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  • 301.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bensalah, Karim
    Canfield, Steven
    Dabestani, Saeed
    Hofmann, Fabian
    Hora, Milan
    Kuczyk, Markus A.
    Lam, Thomas
    Marconi, Lorenzo
    Merseburger, Axel S.
    Mulders, Peter
    Powles, Thomas
    Staehler, Michael
    Volpe, Alessandro
    Bex, Axel
    EAU Guidelines on Renal Cell Carcinoma: 2014 Update2015In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 67, no 5, p. 913-924Article in journal (Refereed)
    Abstract [en]

    Context: The European Association of Urology Guideline Panel for Renal Cell Carcinoma (RCC) has prepared evidence-based guidelines and recommendations for RCC management. Objectives: To provide an update of the 2010 RCC guideline based on a standardised methodology that is robust, transparent, reproducible, and reliable. Evidence acquisition: For the 2014 update, the panel prioritised the following topics: percutaneous biopsy of renal masses, treatment of localised RCC (including surgical and nonsurgical management), lymph node dissection, management of venous thrombus, systemic therapy, and local treatment of metastases, for which evidence synthesis was undertaken based on systematic reviews adhering to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Relevant databases (Medline, Cochrane Library, trial registries, conference proceedings) were searched (January 2000 to November 2013) including randomised controlled trials (RCTs) and retrospective or controlled studies with a comparator arm. Risk of bias (RoB) assessment and qualitative and quantitative synthesis of the evidence were performed. The remaining sections of the document were updated following a structured literature assessment. Evidence synthesis: All chapters of the RCC guideline were updated. For the various systematic reviews, the search identified a total of 10 862 articles. A total of 151 studies reporting on 78 792 patients were eligible for inclusion; where applicable, data from RCTs were included and meta-analyses were performed. For RCTs, there was low RoB across studies; however, clinical and methodological heterogeneity prevented data pooling for most studies. The majority of studies included were retrospective with matched or unmatched cohorts based on single or multi-institutional data or national registries. The exception was for systemic treatment of metastatic RCC, in which several RCTs have been performed, resulting in recommendations based on higher levels of evidence. Conclusions: The 2014 guideline has been updated by a multidisciplinary panel using the highest methodological standards, and provides the best and most reliable contemporary evidence base for RCC management. Patient summary: The European Association of Urology Guideline Panel for Renal Cell Carcinoma has thoroughly evaluated available research data on kidney cancer to establish international standards for the care of kidney cancer patients. 

  • 302.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Campbell, Steven C.
    Section of Urologic Oncology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.
    Cho, Han Yong
    Department of Urology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Korea.
    Jacqmin, Didier
    Service de Chirurgie Urologique, 1 Place de l’Hôpital, Strasbourg, France.
    Lee, Jung Eun
    Department of Food and Nutrition, Sookmyung Women's University, Seoul, Korea.
    Weikert, Steffen
    Department of Urology, Charité – University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
    Kiemeney, Lambertus A.
    Department of Epidemiology, Biostatistics and Health Technology Assessment, Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
    The epidemiology of renal cell carcinoma2011In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 60, no 4, p. 615-621Article, review/survey (Refereed)
    Abstract [en]

    Context: Kidney cancer is among the 10 most frequently occurring cancers in Western communities. Globally, about 270 000 cases of kidney cancer are diagnosed yearly and 116 000 people die from the disease. Approximately 90% of all kidney cancers are renal cell carcinomas (RCC). Objective: The causes of RCC are not completely known. We have reviewed known aetiologic factors.

    Evidence acquisition: The data provided in the current review are based on a thorough review of available original and review articles on RCC epidemiology with a systemic literature search using Medline.

    Evidence synthesis: Smoking, overweight and obesity, and germline mutations in specific genes are established risk factors for RCC. Hypertension and advanced kidney disease, which makes dialysis necessary, also increase RCC risk. Specific dietary habits and occupational exposure to specific carcinogens are suspected risk factors, but results in the literature are inconclusive. Alcohol consumption seems to have a protective effect for reasons yet unknown. Hardly any information is available for some factors that may have a high a priori role in the causation of RCC, such as salt consumption.

    Conclusions: Large collaborative studies with uniform data collection seem to be necessary to elucidate a complete list of established risk factors of RCC. This is necessary to make successful prevention possible for a disease that is diagnosed frequently in a stage where curative treatment is not possible anymore.

  • 303.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Campbell, Steven C.
    Choi, Han Yong
    Jacqmin, Didier
    Lee, Jung Eun
    Weikert, Steffen
    Kiemeney, Lambertus A.
    Corrigendum to "The Epidemiology of Renal Cell Carcinoma" (vol 60, pg 615, 2011)2011In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 60, no 6, p. 1317-1317Article in journal (Refereed)
  • 304.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Cowan, Nigel C
    Hanbury, Damian C
    Hora, Milan
    Kuczyk, Markus A
    Merseburger, Axel S
    Patard, Jean-Jacques
    Mulders, Peter F A
    Sinescu, Ioanel C
    EAU guidelines on renal cell carcinoma: the 2010 update2010In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 58, no 3, p. 398-406Article in journal (Refereed)
    Abstract [en]

    Context and objectives

    The European Association of Urology Guideline Group for renal cell carcinoma (RCC) has prepared these guidelines to help clinicians assess the current evidence-based management of RCC and to incorporate the present recommendations into daily clinical practice.

    Evidence acquisition

    The recommendations provided in the current updated guidelines are based on a thorough review of available RCC guidelines and review articles combined with a systematic literature search using Medline and the Cochrane Central Register of Controlled Trials.

    Evidence synthesis

    A number of recent prospective randomised studies concerning RCC are now available with a high level of evidence, whereas earlier publications were based on retrospective analyses, including some larger multicentre validation studies, meta-analyses, and well-designed controlled studies.

    Conclusions

    These guidelines contain information for the treatment of an individual patient according to a current standardised general approach. Updated recommendations concerning diagnosis, treatment, and follow-up can improve the clinical handling of patients with RCC.

    Take Home Message

    This review of the 2010 European Association of Urology renal cell carcinoma guidelines is intended to help clinicians access knowledge of current evidence-based management according to a standardised general approach. Structured literature searches were carried out in different databases of systematic reviews and clinical trials. Grade of recommendation was assigned based on the underlying evidence.

  • 305.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Gudmundsson, Eirikur
    Christensen, Stina
    Lundstam, Sven
    Practice patterns for the surgical treatment of T1 renal cell carcinoma: a nationwide population-based register study2014In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 48, no 5, p. 445-452Article in journal (Refereed)
    Abstract [en]

    Objective. Treatment of renal cell carcinoma (RCC) with radical nephrectomy (RN) induces chronic kidney disease more frequently compared with nephron-sparing surgery (NSS), which may have an impact on overall survival. Thus, NSS is recommended for RCCs up to 7 cm (T1). The aim of this study was to determine the extent to which these recommendations are implemented in clinical practice. Material and methods. Data were extracted from the Swedish National Kidney Cancer Register, a population-based register covering 98% of all RCCs in Sweden. In total, 3158 patients (1892 men, 1266 women) were primarily diagnosed with cT1N0M0 and treated surgically during 2005-2011. The administered treatments were evaluated between different hospitals as well as between the 21 independent healthcare counties. Results. In all, 742 patients were treated with NSS, 2339 with RN and 77 with minimally invasive ablative treatments. For cT1a RCC, patients treated with NSS increased from 22% in 2005 to 53% in 2011, and for cT1b from 2% to 10%. Nephron-sparing treatments for cT1a RCC were performed in 62% in university hospitals, 34% in intermediate- and 11% in low-volume hospitals. There was significant (p < 0.001) variation (31-67%) between the university hospitals and also for patient care in the 21 different counties (16-78%). There was an increased relative survival after NSS for T1a patients compared with RN. The register design by itself indicates limitations using data gathered from all Swedish hospitals. Conclusions. NSS was underutilized in many hospitals and a patient's chance of being offered NSS varied according to their place of residence. Patients with cT1a RCC treated with NSS had a significantly better relative survival than those treated with RN.

