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1.  Serum glucose and risk of cancer: a meta-analysis 
BMC Cancer  2014;14:985.
Raised serum glucose has been linked to increased risk of many solid cancers. We performed a meta-analysis to quantify and summarise the evidence for this link.
Pubmed and Embase were reviewed, using search terms representing serum glucose and cancer. Inclusion and exclusion criteria focused on epidemiological studies with clear definitions of serum glucose levels, cancer type, as well as well-described statistical methods with sufficient data available. We used 6.1 mmol/L as the cut-off for high glucose, consistent with the WHO definition of metabolic syndrome. Random effects analyses were performed to estimate the pooled relative risk (RR).
Nineteen studies were included in the primary analysis, which showed a pooled RR of 1.32 (95% CI: 1.20 – 1.45). Including only those individuals with fasting glucose measurements did not have a large effect on the pooled RR (1.32 (95% CI: 1.11-1.57). A stratified analysis showed a pooled RR of 1.34 (95% CI: 1.02-1.77) for hormonally driven cancer and 1.21 (95% CI: 1.09-1.36) for cancers thought to be driven by Insulin Growth Factor-1.
A positive association between serum glucose and risk of cancer was found. The underlying biological mechanisms remain to be elucidated but our subgroup analyses suggest that the insulin- IGF-1 axis does not fully explain the association. These findings are of public health importance as measures to reduce serum glucose via lifestyle and dietary changes could be implemented in the context of cancer mortality.
PMCID: PMC4320469  PMID: 25526881
Glucose; Cancer; Metabolic syndrome; Meta-analysis; Diabetes
2.  Obesity and cancer: the role of vitamin D 
BMC Cancer  2014;14(1):712.
It is estimated that 20% of all cancer cases are caused by obesity. Vitamin D is thought to be one of the mechanisms underlying this association. This review aims to summarise the evidence for the mediating effect of vitamin D on the link between obesity and cancer.
Three literature searches using PubMed and Embase were conducted to assess whether vitamin D plays an important role in the pathway between obesity and cancer: (1) obesity and cancer; (2) obesity and vitamin D; and (3) vitamin D and cancer. A systematic review was performed for (1) and (3), whereas a meta-analysis including random effects analyses was performed for (2).
(1) 32 meta-analyses on obesity and cancer were identified; the majority reported a positive association between obesity and risk of cancer. (2) Our meta-analysis included 12 original studies showing a pooled relative risk of 1.52 (95% CI: 1.33-1.73) for risk of vitamin D deficiency (<50 nmol/L) in obese people (body mass index >30 kg/m2). (3) 21 meta-analyses on circulating vitamin D levels and cancer risk were identified with different results for different types of cancer.
There is consistent evidence for a link between obesity and cancer as well as obesity and low vitamin D. However, it seems like the significance of the mediating role of vitamin D in the biological pathways linking obesity and cancer is low. There is a need for a study including all three components while dealing with bias related to dietary supplements and vitamin D receptor polymorphisms.
PMCID: PMC4182855  PMID: 25255691
Cancer; Obesity; Vitamin D
3.  Mortality following Hip Fracture in Men with Prostate Cancer 
PLoS ONE  2013;8(9):e74492.
Hip fractures are associated with increased mortality and are a known adverse effect of androgen deprivation therapy (ADT) for prostate cancer (PCa). It was our aim to evaluate how mortality after hip fracture is modified by PCa and ADT.
PCa dataBase Sweden (PCBaSe 2.0) is based on the National PCa Register and also contains age and county-matched PCa-free men. We selected all men (n = 14,205) who had been hospitalized with a hip fracture between 2006 and 2010; 2,300 men had a prior PCa diagnosis of whom 1,518 (66%) were on ADT prior to date of fracture. Risk of death was estimated with cumulative incidence and standardized mortality ratios (SMRs) to make comparisons with the entire PCa population and the general population.
