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  • 1. Akre, Olof
    et al.
    Garmo, Hans
    Adolfsson, Jan
    Lambe, Mats
    Bratt, Ola
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Mortality among men with locally advanced prostate cancer managed with noncurative intent: a nationwide study in PCBaSe Sweden2011In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 60, no 3, p. 554-563Article in journal (Refereed)
    Abstract [en]

    The PCa-specific mortality within 8 yr of diagnosis is high in locally advanced PCa, suggesting undertreatment, particularly among men in older age groups. Our results underscore the need for more studies of treatment with curative intent for locally advanced tumors.

  • 2. Albiges, Laurence
    et al.
    Powles, Tom
    Staehlerr, Michael
    Bensalan, Karim
    Giles, Rachel H.
    Horag, Milan
    Kuczyk, Markus A.
    Lam, Thomas B.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Marconi, Lorenzo
    Merseburger, Axel S.
    Volpe, Alessandro
    Abu-Ghanem, Yasmin
    Dabestani, Saeed
    Fernndez-Pello, Sergio
    Hofmann, Fabian
    Kuusk, Teele
    Tahbaz, Rana
    Bex, Axel
    Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibition Is the New Backbone in First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma2019In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 76, no 2, p. 151-156Article in journal (Refereed)
    Abstract [en]

    Recent randomised trials have demonstrated a survival benefit for a front-line ipilimumab and nivolumab combination therapy, and pembrolizumab and axitinib combination therapy in metastatic clear-cell renal cell carcinoma. The European Association of Urology Guidelines Panel has updated its recommendations based on these studies.

    Patient summary: Pembrolizumab plus axitinib is a new standard of care for patients diagnosed with kidney cancer spread outside the kidney and who did not receive any prior treatment for their cancer (treatment naive). This applies to all risk groups as determined by the International Metastatic Renal Cell Carcinoma Database Consortium criteria.

  • 3. Assel, Melissa
    et al.
    Dahlin, Anders
    Ulmert, David
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Lilja, Hans
    Vickers, Andrew J.
    Association Between Lead Time and Prostate Cancer Grade: Evidence of Grade Progression from Long-term Follow-up of Large Population-based Cohorts Not Subject to Prostate-specific Antigen Screening2018In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 73, no 6, p. 961-967Article in journal (Refereed)
    Abstract [en]

    Background: Lead time (LT) is of key importance in early detection of cancer, but cannot be directly measured. We have previously provided LT estimates for prostate cancer (PCa) using archived blood samples from cohorts followed for many years without screening. Objective: To determine the association between LT and PCa grade at diagnosis to provide an insight into whether grade progresses or is stable over time. Design, setting, and participants: The setting was three long-term epidemiologic studies in Sweden including men not subject to prostate-specific antigen (PSA) screening. The cohort included 1041 men with PSA of 3-10 ng/ml at blood draw and subsequently diagnosed with PCa with grade data available. Outcome measurements and statistical analysis: Multivariable logistic regression was used to predict high-grade (Gleason grade group >= 2 or World Health Organization grade 3) versus low-grade PCa at diagnosis in terms of LT, defined as the time between the date of elevated PSA and the date of PCa diagnosis with adjustment for cohort and age. Results and limitations: The probability that PCa would be high grade at diagnosis increased with LT. Among all men combined, the risk of high-grade disease increased with LT (odds ratio 1.13, 95% confidence interval [CI] 1.10-1.16; p < 0.0001), with no evidence of differences in effect by age group or cohort. Higher PSA predicted shorter LT by 0.46 yr (95% CI 0.28-0.64; p < 0.0001) per 1 ng/ml increase in PSA. However, there was no interaction between PSA and grade, suggesting that the longer LT for high-grade tumors is not simply related to age. Limitations include the assumption that men with elevated PSA and subsequently diagnosed with PCa would have had biopsy-detectable PCa at the time of PSA elevation. Conclusions: Our data support grade progression, whereby following a prostate over time would reveal transitions from benign to low-grade and then high-grade PCa. Patient summary: Men with a longer lead time between elevated prostate-specific antigen and subsequent prostate cancer diagnosis were more likely to have high-grade cancers at diagnosis.

  • 4. Bekema, Hendrika J.
    et al.
    MacLennan, Steven
    Imamura, Mari
    Lam, Thomas B. L.
    Stewart, Fiona
    Scott, Neil
    MacLennan, Graeme
    McClinton, Sam
    Griffiths, T. R. Leyshon
    Skolarikos, Andreas
    MacLennan, Sara J.
    Sylvester, Richard
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    N'Dow, James
    Systematic Review of Adrenalectomy and Lymph Node Dissection in Locally Advanced Renal Cell Carcinoma2013In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 64, no 5, p. 799-810Article, review/survey (Refereed)
    Abstract [en]

    Context: Controversy remains over whether adrenalectomy and lymph node dissection (LND) should be performed concomitantly with radical nephrectomy (RN) for locally advanced renal cell carcinoma (RCC) cT3-T4N0M0. Objective: To systematically review all relevant literature comparing oncologic, perioperative, and quality-of-life (QoL) outcomes for locally advanced RCC managed with RN with or without concomitant adrenalectomy or LND.

    Evidence acquisition: Relevant databases were searched up to August 2012. Randomised controlled trials (RCTs) and comparative studies were included. Outcome measures were overall survival, QoL, and perioperative adverse effects. Risks of bias (RoB) were assessed using Cochrane RoB tools. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach.

    Evidence synthesis: A total of 3658 abstracts and 252 full-text articles were screened. Eight studies met the inclusion criteria: six LNDs (one RCT and five nonrandomised studies [NRSs]) and two adrenalectomies (two NRSs). RoB was high across the evidence base, and the quality of evidence from outcomes ranged from moderate to very low. Meta-analyses were not undertaken because of diverse study designs and data heterogeneity. There was no significant difference in survival between the groups, even though 5-yr overall survival appears better for the RN plus LND group compared with the no-LND group in one randomised study. There was no evidence of a difference in adverse events between the RN plus LND and no-LND groups. No studies reported QoL outcomes. There was no evidence of an oncologic difference between the RN with adrenalectomy and RN without adrenalectomy groups. No studies reported adverse events or QoL outcomes.

    Conclusions: There is insufficient evidence to draw any conclusions on oncologic outcomes for patients having concomitant LND or ipsilateral adrenalectomy compared with patients having RN alone for cT3-T4N0M0 RCC. The quality of evidence is generally low and the results potentially biased. Further research in adequately powered trials is needed to answer these questions.

  • 5. Bessa, Agustina
    et al.
    Maclennan, Steven
    Enting, Deborah
    Bryan, Richard
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Van Hemelrijck, Mieke
    Reply to Jon Mikel Inarritu, Daniele Castellani, and Jeremy YC Teoh's Letter to the Editor re: Agustina Bessa, Steven Maclennan, Deborah Enting, et al. Consensus in Bladder Cancer Research Priorities Between Patients and Healthcare Professionals Using a Four-stage Modified Delphi Method. Eur Urol 2019;76:260-12019In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 76, no 2, p. E45-E46Article in journal (Refereed)
  • 6. Bessa, Agustina
    et al.
    Maclennan, Steven
    Enting, Deborah
    Bryan, Richard
    Josephs, Debra
    Hughes, Simon
    Amery, Suzanne
    Khan, Muhammad Shamim
    Malde, Sachin
    Nair, Rajesh
    Cahill, Fidelma
    Wylie, Harriet
    Thurairaja, Ramesh
    Chatterton, Kathryn
    Kinsella, Netty
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Van Hemelrijck, Mieke
    Consensus in Bladder Cancer Research Priorities Between Patients and Healthcare Professionals Using a Four-stage Modified Delphi Method2019In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560Article in journal (Refereed)
  • 7. Bex, Axel
    et al.
    Albiges, Laurence
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bensalah, Karim
    Dabestani, Saeed
    Giles, Rachel H.
    Hofmann, Fabian
    Hora, Milan
    Kuczyk, Markus A.
    Lam, Thomas B.
    Marconi, Lorenzo
    Merseburger, Axel S.
    Fernandez-Pello, Sergio
    Tahbaz, Rana
    Abu-Ghanem, Yasmin
    Staehler, Michael
    Volpe, Alessandro
    Powles, Thomas
    Updated European Association of Urology Guidelines for Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Clear-cell Renal Cell Carcinoma2018In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 74, no 6, p. 805-809Article in journal (Refereed)
    Abstract [en]

    Cytoreductive nephrectomy (CN) has been the standard of care in patients with metastatic clear-cell renal cancer who present with the tumour in place. The CARMENA trial compared systemic therapy alone with CN followed by systemic therapy. This article outlines the new guidelines based on these data.