  • 306.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Guomundsson, Eirikur
    Hellborg, Henrik
    Erikson, Stina
    Lundstam, Sven
    Reply from Authors re: Eric C. Umbreit, R. Houston Thompson. Metastatic Potential of the Small Renal Mass: Why Can't We Agree? Eur Urol 2011;60:983-52011In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 60, no 5, p. 985-986Article in journal (Refereed)
  • 307.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Hanbury, D C
    Kuczyk, M A
    Merseburger, A S
    Mulders, P F A
    Patard, J-J
    Sinescu, I C
    Guidelines on Renal Cell Carcinoma2007In: European Association of Urology Guidelines, European Association of Urology , 2007, p. 1-28Chapter in book (Other academic)
  • 308.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Hanbury, D C
    Kuczyk, M A
    Merseburger, A S
    Mulders, P F A
    Patard, J-J
    Sinescu, I C
    Guidelines on Renal Cell Carcinoma2006In: European Association of Urology Guidelines, European Association of Urology , 2006, p. 1-26Chapter in book (Other academic)
  • 309.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Hanbury, D C
    Kuczyk, M A
    Mulders, P F A
    Sinescu, I C
    Reply to Guiseppe Di Lorenzo`s Letter to the Editor re: B Ljungberg, DC Hanbury, MA Kuczyk, AS Merseburg, PFA Mulders, J-J Patard, I Sinescu. Renal Cell Carcinoma Guideline. Eur Urol 2007;51:1502-102007In: European Urology, ISSN 0302-2838, Vol. 52, p. 928-Article, book review (Refereed)
  • 310.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Hanbury, Damian C
    Kuczyk, Marcus A
    Merseburger, Axel S
    Mulders, Peter F A
    Patard, Jean-Jacques
    Sinescu, Ioanel C
    Renal cell carcinoma guideline.2007In: Eur Urol, ISSN 0302-2838, Vol. 51, no 6, p. 1502-10Article in journal (Refereed)
  • 311.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Hanbury, Damian C
    Kuczyk, Marcus A
    Merseburger, Axel S
    Mulders, Peter FA
    Patard, Jean-Jacques
    Sinescu, Ioanel C
    Reply to Giuseppe Di Lorenzo's Letter to the Editor. re: Börje Ljungberg, Damian C Hanbury, Marcus A Kuczyk, Axel S Merseburger, Peter FA Mulders, Jean-Jaques Patard and Ioanel Sinescu. Renal cell Carcinoma Guideline2007In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 52, p. 928-928Article in journal (Refereed)
  • 312.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hedin, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lundstam, Sven
    Warnolf, Asa
    Forsberg, Annika Mandahl
    Hjelle, Karin M.
    Stief, Christian G.
    Borlinghaus, Claudia
    Beisland, Christian
    Staehler, Michael
    Nephron Sparing Surgery Associated With Better Survival Than Radical Nephrectomy in Patients Treated for Unforeseen Benign Renal Tumors2016In: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 93, p. 117-121Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate the role of the surgical technique used for the treatment of benign renal tumors, with regard to renal function and overall survival (OS) in patients without cancer-related mortality.

    Patients and methods: The study included 506 patients, mean age of 63.3 years, with histologically proven benign renal lesions originating from 5 European centers. Retrospective data from each hospital were retrieved and merged into a common database for analyses. OS, American Society of Anesthesiology score, and renal functions were measured in relation to surgical technique. The Mann-Witney U-test, the paired t-test, and Cox's multivariate analysis were used.

    Results: Patients treated with radical nephrectomy had significantly reduced renal function postoperatively compared with nephron sparing surgery (NSS). OS was significantly reduced after radical nephrectomy compared with NSS (P = .012), a survival difference that remained significant [hazard ratio (HR) 0.042, 95% confidence interval (CI) 0.221-0.972, P = .042] in multivariate analysis, together with age at diagnosis (HR 1.065, 95% CI 1.026-1.106, P = .001) and American Society of Anesthesiology score (HR 2.361, 95% CI 1.261-4.419, P = .007). Also renal function assessed by estimated glomerular filtration rate significantly correlated to survival in univariate analysis, but did not remain independent after multivariate analysis. Oncocytoma was the most frequent benign lesion, followed by angiomyolipoma.

    Conclusion: The present study in patients with benign renal tumors shows that the remaining renal function and OS correspond to the choice of surgical procedure. Our results support the recommendation to perform NSS whenever possible when surgery is performed for patients with renal masses. The limitations of the study are the retrospective design and the selection bias for the surgical approach.

  • 313.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hedin, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lundstam, Sven
    Warnolf, Asa
    Forsberg, Annika Mandahl
    Hjelle, Karin M.
    Stief, Christian G.
    Borlinghaus, Claudia
    Beisland, Christian
    Staehler, Michael
    Untitled2016In: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 93, p. 122-123Article in journal (Other academic)
  • 314.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Jacobsen, Jan
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Häggström Rudolfsson, Stina
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Lindh, Gudrun
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Different vascular endothelial growth factor (VEGF), VEGF-receptor 1 and -2 mRNA expression profiles between clear cell and papillary renal cell carcinoma.2006In: BJU Int, ISSN 1464-4096, Vol. 98, no 3, p. 661-667Article in journal (Refereed)
  • 315.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Jacobsen, Jan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Häggström-Rudolfssson, Stina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lindh, Gudrun
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Tumour vascular endothelial growth factor (VEGF) mRNA in relation to serum VEGF protein levels and tumour progression in human renal cell carcinoma2003In: Urological research, ISSN 0300-5623, E-ISSN 1434-0879, Vol. 31, no 5, p. 335-40Article in journal (Refereed)
    Abstract [en]

    Angiogenesis is gaining interest because of its importance in tumour growth and metastasis. Renal cell carcinoma (RCC) is known to be a well-vascularized tumour. The aim of this study was to evaluate the expression of VEGF mRNA and receptor flt-1 mRNA (VEGF R1) in a clinical material of RCCs compared with clinicopathological variables and serum VEGF levels. Total RNA was extracted from snap-frozen tumour tissue obtained from 61 patients. Expression of mRNA for VEGF121, VEGF165 and flt-1 were analysed using quantitative RT-PCR. Relative VEGF mRNA levels, corrected for corresponding cyclophilin value, were related to stage, grade, RCC type and survival time. Serum VEGF165 protein was analysed using a quantitative ELISA. Papillary RCC had significantly lower VEGF121 and flt-1 mRNA levels compared with conventional RCC (p=0.001). VEGF121 mRNA levels were significantly lower in locally advanced tumours in relation to tumours limited to the kidney and those with metastatic disease (p=0.047 and p=0.036). This statistical difference disappeared when only conventional RCCs were evaluated. No association was found between VEGF mRNA levels and nuclear grade. Patients with lower VEGF121 mRNA levels had significantly longer survival time compared with those with higher levels (when adjusted to stage, p=0.0097, log rank test). There was an inverse relation between VEGF165 mRNA and serum VEGF165 levels. The trend to lower VEGF121 mRNA levels in locally advanced RCC indicate that angiogenic activity and degradation might be up-regulated in tumours with a high ability to invade. The association with tumour progression shows that VEGF is a promising angiogenic factor especially important in conventional RCCs. VEGF expression might possibly be of help to identify RCCs susceptible for anti-angiogenic therapies.

