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  • 1. Ahlén Bergman, Emma
    et al.
    Hartana, Ciputra Adijaya
    Johansson, Markus
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Sundsvall Hospital, Sundsvall, Sweden..
    Linton, Ludvig B
    Berglund, Sofia
    Hyllienmark, Martin
    Lundgren, Christian
    Holmström, Benny
    Palmqvist, Karin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgery, Urology Section, Östersund County Hospital, Östersund, Sweden.
    Hansson, Johan
    Alamdari, Farhood
    Huge, Ylva
    Aljabery, Firas
    Riklund, Katrine
    Winerdal, Malin E
    Krantz, David
    Zirakzadeh, Ali A .
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Unit of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Marits, Per
    Sjöholm, Louise K
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Winqvist, Ola
    Increased CD4+ T cell lineage commitment determined by CpG methylation correlates with better prognosis in urinary bladder cancer patients.2018In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, article id 102Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Urinary bladder cancer is a common malignancy worldwide. Environmental factors and chronic inflammation are correlated with the disease risk. Diagnosis is performed by transurethral resection of the bladder, and patients with muscle invasive disease preferably proceed to radical cystectomy, with or without neoadjuvant chemotherapy. The anti-tumour immune responses, known to be initiated in the tumour and draining lymph nodes, may play a major role in future treatment strategies. Thus, increasing the knowledge of tumour-associated immunological processes is important. Activated CD4+ T cells differentiate into four main separate lineages: Th1, Th2, Th17 and Treg, and they are recognized by their effector molecules IFN-γ, IL-13, IL-17A, and the transcription factor Foxp3, respectively. We have previously demonstrated signature CpG sites predictive for lineage commitment of these four major CD4+ T cell lineages. Here, we investigate the lineage commitment specifically in tumour, lymph nodes and blood and relate them to the disease stage and response to neoadjuvant chemotherapy.

    RESULTS: Blood, tumour and regional lymph nodes were obtained from patients at time of transurethral resection of the bladder and at radical cystectomy. Tumour-infiltrating CD4+ lymphocytes were significantly hypomethylated in all four investigated lineage loci compared to CD4+ lymphocytes in lymph nodes and blood (lymph nodes vs tumour-infiltrating lymphocytes: IFNG -4229 bp p < 0.0001, IL13 -11 bp p < 0.05, IL17A -122 bp p < 0.01 and FOXP3 -77 bp p > 0.05). Examination of individual lymph nodes displayed different methylation signatures, suggesting possible correlation with future survival. More advanced post-cystectomy tumour stages correlated significantly with increased methylation at the IFNG -4229 bp locus. Patients with complete response to neoadjuvant chemotherapy displayed significant hypomethylation in CD4+ T cells for all four investigated loci, most prominently in IFNG p < 0.0001. Neoadjuvant chemotherapy seemed to result in a relocation of Th1-committed CD4+ T cells from blood, presumably to the tumour, indicated by shifts in the methylation patterns, whereas no such shifts were seen for lineages corresponding to IL13, IL17A and FOXP3.

    CONCLUSION: Increased lineage commitment in CD4+ T cells, as determined by demethylation in predictive CpG sites, is associated with lower post-cystectomy tumour stage, complete response to neoadjuvant chemotherapy and overall better outcome, suggesting epigenetic profiling of CD4+ T cell lineages as a useful readout for clinical staging.

  • 2. Bergman, Emma Ahlen
    et al.
    Hartana, Ciputra Adijaya
    Linton, Ludvig
    Winerdal, Malin E.
    Krantz, David
    Rosenblatt, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lundgren, Christian
    Marits, Per
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Epigenetic methylation profiles of CD4 T cell signature loci from patients with urinary bladder cancer2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 264-264Article in journal (Other academic)
  • 3. 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.

  • 4. 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.

  • 5. Hartana, C. A.
    et al.
    Ahlén Bergman, E.
    Broomé, A.
    Berglund, S.
    Johansson, M.
    Alamdari, F.
    Jakubczyk, T.
    Huge, Y.
    Aljabery, F.
    Palmqvist, K.
    Holmström, B.
    Glise, H.
    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.
    Winqvist, O.
    Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 1, p. 39-53Article in journal (Refereed)
    Abstract [en]

    Tissue-resident memory T (TRM ) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty-three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in-vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32·9% methylation), which corresponds to increased numbers of perforin-expressing TRM cells. Surprisingly, programmed cell death 1 (PD-1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin-15 and T cell receptor stimulation, perforin and T-bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy.