    Patient summary: The CARMENA trial demonstrates that immediate cytoreductive nephrectomy should no longer be considered the standard of care in patients diagnosed with intermediate and poor risk metastatic renal cell carcinoma when medical treatment is required. However, the psychological burden poor risk patients experience hearing that removal of their primary tumour will not be beneficial, should be carefully considered. 

  • 8. Bex, Axel
    et al.
    Albiges, Laurence
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bensalah, Karim
    Dabestani, Saeed
    Giles, Rachel H.
    Hofmann, Fabian
    Hora, Milan
    Kuczyk, Markus A.
    Lam, Thomas B.
    Marconi, Lorenzo
    Merseburger, Axel S.
    Staehler, Michael
    Volpe, Alessandro
    Powles, Thomas
    Updated European Association of Urology Guidelines Regarding Adjuvant Therapy for Renal Cell Carcinoma2017In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 71, no 5, p. 719-722Article in journal (Refereed)
    Abstract [en]

    The European Association of Urology Renal Cell Carcinoma (RCC) guidelines panel updated their recommendation on adjuvant therapy in unfavourable, clinically nonmetastatic RCC following the recently reported results of a second randomised controlled phase 3 trial comparing 1-yr sunitinib to placebo for high-risk RCC after nephrectomy (S-TRAC). On the basis of conflicting results from the two available studies, the panel rated the quality of the evidence, the harm-to-benefit ratio, patient preferences, and costs. Finally, the panel, including representatives from a patient advocate group (International Kidney Cancer Coalition) voted and reached a consensus to not recommend adjuvant therapy with sunitinib for patients with high-risk RCC after nephrectomy. Patient summary: In two studies, sunitinib was given for 1 yr and compared to no active treatment (placebo) in patients who had their kidney tumour removed and who had a high risk of cancer coming back after surgery. Although one study demonstrated that 1 yr of sunitinib therapy resulted in a 1.2-yr longer time before the disease recurred, the other study did not show a benefit and it has not been shown that patients live longer. Despite having been diagnosed with high-risk disease, many patients remain without recurrence, and the side effects of sunitinib are high. Therefore, the panel members, including patient representatives, do not recommend sunitinib after tumour removal in these patients.

  • 9. Bex, Axel
    et al.
    Albiges, Laurence
    Staehler, Michael
    Bensalah, Karim
    Giles, Rachel H.
    Dabestani, Saeed
    Hofmann, Fabian
    Hora, Milan
    Kuczyk, Markus A.
    Lam, Thomas B.
    Marconi, Lorenzo
    Merseburger, Axel S.
    Fernández-Pello, Sergio
    Tahbaz, Rana
    Abu-Ghanem, Yasmin
    Volpe, Alessandro
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Escudier, Bernard
    Powles, Thomas
    A Joint Statement from the European Association of Urology Renal Cell Cancer Guidelines Panel and the International Kidney Cancer Coalition: The Rejection of Ipilimumab and Nivolumab for Renal Cancer by the Committee for Medicinal Products for Human Use Does not Change Evidence-based Guideline Recommendations2018In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 74, no 6, p. 849-851, article id S0302-2838(18)30624-9Article in journal (Refereed)
  • 10. Bex, Axel
    et al.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Comparing Everolimus to Sunitinib in Non-clear-cell Renal Cell Carcinoma2016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 69, no 5, p. 875-876Article in journal (Other academic)
  • 11. Bex, Axel
    et al.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    van Poppel, Hein
    Powles, Thomas
    The Role of Cytoreductive Nephrectomy: European Association of Urology Recommendations in 20162016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 70, no 6, p. 901-905Article in journal (Refereed)
    Abstract [en]

    Patient summary: After the introduction of systemic targeted therapies, the use of nephrectomy in patients with metastatic renal cell carcinoma has declined. Currently, systemic therapy is offered to more patients first as a means to select those candidates that will likely benefit from removal of their primary tumour. Although studies consistently demonstrate a survival benefit after nephrectomy, most patients with poor risk metastatic disease are unlikely to benefit from surgery. Soon studies will report on the effect of nephrectomy in patients with metastatic disease at diagnosis.

  • 12. Bill-Axelson, Anna
    et al.
    Garmo, Hans
    Lambe, Mats
    Bratt, Ola
    Adolfsson, Jan
    Nyberg, Ullakarin
    Steineck, Gunnar
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Suicide risk in men with prostate-specific antigen-detected early prostate cancer: a nationwide population-based cohort study from PCBaSe Sweden.2010In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 57, no 3, p. 390-395Article in journal (Refereed)
    Abstract [en]

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

  • 13.
    Bovinder Ylitalo, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jernberg, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Egevad, Lars
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Subgroups of castration-resistant prostate cancer bone metastases defined through an inverse relationship between androgen receptor activity and immune response2017In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 71, no 5, p. 776-787Article in journal (Refereed)
    Abstract [en]

    Background: Novel therapies for men with castration-resistant prostate cancer (CRPC) are needed, particularly for cancers not driven by androgen receptor (AR) activation. Objectives: To identify molecular subgroups of PC bone metastases of relevance for therapy.

    Design, setting, and participants: Fresh-frozen bone metastasis samples from men with CRPC (n = 40), treatment-naïve PC (n = 8), or other malignancies (n = 12) were characterized using whole-genome expression profiling, multivariate principal component analysis (PCA), and functional enrichment analysis. Expression profiles were verified by reverse transcription–polymerase chain reaction (RT-PCR) in an extended set of bone metastases (n = 77) and compared to levels in malignant and adjacent benign prostate tissue from patients with localized disease (n = 12). Selected proteins were evaluated using immunohistochemistry. A cohort of PC patients (n = 284) diagnosed at transurethral resection with long follow-up was used for prognostic evaluation.

    Results and limitations: The majority of CRPC bone metastases (80%) was defined as AR-driven based on PCA analysis and high expression of the AR, AR co-regulators (FOXA1, HOXB13), and AR-regulated genes (KLK2, KLK3, NKX3.1, STEAP2, TMPRSS2); 20% were non–AR-driven. Functional enrichment analysis indicated high metabolic activity and low immune responses in AR-driven metastases. Accordingly, infiltration of CD3+ and CD68+ cells was lower in AR-driven than in non–AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity. RT-PCR analysis showed low MHC class I expression (HLA-A, TAP1, and PSMB9 mRNA) in PC bone metastases compared to benign and malignant prostate tissue and bone metastases of other origins. In primary PC, low HLA class I ABC immunoreactivity was associated with high Gleason score, bone metastasis, and short cancer-specific survival. Limitations include the limited number of patients studied and the single metastasis sample studied per patient.

    Conclusions: Most CRPC bone metastases show high AR and metabolic activities and low immune responses. A subgroup instead shows low AR and metabolic activities, but high immune responses. Targeted therapy for these groups should be explored. Patient summary: We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possible importance for therapy selection in individual patients.

