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  • 201. Jahnson, Staffan
    et al.
    Damm, Ole
    Hellsten, Sverker
    Holmäng, Sten
    Liedberg, Fredrik
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Malmström, Per-Uno
    Månsson, Wiking
    Strömberg, Fredrik
    Wijkstöm, Hans
    A population-based study of patterns of care for muscle-invasive bladder cancer in Sweden.2009In: Scandinavian journal of urology and nephrology, ISSN 1651-2065, Vol. 43, no 4, p. 271-6Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To analyse the management of muscle-invasive bladder cancer in a population-based national register, and specifically to investigate the role of curative therapy (i.e. cystectomy or radiotherapy) in relation to patient, tumour and hospital characteristics. MATERIAL AND METHODS: The Swedish Bladder Cancer Register covers more than 90% of all patients in the country who have been diagnosed with such disease since 1997. Results from 1997-2003 were analysed regarding curative-intent treatment given within 3-6 months of diagnosis of muscle-invasive bladder cancer. RESULTS: In total, 3463 patients with clinical T2-T4 bladder cancer were included in the analysis. Of those patients, 1426 (41%) received curative-intent treatment in the form of radiotherapy (285, 20%) or cystectomy (1141, 80%). Male gender, age < 76 years, favourable TNM category and registration at a high-volume hospital were associated with such treatment. Curative-intent treatment was given to significantly more patients registered at high-volume hospitals (1003/2227, 45%) than at low-volume hospitals (423/1235, 34%) (chi(2)=37.7, p<0.00001). Cystectomy was performed more often in those registered at high-volume than at low-volume hospitals (826/2227, 37%, and 316/1235, 26%, respectively, chi(2)=47.3, p<0.00001). CONCLUSIONS: Lower rates of curative-intent treatment were found in patients registered at low-volume than at high-volume facilities, and the same was seen when comparing females with males, and patients aged 76-80 years with younger patients. Since many of these bladder cancer patients were registered at and eventually treated at hospitals handling fewer than 10 such cases annually, it seems desirable to concentrate treatment of this disease at more specialized centres.

  • 202. Jahnson, Staffan
    et al.
    Gårdmark, Truls
    Hosseini, Abolfazl
    Jerlström, Tomas
    Liedberg, Fredrik
    Malmström, Per-Uno
    Rosell, Johan
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ströck, Viveka
    Häggström, Christel
    Holmberg, Lars
    Aljabery, Firas
    Management and outcome of TaG3 tumours of the urinary bladder in the nationwide, population-based bladder cancer database Sweden (BladderBaSe)2019In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, p. 1-6Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate the management of TaG3 tumours of the urinary bladder using nationwide population-based data in relation to the prevailing guidelines, patients' characteristics, and outcome.

    Materials and methods: The Bladder Cancer Data Base Sweden (BladderBaSe), including data from the Swedish National Register for Urinary Bladder Cancer (SNRUBC), was used to study all patients with TaG3 bladder cancer diagnosed from 2008 to 2014. Patients were divided into the following management groups: (1) transurethral resection (TUR) only, (2) TUR and intravesical instillation therapy (IVIT), (3) TUR and second-look resection (SLR), and (4) TUR with both SLR and IVIT. Patient and tumour characteristics and outcome were studied.

    Results: There were 831 patients (83% males) with a median age of 74 years. SLR was performed more often on younger patients, on men, and less often in the Western and Uppsala/Örebro Healthcare regions. IVIT was performed more often with younger patients, with men, in the Western Healthcare region, and less often in the Uppsala/Örebro Healthcare region. Death from bladder cancer occurred in 6% of cases within a median of 29 months (0-84 months) and was lower in the TUR/IVIT and TUR/SLR/IVIT groups compared to the other two groups.

    Conclusion: In the present study, there was, according to the prevailing treatment guidelines, an under-treatment with SLR for older patients, women, and in some healthcare regions and, similarly, there was an under-treatment with IVIT for older patients. Cancer-specific survival and relative survival were lower in the TUR only group compared to the TUR/IVIT and TUR/SLR/IVIT groups.

  • 203. Jahnson, Staffan
    et al.
    Wiklund, Fredrik
    Duchek, Milos
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Mestad, Oddvar
    Rintala, Erkki
    Hellsten, Sverker
    Malmström, Per-Uno
    Results of second-look resection after primary resection of T1 tumour of the urinary bladder.2005In: Scand J Urol Nephrol, ISSN 0036-5599, Vol. 39, no 3, p. 206-10Article in journal (Refereed)
  • 204. Jakszyn, Paula G
    et al.
    Allen, Naomi E
    Lujan-Barroso, Leila
    Gonzalez, Carlos A
    Key, Timothy J
    Fonseca-Nunes, Ana
    Tjønneland, Anne
    Føns-Johnsen, Nina
    Overvad, Kim
    Teucher, Birgit
    Li, Kuanrong
    Boeing, Heiner
    Trichopoulou, Antonia
    Oikonomou, Eleni
    Sarantopoulou, Maria
    Saieva, Calogero
    Krogh, Vittorio
    Tumino, Rosario
    Ricceri, Fulvio
    Bueno-de-Mesquita, H Bas
    Huerta, José M
    Ardanaz, Eva
    Arguelles, Marcial V
    Molina-Montes, Esther
    Larrañaga, Nerea
    Wirfält, Elisabet
    Wallström, Peter
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York.
    Khaw, Kay-Tee
    Jenab, Mazda
    Fedirko, Veronika
    Riboli, Elio
    Nitrosamines and Heme Iron and Risk of Prostate Cancer in the European Prospective Investigation into Cancer and Nutrition.2012In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 21, no 3, p. 547-551Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The evidence about nitrosamines and heme iron intake and cancer risk is limited, despite the biologic plausibility of the hypothesis that these factors might increase cancer risk. We investigated the association between dietary nitrosamines and heme iron and the risk of prostate cancer among participants of European Prospective Investigation into Cancer and Nutrition (EPIC).METHODS: Data on food consumption and complete follow-up for cancer occurrence was available for 139,005 men, recruited in 8 European countries. Estimates of HRs were obtained by proportional hazard models, stratified by age at recruitment, and study center, and adjusted for total energy intake, smoking status, marital status, dairy products, educational level, and body mass index.RESULTS: After a mean follow-up of 10 years, 4,606 participants were diagnosed with first incident prostate cancer. There was no overall association between prostate cancer risk and nitrosamines exposure (preformed and endogenous) or heme iron intake (HR for a doubling of intake: 1.00; 95% CI: 0.98-1.03 for N-Nitrosodimethlyamine, 0.95; 95% CI: 0.88-1.03 for endogenous Nitrosocompounds, and 1.00; 95 CI: 0.97-1.03 for heme iron).Conclusions and Impact: Our findings do not support an effect of nitrosamines (endogenous and exogenous) and heme iron intake on prostate cancer risk.