Cumulative incidences indicated that there was a higher risk of death following a hip fracture for PCa men on ADT than for PCa men not on ADT or PCa-free men, particularly in the first year. The SMRs showed that PCa men on ADT with a hip fracture were 2.44 times more likely to die than the comparison cohort of all PCa men (95%CI: 2.29-2.60). This risk was especially increased during the first month (5.64 (95%CI: 4.16–7.48)). In absolute terms, hip fractures were associated with 20 additional deaths per 1,000 person-years in PCa men not on ADT, but 30 additional deaths per 1,000 person-years for PCa men on ADT, compared to all PCa men.
Hip fractures are associated with higher all-cause mortality in PCa men on ADT than in PCa men not on ADT or PCa-free men, especially within the first three months.
PMCID: PMC3785484  PMID: 24086350
4.  Serum calcium and risk of gastrointestinal cancer in the Swedish AMORIS study 
BMC Public Health  2013;13:663.
Observational studies have indicated that high calcium intake may prevent colorectal cancer, but as for randomized trials the results are inconclusive. Meanwhile, limited data on the link between serum calcium and cancer risk is available. We investigated the relation between serum calcium and risk of different gastrointestinal cancers in a prospective study.
A cohort based on 492,044 subjects with baseline information on calcium (mmol/L) and albumin (g/L) was selected from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study. Multivariable Cox proportional hazard models were used to analyse associations between standardised levels, quartiles and age/sex-specific categories of serum calcium and risk of oesophageal, stomach, colon, rectal cancer and also colorectal cancer combined, while taking into account serum albumin and other comorbidities.
During 12 years of follow-up, we identified 323 incident oesophageal cancers, 782 stomach cancers, 2519 colon cancers, and 1495 rectal cancers. A positive association was found between albumin-adjusted serum calcium and risk of oesophageal [HR: 4.82 (95% CI: 2.07 – 11.19) for high compared to normal age-specific calcium levels] and colon cancer [e.g. HR: 1.07 (95% CI: 1.00 – 1.14) for every SD increase of calcium] as well as colorectal cancer [e.g. HR: 1.06 (95% CI: 1.02-1.11) for every SD increase of calcium] in women. In men there were similar but weaker non-statistically significant trends.
The positive relation between serum calcium, oesophageal cancer and colorectal cancer calls for further studies including calcium regulators to evaluate whether there is a true link between calcium metabolism and development of gastrointestinal cancer.
PMCID: PMC3729677  PMID: 23866097
Gastrointestinal cancer; Calcium; Albumin
5.  Inorganic phosphate and the risk of cancer in the Swedish AMORIS study 
BMC Cancer  2013;13:257.
Both dietary and serum levels of inorganic phosphate (Pi) have been linked to development of cancer in experimental studies. This is the first population-based study investigating the relation between serum Pi and risk of cancer in humans.
From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected all participants (> 20 years old) with baseline measurements of serum Pi, calcium, alkaline phosphatase, glucose, and creatinine (n = 397,292). Multivariable Cox proportional hazards regression analyses were used to assess serum Pi in relation to overall cancer risk. Similar analyses were performed for specific cancer sites.
We found a higher overall cancer risk with increasing Pi levels in men ( HR: 1.02 (95% CI: 1.00-1.04) for every SD increase in Pi), and a negative association in women (HR: 0.97 (95% CI: 0.96-0.99) for every SD increase in Pi). Further analyses for specific cancer sites showed a positive link between Pi quartiles and the risk of cancer of the pancreas, lung, thyroid gland and bone in men, and cancer of the oesophagus, lung, and nonmelanoma skin cancer in women. Conversely, the risks for developing breast and endometrial cancer as well as other endocrine cancer in both men and women were lower in those with higher Pi levels.
Abnormal Pi levels are related to development of cancer. Furthermore, the in verse association between Pi levels and risk of breast, endometrial and other endocrine cancers may indicate the role of hormonal factors in the relation between Pi metabolism and cancer.
PMCID: PMC3664604  PMID: 23706176
Cancer; Inorganic phosphate; Prospective cohort study
6.  Iron metabolism and risk of cancer in the Swedish AMORIS study 
Cancer Causes & Control  2013;24(7):1393-1402.