  • 316.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Thurm, Mascha
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Kröger Dahlin, Britt-Inger
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Winsö, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    A randomized controlled study of spinal analgesia show improved surgical outcome after open nephrectomy for renal cell carcinoma as compared with epidural analgesia2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, p. 47-47Article in journal (Other academic)
  • 317. Loeb, Stacy
    et al.
    Berglund, Anders
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Population Based Study of Use and Determinants of Active Surveillance and Watchful Waiting for Low and Intermediate Risk Prostate Cancer2013In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 190, no 5, p. 1742-1749Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 318. Loeb, Stacy
    et al.
    Drevin, Linda
    Robinson, David
    Holmberg, Erik
    Carlsson, Sigrid
    Lambe, Mats
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Risk of localized and advanced prostate cancer among immigrants versus native-born Swedish men: a nation-wide population-based study2013In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 24, no 2, p. 383-390Article in journal (Refereed)
    Abstract [en]

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

  • 319. Loeb, Stacy
    et al.
    Folkvaljon, Yasin
    Makarov, Danil V.
    Bratt, Ola
    Bill-Axelson, Anna
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Five-year Nationwide Follow-up Study of Active Surveillance for Prostate Cancer2015In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 67, no 2, p. 233-238Article in journal (Refereed)
    Abstract [en]

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

  • 320. Loeb, Stacy
    et al.
    Folkvaljon, Yasin
    Robinson, David
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Schlomm, Thorsten
    Garmo, Hans
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Uppsala University Hospital, Uppsala, Sweden.
    Phosphodiesterase Type 5 Inhibitor Use and Disease Recurrence After Prostate Cancer Treatment2016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 70, no 5, p. 824-828Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

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

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

  • 321. Loeb, Stacy
    et al.
    Folkvaljon, Yasin
    Robinson, David
    Schlomm, Thorsten
    Garmo, Hans
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Phosphodiesterase type 5 inhibitors (PDE5i) and prostate cancer recurrence2016In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 34, no 2Article in journal (Other academic)
  • 322. Loeb, Stacy
    et al.
    Lambe, Mats
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Uppsala University Hospital, Uppsala, Sweden.
    Re: Editorial Comment on Use of Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction and Risk of Malignant Melanoma2016In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 195, no 4, p. 1172-1173Article in journal (Refereed)
  • 323.
    Loeb, Stacy
    et al.
    New York, NY, USA.
    Schlomm, Thorsten
    Hamburg, Germany.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Associations Do Not Equal Causation: clinical Relevance of Statistical Associations of Phosphodiesterase Type 5 Inhibitors with Prostate Cancer Progression and Melanoma2015In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 68, no 5, p. 754-755Article in journal (Other academic)
  • 324. Loeb, Stacy
    et al.
    Ventimiglia, Eugenio
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Division of Experimental Oncology, Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy; Universita Vita-Salute San Raffaele, Milan, Italy.
    Salonia, Andrea
    Folkvaljon, Yasin
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden .
    Meta-Analysis of the Association Between Phosphodiesterase Inhibitors (PDE5Is) and Risk of Melanoma2017In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 109, no 8, article id djx086Article in journal (Refereed)
    Abstract [en]

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

  • 325.
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Endogenous hormones in the etiology of ovarian and endometrial cancers2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The main purpose of this thesis was to examine the relationship of pre-diagnostic circulating levels of sex-steroids (androgens and estrogens), sex hormone binding globuline (SHBG), insulin-like growth factor-I (IGF-I), IGF binding proteins (BP) and C-peptide (as a marker of pancreatic insulin secretion) with risk of ovarian and endometrial cancer. Additionally, the interrelationships of body mass index (BMI), sex-steroids, IGF-I and IGFBP-3 were examined. Two case-control studies were nested within 3 prospective cohort studies centered in New York (USA), Umeå (Sweden) and Milan (Italy). The ovarian study included 132 cancer cases. The endometrial study included 166 cancer cases in the IGF-I and C-peptide component and 124 postmenopausal cases in the sex-steroids component. For each case, two controls matching the case for cohort, age, menopausal status and date at recruitment were selected. In total 286 and 315 controls were included in the ovarian and endometrial cancer studies, respectively. Odds ratios (OR) and their 95% confidence intervals (CI) for cancer risk associated with increasing hormone concentrations were estimated by conditional logistic regression. The cross-sectional analysis was based on anthropometric and hormonal data from 620 controls selected for the two nested case-control studies. There was no association of prediagnostic androstenedione, testosterone, DHEAS, SHBG or estrone with ovarian cancer risk in the whole study population or in women who were pre- or postmenopausal at blood donation. In the premenopausal group, risk appeared to increase with increasing androstenedione (OR (95% CI) for the highest tertile: 2.35 (0.81-6.82), p=0.12). There was no association of IGF-I, IGFBP-1, 2, 3 or C-peptide concentrations with risk of ovarian cancer risk in the study group as a whole. In analyses restricted to subjects who had developed ovarian cancer at an early age (<55), circulating IGF-I was directly and strongly associated with risk (OR (95% CI): 4.74 (1.20-18.7), p<0.05 for the highest IGF-I tertile). In the endometrial study, previous observations were confimed that elevated circulating estrogens and androgens and decreased SHBG increase risk of developing endometrial malignancy after menopause. Multivariate ORs (95% CI) for endometrial cancer for quartiles with the highest hormone levels were: 4.13 (1.76-9.72), p<0.001 for estradiol; 3.67 (1.71-7.88), p=0.001 for estrone; 2.15 (1.05-4.40), p<0.04 for androstenedione; 1.74 (0.88-3.46), p=0.06 for testosterone; 2.90 (1.42-5.90), p<0.01 for DHEAS and 0.46 (0.20-1.05), p<0.01 for SHBG. Prediagnostic IGF-I, IGFBP-1, -2 and –3 were not related to risk of endometrial cancer in the whole study population. In postmenopausal women, levels of IGFBP-1 were inversely related to risk with an OR for the highest quartile of 0.36 (0.13-0.95), p<0.05. Endometrial cancer risk increased with increasing levels of C-peptide (p<0.01), up to an OR of 4.40 (1.65-11.7) for the highest quintile after adjustment for BMI and other confounders. The cross-sectional analyses showed that in both pre- and postmenopausal women SHBG decreased with increasing BMI. In the postmenopausal group, estrogens, testosterone and androstenedione increased with BMI, while the association with IGF-I was non-linear, the highest mean IGF-I concentration being observed in women with BMI between 24 and 25. In postmenopausal women, IGF-I was positively related to androgens, inversely correlated with SHBG, and was not correlated with estrogens. In conclusion, elevated pre-diagnostic sex-steroids, IGF-I or C-peptide increase risk of developing ovarian and endometrial cancer. BMI influences the circulating levels of these hormones, especially after menopause.

  • 326.
    Lukanova, Annekatrin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Björ, Ove
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kaaks, Rudolf
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lindahl, Bernt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    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.
    Body mass index and cancer: results from the Northern Sweden Health and Disease Cohort2006In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 118, no 2, p. 458-466Article in journal (Refereed)
    Abstract [en]

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

  • 327.
    Lukanova, Annekatrin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Micheli, Andrea
    Arslan, Alan
    Ferrari, Pietro
    Rinaldi, Sabina
    Krogh, Vittorio
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Shore, Roy E
    Biessy, Carine
    Muti, Paola
    Riboli, Elio
    Koenig, Karen L
    Levitz, Mortimer
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Berrino, Franco
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Kaaks, Rudolf
    Toniolo, Paolo
    Zeleniuch-Jacquotte, Anne
    Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women.2004In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 108, no 3, p. 425-432Article in journal (Refereed)
    Abstract [en]

    Experimental and epidemiological data support a role for sex steroid hormones in the pathogenesis of endometrial cancer. The associations of pre-diagnostic blood concentrations of estradiol, estrone, testosterone, androstenedione, DHEAS and SHBG with endometrial cancer risk were investigated. A case-control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). Cases were 124 postmenopausal women with invasive endometrial cancer. For each case, 2 controls were selected, matching the case on cohort, age and date of recruitment. Only postmenopausal women who did not use exogenous hormones at the time of blood donation were included. Odds ratios (OR) and their 95% confidence intervals (CI) were estimated by conditional logistic regression. ORs (95% CI) for endometrial cancer for quartiles with the highest hormone levels, relative to the lowest were as follows: 4.13 (1.76-9.72), p(trend) = 0.0008 for estradiol, 3.67 (1.71-7.88), p(trend) = 0.0007 for estrone, 2.15 (1.05-4.40), p(trend) = 0.04 for androstenedione, 1.74 (0.88-3.46), p(trend) = 0.06 for testosterone, 2.90 (1.42-5.90), p(trend) = 0.002 for DHEAS and 0.46 (0.20-1.05), p(trend) = 0.01 for SHBG after adjustment for body mass index, use of oral contraceptives and hormone replacement therapy. The results of our multicenter prospective study showed a strong direct association of circulating estrogens, androgens and an inverse association of SHBG levels with endometrial cancer in postmenopausal women. The effect of elevated androstenedione and testosterone levels on disease risk seems to be mediated mainly through their conversion to estrogens, although an independent effect of androgens on tumor growth cannot be ruled out, in particular in the years close to diagnosis.

