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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.

Background: Management of frailty is the cornerstone of geriatric medicine, but there remains a need to identify biomarkers that can predict early death, and thereby lead to effective clinical interventions. We aimed to study the combination of C-reactive protein (CRP), albumin, gamma-glutamyl transferase (GGT), and HDL to predict mortality., Methods: A total of 44,457 persons aged 50+ whose levels of CRP, albumin, GGT, and HDL were measured at baseline were selected from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study. A mortality score, ranging from 0 to 4, was created by adding the number of markers with abnormal values according to the clinical cut-off (CRP > 10 mg/L, albumin < 35 mg/L, GGT > 36 kU/L, HDL < 1.04 mmol/L). Mortality was studied with multivariate Cox proportional hazards models., Results: 2,245 persons died from cancer, 3,276 from circulatory disease, and 1,860 from other causes. There was a positive trend between mortality score and all-cause mortality as well as cancer and circulatory disease-specific death (e.g. HR for all-cause mortality: 1.39 (95%CI: 1.32-1.46), 2.04 (1.89-2.21), and 3.36 (2.87-3.93), for score=1, 2, and 3+, compared to score=0). Among cancer patients with no other co-morbidities (n=1,955), there was a positive trend between the score and mortality (HR: 1.24 (95%CI: 1.0.-1.49), 2.38 (95%CI: 1.76-3.22), and 5.47 (95%CI: 2.98-10.03) for score=1, 2, and 3+ compared to score=0)., Conclusions: By combining biomarkers of different mechanisms contributing to patient frailty, we found a strong marker for mortality in persons aged 50+. Elevated risks among cancer patients with no other co-morbidities prior to biomarker assessment call for validation in other cohorts and testing of different combinations and cut-offs than those used here, in order to aid decision-making in treatment of older cancer patients.

Studies comparing the prognosis after contralateral breast cancer (CBC) with that after unilateral breast cancer (UBC) shows conflicting results. We assessed the risk of breast cancer-specific death for women with metachronous CBC compared to those with a UBC in 8,478 women with invasive primary breast cancer registered in the Guy's and St. Thomas' Breast Cancer Tissue and Data Bank. Risk factors associated with breast cancer-specific death for women with CBC were estimated using Cox proportional hazards modelling. Prognoses after UBC and CBC were compared, with survival time for women with CBC calculated: (i) from CBC, (ii) from the initial cancer with CBC as a time-dependent covariate. Women diagnosed with CBC within 5 years after the initial primary breast cancer had a worse prognosis than those with CBC after 5 years and those with UBC. Women with CBC who had positive lymph nodes at the initial breast cancer diagnosis were at an increased risk of dying from breast cancer compared to those without [HR 2.5 (95% CI 1.5-4.0)]. For all stages of the initial breast cancer, a worse prognosis was observed after CBC. CBC increased the hazard originating from the initial cancer at any follow-up time, but the highest hazards were associated with a short interval to CBC. Metachronous CBC adds to the risk of dying from breast cancer. The risk increases substantially when it occurs shortly after the initial cancer, indicating a CBC in some instances may be an indicator of active distant disease. The occurrence of CBC implies a new surveillance and therapeutic situation.

Background: Serum selenium level (s-Se) has been associated with prostate cancer (PrCa) risk. We investigated the relation between s-Se, smoking and non-screening detected PrCa and explored if polymorphisms in two DNA repair genes: OGG1 and MnSOD, influenced any effect of s-Se., Methods: ULSAM, a population based Swedish male cohort (n = 2322) investigated at age 50 for s-Se and s-Se influencing factors: serum cholesterol, erythrocyte sedimentation rate and smoking habits. At age 71 a subcohort, (n = 1005) was genotyped for OGG1 and MnSOD polymorphisms., Results: In a 34-year-follow-up, national registries identified 208 PrCa cases further confirmed in medical records. Participants with s-Se in the upper tertile had a non-significantly lower risk of PrCa. Smokers with s-Se in the two lower tertiles (≤80 μg/L) experienced a higher cumulative incidence of PrCa than smokers in the high selenium tertile (Hazard Ratio 2.39; 95% CI: 1.09-5.25). A high tertile selenium level in combination with non-wt rs125701 of the OGG1 gene in combination with smoking status or rs4880 related variation of MnSOD gene appeared to protect from PrCa., Conclusions: S-Se levels and smoking habits influence long-term risk of PrCa. Smoking as a risk factor for PrCa in men with low s-Se is relevant to explore further. Exploratory analyses of variations in OGG1 and MnSOD genes indicate that hypotheses about patterns of exposure to selenium and smoking combined with data on genetic variation in genes involved in DNA repair can be valuable to pursue.

Most population-based studies studied the association between inflammation and prostate cancer (PCa) by assessing C-reactive protein (CRP). As these findings have shown inconsistent results, we aimed to also study different markers that have been commonly taken as indications of inflammation. A cohort based on four groups of men (n = 34,891), according to age at cohort entry (45, 55, 65 and 75 years), with measurements of glucose, triglycerides, total cholesterol, haptoglobin, albumin, hemoglobin and leukocytes were selected from the Apolipoprotein Mortality Risk database. A total of 17,937 men had measurements of non-high-sensitive CRP. Multivariate Cox proportional hazard models were used to analyze associations between inflammatory markers and PCa. A total of 49 of 12,063 men developed PCa in the age 45 group, whereas 207 of 9,940, 472 of 8,266 and 276 of 3,618 were diagnosed in the age 55, 65 and 75 groups, respectively. Mean follow-up time was 7.5 years (SD: 3.9). No markers showed an association with PCa risk, nor was there a trend by quartiles or an indication for different PCa risks by strata of hypercholesterolemia, hyperglycemia and hypertriglyceridemia status. The studied markers were not found to be associated with PCa risk. These null findings might be due to methodological issues; however, it is unlikely that strong and long-lasting associations between inflammation and PCa risk were missed as this was a large database with long follow-up. This indicates need for international consensus on appropriate inflammatory markers in the context of cancer that may be practically applied in large studies., (Copyright © 2011 UICC.)

Background: Apart from using gamma-glutamyltransferase (GGT) as a predictor of diabetes, cardiovascular and chronic kidney disease, some evidence suggests GGT as an indicator of cancer risk. We aimed to study the association between GGT and cancer in a large Swedish cohort with 37,809 primary cancers., Methods: In a cohort of 545,460 persons (aged >20 years) who had a measurement of GGT in the Apolipoprotein Mortality Risk (AMORIS) study, multivariate Cox proportional hazards regression was used to investigate categories of GGT (<18, 18-36,36-72, ≥72 U/L) in relation to cancer risk. Stratified analyses were conducted by gender, levels of alanine aminotransferase (ALT) (