  • 14. Bratt, Ola
    et al.
    Folkvaljon, Yasin
    Eriksson, Marie Hjälm
    Akre, Olof
    Carlsson, Stefan
    Drevin, Linda
    Lissbrant, Ingela Franck
    Makarov, Danil
    Loeb, Stacy
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Undertreatment of Men in Their Seventies with High-risk Nonmetastatic Prostate Cancer2015In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 68, no 1, p. 53-58Article in journal (Refereed)
    Abstract [en]

    Background: Many elderly men with high-risk nonmetastatic prostate cancer (HRnMPCa) do not receive radical treatment, despite the high mortality associated with conservative management. Objective: To investigate how age and comorbidity affect treatment of men with HRnMPCa. Design, setting, and participants: This was an observational nationwide register study during 2001-2012. We identified 19 190 men of <80 yr of age diagnosed with HRnMPCa in the National Prostate Cancer Register of Sweden and 95 948 age-matched men without prostate cancer in the register of the total population. Outcome measurements and statistical analysis: The outcome was the proportion of men with HRnMPCa receiving radical treatment (radical prostatectomy or radiotherapy). Vital status and the Charlson comorbidity index (CCI) were obtained from nationwide registers. The 10-yr survival of men without prostate cancer, stratified by age and CCI, was used as a measure of the life expectancy of the men with prostate cancer. Results and limitations: The proportions receiving radical treatment varied with life expectancy among men younger than 70 yr, whereas use of these treatments did not match the long life expectancy of men in their seventies with CCI 0-1. Only 10% of men aged 75-80 yr with CCI 0 received radical treatment despite 52% probability of 10-yr life expectancy, compared with approximately half of the men younger than 70 yr with a similar life expectancy. The use of radical treatment for HRnMPCa increased with time in all Swedish counties, but a threefold difference between counties remained in 2009-2012 for patients aged 70-80 yr with CCI 0-1. Uncertain external validity is a study limitation, and the impact of physician versus patient preferences on treatment selection could not be assessed. Conclusions: Otherwise healthy men in their seventies with HRnMPCa were less likely to receive radical treatment than younger men with a similar life expectancy, although increasing use of radical treatment was observed during the study period. Our findings highlight the need for improved methods for clinical decision-making, including improved assessment of life expectancy. Patient summary: We performed a nationwide register study that showed that many healthy men in their seventies live for at least another 10 yr. Despite this long life expectancy, men in their seventies with high-risk nonmetastatic prostate cancer were often not treated with radical prostatectomy or radiotherapy, possibly because their life expectancy was underestimated. Our study highlights the need for improved clinical decision-making, which should incorporate an assessment of the patient's life expectancy.

  • 15. Bruins, Harman M
    et al.
    Veskimae, Erik
    Hernandez, Virginia
    Imamura, Mari
    Neuberger, Molly M
    Dahm, Philip
    Stewart, Fiona
    Lam, Thomas B
    N'Dow, James
    van der Heijden, Antoine G
    Compérat, Eva
    Cowan, Nigel C
    De Santis, Maria
    Gakis, Georgios
    Lebret, Thierry
    Ribal, Maria J
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Witjes, J Alfred
    The impact of the extent of lymphadenectomy on oncologic outcomes in patients undergoing radical cystectomy for bladder cancer: a systematic review2014In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 66, no 6, p. 1065-1077Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Controversy exists regarding the therapeutic value of lymphadenectomy (LND) in patients undergoing radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). OBJECTIVE: To systematically review the relevant literature assessing the impact of LND on oncologic and perioperative outcomes in patients undergoing RC for MIBC. EVIDENCE ACQUISITION: Medline, Medline In-Process, Embase, the Cochrane Central Register of Controlled Trials, and the Latin American and Caribbean Center on Health Sciences Information (LILACS) were searched up to December 2013. Comparative studies reporting on no LND, limited LND (L-LND), standard LND (S-LND), extended LND (E-LND), superextended LND (SE-LND), and oncologic and perioperative outcomes were included. Risk-of-bias and confounding assessments were performed. EVIDENCE SYNTHESIS: Twenty-three studies reporting on 19 793 patients were included. All but one study were retrospective. Planned meta-analyses were not possible because of study heterogeneity; therefore, data were synthesized narratively. There were high risks of bias and confounding across most studies as well as extreme heterogeneity in the definition of the anatomic boundaries of LND templates. All seven studies comparing LND with no LND favored LND in terms of better oncologic outcomes. Seven of 14 studies comparing (super)extended LND with L-LND or S-LND reported a beneficial outcome for (super)extended LND in at least a subset of patients. No difference in outcome was reported in two studies comparing E-LND and S-LND. The comparative harms of different extents of LND remain unclear. CONCLUSIONS: Although the quality of the data was poor, the available evidence indicates that any kind of LND is advantageous over no LND. Similarly, E-LND appears to be superior to lesser degrees of dissection, while SE-LND offered no additional benefits. It is hoped that data from ongoing randomized clinical trials will clarify remaining uncertainties. PATIENT SUMMARY: The current literature suggests that removal of lymph nodes in bladder cancer surgery is beneficial and might result in better outcomes in terms of prolonging survival; however, the quality of the available studies is poor, and high-quality studies are needed.

  • 16. Budäus, Lars
    et al.
    Bolla, Michel
    Bossi, Alberto
    Cozzarini, Cesare
    Crook, Juanita
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wiegel, Thomas
    Functional Outcomes and Complications Following Radiation Therapy for Prostate Cancer: A Critical Analysis of the Literature2012In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 61, no 1, p. 112-127Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Prostate cancer (PCa) patients have many options within the realms of surgery or radiation therapy (RT). Technical advancements in RT planning and delivery have yielded different approaches, such as external beam, brachytherapy, and newer approaches such as image-guided tomotherapy or volumetric-modulated arc therapy. The selection of the optimal RT treatment for the individual is still a point of discussion, and the debate centres on two important outcomes-namely, cancer control and reduction of side-effects.

    OBJECTIVE: To critically review and summarise the available literature on functional outcomes and rectal sequelae following RT for PCa treatment.

    EVIDENCE ACQUISITION: A review of the literature published between 1999 and 2010 was performed using Medline and Scopus search. Relevant reports were identified using the terms prostate cancer, radiotherapy, functional outcomes, external beam radiation, brachytherapy, IMRT, quality of life, and tomotherapy and were critically reviewed and summarised.

    EVIDENCE SYNTHESIS: Related to nonuniform definition of their assessed functional end points and uneven standards of reporting, only a minority of series retrieved could be selected for analyses. Moreover, patterns of patient selection for different types of RT, inherent differences in the RT modalities, and the presence or absence of hormonal treatment also limit the ability to synthesise results from different publications or perform meta-analyses across the different treatment types. Nonetheless, several studies agree that recent technical improvements in the field of RT planning and delivery enable the administration of higher doses with equal or less toxicity. Regardless of the type of RT, the most frequently considered functional end points in the published analyses are gastrointestinal (GI) complications and rectal bleeding. Established risk factors for acute or late toxicities after RT include advanced age, larger rectal volume, a history of prior abdominal surgery, the concomitant use of androgen deprivation, preexisting diabetes mellitus, haemorrhoids, and inflammatory bowel disease (IBD). Similarly, mild acute irritative urinary symptoms are reported in several studies, whereas total urinary incontinence and other severe urinary symptoms are rare. Pretreatment genitourinary complaints, prior transurethral resection of the prostate (TURP), and the presence of acute genitourinary toxicity are suggested as contributing to long-term urinary morbidity. Erectile dysfunction (ED) is not an immediate side-effect of RT, and the occurrence of spontaneous erections before treatment is the best predictor for preserving erections sufficient for intercourse. In addition, the use of magnetic resonance imaging (MRI) permits a reduction in the dose delivered to vascular structures critical for erectile function.