  • 205. Jakszyn, Paula
    et al.
    González, Carlos A
    Luján-Barroso, Leila
    Ros, Martine M
    Bueno-de-Mesquita, H Bas
    Roswall, Nina
    Tjønneland, Anne M
    Büchner, Frederike L
    Egevad, Lars
    Overvad, Kim
    Raaschou-Nielsen, Ole
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Touillaud, Marina S
    Chang-Claude, Jenny
    Allen, Naomi E
    Kiemeney, Lambertus A
    Key, Timothy J
    Kaaks, Rudolf
    Boeing, Heiner
    Weikert, Steffen
    Trichopoulou, Antonia
    Oikonomou, Eleni
    Zylis, Dimosthenis
    Palli, Domenico
    Berrino, Franco
    Vineis, Paolo
    Tumino, Rosario
    Mattiello, Amalia
    Peeters, Petra H M
    Parr, Christine L
    Gram, Inger T
    Skeie, Guri
    Sánchez, Maria-Jose
    Larrañaga, Nerea
    Ardanaz, Eva
    Navarro, Carmen
    Rodríguez, Laudina
    Ulmert, David
    Ehrnström, Roy
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Roddam, Andrew Wilfred
    Bingham, Sheila A
    Khaw, Kay-Tee
    Slimani, Nadia
    Boffetta, Paolo A
    Jenab, Mazda
    Mouw, Traci
    Michaud, Dominique S
    Riboli, Elio
    Red meat, dietary nitrosamines, and heme iron and risk of bladder cancer in the European prospective investigation into cancer and nutrition (EPIC)2011In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 20, no 3, p. 555-559Article in journal (Refereed)
    Abstract [en]

    Our findings do not support an effect of red meat intake, nitrosamines (endogenous or exogenous), or heme iron intake on bladder cancer risk. Cancer Epidemiol Biomarkers Prev; 20(3); 555-9. ©2011 AACR.

  • 206.
    Jalkanen, Ville
    et al.
    Umeå University, Faculty of Science and Technology, Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics.
    Andersson, Britt
    Umeå University, Faculty of Science and Technology, Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Lindahl, Olof
    Umeå University, Faculty of Science and Technology, Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics.
    Detection of prostate cancer with a resonance sensor2005In: IFMBE Proccedings: NBC'05 Umeå 13th Nordic Baltic Conferenceon Biomedical Engineering and Medical Physics, Umeå, 2005, p. 130-131Conference paper (Refereed)
  • 207.
    Jalkanen, Ville
    et al.
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Andersson, Britt
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lindahl, Olof
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Indentation loading response of a resonance sensor: discriminating prostate cancer and normal tissue2013In: Journal of Medical Engineering & Technology, ISSN 0309-1902, E-ISSN 1464-522X, Vol. 37, no 7, p. 416-423Article in journal (Refereed)
    Abstract [en]

    Prostate cancer is the most common type of cancer among men worldwide. Mechanical properties of prostate tissue are promising for distinguishing prostate cancer from healthy prostate tissue. The aim was to investigate the indentation loading response of a resonance sensor for discriminating prostate cancer tissue from normal tissue. Indentation measurements were done on prostate tissue specimens ex vivo from 10 patients from radical prostatectomy. The measurement areas were analysed using standard histological methods. The stiffness parameter was linearly dependent on the loading force (average R2 = 0.90) and an increased loading force caused a greater stiffness contrast of prostate cancer vs normal tissue. The accuracy of the stiffness contrast was assessed by the ROC curve with the area under the curve being 0.941 for a loading force of 12.8 mN. The results are promising for the development of a resonance sensor instrument for detecting prostate cancer.

  • 208.
    Jalkanen, Ville
    et al.
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Andersson, Britt M
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lindahl, Olof A
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Explanatory models for a tactile resonance sensor system-elastic and density-related variations of prostate tissue in vitro2008In: Physiological Measurement, ISSN 0967-3334, E-ISSN 1361-6579, Vol. 29, no 7, p. 729-745Article in journal (Refereed)
    Abstract [en]

    Tactile sensors based on piezoelectric resonance have been adopted for medical applications. The sensor consists of an oscillating piezoelectric sensor–circuit system, and a change in resonance frequency is observed when the sensor tip contacts a measured object such as tissue. The frequency change at a constant applied force or mass load is used as a stiffness-sensitive parameter in many applications. Differential relations between force and frequency have also been used for monitoring intraocular pressure and stiffness variations in prostate tissue in vitro. The aim of this study was to relate the frequency change (Δf), measured force (F) and the material properties, density and elasticity to an explanatory model for the resonance sensor measurement principle and thereby to give explanatory models for the stiffness parameters used previously. Simulations of theoretical equations were performed to investigate the relation between frequency change and contact impedance. Measurements with a resonance sensor system on prostate tissue in vitro were used for experimental validation of the theory. Tissue content was quantified with a microscopic-based morphometrical method. Simulation results showed that the frequency change was dependent upon density (ρ) and contact area (S) according to Δf ∝ ρS3/2. The experiments followed the simulated theory at small impression depths. The measured contact force followed a theoretical model with the dependence of the elastic modulus (E) and contact area, FES3/2. Measured density variations related to histological variations were statistically weak or non-significant. Elastic variations were statistically significant with contributions from stroma and cancer relative to normal glandular tissue. The theoretical models of frequency change and force were related through the contact area, and a material-dependent explanatory model was found as Δf ∝ ρE−1F. It explains the measurement principle and the previously established stiffness parameters from the material properties point of view.