Background: There are limited prognostic data for locally advanced prostate cancer PCa to guide in the choice of treatment., Objective: To assess mortality in different prognostic categories among men with locally advanced PCa managed with noncurative intent., Design, Setting, and Participants: We conducted a register-based nationwide cohort study within the Prostate Cancer DataBase Sweden. The entire cohort of locally advanced PCa included 14 908 men. After the exclusion of 2724 (18%) men treated with curative intent, 12 184 men with locally advanced PCa either with local clinical stage T3 or T4 or with T2 with serum levels of prostate-specific antigen (PSA) between 50 and 99 ng/ml and without signs of metastases remained for analysis., Measurements: We followed up the patient cohort in the Cause of Death Register for ≤ 11 yr and assessed cumulative incidence of PCa -specific death stratified by age and clinical characteristics., Results and Limitations: The PCa -specific mortality at 8 yr of follow-up was 28% (95% confidence interval [CI], 25-32%) for Gleason score (GS) 2-6, 41% (95% CI, 38-44%) for GS 7, 52% (95% CI, 47-57%) for GS 8, and 64% (95% CI, 59-69%) for GS 9-10. Even for men aged >85 yr at diagnosis with GS 8-10, PCa was a major cause of death: 42% (95% CI, 37-47%). Men with locally advanced disease and a PSA<4 ng/ml at diagnosis were at particularly increased risk of dying from PCa. One important limitation is the lack of bone scans in 42% of the patient cohort, but results remained after exclusion of patients with unknown metastasis status., Conclusions: The PCa-specific mortality within 8 yr of diagnosis is high in locally advanced PCa, suggesting undertreatment, particularly among men in older age groups. Our results underscore the need for more studies of treatment with curative intent for locally advanced tumors., (Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Aim: To explore whether the self-reported psychological distress among men with prostate cancer was to the extent that it required psychiatric treatment., Methods: PCBaSe Sweden, a merged database based on the National Prostate Cancer Register including 97% of all prostate cancers registered as well as age-matched controls. We calculated relative risks and 95% confidence intervals to compare risks of psychiatric treatment due to depression, anxiety, and post-traumatic stress disorder controlling for age and socio-economic factors. We used odds ratios to compare use or no use of antidepressants., Findings: In total 72,613 men with prostate cancer and 217,839 men without prostate cancer were included for analyses. Psychiatric hospitalisation due to depression, anxiety and post-traumatic stress disorder were significantly increased (RR 1.29, (95% CI 1.14-1.45), RR 1.42 (95% CI 1.12-1.80) and RR 1.61 (95% CI 1.16-2.24), respectively). However, hospitalisations due to anxiety were only increased in men with more advanced tumours RR 2.28 (95% CI 1.45-3.57). The use of antidepressants was increased for all men with prostate cancer RR 1.65 (95% CI 1.54-1.77) and treatment strategies RR 1.93 (95% CI 1.75-2.13)., Interpretation: Men diagnosed with prostate cancer had increased risk of psychiatric treatment for depression, post-traumatic stress disorder and use of antidepressants regardless of risk group and treatment strategy compared to age-matched controls, whilst more advanced prostate cancer was associated with severe anxiety disorders., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Epidemiological evidence indicates that individuals with type 2 diabetes are at an increased risk of cancer. Elevated glucose levels, below the diagnostic threshold for diabetes, have also been suggested to be associated with increased cancer risks., Methods: We investigated possible associations between glucose levels and the risk of breast, endometrial, and ovarian cancer in a cohort of more than 230,000 women, for which information on outcome and potential confounders was obtained by record linkage to population-based registers., Results: Diabetes was associated with an increased risk of postmenopausal breast cancer (HR = 1.22, 95% CI 1.04-1.43). An indication of a slightly elevated breast cancer risk was also found in postmenopausal women with impaired glucose metabolism (HR = 1.11, 95% CI 0.96-1.28). Diabetes (HR = 1.46, 95% CI 1.09-1.96) and impaired glucose metabolism (HR = 1.41, 95% CI 1.08-1.85) were associated with an increased risk of endometrial cancer. No associations were found between glucose levels and ovarian cancer risk. Following adjustment for BMI, estimates were attenuated for endometrial cancer, while point estimates for breast and ovarian cancer remained essentially unchanged., Conclusions: Our results indicate that glucose levels below the diagnostic threshold for diabetes modify the risk not only of endometrial cancer but possibly also of postmenopausal breast cancer.

Background: A detailed analysis of lipid profiles, using apolipoproteins, has not yet been conducted for prostate cancer (PCa). Since several etiological pathways have been proposed for PCa and lipids, we aimed to study this in a large Swedish cohort with 1,469 primary prostate cancers., Methods: A cohort (n = 69,735) of all men aged 35 years or older, whose levels of triglycerides (TG) (mmol/L), total cholesterol (mmol/L), glucose (mmol/L), LDL (mmol/L), HDL (mmol/L), apoB (g/L), and apoA-I (g/L) were measured at baseline, was selected from the Apolipoprotein MOrtality RISk (AMORIS) database. About 2,008 men developed PCa. Multivariate Cox proportional hazard models were used to analyze associations between lipid components and PCa., Results: ApoA-I and HDL were inversely associated with PCa risk (e.g., HR for HDL: 0.93 (95% CI: 0.81-1.07), 0.88 (0.76-1.01), 0.81 (0.70-0.94), for second, third, and fourth quartiles compared with the first quartile; with p for trend: 0.004; HR for apoA-I: 1.00 (0.88-1.13), 0.93 (0.82-1.05), 0.88 (0.77-0.99),), for second, third, and fourth quartiles compared with the first quartile; with p for trend: 0.022). ApoB, LDL, and non-HDL were not associated with PCa risk., Conclusions: Our results show that low HDL and ApoA-I as well as increased lipid ratios are related to increased PCa risk. Experimental studies are required to tease out the underlying biological mechanisms linking these lipid components to PCa.

Background: In a cohort including 5112 prostate cancer (pCa) patients, the authors investigated associations among triglycerides (TG), total cholesterol (TC), and pCa while taking into account glucose., Methods: A cohort (n = 200,660) based on 4 groups of men, according to age at cohort entry, with TG, TC, and glucose measurements was selected from the Apolipoprotein MOrtality RISk (AMORIS) database. Of these, 5112 men developed pCa. Multivariate Cox proportional hazard models were used to analyze associations among TG, TC, and pCa. Competing risks were assessed graphically., Results: Age-stratified analyses for quartiles of TG, TC, and glucose showed a negative association between glucose and pCa risk (HR, 0.93; 95% CI, 0.86-1.01), 0.93 (0.86-1.01), 0.87 (0.81-0.94) for the second, third, and fourth quartiles compared with the first (P(trend) = .001). Stratified analysis by glucose levels (<6.11 or ≥ 6.11 mmol/L) showed a positive association between hypertriglyceridemia (TG ≥ 1.71 mmol/L) and pCa risk, when there were high glucose levels (HR, 1.23; 95% CI, 1.01-1.48). No association was found for hypercholesterolemia (TC ≥ 6.50 mmol/L). Competing risk analysis showed that protective effects of glucose were overestimated in conventional Cox proportional hazard models and strengthened positive findings between TG and pCa risk., Conclusions: The authors'; findings supported the hypothesis that factors of the glucose and lipid metabolism influence pCa risk. Competing risk assessment showed that it is important to take into account the long natural history and age distribution of pCa when interpreting results. The authors'; findings indicate another reason to fight the increasing prevalence of obesity and dyslipidemia., (2010 American Cancer Society.)

Background: In 2008, we reported that radical prostatectomy, as compared with watchful waiting, reduces the rate of death from prostate cancer. After an additional 3 years of follow-up, we now report estimated 15-year results., Methods: From October 1989 through February 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy. Follow-up was complete through December 2009, with histopathological review of biopsy and radical-prostatectomy specimens and blinded evaluation of causes of death. Relative risks, with 95% confidence intervals, were estimated with the use of a Cox proportional-hazards model., Results: During a median of 12.8 years, 166 of the 347 men in the radical-prostatectomy group and 201 of the 348 in the watchful-waiting group died (P=0.007). In the case of 55 men assigned to surgery and 81 men assigned to watchful waiting, death was due to prostate cancer. This yielded a cumulative incidence of death from prostate cancer at 15 years of 14.6% and 20.7%, respectively (a difference of 6.1 percentage points; 95% confidence interval [CI], 0.2 to 12.0), and a relative risk with surgery of 0.62 (95% CI, 0.44 to 0.87; P=0.01). The survival benefit was similar before and after 9 years of follow-up, was observed also among men with low-risk prostate cancer, and was confined to men younger than 65 years of age. The number needed to treat to avert one death was 15 overall and 7 for men younger than 65 years of age. Among men who underwent radical prostatectomy, those with extracapsular tumor growth had a risk of death from prostate cancer that was 7 times that of men without extracapsular tumor growth (relative risk, 6.9; 95% CI, 2.6 to 18.4)., Conclusions: Radical prostatectomy was associated with a reduction in the rate of death from prostate cancer. Men with extracapsular tumor growth may benefit from adjuvant local or systemic treatment. (Funded by the Swedish Cancer Society and the National Institutes of Health.).