  • 328.
    Lukanova, Annekatrin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zeleniuch-Jacquotte, A
    Muti, P
    Mure, A
    Rinaldi, S
    Dossus, L
    Micheli, A
    Arslan, A
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Shore, R E
    Krogh, V
    Koenig, K L
    Riboli, E
    Berrino, F
    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.
    Toniolo, P
    Kaaks, R
    Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women.2004In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 150, no 2, p. 161-171Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Excess weight has been associated with increased risk of cancer at several organ sites. In part, this effect may be modulated through alterations in the metabolism of sex steroids and IGF-I related peptides. The objectives of the study were to examine the association of body mass index (BMI) with circulating androgens (testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS)), estrogens (estrone and estradiol), sex hormone-binding globulin (SHBG), IGF-I and IGF-binding protein (IGFBP)-3, and the relationship between sex steroids, IGF-I and IGFBP-3. DESIGN AND METHODS: A cross-sectional analysis was performed using hormonal and questionnaire data of 620 healthy women (177 pre- and 443 post-menopausal). The laboratory measurements of the hormones of interest were available from two previous case-control studies on endogenous hormones and cancer risk. RESULTS: In the pre-menopausal group, BMI was not related to androgens and IGF-I. In the post-menopausal group, estrogens, testosterone and androstenedione increased with increasing BMI. The association with IGF-I was non-linear, with the highest mean concentrations observed in women with BMI between 24 and 25. In both pre- and post-menopausal subjects, IGFBP-3 did not vary across BMI categories and SHBG decreased with increasing BMI. As for the correlations between peptide and steroid hormones, in the post-menopausal group, IGF-I was positively related to androgens, inversely correlated with SHBG, and not correlated with estrogens. In the pre-menopausal group, similar but weaker correlations between IGF-I and androgens were observed. CONCLUSIONS: These observations offer evidence that obesity may influence the levels of endogenous sex-steroid and IGF-related hormones in the circulation, especially after menopause. Circulating IGF-I, androgens and SHBG appear to be related to each other in post-menopausal women.

  • 329. Lukanova, Annekatrin
    et al.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
    Kaaks, Rudolf
    Jellum, Egil
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Serum adiponectin is not associated with risk of colorectal cancer.2006In: Cancer Epidemiol Biomarkers Prev, ISSN 1055-9965, Vol. 15, no 2, p. 401-2Article in journal (Refereed)
  • 330.
    Lukanova, Annekatrin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zeleniuch-Jacquotte, Anne
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Micheli, Andrea
    Arslan, Alan A
    Rinaldi, Sabina
    Muti, Paola
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Koenig, Karen L
    Biessy, Carine
    Krogh, Vittorio
    Riboli, Elio
    Shore, Roy E
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Berrino, Franco
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Toniolo, Paolo
    Kaaks, Rudolf
    Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer.2004In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 108, no 2, p. 262-268Article in journal (Refereed)
    Abstract [en]

    Conditions related to chronic hyperinsulinemia, such as obesity, noninsulin dependent diabetes mellitus and polycystic ovary syndrome, are associated with an increased risk of endometrial cancer. Elevated plasma IGF-I and decreased levels of IGF-binding proteins have been shown to be associated with increased risk of several cancer types that are frequent in affluent societies. We investigated for the first time in a prospective study the association of pre-diagnostic blood concentrations of C-peptide (a marker of pancreatic insulin production), IGF-I, IGFBP-1, -2 and -3 with endometrial cancer risk. A case-control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). It included 166 women with primary invasive endometrial cancer and 315 matched controls, of which 44 case and 78 control subjects were premenopausal at recruitment. Endometrial cancer risk increased with increasing levels of C-peptide (ptrend = 0.0002), up to an odds ratio (OR) of 4.76 [95% confidence interval (CI) = 1.91-11.8] for the highest quintile. This association remained after adjustment for BMI and other confounders [OR for the top quintile = 4.40 (1.65-11.7)]. IGFBP-1 levels were inversely related to endometrial cancer [ptrend = 0.002; OR in the upper quintile = 0.30 (0.15-0.62)], but the association was weakened and lost statistical significance after adjustment for confounders [ptrend = 0.06; OR in the upper quintile = 0.49 (0.22-1.07)]. Risk was unrelated to levels of IGF-I, IGFBP-2 and IGFBP-3. Chronic hyperinsulinemia, as reflected by increased circulating C-peptide, is associated with increased endometrial cancer risk. Decrease in the prevalence of chronic hyperinsulinemia, through changes in lifestyle or medication, is expected to prevent endometrial cancer.

  • 331. Lumme, Sonja
    et al.
    Tenkanen, Leena
    Langseth, Hilde
    Gislefoss, Randi
    Hakama, Matti
    Stattin, Pär
    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.
    Adlercreutz, Herman
    Saikku, Pekka
    Stenman, Ulf-Hakan
    Tuohimaa, Pentti
    Luostarinen, Tapio
    Dillner, Joakim
    Longitudinal biobanks-based study on the joint effects of infections, nutrition and hormones on risk of prostate cancer2016In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 7, p. 839-845Article in journal (Refereed)
    Abstract [en]

    Background To evaluate the individual and combined effects of enterolactone, vitamin D, free testosterone, Chlamydia trachomatis and HPV-18 on the risk of prostate cancer in a large population-based biochemical material that combined three Nordic serum sample banks. Material and methods A joint cohort of 209000 healthy men was followed using cancer registry linkages. From this cohort altogether 699 incident cases of prostate cancer were identified. Four controls were selected by incidence density sampling and matching for country, age and date of the blood sampling. Complete data for all investigated exposures was available for 483 eligible cases and 1055 eligible controls. Multivariate regression analyses were performed to investigate the solitary and combined effects. Results The solitary effects were small. Significantly increased risk [rate ratio 1.6 (95% CI 1.0-2.5)] was found in those seronegative for C. trachomatis infection. The joint effect in risk levels of enterolactone and vitamin D was antagonistic [observed rate ratio (RR) 1.4 (1.0-2.1), expected RR 2.0 (1.0-4.1)] as well as that of HPV-18 and C. trachomatis [observed RR 1.9 (0.8-4.5), expected RR 9.9 (1.1-87.0)]. Conclusion A large follow-up study combining data from several previously investigated exposures to investigate joint effects found no evidence that exposure to two risk factors would increase the risk of prostate cancer from that expected on basis of exposure to one risk factor. If anything, the results were consistent with antagonistic interactions.

  • 332. Lund, Lars
    et al.
    Nisen, Harry
    Jarvinen, Petrus
    Fovaeus, Magnus
    Gudmundson, Eirikur
    Kromann-Andersen, Bjarne
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Nilsen, Frode
    Sundqvist, Pernilla
    Clark, Peter
    Beisland, Christian
    Use of venous-thrombotic-embolic (vte) prophylaxis in patients undergoing surgery for renal tumors in Nordic countries (the Norenca-II study)2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, p. 48-48Article in journal (Other academic)
  • 333. Lund, Lars
    et al.
    Nisen, Harry
    Jarvinen, Petrus
    Fovaeus, Magnus
    Gudmundson, Eirikur
    Kromann-Andersen, Bjarne
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Nilsen, Frode
    Sundqvist, Pernilla
    Clark, Peter E.
    Beisland, Christian
    Use of venous-thrombotic-embolic prophylaxis in patients undergoing surgery for renal tumors: a questionnaire survey in the Nordic countries (The NORENCA-2 study)2018In: Open Access Journal of Urology, ISSN 2253-2447, E-ISSN 1179-1551, Vol. 10, p. 181-187Article in journal (Refereed)
    Abstract [en]

    Purpose: To examine the variation in venous thromboembolism prophylactic treatment (VTEP) among renal cancer patients undergoing surgery.