    CONCLUSIONS: In the future, further improvement in RT planning and delivery will decrease side-effects and permit administration of higher doses. Related to the anatomy of the prostate, these higher doses may favour rectal sparing while not readily sparing the urethra and bladder neck. As a consequence, there may be a future shift from dose-limiting long-term rectal morbidity towards long-term urinary morbidity. In the absence of prospective randomised trials comparing different types of surgical and RT-based treatments in PCa, the introduction of validated tools for reporting functional and clinical outcomes is crucial for evaluating and identifying each individual's best treatment choice.

  • 17. Dabestani, Saeed
    et al.
    Beisland, Christian
    Stewart, Grant D.
    Bensalah, Karim
    Gudmundsson, Eirikur
    Lam, Thomas B.
    Gietzmann, William
    Zakikhani, Paimaun
    Marconi, Lorenzo
    Fernandez-Pello, Sergio
    Monagas, Serenella
    Williams, Samuel Paul
    Torbrand, Christian
    Powles, Thomas
    Van Werkhoven, Erik
    Meijer, Richard
    Volpe, Alessandro
    Staehler, Michael
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bex, Axel
    Intensive Imaging-based Follow-up of Surgically Treated Localised Renal Cell Carcinoma Does Not Improve Post-recurrence Survival: Results from a European Multicentre Database (RECUR)2019In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 75, no 2, p. 261-264Article in journal (Refereed)
    Abstract [en]

    The optimal follow-up (FU) strategy for patients treated for localised renal cell carcinoma(RCC) remains unclear. Using the RECUR database, we studied imaging intensity utilised in contemporary FU to evaluate its association with outcome after detection of disease recurrence. Consecutive patients with nonmetastatic RCC (n = 1612) treated with curative intent at 12 institutes across eight European countries between 2006 and 2011 were included. Recurrence occurred in 336 patients. Cross-sectional (computed tomography, magnetic resonance imaging) and conventional (chest X-ray, ultrasound) methods were used in 47% and 53%, respectively. More intensive FU imaging (more than twofold) than recommended by the European Association of Urology (EAU) was not associated with improved overall survival (OS) after recurrence. Overall, per patient treated for recurrence remaining alive with no evidence of disease, the number of FU images needed was 542, and 697 for high-risk patients. The study results suggest that use of more imaging during FU than that recommended in the 2017 EAU guidelines is unlikely to improve OS after recurrence. Prospective studies are needed to design optimal FU strategies for the future.

    Patient summary: After curative treatment for localised kidney cancer, follow-up is necessary to detect any recurrence. This study illustrates that increasing the imaging frequency during follow-up, even to double the number of follow-up imaging procedures recommended by the European Association of Urology guidelines, does not translate into improved survival for those with recurrence.

  • 18.
    Duchek, Milos
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Jahnson, Staffan
    Mestad, Oddvar
    Hellström, Pekka
    Hellsten, Sverker
    Malmström, Per-Uno
    Bacillus Calmette-Guérin is superior to a combination of epirubicin and interferon-alpha2b in the intravesical treatment of patients with stage T1 urinary bladder cancer. A prospective, randomized, Nordic study.2010In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 57, no 1, p. 25-31Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bacillus Calmette-Guérin (BCG) instillation is regarded as the most effective bladder-sparing treatment for patients with high-grade T1 tumours and carcinoma in situ (CIS). The major problem with this therapy is the side-effects, making maintenance therapy difficult, even impossible, in a proportion of patients. Thus, alternative schedules and drugs have been proposed.

    OBJECTIVE: To compare BCG to the combination of epirubicin and interferon-alpha2b as adjuvant therapy of T1 tumours.

    DESIGN, SETTING, AND PARTICIPANTS: This is a Nordic multicenter, prospective, randomised trial in patients with primary T1 G2-G3 bladder cancer. Initial transurethral resection (TUR) was followed by a second-look resection. Patients were randomised to receive either regimen, given as induction for 6 wk followed by maintenance therapy for 2 yr.

    MEASUREMENTS: The drugs were compared with respect to time to recurrence and progression. Also, side-effects were documented.

    RESULTS AND LIMITATIONS: A total of 250 patients were randomised. At the primary end point, 62% were disease free in the combination arm as opposed to 73% in the BCG arm (p=0.065). At 24 mo, there was a significant difference in favour of the BCG-treated patients (p=0.012) regarding recurrence, although there was no difference regarding progression. The subgroup analysis showed that the superiority of BCG was mainly in those with concomitant CIS. In a multivariate analysis of association with recurrence/progression status, significant variables for outcome were type of drug, tumour size, multiplicity, status at second-look resection, and grade. A corresponding analysis was performed separately in the two treatment arms. Tumour size was the only significant variable for BCG-treated patients, while multiplicity, status at second-look resection, and grade were significant for patients treated with the combination.

    CONCLUSIONS: For prophylaxis of recurrence, BCG was more effective than the combination. There were no differences regarding progression and adverse events between the two treatments.

  • 19. Fernández-Pello, Sergio
    et al.
    Hofmann, Fabian
    Tahbaz, Rana
    Marconi, Lorenzo
    Lam, Thomas B
    Albiges, Laurence
    Bensalah, Karim
    Canfield, Steven E
    Dabestani, Saeed
    Giles, Rachel H
    Hora, Milan
    Kuczyk, Markus A
    Merseburger, Axel S
    Powles, Thomas
    Staehler, Michael
    Volpe, Alessandro
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bex, Axel
    A Systematic Review and Meta-analysis Comparing the Effectiveness and Adverse Effects of Different Systemic Treatments for Non-clear Cell Renal Cell Carcinoma.2017In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 71, no 3, p. 426-436Article, review/survey (Refereed)
    Abstract [en]

    CONTEXT: While vascular endothelial growth factor-targeted therapy and mammalian target of rapamycin inhibition are effective strategies in treating clear cell renal cell carcinoma (ccRCC), the most effective therapeutic approach for patients with non-clear cell RCC (non-ccRCC) is unknown.

    OBJECTIVE: To systematically review relevant literature comparing the oncological outcomes and adverse events of different systemic therapies for patients with metastatic non-ccRCC.

    EVIDENCE ACQUISITION: Relevant databases including MEDLINE, Embase, and the Cochrane Library were searched up to March 24, 2016. Only comparative studies were included. Risk of bias and confounding assessments were performed. A meta-analysis was planned for and only performed if methodologically appropriate; otherwise, a narrative synthesis was undertaken.

    EVIDENCE SYNTHESIS: The literature search identified 812 potential titles and abstracts. Five randomized controlled trials, recruiting a total of 365 patients, were included. Three studies compared sunitinib against everolimus, one of which reported the results for non-ccRCC as a subgroup rather than as an entire randomized cohort. Individually, the studies showed a trend towards favoring sunitinib in terms of overall survival and progression-free survival (PFS; Everolimus versus Sunitinib in Patients with Metastatic Non-clear Cell Renal Cell Carcinoma hazard ratio [HR]: 1.41, 80% confidence interval [CI] 1.03-1.92 and 1.41, 95% CI: 0.88-2.27, Evaluation in Metastatic Non-clear Cell Renal Cell Carcinoma HR: 1.16, 95% CI: 0.67-2.01, Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients with Metastatic Renal Cell Carcinoma HR: 1.5, 95% CI: 0.9-2.8), but this trend did not reach statistical significance in any study. Meta-analysis was performed on two studies which solely recruited patients with non-ccRCC reporting on PFS, the results of which were inconclusive (HR: 1.30, 95% CI: 0.91-1.86). Sunitinib was associated with more Grade 3-4 adverse events than everolimus, although this was not statistically significant.

