinicians as one way of improving prognosis after cancer is through adapting treatment strategies and follow-up of patients towards reducing the excess mortality caused by side effects of the treatment.
PMCID: PMC3526518  PMID: 22726307
Survival analysis; Cancer; Relative survival; Regression models; Competing risks
4.  Associations of gene sequence variation and serum levels of C-reactive protein and Interleukin-6 with Alzheimer’s disease and dementia 
Inflammatory mechanisms have been implicated in Alzheimer’s disease (AD) and dementia. We therefore sought to study DNA sequence variation and serum levels of the potent inflammatory mediators Interleukin-6 (IL6) and C-reactive protein (CRP) in relation to AD and dementia.
Tagging single nucleotide polymorphisms (tagSNPs) were chosen to capture most variation in and around CRP and IL6 in 3937 elderly Swedish men and women (1,265 AD cases). A subset of the population (N=723) with serum measurements of CRP and IL6 was included in A) a nested case-control study of incident dementia cases, and B) a case-control study of prevalent dementia cases. None of the SNPs or haplotypes was significantly associated with AD or dementia after correcting for multiple testing nor were elevated baseline levels of hsCRP or IL6 (measured on average 4.3 years before dementia onset) significantly associated with risk of future AD or dementia. However, prevalent AD cases had higher levels of IL6 (measured on average 5.5 years after dementia onset) than age- and sex-matched controls, OR 2.24 (95% CI 1.27–3.95), p-value 0.006.
In summary, this data suggests that AD patients have an altered immune profile with higher circulating levels of IL6 than age-and sex-matched controls. However, neither variation in the CRP and IL6 genes nor circulating levels of their respective protein products were associated with an increased risk of developing late-life dementias.
PMCID: PMC3237048  PMID: 21116047
Alzheimer disease; dementia; inflammation; interleukin-6; C-reactive protein; biological markers; candidate gene analysis; matched case-control studies; nested case-control studies
5.  Non-Stroke Cardiovascular Disease and Risk of Alzheimer's Disease and Dementia 
Unresolved issues in dementia research include 1) the association between non-stroke cardiovascular disease (CVD) and Alzheimer's disease (AD) and 2) whether the association between CVD and dementia is mediated by familial factors (i.e. genes and early life environment). We therefore conducted a study with both a longitudinal and a co-twin control design in 2,214 Swedish twins with clinical dementia evaluation and APOE4 genotyping. The analyses were then replicated in a register-based cohort of 18,405 individuals. Results show that CVD increases the risk of AD in carriers (but not non-carriers) of the APOE4 allele (Hazard Ratio [HR] 2.39, 95% confidence interval 1.15-4.96). CVD was also associated with an almost two-fold increased risk of developing late-life dementia (HR 1.83, 1.23-2.72). Within twin pairs, the dementia-affected twin was more likely to have had CVD than the non-demented twin partner (Odds Ratio 1.86, 1.11-3.13). In conclusion, this study shows that 1) non-stroke CVD increases the risk of late-life dementia but that it is only a risk factor for AD in carriers of the APOE4 allele and 2) the association between CVD and dementia is not explained by genetic or early life environmental factors in common to both disorders.
PMCID: PMC2924456  PMID: 20473139
Alzheimer's disease; cardiovascular disease; risk factor; APOE; longitudinal; co-twin control
6.  Estimating and modelling cure in population-based cancer studies within the framework of flexible parametric survival models 
When the mortality among a cancer patient group returns to the same level as in the general population, that is, the patients no longer experience excess mortality, the patients still alive are considered "statistically cured". Cure models can be used to estimate the cure proportion as well as the survival function of the "uncured". One limitation of parametric cure models is that the functional form of the survival of the "uncured" has to be specified. It can sometimes be hard to find a survival function flexible enough to fit the observed data, for example, when there is high excess hazard within a few months from diagnosis, which is common among older age groups. This has led to the exclusion of older age groups in population-based cancer studies using cure models.