    Materials and methods: An Internet-based questionnaire on renal tumor management before and after surgery was mailed to all Nordic departments of urology. The questions focused on the use of VTEP and were subdivided into different surgical modalities.

    Results: Questionnaires were mailed to 91 institutions (response rate 53%). None of the centers used VTEP before surgery, unless the patient had a vena caval tumor thrombus. Overall, the VTEP utilized during hospitalization for patients undergoing renal surgery included early mobilization (45%), compression stockings (52%) and low-molecular-weight heparin (89%). In patients undergoing open radical Nx, 80% of institutions used VTEP during their hospitalization (23% compression stockings and 94% low-molecular-weight heparin). After leaving the hospital, the proportion and type of VTEP received varied considerably across institutions. The most common interval, used in 60% of the institutions, was for a period of 4 weeks. The restriction to the Nordic countries was a limitation and, therefore, may not reflect the practice patterns elsewhere. It is a survey study and, therefore, cannot measure the behaviors of those institutions that did not participate.

    Conclusion: We found variation in the type and duration of VTEP use for each type of local intervention for renal cancer. These widely disparate variations in care strongly argue for the establishment of national and international guidelines regarding VTEP in renal surgery.

  • 334.
    Lundberg, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hagberg, Oskar
    Jahnson, Staffan
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Association between occurrence of urinary bladder cancer and treatment with statin medication2019In: Turkish Journal of Urology, ISSN 2149-3235, Vol. 45, no 2, p. 97-102Article in journal (Refereed)
    Abstract [en]

    Objective: The incidence of urinary bladder cancer (UBC) has increased in Sweden despite decreased smoking, indicating that other factors might be associated. The increased use of statin medication for elevated blood lipids might be one such influencing factor. The aim of the present study was to assess whether statins are afflicted with an increased incidence of UBC.

    Material and methods: Data from the Swedish National Register of Urinary Bladder Cancer, National Population Register, and Swedish Prescribed Drug Register were extracted. There were 22,936 patients with new diagnosed UBC between 2005 and 2014. Statin prescription was defined as any medication prescribed with the Anatomical Therapeutic Classification code C10A. For each patient, 10 control individuals were matched by age, gender, and living area, comprising 229,326 individuals. The Cochran-Mantel-Haenszel test was used to evaluate the hazards ratios.

    Results: Statins were more frequently used in patients with UBC (33.8%) than in controls (29.8%, p<0.0001). The use of statins was afflicted with a 23% increased odds ratio (OR) for UBC (OR 1.23 (1.19-1.27), p<0.001). Subgroup analyses showed that an increased OR was found in non-muscle invasive UBC only. There was a tendency that OR was stronger for men and for younger patients. Limitations include its retrospective register-based design and potential risk of bias of confounding factors, such as smoking and body mass index.

    Conclusion: This nationwide register study suggests an association between the occurrence of UBC and patients using statins. The association was found in patients with non-muscle invasive disease only. Confounding factors, such as smoking, cannot be overruled.

  • 335.
    Lundholm, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. anders.bergh@umu.se.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Secreted Factors from Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15651Article in journal (Refereed)
    Abstract [en]

    Macrophage infiltration has been associated with an improved prognosis in patients with colorectal cancer (CRC), but a poor prognosis in prostate cancer (PC) patients. In this study, the distribution and prognostic value of proinflammatory M1 macrophages (NOS2(+)) and immunosuppressive M2 macrophages (CD163(+)) was evaluated in a cohort of 234 PC patients. We found that macrophages infiltrating PC were mainly of an M2 type and correlated with a more aggressive tumor and poor patient prognosis. Furthermore, the M1/M2 ratio was significantly decreased in PC compared to CRC. Using in vitro cell culture experiments, we could show that factors secreted from CRC and PC cells induced macrophages of a proinflammatory or immunosuppressive phenotype, respectively. These macrophages differentially affected autologous T lymphocyte proliferation and activation. Consistent with this, CRC specimens were found to have higher degrees of infiltrating T-helper 1 cells and active cytotoxic T lymphocytes, while PC specimens displayed functionally inactive T cells. In conclusion, our results imply that tumour-secreted factors from cancers of different origin can drive macrophage differentiation in opposite directions and thereby regulate the organization of the anti-tumour immune response. Our findings suggest that reprogramming of macrophages could be an important tool in the development of new immunotherapeutic strategies.

  • 336.
    Lundin, Joakim
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Albumin Levels in Patients with Renal Cell Carcinoma and Association to the Clinical Course after Nephrectomy2016Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 337. Lundstig, Annika
    et al.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Persson, Kenneth
    Sasnauskas, Kestutis
    Viscidi, Raphael P
    Gislefoss, Randi Elin
    Dillner, Joakim
    No excess risk for colorectal cancer among subjects seropositive for the JC polyomavirus.2007In: Int J Cancer, ISSN 0020-7136, Vol. 121, no 5, p. 1098-102Article in journal (Refereed)
  • 338.
    Lundström, Karl-Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Drevin, Linda
    Carlsson, Stefan
    Garmo, Hans
    Loeb, Stacy
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bill-Axelson, Anna
    Nationwide Population Based Study of Infections after Transrectal Ultrasound Guided Prostate Biopsy2014In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 192, no 4, p. 1116-1122Article in journal (Refereed)
    Abstract [en]

    Purpose: Transrectal ultrasound guided biopsy is the gold standard for detecting prostate cancer but international reports suggest that increasing risks are associated with the procedure. We estimated incidence and risk factors for infection after prostate biopsy as well as 90-day mortality using a nationwide Swedish sample. Material and Methods: We performed a population based study of 51,321 men from PCBaSe between 2006 and 2011. Primary outcome measures were dispensed prescriptions of antibiotics for urinary tract infection and hospitalization with a discharge diagnosis of urinary tract infection. Multivariable logistic regression was used to examine risk factors for infection in men who underwent prostate biopsy. Results: During the 6 months before biopsy the background incidence of urinary tract infection was approximately 2%. Within 30 days after biopsy 6% of the men had a dispensed prescription for urinary tract antibiotics and 1% were hospitalized with infection. The strongest risk factors for an antibiotic prescription were prior infection (OR 1.59, 95% CI 1.45-1.73), high Charlson comorbidity index (OR 1.25, 95% CI 1.11-1.41) and diabetes (OR 1.32, 95% CI 1.17-1.49). Risk of an antibiotic prescription after biopsy decreased from 2006 to 2011 (OR 0.79, 95% CI 0.70-0.90) but the risk of hospital admission increased (OR 2.14, 95% CI 1.58-2.94). No significant increase was observed in 90-day mortality. Conclusions: Severe infections with hospitalization after prostate biopsy are increasing in Sweden. The risk of post-biopsy infection is highest in men with a history of urinary tract infection and those with significant comorbidities.

  • 339.
    Lundström, Karl-Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Folkvaljon, Yasin
    Loeb, Stacy
    Axelson, Anna Bill
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Nordin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Small bowel obstruction and abdominal pain after robotic versus open radical prostatectomy2016In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 50, no 3, p. 155-159Article in journal (Refereed)
    Abstract [en]

    Objective The aim of this study was to examine whether intraperitoneal robot-assisted surgery leads to small bowel obstruction (SBO), possibly caused by the formation of intra-abdominal adhesions. Materials and methods In total, 7256 men treated by intraperitoneal robot-assisted radical prostatectomy (RARP) and 9787 men treated by retropubic radical prostatectomy (RRP) in 2005-2012 were identified in the Prostate Cancer data Base Sweden (PCBaSe). Multivariable Cox proportional hazards models were used to calculate the risk of readmission for SBO, SBO-related surgery and admissions due to abdominal pain up to 5 years postoperatively. Results During the first postoperative year, the risk of readmission for SBO was higher after RARP than after RRP [hazard ratio (HR) 1.92, 95% confidence interval (CI) 1.14-3.25] but after 5 years there was no significant difference (HR 1.28, 95% CI 0.86-1.91), and there was no difference in the risk of SBO surgery during any period. The risk of admission for abdominal pain was significantly increased after RARP during the first year (HR 2.24, 95% CI 1.50-3.33) but not after 5 years (HR 1.23, 95% CI 0.92-1.63). Conclusion Intraperitoneal RARP had an increased risk of SBO and abdominal pain in the short term during the first year, but not in the long term, compared to RRP.