    CONCLUSIONS: This systematic review and meta-analysis represent a robust summary of the evidence base for systemic treatment of metastatic non-ccRCC. The results show a trend towards favoring vascular endothelial growth factor-targeted therapy for PFS and overall survival compared with mammalian target of rapamycin inhibitors, although statistical significance was not reached. The relative benefits and harms of these treatments remain uncertain. Further research, either in the form of an individual patient data meta-analysis involving all relevant trials, or a randomized controlled trial with sufficient power to detect potential differences between treatments, is needed.

    PATIENT SUMMARY: We examined the literature to determine the most effective treatments for advanced kidney cancer patients whose tumors are not of the clear cell subtype. The results suggest that a drug called sunitinib might be more effective than everolimus, but the statistics supporting this statement are not yet entirely reliable. Further research is required to clarify this unmet medical need.

  • 20. Fossa, Sophie D.
    et al.
    Wiklund, Fredrik
    Klepp, Olbjorn
    Angelsen, Anders
    Solberg, Arne
    Dumber, Jan-Erik
    Hoyer, Morten
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ten- and 15-yr Prostate Cancer-specific Mortality in Patients with Nonmetastatic Locally Advanced or Aggressive Intermediate Prostate Cancer, Randomized to Lifelong Endocrine Treatment Alone or Combined with Radiotherapy: Final Results of The Scandinavian Prostate Cancer Group-72016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 70, no 4, p. 684-691Article in journal (Refereed)
    Abstract [en]

    Background: In high-risk prostate cancer (PCa), no study with observation times beyond 10 yr has demonstrated survival improvement after addition of prostatic radiotherapy (RAD) to endocrine treatment (ET) alone. Objective: To compare mortality rates in patients receiving ET alone versus ET + RAD. Design, settings, and participants: From 1996 to 2002, 875 Scandinavian patients with high-risk (90%) or intermediate PCa were randomized to ET or ET + RAD (The Scandinavian Prostate Cancer Group-7). After 3 mo with total androgen blockade in all patients, all individuals continued lifelong antiandrogen monotherapy. Those randomized to ET + RAD started prostate radiotherapy (70 Gy) at 3 mo. Outcome, measurements and statistical analysis: PCa-specific 15-yr mortality represented the primary endpoint. Assessment of the combination treatment effect and prognostic factors was performed in competing risk analyses and Cox proportional-hazard models. Intervention: RAD added to ET. Results and limitations: With a median observation time of 12 yr, the 15-yr PCa-specific mortality rates were 34% (95% confidence interval, 29-39%) and 17% (95% confidence interval, 13-22%) in the ET and ET + RAD arms respectively (p < 0.001). Compared with the ET arm, the median overall survival in the ET + RAD arm was prolonged by 2.4 yr. Treatment with ET alone, age >= 65 yr and increasing histology grade independently increased the risk of PCa-specific and overall mortality. Limitations include nonformal evaluation of comorbidity, the inability to calculate progression-free survival, and lack of information about salvage therapy and toxicity. Conclusions: In patients with nonmetastatic locally advanced or aggressive PCa, ET + RAD reduces the absolute risk of PCa-specific death by 17% at 15 yr compared with ET alone; the comparable 15-yr PCa-specific mortality rates being 17% and 34%. The results warrant a phase 3 study comparing ET + RAD with radical prostatectomy in high-risk PCa. Patient summary: Adding prostatic therapy to lifelong antiandrogen therapy halves the absolute risk of death from prostate cancer from 34% to 17% 15 yr after diagnosis. 

  • 21. Gakis, Georgios
    et al.
    Witjes, J. Alfred
    Comperat, Eva
    Cowan, Nigel C.
    De Santis, Maria
    Lebret, Thierry
    Ribal, Maria J.
    Sherif, Amir M.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    EAU Guidelines on Primary Urethral Carcinoma2013In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 64, no 5, p. 823-830Article in journal (Refereed)
    Abstract [en]

    Context: The European Association of Urology (EAU) Guidelines Group on Muscle-Invasive and Metastatic Bladder Cancer prepared these guidelines to deliver current evidence-based information on the diagnosis and treatment of patients with primary urethral carcinoma (UC).

    Objective: To review the current literature on the diagnosis and treatment of patients with primary UC and assess its level of scientific evidence.

    Evidence acquisition: A systematic literature search was performed to identify studies reporting urethral malignancies. Medline was searched using the controlled vocabulary of the Medical Subject Headings database, along with a free-text protocol.

    Evidence synthesis: Primary UC is considered a rare cancer, accounting for <1% of all malignancies. Risk factors for survival include age, tumour stage and grade, nodal stage, presence of distant metastasis, histologic type, tumour size, tumour location, and modality of treatment. Pelvic magnetic resonance imaging is the preferred method to assess the local extent of urethral tumour; computed tomography of the thorax and abdomen should be used to assess distant metastasis. In localised anterior UC, urethra-sparing surgery is an alternative to primary urethrectomy in both sexes, provided negative surgical margins can be achieved. Patients with locally advanced UC should be discussed by a multidisciplinary team of urologists, radiation oncologists, and oncologists. Patients with noninvasive UC or carcinoma in situ of the prostatic urethra and prostatic ducts can be treated with a urethra-sparing approach with transurethral resection and bacillus Calmette-Guerin (BCG). Cystoprostatectomy with extended pelvic lymphadenectomy should be reserved for patients not responding to BCG or as a primary treatment option in patients with extensive ductal or stromal involvement.

    Conclusions: The 2013 guidelines document on primary UC is the first publication on this topic by the EAU. It aims to increase awareness in the urologic community and provide scientific transparency to improve outcomes of this rare urogenital malignancy.

  • 22. Gontero, Paolo
    et al.
    Sylvester, Richard
    Pisano, Francesca
    Joniau, Steven
    Eeckt, Kathy Vander
    Serretta, Vincenzo
    Larre, Stephane
    Di Stasi, Savino
    Van Rhijn, Bas
    Witjes, Alfred J.
    Grotenhuis, Anne J.
    Kiemeney, Lambertus A.
    Colombo, Renzo
    Briganti, Alberto
    Babjuk, Marek
    Malmström, Per-Uno
    Oderda, Marco
    Irani, Jacques
    Malats, Nuria
    Baniel, Jack
    Mano, Roy
    Cai, Tommaso
    Cha, Eugene K.
    Ardelt, Peter
    Varkarakis, John
    Bartoletti, Riccardo
    Spahn, Martin
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Frea, Bruno
    Soukup, Viktor
    Xylinas, Evanguelos
    Dalbagni, Guido
    Karnes, R. Jeffrey
    Shariat, Shahrokh F.
    Palou, Joan
    Prognostic Factors and Risk Groups in T1G3 Non-Muscle-invasive Bladder Cancer Patients Initially Treated with Bacillus Calmette-Guerin: Results of a Retrospective Multicenter Study of 2451 Patients2015In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 67, no 1, p. 74-82Article in journal (Refereed)
    Abstract [en]

    Background: The impact of prognostic factors in T1G3 non-muscle-invasive bladder cancer (BCa) patients is critical for proper treatment decision making. Objective: To assess prognostic factors in patients who received bacillus Calmette Guerin (BCG) as initial intravesical treatment of T1G3 tumors and to identify a subgroup of high-risk patients who should be considered for more aggressive treatment. Design, setting, and participants: Individual patient data were collected for 2451 T1G3 patients from 23 centers who received BCG between 1990 and 2011. Outcome measurements and statistical analysis: Using Cox multivariable regression, the prognostic importance of several clinical variables was assessed for time to recurrence, progression, BCa-specific survival, and overall survival (OS). Results and limitations: With a median follow-up of 5.2 yr, 465 patients (19%) progressed, 509 (21%) underwent cystectomy, and 221 (9%) died because of BCa. In multivariable analyses, the most important prognostic factors for progression were age, tumor size, and concomitant carcinoma in situ (CIS); the most important prognostic factors for BCa-specific survival and OS were age and tumor size. Patients were divided into four risk groups for progression according to the number of adverse factors among age >= 70 yr, size >= 3 cm, and presence of CIS. Progression rates at 10 yr ranged from 17% to 52%. BCa-specific death rates at 10 yr were 32% in patients >= 70 yr with tumor size >= 3 cm and 13% otherwise. Conclusions: T1G3 patients >= 70 yr with tumors >= 3 cm and concomitant CIS should be treated more aggressively because of the high risk of progression. Patient summary: Although the majority of T1G3 patients can be safely treated with intravesical bacillus Calmette-Guerin, there is a subgroup of T1G3 patients with age >= 70 yr, tumor size >= 3 cm, and concomitant CIS who have a high risk of progression and thus require aggressive treatment.