Here we have extended the flexible parametric survival model to incorporate cure as a special case to estimate the cure proportion and the survival of the "uncured". Flexible parametric survival models use splines to model the underlying hazard function, and therefore no parametric distribution has to be specified.
We have compared the fit from standard cure models to our flexible cure model, using data on colon cancer patients in Finland. This new method gives similar results to a standard cure model, when it is reliable, and better fit when the standard cure model gives biased estimates.
Cure models within the framework of flexible parametric models enables cure modelling when standard models give biased estimates. These flexible cure models enable inclusion of older age groups and can give stage-specific estimates, which is not always possible from parametric cure models.
PMCID: PMC3145604  PMID: 21696598
7.  Model selection in Medical Research: A simulation study comparing Bayesian Model Averaging and Stepwise Regression 
Automatic variable selection methods are usually discouraged in medical research although we believe they might be valuable for studies where subject matter knowledge is limited. Bayesian model averaging may be useful for model selection but only limited attempts to compare it to stepwise regression have been published. We therefore performed a simulation study to compare stepwise regression with Bayesian model averaging.
We simulated data corresponding to five different data generating processes and thirty different values of the effect size (the parameter estimate divided by its standard error). Each data generating process contained twenty explanatory variables in total and had between zero and two true predictors. Three data generating processes were built of uncorrelated predictor variables while two had a mixture of correlated and uncorrelated variables. We fitted linear regression models to the simulated data. We used Bayesian model averaging and stepwise regression respectively as model selection procedures and compared the estimated selection probabilities.
The estimated probability of not selecting a redundant variable was between 0.99 and 1 for Bayesian model averaging while approximately 0.95 for stepwise regression when the redundant variable was not correlated with a true predictor. These probabilities did not depend on the effect size of the true predictor. In the case of correlation between a redundant variable and a true predictor, the probability of not selecting a redundant variable was 0.95 to 1 for Bayesian model averaging while for stepwise regression it was between 0.7 and 0.9, depending on the effect size of the true predictor. The probability of selecting a true predictor increased as the effect size of the true predictor increased and leveled out at between 0.9 and 1 for stepwise regression, while it leveled out at 1 for Bayesian model averaging.
Our simulation study showed that under the given conditions, Bayesian model averaging had a higher probability of not selecting a redundant variable than stepwise regression and had a similar probability of selecting a true predictor. Medical researchers building regression models with limited subject matter knowledge could thus benefit from using Bayesian model averaging.
PMCID: PMC3017523  PMID: 21134252
8.  The influence of menopausal hormone therapy on tumour characteristics and survival in endometrial cancer patients 
Menopausal hormone therapy (MHT) is a well established factor in endometrial carcinogenesis, and therefore, could have prognostic implications. We investigated the effects of ever use of MHT on tumour grade and depth of myometrial invasion, and 5-year relative survival in postmenopausal endometrial cancer patients.
Materials and Methods
We used a nationwide, population-based case-case design, of 683 Swedish women aged 50–74 years diagnosed with endometrial cancer during 1994 to 1995, followed up to 5 years after diagnosis. We applied polytomous multiple logistic regression to investigate the associations between use of MHT and tumour grade, and myometrial invasion and Poisson regression for modelling 5-year excess mortality.
Compared to never use, ever use of any MHT entailed lower risks of having moderately and poorly differentiated tumours. The lowest odds ratios for poorly differentiated tumours were seen for ever users of cyclically combined oestrogen-progestin [OR = 0.23 (95% CI = 0.07–0.73)]. Ever users of any form of MHT; particularly, medium potency MHT users, had significantly lower risks for tumours with deep myometrial invasion. Adjusted estimated relative excess hazard ratios revealed significantly improved survival for ever users of any form of MHT [RER = 0.40 (95% CI = 0.16–0.97)]; in particular ever users of any form of oestrogens [RER = 0.38 (95% CI = 0.15–0.99)].
Endometrial cancer patients who were ever users of MHT had more favourable tumour characteristics and better survival compared to never users of MHT. These findings support the notion that MHT induces endometrial cancer with less aggressive characteristics.
