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  • 101.
    Johansson, Ingegerd
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Kariologi.
    Van Guelpen, Bethany
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hultdin, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Johansson, M
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Validity of food frequency questionnaire estimated intakes of folate and other B vitamins in a region without folic acid fortification.2010Ingår i: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 64, nr 8, s. 905-913Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background/Objectives: 

    B vitamins have been implicated in major chronic diseases but results have been inconsistent. This study evaluated the accuracy of dietary intakes of folate, vitamin B12, riboflavin and vitamin B6 as measured by the Northern Sweden Food Frequency Questionnaire (FFQ) against repeated 24-h recalls (24HR) and plasma levels, taking into consideration the MTHFR 677C>T polymorphism.

    Subjects/Methods: 

    B vitamin intakes assessed by a semi-quantitative FFQ designed to measure the intake over the previous year were compared with those from 10 24HR, as well as to plasma levels of folate and vitamin B12, in randomly selected men (n=96) and women (n=99) aged 30–60 years. FFQ-based B-vitamin intakes were also compared with plasma levels of B-vitamins and with MTHFR 677C4T genotype in 878 men, aged 40–61 years.

    Results: 

    Intakes of vitamins B12 and riboflavin were similar, whereas folate and B6 intakes were 16–27% higher, as estimated by FFQ versus 24HR. Spearman correlation coefficients between the two methods ranged from 0.31 to 0.63 (all P0.002), and were lowest for vitamin B12. Intakes estimated by FFQ were correlated with plasma levels, but coefficients were lower (range: 0.13–0.33), particularly for vitamin B12 in men (0.15–0.18). Folate intake was not correlated with plasma levels in subjects with the MTHFR 677 T/T genotype.

    Conclusions: 

    The validity of the Northern Sweden FFQ for assessing B vitamin intake is similar to that of many other FFQs used in large-scale studies. The FFQ is suitable for ranking individuals by intake of folate, riboflavin, vitamin B6 and to a lesser extent vitamin B12.

  • 102.
    Johansson, Mattias
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Appleby, Paul N
    Allen, Naomi E
    Travis, Ruth C
    Roddam, Andrew W
    Egevad, Lars
    Jenab, Mazda
    Rinaldi, Sabina
    Kiemeney, Lambertus A
    Bueno-de-Mesquita, H Bas
    Vollset, Stein Emil
    Ueland, Per M
    Sánchez, Maria-José
    Quirós, J Ramón
    González, Carlos A
    Larrañaga, Nerea
    Chirlaque, María Dolores
    Ardanaz, Eva
    Sieri, Sabina
    Palli, Domenico
    Vineis, Paolo
    Tumino, Rosario
    Linseisen, Jakob
    Kaaks, Rudolf
    Boeing, Heiner
    Pischon, Tobias
    Psaltopoulou, Theodora
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Khaw, Kay-Tee
    Bingham, Sheila
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Riboli, Elio
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Urologi och andrologi.
    Key, Timothy J
    Circulating concentrations of folate and vitamin B12 in relation to prostate cancer risk: results from the European prospective investigation into cancer and nutrition study2008Ingår i: Cancer Epidemiol Biomarkers Prev, ISSN 1055-9965, Vol. 17, nr 2, s. 279-285Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Determinants of one-carbon metabolism, such as folate and vitamin B12, have been implicated in cancer development. Previous studies have not provided conclusive evidence for the importance of circulating concentrations of folate and vitamin B12 in prostate cancer etiology. The aim of the present study was to investigate the relationship between prostate cancer risk and circulating concentrations of folate and vitamin B12 in a large prospective cohort. Methods: We analyzed circulating concentrations of folate and vitamin B12 in 869 cases and 1,174 controls, individually matched on center, age, and date of recruitment, nested within the European Prospective Investigation into Cancer and Nutrition cohort. Relative risks (RR) for prostate cancer were estimated using conditional logistic regression models. Results: Overall, no significant associations were observed for circulating concentrations of folate (Ptrend = 0.62) or vitamin B12 (Ptrend = 0.21) with prostate cancer risk. RRs for a doubling in folate and vitamin B12 concentrations were 1.03 [95% confidence interval (95% CI), 0.92-1.16] and 1.12 (95% CI, 0.94-1.35), respectively. In the subgroup of cases diagnosed with advanced stage prostate cancer, elevated concentrations of vitamin B12 were associated with increased risk (RR for a doubling in concentration, 1.69; 95% CI, 1.05-2.72, Ptrend = 0.03). No other subgroup analyses resulted in a statistically significant association. Conclusion: This study does not provide strong support for an association between prostate cancer risk and circulating concentrations of folate or vitamin B12. Elevated concentrations of vitamin B12 may be associated with an increased risk for advanced stage prostate cancer, but this association requires examination in other large prospective studies. (Cancer Epidemiol Biomarkers Prev 2007;17(2):279–85)

  • 103.
    Johansson, Mattias
    et al.
    International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Holmström, Benny
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Hinchliffe, Sally R
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Stenman, Ulf-Håkan
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Wiklund, Fredrik
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Combining 33 genetic variants with prostate-specific antigen for prediction of prostate cancer: longitudinal study2012Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 130, nr 1, s. 129-137Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to investigate if a genetic risk score including 33 common genetic variants improves prediction of prostate cancer when added to measures of prostate-specific antigen (PSA). We conducted a case-control study nested within the Northern Sweden Health and Disease Cohort (NSHDC), a prospective cohort in northern Sweden. A total of 520 cases and 988 controls matched for age, and date of blood draw were identified by linkage between the regional cancer register and the NSHDC. Receiver operating characteristic curves with area under curve (AUC) estimates were used as measures of prostate cancer prediction. The AUC for the genetic risk score was 64.3% [95% confidence interval (CI) = 61.4-67.2], and the AUC for total PSA and the ratio of free to total PSA was 86.2% (95% CI = 84.4-88.1). A model including the genetic risk score, total PSA and the ratio of free to total PSA increased the AUC to 87.2% (95% CI = 85.4-89.0, p difference = 0.002). The addition of a genetic risk score to PSA resulted in a marginal improvement in prostate cancer prediction that would not seem useful for clinical risk assessment.

  • 104.
    Johansson, Mattias
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    McKay, James D.
    Rinaldi, Sabina
    Wiklund, Fredrik
    Adami, Hans-Olov
    Grönberg, Henrik
    Kaaks, Rudolf
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Genetic and plasma variation of insuline-like growth factor binding proteins in relation to prostate cancer incidence and survivalManuskript (Övrig (populärvetenskap, debatt, mm))
  • 105.
    Johansson, Mattias
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. International Agency for Research against Cancer, Lyon, France.
    McKay, James D
    Rinaldi, Sabina
    Wiklund, Fredrik
    Adami, Hans-Olov
    Grönberg, Henrik
    Kaaks, Rudolf
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Genetic and plasma variation of insulin-like growth factor binding proteins in relation to prostate cancer incidence and survival2009Ingår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 69, nr 12, s. 1281-1291Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Binding proteins regulate bioavailability of insulin-like growth factor-I (IGF-I) in the circulation and affect apoptosis of tumor cells in the prostate. We analyzed genetic variation within genes coding for IGF binding proteins in relation to prostate cancer incidence and survival. We also investigated if circulating IGFBP3 affects prostate cancer-specific survival. MATERIALS AND METHODS: Eleven haplotype tagging SNPs and two single SNPs in the IGFBP1, IGFBP3, and IGFALS genes were genotyped within the CAncer Prostate in Sweden (CAPS) study including 2,774 cases and 1,736 controls. Plasma samples for analyses of total- and intact IGFBP3 levels were available for 1,521 cases and 909 controls. Complete follow-up of vital status was achieved by linkage to the Swedish Cause of Death Register. RESULTS: We found no clear association between the genetic variants and prostate cancer incidence or survival. The rare allele of the IGFBP3 SNP rs2854744 was associated with elevated plasma levels of total IGFBP3 (P(trend) = 9 x 10(-8)), but not intact IGFBP3 (P(trend) = 0.16). Elevated levels of total- (P(trend) = 0.03) and intact IGFBP3 (P(trend) = 6 x 10(-14)) were associated with increased risk of prostate cancer specific death. Treatment and tumor characteristics accounted for the association with total IGFBP3, whereas the association with intact IGFBP3 was attenuated, but still statistically significant in adjusted analysis (P(trend-adjusted) = 0.0004). Elevated intact IGFBP3 was also significantly associated with increased risk of prostate cancer-specific death among patients who were chemically or surgically castrated (P(trend-adjusted) = 0.0003), and among patients who had not been treated (P(trend-adjusted) = 0.02). CONCLUSIONS: Circulating levels of intact IGFBP3 measured after diagnosis is associated with increased risk of prostate cancer-specific death.

  • 106.
    Johansson, Mattias
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    McKay, James D
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Canzian, Federico
    Boillot, Catherine
    Wiklund, Fredrik
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Adami, Hans-Olov
    Bälter, Katarina
    Grönberg, Henrik
    Kaaks, Rudolf
    Comprehensive evaluation of genetic variation in the IGF1 gene and risk of prostate cancer2007Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 120, nr 3, s. 539-542Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Insulin-like growth factor-I (IGF1) stimulates cell proliferation, decreases apoptosis, and has been implicated in cancer development. Epidemiological studies have shown elevated levels of circulating IGF1 to be associated with increased risk of prostate cancer. To what extent genetic variation in the IGF1 gene is related to prostate cancer risk is largely unknown. We performed a comprehensive haplotype tagging (HT) assessment of single nucleotide polymorphisms (SNPs) representing the common haplotype variation in the IGF1 gene. We genotyped 10 SNPs (9 haplotype tagging SNPs (htSNPs)) within Cancer Prostate in Sweden (CAPS), a case–control study of 2,863 cases and 1,737 controls, in order to investigate if genetic variation in the IGF1 gene is associated with prostate cancer risk. Three haplotype blocks were identified across the IGF1 gene and 9 SNPs were selected as haplotype tagging SNPs. Common haplotypes in the block covering the 3′ region of the IGF1 gene showed significant global association with prostate cancer risk (p = 0.004), with one particular haplotype giving an odds ratio of 1.46 (95% CI = 1.15–1.84, p = 0.002). This haplotype had a prevalence of 5% in the study population. Our results indicate that common variation in the IGF1 gene, particularly in the 3′ region, may affect prostate cancer risk. Further studies on genetic variations in the IGF1 gene in relation to prostate cancer risk as well as to circulating levels of IGF1 are needed to confirm this novel finding.