Purpose: We examined associations among comorbidity, treatment decisions and mortality in patients with prostate cancer., Materials and Methods: A total of 77,536 men diagnosed with prostate cancer between 1997 and 2006 were identified in PCBaSe Sweden from the National Prostate Cancer Register of Sweden. Logistic, Cox and competing risk regression were used to assess associations among Charlson comorbidity index, treatment and mortality. The Charlson comorbidity index was categorized into no (0), mild (1) and severe comorbidity (2+)., Results: In men with low risk prostate cancer 5,975 of the 13,245 (45.1%) patients without comorbidity underwent radical prostatectomy compared to 256 of the 1,399 (18.9%) men with severe comorbidity. Following adjustment for age and period of diagnosis, radical prostatectomy was less likely to be offered to men with severe comorbidity (OR 0.48, 95% CI 0.41-0.55). In men with high risk prostate cancer, radiotherapy was more common (range 7.7% to 21.3%) than radical prostatectomy (range 3.0% to 11.2%) regardless of comorbidity burden. All cause and competing cause but not prostate cancer specific mortality were increased in men with severe comorbidity (all cause HR 1.99, 95% CI 1.93-2.05; competing cause sHR 2.66, 95% CI 2.56-2.78; prostate cancer specific sHR 0.98, 95% CI 0.93-1.03). The cumulative probability of prostate cancer death given no death from competing causes was significantly higher in men with severe comorbidity in all risk groups (p<0.01)., Conclusions: Comorbidity affects treatment choices, and is associated with all cause, competing cause and conditional prostate cancer specific mortality. An increased conditional prostate cancer specific mortality in men with severe comorbidity may reflect less aggressive treatment, impaired tumor defense, lifestyle factors and poor general health behavior., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To study levels of C-reactive protein (CRP) and leukocytes, as inflammatory markers, in the context of cancer risk., Methods: 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 of more than 10 mg/L combined with leukocytes of more than 10×10(9)/L. Reverse causality was assessed by excluding those with less than 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., Results: In the cohort with one measurement, there was a positive trend between CRP and risk of developing cancer, with the lowest category being the 0.99 (0.92-1.06), 1.28 (1.11-1.47), 1.27 (1.09-1.49), and 1.22 (1.01-1.48) for the second to fifth categories, respectively. This association disappeared when excluding those with follow-up of less than 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), and 4.46 (1.43-13.87) for IPSr=1, 2, and 3 compared with IPSr=0. The association remained after excluding those with follow-up of less than 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., (©2011 AACR.)

Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).

We quantified associations between IgE and cancer in a meta-analysis and cohort study. Pubmed and Embase were searched to extract information using predefined inclusion criteria. In the Apolipoprotein MOrtality RISk (AMORIS) database, 24,820 persons had IgE measurements. Multivariate Cox proportional hazard models were used to analyze associations between IgE and cancer. Twenty-seven studies were reviewed from which seven case-control studies were included for analysis. The pooled relative risk (random effects model) was 0.97 (95% CI 0.86-1.09). Cell types of tumor origin (mesenchymal tissue or cells of the nervous system, lymphatic or hematopoietic tissue, and epithelium) modified the effect. In the AMORIS cohort, 862 persons developed cancer. Hazard ratios comparing quartiles of IgE were similar to the findings in the meta-analysis (HR 0.87 (95% CI 0.72-1.06); 0.94 (0.78-1.14); 0.90 (0.74-1.10) for the 2nd, 3rd, and 4th quartile compared to the 1st quartile), but there was no pattern by tumor origin. Both studies showed a weak inverse association between IgE and cancer, but a pattern by cancer type was only seen in the meta-analysis. Our findings suggest the need for prospective studies studying IgE and cancer. Measurements of IgE should be combined with other information, e.g., bio-banked samples containing other key immunological discriminators.

Background: Vitamin D status is known to be important for bone health but may also affect the development of several chronic diseases, including cancer and cardiovascular diseases, which are 2 major causes of death., Objective: We aimed to examine how vitamin D status relates to overall and cause-specific mortality., Design: The Uppsala Longitudinal Study of Adult Men, a community-based cohort of elderly men (mean age at baseline: 71 y; n = 1194), was used to investigate the association between plasma 25-hydroxyvitamin D [25(OH)D] and mortality. Total plasma 25(OH)D was determined with HPLC atmospheric pressure chemical ionization mass spectrometry. Proportional hazards regression was used to compute hazard ratios (HRs)., Results: During follow-up (median: 12.7 y), 584 (49%) participants died. There was a U-shaped association between vitamin D concentrations and total mortality. An approximately 50% higher total mortality rate was observed among men in the lowest 10% (<46 nmol/L) and the highest 5% (>98 nmol/L) of plasma 25(OH)D concentrations compared with intermediate concentrations. Cancer mortality was also higher at low plasma concentrations (multivariable-adjusted HR: 2.20; 95% CI: 1.44, 3.38) and at high concentrations (HR: 2.64; 95% CI: 1.46, 4.78). For cardiovascular death, only low (HR: 1.89; 95% CI: 1.21, 2.96) but not high (HR: 1.33; 95% CI: 0.69, 2.54) concentrations indicated higher risk., Conclusions: Both high and low concentrations of plasma 25(OH)D are associated with elevated risks of overall and cancer mortality. Low concentrations are associated with cardiovascular mortality.

Background: Family history is a strong risk factor for prostate cancer. The aim of this study was to investigate whether increased diagnostic activity is related to the incidence of prostate cancer among brothers of men with prostate cancer., Methods: Data were from the nationwide population-based Prostate Cancer Database Sweden (PCBaSe Sweden), which includes data from the National Prostate Cancer Register, the Swedish Cancer Register, the Register of the Total Population, the Multi-Generation Register, and the Census database. We investigated the relationship of tumor characteristics, time from diagnosis of the index patient (i.e., prostate cancer patients in the National Prostate Cancer Register for whom at least one brother and their father could be identified), calendar period, geographic factors, and socioeconomic status to standardized incidence ratios (SIRs) for prostate cancer among 22 511 brothers of 13 975 index patients in PCBaSe Sweden., Results: Brothers of index patients with prostate cancer were at increased risk for a diagnosis of prostate cancer (SIR = 3.1, 95% confidence interval [CI] = 2.9 to 3.3). Risk was higher for T1c tumors (SIR = 3.4, 95% CI = 3.2 to 3.8) than for metastatic tumors (SIR = 2.0, 95% CI = 1.5 to 2.6), and risk of T1c tumors was especially high during the first year after the diagnosis of the index patient (SIR = 4.3, 95% CI = 3.8 to 4.9), compared with the following years (SIR range = 2.8-3.3), and for brothers of index patients who had a higher socioeconomic status (SIR = 4.2, 95% CI = 3.7 to 4.7), compared with brothers of index patients with lower socioeconomic status (SIR = 2.8, 95% CI = 2.4 to 3.2)., Conclusions: Increased diagnostic activity among men with a family history of prostate cancer appears to contribute to their increased risk of prostate cancer and to lead to detection bias in epidemiological and genetic studies of familial prostate cancer.