PMCID: PMC2783257  PMID: 19493676
Endometrial cancer; menopause hormone therapy; postmenopausal; tumour grade; myometrial invasion; relative survival; mortality
9.  Change in depressive symptoms over higher education and professional establishment - a longitudinal investigation in a national cohort of Swedish nursing students 
BMC Public Health  2010;10:343.
There are indications of a high prevalence of psychological distress among students in higher education and also that distress increases over the course of study. However, not all studies on student distress controlled for sociodemographic differences and few followed development of distress over an extended period through professional establishment. We investigated if there is an independent effect of time in education and the first two years in the profession on depressive symptoms and mapped change over the period in a national cohort of students.
Data came from LANE, a nation-wide longitudinal panel survey of Swedish nursing students (N = 1700) who responded to annual questionnaires over five years from 2002 to 2007. Depressive symptoms were measured by the Major Depression Inventory and change over time analysed in a linear mixed effects model for repeated measures.
There was a significant change in level of depressive symptoms over time: an increase from the first to later years in education and a decrease to levels similar to baseline after graduation and a year in the profession. The change in symptoms remained significant after adjustment for sociodemographic factors (p < 0.01). Symptom levels differed due to age, gender, household composition and prior nurse assistant training but change over time was similar in all groups. The correlation among the repeated measures, representing within individual correlation over time, varied between 0.44-0.60.
The findings indicate an independent but transitional effect of time in education and professional establishment on depressive symptoms. We think heightened distress over education abates as the graduate accommodates to the profession. Nevertheless, within education, the differences in depressive symptoms associated to demographic factors can help identify student groups more vulnerable to distress. Also, as individual differences in distress seem to persist over time, perhaps students highly distressed in the beginning of education can be helped by awareness among educators of the elevated levels of distress in late education.
PMCID: PMC2905329  PMID: 20550704
10.  Placental Weight and Risk of Invasive Epithelial Ovarian Cancer with an Early Age of Onset 
Epithelial ovarian cancer is associated with reproductive factors, but we lack knowledge if hormonal factors during pregnancy influence the mother’s risk. Because pregnancy hormones are primarily produced by the placenta, placental weight may be an indirect marker of hormone exposure during pregnancy.
In a nationwide Swedish cohort study, we included women with singleton births from 1982 to 1989. Women were followed for occurrence of invasive epithelial ovarian cancer, death, or emigration through 2004. Hazard ratios (HR) with 95% confidence intervals (95% CI) from Cox models were used to estimate associations between pregnancy exposures and epithelial ovarian cancer.
Among 395,171 women with information on placental weight in their first recorded birth, 316 women developed invasive epithelial ovarian cancer. Mean age at diagnosis was 44 years. Compared with women with a placental weight of 500 to 699 g, women with a high (≥700 g) placental weight had an increased riskof developing epithelial ovarian cancer (HR, 1.47; 95% CI, 1.14–1.90). Compared with women with term pregnancies (40–41 weeks), women with post-term (≥42 weeks) pregnancies had an increased risk of developing epithelial ovarian cancer (HR, 1.48; 95% CI, 1.00–2.19). These associations were slightly stronger when we included information about women’s overall first birth, and slightly weaker when we included information about last recorded birth or ever last birth from 1982 to 1989.
Because pregnancy hormone levels increase with placental weight, our study supports the hypothesis that hormone exposures during pregnancy influence the risk of invasive epithelial ovarian cancer among young women.
PMCID: PMC2643070  PMID: 18768502
11.  Gestational Age and Fetal Growth in Relation to Maternal Ovarian Cancer Risk in a Swedish Cohort 
Pregnancy influences subsequent maternal ovarian cancer risk. To date, there is limited evidence whether two characteristics of pregnancy, gestational age and birth weight, could modify risk.