  • 209.
    Jalkanen, Ville
    et al.
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Andersson, Britt M.
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lindahl, Olof A.
    Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Resonanssensorteknik för detektering av prostatacancer2010In: Medicinteknikdagarna 2010 / [ed] Ronnie Lundström, Umeå: Svensk förening för medicinsk teknik och fysik , 2010, p. 193-193Conference paper (Refereed)
  • 210. Jamshidi, Neema
    et al.
    Jonasch, Eric
    Zapala, Matthew
    Korn, Ronald L
    Brooks, James D
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Kuo, Michael D
    The radiogenomic risk score stratifies outcomes in a renal cell cancer phase 2 clinical trial2016In: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084, Vol. 26, no 8, p. 2798-2807Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To characterize a radiogenomic risk score (RRS), a previously defined biomarker, and to evaluate its potential for stratifying radiological progression-free survival (rPFS) in patients with metastatic renal cell carcinoma (mRCC) undergoing pre-surgical treatment with bevacizumab.

    METHODOLOGY: In this IRB-approved study, prospective imaging analysis of the RRS was performed on phase II clinical trial data of mRCC patients (n = 41) evaluating whether patient stratification according to the RRS resulted in groups more or less likely to have a rPFS to pre-surgical bevacizumab prior to cytoreductive nephrectomy. Survival times of RRS subgroups were analyzed using Kaplan-Meier survival analysis.

    RESULTS: The RRS is enriched in diverse molecular processes including drug response, stress response, protein kinase regulation, and signal transduction pathways (P < 0.05). The RRS successfully stratified rPFS to bevacizumab based on pre-treatment computed tomography imaging with a median progression-free survival of 6 versus >25 months (P = 0.005) and overall survival of 25 versus >37 months in the high and low RRS groups (P = 0.03), respectively. Conventional prognostic predictors including the Motzer and Heng criteria were not predictive in this cohort (P > 0.05).

    CONCLUSIONS: The RRS stratifies rPFS to bevacizumab in patients from a phase II clinical trial with mRCC undergoing cytoreductive nephrectomy and pre-surgical bevacizumab.

    KEY POINTS: • The RRS SOMA stratifies patient outcomes in a phase II clinical trial. • RRS stratifies subjects into prognostic groups in a discrete or continuous fashion. • RRS is biologically enriched in diverse processes including drug response programs.

  • 211. Jan, Michael
    et al.
    Bonn, Stephanie E.
    Sjölander, Arvid
    Wiklund, Fredrik
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Holmberg, Erik
    Grönberg, Henrik
    Bälter, Katarina
    The roles of stress and social support in prostate cancer mortality2016In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 50, no 1, p. 47-55Article in journal (Refereed)
    Abstract [en]

    Objective: This study aimed to evaluate the association between perceived stress, social support, disease progression and mortality in a nationwide population-based cohort of men with prostate cancer. Materials and methods: The study surveyed 4105 Swedish men treated for clinically localized prostate cancer regarding stress, grief, sleep habits and social support. Associations between these factors and mortality were assessed using multivariate Cox regression analysis. Results: Men with the highest levels of perceived stress had a statistically significantly increased rate of prostate cancer-specific mortality compared with men with low stress levels (hazard ratio 1.66, 95% confidence interval 1.05-2.63). Men with high stress levels also had a high frequency of grieving and sleep loss. They also had fewer people with whom to share their emotional problems and felt an inability to share most of their problems with partners, friends and family. Conclusions: This study contributes to the growing field of psychosocial quality of life research in men with prostate cancer. The findings show a significant association between prostate cancer-specific mortality and perceived stress in patients initially diagnosed with localized, non-metastatic prostate cancer. Significant associations between perceived stress and various psychosocial factors were also seen. The findings of this study could prove useful to target interventions to improve quality of life in men with prostate cancer.

  • 212. Jansson, K. Fredrik
    et al.
    Akre, Olof
    Garmo, Hans
    Bill-Axelson, Anna
    Adolfsson, Jan
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bratt, Ola
    Concordance of tumor differentiation among brothers with Prostate Cancer2012In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 62, no 4, p. 656-661Article in journal (Refereed)
    Abstract [en]

    Background: Genetic factors seem to be of greater importance in prostate cancer than in other forms of cancer. Studies have suggested familial concordance in survival, but the extent to which that is due to tumor characteristics is not known. Objective: We hypothesized that a brother of an index case with prostate cancer is at particularly increased risk of prostate cancer with the same tumor differentiation as the index case. Design, setting and participants: We identified 21 930 brothers of index cases with prostate cancer in the Prostate Cancer Data Base Sweden and followed them up for incidence of prostate cancer. Outcome measurements and statistical analysis: The relative risk of Gleason score-specific prostate cancer in the cohort of brothers was estimated by using the standardized incidence ratio (SIR) stratified by Gleason score of the index case. We estimated 95% confidence intervals (CIs) assuming a Poisson distribution. Results and limitations: Among brothers of index cases with Gleason score 8-10 cancer, the SIR was 2.53 (95% CI, 1.97-3.21) for a Gleason score 2-6 cancer and 4.00 (95% CI, 2.63-5.82) for a Gleason score 8-10 cancer. SIR for Gleason score 2-6 cancer among brothers decreased with time since the date of the index cases' diagnoses, whereas the risk of Gleason 8-10 cancer increased over time for brothers of index cases with Gleason 8-10 cancer (p for trend = 0.009). Conclusions: Brothers of men with high-grade prostate cancer are at particularly increased risk of high-grade prostate cancer. Likewise, there is a concordance of less malignant prostate cancers within families. These findings may have direct clinical relevance for counseling men with a family history of prostate cancer. (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved.