  • 107.
    Johansson, Mattias
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. International Agency for Research on Cancer (IARC), Lyon, France.
    McKay, James D
    Wiklund, Fredrik
    Rinaldi, Sabina
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Bälter, Katarina
    Adami, Hans-Olov
    Grönberg, Henrik
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Kaaks, Rudolf
    Genetic variation in the SST gene and its receptors in relation to circulating levels of insulin-like growth factor-I, IGFBP3, and prostate cancer risk2009Ingår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, nr 5, s. 1644-1650Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Somatostatin (SST) and its receptors (SSTR1-5) may have a role in prostate cancer by influencing the IGFI hormone axis or through direct effects on prostate epithelia. We have investigated if genetic variation in the SST and SSTR1-5 genes influences prostate cancer risk and/or circulating IGFI and IGFBP3 hormone levels. MATERIALS AND METHODS: We analyzed 28 haplotype tagging single nucleotide polymorphisms in the SST and SSTR1-5 genes in a case-control/genetic association study to investigate the association between genetic variation and prostate cancer risk. The study included 2863 cases and 1737 controls from the Cancer Prostate in Sweden (CAPS) study. To investigate the genetic influence on circulating hormone levels, plasma concentrations of IGFI and IGFBP3 were analyzed in 874 controls of the CAPS study and 550 male subjects from the Northern Sweden Health and Disease Cohort (NSHDC). RESULTS: No clear association between prostate cancer risk and genetic variation of the SST and SSTR1-5 genes was identified. The SSTR5 missense single nucleotide polymorphism rs4988483 was associated with circulating IGFI (P = 0.002) and IGFBP3 (P = 0.0003) hormone levels in CAPS controls, with a per allele decrease of approximately 11%. This decrease was replicated in NSHDC for circulating IGFBP3 (P = 0.01) but not for IGFI (P = 0.09). Combining CAPS and NSHDC subjects indicated evidence of association between rs4988483 and both IGFBP3 (P = 2 x 10(-5)) and IGFI (P = 0.0004) hormone levels. CONCLUSIONS: Our results suggest that genetic variation in the SSTR5 gene and, particularly, the rs4988483 single nucleotide polymorphism influence circulating IGFI and IGFBP3 hormone levels with no measurable effect on prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1644-50).

  • 108.
    Johansson, Mattias
    et al.
    International Agency for Research on Cancer, Lyon, France.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York.
    Guidelines are too important to be left to clinical experts2012Ingår i: CMJA. Canadian Medical Association Journal. Onlineutg. Med tittel: ECMAJ. ISSN 1488-2329, ISSN 0820-3946, E-ISSN 1488-2329, Vol. 184, nr 2, s. 159-160Artikel i tidskrift (Refereegranskat)
  • 109.
    Johansson, Mattias
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Van Guelpen, Bethany
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hultdin, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Wiklund, Fredrik
    Adami, Hans-Olov
    Bälter, Katarina
    Grönberg, Henrik
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    The MTHFR 677C --> T polymorphism and risk of prostate cancer: results from the CAPS study2007Ingår i: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 18, nr 10, s. 1169-1174Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The methylenetetrahydrafolate reductase (MTHFR) enzyme may influence cancer development by affecting DNA methylation, synthesis and repair. The MTHFR 677C→T single nucleotide polymorphism (SNP) has been associated with decreased enzyme activity and has therefore been implicated in cancer development. We analyzed the MTHFR 677C→T SNP in 2,777 incident prostate cancer cases and 1,639 population controls from the CAncer Prostate in Sweden study (CAPS). No significant association was found overall between prostate cancer risk and the 677C→T SNP (p = 0.27) with heterozygote (CT) and homozygote (TT) allele carriers showing ORs of 1.12 (95% CI: 0.98–1.27) and 1.02 (95% CI: 0.80–1.30), respectively. In the subgroup of low risk prostate cancer, heterozygote—but not homozygote—allele carriers displayed a slight over-risk with an OR of 1.21 (95% CI: 1.03–1.41). Among men under 65 years of age, the 677C→T SNP was associated with prostate cancer risk (p = 0.007), with odds ratios of 1.33 (95% CI: 1.09–1.63) for heterozygote allele carriers and 0.86 (95% CI: 0.6–1.24) for homozygote allele carriers. However, this association was attributed to a shift in the genotype distribution in the young controls. In conclusion, our results do not provide strong support for the hypothesis that the MTHFR 677C→T polymorphism is related to prostate cancer risk.

  • 110.
    Johansson, Mattias
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Van Guelpen, Bethany
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Vollset, Stein Emil
    Hultdin, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Key, Tim
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Ueland, Per M
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Prospective investigation of one-carbon metabolism in relation to prostate cancer risk: results from the NSHDC studyManuskript (Övrigt vetenskapligt)
  • 111.
    Johansson, Mattias
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Van Guelpen, Bethany
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Vollset, Stein Emil
    Hultdin, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Key, Tim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Midttun, Øivind
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Ueland, Per M
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    One-carbon metabolism and prostate cancer risk: prospective investigation of seven circulating B vitamins and metabolites2009Ingår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, nr 5, s. 1538-1543Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: Components of one-carbon metabolism are believed to influence cancer development with suggested mechanisms, including DNA methylation and DNA repair mechanisms. However, few prospective studies have investigated one-carbon metabolism in relation to prostate cancer risk, and the results have been conflicting. The aim of this study was to do a comprehensive investigation of the components of one-carbon metabolism in relation to prostate cancer risk. A panel of seven circulating B vitamins and related metabolites was selected, most of which have not been studied before. MATERIALS AND METHODS: We analyzed plasma concentrations of betaine, choline, cysteine, methionine, methylmalonic acid (MMA), vitamin B2, and vitamin B6 in 561 cases and 1,034 controls matched for age and recruitment date, nested within the population-based Northern Sweden Health and Disease Cohort. Relative risks of prostate cancer were estimated by conditional logistic regression. RESULTS: Positive associations with prostate cancer risk were observed for choline and vitamin B2, and an inverse association was observed for MMA. The relative risks for a doubling in concentrations were 1.46 [95% confidence interval (95% CI), 1.04-2.05; P(trend) = 0.03] for choline, 1.11 (95% CI, 1.00-1.23; P(trend) = 0.04) for vitamin B2, and 0.78 (95% CI, 0.63-0.97; P(trend) = 0.03) for MMA. Concentrations of betaine, cysteine, methionine, and vitamin B6 were not associated with prostate cancer risk. CONCLUSION: The results of this large prospective study suggest that elevated plasma concentrations of choline and vitamin B2 may be associated with an increased risk of prostate cancer. These novel findings support a role of one-carbon metabolism in prostate cancer etiology and warrant further investigation. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1538-43).

  • 112.
    Jonsson, Björn-Anders
    et al.
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Adami, Hans-Olov
    Hägglund, Maria
    Bergh, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Göransson, Ingela
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Stattin, Pär
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Wiklund, Fredrik
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Grönberg, Henrik
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    -160C/A polymorphism in the E-cadherin gene promoter and risk of hereditary, familial and sporadic prostate cancer2004Ingår i: Int J Cancer, ISSN 0020-7136, Vol. 109, nr 3, s. 348-352Artikel i tidskrift (Refereegranskat)
  • 113.
    Jonsson, Håkan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Holmström, Benny
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Duffy, Stephen W
    Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Uptake of prostate-specific antigen testing for early prostate cancer detection in Sweden2011Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 129, nr 8, s. 1881-1888Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to estimate uptake of PSA testing in an entire country, including time trends and geographical differences. Data from the Swedish Cancer Register on prostate cancer incidence between 1980 and 2007 and published data from the Gothenburg branch of the European Randomized Study of Screening for Prostate Cancer (ERSPC), a population-based PSA screening study, were used in a multiplicative model of changes in incidence of prostate cancer as a proxy for uptake of PSA testing in all 24 Swedish counties. The estimated PSA testing in any one year, irrespective of previous years' exposure, reached a peak of 12% of all men in 2004 and decreased thereafter to 6% in 2007 and varied between 5% and 20% between counties. Under the assumption that men who underwent PSA testing were previously unexposed to PSA testing, the cumulated uptake of PSA testing in men aged 55-69 years in Sweden increased from zero in 1997 to 56% in 2007. This study shows that it is possible to estimate uptake of PSA testing in the population from the prostate cancer incidence pattern. There were large geographical variations in uptake of PSA testing despite a uniform health care system in Sweden and there was a substantial increase in the uptake of PSA testing during the study period, despite that there were no national recommendations for PSA-based prostate cancer screening.

  • 114.
    Jonsson, Pär
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wuolikainen, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Chorell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Constrained randomization and multivariate effect projections improve information extraction and biomarker pattern discovery in metabolomics studies involving dependent samples2015Ingår i: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 11, nr 6, s. 1667-1678Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Analytical drift is a major source of bias in mass spectrometry based metabolomics confounding interpretation and biomarker detection. So far, standard protocols for sample and data analysis have not been able to fully resolve this. We present a combined approach for minimizing the influence of analytical drift on multivariate comparisons of matched or dependent samples in mass spectrometry based metabolomics studies. The approach is building on a randomization procedure for sample run order, constrained to independent randomizations between and within dependent sample pairs (e.g. pre/post intervention). This is followed by a novel multivariate statistical analysis strategy allowing paired or dependent analyses of individual effects named OPLS-effect projections (OPLS-EP). We show, using simulated data that OPLS-EP gives improved interpretation over existing methods and that constrained randomization of sample run order in combination with an appropriate dependent statistical test increase the accuracy and sensitivity and decrease the false omission rate in biomarker detection. We verify these findings and prove the strength of the suggested approach in a clinical data set consisting of LC/MS data of blood plasma samples from patients before and after radical prostatectomy. Here OPLS-EP compared to traditional (independent) OPLS-discriminant analysis (OPLS-DA) on constrained randomized data gives a less complex model (3 versus 5 components) as well a higher predictive ability (Q2 = 0.80 versus Q2 = 0.55). We explain this by showing that paired statistical analysis detects 37 unique significant metabolites that were masked for the independent test due to bias, including analytical drift and inter-individual variation.