  • 6. Hartana, Ciputra Adijaya
    et al.
    Kinn, Johan
    Rosenblatt, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Anania, Stefan
    Alamdari, Farhood
    Glise, Hans
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Detection of micrometastases by flow cytometry in sentinel lymph nodes from patients with renal tumours2016In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 115, no 8, p. 957-966Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Stage is an important prognostic factor in renal tumours and dissemination to regional lymph nodes is associated with poor outcomes. Lymph nodes are routinely assessed by immunohistochemistry and microscopic evaluation, a time-consuming process where micrometastases might go undiagnosed. We evaluate an alternative method for detecting metastatic cells in sentinel nodes (SNs) by flow cytometry.

    METHODS: A total of 15 nodes from 5 patients diagnosed with renal tumours were analysed by flow cytometry. Staining for the intracellular marker cytokeratin 18 (CK18) with the surface markers carbonic anhydrase IX (CA9) and Cadherin 6 were used in flow cytometry analysis. Peripheral blood mononuclear cells (PBMCs) with the addition of known concentrations of cancer cell lines were analysed to investigate the sensitivity of micrometastasis detection.

    RESULTS: Stability of the assay was marked by low intra-assay variability (coefficient of variance ⩽16%) and low inter-assay variability (R(2)=0.9996-1). Eight nodes in four patients were positive for metastasis; six of them were considered being micrometastatic. These metastases were undetected by routine pathology and the patients were restaged from pN0 to pN1.

    CONCLUSIONS: Flow cytometry is able to detect micrometastases in lymph nodes of renal tumour patients that were undetected under H&E examination.

  • 7. Hu, J.
    et al.
    Kinn, J.
    Zirakzadeh, A. A.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Norstedt, G.
    Wikstrom, A. -C
    Winqvist, O.
    The effects of chemotherapeutic drugs on human monocyte-derived dendritic cell differentiation and antigen presentation2013In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 172, no 3, p. 490-499Article in journal (Refereed)
    Abstract [en]

    Recent studies indicate that chemotherapeutic agents may increase the anti-tumoral immune response. Based on the pivotal role of dendritic cells (DCs) in host tumour-specific immune responses, we investigated the effect of commonly used chemotherapeutic drugs dexamethasone, doxorubicin, cisplatin and irinotecan and glucocorticoids on monocyte-derived DCs (moDCs). Dexamethasone displayed the strongest inhibitory effect on DC differentiation. The effect of cisplatin and irinotecan was moderate, while only weak effects were noticed for doxorubicin. Surprisingly, when the functional consequence of chemotherapy-treated CD14+ monocytes and their capacity to activate CD4+ T responders cells were investigated, cisplatin-treated monocytes gave rise to increased T cell proliferation. However, dexamethasone, doxorubicin and irinotecan-pretreated monocytes did not stimulate any increased T cell proliferation. Further investigation of this observation revealed that cisplatin treatment during DC differentiation up-regulated significantly the interferon (IFN)- transcript. By contrast, no effect was evident on the expression of interleukin (IL)-1, tumour necrosis factor (TNF)-, IL-6 or IFN- transcripts. Blocking IFN- attenuated the cisplatin-enhanced T cell proliferation significantly. In conclusion, cisplatin treatment enhanced the immune stimulatory ability of human monocytes, a mechanism mediated mainly by the increased production of IFN-.

  • 8.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Liedberg, Fredrik
    Hagberg, Oskar
    Aljabery, Firas
    Ströck, Viveka
    Hosseini, Abolfazl
    Gårdmark, Truls
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Malmström, Per-Uno
    Garmo, Hans
    Jahnson, Staffan
    Holmberg, Lars
    Cohort profile: The Swedish National Register of Urinary Bladder Cancer (SNRUBC) and the Bladder Cancer Data Base Sweden (BladderBaSe)2017In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, no 9, article id e016606Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To monitor the quality of bladder cancer care, the Swedish National Register of Urinary Bladder Cancer (SNRUBC) was initiated in 1997. During 2015, in order to study trends in incidence, effects of treatment and survival of men and women with bladder cancer, we linked the SNRUBC to other national healthcare and demographic registers and constructed the Bladder Cancer Data Base Sweden (BladderBaSe).