Materials and Methods
We studied 1.1 million Swedish women who delivered singleton births between 1973 and 2001. Information on infant gestational age and birth weight was abstracted from the nationwide Swedish Birth Register. Women were followed prospectively through linkage with other population-based registers for occurrence of ovarian cancer, death, or emigration through 2001. Hazard ratios [relative risk (RR), 95% confidence interval (95% CI)] from Cox models were used to estimate associations between gestational age, birth weight, and epithelial ovarian cancer risk.
During 12.6 million person-years, 1,017 epithelial ovarian cancers occurred. Mean age at diagnosis was 43 years. Compared with women with term deliveries (≥40 weeks), women with moderately (35–36 weeks) or very (<35 weeks) preterm deliveries had increased risks of epithelial ovarian cancer (RR 1.4, 95% CI 1.0–2.0 and RR 2.3, 95% CI 1.3–3.8, respectively). In contrast, women giving birth to small-for-gestational-age babies had a reduced risk (RR 0.7, 95% CI 0.4–1.0). Stratifying on birth weight and gestational age, there was a strong protective effect of low birth weight on maternal risk of epithelial ovarian cancer among term deliveries, whereas birth weight seemed to have little effect among preterm births (Pinteraction = 0.022).
Our results lend further support that the hormonal milieu of a pregnancy may modify long-term risk of developing ovarian cancer.
PMCID: PMC2646123  PMID: 17855701
12.  Menopausal hormone therapy in relation to breast cancer characteristics and prognosis: a cohort study 
Menopausal hormone therapy has been reported to increase the risk of certain subtypes of breast cancer and to be associated with a favorable survival. These associations could either be due to an increased mammographic surveillance or to a biological effect. We assessed these associations in a Swedish cohort of postmenopausal breast cancer patients holding information on mammographic examinations, menopausal hormone therapy use, other breast cancer risk factors, and cancer treatment.
We analyzed 2,660 postmenopausal women aged 50 to 74 years, diagnosed with invasive breast cancer in 1993 to 1995 and followed until the end of 2003 (median follow-up, 9 years and 3 months). We assessed the influence of hormone therapy before diagnosis on tumor characteristics and breast cancer-specific survival. We analyzed hormone therapy before diagnosis by regimen (estrogen–progestin therapy or estrogen alone therapy), recency (current or past), and duration of use (<5 years or ≥ 5 years).
Current use, but not past use, compared with never use of hormone therapy before diagnosis seemed to be associated with tumors of low grade and with improved breast cancer-specific survival. The associations were stronger with longer duration, but did not vary significantly by regimen. The favorable survival among current users of hormone therapy was only partly explained by differences in available tumor characteristics and mammographic surveillance.
We conclude that current menopausal hormone therapy, especially long term, is associated with favorable tumor characteristics and survival.
PMCID: PMC2614511  PMID: 18803850
13.  Is breast cancer prognosis inherited? 
Breast Cancer Research  2007;9(3):R39.
A genetic component is well established in the etiology of breast cancer. It is not well known, however, whether genetic traits also influence prognostic features of the malignant phenotype.
We carried out a population-based cohort study in Sweden based on the nationwide Multi-Generation Register. Among all women with breast cancer diagnosed from 1961 to 2001, 2,787 mother-daughter pairs and 831 sister pairs with breast cancer were identified; we achieved complete follow-up and classified 5-year breast cancer-specific prognosis among proband (mother or oldest sister) into tertiles as poor, intermediary, or good. We used Kaplan-Meier estimates of survival proportions and Cox models to calculate relative risks of dying from breast cancer within 5 years depending on the proband's outcome.
The 5-year survival proportion among daughters whose mothers died within 5 years was 87% compared to 91% if the mother was alive (p = 0.03). Among sisters, the corresponding proportions were 70% and 88%, respectively (p = 0.001). After adjustment for potential confounders, daughters and sisters of a proband with poor prognosis had a 60% higher 5-year breast cancer mortality compared to those of a proband with good prognosis (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.2 to 2.2; p for trend 0.002). This association was slightly stronger among sisters (HR, 1.8; 95% CI, 1.0 to 3.4) than among daughters (HR, 1.6; 95% CI, 1.1 to 2.3).