  • 115.
    Josefsson, Andreas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Adamo, Hani
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hammarsten, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Granfors, Torvald
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Egevad, Lars
    Laurent, Anna Engström
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Prostate cancer increases hyaluronan in surrounding nonmalignant stroma, and this response is associated with tumor growth and an unfavorable outcome2011Ingår i: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 179, nr 4, s. 1961-1968Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Our objective was to investigate whether the presence of a tumor increases hyaluronan (HA) levels in surrounding prostate tissues and whether this extratumoral HA influences tumor growth and outcome. From a series of 287 men diagnosed with prostate cancer at transurethral resection and followed up with watchful waiting, tissue microarrays were constructed, stained, and scored for HA. A high HA staining score in the tumor stroma or in nonmalignant prostate tissue stroma were both associated positively with higher Gleason score and larger tumor volume, and was associated with a poor outcome. HA staining score was not an independent marker for outcome (multivariate Cox, with Gleason score, tumor volume, stage, and HA variables). In an orthotopic rat prostate cancer model, hyaluronic acid synthase-1 mRNA levels and HA staining were increased in normal prostate tissue surrounding prostate cancer. Orthotopic prostate cancer growth was increased by intraprostatic injection of HA. In conclusion, cancer in the prostate apparently stimulates HA synthesis both in tumor stroma and in the surrounding normal tissue. This promoted tumor growth and was associated with an unfavorable outcome.

  • 116.
    Josefsson, Andreas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikstrom, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Egevad, Lars
    Granfors, Torvald
    Karlberg, Lars
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Low endoglin vascular density and Ki67 index in Gleason score 6 tumours may identify prostate cancer patients suitable for surveillance2012Ingår i: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 46, nr 4, s. 247-257Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: The aim of this study was to explore whether vascular density and tumour cell proliferation are related to the risk of prostate cancer death in patients managed by watchful waiting. Material and methods. From a consecutive series of men diagnosed with prostate cancer at transurethral resection in 1975-1990, tissue microarrays (TMAs) were constructed. A majority of men had no metastases at diagnosis and were followed by watchful waiting (n = 295). The TMAs were stained for Ki67, endoglin and factor VIII-related antigen (vWf).

    Results: In univariate Cox analyses, increased Ki67 index, endoglin vascular density and vWf vascular density were associated with shorter cancer-specific survival. Ki67 index and endoglin vascular density added independent prognostic information to clinical stage, estimated tumour size and Gleason score (GS) in multivariate Cox analysis. In GS 6 tumours, high Ki67 index and high endoglin vascular density identified patients with poor outcome. After 15 years of follow-up not a single man out of 34 men with low staining for both markers (35% of all GS 6 tumours) had died of prostate cancer, in contrast to 15 prostate cancer deaths among the remaining 63 men with GS 6 tumours (65% cumulative risk of prostate cancer death). vWf vascular density in benign areas was a prognostic marker in GS 6 and 7 tumours.

    Conclusions: Men with GS 6 tumours with both low Ki67 index and endoglin vascular density staining scores have a low risk of progression. Additional studies are needed to test whether these two markers can be applied to core biopsies to select patients suitable for surveillance.

  • 117.
    Josefsson, Andreas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Egevad, Lars
    Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Granfors, Torvald
    Department of Urology, Central Hospital Västerås, Västerås, Sweden.
    Karlberg, Lars
    Department of Urology, Central Hospital Västerås, Västerås, Sweden.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Low endoglin vascular density and Ki67 index in Gleason score 6 tumours may identify prostate cancer patients suitable for surveillanceArtikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Objectives: To explore if vascular density and tumour cell proliferation are related to the risk of prostate cancer death in patients managed by watchful waiting.

    Methods: From a consecutive series of men diagnosed with prostate cancer at transurethral resection in 1975-1990, tissue micro-arrays (TMAs) were constructed. A majority of men had no metastases at diagnosis and was followed by watchful waiting (n=295). The TMAs were stained for Ki67, endoglin and factor VIII related antigen (vWf).

    Results: In univariate Cox analyses, increased Ki67 index, endoglin vascular density (v.d.) and vWf v.d. were associated with shorter cancer specific survival. : Ki67 index and endoglin v.d. added independent prognostic information to clinical stage, estimated tumour size and Gleason score (GS) in multivariate Cox analysis. In GS 6 tumours high Ki67 index and high endoglin v.d. indentified patients with poor outcome. After 15 years of follow-up not a single man out of 34 men with low staining for both markers (35% of all GS 6 tumours) had died of prostate cancer, in contrast to 15 prostate cancer deaths among the remaining 63 men with GS 6 tumours (65 % cumulative risk of prostate cancer death). vWf v.d. in benign areas was a prognostic marker in GS 6 and GS 7 tumours.

    Conclusions: Men with GS 6 tumours with both low Ki67 index and endoglin v.d. staining scores have a low risk of progression. Additional studies are needed to test if these two markers can be applied to core biopsies to select patients suitable for surveillance.

  • 118.
    Josefsson, Andreas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Granfors, Torvald
    Egevad, Lars
    Karlberg, Lars
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Tumor size, vascular density and proliferation as prognostic markers in GS 6 and GS 7 prostate tumors in patients with long follow-up and non-curative treatment2005Ingår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 48, nr 4, s. 577-583Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: To investigate the prognostic value of potential markers in localized, Gleason score 6 and 7 prostate cancer (PC).

    Methods: From a consecutive series of men with PC diagnosed at transurethral resection (1975-1990),. specimens from 132 patients without metastases, with Gleason score (GS) 6 (n = 80) or 7 (n = 52) tumors followed with watchful waiting were examined. The fraction of resected prostate tissue containing cancer, the micro-vessel density (v.d.) when stained for endoglin or von Willebrand factor (vWf), and the percentage of Ki-67 labeled tumor cells were measured using immunohistochemistry.

    Results: High levels of vWf v.d., endoglin v.d., and percent cancer of the TURP specimen were significantly associated with short cancer-specific survival in Kaplan-Meier analysis of all patients with GS 6 and 7 tumors. Interestingly, a combined estimate of percent cancer and vWF v.d. could be used to identify a large subset (50%) of GS 6 tumors with only a 2.5% risk of PC death within 15 years. None of the tested markers gave independent prognostic information for the GS 7 tumors.

    Conclusions: Estimates of tumor size and vascular density may identify a large proportion of non-aggressive GS 6, but not GS 7, tumors.

  • 119. Kaaks, Rudolf
    et al.
    Stattin, Pär
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Obesity, endogenous hormone metabolism, and prostate cancer risk: a conundrum of "highs" and "lows".2010Ingår i: Cancer prevention research (Philadelphia, Pa.), ISSN 1940-6215, Vol. 3, nr 3, s. 259-262Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This perspective on the report by Neuhouser et al. (beginning on page 279 in this issue of the journal) examines the associations that have been observed between body mass index, serum insulin, preexisting diabetes, androgen metabolism, and prostate cancer risk. Based on data of the Prostate Cancer Prevention Trial, the observations by Neuhouser et al. plus findings from other studies suggest a complex mix of higher and lower risks for high- and low-grade cancer in association with obesity and endogenous hormone metabolism.

  • 120. Kaaks, Rudolf
    et al.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Villar, Stéphanie
    Poetsch, Anna R
    Dossus, Laure
    Nieters, Alexandra
    Riboli, Elio
    Palmqvist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Plass, Christoph
    Friesen, Marlin D
    Insulin-like Growth Factor-II Methylation Status in Lymphocyte DNA and Colon Cancer Risk in the Northern Sweden Health and Disease Cohort2009Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 69, nr 13, s. 5400-5405Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Loss of imprinting (LOI) of the insulin-like growth factor II (IGFII) gene is a frequent phenomenon in colorectal tumor tissues. Previous reports indicated that subjects with colorectal neoplasias show LOI of IGFII in circulating lymphocytes. Furthermore, LOI of IGFII is strongly related to the methylation of a differentially methylated region (DMR) in intron 2 of IGFII, suggesting that the methylation status could serve as a biomarker for early detection. Thus, hypermethylation of this DMR, even at a systemic level, e.g., in lymphocyte DNA, could be used for screening for colon cancer. To validate this, we performed a case-control study of 97 colon cancer cases and 190 age-matched and gender-matched controls, nested within the prospective Northern Sweden Health and Disease Study cohort. Methylation levels of the IGFII-DMR in lymphocyte DNA were measured at two specific CpG sites of the IGFII-DMR using a mass-spectrometric method called short oligonucleotide mass analysis, the measurements of which showed high reproducibility between replicate measurements for the two CpG sites combined and showed almost perfect validity when performed on variable mixtures of methylated and unmethylated standards. Mean fractions of CpG methylation, for the two CpG sites combined, were identical for cases and controls (0.47 and 0.46, respectively; Pdifference = 0.75), and logistic regression analyses showed no relationship between colon cancer risk and quartile levels of CpG methylation. The results from this study population do not support the hypothesis that colon cancer can be predicted from the different degrees of methylation of DMR in the IGFII gene from lymphocyte DNA. [Cancer Res 2009;69(13):5400-5].