Background: Associations between metabolic syndrome (MetS) components and prostate cancer development have not been studied comprehensively; results have been divergent. Using the National Cholesterol Education Program Adult Treatment panel III (NCEP) and International Diabetes Federation (IDF) definitions of the MetS, we investigated such associations taking competing risks of death into consideration., Methods: In the prospective Uppsala Longitudinal Study of Adult Men of 2,322 Caucasian men with 34 years of follow-up baseline, MetS measurements at age 50 years were used. Cumulative incidence of prostate cancer and death with/without the MetS were calculated. Competing risk of dying was taken into account by calculating the conditional probability of prostate cancer with/without the MetS., Results: Two hundred and thirty-seven prostate cancers were identified. Prostate cancer probability by age 80 years with baseline MetS compared with without MetS was nonsignificantly higher [5.2 percent units (confidence interval (CI), -0.8% to 11.3%; NCEP); 2.7 percent units (CI, -2.7% to 8.0%; IDF)]; cumulative incidence proportions of death was significantly higher [19.3 percent units (CI, 13.4-25.3%; NCEP); 15.3 percent units (CI, 9.5-21.1%; IDF)]; and conditional probability of prostate cancer considering death from other causes was significantly higher [7.3 percent-units (CI, 0.2-14.5%); odds ratio of 1.64 (CI, 1.03-2.23; NCEP)] and nonsignificantly higher [5.0 percent-units (CI, -1.6% to 11.6%); odds ratio of 1.43 (CI, 0.89-1.90; IDF]., Conclusions: The MetS by the NCEP definition is associated with prostate cancer, taking the competing risk of early death from other causes into account., Impact: The results further highlight the public health effect of the increasing prevalence of MetS and the importance of considering competing risks when studying risk factors for cancer., ((c)2010 AACR.)

Background: 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., Methods: 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., Findings: 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., Interpretation: 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., Funding: Swedish Research Council, Stockholm Cancer Society, and Cancer Research UK., (2010 Elsevier Ltd. All rights reserved.)

Background: The risk of suicide is increased among cancer patients including men with prostate cancer (PCa). However, whether this increased risk applies to men diagnosed subsequent to prostate-specific antigen (PSA) testing is not known., Objective: To assess the risk of suicide among men diagnosed with PCa subsequent to PSA testing., Design, Setting, and Participants: The Prostate Cancer Base Sweden (PCBaSe Sweden) database, the Swedish Cause of Death Register, and the Swedish census database were used. The PCBaSe Sweden is a merged database that includes data from the Swedish National Prostate Cancer Register (NPCR) for cases diagnosed between January 1, 1997, and December 31, 2006. The number of suicides registered for cases in the PCBaSe cohort was compared with the expected number of suicides in an age-matched general male Swedish population., Measurements: Standardised mortality ratios (SMRs) with 95% confidence intervals (CIs) were calculated for different categories of cases., Results and Limitations: There were 128 suicides among the 77,439 PCa cases in the NPCR compared with an expected number of 85 (SMR: 1.5; 95% CI, 1.3-1.8). The risk of suicide was not increased for the 22,405 men with PSA-detected T1c tumours (SMR: 1.0; 95% CI, 0.6-1.5), whereas the 22,929 men with locally advanced nonmetastatic tumours (SMR: 2.2; 95% CI, 1.6-2.9) and the 8350 men with distant metastases (SMR: 2.1; 95% CI, 1.2-3.6) had statistically significant increased SMRs for suicide. Potential effects of comorbid medical and psychiatric conditions could not be investigated., Conclusions: No increased risk of committing suicide was observed among men with PCa diagnosed subsequent to PSA testing, whereas the risk was twice as high among men with locally advanced or metastatic disease, compared with an age-matched male population., (2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Prostate-specific antigen (PSA) measurements are increasingly used to monitor men with localised prostate cancer (PCa), but there is little consensus about the method to use., Objective: To apply age-specific predictions of PSA level (developed in men without cancer) to one cohort of men with clinically identified PCa and one cohort of men with PSA-detected PCa. We hypothesise that among men with clinically identified cancer, the annual increase in PSA level would be steeper than in men with PSA-detected cancer., Design, Setting, and Participants: The Scandinavian Prostate Cancer Group 4 (SPCG-4) cohort consisted of 321 men assigned to the watchful waiting arm of the SPCG-4 trial. The UK cohort consisted of 320 men with PSA-detected PCa in the Prostate testing for cancer and Treatment (ProtecT) study who opted for monitoring. Multilevel models describing changes in PSA level were fitted to the two cohorts, and average PSA level at age 50, change in PSA level with age, and predicted PSA values were derived., Measurements: PSA level., Results and Limitations: In the SPCG-4 cohort, mean PSA at age 50 was similar to the cancer-free cohort but with a steeper yearly increase in PSA level (16.4% vs 4.0%). In the UK cohort, mean PSA level was higher than that in the cancer-free cohort (due to a PSA biopsy threshold of 3.0 ng/ml) but with a similar yearly increase in PSA level (4.1%). Predictions were less accurate for the SPCG-4 cohort (median difference between observed and predicted PSA level: -2.0 ng/ml; interquartile range [IQR]: -7.6-0.7 ng/ml) than for the UK cohort (median difference between observed and predicted PSA level: -0.8 ng/ml; IQR: -2.1-0.1 ng/ml)., Conclusions: In PSA-detected men, yearly change in PSA was similar to that in cancer-free men, whereas in men with symptomatic PCa, the yearly change in PSA level was considerably higher. Our method needs further evaluation but has promise for refining active monitoring protocols., (2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Aims: We estimated measurement error (ME) corrected effects of insulin sensitivity (M/I), from euglycaemic insulin clamp, and insulin secretion, measured as early insulin response (EIR) from oral glucose tolerance test (OGTT), on fasting plasma glucose, HbA1c and type 2 diabetes longitudinally and cross-sectional., Methods: In a population-based study (n=1128 men) 17 men made replicate measurements to estimate ME at age 71 years. Effect of 1 SD decrease of predictors M/I and EIR on longitudinal response variables fasting plasma glucose (FPG) and HbA1c at follow-ups up to 11 years, were estimated using uncorrected and ME-corrected (with the regression calibration method) regression models., Results: Uncorrected effect on FPG at age 77 years was larger for M/I than for EIR (effect difference 0.10mmol/l, 95% CI 0.00;0.21), while ME-corrected effects were similar (0.02mmol/l, 95% CI -0.13;0.15mmol/l). EIR had greater ME-corrected impact than M/I on HbA1c at age 82 years (-0.11%, -0.28; -0.01%)., Conclusions: Due to higher ME effect of EIR on glycaemia is underestimated as compared with M/I. By correcting for ME valid estimates of relative contributions of insulin secretion and insulin sensitivity on glycaemia are obtained.