  • 340.
    Lundström, Karl-Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Soederstrom, Lars
    Jernow, Henning
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Nordin, Par
    Epidemiology of hydrocele and spermatocele; incidence, treatment and complications2019In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813Article in journal (Refereed)
    Abstract [en]

    Objectives: To estimate the incidence of men seeking specialized care and receiving treatment for hydro or spermatocele complaints. Also, to determine the risk of complications of treatment. Materials and methods: The total number of men living in Sweden each year from 2005 to 2014 was used to calculate incidence and age distribution of adult (>= 18 years) men seeking specialized healthcare with either hydro or spermatocele. This was done by using nationwide registries, mandatory by law. They contain information on primary or discharge diagnosis, procedure codes and antibiotic prescriptions. Also, complication rates comparing aspiration (with or without sclerotherapy) and conventional surgery were analysed. Results: The incidence of men with either hydro or spermatocele diagnosis in specialized healthcare was similar to 100/100,000 men. The treatment incidence was 17/100,000 men. Orchiectomy was used as primary treatment in 2.4% of cases. The risk of experiencing a complication was clinically and statistically significantly increased with conventional surgery as compared with aspiration, 17.5% (1607/9174) vs 4.6% (181/3920), corresponding to relative risk of 3.79 (95% CI = 3.27-4.40). Hematoma and infections were the most common complications. Conclusion: Hydro and spermatoceles are common, affecting elderly men. Aspiration seems advantageous with respect to complications and can be recommended due to the benign course of the disease. The indication for conventional surgery might be questioned such as the use of orchiectomy as primary treatment.

  • 341. Lycken, Magdalena
    et al.
    Garmo, Hans
    Adolfsson, Jan
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Holmberg, Lars
    Bill-Axelson, Anna
    Patterns of androgen deprivation therapies among men diagnosed with localised prostate cancer: A population-based study2014In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, no 10, p. 1789-1798Article in journal (Refereed)
    Abstract [en]

    Aim: Many men diagnosed with localised prostate cancer will eventually be treated with androgen deprivation therapy (ADT). ADT is associated with adverse effects and its timing is controversial. Data on patterns of use are scarce. We describe patterns of ADT use, defined as castration (medical and surgical) or antiandrogen monotherapy initiated after primary treatment, in a population-based cohort. Methods and materials: Data were extracted from the population-based Prostate Cancer data Base Sweden (PCBaSe). Totally 45,147 men diagnosed between 1997 and 2009 with clinical stage T1-2, N0-NX, M0-MX and prostate specific antigen (PSA) <50 ng/ml without primary ADT were included. Outcomes in the period 2006 through 2010 were analysed using a period analysis approach. Results: The cumulative incidence of castration at 10 years after diagnosis was 11.6% (95% confidence interval (CI), 11.0-12.2%). The corresponding proportion of antiandrogen monotherapy was 10.8% (95% CI, 10.2-11.4%). Castration was the dominant therapy among men on deferred treatment. The probability of receiving castration rather than antiandrogen monotherapy increased with age. Estimated median durations of castration ranged from 4 years in the deferred treatment high-risk group to 17 years in the prostatectomy low-risk group. The main limitation was the lack of information on progression to metastatic disease and PSA at the time for initiation of ADT. Conclusion: When initiated early after curative treatment, the duration of castration can be decades. The findings indicate that more accurate tools are necessary to guide which men should be selected for ADT as secondary treatment. (C) 2014 Elsevier Ltd. All rights reserved.

  • 342.
    Löfbacka, Viktor
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    99mTc-DPD scintigraphy: a functional tool in cardiac transthyretin amyloidosis?2018Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 343. Machiela, Mitchell J.
    et al.
    Hofmann, Jonathan N.
    Carreras-Torres, Robert
    Brown, Kevin M.
    Johansson, Mattias
    Wang, Zhaoming
    Foll, Matthieu
    Li, Peng
    Rothman, Nathaniel
    Savage, Sharon A.
    Gaborieau, Valerie
    McKay, James D.
    Ye, Yuanqing
    Henrion, Marc
    Bruinsma, Fiona
    Jordan, Susan
    Severi, Gianluca
    Hveem, Kristian
    Vatten, Lars J.
    Fletcher, Tony
    Koppova, Kvetoslava
    Larsson, Susanna C.
    Wolk, Alicja
    Banks, Rosamonde E.
    Selby, Peter J.
    Easton, Douglas F.
    Pharoah, Paul
    Andreotti, Gabriella
    Freeman, Laura E. Beane
    Koutros, Stella
    Albanes, Demetrius
    Mannisto, Satu
    Weinstein, Stephanie
    Clark, Peter E.
    Edwards, Todd E.
    Lipworth, Loren
    Gapstur, Susan M.
    Stevens, Victoria L.
    Carol, Hallie
    Freedman, Matthew L.
    Pomerantz, Mark M.
    Cho, Eunyoung
    Kraft, Peter
    Preston, Mark A.
    Wilson, Kathryn M.
    Gaziano, J. Michael
    Sesso, Howard S.
    Black, Amanda
    Freedman, Neal D
    Huang, Wen-Yi
    Anema, John G.
    Kahnoski, Richard J.
    Lane, Brian R.
    Noyes, Sabrina L.
    Petillo, David
    Colli, Leandro M.
    Sampson, Joshua N.
    Besse, Celine
    Blanche, Helene
    Boland, Anne
    Burdette, Laurie
    Prokhortchouk, Egor
    Skryabin, Konstantin G.
    Yeager, Meredith
    Mijuskovic, Mirjana
    Ognjanovic, Miodrag
    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
    Szeszenia-Dabrowska, Neonila
    Benhamou, Simone
    Cancel-Tassin, Geraldine
    Cussenot, Olivier
    Bueno-de-Mesquita, H. B. As
    Canzian, Federico
    Duell, Eric J.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Sitaram, Raviprakash T.
    Peters, Ulrike
    White, Emily
    Anderson, Garnet L.
    Johnson, Lisa
    Luo, Juhua
    Buring, Julie
    Lee, I-Min
    Chow, Wong-Ho
    Moore, Lee E.
    Wood, Christopher
    Eisen, Timothy
    Larkin, James
    Choueiri, Toni K.
    Lathrop, G. Mark
    Teh, Bin Tean
    Deleuze, Jean-Francois
    Wu, Xifeng
    Houlston, Richard S.
    Brennan, Paul
    Chanock, Stephen J.
    Scelo, Ghislaine
    Purdue, Mark P.
    Corrigendum re "Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma" [Eur Urol 2017;72: 747-54].2018In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 74, no 3, p. e85-e86, article id S0302-2838(18)30366-XArticle in journal (Refereed)
    Abstract [en]

    It has come to our attention that authors Lenka Foretova, Ivana Holcatova, Vladimir Janout, Dana Mates, Anush Mukeriya, Stefan Rascu, David Zaridze, Vladimir Bencko, and Cezary Cybulski were not assigned to the correct affiliations. Their correct affiliations are as in the list above.