  • 121. Key, Timothy J
    et al.
    Allen, Naomi
    Appleby, Paul
    Overvad, Kim
    Tjönneland, Anne
    Miller, Anthony
    Boeing, Heiner
    Karalis, Dimitrios
    Psaltopoulou, Theodora
    Berrino, Franco
    Palli, Domenico
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Bueno-De-Mesquita, H B
    Kiemeney, Lambertus
    Peeters, Petra H M
    Martinez, Carmen
    Dorronsoro, Miren
    Gonzalez, Carlos A
    Chirlaque, M D
    Quiros, J Ramon
    Ardanaz, Eva
    Berglund, Göran
    Egevad, Lars
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Urologi och andrologi.
    Bingham, Sheila
    Day, Nicholas
    Gann, Peter
    Kaaks, Rudolf
    Ferrari, Pietro
    Riboli, Elio
    Fruits and vegetables and prostate cancer: no association among 1104 cases in a prospective study of 130544 men in the European Prospective Investigation into Cancer and Nutrition (EPIC).2004Ingår i: International Journal of Cancer, ISSN 0020-7136, Vol. 109, nr 1, s. 119-24Artikel i tidskrift (Refereegranskat)
  • 122. Key, Timothy J
    et al.
    Appleby, Paul N
    Allen, Naomi E
    Travis, Ruth C
    Roddam, Andrew W
    Jenab, Mazda
    Egevad, Lars
    Tjønneland, Anne
    Johnsen, Nina F
    Overvad, Kim
    Linseisen, Jakob
    Rohrmann, Sabine
    Boeing, Heiner
    Pischon, Tobias
    Psaltopoulou, Theodora
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Palli, Domenico
    Vineis, Paolo
    Tumino, Rosario
    Berrino, Franco
    Kiemeney, Lambertus
    Bueno-de-Mesquita, H Bas
    Quirós, J Ramón
    González, Carlos A
    Martinez, Carmen
    Larrañaga, Nerea
    Chirlaque, María Dolores
    Ardanaz, Eva
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Urologi och andrologi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Khaw, Kay-Tee
    Bingham, Sheila
    Slimani, Nadia
    Ferrari, Pietro
    Rinaldi, Sabina
    Riboli, Elio
    Plasma carotenoids, retinol, and tocopherols and the risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition study.2007Ingår i: American Journal of Clinical Nutrition, ISSN 0002-9165, Vol. 86, nr 3, s. 672-81Artikel i tidskrift (Refereegranskat)
  • 123. Klein, Robert J
    et al.
    Halldén, Christer
    Cronin, Angel M
    Ploner, Alexander
    Wiklund, Fredrik
    Bjartell, Anders S
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Xu, Jianfeng
    Scardino, Peter T
    Offit, Kenneth
    Vickers, Andrew J
    Grönberg, Henrik
    Lilja, Hans
    Blood biomarker levels to aid discovery of cancer-related single-nucleotide polymorphisms: kallikreins and prostate cancer2010Ingår i: Cancer Prevention Research, ISSN 1940-6207, E-ISSN 1940-6215, Vol. 3, nr 5, s. 611-619Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polymorphisms associated with prostate cancer include those in three genes encoding major secretory products of the prostate: KLK2 (encoding kallikrein-related peptidase 2; hK2), KLK3 (encoding prostate-specific antigen; PSA), and MSMB (encoding beta-microseminoprotein). PSA and hK2, members of the kallikrein family, are elevated in sera of men with prostate cancer. In a comprehensive analysis that included sequencing of all coding, flanking, and 2 kb of putative promoter regions of all 15 kallikrein (KLK) genes spanning approximately 280 kb on chromosome 19q, we identified novel single-nucleotide polymorphisms (SNP) and genotyped 104 SNPs in 1,419 cancer cases and 736 controls in Cancer Prostate in Sweden 1, with independent replication in 1,267 cases and 901 controls in Cancer Prostate in Sweden 2. This verified prior associations of SNPs in KLK2 and in MSMB (but not in KLK3) with prostate cancer. Twelve SNPs in KLK2 and KLK3 were associated with levels of PSA forms or hK2 in plasma of control subjects. Based on our comprehensive approach, this is likely to represent all common KLK variants associated with these phenotypes. A T allele at rs198977 in KLK2 was associated with increased cancer risk and a striking decrease of hK2 levels in blood. We also found a strong interaction between rs198977 genotype and hK2 levels in blood in predicting cancer risk. Based on this strong association, we developed a model for predicting prostate cancer risk from standard biomarkers, rs198977 genotype, and rs198977 x hK2 interaction; this model had greater accuracy than did biomarkers alone (area under the receiver operating characteristic curve, 0.874 versus 0.866), providing proof in principle to clinical application for our findings.

  • 124. Korodi, Zoltan
    et al.
    Dillner, Joakim
    Jellum, Egil
    Lumme, Sonja
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Thoresen, Steinar
    Hakulinen, Timo
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Urologi och andrologi.
    Luostarinen, Tapio
    Lehtinen, Matti
    Hakama, Matti
    Human papillomavirus 16, 18, and 33 infections and risk of prostate cancer: a Nordic nested case-control study.2005Ingår i: Cancer Epidemiology Biomarkers & Prevention, ISSN 1055-9965, Vol. 14, nr 12, s. 2952-5Artikel i tidskrift (Refereegranskat)
  • 125. Kristiansen, Anna
    et al.
    Drevin, Linda
    Delahunt, Brett
    Samaratunga, Hemamali
    Robinson, David
    Lissbrant, Ingela Franck
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Egevad, Lars
    Prognostic significance and biopsy characteristics of prostate cancer with seminal vesicle invasion on radical prostatectomy: a nationwide population-based study2017Ingår i: Pathology (Sydney), ISSN 0031-3025, E-ISSN 1465-3931, Vol. 49, nr 7, s. 715-720Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The objective of this study was to evaluate the prognostic significance of seminal vesicle invasion (SVI, pT3b) compared with extraprostatic extension (EPE) alone (pT3a) after radical prostatectomy, and to correlate pre-operative biopsy pathology with SVI and EPE. The National Prostate Cancer Register includes all prostate cancers diagnosed in Sweden. We analysed 4063 cases with stage category pT3a and 1371 cases with pT3b at radical prostatectomy between 2000 and 2012. Associations between pT3a and pT3b and progression were evaluated and adjusted for year, age, biopsy grade and s-PSA. Needle biopsy findings in these stages were compared. Patients with pT3b (n = 1371) had a higher risk of death from prostate cancer (HR 2.3, 95% CI 1.5-3.3, p < 0.001) and death from any cause (HR 1.5, 95% CI 1.2-1.8, p < 0.001) than those with pT3a (n = 4063). They were also more likely to be treated with post-operative radiotherapy (HR 1.5, 95% CI 1.4-1.7, p < 0.001) or androgen deprivation therapy (HR 3.0, 95% CI 2.5-3.7, p < 0.001), indicating clinical progression. Yet, disease-specific survival of patients with stage pT3b was 94% after 6 years. Median cancer extent in pre-operative biopsies of pT3a and pT3b was 14 and 24 mm (p < 0.001), number of positive cores was four and five, (p < 0.001) and biopsy Gleason score was 8-10 in 11.6% and 27.3%, respectively (p < 0.001). SVI of prostate cancer is associated with worse outcome after radical prostatectomy than EPE alone. However, few patients with SVI die within 6 years from surgery, suggesting that radical prostatectomy may be curative in locally advanced cancers.

  • 126. Licciardello, Marco P.
    et al.
    Ringler, Anna
    Markt, Patrick
    Klepsch, Freya
    Lardeau, Charles-Hugues
    Sdelci, Sara
    Schirghuber, Erika
    Mueller, Andre C.
    Caldera, Michael
    Wagner, Anja
    Herzog, Rebecca
    Penz, Thomas
    Schuster, Michael
    Boidol, Bernd
    Duernberger, Gerhard
    Folkvaljon, Yasin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Ivanov, Vladimir
    Colinge, Jacques
    Bock, Christoph
    Kratochwill, Klaus
    Menche, Joerg
    Bennett, Keiryn L.
    Kubicek, Stefan
    A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor2017Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 13, nr 7, s. 771-778Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered a synergistic interaction between flutamide and phenprocoumon (PPC). The combination of these drugs modulates the stability of the androgen receptor (AR) and resensitizes AR-mutant prostate cancer cells to flutamide. Mechanistically, we show that the AR is a substrate for gamma-carboxylation, a post-translational modification inhibited by PPC. Collectively, our data suggest that PPC could be repurposed to tackle resistance to antiandrogens in prostate cancer patients.

  • 127.
    Lin, Daniel W.
    et al.
    Department of Urology, University of Washington School of Medicine, Seattle, WA.
    FitzGerald, Liesel M.
    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
    Fu, Rong
    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Biostatistics, University of Washington, Seattle, WA.
    Kwon, Erika M.
    Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD.
    Zheng, Siqun Lilly
    Center for Cancer Genomics and Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC.
    Kolb, Suzanne
    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
    Wiklund, Fredrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Stattin, Paer
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Isaacs, William B.
    Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
    Xu, Jianfeng
    Center for Cancer Genomics and Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC.
    Ostrander, Elaine A.
    Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD.
    Feng, Ziding
    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Biostatistics, University of Washington, Seattle, WA.
    Grönberg, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Stanford, Janet L.
    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington.
    Genetic variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes are prognostic markers of prostate cancer-specific mortality2011Ingår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 20, nr 9, s. 1928-1936Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Prostate cancer is the second leading cause of cancer-related deaths in men, accounting for more than 30,000 deaths annually. The purpose of this study was to test whether variation in selected candidate genes in biological pathways of interest for prostate cancer progression could help distinguish patients at higher risk for fatal prostate cancer.

    Methods: In this hypothesis-driven study, we genotyped 937 single nucleotide polymorphisms (SNPs) in 156 candidate genes in a population-based cohort of 1,309 prostate cancer patients. We identified 22 top-ranking SNPs (P <= 0.01, FDR <= 0.70) associated with prostate cancer-specific mortality (PCSM). A subsequent validation study was completed in an independent population-based cohort of 2,875 prostate cancer patients.

    Results: Five SNPs were validated (P <= 0.05) as being significantly associated with PCSM, one each in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes. Compared with patients with 0 to 2 of the at-risk genotypes those with 4 to 5 at-risk genotypes had a 50% (95% CI, 1.2-1.9) higher risk of PCSM and risk increased with the number of at-risk genotypes carried (P(trend) = 0.001), adjusting for clinicopathologic factors known to influence prognosis.

    Conclusion: Five genetic markers were validated to be associated with lethal prostate cancer.

    Impact: This is the first population-based study to show that germline genetic variants provide prognostic information for prostate cancer-specific survival. The clinical utility of this five-SNP panel to stratify patients at higher risk for adverse outcomes should be evaluated. Cancer Epidemiol Biomarkers Prev; 20(9); 1928-36. (C)2011 AACR.