    PARTICIPANTS: The SNRUBC is a nationwide register with detailed information on 97% of bladder cancer cases in Sweden as compared with the Swedish Cancer Register. Participants in the SNRUBC have registered data on tumour characteristics at diagnosis, and for 98% of these treatment data have been captured. From 2009, the SNRUBC holds data on 88% of eligible participants for follow-up 5 years after diagnosis of non-muscle invasive bladder cancer, and from 2011, data on surgery details and complications for 85% of participants treated with radical cystectomy. The BladderBaSe includes all data in the SNRUBC from 1997 to 2014, and additional covariates and follow-up data from linked national register sources on comorbidity, socioeconomic factors, detailed information on readmissions and treatment side effects, and causes of death.

    FINDINGS TO DATE: Studies based on data in the SNRUBC have shown inequalities in survival and treatment indication by gender, regions and hospital volume. The BladderBaSe includes 38 658 participants registered in SNRUBC with bladder cancer diagnosed from 1 January 1997 to 31 December 2014. The BladderBaSe initiators are currently in collaboration with researchers from the SNRUBC investigating different aspects of bladder cancer survival.

    FUTURE PLANS: The SNRUBC and the BladderBaSe project are open for collaborations with national and international research teams. Collaborators can submit proposals for studies and study files can be uploaded to servers for remote access and analysis. For more information, please contact the corresponding author.

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

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

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

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

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

  • 10. Jancke, Georg
    et al.
    Liedberg, Fredrik
    Aljabery, Firas
    Sherif, Amir
    Norrland University Hospital.
    Ströck, Viveka
    Malmström, Per-Uno
    Hosseini-Aliabad, Abolfazl
    Jahnson, Staffan
    Intravesical instillations and cancer-specific survival in patients with primary carcinoma in situ of the urinary bladder2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, no 2, p. 124-129Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study was to evaluate the use of intravesical treatment and cancer-specific survival of patients with primary carcinoma in situ (CIS).

    MATERIALS AND METHODS: Data acquisition was based on the Swedish National Registry of Urinary Bladder Cancer by selecting all patients with primary CIS. The analysis covered gender, age, hospital type and hospital volume. Intravesical treatment and death due to bladder cancer were evaluated by multivariate logistic regression and multivariate Cox analysis, respectively.

    RESULTS: The study included 1041 patients (median age at diagnosis 72 years) with a median follow-up of 65 months. Intravesical instillation therapy was given to 745 patients (72%), and 138 (13%) died from bladder cancer during the observation period. Male gender [odds ratio (OR) = 1.56, 95% confidence interval (CI) 1.13-2.17] and treatment at county (OR = 1.65, 95% CI 1.17-2.33), university (OR =2.12, 95% CI 1.48-3.03) or high-volume (OR = 1.92, 95% CI 1.34-2.75) hospitals were significantly associated with higher odds of intravesical instillations. The age category ≥80 years had a significantly lower chance of receiving intravesical therapy (OR = 0.44, 95% CI 0.26-0.74) and a significantly higher risk of dying from bladder cancer (hazard ratio = 3.03, 95% CI 1.71-5.35).

    CONCLUSION: Significantly more frequent use of intravesical treatment of primary CIS was found for males and for patients treated at county, university and high-volume hospitals. Age ≥80 years was significantly related to less intravesical treatment and poorer cancer-specific survival.