Pre-clinical studies have shown that iron can be carcinogenic, but few population-based studies investigated the association between markers of the iron metabolism and risk of cancer while taking into account inflammation. We assessed the link between serum iron (SI), total-iron binding capacity (TIBC), and risk of cancer by levels of C-reactive protein (CRP) in a large population-based study (n = 220,642).
From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected all participants (>20 years old) with baseline measurements of serum SI, TIBC, and CRP. Multivariate Cox proportional hazards regression was carried out for standardized and quartile values of SI and TIBC. Similar analyses were performed for specific cancers (pancreatic, colon, liver, respiratory, kidney, prostate, stomach, and breast cancer). To avoid reverse causation, we excluded those with follow-up <3 years.
We found a positive association between standardized TIBC and overall cancer [HR 1.03 (95 % CI 1.01–1.05)]. No statistically significant association was found between SI and cancer risk except for postmenopausal breast cancer [HR for standardized SI 1.09 (95 % CI 1.02–1.15)]. The association between TIBC and specific cancer was only statistically significant for colon cancer [i.e., HR for standardized TIBC: 1.17 (95 % CI 1.08–1.28)]. A borderline interaction between SI and levels of CRP was observed only in stomach cancer.
As opposed to pre-clinical findings for serum iron and cancer, this population-based epidemiological study showed an inverse relation between iron metabolism and cancer risk. Minimal role of inflammatory markers observed warrants further study focusing on developments of specific cancers.
PMCID: PMC3675271  PMID: 23649231
Cancer; C-reactive protein; Iron; Iron-binding capacity; Sweden
7.  Serum Glucose and Fructosamine in Relation to Risk of Cancer 
PLoS ONE  2013;8(1):e54944.
Impaired glucose metabolism has been linked with increased cancer risk, but the association between serum glucose and cancer risk remains unclear. We used repeated measurements of glucose and fructosamine to get more insight into the association between the glucose metabolism and risk of cancer.
We selected 11,998 persons (>20 years old) with four prospectively collected serum glucose and fructosamine measurements from the Apolipoprotein Mortality Risk (AMORIS) study. Multivariate Cox proportional hazards regression was used to assess standardized log of overall mean glucose and fructosamine in relation to cancer risk. Similar analyses were performed for tertiles of glucose and fructosamine and for different types of cancer.
A positive trend was observed between standardized log overall mean glucose and overall cancer risk (HR = 1.08; 95% CI: 1.02–1.14). Including standardized log fructosamine in the model resulted in a stronger association between glucose and cancer risk and aninverse association between fructosamine and cancer risk (HR = 1.17; 95% CI: 1.08–1.26 and HR: 0.89; 95% CI: 0.82–0.96, respectively). Cancer risks were highest among those in the highest tertile of glucose and lowest tertile of fructosamine. Similar findings were observed for prostate, lung, and colorectal cancer while none observed for breast cancer.
The contrasting effect between glucose, fructosamine, and cancer risk suggests the existence of distinct groups among those with impaired glucose metabolism, resulting in different cancer risks based on individual metabolic profiles. Further studies are needed to clarify whether glucose is a proxy of other lifestyle-related or metabolic factors.
PMCID: PMC3556075  PMID: 23372798
8.  Serum Lipid Profiles and Cancer Risk in the Context of Obesity: Four Meta-Analyses 
Journal of Cancer Epidemiology  2013;2013:823849.