  • 128.
    Lind, Anna Johansson
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap.
    Wikström, Pernilla
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi. Patologi.
    Granfors, Torvald
    Egevad, Lars
    Stattin, Pär
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi. Urologi och andrologi.
    Bergh, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi. Patologi.
    Angiopoietin 2 expression is related to histological grade, vascular density, metastases, and outcome in prostate cancer.2005Ingår i: Prostate, ISSN 0270-4137, Vol. 62, nr 4, s. 394-399Artikel i tidskrift (Refereegranskat)
  • 129. Lindhagen, Lars
    et al.
    Van Hemelrijck, Mieke
    Robinson, David
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Garmo, Hans
    How to model temporal changes in comorbidity for cancer patients using prospective cohort data2015Ingår i: BMC Medical Informatics and Decision Making, ISSN 1472-6947, E-ISSN 1472-6947, Vol. 15, artikel-id 96Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The presence of comorbid conditions is strongly related to survival and also affects treatment choices in cancer patients. This comorbidity is often quantified by the Charlson Comorbidity Index (CCI) using specific weights (1, 2, 3, or 6) for different comorbidities. It has been shown that the CCI increases at different times and with different sizes, so that traditional time to event analysis is not adequate to assess these temporal changes. Here, we present a method to model temporal changes in CCI in cancer patients using data from PCBaSe Sweden, a nation-wide population-based prospective cohort of men diagnosed with prostate cancer. Our proposed model is based on the assumption that a change in comorbidity, as quantified by the CCI, is an irreversible one-way process, i.e., CCI accumulates over time and cannot decrease.

    Methods: CCI was calculated based on 17 disease categories, which were defined using ICD-codes for discharge diagnoses in the National Patient Register. A state transition model in discrete time steps (i.e., four weeks) was applied to capture all changes in CCI. The transition probabilities were estimated from three modelling steps: 1) Logistic regression model for vital status, 2) Logistic regression model to define any changes in CCI, and 3) Poisson regression model to determine the size of CCI change, with an additional logistic regression model for CCI changes ≥ 6. The four models combined yielded parameter estimates to calculate changes in CCI with their confidence intervals.

    Results: These methods were applied to men with low-risk prostate cancer who received active surveillance (AS), radical prostatectomy (RP), or curative radiotherapy (RT) as primary treatment. There were large differences in CCI changes according to treatment.

    Conclusions: Our method to model temporal changes in CCI efficiently captures changes in comorbidity over time with a small number of regression analyses to perform – which would be impossible with tradition time to event analyses. However, our approach involves a simulation step that is not yet included in standard statistical software packages. In our prostate cancer example we showed that there are large differences in development of comorbidities among men receiving different treatments for prostate cancer.

  • 130. Lindkvist, Björn
    et al.
    Almquist, Martin
    Bjørge, Tone
    Stocks, Tanja
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Institute of Preventive Medicine, Copenhagen University Hospitals, Copenhagen, Denmark.
    Borena, Wegene
    Johansen, Dorthe
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Engeland, Anders
    Nagel, Gabriele
    Jonsson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Selmer, Randi
    Diem, Guenter
    Häggström, Christel
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Tretli, Steinar
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Manjer, Jonas
    Prospective cohort study of metabolic risk factors and gastric adenocarcinoma risk in the Metabolic Syndrome and Cancer Project (Me-Can)2013Ingår i: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 24, nr 1, s. 107-116Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: Little is known about the association between the metabolic syndrome (MetS) and the risk of gastric adenocarcinoma. The aim of this study was to investigate whether metabolic risk factors, together or combined, were associated with the risk of gastric adenocarcinoma. Methods: The Metabolic Syndrome and Cancer Project (Me-Can) is a pooling of prospective cohorts in Austria, Norway, and Sweden with information on blood pressure, lipids, glucose, and BMI available in 578,700 individuals. Cox proportional hazards analysis was used to calculate hazard ratio (HR) of gastric adenocarcinoma using metabolic risk factors categorized into quintiles and transformed into z-scores (with mean = 0 and SD = 1). The standardized sum of all z-scores created a composite MetS score. Results: In total, 1,210 incident cases of gastric adenocarcinoma were identified. Glucose was significantly associated with the risk of gastric adenocarcinoma [calibrated HR 1.58 (1.14-2.20) per one unit increment in z-score] in women. There was a statistically significant association between triglycerides and risk of gastric adenocarcinoma per mmol increment in triglycerides [HR 1.20 (1.06-1.36) per mmol] but not for the adjusted z-score in women. There were no significant association between any metabolic factors and gastric cancer among men. The composite MetS score was associated with the risk of gastric adenocarcinoma in women [HR 1.18 (1.00-1.38) per one unit increment in z-score] but not in men. Conclusions: Glucose and high levels of the composite MetS score were associated with an increased risk of gastric adenocarcinoma in women but not in men.

  • 131. Lindkvist, Björn
    et al.
    Johansen, Dorthe
    Stocks, Tanja
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Concin, Hans
    Bjorge, Tone
    Almquist, Martin
    Häggström, Christel
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Engeland, Anders
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Nagel, Gabriele
    Jonsson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Selmer, Randi
    Ulmer, Hanno
    Tretli, Steinar
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Manjer, Jonas
    Metabolic risk factors for esophageal squamous cell carcinoma and adenocarcinoma: a prospective study of 580 000 subjects within the Me-Can project2014Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, s. 103-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Obesity is associated with an increased risk of esophageal adenocarcinoma (EAC) and a decreased risk of esophageal squamous cell carcinoma (ESCC). However, little is known about the risk of EAC and ESCC related to other metabolic risk factors. We aimed to examine the risk of EAC and ESCC in relation to metabolic risk factors, separately and combined in a prospective cohort study. Methods: The Metabolic Syndrome and Cancer cohort includes prospective cohorts in Austria, Norway and Sweden, with blood pressure, lipids, glucose and BMI available from 578 700 individuals. Relative risk (RR) for EAC and ESCC was calculated using Cox's proportional hazards analysis for metabolic risk factors categorized into quintiles and transformed into z-scores. The standardized sum of all z-scores was used as a composite score for the metabolic syndrome (MetS). Results: In total, 324 histologically verified cases of esophageal cancer were identified (114 EAC, 184 ESCC and 26 with other histology). BMI was associated with an increased risk of EAC (RR 7.34 (95% confidence interval, 2.88-18.7) top versus bottom quintile) and negatively associated with the risk of ESCC (RR 0.38 (0.23-0.62)). The mean value of systolic and diastolic blood pressure (mid blood pressure) was associated with the risk of ESCC (RR 1.77 (1.37-2.29)). The composite MetS score was associated with the risk of EAC (RR 1.56 (1.19-2.05) per one unit increase of z-score) but not ESCC. Conclusions: In accordance with previous studies, high BMI was associated with an increased risk of EAC and a decreased risk of ESCC. An association between high blood pressure and risk of ESCC was observed but alcohol consumption is a potential confounding factor that we were not able to adjust for in the analysis. The MetS was associated with EAC but not ESCC. However this association was largely driven by the strong association between BMI and EAC. We hypothesize that this association is more likely to be explained by factors directly related to obesity than the metabolic state of the MetS, considering that no other metabolic factor than BMI was associated with EAC.

  • 132.
    Lindmark, Fredrik
    et al.
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Jonsson, Björn-Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Stattin, Pär
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Zheng, S Lilly
    Meyers, Deborah A
    Xu, Jianfeng
    Grönberg, Henrik
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Analysis of the macrophage scavenger receptor 1 gene in Swedish hereditary and sporadic prostate cancer.2004Ingår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 59, nr 2, s. 132-140Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The macrophage scavenger receptor 1 (MSR1) gene on chromosome 8p22 was recently reported as a candidate gene for hereditary prostate cancer (HPC). Here, we further elucidate the role of MSR1 in both Swedish families with HPC and in a cohort of unselected prostate cancer. METHODS: DNA samples from 83 Swedish HPC families and 215 unselected population based cases of prostate cancer as well as 425 age-matched controls were genotyped. RESULTS: A total of 18 variants were identified, including 2 exonic, 7 intronic changes, and 9 changes in the 5'- or 3'-uncoding region. Of the two exonic changes, one previously reported truncation mutation was identified, a R293X nonsense mutation. This mutation was found in 2 of the 83 (2.4%) HPC families. The R293X mutation was found more frequently in men with PC (4.9%) than in unaffected men (2.7%), consistent with previous published results, however our results were not significant (P = 0.16). To additionally test for potential association of common sequence variants and increased risk for the disease, five common polymorphisms (PRO3, INDEL1, IVS5-57, P275A, INDEL7) were genotyped in the group of 215 prostate cancer cases and 425 age-matched controls. No association between any of the five common sequence variants and prostate cancer were found. CONCLUSION: Our results suggest that mutations in MSR1 gene might play a role in prostate cancer susceptibility, particularly the R293X mutation. This study warrants further investigations of the role of MSR1 in prostate cancer etiology.

  • 133.
    Lindmark, Fredrik
    et al.
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Zheng, S Lilly
    Wiklund, Fredrik
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Bensen, Jeannette
    Augustsson Bälter, Katarina
    Chang, Baoli
    Hedelin, Maria
    Clark, Jonathan
    Stattin, Pär
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Meyers, Deborah A
    Adami, Hans-Olov
    Isaacs, William
    Grönberg, Henrik
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Xu, Jianfeng
    H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer2004Ingår i: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 96, nr 16, s. 1248-1254Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Accumulating epidemiologic and molecular evidence suggest that inflammation is an important component in the etiology of prostate cancer. Macrophage-inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor beta superfamily, is thought to play an important role in inflammation by regulating macrophage activity. We examined whether sequence variants in the MIC-1 gene are associated with the risk of prostate cancer. METHODS: The study population, a population-based case-control study in Sweden, consisted of 1383 prostate cancer case patients and 780 control subjects. From 94 of the control subjects, we constructed gene-specific haplotypes of MIC-1 and identified four haplotype-tagging single-nucleotide polymorphisms (SNPs): Exon1+25 (V9L), Exon1+142 (S48T), IVS1+1809, and Exon2+2423 (H6D). All study subjects were genotyped for the four SNPs, and conditional logistic regression analysis was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A statistically significant difference (P =.006) in genotype frequency was observed for the nonsynonymous change H6D (histidine to aspartic acid at position 6) between prostate cancer patients and control subjects. Carriers of the GC genotype, which results in the H6D change, experienced a lower risk of sporadic prostate cancer (OR = 0.80, 95% CI = 0.66 to 0.97) and of familial prostate cancer (OR = 0.61, 95% CI = 0.42 to 0.89) than the CC genotype carriers. In the study population, the proportion of prostate cancer cases attributable to the CC genotype was 7.2% for sporadic cancer and 19.2% for familial cancer. None of the other SNPs or haplotypes was associated with prostate cancer. CONCLUSION: This study shows an association between a nonsynonymous change (H6D) in the MIC-1 gene and prostate cancer. This finding supports the hypothesis that genetic variation in the inflammatory process contributes to prostate cancer susceptibility.