  • 344. Machiela, Mitchell J.
    et al.
    Hofmann, Jonathan N.
    Carreras-Torres, Robert
    Brown, Kevin M.
    Johansson, Mattias
    Wang, Zhaoming
    Foll, Matthieu
    Li, Peng
    Rothman, Nathaniel
    Savage, Sharon A.
    Gaborieau, Valerie
    Mckay, James D.
    Ye, Yuanqing
    Henrion, Marc
    Bruinsma, Fiona
    Jordan, Susan
    Severi, Gianluca
    Hveem, Kristian
    Vatten, Lars J.
    Fletcher, Tony
    Koppova, Kvetoslava
    Larsson, Susanna C.
    Wolk, Alicja
    Banks, Rosamonde E.
    Selby, Peter J.
    Easton, Douglas F.
    Pharoah, Paul
    Andreotti, Gabriella
    Freeman, Laura E. Beane
    Koutros, Stella
    Albanes, Demetrius
    Mannisto, Satu
    Weinstein, Stephanie
    Clark, Peter E.
    Edwards, Todd E.
    Lipworth, Loren
    Gapstur, Susan M.
    Stevens, Victoria L.
    Carol, Hallie
    Freedman, Matthew L.
    Pomerantz, Mark M.
    Cho, Eunyoung
    Kraft, Peter
    Preston, Mark A.
    Wilson, Kathryn M.
    Michael Gaziano, J.
    Sesso, Howard S.
    Black, Amanda
    Freedman, Neal D.
    Huang, Wen-Yi
    Anema, John G.
    Kahnoski, Richard J.
    Lane, Brian R.
    Noyes, Sabrina L.
    Petillo, David
    Colli, Leandro M.
    Sampson, Joshua N.
    Besse, Celine
    Blanche, Helene
    Boland, Anne
    Burdette, Laurie
    Prokhortchouk, Egor
    Skryabin, Konstantin G.
    Yeager, Meredith
    Mijuskovic, Mirjana
    Ognjanovic, Miodrag
    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
    Szeszenia-Dabrowska, Neonila
    Benhamou, Simone
    Cancel-Tassin, Geraldine
    Cussenot, Olivier
    Bueno-de-Mesquita, H. Bas
    Canzian, Federico
    Duell, Eric J.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Sitaram, Raviprakash T.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Peters, Ulrike
    White, Emily
    Anderson, Garnet L.
    Johnson, Lisa
    Luo, Juhua
    Buring, Julie
    Lee, I-Min
    Chow, Wong-Ho
    Moore, Lee E.
    Wood, Christopher
    Eisen, Timothy
    Larkin, James
    Choueiri, Toni K.
    Lathrop, G. Mark
    Teh, Bin Tean
    Deleuze, Jean-Francois
    Wu, Xifeng
    Houlstonmmm, Richard S.
    Brennan, Paul
    Chanock, Stephen J.
    Scelo, Ghislaine
    Purdue, Mark P.
    Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma2017In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 72, no 5, p. 747-754Article in journal (Refereed)
    Abstract [en]

    Background: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.

    Objective: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.

    Design, setting, and participants: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.

    Outcome measurements and statistical analysis: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.

    Results and limitations: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR = 2.07 per predicted kilobase increase, 95% confidence interval [CI]: = 1.70-2.53, p < 0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R-2 > 0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR = 1.73, 95% CI = 1.36-2.21, p < 0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N = 5573, OR = 1.93, 95% CI = 1.50-2.49, p < 0.0001), papillary (N = 573, OR = 1.96, 95% CI = 1.01-3.81, p = 0.046), and chromophobe RCC (N = 203, OR = 2.37, 95% CI = 0.78-7.17, p = 0.13).

    Conclusions: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.

    Patient summary: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.

  • 345. MacLennan, Sara J
    et al.
    MacLennan, Steven
    Bex, Axel
    Catto, James W F
    De Santis, Maria
    Glaser, Adam W
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    N'Dow, James
    Plass, Karin
    Trapero-Bertran, Marta
    Van Poppel, Hendrik
    Wright, Penny
    Giles, Rachel H
    Changing Current Practice in Urology: Improving Guideline Development and Implementation Through Stakeholder Engagement2017In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 72, no 2, p. 161-163Article in journal (Refereed)
    Abstract [en]

    Effective stakeholder integration for guideline development should improve outcomes and adherence to clinical practice guidelines.

  • 346. MacLennan, Steven
    et al.
    Imamura, Mari
    Lapitan, Marie C.
    Omar, Muhammad Imran
    Lam, Thomas B. L.
    Hilvano-Cabungcal, Ana M.
    Royle, Pam
    Stewart, Fiona
    MacLennan, Graeme
    MacLennan, Sara J.
    Canfield, Steven E.
    McClinton, Sam
    Griffiths, T. R. Leyshon
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    N'Dow, James
    Systematic Review of Oncological Outcomes Following Surgical Management of Localised Renal Cancer2012In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 61, no 5, p. 972-993Article, review/survey (Refereed)
    Abstract [en]

    Context: Renal cell carcinoma (RCC) accounts for 2-3% of adult malignancies. There remain uncertainties over the oncological outcomes for the surgical management of localised RCC. Objective: Systematically review relevant literature comparing oncological outcomes of surgical management of localised RCC (T1-2N0M0). Evidence acquisition: Relevant databases including Medline, Embase, and the Cochrane Library were searched up to October 2010, and an updated scoping search was performed up to January 2012. Randomised controlled trials (RCTs) or quasi-RCTs, prospective observational studies with controls, retrospective matched-pair studies, and comparative studies from well-defined registries/databases were included. The main outcomes were overall survival, cancer-specific survival, recurrence, and metastases. The Cochrane risk of bias tool was used to assess RCTs, and an extended version was used to assess nonrandomised studies (NRSs). The quality of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Evidence synthesis: A total of 4580 abstracts and 389 full-text articles were assessed. Thirty-four studies met the inclusion criteria (6 RCTs and 28 NRSs). Meta-analyses were planned but were deemed inappropriate due to data heterogeneity. There were high risks of bias and low-quality evidence across the evidence base. Open radical nephrectomy and open partial nephrectomy showed similar cancer-specific and overall survival, but when both open and laparoscopic approaches are considered together, the evidence showed improved survival for partial nephrectomy for tumours <= 4 cm. The overall evidence suggests either equivalent or better survival with partial nephrectomy. Laparoscopic radical nephrectomy offered equivalent survival to open radical nephrectomy, and all laparoscopic approaches achieved equivalent survival. Open and laparoscopic partial nephrectomy achieved equivalent survival. The issue of ipsilateral adrenalectomy or complete lymph node dissection with radical nephrectomy or partial nephrectomy remains unresolved. Conclusions: The evidence base suggests localised RCCs are best managed by nephron-sparing surgery where technically feasible. However, the current evidence base has significant limitations due to studies of low methodological quality marked by high risks of bias. (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved.

  • 347. MacLennan, Steven
    et al.
    Imamura, Mari
    Lapitan, Marie C
    Omar, Muhammad Imran
    Lam, Thomas BL
    Hilvano-Cabungcal, Ana M
    Royle, Pam
    Stewart, Fiona
    MacLennan, Graeme
    MacLennan, Sara J
    Dahm, Philipp
    Canfield, Steven E
    McClinton, Sam
    Griffiths, TR Leyshon
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    N'Dow, James
    Systematic review of perioperative and quality-of-life outcomes following surgical management of localised renal cancer2012In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 62, no 6, p. 1097-1117Article, review/survey (Refereed)
    Abstract [en]

    Context: For the treatment of localised renal cell carcinoma (RCC), uncertainties remain over the perioperative and quality-of-life (QoL) outcomes for the many different surgical techniques and approaches of nephrectomy. Controversy also remains on whether newer minimally invasive nephron-sparing interventions offer better QoL and perioperative outcomes, and whether adrenalectomy and lymphadenectomy should be performed simultaneously with nephrectomy. These non-oncological outcomes are important because they may have a considerable impact on localised RCC treatment decision making.

    Objective: To review systematically all the relevant published literature comparing perioperative and QoL outcomes of surgical management of localised RCC (T1-2N0M0).