  • 23. Guomundsson, Eirikur
    et al.
    Hellborg, Henrik
    Lundstam, Sven
    Erikson, Stina
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Metastatic potential in renal cell carcinomas <= 7 cm: swedish kidney cancer quality register data2011In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 60, no 5, p. 975-982Article in journal (Refereed)
    Abstract [en]

    Background: Renal cell carcinoma(RCC) represents 2-3% of all malignancies and accounts for approximately 90% of all kidney malignancies. An increasing proportion of RCCs are discovered incidentally, and the average tumor diameter at diagnosis has decreased over the last few decades. Small RCCs have often been regarded by many as relatively harmless.

    Objective: The objective was to evaluate the incidence of local T-category distribution and lymph node and distant metastases in relation to tumor size in RCCs <= 7 cm in a nationally based patient population. Design, setting, and participants: Data were extracted from the National Swedish Kidney Cancer Register containing 3489 RCCs diagnosed between 2005 and 2008. This is a population-based registry including 99% of all RCCs diagnosed nationwide. The study included 2033 patients having a tumor <= 7 cm in diameter.

    Measurements: The size of the tumors was compared with sex, age, cause of diagnosis, Fuhrman grade, RCC type, and TNM category.

    Results and limitations: Most RCCs were discovered incidentally and incidence correlated inversely to tumor size. There were 887 (43%) patients with category T1a tumors, 836 (40%) with category T1b, 174 (8%) with T3a, 131 (6%) with T3b/c, and 12 (1%) patients had invasion of adjacent organs (T4). A total of 309 (15%) patients had lymph node and/or distant metastases. Of the 177 1- to 2-cm RCCs, category T3 tumors were identified in three patients and lymph node and/or distant metastases were identified in 8 (5%). Only for tumors <= 1 cm was there neither advanced stage nor metastasis. The occurrence of locally advanced growth, lymph node and distant metastases, and high tumor grade correlated to tumor size. Patients with Fuhrman grade III or IV had a fourfold greater risk of metastases than grades I or II.

    Conclusions: Lymph node and distant metastases occur even in small RCCs. Risk of metastases increases with tumor size. The data clearly show that small RCCs also have a malignant potential and should be properly evaluated and adequately treated. (C) 2011 European Association of Urology. Published by Elsevier B. V. All rights reserved.

  • 24. Iglesias-Gato, Diego
    et al.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tyanova, Stefka
    Lavallee, Charlotte
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Carlsson, Jessica
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Cox, Juergen
    Andren, Ove
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Egevad, Lars
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bjartell, Anders
    Collins, Colin C.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Geiger, Tamar
    Mann, Matthias
    Flores-Morales, Amilcar
    The Proteome of Primary Prostate Cancer2016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 69, no 5, p. 942-952Article in journal (Refereed)
    Abstract [en]

    Background: Clinical management of the prostate needs improved prognostic tests and treatment strategies. Because proteins are the ultimate effectors of most cellular reactions, are targets for drug actions and constitute potential biomarkers; a quantitative systemic overview of the proteome changes occurring during prostate cancer (PCa) initiation and progression can result in clinically relevant discoveries. Objectives: To study cellular processes altered in PCa using system-wide quantitative analysis of changes in protein expression in clinical samples and to identify prognostic biomarkers for disease aggressiveness. Design, setting, and participants: Mass spectrometry was used for genome-scale quantitative proteomic profiling of 28 prostate tumors (Gleason score 6-9) and neighboring nonmalignant tissue in eight cases, obtained from formalin-fixed paraffin-embedded prostatectomy samples. Two independent cohorts of PCa patients (summing 752 cases) managed by expectancy were used for immunohistochemical evaluation of proneuropeptide-Y (pro-NPY) as a prognostic biomarker. Results and limitations: Over 9000 proteins were identified as expressed in the human prostate. Tumor tissue exhibited elevated expression of proteins involved in multiple anabolic processes including fatty acid and protein synthesis, ribosomal biogenesis and protein secretion but no overt evidence of increased proliferation was observed. Tumors also showed increased levels of mitochondrial proteins, which was associated with elevated oxidative phosphorylation capacity measured in situ. Molecular analysis indicated that some of the proteins overexpressed in tumors, such as carnitine palmitoyltransferase 2 (CPT2, fatty acid transporter), coatomer protein complex, subunit alpha (COPA, vesicle secretion), and mitogen-and stress-activated protein kinase 1 and 2 (MSK1/2, protein kinase) regulate the proliferation of PCa cells. Additionally, pro-NPY was found overexpressed in PCa (5-fold, p < 0.05), but largely absent in other solid tumor types. Pro-NPY expression, alone or in combination with the ERG status of the tumor, was associated with an increased risk of PCa specific mortality, especially in patients with Gleason score <= 7 tumors. Conclusions: This study represents the first system-wide quantitative analysis of proteome changes associated to localized prostate cancer and as such constitutes a valuable resource for understanding the complex metabolic changes occurring in this disease. We also demonstrated that pro-NPY, a protein that showed differential expression between high and low risk tumors in our proteomic analysis, is also a PCa specific prognostic biomarker associated with increased risk for disease specific death in patients carrying low risk tumors. Patient summary: The identification of proteins whose expression change in prostate cancer provides novel mechanistic information related to the disease etiology. We hope that future studies will prove the value of this proteome dataset for development of novel therapies and biomarkers. 

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

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

  • 26.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Granfors, Torvald
    Egevad, Lars
    Karlberg, Lars
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tumor size, vascular density and proliferation as prognostic markers in GS 6 and GS 7 prostate tumors in patients with long follow-up and non-curative treatment2005In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 48, no 4, p. 577-583Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 27. Krantz, David
    et al.
    Hartana, Ciputra Adijaya
    Winerdal, Malin E
    Johansson, Markus
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Sundsvall Hospital, Sundsvall, Sweden.
    Alamdari, Farhood
    Jakubczyk, Tomasz
    Huge, Ylva
    Aljabery, Firas
    Palmqvist, Karin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urology Section, Department of Surgery, Östersund County Hospital, Östersund, Sweden.
    Zirakzadeh, A Ali
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Holmström, Benny
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Division of Urology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Winqvist, Ola
    Neoadjuvant Chemotherapy Reinforces Antitumour T cell Response in Urothelial Urinary Bladder Cancer2018In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 74, no 6, p. 688-692Article in journal (Refereed)
    Abstract [en]

    Evidence indicates that neoadjuvant chemotherapy (NAC) may promote antitumour immune responses by activating T cells. The tumour-draining sentinel node (SN) is a key site to study tumour-specific T cell activation, being the primary immunological barrier against the tumour. In this prospective study, we set out to elucidate the effects of NAC on T cell subsets in the SNs of patients with muscle-invasive urothelial bladder cancer. We found that CD8+ effector T (Teff) cell exhaustion was reduced after NAC treatment, while cytotoxicity was increased. Additionally, in complete responders (CR patients), these cells were functionally committed effectors, as displayed by epigenetic analysis. In CD4+ Teffs, NAC treatment was associated with increased clonal expansion of tumour-specific SN-derived cells, as demonstrated by a specific cell reactivity assay. In contrast, we observed an attenuating effect of NAC on regulatory T cells (Tregs) with a dose-dependent decrease in Treg frequency and reduced effector molecule expression in the remaining Tregs. In addition, multicolour flow cytometry analysis revealed that CR patients had higher Teff to activated Treg ratio, promoting antitumoural T cell activation. These results suggest that NAC reinforces the antitumour immune response by activating the effector arm of the T cell compartment and diminishing the influence of suppressive Tregs.