  • 11. Jerlström, Tomas
    et al.
    Chen, Ruoqing
    Liedberg, Fredrik
    Andrén, Ove
    Ströck, Viveka
    Aljabery, Firas A S
    Hosseini, Abolfazl
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Malmström, Per-Uno
    Ullén, Anders
    Gårdmark, Truls
    Fall, Katja
    No increased risk of short-term complications after radical cystectomy for muscle-invasive bladder cancer among patients treated with preoperative chemotherapy: a nation-wide register-based study2019In: World journal of urology, ISSN 0724-4983, E-ISSN 1433-8726Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 12. Jerlström, Tomas
    et al.
    Gårdmark, Truls
    Ströck, Viveka
    Aljabery, Firas A. -S.
    Hosseini, Abolfazl A.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ullén, Anders
    Malmström, Per-Uno
    Liedberg, Fredrik
    Jahnson, Staffan
    Carringer, Malcolm
    Significantly more downstaging in patients recieving preoperative (neoadjuvant and induction) chemotherapy prior to cystectomy for muscle-invasive bladder cancer2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, p. 34-35Article in journal (Other academic)
  • 13.
    Kirrander, Peter
    et al.
    Örebro, Sweden.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Friedrich, Bengt
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lambe, Mats
    Uppsala, Sweden; Stockholm, Sweden.
    Håkansson, Ulf
    Malmö, Sweden.
    The Swedish National Penile Cancer Register: Incidence, Tumour Characteristics, Management and Survival2016In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 117, no 2, p. 287-292Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 14.
    Klinga, Gustaf
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    A retrospective evaluation of preoperative anemia in patients undergoing radical cystectomy for muscle-invasive urothelial urinary bladder cancer, with or without neoadjuvant chemotherapy2016In: SpringerPlus, E-ISSN 2193-1801, Vol. 5, article id 1167Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVE: Neoadjuvant chemotherapy (NAC) can be associated with anemia, which can lead to more perioperative blood transfusions (PBT). Usage of PBT is associated with worse oncological outcomes. We evaluated the prevalence of preoperative anemia (PA) and the effect on hemoglobin levels depending on surgery timing after NAC.

    METHODS: A retrospective single-center study with 240 consecutive patients undergoing radical cystectomy (RC) between 2001 and 2014 for muscle-invasive urothelial carcinoma (MIBC). Anemia was defined according to the WHO classification (male ≤ 130 g/L, female ≤ 120 g/L). Multivariable logistical regression was used to identify factors associated with PA and Pearson correlation for evaluating the change in hemoglobin levels depending on surgery timing.

    RESULTS: Overall, 128 (53.3 %) patients were anemic pre-RC and 87 (36.3 %) patients received NAC. In a multivariable analysis, age, receipt of NAC, female gender, and low BMI were independent predictors of PA. In patients receiving NAC, the time to surgery from the last NAC cycle was correlated with the change in hemoglobin levels between the initiation of NAC and surgery.

    CONCLUSIONS: PA was common in patients undergoing RC for MIBC. Receipt of NAC was found to be a strong predictor of PA.

    CLINICAL MESSAGE: The emerging treatment of cisplatin based neoadjuvant chemotherapy for muscle-invasive bladder cancer, confers an increased risk for preoperative anemia. In the management of this malignancy, preoperative anemia renders further attention and focus.

  • 15. 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.

  • 16. Liedberg, Fredrik
    et al.
    Hagberg, Oskar
    Aljabery, Firas
    Gårdmark, Truls
    Hosseini, Abolfazl
    Jahnson, Staffan
    Jancke, Georg
    Jerlström, Tomas
    Malmström, Per-Uno
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ströck, Viveka
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala.
    Holmberg, Lars
    Period-specific mean annual hospital volume of radical cystectomy is associated with outcome and perioperative quality of care: a nationwide population-based study2019In: BJU International, ISSN 1464-4096, E-ISSN 1464-410XArticle in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the association between hospital volume and overall survival (OS), cancer-specific survival (CSS), and quality of care of patients with bladder cancer who undergo radical cystectomy (RC), defined as the use of extended lymphadenectomy (eLND), continent reconstruction, neoadjuvant chemotherapy (NAC), and treatment delay of <3 months.

    PATIENTS AND METHODS: We used the Bladder Cancer Data Base Sweden (BladderBaSe) to study survival and indicators of perioperative quality of care in all 3172 patients who underwent RC for primary invasive bladder cancer stage T1-T3 in Sweden between 1997 and 2014. The period-specific mean annual hospital volume (PSMAV) during the 3 years preceding surgery was applied as an exposure and analysed using univariate and multivariate mixed models, adjusting for tumour and nodal stage, age, gender, comorbidity, educational level, and NAC. PSMAV was either categorised in tertiles, dichotomised (at ≥25 RCs annually), or used as a continuous variable for every increase of 10 RCs annually.