    Evidence acquisition: Relevant databases including Medline, Embase, and the Cochrane Library were searched up to January 2012. Randomised controlled trials (RCTs) or quasi-randomised controlled trials, prospective observational studies with controls, retrospective matched-pair studies, and comparative studies from well-defined registries/databases were included. The outcome measures were QoL, analgesic requirement, length of hospital stay, time to normal activity level, surgical morbidity and complications, ischaemia time, renal function, blood loss, length of operation, need for blood transfusion, and perioperative mortality. The Cochrane risk of bias tool was used to assess RCTs, and an extended version was used to assess nonrandomised studies (NRSs). The quality of evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluation.

    Evidence synthesis: A total of 4580 abstracts and 380 full-text articles were assessed, and 29 studies met the inclusion criteria (7 RCTs and 22 NRSs). There were high risks of bias and low-quality evidence for studies meeting the inclusion criteria. There is good evidence indicating that partial nephrectomy results in better preservation of renal function and better QoL outcomes than radical nephrectomy regardless of technique or approach. Regarding radical nephrectomy, the laparoscopic approach has better perioperative outcomes than the open approach, and there is no evidence of a difference between the transperitoneal and retroperitoneal approaches. Alternatives to standard laparoscopic radical nephrectomy (LRN) such as hand-assisted, robot-assisted, or single-port techniques appear to have similar perioperative outcomes. There is no good evidence to suggest that minimally invasive procedures such as cryotherapy or radiofrequency ablation have superior perioperative or QoL outcomes to nephrectomy. Regarding concomitant lymphadenectomy during nephrectomy, there were low event rates for complications, and no definitive difference was observed. There was no evidence to base statements about concomitant ipsilateral adrenalectomy during nephrectomy.

    Conclusions: Partial nephrectomy results in significantly better preservation of renal function over radical nephrectomy. For tumours where partial nephrectomy is not technically feasible, there is no evidence that alternative procedures or techniques are better than LRN in terms of perioperative or QoL outcomes. In making treatment decisions, perioperative and QoL outcomes should be considered in conjunction with oncological outcomes. Overall, there was a paucity of data regarding QoL outcomes, and when reported, both QoL and perioperative outcomes were inconsistently defined, measured, or reported. The current evidence base has major limitations due to studies of low methodological quality marked by high risks of bias.

    (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved.

  • 348. Makarov, Danil V.
    et al.
    Loeb, Stacy
    Ulmert, David
    Drevin, Linda
    Lambe, Mats
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prostate Cancer Imaging Trends After a Nationwide Effort to Discourage Inappropriate Prostate Cancer Imaging2013In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 105, no 17, p. 1306-1313Article in journal (Refereed)
    Abstract [en]

    Background: Reducing inappropriate use of imaging to stage incident prostate cancer is a challenging problem highlighted recently as a Physician Quality Reporting System quality measure and by the American Society of Clinical Oncology and the American Urological Association in the Choosing Wisely campaign. Since 2000, the National Prostate Cancer Register (NPCR) of Sweden has led an effort to decrease national rates of inappropriate prostate cancer imaging by disseminating utilization data along with the latest imaging guidelines to urologists in Sweden. We sought to determine the temporal and regional effects of this effort on prostate cancer imaging rates.

    Methods: We performed a retrospective cohort study among men diagnosed with prostate cancer from the NPCR from 1998 to 2009 (n = 99 879). We analyzed imaging use over time stratified by clinical risk category (low, intermediate, high) and geographic region. Generalized linear models with a logit link were used to test for time trend.

    Results: Thirty-six percent of men underwent imaging within 6 months of prostate cancer diagnosis. Overall, imaging use decreased over time, particularly in the low-risk category, among whom the imaging rate decreased from 45% to 3% (P < .001), but also in the high-risk category, among whom the rate decreased from 63% to 47% (P < .001). Despite substantial regional variation, all regions experienced clinically and statistically (P < .001) significant decreases in prostate cancer imaging.

    Conclusions: A Swedish effort to provide data on prostate cancer imaging use and imaging guidelines to clinicians was associated with a reduction in inappropriate imaging over a 10-year period, as well as slightly decreased appropriate imaging in high-risk patients. These results may inform current efforts to promote guideline-concordant imaging in the United States and internationally.

  • 349.
    Mallikarjuna, Pramod
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tumkur Sitaram, Raviprakash
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Aripaka, Karthik
    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.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Interactions between TGF-β type I receptor and hypoxia-inducible factor-alpha mediates a synergistic crosstalk leading to poor prognosis for patients with clear cell renal cell carcinoma2019In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 18, no 17, p. 2141-2156Article in journal (Refereed)
    Abstract [en]

    To investigate the significance of expression of HIF-1 alpha, HIF-2 alpha, and SNAIL1 proteins; and TGF-beta signaling pathway proteins in ccRCC, their relation with clinicopathological parameters and patient's survival were examined. We also investigated potential crosstalk between HIF-alpha and TGF-beta signaling pathway, including the TGF-beta type 1 receptor (ALK5-FL) and the intracellular domain of ALK5 (ALK5-ICD). Tissue samples from 154 ccRCC patients and comparable adjacent kidney cortex samples from 38 patients were analyzed for HIF-1 alpha/2 alpha, TGF-beta signaling components, and SNAIL1 proteins by immunoblot. Protein expression of HIF-1 alpha and HIF-2 alpha were significantly higher, while SNAIL1 had similar expression levels in ccRCC compared with the kidney cortex. HIF-2 alpha associated with poor cancer-specific survival, while HIF-1 alpha and SNAIL1 did not associate with survival. Moreover, HIF-2 alpha positively correlated with ALK5-ICD, pSMAD2/3, and PAI-1; HIF-1 alpha positively correlated with pSMAD2/3; SNAIL1 positively correlated with ALK5-FL, ALK5-ICD, pSMAD2/3, PAI-1, and HIF-2 alpha. Intriguingly, in vitro experiments performed under normoxic conditions revealed that ALK5 interacts with HIF-1 alpha and HIF-2 alpha, and promotes their expression and the expression of their target genes GLUT1 and CA9, in a VHL dependent manner. We found that ALK5 induces expression of HIF-1 alpha and HIF-2 alpha, through its kinase activity. Under hypoxic conditions, HIF-alpha proteins correlated with the activated TGF-beta signaling pathway. In conclusion, we reveal that ALK5 plays a pivotal role in synergistic crosstalk between TGF-beta signaling and hypoxia pathway, and that the interaction between ALK5 and HIF-alpha contributes to tumor progression.

  • 350.
    Mallikarjuna, Pramod
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tumkur Sitaram, Raviprakash
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Landström, Maréne
    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.
    VHL status regulates transforming growth factor-β signaling pathways in renal cell carcinoma2018In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 23, p. 16297-16310Article in journal (Refereed)
    Abstract [en]

    To evaluate the role of pVHL in the regulation of TGF-β signaling pathways in clear cell renal cell carcinoma (ccRCC) as well as in non-ccRCC; the expression of pVHL, and the TGF-β pathway components and their association with clinicopathological parameters and patient’s survival were explored. Tissue samples from 143 ccRCC and 58 non-ccRCC patients were examined by immunoblot. ccRCC cell lines were utilized for mechanistic in-vitro studies. Expression levels of pVHL were significantly lower in ccRCC compared with non-ccRCC. Non-ccRCC and ccRCC pVHL-High expressed similar levels of pVHL. Expression of the TGF-β type I receptor (ALK5) and intra-cellular domain were significantly higher in ccRCC compared with non-ccRCC. In non-ccRCC, expressions of ALK5-FL, ALK5-ICD, pSMAD2/3, and PAI-1 had no association with clinicopathological parameters and survival. In ccRCC pVHL-Low, ALK5-FL, ALK5-ICD, pSMAD2/3, and PAI-1 were significantly related with tumor stage, size, and survival. In ccRCC pVHL-High, the expression of PAI-1 was associated with stage and survival. In-vitro studies revealed that pVHL interacted with ALK5 to downregulate its expression through K48-linked poly-ubiquitination and proteasomal degradation, thus negatively controlling TGF-β induced cancer cell invasiveness. The pVHL status controls the ALK5 and can thereby regulate the TGF-β pathway, aggressiveness of tumors, and survival of the ccRCC and non-ccRCC patients.

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