    PATIENT SUMMARY: In this report, we analysed the effect of chemotherapy on immune cell subsets of 40 patients with advanced bladder cancer. We found that chemotherapy has a positive effect on immune effector T cells, whereas an opposite, diminishing effect was observed for immune-suppressive regulatory T cells. We conclude that chemotherapy reinforces the antitumour immune response in bladder cancer patients.

  • 28. Lardas, Michael
    et al.
    Stewart, Fiona
    Scrimgeour, Duncan
    Hofmann, Fabian
    Marconi, Lorenzo
    Dabestani, Saeed
    Bex, Axel
    Volpe, Alessandro
    Canfield, Steven E
    Staehler, Michael
    Hora, Milan
    Powles, Thomas
    Merseburger, Axel S
    Kuczyk, Markus A
    Bensalah, Karim
    Mulders, Peter F A
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lam, Thomas B L
    Systematic Review of Surgical Management of Nonmetastatic Renal Cell Carcinoma with Vena Caval Thrombus2016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 70, no 2, p. 265-280Article, review/survey (Refereed)
    Abstract [en]

    CONTEXT: Overall, 4-10% of patients with renal cell carcinoma (RCC) present with venous tumour thrombus. It is uncertain which surgical technique is best for these patients. Appraisal of outcomes with differing techniques would guide practice.

    OBJECTIVE: To systematically review relevant literature comparing the outcomes of different surgical therapies and approaches in treating vena caval thrombus (VCT) from nonmetastatic RCC.

    EVIDENCE ACQUISITION: Relevant databases (Medline, Embase, and the Cochrane Library) were searched to identify relevant comparative studies. Risk of bias and confounding assessments were performed. A narrative synthesis of the evidence was presented.

    EVIDENCE SYNTHESIS: The literature search identified 824 articles. Fourteen studies reporting on 2262 patients were included. No distinct surgical method was superior for the excision of VCT, although the method appeared to be dependent on tumour thrombus level. Minimal access techniques appeared to have better perioperative and recovery outcomes than traditional median sternotomy, but the impact on oncologic outcomes is unknown. Preoperative renal artery embolisation did not offer any oncologic benefits and instead resulted in significantly worse perioperative and recovery outcomes, including possibly higher perioperative mortality. The comparison of cardiopulmonary bypass versus no cardiopulmonary bypass showed no differences in oncologic outcomes. Overall, there were high risks of bias and confounding.

    CONCLUSIONS: The evidence base, although derived from retrospective case series and complemented by expert opinion, suggests that patients with nonmetastatic RCC and VCT and acceptable performance status should be considered for surgical intervention. Despite a robust review, the findings were associated with uncertainty due to the poor quality of primary studies available. The most efficacious surgical technique remains unclear.

    PATIENT SUMMARY: We examined the literature on the benefits of surgery to remove kidney cancers that have spread to neighbouring veins. The results suggest such surgery, although challenging and associated with high risk of complications, appears to be feasible and effective and should be contemplated for suitable patients if possible; however, many uncertainties remain due to the poor quality of the data.

  • 29. Li, Weiqiang
    et al.
    Middha, Mridu
    Bicak, Mesude
    Sjoberg, Daniel D.
    Vertosick, Emily
    Dahlin, Anders
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rönn, Ann-Charlotte
    Stattin, Par
    Melander, Olle
    Ulmert, David
    Lilja, Hans
    Klein, Robert J.
    Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival2018In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 74, no 6, p. 710-719Article in journal (Refereed)
    Abstract [en]

    Background: Most men diagnosed with prostate cancer have low-risk cancers. How to predict prostate cancer progression at the time of diagnosis remains challenging.

    Objective: To identify single nucleotide polymorphisms (SNPs) associated with death from prostate cancer.

    Design, setting, and participants: Blood samples from 11 506 men in Sweden were collected during 1991–1996. Of these, 1053 men were diagnosed with prostate cancer and 245 died from the disease. Stage and grade at diagnosis and outcome information were obtained, and DNA from all cases was genotyped.

    Outcome measurements and statistical analysis: A total of 6 126 633 SNPs were tested for association with prostate-cancer-specific survival time using a Cox proportional hazard model, adjusted for age, stage, and grade at diagnosis. A value of 1 × 10−6 was used as suggestive significance threshold. Positive candidate SNPs were tested for association with gene expression using expression quantitative trait locus analysis.

    Results and limitations: We found 12 SNPs at seven independent loci associated with prostate-cancer-specific survival time. One of 6 126 633 SNPs tested reached genome-wide significance (p < 5 × 10−8) and replicated in an independent cohort: rs73055188 (p = 5.27 × 10−9, per-allele hazard ratio [HR] = 2.27, 95% confidence interval [CI] 1.72–2.98) in the AOX1 gene. A second SNP reached a suggestive level of significance (p < 1 × 10−6) and replicated in an independent cohort: rs2702185 (p = 7.1 × 10−7, per-allele HR = 2.55, 95% CI = 1.76–3.69) in the SMG7 gene. The SNP rs73055188 is correlated with AOX1 expression levels, which is associated with biochemical recurrence of prostate cancer in independent cohorts. This association is yet to be validated in other ethnic groups.

    Conclusions: The SNP rs73055188 at the AOX1 locus is associated with prostate-cancer-specific survival time, and AOX1 gene expression level is correlated with biochemical recurrence of prostate cancer.

    Patient summary: We identify two genetic markers that are associated with prostate-cancer-specific survival time.

  • 30.
    Lidgren, Anders
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Hedberg, Ylva
    Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Clinical Microbiology. Umeå University, Faculty of Medicine, Clinical Microbiology, Biomedical Laboratory Science.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology. Onkologi.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Hypoxia-inducible factor 1alpha expression in renal cell carcinoma analyzed by tissue microarray2006In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 50, no 6, p. 1272-1277Article in journal (Refereed)
  • 31. Lindberg, Johan
    et al.
    Mills, Ian G.
    Klevebring, Daniel
    Liu, Wennuan
    Neiman, Marten
    Xu, Jianfeng
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wiklund, Peter
    Wiklund, Fredrik
    Egevad, Lars
    Gronberg, Henrik
    The Mitochondrial and Autosomal Mutation Landscapes of Prostate Cancer2013In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 63, no 4, p. 702-708Article in journal (Refereed)
    Abstract [en]