Context: Recent studies indicate common etiologies for cardiovascular disease (CVD) and osteoporotic fractures., Objectives: To examine the relation between CVD and risk of hip fracture in twins and evaluate the relative importance of genetics and lifestyle factors in this association., Design, Setting, and Participants: A cohort of all 31,936 Swedish twins born from 1914-1944 was followed up from the age of 50 years. The National Patient Registry identified twins with CVDs and fractures from 1964 through 2005. Time-dependent exposures using Cox proportional hazard regression models were evaluated., Main Outcome Measure: Time to hip fracture after diagnosis of CVD., Results: The crude absolute rate of hip fractures was 12.6 per 1000 person-years after a diagnosis of heart failure, 12.6 per 1000 person-years after a stroke, 6.6 per 1000 person-years after a diagnosis of peripheral atherosclerosis, and 5.2 per 1000 person-years after a diagnosis of ischemic heart disease compared with 1.2 per 1000 person-years for those without a CVD diagnosis. The multivariable-adjusted hazard ratio (HR) of hip fracture after a diagnosis of heart failure was 4.40 (95% confidence interval [CI], 3.43-5.63); after a stroke, the HR was 5.09 (95% CI, 4.18-6.20); after a diagnosis of peripheral atherosclerosis, the HR was 3.20 (95% CI, 2.28-4.50); and after an ischemic heart disease event, the HR was 2.32 (95% CI, 1.91-2.84). Identical twins without heart failure and stroke also had, after their co-twins had been exposed to these respective diseases, an increased rate of hip fracture. These sibling twins pseudoexposed for heart failure had a multivariable-adjusted HR of 3.74 (95% CI, 1.97-7.10) for hip fracture, whereas pseudoexposure for stroke had an HR of 2.29 (95% CI, 1.20-4.35)., Conclusions: A diagnosis of CVD was significantly associated with risk of subsequent hip fracture. Increased risks in co-twins without an index diagnosis suggest genetic factors in the association between CVD and osteoporotic fractures.

Background: The Swedish quality improvement initiative Quality Improvement in Coronary Care previously demonstrated significant improvements in caregiver adherence to national guidelines for acute myocardial infarction. The associated impact on 1-year clinical outcome is presented here., Methods and Results: During the baseline period July 2001 to June 2002, 6878 consecutive acute myocardial infarction patients <80 years were included at the 19 intervention and 19 control hospitals and followed for a mean of 12 months. During the postintervention period of May 2003 to April 2004, 6484 patients were included and followed in the same way. From baseline to postintervention, improvements in mortality and cardiovascular readmission rates (events per 100 patient-years) were significant in the intervention group (-2.82, 95% CI -5.26 to -0.39; -9.31, 95% CI -15.48 to -3.14, respectively). However, in the control hospitals, there were no significant improvements (0.04, 95% CI -2.40 to 2.47; -4.93, 95% CI -11.10 to 1.24, respectively). Bleedings in the control group increased in incidence (0.92, 95% CI 0.41 to 1.43), whereas the incidence remained unchanged in the intervention group (0.07, 95% CI -0.44 to 0.58). When the difference of changes between the study groups were evaluated, the results still were in favor of the intervention group, albeit significant only for bleeding complications (mortality: -2.70, 95% CI -6.37 to 0.97; cardiovascular readmissions: -6.85, 95% CI -16.62 to 2.93; bleeding complications: -0.82, 95% CI -1.66 to 0.01)., Conclusions: With a systematic quality improvement initiative aiming to increase the adherence to acute myocardial infarction guidelines, it is possible to achieve long-term positive effects on clinical outcome.

Background: Identification of women treated for breast cancer who have a low risk of locoregional recurrence or contralateral breast cancer, and who can be discharged safely from follow-up, would lower costs without compromising prognosis. This study investigated the risk of locoregional recurrence and contralateral breast cancer in women treated for grade 1 breast cancer., Methods: Some 1143 women who had surgery for breast cancer were followed, and the rate of locoregional recurrence or contralateral breast cancer was determined. The risk was compared to the tumour grade., Results: At a mean follow-up of 9.1 years, 10-year estimates of the cumulative risk of locoregional recurrence or contralateral breast cancer for grade 1, 2 and 3 breast cancer were 0.03 (95 per cent confidence interval (c.i.) 0.01 to 0.08), 0.12 (0.09 to 0.15) and 0.16 (0.13 to 0.20) respectively. Grade 1 tumours had a risk of locoregional recurrence or contralateral breast cancer of 285 (95 per cent c.i. 93 to 670) per 100,000 person-years., Conclusion: Women treated for grade 1 breast cancer could be discharged from follow-up after completion of the primary treatment, without compromising their quality of care., ((c) 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Background: Patients with breast or prostate cancer diagnosed during the summer season have been observed to have better survival. The extent to which this is due to biological and/or health care system related factors is unclear., Methods: Using the Swedish Cancer Register and clinical databases, we analyzed overall survival by month of diagnosis among the incident cases of breast (n = 89,630) cancer and prostate (n = 72,375) cancer diagnosed from 1960 to 2004. We retrieved data on tumor stage from 1976 for breast cancer and 1997 for prostate cancer. Cox proportional hazards models were used to calculate relative risk of survival by the season of diagnosis., Results: There was a higher hazard ratio of death in men and women diagnosed with cancer in the summer with a relative hazard of 1.20 (95% confidence interval 1.15-1.25) for July for prostate cancer and 1.14 (95% confidence interval 1.09-1.19) for August for breast cancer when compared to being diagnosed in January. This difference coincided with a lower mean number of cases diagnosed per day, and a higher proportion of advanced cases diagnosed in the summer. This pattern of presentation was stronger in the later years., Conclusion: The difference in stage distribution explains the seasonal variation in prognosis seen in this study. The variation may be because of structure of the health care system and a strong tradition of vacationing from mid June to mid August. Thus, the health care infrastructure and the late presentation of symptomatic disease may influence cancer survival studied by season of diagnosis substantially.

Objective. To construct a database for clinical epidemiological prostate cancer research based on linkages between the National Prostate Cancer Register (NPCR) of Sweden, a population-based, nationwide quality database, and other nationwide registries. Material and methods. By use of the individually unique Swedish Personal Identity Number, the NPCR was linked to the Swedish Cancer Registry, the Cause of Death Register, the Prescribed Drug Register, the National Patient Register and the Acute Myocardial Infarction Register, all held at the Centre for Epidemiology at the National Board of Health and Welfare, and the Register of the Total Population, the Longitudinal Integration Database for Health Insurance and Labor Market Studies and the Multi-Generation Register, held at Statistics Sweden, and to the Swedish Hernia Register. Results. Record linkages between the NPCR and the Swedish Cancer Registry, the Cause of Death Register and the Register of the Total Population generated a database, named PCBaSe Sweden, including 80 079 prostate cancer cases, diagnosed between 1 January 1996 and 31 December 2006. Record linkage between PCBaSe Sweden and the Prescribed Drug Register generated 59 721 unique matches and linkage to the Acute Myocardial Infarction Register resulted in 11 459 matches. Conclusion. PCBaSe Sweden is a newly created and unique database with over 80 000 cases of prostate cancer with comprehensive data on inpatient and outpatient care, patterns of use of prescribed drugs and socioeconomic and familial factors. Many topics in clinical prostate cancer epidemiology can be investigated. using PCBaSe Sweden.

The aim of the study was to investigate long-term trends in the incidence of borderline tumors and ovarian cancer in Sweden during 1960-2005, based on data from the population-based Swedish Cancer Register. We identified 6,288 patients with borderline ovarian tumors and a total of 34,977 cases of ovarian cancer during the study period. The age-standardized incidence of borderline ovarian tumors increased from 1.0 to 5.3 per 100,000 women-years from 1960-1964 to 2000-2005 and the incidence of ovarian cancer increased from 16.4 to 19.7 per 100,000 women-years from 1960-1964 to 1980-1989 and then declined to 16.6 per 100,000 women-years to the period 2000-2005. Borderline ovarian tumors comprised 15% of all primary ovarian neoplasms and the proportion increased from 8.3 to 23.6% during the study period. The median age at diagnosis for patients with borderline ovarian tumors and ovarian cancer was 55.2 and 61.6 years, respectively. In women younger than 40 years, 34% of all primary ovarian malignancies consisted of borderline ovarian tumors. For the 5 birth cohorts evaluated, the peaks of incidence occurred in stepwise younger age for each younger birth cohort for both borderline tumors and ovarian cancer. The increasing incidence of borderline ovarian tumors could be explained by an increase in diagnostic activity and by a lack of protective effect of oral contraceptive use. The decline in invasive tumors could be explained by a combination of factors, where the contribution of each is uncertain: shifting exposure to risk factors, a protective effect of oral contraceptive use, and increased detection of and removal of precancerous lesions.