  • 213.
    Jansson Palmer, Erik
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Testicular cancer - a genealogical study of patients with testicular germ cell tumours in Västerbotten county between 2000-2015: A retrospective study2016Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 214. Jerlström, Tomas
    et al.
    Chen, Ruoqing
    Liedberg, Fredrik
    Andrén, Ove
    Ströck, Viveka
    Aljabery, Firas A S
    Hosseini, Abolfazl
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Malmström, Per-Uno
    Ullén, Anders
    Gårdmark, Truls
    Fall, Katja
    No increased risk of short-term complications after radical cystectomy for muscle-invasive bladder cancer among patients treated with preoperative chemotherapy: a nation-wide register-based study2019In: World journal of urology, ISSN 0724-4983, E-ISSN 1433-8726Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Preoperative chemotherapy is underused in conjunction with radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) due to concerns for complications and delay of surgery. Prospective data on short-term complications from population-based settings with frequent use of preoperative chemotherapy and standardised reporting of complications is lacking.

    METHODS: We identified 1,340 patients who underwent RC between 2011 and 2015 in Sweden due to MIBC according to the Swedish Cystectomy Register. These individuals were followed through linkages to several national registers. Propensity score adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for complications and death within 90 days of surgery, comparing patients receiving preoperative chemotherapy or not.

    RESULTS: Minimum two cycles of preoperative chemotherapy were given to 519 (39%) of the patients, who on average tended to be younger, have higher education, better physical status, and more advanced bladder cancer than patients not receiving chemotherapy. After adjusting for these and other parameters, there was no association between treatment with preoperative chemotherapy and short-term complications (OR 1.06 95% CI 0.82-1.39) or mortality (OR 0.75 95% CI 0.36-1.55). We observed a risk reduction for gastrointestinal complications among patients who received preoperative chemotherapy compared with those who did not (OR 0.49 95% CI 0.30-0.81).

    CONCLUSION: This nation-wide population-based observational study does not suggest that preoperative chemotherapy, in a setting with high utilisation of such treatment, is associated with an increased risk of short-term complications in MIBC patients treated with radical cystectomy.

  • 215. Jerlström, Tomas
    et al.
    Gårdmark, Truls
    Carringer, Malcolm
    Holmäng, Sten
    Liedberg, Fredrik
    Hosseini, Abolfazl
    Malmström, Per-Uno
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hagberg, Oskar
    Jahnson, Staffan
    Urinary bladder cancer treated with radical cystectomy: perioperative parameters and early complications prospectively registered in a national population-based database2014In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 48, no 4, p. 334-340Article in journal (Refereed)
    Abstract [en]

    Objective. Cystectomy combined with pelvic lymph-node dissection and urinary diversion entails high morbidity and mortality. Improvements are needed, and a first step is to collect information on the current situation. In 2011, this group took the initiative to start a population-based database in Sweden (population 9.5 million in 2011) with prospective registration of patients and complications until 90 days after cystectomy. This article reports findings from the first year of registration. Material and methods. Participation was voluntary, and data were reported by local urologists or research nurses. Perioperative parameters and early complications classified according to the modified Clavien system were registered, and selected variables of possible importance for complications were analysed by univariate and multivariate logistic regression. Results. During 2011, 285 (65%) of 435 cystectomies performed in Sweden were registered in the database, the majority reported by the seven academic centres. Median blood loss was 1000 ml, operating time 318 min, and length of hospital stay 15 days. Any complications were registered for 103 patients (36%). Clavien grades 1-2 and 3-5 were noted in 19% and 15%, respectively. Thirty-seven patients (13%) were reoperated on at least once. In logistic regression analysis elevated risk of complications was significantly associated with operating time exceeding 318 min in both univariate and multivariate analysis, and with age 76-89 years only in multivariate analysis. Conclusions. It was feasible to start a national population-based registry of radical cystectomies for bladder cancer. The evaluation of the first year shows an increased risk of complications in patients with longer operating time and higher age. The results agree with some previously published series but should be interpreted with caution considering the relatively low coverage, which is expected to be higher in the future.

  • 216. Jerlström, Tomas
    et al.
    Gårdmark, Truls
    Ströck, Viveka
    Aljabery, Firas A. -S.
    Hosseini, Abolfazl A.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ullén, Anders
    Malmström, Per-Uno
    Liedberg, Fredrik
    Jahnson, Staffan
    Carringer, Malcolm
    Significantly more downstaging in patients recieving preoperative (neoadjuvant and induction) chemotherapy prior to cystectomy for muscle-invasive bladder cancer2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, p. 34-35Article in journal (Other academic)
  • 217. Johansen, Dorthe
    et al.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lindkvist, Björn
    Björge, Tone
    Concin, Hans
    Almquist, Martin
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Engeland, Anders
    Ulmer, Hanno
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Selmer, Randi
    Nagel, Gabriele
    Tretli, Steinar
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Manjer, Jonas
    Metabolic factors and the risk of pancreatic cancer: a prospective analysis of almost 580,000 men and women in the Metabolic Syndrome and Cancer Project2010In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, no 9, p. 2307-2317Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of this study was to investigate the association between factors in metabolic syndrome (MetS; single and combined) and the risk of pancreatic cancer. METHODS: The Metabolic Syndrome and Cancer Project is a pooled cohort containing data on body mass index, blood pressure, and blood levels of glucose, cholesterol, and triglycerides. During follow-up, 862 individuals were diagnosed with pancreatic cancer. Cox proportional hazards analysis was used to calculate relative risks (RR) with 95% confidence intervals using the above-mentioned factors categorized into quintiles and transformed into z-scores. All z-scores were summarized and a second z-transformation creating a composite z-score for MetS was done. All risk estimates were calibrated to correct for a regression dilution bias. RESULTS: The trend over quintiles was positively associated with the risk of pancreatic cancer for mid-blood pressure (mid-BP) and glucose in men and for body mass index, mid-BP, and glucose in women. The z-score for the adjusted mid-BP (RR, 1.10; 1.01-1.20) and the calibrated z-score for glucose (RR, 1.37; 1.14-1.34) were positively associated with pancreatic cancer in men. In women, a positive association was found for calibrated z-scores for mid-BP (RR, 1.34; 1.08-1.66), for the calibrated z-score for glucose (RR, 1.98; 1.41-2.76), and for the composite z-score for MetS (RR, 1.58; 1.34-1.87). CONCLUSION: Our study adds further evidence to a possible link between abnormal glucose metabolism and risk of pancreatic cancer. IMPACT: To our knowledge, this is the first study on MetS and pancreatic cancer using prediagnostic measurements of the examined factors.