    Background: Prostate cancer (PCa) is the most common cancer in men. PCa is strongly age associated; low death rates in surveillance cohorts call into question the widespread use of surgery, which leads to overtreatment and a reduction in quality of life. There is a great need to increase the understanding of tumor characteristics in the context of disease progression. Objective: To perform the first multigenome investigation of PCa through analysis of both autosomal and mitochondrial DNA, and to integrate exome sequencing data, and RNA sequencing and copy-number alteration (CNA) data to investigate how various different tumor characteristics, commonly analyzed separately, are interconnected. Design, setting, and participants: Exome sequencing was applied to 64 tumor samples from 55 PCa patients with varying stage and grade. Integrated analysis was performed on a core set of 50 tumors from which exome sequencing, CNA, and RNA sequencing data were available. Outcome measurements and statistical analysis: Genes, mutated at a significantly higher rate relative to a genomic background, were identified. In addition, mitochondrial and autosomal mutation rates were correlated to CNAs and proliferation, assessed as a cell cycle gene expression signature. Results and limitations: Genes not previously reported to be significantly mutated in PCa, such as cell division cycle 27 homolog (Saccharomyces cerevisiae) (CDC27), myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3), lysine (K)-specific demethylase 6A (KDM6A), and kinesin family member 5A (KIF5A) were identified. The mutation rate in the mitochondrial genome was 55 times higher than that of the autosomes. Multilevel analysis demonstrated a tight correlation between high reactive-oxygen exposure, chromosomal damage, high proliferation, and in parallel, a transition from multiclonal indolent primary PCa to monoclonal aggressive disease. As we only performed targeted sequence analysis; copy-number neutral rearrangements recently described for PCa were not accounted for. Conclusions: The mitochondrial genome displays an elevated mutation rate compared to the autosomal chromosomes. By integrated analysis, we demonstrated that different tumor characteristics are interconnected, providing an increased understanding of PCa etiology. (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved.

  • 32.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Re: can partial nephrectomy preserve renal function and modify survival in comparison with radical nephrectomy?2011In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 60, no 3, p. 595-596Article in journal (Refereed)
  • 33.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Albiges, Laurance
    Abu-Ghanem, Yasmin
    Bensalan, Karim
    Dabestani, Saeed
    Montes, Sergio Fernandez-Pello
    Giles, Rachel H.
    Hofmann, Fabian
    Hora, Milan
    Kuczyk, Markus A.
    Kuusk, Teele
    Lam, Thomas B.
    Marconi, Lorenzo
    Merseburger, Axel S.
    Powles, Thomas
    Staehler, Michael
    Tahbaz, Rana
    Volpe, Alessandro
    Bex, Axel
    European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update2019In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 75, no 5, p. 799-810Article in journal (Refereed)
    Abstract [en]

    Context: The European Association of Urology Renal Cell Carcinoma (RCC) Guideline Panel has prepared evidence-based guidelines and recommendations for the management of RCC.

    Objective: To provide an updated RCC guideline based on standardised methodology including systematic reviews, which is robust, transparent, reproducible, and reliable.

    Evidence acquisition: For the 2019 update, evidence synthesis was undertaken based on a comprehensive and structured literature assessment for new and relevant data. Where necessary, formal systematic reviews adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were undertaken. Relevant databases (Medline, Cochrane Libraries, trial registries, conference proceedings) were searched until June 2018, including randomised controlled trials (RCTs) and retrospective or controlled studies with a comparator arm, systematic reviews, and meta-analyses. Where relevant, risk of bias (RoB) assessment, and qualitative and quantitative syntheses of the evidence were performed. The remaining sections of the document were updated following a structured literature assessment. Clinical practice recommendations were developed and issued based on the modified GRADE framework.

    Evidence synthesis: All chapters of the RCC guidelines were updated based on a structured literature assessment, for prioritised topics based on the availability of robust data. For RCTs, RoB was low across studies. For most non-RCTs, clinical and methodological heterogeneity prevented pooling of data. The majority of included studies were retrospective with matched or unmatched cohorts, based on single- or multi-institutional data or national registries. The exception was for the treatment of metastatic RCC, for which there were several large RCTs, resulting in recommendations based on higher levels of evidence.

    Conclusions: The 2019 RCC guidelines have been updated by the multidisciplinary panel using the highest methodological standards. These guidelines provide the most reliable contemporary evidence base for the management of RCC in 2019.

    Patient summary: The European Association of Urology Renal Cell Carcinoma Guideline Panel has thoroughly evaluated the available research data on kidney cancer to establish international standards for the care of kidney cancer patients.

  • 34.
    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. 

  • 35.
    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.

  • 36.
    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)
  • 37.
    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.

  • 38.
    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)
  • 39.
    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)
  • 40. 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.

  • 41. Loeb, Stacy
    et al.
    Folkvaljon, Yasin
    Robinson, David
    Lissbrant, Ingela Franck
    Egevad, Lars
    Stattin, Pär
    Evaluation of the 2015 Gleason Grade Groups in a Nationwide Population-based Cohort2016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 69, no 6, p. 1135-1141Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

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

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

  • 42. 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.

  • 43.
    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)
  • 44. 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.

  • 45. 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.

  • 46. 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.

  • 47. 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.

  • 48. 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.

  • 49. Marconi, Lorenzo
    et al.
    Dabestani, Saeed
    Lam, Thomas B.
    Hofmann, Fabian
    Stewart, Fiona
    Norrie, John
    Bex, Axel
    Bensalah, Karim
    Canfield, Steven E.
    Hora, Milan
    Kuczyk, Markus A.
    Merseburger, Axel S.
    Mulders, Peter F. A.
    Powles, Thomas
    Staehler, Michael
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Volpe, Alessandro
    Systematic Review and Meta-analysis of Diagnostic Accuracy of Percutaneous Renal Tumour Biopsy2016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 69, no 4, p. 660-673Article, review/survey (Refereed)
    Abstract [en]

    Context: The role of percutaneous renal tumour biopsy (RTB) remains controversial due to uncertainties regarding its diagnostic accuracy and safety.

    Objective: We performed a systematic review and meta-analysis to determine the safety and accuracy of percutaneous RTB for the diagnosis of malignancy, histologic tumour subtype, and grade.

    Evidence acquisition: Medline, Embase, and Cochrane Library were searched for studies providing data on diagnostic accuracy and complications of percutaneous core biopsy (CB) or fine-needle aspiration (FNA) of renal tumours. A meta-analysis was performed to obtain pooled estimates of sensitivity and specificity for diagnosis of malignancy. The Cohen kappa coefficient (κ) was estimated for the analysis of histotype/grade concordance between diagnosis on RTB and surgical specimen. Risk of bias assessment was performed (QUADAS-2).

    Evidence synthesis: A total of 57 studies recruiting 5228 patients were included. The overall median diagnostic rate of RTB was 92%. The sensitivity and specificity of diagnostic CBs and FNAs were 99.1% and 99.7%, and 93.2% and 89.8%, respectively. A good (κ = 0.683) and a fair (κ = 0.34) agreement were observed between histologic subtype and Fuhrman grade on RTB and surgical specimen, respectively. A very low rate of Clavien ≥2 complications was reported. Study limitations included selection and differential-verification bias.

    Conclusions: RTB is safe and has a high diagnostic yield in experienced centres. Both CB and FNA have good accuracy for the diagnosis of malignancy and histologic subtype, with better performance for CB. The accuracy for Fuhrman grade is fair. Overall, the quality of the evidence was moderate. Prospective cohort studies recruiting consecutive patients and using homogeneous reference standards are required.

    Patient summary: We systematically reviewed the literature to assess the safety and diagnostic performance of renal tumour biopsy (RTB). The results suggest that RTB has good accuracy in diagnosing renal cancer and its subtypes, and it appears to be safe. However, the quality of evidence was moderate, and better quality studies are required to provide a more definitive answer.

  • 50. Marconi, Lorenzo
    et al.
    Lam, Thomas B.
    Bex, Axel
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Volpe, Alessandro
    Reply to E. Jason Abel Letter to the Editor re: Lorenzo Marconi, Saeed Dabestani, Thomas B. Lam, et al. Systematic Review and Meta-analysis of Diagnostic Accuracy of Percutaneous Renal Tumour Biopsy. Eur Urol 2016;69:660-732016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 69, no 6, p. E119-E120Article in journal (Refereed)
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