Objectives: To assess the value of prostate-specific antigen (PSA) kinetics in predicting survival and relate this to the baseline variables in men with metastatic hormone-refractory prostate cancer (HRPC)., Methods: The data from 417 men with HRPC were included in a logistic regression model that included hemoglobin, PSA, alkaline phosphatase, Soloway score, and performance status pain analgesic score at baseline. The posttreatment variables included the PSA level halving time after the start of treatment, PSA level at nadir, interval to nadir, PSA velocity (PSAV), PSA doubling time after reaching a nadir, patient age, and treatment. These variables were added to the baseline model, forming new logistic regression models that were tested for net reclassification improvement., Results: The area under the receiver operating characteristics curve for the baseline model was 0.67. Of all variables related to PSA kinetics, the PSAV was the best predictor. The addition of PSAV to the baseline model increased the area under the receiver operating characteristics curve to 0.81. Only a moderate increase in the area under the receiver operating characteristics curve (0.83) was achieved by combining the baseline model in a multivariate model with PSAV, PSA doubling time, interval to nadir, and patient age at diagnosis of HRPC., Conclusions: The PSAV alone gave a better prediction of survival value than all other PSA kinetics variables. By combining PSAV with the variables available at baseline, a better ground for treatment decision-making in men with HRPC can be achieved.

The least-squares estimator of the slope in a simple linear regression model is biased towards zero when the predictor is measured with random error. A corrected slope may be estimated by adding data from a reliability study, which comprises a subset of subjects from the main study. The precision of this corrected slope depends on the design of the reliability study and estimator choice. Previous work has assumed that the reliability study constitutes a random sample from the main study. A more efficient design is to use subjects with extreme values on their first measurement. Previously, we published a variance formula for the corrected slope, when the correction factor is the slope in the regression of the second measurement on the first. In this paper we show that both designs improve by maximum likelihood estimation (MLE). The precision gain is explained by the inclusion of data from all subjects for estimation of the predictor's variance and by the use of the second measurement for estimation of the covariance between response and predictor. The gain of MLE enhances with stronger true relationship between response and predictor and with lower precision in the predictor measurements. We present a real data example on the relationship between fasting insulin, a surrogate marker, and true insulin sensitivity measured by a gold-standard euglycaemic insulin clamp, and simulations, where the behavior of profile-likelihood-based confidence intervals is examined. MLE was shown to be a robust estimator for non-normal distributions and efficient for small sample situations., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

Background and Purpose: A low-dose hypersensitivity to radiation can be observed in vitro for many human cell types in terms of increased cell kill per dose unit for doses below 0.5Gy. Quantification of the double-strand break marker gammaH2AX in samples taken in clinical radiotherapy practice has the potential to provide important information about how induction and repair of severe DNA damage and apoptosis are linked to low-dose hypersensitivity., Material and Methods: The effects of exposure to low doses (0.05-1.1Gy) were investigated in skin biopsies taken from prostate cancer patients undergoing the first week of radiotherapy. gammaH2AX foci and apoptotic cells were visualised by immunohistochemistry and quantified by image analysis., Results: The gammaH2AX foci pattern in biopsies taken 30min after a single fraction revealed a low-dose hypersensitivity below 0.3Gy (p=0.0009). The result was consistent for repeated fractions (p=0.00001). No decrease in foci numbers could be detected when comparing biopsies taken 30min and 2h after single fractions of 0.4 and 1.2Gy. The result was consistent for repeated fractions. Only 43 of 168,000 cells in total were identified as apoptotic, yet a dose dependency could be detected after 1week of radiotherapy (p=0.003)., Conclusions: We describe a method based on gammaH2AX to study DNA damage response and apoptosis in a clinical setting. A gammaH2AX hypersensitive response to low doses can be observed in epidermal skin, already 30min following delivered fraction. A very low frequency of apoptosis in normal epithelium suggests that this effect is not an important part of the in vivo response to low doses.

Background: The benefit of radical prostatectomy in patients with early prostate cancer has been assessed in only one randomized trial. In 2005, we reported that radical prostatectomy improved prostate cancer survival compared with watchful waiting after a median of 8.2 years of follow-up. We now report results after 3 more years of follow-up., Methods: From October 1, 1989, through February 28, 1999, 695 men with clinically localized prostate cancer were randomly assigned to radical prostatectomy (n = 347) or watchful waiting (n = 348). Follow-up was complete through December 31, 2006, with histopathologic review and blinded evaluation of causes of death. Relative risks (RRs) were estimated using the Cox proportional hazards model. Statistical tests were two-sided., Results: During a median of 10.8 years of follow-up (range = 3 weeks to 17.2 years), 137 men in the surgery group and 156 in the watchful waiting group died (P = .09). For 47 of the 347 men (13.5%) who were randomly assigned to surgery and 68 of the 348 men (19.5%) who were not, death was due to prostate cancer. The difference in cumulative incidence of death due to prostate cancer remained stable after about 10 years of follow-up. At 12 years, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate cancer (difference = 5.4%, 95% confidence interval [CI] = 0.2 to 11.1%), for a relative risk of 0.65 (95% CI = 0.45 to 0.94; P = .03). The difference in cumulative incidence of distant metastases did not increase beyond 10 years of follow-up. At 12 years, 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases (difference = 6.7%, 95% CI = 0.2 to 13.2%), for a relative risk of 0.65 (95% CI = 0.47 to 0.88; P = .006). Among men who underwent radical prostatectomy, those with extracapsular tumor growth had 14 times the risk of prostate cancer death as those without it (RR = 14.2, 95% CI = 3.3 to 61.8; P < .001)., Conclusion: Radical prostatectomy reduces prostate cancer mortality and risk of metastases with little or no further increase in benefit 10 or more years after surgery.

Background: To compare irinotecan with the Nordic 5-fluorouracil (5-FU) and folinic acid (FA) bolus schedule [irinotecan 180 mg/m(2) on day 1, 5-FU 500 mg/m(2) and FA 60 mg/m(2) on day 1 and 2 (FLIRI)] or the Lv5FU2 schedule [irinotecan 180 mg/m(2) on day 1, FA 200 mg/m(2), 5-FU bolus 400 mg/m(2) and infused 5-FU 600 mg/m(2) on day 1 and 2 (Lv5FU2-IRI)] due to uncertainties about how to administrate 5-FU with irinotecan., Patients and Methods: Patients (n = 567) with metastatic colorectal cancer were randomly assigned to receive FLIRI or Lv5FU2-IRI. Primary end point was progression-free survival (PFS)., Results: Patient characteristics were well balanced. PFS did not differ between groups (median 9 months, P = 0.22). Overall survival (OS) was also similar (median 19 months, P = 0.9). Fewer objective responses were seen in the FLIRI group (35% versus 49%, P = 0.001) but the metastatic resection rate did not differ (4% versus 6%, P = 0.3). Grade 3/4 neutropenia (11% versus 5%, P = 0.01) and grade 2 alopecia (18% versus 9%, P = 0.002) were more common in the FLIRI group. The 60-day mortality was 2.4% versus 2.1%., Conclusions: Irinotecan with the bolus Nordic schedule (FLIRI) is a convenient treatment with PFS and OS comparable to irinotecan with the Lv5FU2 schedule. Neutropenia and alopecia are more prevalent, but both regimens are equally well tolerated.