  • 218.
    Johansson, Anna
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Häggström Rudolfsson, Stina
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Halin, Sofia
    Pietras, Kristian
    Bergh, Anders
    Mast cell targeted therapy with imatinib mesylate or sodium cromoglycate: a novel approach to inhibit angiogenesis and prostate tumour growthManuscript (Other (popular science, discussion, etc.))
  • 219.
    Johansson, Anna
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Jones, Jonathan
    Umeå University, Faculty of Medicine, Radiation Sciences. Umeå University, Faculty of Medicine, Radiation Sciences, Diagnostic Radiology.
    Pietras, Kristian
    Kilter, Sigrid
    Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Skytt, Asa
    Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Rudolfsson, Stina Häggström
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    A stroma targeted therapy enhances castration effects in a transplantable rat prostate cancer model.2007In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 15, p. 1664-1676Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Castration results in a major involution of the normal prostate gland. This process is initiated by effects in the prostate stroma and vasculature. Castration-induced regression of androgen sensitive prostate tumors is however less prominent and hypothetically this could be related to a limited stromal/vascular response. We therefore used animal tumor models to explore the importance of stroma and vascular effects, and if castration effects could be enhanced by a simultaneous therapy targeting the tumor stroma. METHODS: Using rats with Dunning PAP and H tumors, stereological methods, immunohistochemistry, and Western blotting, we studied the tumor response 7 and 28 days after castration and after the addition of stroma targeted therapies. RESULTS: In the normal ventral prostate (VP) nuclear androgen receptors (AR) were rapidly downregulated after castration. In contrast, the Dunning tumors downregulated the AR in the cancerous epithelium, but not in the surrounding stroma. Vascular regulators such as the angiopoietins, tie 2, and PDGF-Rbeta were not decreased in the stroma after castration, as observed in the VP, creating an environment that prevents vascular involution. When a tumor stroma targeted therapy inhibiting the tie 2 receptor and the PDGF-Rbeta simultaneously was added to castration it resulted in a decreased vascular density, increased tumor cell apoptosis and decreased tumor growth compared to castration alone. CONCLUSIONS: The stroma in highly differentiated androgen sensitive Dunning tumors is apparently androgen insensitive. If this unresponsive stroma is targeted the effects of castration can be enhanced.

  • 220.
    Johansson, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rudolfsson, Stina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Halin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pietras, Kristian
    Jones, Jonathan
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Granfors, Torvald
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mast cells are novel independent prognostic markers in prostate cancer and represent a target for therapy2010In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 177, no 2, p. 1031-1041Article in journal (Refereed)
    Abstract [en]

    Mast cells affect growth in various human tumors, but their role in prostate cancer (PC) is unclear. Here, we identify mast cells as independent prognostic markers in PC using a large cohort of untreated PC patients with a long follow-up. By analyzing mast cells in different tissue compartments, our data indicate that intratumoral and peritumoral mast cells have anti- opposed to protumor properties. Intratumoral mast cells negatively regulate angiogenesis and tumor growth, whereas peritumoral mast cells stimulate the expansion of human prostate tumors. We also observed mast cell recruitment particularly to the peritumoral compartment in men during the formation of castrate-resistant prostate tumors. In our ortothopic rat model, mast cells accumulated in the peritumoral tissue where they enhanced angiogenesis and tumor growth. In line with this, prostate mast cells expressed high levels of the angiogenic factor FGF-2. Similar to the situation in men, mast cells infiltrated rat prostate tumors that relapsed after initially effective castration treatment, concurrent with a second wave of angiogenesis and an up-regulation of FGF-2. We conclude that mast cells are novel independent prognostic markers in PC and affect tumor progression in animals and patients. In addition, peritumoral mast cells provide FGF-2 to the tumor micro environment, which may contribute to their stimulating effect on angiogenesis.

  • 221.
    Johansson, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Rudolfsson, Stina Häggström
    Kilter, Sigrid
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Targeting castration-induced tumour hypoxia enhances the acute effects of castration therapy in a rat prostate cancer model2011In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 107, no 11, p. 1818-1824Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: •  To explore the effects of castration therapy, the standard treatment for advanced prostate cancer, in relation to tumour hypoxia and to elicit its importance for the short- and long-term therapeutic response.

    MATERIAL AND METHODS: •  We used the androgen-sensitive rat Dunning H prostate tumour model that transiently responds to castration treatment followed by a subsequent relapse, much like the scenario in human patients. •  Tumour tissues were analysed using stereological methods in intact, 1 and 7 days after castration therapy.

    RESULTS: •  Hypoxia was transiently up-regulated after castration therapy and correlated with the induction of tumour cell apoptosis. •  When castration therapy was combined with tirapazamine (TPZ), a drug that targets hypoxic cells and the vasculature, the effects on tumour cell apoptosis and tumour volume were enhanced in comparison to either castration or TPZ alone.

    CONCLUSION: •  The present study suggests that castration-induced tumour hypoxia is a novel target for therapy.

  • 222.
    Johansson, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Rudolfsson, Stina Häggström
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Altered levels of angiopoietin 1 and tie 2 are associated with androgen-regulated vascular regression and growth in the ventral prostate in adult mice and rats.2005In: Endocrinology, ISSN 0013-7227, Vol. 146, no 8, p. 3463-3470Article in journal (Refereed)
  • 223.
    Johansson, Ingegerd
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, M
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Validity of food frequency questionnaire estimated intakes of folate and other B vitamins in a region without folic acid fortification.2010In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 64, no 8, p. 905-913Article in journal (Refereed)
    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.