  • 134.
    Lindström, Sara
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Adami, Hans-Olov
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bälter, Katarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Xu, Jianfeng
    Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
    Zheng, S Lilly
    Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
    Sun, Jielin
    Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Grönberg, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Wiklund, Fredrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Genetic variation in the upstream region of ERG and prostate cancer.2009Ingår i: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 20, nr 7, s. 1173-1180Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: A considerable fraction of prostate cancers harbor a gene fusion between the androgen-regulated TMPRSS2 and ERG, one of the most frequently over-expressed proto-oncogenes in prostate cancer. Here, we investigated if inherited genetic variation upstream of ERG alters prostate cancer risk and survival. METHODS: We genotyped 21 haplotype tagging SNPs (htSNPs) covering 123 kb of 5'UTR DNA including exon 3 of ERG in 2,760 incident prostate cancer cases and 1,647 controls from a population-based Swedish case-control study (CAPS). Individual SNPs and haplotypes were tested for association with prostate cancer risk and survival. RESULTS: One haplotype-'CTCGTATG' located 100 kb upstream of ERG-was associated with lethal prostate cancer (HR, 1.36; 95% CI, 1.2-1.9, p = 0.006). Carriers of the variant 'T' allele of rs2836626 were diagnosed with higher TNM-stage (p = 0.009) and had an increased risk of prostate cancer-specific death (HR = 1.3; 95% CI, 1.1-1.7, p = 0.009). However, this association did not remain statistically significant after adjusting for multiple testing. We found overall no association between ERG variation and prostate cancer risk. CONCLUSIONS: Genetic variation upstream of ERG may alter prostate cancer stage and ultimately prostate cancer-specific death but it is unlikely that it plays a role in prostate cancer development.

  • 135. Lindström, Sara
    et al.
    Hunter, David J
    Grönberg, Henrik
    Stattin, Pär
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Wiklund, Fredrik
    Xu, Jianfeng
    Chanock, Stephen J
    Hayes, Richard
    Kraft, Peter
    Sequence variants in the TLR4 and TLR6-1-10 genes and prostate cancer risk. Results based on pooled analysis from three independent studies.2010Ingår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, nr 3, s. 873-876Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Genetic variation in two members of the Toll-like receptor family, TLR4 and the gene cluster TLR6-1-10, has been implicated in prostate cancer in several studies but the associated alleles have not been consistent across reports. METHODS: We did a pooled analysis combining genotype data from three case-control studies, Cancer of the Prostate in Sweden, the Health Professionals Follow-up Study, and the Prostate, Lung, Colon and Ovarian Cancer Screening Trial, with data from 3,101 prostate cancer cases and 2,523 controls. We did imputation to obtain dense coverage of the genes and comparable genotype data for all cohorts. In total, 58 single nucleotide polymorphisms in TLR4 and 96 single nucleotide polymorphisms in TLR6-1-10 were genotyped or imputed and analyzed in the entire data set. We did a cohort-specific analysis as well as meta-analysis and pooled analysis. We also evaluated whether the analyses differed by age or disease severity. RESULTS: We observed no overall association between genetic variation at the TLR4 and TLR6-1-10 loci and risk of prostate cancer. CONCLUSIONS: Common germ line genetic variation in TLR4 and TLR6-1-10 did not seem to have a strong association with risk of prostate cancer. IMPACT: This study suggests that earlier associations between prostate cancer risk and TLR4 and TLR6-1-10 sequence variants were chance findings. To definitely assess the causal relationship between TLR sequence variants and prostate cancer risk, very large sample sizes are needed.

  • 136. Lindström, Sara
    et al.
    Ma, Jing
    Altshuler, David
    Giovannucci, Edward
    Riboli, Elio
    Albanes, Demetrius
    Allen, Naomi E
    Berndt, Sonja I
    Boeing, Heiner
    Bueno-de-Mesquita, H Bas
    Chanock, Stephen J
    Dunning, Alison M
    Feigelson, Heather Spencer
    Gaziano, J Michael
    Haiman, Christopher A
    Hayes, Richard B
    Henderson, Brian E
    Hunter, David J
    Kaaks, Rudolf
    Kolonel, Laurence N
    Le Marchand, Loic
    Martínez, Carmen
    Overvad, Kim
    Siddiq, Afshan
    Stampfer, Meir
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Stram, Daniel O
    Thun, Michael J
    Trichopoulos, Dimitrios
    Tumino, Rosario
    Virtamo, Jarmo
    Weinstein, Stephanie J
    Yeager, Meredith
    Kraft, Peter
    Freedman, Matthew L
    A large study of androgen receptor germline variants and their relation to sex hormone levels and prostate cancer risk: Results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium2010Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, nr 9, s. E121-E127Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Androgens are key regulators of prostate gland maintenance and prostate cancer growth, and androgen deprivation therapy has been the mainstay of treatment for advanced prostate cancer for many years. A long-standing hypothesis has been that inherited variation in the androgen receptor (AR) gene plays a role in prostate cancer initiation. However, studies to date have been inconclusive and often suffered from small sample sizes.

    Objective and Methods: We investigated the association of AR sequence variants with circulating sex hormone levels and prostate cancer risk in 6058 prostate cancer cases and 6725 controls of Caucasian origin within the Breast and Prostate Cancer Cohort Consortium. We genotyped a highly polymorphic CAG microsatellite in exon 1 and six haplotype tagging single nucleotide polymorphisms and tested each genetic variant for association with prostate cancer risk and with sex steroid levels.

    Results: We observed no association between AR genetic variants and prostate cancer risk. However, there was a strong association between longer CAG repeats and higher levels of testosterone (P = 4.73 × 10−5) and estradiol (P = 0.0002), although the amount of variance explained was small (0.4 and 0.7%, respectively).

    Conclusions: This study is the largest to date investigating AR sequence variants, sex steroid levels, and prostate cancer risk. Although we observed no association between AR sequence variants and prostate cancer risk, our results support earlier findings of a relation between the number of CAG repeats and circulating levels of testosterone and estradiol.

  • 137. Lissbrant, Ingela Franck
    et al.
    Garmo, Hans
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Population-based study on use of chemotherapy in men with castration resistant prostate cancer2013Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, nr 8, s. 1593-1601Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. Chemotherapy prolongs life and relieves symptoms in men with castration resistant prostate cancer (CRPC). There is limited information on a population level on the use of chemotherapy for CRPC. Material and methods. To assess the use of chemotherapy in men with CRPC we conducted a register-based nationwide population-based study in Prostate Cancer data Base Sweden (PCBaSe) and a nationwide in-patient drug register (SALT database) between May 2009 and December 2010. We assumed that men who died of prostate cancer (PCa) underwent a period of CRPC before they died. Results. Among the 2677 men who died from PCa during the study inclusion period, 556 (21%) had received chemotherapy (intravenous or per oral) detectable within the observation period in SALT database. Specifically, 239 (61%) of men <70 years had received chemotherapy, 246 (30%) of men between 70 and 79 years and 71 (5%) men older than 80 years. The majority of men 465/556 (84%) had received a docetaxel-containing regimen. Among chemotherapy treated men, 283/556 (51%) received their last dose of chemotherapy during the last six months prior to death. Treatment with chemotherapy was more common among men with little comorbidity and high educational level, as well as in men who had received curatively intended primary treatment. Conclusion. A majority of men younger than 70 years with CRPC were treated with chemotherapy in contrast to men between 70 and 79 years of whom half as many received chemotherapy. Chemotherapy treatment was often administered shortly prior to death. The low uptake of chemotherapy in older men with CRPC may be caused by concerns about tolerability of treatment, as well as treatment decisions based on chronological age rather than global health status.

  • 138. Liu, Wennuan
    et al.
    Sun, Jishan
    Li, Ge
    Zhu, Yi
    Zhang, Scott
    Kim, Seong-Tae
    Sun, Jielin
    Wiklund, Fredrik
    Wiley, Kathleen
    Isaacs, Sarah D
    Stattin, Pär
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Xu, Jianfeng
    Duggan, David
    Carpten, John D
    Isaacs, William B
    Grönberg, Henrik
    Zheng, S Lilly
    Chang, Bao-Li
    Association of a germ-line copy number variation at 2p24.3 and risk for aggressive prostate cancer.2009Ingår i: Cancer research, ISSN 1538-7445, Vol. 69, nr 6, s. 2176-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We searched for deletions in the germ-line genome among 498 aggressive prostate cancer cases and 494 controls from a population-based study in Sweden [CAncer of the Prostate in Sweden (CAPS)] using Affymetrix SNP arrays. By comparing allele intensities of approximately 500,000 SNP probes across the genome, a germ-line deletion at 2p24.3 was observed to be significantly more common in cases (12.63%) than in controls (8.28%); P = 0.028. To confirm the association, we genotyped this germ-line copy number variation (CNV) in additional subjects from CAPS and from Johns Hopkins Hospital (JHH). Overall, among 4,314 cases and 2,176 controls examined, the CNV was significantly associated with prostate cancer risk [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.06-1.48; P = 0.009]. More importantly, the association was stronger for aggressive prostate cancer (OR, 1.31; 95% CI, 1.08-1.58; P = 0.006) than for nonaggressive prostate cancer (OR, 1.19; 95% CI, 0.98-1.45; P = 0.08). The biological effect of this germ-line CNV is unknown because no known gene resides in the deletion. Results from this study represent the first novel germ-line CNV that was identified from a genome-wide search and was significantly, but moderately, associated with prostate cancer risk. Additional confirmation of this association and functional studies are warranted.