We studied risk of second malignancies and causes of death in 1829 cases of adenocarcinoma and 3055 cases of carcinoid tumours in the small bowel reported to the Swedish Cancer Registry from 1960 through to 2000. Data on causes of death were analysed as from 1966 whereas data on second tumours was available during the whole registry-period. Follow-up was available until 2001. Standard mortality ratio (SMR) and standard incidence ratio (SIR) were calculated. Female patients with adenocarcinoma had increased risk of acquiring cancer in the female genital organs (SIR 3.2; 95% confidence intervals (CI) 1.9-5.0) and breasts (SIR 2.7; 95% CI 1.1-5.4). Both sexes combined had increased risk of second tumours in the gastrointestinal tract (SIR 1.5; 95% CI 1.1-2.1) and skin (SIR 4.6; 95% CI 1.2-12). Men with carcinoid tumour had increased risk of prostate cancer (SIR 2.8; 95% CI 1.6-4.6). Increased risk was seen for both sexes with carcinoid for malignant melanoma (SIR 6.3; 95% CI 2.7-12), malignant skin tumours (SIR 3.6; 95% CI 1.7-6.7) and malignancies of endocrine organs (SIR 2.3 95% CI 1.3-3.8). Patients with adenocarcinoma had increased risk of dying from malignant diseases other than the primary cancer (SMR 9.5; 95% CI 8.6-10) and gastrointestinal disease (SMR 2.6 95% CI 1.6-4.2). The cohort with carcinoid had higher than expected risk of dying from malignant disease (SMR 4.3; 95% CI 4.0-4.6), gastrointestinal disease (SMR 2.8; 95% CI 2.1-3.6) and cardiovascular disease (SMR 1.1; 95% CI 1.0-1.3). The increased risk of second malignant tumours is an indication of common aetiology, or possibly, a general vulnerability to malignant disease for these patients. A detailed analysis of causes of death in a population-based cohort of small intestinal malignancies has not been presented before in the literature.

Background: To evaluate the predictive value of prostate-specific antigen (PSA) in a population-based cohort, the authors analyzed relative survival in all men with localized prostate cancer who were registered in the Swedish National Prostate Cancer Register (NPCR) from 1996 to 2005., Methods: All men aged <75 years with localized tumors were identified in the NPCR. A Poisson regression analysis was performed using observed death as response and the expected death rate as offset. The expected and observed numbers of survivors were calculated with stratification for PSA level and 3 categories of tumor differentiation (Gleason score 2-6, 7, and 8-10). The regression model included PSA as linear splines with a breakpoint at a PSA level of 4 ng/mL and with tumor differentiation as a categoric variable., Results: The Poisson regression analysis indicated a U-shaped curve for all 3 groups, with a negative correlation between PSA and relative survival in men with PSA levels <4 ng/mL and a positive correlation for men with PSA levels >4 ng/mL. The correlation was significant for all 3 groups, but the negative correlation between PSA and relative survival was significantly more pronounced in the group with Gleason scores from 8 to 10 than in the other 2 Gleason score groups., Conclusions: The demonstration of an inverse correlation between PSA level and relative survival in the group of men with PSA levels <4 ng/mL indicated the presence of a small but clinically important subgroup with undifferentiated tumors who have cells that have lost the ability to secrete PSA. This group should be taken into consideration when deciding on treatment and when choosing a cutoff level in PSA screening programs., (Cancer 2008. (c) 2007 American Cancer Society.)

Purpose: We determined how serial measurements of prostate specific antigen and alkaline phosphatase can be used to predict survival early in the course of hormone treated metastatic prostate cancer., Materials and Methods: The study was based on a prospective randomized trial of 915 patients with metastatic prostate carcinoma designed to compare parenteral estrogen (polyestradiol phosphate) vs total androgen blockade. We included 697 men who survived at least 6 months and had complete serial measurements of prostate specific antigen and alkaline phosphatase. Six models were constructed based on prostate specific antigen and alkaline phosphatase at start, and after 6 months of treatment, alkaline phosphatase flare and relative prostate specific antigen velocity. We constructed time dependent receiver operating characteristic curves with corresponding area under the curve to predict death from prostate cancer within 3 years., Results: The best variables to predict outcome were alkaline phosphatase at 6 months (AUC 0.79 for polyestradiol phosphate and 0.72 for total androgen blockade), alkaline phosphatase at baseline (AUC 0.70 for polyestradiol phosphate and total androgen blockade) and prostate specific antigen at 6 months (AUC 0.70 for polyestradiol phosphate and total androgen blockade). Prostate specific antigen and alkaline phosphatase levels 6 months after start of treatment give better prediction of survival than baseline levels., Conclusions: Alkaline phosphatase at start of treatment and alkaline phosphatase and prostate specific antigen after 6 months can be used to predict survival of hormone treated metastatic prostate cancer.

The least squares estimator of the slope in a simple linear regression model will be biased towards zero when the predictor is measured with random error, i.e. intra-individual variation or technical measurement error. A correction factor can be estimated from a reliability study where one replicate is available on a subset of subjects from the main study. Previous work in this field has assumed that the reliability study constitutes a random subsample from the main study. We propose that a more efficient design is to collect replicates for subjects with extreme values on their first measurement. A variance formula for this estimator of the correction factor is presented. The variance for the corrected estimated regression coefficient for the extreme selection technique is also derived and compared with random subsampling. Results show that variances for corrected regression coefficients can be markedly reduced with extreme selection. The variance gain can be estimated from the main study data. The results are illustrated using Monte Carlo simulations and an application on the relation between insulin sensitivity and fasting insulin using data from the population-based ULSAM study. In conclusion, an investigator faced with the planning of a reliability study may wish to consider an extreme selection design in order to improve precision at a given number of subjects or alternatively decrease the number of subjects at a given precision., (Copyright 2006 John Wiley & Sons, Ltd.)

Background: Rates of long-term survival among patients with untreated localized prostate cancer are high. To avoid unnecessary treatment, tools are needed to identify the small proportion of patients who are destined to develop lethal prostate cancer., Methods: To evaluate the accuracy of early changes in prostate-specific antigen (PSA) levels as predictors of prostate cancer outcome, we assessed serial measurements of PSA level among 267 men with localized prostate cancer in a Scandinavian cohort of men who were diagnosed between 1989 and 1999 and who were managed by watchful waiting. We then 1) fitted individual regression lines to the PSA values assessed for each patient during the first 2 years of follow-up by using three different models, 2) evaluated early PSA curve characteristics as determinants of the cumulative incidence of lethal prostate cancer and calculated hazard ratios for baseline PSA value and rate of change in PSA level to prostate cancer outcome, and 3) plotted time-dependent receiver operating characteristic (ROC) curves. All P values are two-sided., Results: During complete follow-up for a mean of 8.5 years, 34 patients (13%) died from prostate cancer, and 18 (7%) developed metastases but were still alive at end of follow-up. In a log-linear model, both PSA value at baseline (P = .05) and the rate of PSA change (P<.001) were associated with the development of lethal prostate cancer. In the ROC analysis, however, the accuracy of classifying the disease as either indolent or destined to progress was low, regardless of the cut point chosen for initial PSA level or rate of change in PSA level., Conclusions: Although baseline PSA value and rate of PSA change are prognostic factors for lethal prostate cancer, they are poor predictors of lethal prostate cancer among patients with localized prostate cancer who are managed by watchful waiting.