  • 224.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    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 University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Riboli, Elio
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. 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 study2008In: Cancer Epidemiol Biomarkers Prev, ISSN 1055-9965, Vol. 17, no 2, p. 279-285Article in journal (Refereed)
    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)

  • 225. Johansson, Mattias
    et al.
    Carreras-Torres, Robert
    Scelo, Ghislaine
    Purdue, Mark P.
    Mariosa, Daniela
    Muller, David C.
    Timpson, Nicolas J.
    Haycock, Philip C.
    Brown, Kevin M.
    Wang, Zhaoming
    Ye, Yuanqing
    Hofmann, Jonathan N.
    Foll, Matthieu
    Gaborieau, Valerie
    Machiela, Mitchell J.
    Colli, Leandro M.
    Li, Peng
    Garnier, Jean-Guillaume
    Blanche, Helene
    Boland, Anne
    Burdette, Laurie
    Prokhortchouk, Egor
    Skryabin, Konstantin G.
    Yeager, Meredith
    Radojevic-Skodric, Sanja
    Ognjanovic, Simona
    Foretova, Lenka
    Holcatova, Ivana
    Janout, Vladimir
    Mates, Dana
    Mukeriya, Anush
    Rascu, Stefan
    Zaridze, David
    Bencko, Vladimir
    Cybulski, Cezary
    Fabianova, Eleonora
    Jinga, Viorel
    Lissowska, Jolanta
    Lubinski, Jan
    Navratilova, Marie
    Rudnai, Peter
    Benhamou, Simone
    Cancel-Tassin, Geraldine
    Cussenot, Olivier
    Weiderpass, Elisabete
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tumkur Sitaram, Raviprakash
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Sweden.
    Bruinsma, Fiona
    Jordan, Susan J
    Severi, Gianluca
    Winship, Ingrid
    Hveem, Kristian
    Vatten, Lars J
    Fletcher, Tony
    Larsson, Susanna C
    Wolk, Alicja
    Banks, Rosamonde E
    Selby, Peter J
    Easton, Douglas F
    Andreotti, Gabriella
    Beane Freeman, Laura E
    Koutros, Stella
    Männistö, Satu
    Weinstein, Stephanie
    Clark, Peter E
    Edwards, Todd L
    Lipworth, Loren
    Gapstur, Susan M
    Stevens, Victoria L
    Carol, Hallie
    Freedman, Matthew L
    Pomerantz, Mark M
    Cho, Eunyoung
    Wilson, Kathryn M
    Gaziano, J Michael
    Sesso, Howard D
    Freedman, Neal D
    Parker, Alexander S
    Eckel-Passow, Jeanette E
    Huang, Wen-Yi
    Kahnoski, Richard J
    Lane, Brian R
    Noyes, Sabrina L
    Petillo, David
    Teh, Bin Tean
    Peters, Ulrike
    White, Emily
    Anderson, Garnet L
    Johnson, Lisa
    Luo, Juhua
    Buring, Julie
    Lee, I-Min
    Chow, Wong-Ho
    Moore, Lee E
    Eisen, Timothy
    Henrion, Marc
    Larkin, James
    Barman, Poulami
    Leibovich, Bradley C
    Choueiri, Toni K
    Lathrop, G Mark
    Deleuze, Jean-Francois
    Gunter, Marc
    McKay, James D
    Wu, Xifeng
    Houlston, Richard S
    Chanock, Stephen J
    Relton, Caroline
    Richards, J Brent
    Martin, Richard M
    Davey Smith, George
    Brennan, Paul
    The influence of obesity-related factors in the etiology of renal cell carcinoma: A mendelian randomization study2019In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 16, no 1, article id e1002724Article in journal (Refereed)
    Abstract [en]

    Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.

    Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.

    Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

  • 226.
    Johansson, Mattias
    et al.
    International Agency for Research on Cancer, Lyon, France.
    Fanidi, Anouar
    Muller, David C.
    Bassett, Julie K.
    Midttun, Oivind
    Vollset, Stein Emil
    Travis, Ruth C.
    Palli, Domenico
    Mattiello, Amalia
    Sieri, Sabina
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weiderpass, Elisabete
    Skeie, Guri
    Gonzalez, Carlos A.
    Dorronsoro, Miren
    Peeters, Petra H.
    Bueno-de-Mesquita, H. B(as).
    Ros, Martine M.
    Ruault, Marie-Christine Boutron
    Fagherazzi, Guy
    Clavel, Francoise
    Sanchez, Maria-Jose
    Barricarte Gurrea, Aurelio
    Navarro, Carmen
    Ramon Quiros, J.
    Overvad, Kim
    Tjonneland, Anne
    Aleksandrova, Krassimira
    Vineis, Paolo
    Gunter, Marc J.
    Kaaks, Rudolf
    Giles, Graham
    Relton, Caroline
    Riboli, Elio
    Boeing, Heiner
    Ueland, Per Magne
    Severi, Gianluca
    Brennan, Paul
    Circulating Biomarkers of One-Carbon Metabolism in Relation to Renal Cell Carcinoma Incidence and Survival2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 12, article id dju327Article in journal (Refereed)
    Abstract [en]

    Background: The etiology of renal cell carcinoma (RCC) is only partially understood, but a metabolic component appears likely. We investigated biomarkers of one-carbon metabolism and RCC onset and survival. Methods: The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 385 747 participants with blood samples between 1992 and 2000, and this analysis included 556 RCC case-control pairs. A subsequent replication study included 144 case-control pairs nested within the Melbourne Collaborative Cohort Study (MCCS). Plasma concentrations of vitamin B2, vitamin B6, folate, vitamin B12, methionine and homocysteine were measured in prediagnostic samples and evaluated with respect to RCC risk using conditional and unconditional logistic regression models, and to all-cause mortality in RCC cases using Cox regression models. All statistical tests were two-sided. Results: EPIC participants with higher plasma concentrations of vitamin B6 had lower risk of RCC, the odds ratio comparing the 4th and 1st quartiles (OR4vs1) being 0.40 95% confidence interval [CI] = 0.28 to 0.57, P-trend < .001. We found similar results after adjusting for potential confounders (adjusted P-trend < .001). In survival analysis, the hazard ratio for all-cause mortality in RCC cases when comparing the 4th and 1st quartiles (HR4vs1) of vitamin B6 was 0.57 (95% CI = 0.37 to 0.87, P-trend < .001). Subsequent replication of these associations within the MCCS yielded very similar results for both RCC risk (OR4vs1 = 0.47, 95% CI = 0.23 to 0.99, P-trend = .07) and all-cause mortality (HR4vs1 = 0.56, 95% CI = 0.27 to 1.17, P-trend = .02). No association was evident for the other measured biomarkers. Conclusion: Study participants with higher circulating concentrations of vitamin B6 had lower risk of RCC and improved survival following diagnosis in two independent cohorts.