The objective here was to summarize the evidence for, and quantify the link between, serum markers of lipid metabolism and risk of obesity-related cancers. PubMed and Embase were searched using predefined inclusion criteria to conduct meta-analyses on the association between serum levels of TG, TC, HDL, ApoA-I, and risk of 11 obesity-related cancers. Pooled relative risks (RRs) and 95% confidence intervals were estimated using random-effects analyses. 28 studies were included. Associations between abnormal lipid components and risk of obesity-related cancers when using clinical cutpoints (TC ≥ 6.50; TG ≥ 1.71; HDL ≤ 1.03; ApoA-I ≤ 1.05 mmol/L) were apparent in all models. RRs were 1.18 (95% CI: 1.08–1.29) for TC, 1.20 (1.07–1.35) for TG, 1.15 (1.01–1.32) for HDL, and 1.42 (1.17–1.74) for ApoA-I. High levels of TC and TG, as well as low levels of HDL and ApoA-I, were consistently associated with increased risk of obesity-related cancers. The modest RRs suggest serum lipids to be associated with the risk of cancer, but indicate it is likely that other markers of the metabolism and/or lifestyle factors may also be involved. Future intervention studies involving lifestyle modification would provide insight into the potential biological role of lipid metabolism in tumorigenesis.
PMCID: PMC3563167  PMID: 23401687
9.  Gamma-glutamyl transferase and C-reactive protein as alternative markers of metabolic abnormalities and their associated comorbidites: a prospective cohort study 
Background: Recent studies suggested that gamma-glutamyl transferase (GGT) and C-reactive protein (CRP) are good markers of metabolic abnormalities. We assessed the link between GGT, CRP and common metabolic abnormalities, as well their link to related diseases, such as cancer and cardiovascular disease (CVD). Methods: We selected 333,313 subjects with baseline measurements of triglycerides (TG), total cholesterol (TC), glucose, GGT and CRP in the Swedish AMORIS study. Baseline measurement of BMI was available for 63,900 persons and 77,944 had baseline measurements of HDL. Pearson correlation coefficients between CRP, GGT, and metabolic components (TG, HDL, BMI and TC) were calculated. To investigate the combined effect of GGT and CRP we created a score ranging from 0 to 6 and used Cox proportional hazard models to evaluate its association with CVD and cancer. Results: 21,216 individuals developed cancer and 47,939 CVD. GGT and TG had the strongest correlation (r=0.22). An increased risk of cancer was identified with elevated levels of GGT or CRP or both markers (GGT-CRP score ≥3); the greatest risk of cancer was found when GGT-CRP score = 6 (HR: 1.40 (95%CI: 1.31-1.48) and 1.60 (1.47-1.76) compared to GGT-CRP score = 0, respectively). Conclusion: While GGT and CRP have been shown to be associated with metabolic abnormalities previously, their association to the components investigated in this study was limited. Results did demonstrate that these markers were predictive of associated diseases, such as cancer.
PMCID: PMC3508539  PMID: 23205179
GGT; CRP; metabolic abnormalities; cardiovascular disease; cancer
10.  Serum Lipids and the Risk of Gastrointestinal Malignancies in the Swedish AMORIS Study 
Journal of Cancer Epidemiology  2012;2012:792034.
Background. Metabolic syndrome has been linked to an increased cancer risk, but the role of dyslipidaemia in gastrointestinal malignancies is unclear. We aimed to assess the risk of oesophageal, stomach, colon, and rectal cancers using serum levels of lipid components. Methods. From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected 540,309 participants (> 20 years old) with baseline measurements of total cholesterol (TC), triglycerides (TG), and glucose of whom 84,774 had baseline LDL cholesterol (LDL), HDL cholesterol (HDL), apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I). Multivariate Cox proportional hazards regression was used to assess glucose and lipid components in relation to oesophageal, stomach, colon, and rectal cancer risk. Results. An increased risk of oesophageal cancer was observed in persons with high TG (e.g. HR: 2.29 (95% CI: 1.42–3.68) for the 4th quartile compared to the 1st) and low LDL, LDL/HDL ratio, TC/HDL ratio, log (TG/HDL), and apoB/apoA-I ratio. High glucose and TG were linked with an increased colon cancer risk, while high TC levels were associated with an increased rectal cancer risk. Conclusion. The persistent link between TC and rectal cancer risk as well as between TG and oesophageal and colon cancer risk in normoglycaemic individuals may imply their substantiality in gastrointestinal carcinogenesis.