  • 139. Loeb, Stacy
    et al.
    Berglund, Anders
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Population Based Study of Use and Determinants of Active Surveillance and Watchful Waiting for Low and Intermediate Risk Prostate Cancer2013Ingår i: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 190, nr 5, s. 1742-1749Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: Prior studies have reported the underuse of deferred treatment (ie active surveillance or watchful waiting) for low risk prostate cancer in the United States. We examined contemporary trends in active surveillance and watchful waiting in the nationwide Swedish prostate cancer registry. We also examined factors associated with selection of deferred management, which might provide insight into the rational diffusion of this important management strategy.

    Materials and Methods: We identified 57,713 men with very low risk (T1c, Gleason 6 or less, prostate specific antigen less than 10 ng/ml, prostate specific antigen density less than 0.20 ng/ml/cc, 2 or fewer positive biopsy cores or less than 25% of cores positive), low risk (T1-T2, Gleason 6 or less, and prostate specific antigen less than 10 ng/ml) and intermediate risk prostate cancer (T1-T2, Gleason 7 and/or prostate specific antigen 10 to 20 ng/ml) in the PCBaSe (Prostate Cancer database Sweden) from 1998 to 2011. Subclassification of very low risk disease, and active surveillance vs watchful waiting was possible beginning in 2007. We examined primary treatment selection by risk group and used logistic regression to evaluate factors associated with deferred treatment.

    Results: Overall 13,272 (46%) men with low risk and 8,695 (30%) with intermediate risk prostate cancer chose deferred treatment. Since 2007, 59%, 41% and 16% of very low, low and intermediate risk prostate cancer, respectively, chose active surveillance. Age was by far the strongest determinant of deferred treatment. Education, marital status and comorbidity were significantly but weakly associated with deferring treatment.

    Conclusions: Deferred treatment for low and intermediate risk prostate cancer was frequently used in Sweden. Dissociating diagnosis from treatment in men with a low risk of progression can decrease the rate of overtreatment.

  • 140. Loeb, Stacy
    et al.
    Drevin, Linda
    Robinson, David
    Holmberg, Erik
    Carlsson, Sigrid
    Lambe, Mats
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Risk of localized and advanced prostate cancer among immigrants versus native-born Swedish men: a nation-wide population-based study2013Ingår i: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 24, nr 2, s. 383-390Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Prostate cancer (PCa) incidence and prognosis vary geographically. We examined possible differences in PCa risk by clinical risk category between native-born and immigrant populations in Sweden. Our hypothesis was that lower PSA-testing uptake among foreign-born men would result in lower rates of localized disease, and similar or higher risk of metastatic disease. Using the Prostate Cancer database Sweden, we identified 117,328 men with PCa diagnosed from 1991 to 2008, of which 8,332 were foreign born. For each case, 5 cancer-free matched controls were randomly selected from the population register. Conditional logistic regression was used to compare low risk, intermediate risk, high risk, regionally metastatic, and distant metastatic PCa based upon region of origin. Across all risk categories, immigrants had significantly lower PCa risk than native-born Swedish men, except North Americans and Northern Europeans. The lowest PCa risk was observed in men from the Middle East, Southern Europe, and Asia. Multivariable adjustment for socioeconomic factors and comorbidities did not materially change risk estimates. Older age at immigration and more recent arrival in Sweden were associated with lower PCa risk. Non-native men were less likely to be diagnosed with PCa through PSA testing during a health checkup. The risk for all stages of PCa was lower among first-generation immigrants to Sweden compared with native-born men. Older age at immigration and more recent immigration were associated with particularly low risks. Patterns of PSA testing appeared to only partly explain the differences in PCa risk, since immigrant men also had a lower risk of metastatic disease.

  • 141. Loeb, Stacy
    et al.
    Folkvaljon, Yasin
    Curnyn, Caitlin
    Robinson, David
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap. Department of Urology, Ryhov County Hospital, Jönköping, Sweden.
    Bratt, Ola
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Uptake of active surveillance for very-low-risk prostate cancer in Sweden2017Ingår i: JAMA Oncology, ISSN 2374-2437, E-ISSN 2374-2445, Vol. 3, nr 10, s. 1393-1398Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Importance: Active surveillance is an important option to reduce prostate cancer overtreatment, but it remains underutilized in many countries. Models from the United States show that greater use of active surveillance is important for prostate cancer screening to be cost-effective.oObjectives: To perform an up-to-date, nationwide, population-based study on use of active surveillance for localized prostate cancer in Sweden.

    Design, setting, and participants: Cross-sectional study in the National Prostate Cancer Register (NPCR) of Sweden from 2009 through 2014. The NPCR has data on 98% of prostate cancers diagnosed in Sweden and has comprehensive linkages to other nationwide databases. Overall, 32 518 men with a median age of 67 years were diagnosed with favorable-risk prostate cancer, including 4693, 15 403, and 17 115 men with very-low-risk (subset of the low-risk group) (clinical stage, T1c; Gleason score, ≤6; prostate-specific antigen [PSA], <10 ng/mL; PSA density <0.15 ng/mL/cm3; and <8-mm total cancer length in ≤4 positive biopsy cores), low-risk (including all men in the very-low-risk group) (T1-T2; Gleason score, ≤6; and PSA, <10 ng/mL), and intermediate-risk disease (T1-T2 with Gleason score, 7 and/or PSA, 10-20 ng/mL).

    Exposures: Diagnosis with favorable-risk prostate cancer.

    Main outcomes and measures: Utilization of active surveillance.

    Results: The use of active surveillance increased in men of all ages from 57% (380 of 665) to 91% (939 of 1027) for very-low-risk prostate cancer and from 40% (1159 of 2895) to 74% (1951 of 2644) for low-risk prostate cancer, with the strongest increase occurring from 2011 onward. Among men aged 50 to 59 years, 88% (211 of 240) with very-low-risk and 68% (351 of 518) with low-risk disease chose active surveillance in 2014. Use of active surveillance for intermediate-risk disease remained lower, 19% (561 of 3030) in 2014.

    Conclusions and relevance: Active surveillance has become the dominant management for low-risk prostate cancer among men in Sweden, with the highest rates yet reported and almost complete uptake for very-low-risk cancer. These data should serve as a benchmark to compare the use of active surveillance for favorable-risk disease around the world.

  • 142. Loeb, Stacy
    et al.
    Folkvaljon, Yasin
    Lambe, Mats
    Robinson, David
    Department of Surgery and Perioperative Sciences, Urology and Andrology, Umeå University Hospital, Umeå, Sweden .
    Garmo, Hans
    Ingvar, Christian
    Stattin, Pär
    Department of Surgery and Perioperative Sciences, Urology and Andrology, Umeå University Hospital, Umeå, Sweden .
    Use of Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction and Risk of Malignant Melanoma2015Ingår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 313, nr 24, s. 2449-2455Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    IMPORTANCE: The target for the oral erectile dysfunction drugs, phosphodiesterase type 5 (PDE5) inhibitors, is part of a pathway implicated in the development of malignant melanoma. An increased risk of melanoma in sildenafil users was recently reported. OBJECTIVE To examine the association between use of PDE5 inhibitors and melanoma risk, including data on specific PDE5 inhibitors, number of prescriptions, and melanoma stage.

    DESIGN, SETTING, AND PARTICIPANTS: Nationwide, population-based, nested case-control study in the Swedish Prescribed Drug Register, the Swedish Melanoma Register, and other health care registers and demographic databases in Sweden, including 4065 melanoma cases diagnosed from 2006 through 2012 and 5 randomly selected controls per case with matching year of birth.

    EXPOSURES: Number of filled prescriptions for the PDE5 inhibitors sildenafil and vardenafil or tadalafil.

    MAIN OUTCOMES AND MEASURES: Risk of melanoma; overall and by stage and risk of basal cell carcinoma in multivariable logistic regression analyses.

    RESULTS: Of 4065 melanoma cases, 435 men (11%) had filled prescriptions for PDE5 inhibitors, as did 1713 men of 20 325 controls (8%). In multivariable analysis, there was an increased risk of melanoma in men taking PDE5 inhibitors (OR, 1.21 [95% CI, 1.08-1.36]). The most pronounced increase in risk was observed in men who had filled a single prescription (OR, 1.32 [95% CI, 1.10-1.59]; exposure rate, 4% for cases vs 3% for controls), but was not significant among men with multiple filled prescriptions (for 2-5 prescriptions: OR, 1.14 [95% CI, 0.95-1.37], 4% for cases and 3% for controls; for >= 6 prescriptions: OR, 1.17 [95% CI, 0.95-1.44], 3% for cases vs 2% for controls). PDE5 inhibitors were significantly associated with melanoma stage 0 (OR, 1.49 [95% CI, 1.22-1.83], 13% for cases vs 8% for controls) and stage I (OR, 1.21 [95% CI, 1.02-1.43], 12% for cases vs 10% for controls), but not stage II through IV (OR, 0.83 [95% CI, 0.63-1.09], 6% for cases vs 7% for controls). The risk estimates were similar for sildenafil and vardenafil or tadalafil. PDE5 inhibitor use was also associated with an increased risk of basal cell carcinoma (OR, 1.19 [95% CI, 1.14-1.25], 9% for cases vs 8% for controls). Men taking PDE5 inhibitors had a higher educational level and annual income, factors that were also significantly associated with melanoma risk.

    CONCLUSIONS AND RELEVANCE: In a Swedish cohort of men, the use of PDE5 inhibitors was associated with a modest but statistically significant increased risk of malignant melanoma. However, the pattern of association (eg, the lack of association with multiple filled prescriptions) raises questions about whether this association is causal.