  • 227.
    Johansson, Mattias
    et al.
    International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Holmström, Benny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hinchliffe, Sally R
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenman, Ulf-Håkan
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wiklund, Fredrik
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Combining 33 genetic variants with prostate-specific antigen for prediction of prostate cancer: longitudinal study2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 130, no 1, p. 129-137Article in journal (Refereed)
    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.

  • 228.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    McKay, James D.
    Rinaldi, Sabina
    Wiklund, Fredrik
    Adami, Hans-Olov
    Grönberg, Henrik
    Kaaks, Rudolf
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Genetic and plasma variation of insuline-like growth factor binding proteins in relation to prostate cancer incidence and survivalManuscript (Other (popular science, discussion, etc.))
  • 229.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. 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 University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Genetic and plasma variation of insulin-like growth factor binding proteins in relation to prostate cancer incidence and survival2009In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 69, no 12, p. 1281-1291Article in journal (Refereed)
    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.

  • 230.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    McKay, James D
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Canzian, Federico
    Boillot, Catherine
    Wiklund, Fredrik
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Adami, Hans-Olov
    Bälter, Katarina
    Grönberg, Henrik
    Kaaks, Rudolf
    Comprehensive evaluation of genetic variation in the IGF1 gene and risk of prostate cancer2007In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 120, no 3, p. 539-542Article in journal (Refereed)
    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.

  • 231.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer (IARC), Lyon, France.
    McKay, James D
    Wiklund, Fredrik
    Rinaldi, Sabina
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Bälter, Katarina
    Adami, Hans-Olov
    Grönberg, Henrik
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    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 risk2009In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, no 5, p. 1644-1650Article in journal (Refereed)
    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).

  • 232.
    Johansson, Mattias
    et al.
    International Agency for Research on Cancer, Lyon, France.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York.
    Guidelines are too important to be left to clinical experts2012In: CMJA. Canadian Medical Association Journal. Onlineutg. Med tittel: ECMAJ. ISSN 1488-2329, ISSN 0820-3946, E-ISSN 1488-2329, Vol. 184, no 2, p. 159-160Article in journal (Refereed)
  • 233.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Wiklund, Fredrik
    Adami, Hans-Olov
    Bälter, Katarina
    Grönberg, Henrik
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    The MTHFR 677C --> T polymorphism and risk of prostate cancer: results from the CAPS study2007In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 18, no 10, p. 1169-1174Article in journal (Refereed)
    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.

  • 234.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Vollset, Stein Emil
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Key, Tim
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Ueland, Per M
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prospective investigation of one-carbon metabolism in relation to prostate cancer risk: results from the NSHDC studyManuscript (Other academic)
  • 235.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Vollset, Stein Emil
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Key, Tim
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Midttun, Øivind
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Ueland, Per M
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    One-carbon metabolism and prostate cancer risk: prospective investigation of seven circulating B vitamins and metabolites2009In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, no 5, p. 1538-1543Article in journal (Refereed)
    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).

  • 236.
    Jonsson, Björn-Anders
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Adami, Hans-Olov
    Hägglund, Maria
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Göransson, Ingela
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Wiklund, Fredrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    -160C/A polymorphism in the E-cadherin gene promoter and risk of hereditary, familial and sporadic prostate cancer2004In: Int J Cancer, ISSN 0020-7136, Vol. 109, no 3, p. 348-352Article in journal (Refereed)
  • 237.
    Jonsson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Holmström, Benny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Duffy, Stephen W
    Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Uptake of prostate-specific antigen testing for early prostate cancer detection in Sweden2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 129, no 8, p. 1881-1888Article in journal (Refereed)
    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.

  • 238. Jonsson, L.
    et al.
    Sandin, R.
    Lindgren, P.
    Kowalski, J.
    Wahlgren, T.
    Harmenberg, U.
    Sandstrom, P.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Jakobsson, M.
    Survival and costs in metastatic renal cell carcinoma: A comparison of mrcc treatment pre- and post tyrosine kinase inhibitor (tki) introduction using retrospective registry data2012In: Value in Health, ISSN 1098-3015, E-ISSN 1524-4733, Vol. 15, no 7, p. A422-A422Article in journal (Other academic)
  • 239.
    Jonsson, Pär
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Chorell, Elin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Constrained randomization and multivariate effect projections improve information extraction and biomarker pattern discovery in metabolomics studies involving dependent samples2015In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 11, no 6, p. 1667-1678Article in journal (Refereed)
    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.

  • 240.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Adamo, Hani
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Granfors, Torvald
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Laurent, Anna Engström
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Prostate cancer increases hyaluronan in surrounding nonmalignant stroma, and this response is associated with tumor growth and an unfavorable outcome2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 179, no 4, p. 1961-1968Article in journal (Refereed)
    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.