PMCID: PMC3437288  PMID: 22969802
11.  Association between levels of C-reactive protein and leukocytes and cancer: Three repeated measurements in the Swedish AMORIS study 
To study levels of C-reactive protein (CRP) and leukocytes, as inflammatory markers, in the context of cancer risk.
From the Apolipoprotein MOrtality RISk (AMORIS) study, we selected 102,749 persons with one measurement and 9,273 persons with three repeated measurements of CRP and leukocytes. Multivariate Cox proportional hazards regression was applied to categories of CRP (<10, 10-15, 15-25, 25-50, >50 g/L) and quartiles of leukocytes. An Inflammation-based Predictive Score (IPS) indicated whether someone had CRP levels >10mg/L combined with leukocytes >10×109/L. Reverse causality was assessed by excluding those with <3, 5, or 7 years of follow-up. To analyze repeated measurements of CRP and leukocytes the repeated IPS (IPSr) was calculated by adding the IPS of each measurement.
In the cohort with one measurement, there was a positive trend between CRP and cancer, with the lowest category being the reference: 0.99 (0.92-1.06), 1.28 (1.11-1.47), 1.27 (1.09-1.49), 1.22 (1.01-1.48) for the 2nd to 5th categories, respectively. This association disappeared when excluding those with follow-up <3, 5 or 7 years. The association between leukocytes and cancer was slightly stronger. In the cohort with repeated measurements the IPSr was strongly associated with cancer risk: 1.87 (1.33-2.63), 1.51 (0.56-4.06), 4.46 (1.43-13.87) for IPSr =1, 2, and 3, compared to IPSr =0. The association remained after excluding those with follow-up <1 year.
Conclusions and impact
Our large prospective cohort study adds evidence for a link between inflammatory markers and cancer risk by using repeated measurements and ascertaining reverse causality.
PMCID: PMC3078551  PMID: 21297038
cancer; C-reactive protein; leukocytes; Sweden
12.  Risk of thromboembolic diseases in men with prostate cancer: results from the population-based PCBaSe Sweden 
The Lancet Oncology  2010;11(5):450-458.
Cancer is associated with an increased risk of thromboembolic diseases, but data on the association between prostate cancer and thromboembolic diseases are scarce. We investigated the risk of thromboembolic disease in men with prostate cancer who were receiving endocrine treatment, curative treatment, or surveillance.
We analysed data from PCBaSe Sweden, a database based on the National Prostate Cancer Register, which covers over 96% of prostate cancer cases in Sweden. Standardised incidence ratios (SIR) of deep-venous thrombosis (DVT), pulmonary embolism, and arterial embolism were calculated by comparing observed and expected (using the total Swedish male population) occurrences of thromboembolic disease, taking into account age, calendar-time, number of thromboembolic diseases, and time since previous thromboembolic disease.
Between Jan 1, 1997, and Dec 31, 2007, 30 642 men received primary endocrine therapy, 26 432 curative treatment, and 19 526 surveillance. 1881 developed a thromboembolic disease. For men on endocrine therapy, risks for DVT (SIR 2·48, 95% CI 2·25–2·73) and pulmonary embolism (1·95, 1·81–2·15) were increased, although this was not the case for arterial embolism (1·00, 0·82–1·20). Similar patterns were seen for men who received curative treatment (DVT: 1·73, 1·47–2·01; pulmonary embolism: 2·03, 1·79–2·30; arterial embolism: 0·95, 0·69–1·27) and men who were on surveillance (DVT: 1·27, 1·08–1·47; pulmonary embolism: 1·57, 1·38–1·78; arterial embolism: 1·08, 0·87–1·33). Increased risks for thromboembolic disease were maintained when patients were stratified by age and tumour stage.
All men with prostate cancer were at higher risk of thromboembolic diseases, with the highest risk for those on endocrine therapy. Our results indicate that prostate cancer itself, prostate cancer treatments, and selection mechanisms all contribute to increased risk of thromboembolic disease. Thromboembolic disease should be a concern when managing patients with prostate cancer.
Swedish Research Council, Stockholm Cancer Society, and Cancer Research UK.
PMCID: PMC2861771  PMID: 20395174

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