    RESULTS: PSMAV in the highest tertile (≥25 RCs annually) was associated with improved OS (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.75-1.0), whereas the corresponding HR for CSS was 0.87 (95% CI 0.73-1.04). With PSMAV as a continuous variable, OS was improved for every increase of 10 RCs annually (HR 0.95, 95% CI 0.90-0.99). Moreover, higher PSMAV was associated with increased use of eLND, continent reconstruction and NAC, but also more frequently with a treatment delay of >3 months after diagnosis.

    CONCLUSIONS: The current study supports centralisation of RC for bladder cancer, but also underpins the need for monitoring treatment delays associated with referral.

  • 17. Liedberg, Fredrik
    et al.
    Hagberg, Oskar
    Aljabery, Firas
    Gårdmark, Truls
    Hosseini, Abolfazl
    Jahnson, Staffan
    Jancke, Georg
    Jerlström, Tomas
    Malmström, Per-Uno
    Sherif, Amir
    Umeå University.
    Ströck, Viveka
    Häggström, Christel
    Umeå University. Uppsala University, Uppsala, Sweden.
    Holmberg, Lars
    Period-specific mean annual hospital volume of radical cystectomy is associated with outcome and perioperative quality of care in Sweden: a nationwide population-based study2019In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 53, p. 20-20Article in journal (Other academic)
    Abstract [en]

    Objective: To investigate the association between hospital volume on overall survival (OS), cancer-specific survival (CSS), and quality of care defined as use of extended lymphadenectomy, continent reconstruction, neoadjuvant chemotherapy and treatment delay less than 3 months.

    Materials and Methods: We used Bladder Cancer Data Base Sweden (BladderBaSe) to study survival and indicators of perioperative quality of care in all 3172 patients who underwent radical cystectomy for primary invasive bladder cancer stage T1-T3 in Sweden 1997-2014. The period-specific mean annual hospital volume (PSMAV) during the 3 years preceding surgery was applied as an exposure and analysed using univariate and multivariate mixed models, adjusting for tumour and nodal stage, age, gender, comorbidity, educational level and neoadjuvant chemotherapy. PSMAV was either categorised in tertiles, dichotomised (at 25 or more cystectomies annually), or used as a continuous variable for every increase of 10 cystectomies annually.

    Results: PSMAV in the highest tertile (25 or more cystectomies annually) was associated with improved overall survival (HR 0.87, 95% CI 0.751.0), with a similar trend for cancer-specific survival (HR 0.87, 95% CI 0.731.04). With PSMAV as a continuous variable, overall survival was improved for every increase of 10 cystectomies annually (HR 0.95, 95% CI 0.900.99). Moreover, higher PSMAV was associated with increased use of extended lymphadenectomy, continent reconstruction and neoadjuvant chemotherapy, but also more frequently with a treatment delay of more than 3 months after diagnosis.

    Conclusions: The current study supports centralisation of radical cystectomy for bladder cancer, but also underpins the need for monitoring treatment delays associated with referral.

  • 18. Malmström, Per-Uno
    et al.
    Gårdmark, Truls
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ströck, Viveka
    Hosseini-Aliabad, Abolfazl
    Jahnson, Staffan
    Aljabery, Firas
    Liedberg, Fredrik
    Incidence, survival and mortality trends of bladder cancer in Sweden 1997-20162019In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate trends in bladder cancer incidence, survival and mortality in Sweden from 1997-2016.

    Patients and methods: The Swedish National Registry of Urinary Bladder Cancer is a nation-wide quality register that started in 1997. It includes information on initial tumor characteristics and treatment; 41,097 new cases were registered up to 2016. Patients were stratified into four time periods. Deaths were monitored through the national death register. Overall and relative survival in time periods were studied with respect to differences in stage, age and gender.