Breast cancer prognosis of a woman predicts the survival in her first-degree relatives with breast cancer. Our novel findings suggest that breast cancer prognosis might be inherited.
PMCID: PMC1929105  PMID: 17598882
14.  Menopausal hormone therapy and other breast cancer risk factors in relation to the risk of different histological subtypes of breast cancer: a case-control study 
Breast Cancer Research  2006;8(1):R11.
Breast cancers of different histology have different clinical and prognostic features. There are also indications of differences in aetiology. We therefore evaluated the risk of the three most common histological subtypes in relation to menopausal hormone therapy and other breast cancer risk factors.
We used a population-based case-control study of breast cancer to evaluate menopausal hormone therapy and other breast cancer risk factors for risk by histological subtype. Women aged 50 to 74 years, diagnosed with invasive ductal (n = 1,888), lobular (n = 308) or tubular (n = 93) breast cancer in Sweden in 1993 to 1995 were compared with 3,065 age-frequency matched controls randomly selected from the population. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for ductal, lobular, and tubular cancer.
Women who had used medium potency estrogen alone were at increased risks of both ductal and lobular cancer. Medium potency estrogen-progestin was associated with increased risks for all subtypes, but the estimates for lobular and tubular cancer were higher compared with ductal cancer. We found OR 5.6 (95% CI 3.2–9.7) for lobular cancer, OR 6.5 (95% CI 2.8–14.9) for tubular cancer and OR 2.3 (95% CI 1.6–3.3) for ductal cancer with ≥5 years use of medium potency estrogen-progestin therapy. Low potency oral estrogen (mainly estriol) appeared to be associated with an increased risk for lobular cancer, but the association was strongest for short-term use. Reproductive and anthropometric factors, smoking, and past use of oral contraceptives were mostly similarly related to the risks of the three breast cancer subtypes. Recent alcohol consumption of > 10 g alcohol/day was associated with increased risk only for tubular cancer (OR 3.1, 95% CI 1.4–6.8).
Menopausal hormone therapy was associated with increased risks for breast cancer of both ductal and lobular subtype, and medium potency estrogen-progestin therapy was more strongly associated with lobular compared with ductal cancer. We also found medium potency estrogen-progestin therapy and alcohol to be strongly associated with tubular cancer. With some exceptions, most other risk factors seemed to be similarly associated with the three subtypes of breast cancer.
PMCID: PMC1413980  PMID: 16507159
15.  Differences in Management of Older Women Influence Breast Cancer Survival: Results from a Population-Based Database in Sweden 
PLoS Medicine  2006;3(3):e25.
Several reports have shown that less aggressive patterns of diagnostic activity and care are provided to elderly breast carcinoma patients. We sought to investigate whether differences in the management of older women with breast cancer are associated with survival.
Methods and Findings
In an observational study using a population-based clinical breast cancer register of one health-care region in Sweden, we identified 9,059 women aged 50–84 y diagnosed with primary breast cancer between 1992 and 2002. The 5-y relative survival ratio was estimated for patients classified by age group, diagnostic activity, tumor characteristics, and treatment. The 5-y relative survival for breast cancer patients was lower (up to 13%) in women 70–84 y of age compared to women aged 50–69 y, and the difference was most pronounced in stage IIB–III and in the unstaged. Significant differences in disease management were found, as older women had larger tumors, had fewer nodes examined, and did not receive treatment by radiotherapy or by chemotherapy as often as the younger women. Adjustment for diagnostic activity, tumor characteristics, and treatment diminished the relative excess mortality in stages III and in the unstaged, whereas the excess mortality was only marginally affected in stage IIB.
Less diagnostic activity, less aggressive treatment, and later diagnosis in older women are associated with poorer survival. The large differences in treatment of older women are difficult to explain by co-morbidity alone.
A study from Sweden shows that a lower 5-year relative survival for older women with breast cancer was associated with less diagnostic activity, less aggressive treatment, and later diagnosis.
PMCID: PMC1326256  PMID: 16409108

Results 1-15 (15)