  • 143. Loeb, Stacy
    et al.
    Folkvaljon, Yasin
    Makarov, Danil V.
    Bratt, Ola
    Bill-Axelson, Anna
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Five-year Nationwide Follow-up Study of Active Surveillance for Prostate Cancer2015Ingår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 67, nr 2, s. 233-238Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Active surveillance (AS) is an important yet underutilized strategy to reduce prostate cancer (PCa) overtreatment. Objective: To examine the 5-yr outcomes of AS in a population-based setting. Design, setting, and participants: From the National Prostate Cancer Register of Sweden, we identified 11 726 men <= 70 yr diagnosed with very low-risk to intermediate-risk PCa from 2003 to 2007 who completed 5 yr of follow-up. Of these men, 1729 (15%) chose AS for the primary management strategy. Outcome measurements and statistical analysis: We calculated the probability of discontinuation of AS over time, and Cox proportional hazards models were used to determine factors associated with discontinuation. Reasons for discontinuation were assessed by data extraction from medical charts. Results and limitations: By 5 yr, 64% of the men remained on AS. Predictors of discontinuation were younger age, fewer comorbidities, more education, higher prostate-specific antigen (PSA), and clinical stage T2 disease; marital status did not predict discontinuation. In a subset with data on the reason for discontinuation (86%), 20% of men discontinued because of patient preference, 52% because of PSA progression, 24% because of biopsy progression, and 3% for other reasons. Conclusions: In a population-based setting, the majority of men remained on AS at 5 yr. However, one-fifth of the men who discontinued AS did so for nonbiologic reasons. Thus, there is a need for support and counseling for men to continue AS in the absence of signs of progression to improve adherence to AS and decrease overtreatment. Patient summary: Active surveillance (AS) is an important option to delay or avoid treatment for men with favorable prostate cancer features. This study shows that at 5 yr, 64% of men across an entire population remained on AS. We concluded that AS is a durable option and that counseling may be useful to promote adherence for men without progression.

  • 144. Loeb, Stacy
    et al.
    Folkvaljon, Yasin
    Robinson, David
    Lissbrant, Ingela Franck
    Egevad, Lars
    Stattin, Pär
    Evaluation of the 2015 Gleason Grade Groups in a Nationwide Population-based Cohort2016Ingår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 69, nr 6, s. 1135-1141Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: New five-tiered Gleason grade groups (GGGs) were recently proposed, in which Gleason 6 is GGG 1, Gleason 3+4 is GGG 2, Gleason 4+3 is GGG 3, Gleason 8 is GGG 4, and Gleason 9-10 is GGG 5.

    OBJECTIVE: To examine the performance of the new GGGs in men with prostate cancer from a nationwide population-based cohort.

    DESIGN, SETTING, AND PARTICIPANTS: From the National Prostate Cancer Register of Sweden, we identified 5880 men diagnosed with prostate cancer from 2005 to 2007, including 4325 who had radical prostatectomy and 1555 treated with radiation therapy.

    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier survival analysis, Cox proportional hazards models, and concordance indices were used to examine the relationship between the GGGs and biochemical recurrence after radical prostatectomy and radiation therapy.

    RESULTS AND LIMITATIONS: Among men treated with surgery, the 4-yr biochemical recurrence-free survival rates were 89%, 82%, 74%, 77%, and 49% for GGG 1-5 on biopsy, and 92%, 85%, 73%, 63%, and 51% based on prostatectomy GGG, respectively. For men treated by radiation therapy, men with biopsy GGG of 1-5 had 4-yr biochemical recurrence-free survival rates of 95%, 91%, 85%, 78%, and 70%. Adjusting for preoperative serum prostate-specific antigen and clinical stage, biopsy GGGs were significant independent predictors of biochemical recurrence after radical prostatectomy and radiation therapy. The new 5-tier system resulted in virtually no change in predictive accuracy compared with the current 3- and 4-tier classifications. Limitations include a median follow-up of 4.6 yr, precluding the ability to examine long-term oncologic outcomes.

    CONCLUSIONS: The newly proposed GGGs offer a simplified, user-friendly nomenclature to aid in patient counseling, with similar predictive accuracy in a population-based setting to previous classifications.

    PATIENT SUMMARY: The new Gleason grade groups, ranging from 1-5, provide a simplified, user-friendly classification system to predict the risk of recurrence after prostatectomy and radiation therapy.

  • 145. Loeb, Stacy
    et al.
    Folkvaljon, Yasin
    Robinson, David
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Schlomm, Thorsten
    Garmo, Hans
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Department of Urology, Uppsala University Hospital, Uppsala, Sweden.
    Phosphodiesterase Type 5 Inhibitor Use and Disease Recurrence After Prostate Cancer Treatment2016Ingår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 70, nr 5, s. 824-828Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Phosphodiesterase type 5 inhibitor (PDE5i) use is common for management of erectile dysfunction. Single-institution studies have reported conflicting data on the relationship between PDE5i use and biochemical recurrence of prostate cancer (BCR) after radical prostatectomy.

    OBJECTIVE: To evaluate the association between PDE5i use and BCR after radical prostatectomy and radiation therapy in a nationwide population-based cohort.

    DESIGN, SETTING, AND PARTICIPANTS: This was a nested case-control study using the National Prostate Cancer Register of Sweden linked to the Prescribed Drug Register. Among men with localized prostate cancer who underwent primary radical prostatectomy or radiation therapy during 2006-2007 with 5 yr of follow-up, 293 had BCR after treatment (cases). For each case we identified 20 BCR-free controls (n=5767) using incidence density sampling.

    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable conditional logistic regression was used to examine the association between PDE5i use and BCR risk. Separate multivariable models including clinical variables for men undergoing prostatectomy or radiotherapy and including surgical pathology after prostatectomy were also analyzed.

    RESULTS AND LIMITATIONS: PDE5i use was not associated with BCR after radical prostatectomy (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.59-1.03) or radiation therapy (OR 0.98, 95% CI 0.49-1.97) after adjusting for marital status, education, income, prostate-specific antigen, clinical stage, Gleason score, and proportion of positive biopsies. Results were similar after additional adjustment for surgical pathology (OR 0.86, 95% CI 0.64-1.16). Men whose cumulative number of PDE5i pills was above the median had a slightly lower BCR risk after prostatectomy in the clinical model, and no difference in BCR risk after adjustment for pathologic tumor features.

    CONCLUSIONS: Our results from a population-based cohort suggest that BCR risk is not higher among men using PDE5i after prostate cancer treatment.

    PATIENT SUMMARY: Erectile dysfunction medications are not associated with a higher risk of disease recurrence after prostate cancer treatment.

  • 146. Loeb, Stacy
    et al.
    Folkvaljon, Yasin
    Robinson, David
    Schlomm, Thorsten
    Garmo, Hans
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Phosphodiesterase type 5 inhibitors (PDE5i) and prostate cancer recurrence2016Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 34, nr 2Artikel i tidskrift (Övrigt vetenskapligt)
  • 147. Loeb, Stacy
    et al.
    Lambe, Mats
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Department of Urology, Uppsala University Hospital, Uppsala, Sweden.
    Re: Editorial Comment on Use of Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction and Risk of Malignant Melanoma2016Ingår i: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 195, nr 4, s. 1172-1173Artikel i tidskrift (Refereegranskat)
  • 148.
    Loeb, Stacy
    et al.
    New York, NY, USA.
    Schlomm, Thorsten
    Hamburg, Germany.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Associations Do Not Equal Causation: clinical Relevance of Statistical Associations of Phosphodiesterase Type 5 Inhibitors with Prostate Cancer Progression and Melanoma2015Ingår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 68, nr 5, s. 754-755Artikel i tidskrift (Övrigt vetenskapligt)
  • 149. Loeb, Stacy
    et al.
    Ventimiglia, Eugenio
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Division of Experimental Oncology, Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy; Universita Vita-Salute San Raffaele, Milan, Italy.
    Salonia, Andrea
    Folkvaljon, Yasin
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden .
    Meta-Analysis of the Association Between Phosphodiesterase Inhibitors (PDE5Is) and Risk of Melanoma2017Ingår i: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 109, nr 8, artikel-id djx086Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The US Food and Drug Administration recently announced the need to evaluate the association between PDE5is and melanoma. We performed a meta-analysis on the association between PDE5i and melanoma using random effects models and examined whether it met Hill's criteria for causality. A systematic search of Medline, EMBASE, and the Cochrane Library from 1998 to 2016 identified three case-control studies and two cohort studies, including a total of 866 049 men, of whom 41 874 were diagnosed with melanoma. We found a summary estimate indicating an increased risk of melanoma in PDE5i users (relative risk = 1.12, 95% confidence interval = 1.02 to 1.23). However, there was no difference in risk between men with low and high exposure to PDE5i, and risk was higher for in situ melanoma than localized and high-risk melanoma, suggesting a lack of dose response and biological gradient. PDE5i use was also associated with basal cell cancer, suggesting a lack of specificity and likely confounding by ultraviolet exposure. Thus, although this meta-analysis found a statistically significant association between PDE5i and melanoma, it did not satisfy Hill's criteria for causality.

  • 150.
    Lukanova, Annekatrin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Björ, Ove
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Kaaks, Rudolf
    Lenner, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lindahl, Bernt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Body mass index and cancer: results from the Northern Sweden Health and Disease Cohort2006Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 118, nr 2, s. 458-466Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Excess weight has been associated with increased risk of cancer. The effect of body mass index (BMI, kg/m(2)) on overall cancer risk and on risk of developing several common cancer types was examined in a population-based cohort study. Height and weight measurements were available for 35,362 women and 33,424 men recruited in the Northern Sweden Health and Disease Cohort between 1985 and 2003. Among cohort members, 2,691 incident cancer cases were identified. The association of BMI with cancer risk was examined using Poisson regression. Women with BMI > 27.1 (top quartile) had a 29% higher risk of developing any malignancy compared to women with BMI of 18.5-22.2 (lowest quartile), which increased to 47% in analysis limited to nonsmokers. Analyses according to WHO cut-off points showed that obese women (BMI > or = 30) had a 36% higher risk of cancer than women with BMI in the normal range (18.5-25). Individual cancer sites most strongly related to obesity were endometrium (risk for top quartile = 3.53, 95% confidence interval 1.86-7.43), ovary (2.09, 1.13-4.13) and colon (2.05, 1.04-4.41). BMI was inversely related to breast cancer occurring before age 49 (0.58, 0.29-1.11, p(trend) < 0.04). In men, there was no association of BMI with overall cancer risk. Obese men (BMI > or = 30), however, were at increased risk of developing kidney cancer (3.63, 1.23-10.7) and, after exclusion of cases diagnosed within 1 year of recruitment, colon cancer (1.77, 1.04-2.95). Our study provides further evidence that BMI is positively associated with cancer risk. In women from northern Sweden, up to 7% of all cancers were attributable to overweight and obesity and could be avoided by keeping BMI within the recommended range.

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