Objective: The incidence of prostate cancer is rising rapidly in Sweden and there is a need to better understand the pattern of diagnosis, tumor characteristics and treatment., Material and Methods: Between 1996 and 2005, all new cases of adenocarcinoma of the prostate gland were intended to be registered in the National Prostate Cancer Register (NPCR). This register contains information on diagnosing unit, date of diagnosis, cause of diagnosis, tumor grade, tumor stage according to the TNM classification in force, serum prostate-specific antigen (PSA) levels at diagnosis and primary treatment given within the first 6 months after diagnosis., Results: In total, 72,028 patients were registered, comprising >97% of all pertinent incident cases of prostate cancer in the Swedish Cancer Register (SCR). During the study period there was a considerable decrease in median age at the time of diagnosis, a stage migration towards smaller tumors, a decrease in median serum PSA values at diagnosis, a decrease in the age-standardized incidence rate of men diagnosed with distant metastases or with a PSA level of > 100 ng/ml at diagnosis and an increase in the proportion of tumors with Gleason score <6. Relatively large geographical differences in the median age at diagnosis and the age-standardized incidence of cases with category T1c tumors were observed. Treatment with curative intent increased dramatically and treatment patterns varied according to geographical region. In men with localized tumors and a PSA level of <20 ng/ml at diagnosis, expectant treatment was more commonly used in those aged > or =75 years than in those aged <75 years. Also, the pattern of endocrine treatment varied in different parts of Sweden., Conclusions: All changes in the register seen over time are consistent with increased diagnostic activity, especially PSA testing, resulting in an increased number of cases with early disease, predominantly tumors in category T1c. The patterns of diagnosis and treatment of prostate cancer vary considerably in different parts of Sweden. The NPCR continues to be an important source for research, epidemiological surveillance of the incidence, diagnosis and treatment of prostate cancer.

A suitable setting to analyze factors that determine prognosis or treatment response in prostate cancer is an unbiased comparison of radical prostatectomy and watchful waiting as in the Scandinavian Prostate Cancer Group Trial number 4. In our previous presentation of 10-year results, we studied Gleason score, serum prostate-specific antigen (PSA) at diagnosis, and age at diagnosis as modifiers of the effect of radical prostatectomy on survival. Because overall prognostic information obtained by these parameters or by tumor stage was not provided in our publication, we now present these data in the two study arms separately.

We studied the effect of postoperative radiotherapy (RT) after breast sector resection for ductal carcinoma in situ (DCIS). The study protocol stipulated radical surgery but microscopically clear margins were not mandatory. We randomised 1,046 operated women to postoperative RT or control between 1987 and 1999. The primary endpoint was ipsilateral local recurrence. Secondary endpoints were contralateral breast cancer, distant metastasis and death. After a median follow-up of 5.2 years (range 0.1-13.8) there were 44 recurrences in the RT group corresponding to a cumulative incidence of 0.07 (95% confidence interval (CI) 0.05-0.10). In the control group there were 117 recurrences giving a cumulative incidence of 0.22 (95% CI 0.18-0.26) giving an overall hazard ratio of 0.33 (95% CI 0.24-0.47, p < 0.0001). Twenty two percent of the patients had microscopically unknown or involved margins. We found no evidence for different effects of RT on the relative risk of invasive or in situ recurrence. Secondary endpoints did not differ. Women undergoing sector resection for DCIS under conditions of population based screening mammography benefit from postoperative RT to the breast. Seven patients needed RT-treatment to prevent one recurrence.

Meta-analyses have shown an excess of vascular deaths in women with breast cancer given radiotherapy (RT). In women with breast cancer, RT to the supraclavicular lymph nodes gives a substantial radiation dose to the proximal carotid artery. RT is known to increase the risk of carotid stenosis and ischaemic stroke in head and neck cancer. A study base of 25,171 women with breast cancer was defined. A linkage between the study base and the Hospital Discharge Register yielded 1766 women who were diagnosed with a stroke after a breast cancer. The observed number of strokes was compared with the expected number in the background population. The Relative Risk (RR) of stroke in the study group with breast cancer was 1.12 (95% Confidence Interval (CI)=1.07-1.17). The increased risk was confined to the subtype cerebral infarction, RR=1.12 (95% CI=1.05-1.19). A statistically significant increase in the risk of stroke was seen among women with a history of breast cancer. Whether this risk is associated with the breast cancer disease per se or related to any treatment requires further study.

Objectives: To provide a descriptive review of the establishment of the National Prostate Cancer Register (NPCR) in Sweden, to present clinical characteristics at diagnosis and to calculate the relative survival of different risk groups after 5 years., Material and Methods: Since 1998, data on all newly diagnosed prostate cancers, including TNM classification, grade of malignancy, prostate-specific antigen (PSA) level and treatment, have been prospectively collected. For the 35,223 patients diagnosed between 1998 and 2002, relative survival in different risk groups has been calculated., Results: Between 1998 and 2002, 96% of all prostate cancer cases diagnosed in Sweden were registered in the NPCR. The number of new cases increased from 6137 in 1998 to 7385 in 2002. The age-standardized rate rose in those aged < 70 years, while it was stable, or possibly declining from 1999, in the older age groups. The proportion of T1c tumours increased from 14% to 28% of all recorded cases. The age-adjusted incidence of advanced tumours (M1 or PSA > 100 ng/ml) decreased by 17%. The proportion of patients receiving curative treatment doubled. Patients with N1 or M1 disease or poorly differentiated tumours (G3 or Gleason score 8-10) had a markedly reduced relative 5-year survival rate., Conclusions: It is possible to establish a nationwide prostate cancer register including basic data for assessment of the disease in the whole of Sweden. The introduction of PSA screening has increased the detection of early prostate cancer in younger men and, to a lesser extent, decreased the incidence of advanced disease. The effect of these changes on mortality is obscure but the NPCR in Sweden will serve as an important tool in such evaluation.

Midgut carcinoid tumors are rare and have a markedly better prognosis than adenocarcinoma in the small intestine. New diagnostic methods and medical as well as surgical therapies have evolved during the last decades, leading to more active care of these patients. Patients with small intestinal carcinoids diagnosed from 1960 to 2000 in the duodenum (n = 89) and jejunum/ileum (n = 2437) were identified in the Swedish Cancer Registry. Cases without histologic verification and autopsy cases were excluded. Overall, cause-specific and relative survival were calculated. The overall 5-, 10-, and 15 year survivals were, respectively, 60%, 46%, and 28% for duodenal tumors and 56%, 36%, and 23% for jejunal/ileal tumors. Cause-specific 5-, 10-, and 15-year survival was 94% for all three follow-up periods for duodenal tumors and 87%, 80%, and 77% for those in the jejunum/ileum. The corresponding relative survivals were, respectively, 72%, 67%, and 51% for duodenal tumors and 67%, 54%, and 44% for those in the jejunum/ileum. Sex did not influence overall or cause-specific survival. The age at diagnosis correlated inversely with overall and cause-specific survival for tumors in the jejunum/ileum. For tumors in the jejunum/ileum, the overall and cause-specific survival correlated with the time period of diagnosis, with a more favorable prognosis for those diagnosed in recent years. A multivariate Cox proportional hazards model showed similar results. We concluded that young age and diagnosis in recent years are positive predictors of survival for patients with midgut carcinoids. The divergence between cause-specific and relative survival implies the need for a more detailed analysis of the causes of death of these patients.