  • 241.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Damber, Jan-Erik
    Welen, Karin
    AR-V7 expression in circulating tumor cells as a potential prognostic marker in metastatic hormone-sensitive prostate cancer2019In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226XArticle in journal (Refereed)
    Abstract [en]

    Treatment of patients with metastatic hormone-sensitive (mHSPC) depends on androgen deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling. Although the majority of patients respond well to ADT, castration-resistant prostate cancer (CRPC) inevitably develops. Addition of docetaxel, abiraterone acetate, or enzalutamide, to ADT significantly increases cancer-specific survival (CSS) [1–3]. The drawback is that not all patients respond to the therapies equally well and biomarkers to enable personalized treatment are urgently needed. Prostate-specific antigen (PSA) is a powerful biomarker for diagnosis of PC, but there are no validated biomarkers to prognosticate prognosis, let alone prediction of therapy response, of metastatic disease prior to ADT. Mechanisms important for resistance to ADT and development of CRPC include increased AR levels, constitutively active AR variants such as AR-V7, and intratumoral steroid production to sustain AR signaling despite castrate levels of steroids [4–7]. Although these changes mainly have been reported in CRPC, inherent expression could indicate predisposition for CRPC and poor response to ADT and other therapies targeting AR signaling.

    To identify patients with optimal therapeutic benefit from drugs with conceptually different targets, their metastatic disease needs to be characterized. Given the difficulty to access metastatic tissue for analysis, circulating tumor cells (CTCs) have a potential to provide phenotypic information of the tumor, in addition to the prognostic value associated with their abundance [8]. We have demonstrated that gene expression in circulating tumor cells (CTCs) reflects the phenotype of prostate cancer metastases [9]. It has also been suggested that detection of AR-V7 mRNA and AR-V7 localization to the nucleus in CTCs predict poor response to drugs targeting the androgen signaling axis, such as abiraterone acetate and enzalutamide, in patients with CRPC [10,11]. Although the biomarker potential of CTCs mostly has been evaluated in CRPC [10,12,13], two studies have described the presence of CTCs as a prognostic marker for overall survival, progression-free survival (PFS), and time to CRPC also in mHSPC [14,15]. In addition, we previously showed that detection of EGFR mRNA in CTCs is a negative prognostic biomarker for CSS in mHSPC [16].

    The present study investigates expression of genes associated with development of CRPC [17] for their prognostic value in mHSPC response to ADT. We showed that mRNA for the steroidogenic enzymes AKR1C3 and CYP17A1 can be detected in CTCs in high volume mHSPC, and that the detection of mRNA for AR-V7 in CTCs before ADT has prognostic value.

  • 242.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikstrom, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Egevad, Lars
    Granfors, Torvald
    Karlberg, Lars
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Low endoglin vascular density and Ki67 index in Gleason score 6 tumours may identify prostate cancer patients suitable for surveillance2012In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 46, no 4, p. 247-257Article in journal (Refereed)
    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.

  • 243.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    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 University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Low endoglin vascular density and Ki67 index in Gleason score 6 tumours may identify prostate cancer patients suitable for surveillanceArticle in journal (Other academic)
    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.

  • 244.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Granfors, Torvald
    Egevad, Lars
    Karlberg, Lars
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    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 treatment2005In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 48, no 4, p. 577-583Article in journal (Refereed)
    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.

  • 245. Kaaks, Rudolf
    et al.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Obesity, endogenous hormone metabolism, and prostate cancer risk: a conundrum of "highs" and "lows".2010In: Cancer prevention research (Philadelphia, Pa.), ISSN 1940-6215, Vol. 3, no 3, p. 259-262Article in journal (Refereed)
    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.

  • 246. Kaaks, Rudolf
    et al.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Villar, Stéphanie
    Poetsch, Anna R
    Dossus, Laure
    Nieters, Alexandra
    Riboli, Elio
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    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 Cohort2009In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 69, no 13, p. 5400-5405Article in journal (Refereed)
    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].

  • 247. 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 University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. 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).2004In: International Journal of Cancer, ISSN 0020-7136, Vol. 109, no 1, p. 119-24Article in journal (Refereed)
  • 248. 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 University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    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.2007In: American Journal of Clinical Nutrition, ISSN 0002-9165, Vol. 86, no 3, p. 672-81Article in journal (Refereed)
  • 249.
    Kirrander, Peter
    et al.
    Örebro, Sweden.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Friedrich, Bengt
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lambe, Mats
    Uppsala, Sweden; Stockholm, Sweden.
    Håkansson, Ulf
    Malmö, Sweden.
    The Swedish National Penile Cancer Register: Incidence, Tumour Characteristics, Management and Survival2016In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 117, no 2, p. 287-292Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:  To assess penile cancer incidence, stage distribution, adherence to guidelines, and prognostic factors in a population-based setting.

    PATIENTS AND METHODS:  The population-based Swedish National Penile Cancer Register (NPECR) contains detailed information on tumour characteristics and management patterns. ● A total of 1678 men with primary squamous cell carcinoma of the penis identified in the NPECR between 2000 and 2012 were included in the study. 

    RESULTS:  The mean age-adjusted incidence of penile cancer was 2.1/100,000 men, remaining virtually unchanged during the study period. At diagnosis, 14% and 2% were clinically N+ and M+, respectively. Most patients were staged pTis (34%), pT2 (19%), or pT1 (18%), whereas stage was unavailable in 18%. Organ-preserving treatment was used in 71% of Tis-T1 tumours. In cN0 and ≥pT1G2 patients, 50% underwent lymph node staging, while 74% of cN1-3 patients underwent lymph node dissection. The overall 5-year relative survival was 82%. Men aged ≥40 years and those with pT2-3, G2-3 and N+ tumours had worse outcome.

    CONCLUSION: The incidence of penile cancer in Sweden is stable. Most men presented with localised disease, and the proportion of non-invasive tumours was high. During the period under study, adherence to guidelines was suboptimal. The overall 5-year relative survival was 82%. Older age, increasing tumour stage and grade, and increasing lymph node stage were associated with poorer survival.

  • 250. Klein, Robert J
    et al.
    Halldén, Christer
    Cronin, Angel M
    Ploner, Alexander
    Wiklund, Fredrik
    Bjartell, Anders S
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    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 cancer2010In: Cancer Prevention Research, ISSN 1940-6207, E-ISSN 1940-6215, Vol. 3, no 5, p. 611-619Article in journal (Refereed)
    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.

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