    Results: The number of new cases increased by 38% for men and 39% for women from 1997 to 2016. The corresponding age-standardized incidence per 100,000 was less dramatic, with increases of 6% and 21%, respectively, and the increase was most evident in the oldest age group. The survival rate was stable until 2012, but thereafter a significant improvement occurred. The survival trends in stage-groups show that this improvement is found in all categories as well as irrespective of age and gender. The mortality rate during this period was stable for women, but showed a slight decrease for men. The main limitation of this study is the use of administrative data for defining some of the endpoints.

    Conclusion: The most recent Swedish bladder cancer statistics show an increased incidence, improved survival, but stable mortality.

  • 19. Marits, Per
    et al.
    Zirakzadeh, Ali A.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Response to Comment on "Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies"2013In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 191, no 9, p. 4471-4472Article in journal (Refereed)
  • 20. Marits, Per
    et al.
    Zirakzadeh, Ali A
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    The many flavors of tumor-associated B cells2013In: Oncoimmunology, ISSN 2162-4011 (print), 2162-402X (online), Vol. 2, no 8, p. e25237-Article in journal (Refereed)
    Abstract [en]

    Little is known on the role of distinct B-cell subtypes in human malignancies. We have recently performed a multiplex characterization of B cells in patient-derived tumor-associated tissues, documenting the activation and antigen-driven differentiation of B cells in metastatic lymph nodes and neoplastic lesions. Here we discuss the role of B lymphocytes as antigen-presenting cells and catalysts of T cell-based immunotherapies in view of these findings.

  • 21.
    Mints, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Hiltbrunner, Stefanie
    Eldh, Maria
    Rosenblatt, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Holmström, Benny
    Alamdari, Farhood
    Johansson, Markus
    Hansson, Johan
    Vasko, Jonas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Winqvist, Ola
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Gabrielsson, Susanne
    Exosomes in urine retain a malignant protein profile after primary tumour ablation in patients with invasive urinary bladder cancer2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, p. 38-39Article in journal (Other academic)
  • 22.
    Mints, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Krantz, David
    Johansson, Markus
    Hansson, Johan
    Vasko, Jonas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Winerdal, Malin
    Zirakzadeh, Ali
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Riklund, Katrin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Zubarev, Roman
    Rutishauser, Dorothea
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Winqvist, Ola
    Individual immunoproteomics identifies il-16 processing in tregs as a factor in bladder cancer tumour immunity2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, p. 36-37Article in journal (Other academic)
  • 23. Porserud, Andrea
    et al.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tollbäck, Anna
    The effects of a physical exercise programme after radical cystectomy for urinary bladder cancer. A pilot randomized controlled trial.2014In: Clinical Rehabilitation, ISSN 0269-2155, E-ISSN 1477-0873, Vol. 28, no 5, p. 451-459Article in journal (Refereed)
    Abstract [en]

    Objective: Assessment of feasibility and effects of an exercise training programme in patients following cystectomy due to urinary bladder cancer.

    Design: Single-blind, pilot, randomized controlled trial.Setting:University hospital, Sweden.

    Subjects: Eighteen patients (64-78 years), of 89 suitable, cystectomized due to urinary bladder cancer, were randomized after hospital discharge to intervention or control.

    Interventions: The 12-week exercise programme included group exercise training twice a week and daily walks. The control group received only standardized information at discharge.

    Main outcome measures: Trial eligibility and compliance to inclusion were registered. Assessments of functional capacity, balance, lower body strength and health-related quality of life (HRQoL) with SF-36.

    Results: Out of 122 patients 89 were eligible, but 64 did not want to participate/were not invited. Twenty-five patients were included, but 7 dropped out before randomization. Eighteen patients were randomized to intervention or control. Thirteen patients completed the training period. The intervention group increased walking distance more than the control group, 109 m (75-177) compared to 62 m (36-119) (P = 0.013), and role physical domain in SF-36 more than the control group (P = 0.031). Ten patients were evaluated one year postoperatively. The intervention group had continued increasing walking distance, 20 m (19-36), whereas the control group had shortened the distance -15.5 m (-43 to -5) (P = 0.010).

    Conclusions: A 12-week group exercise training programme was not feasible for most cystectomy patients. However, functional capacity and the role-physical domain in HRQoL increased in the short and long term for patients in the intervention group compared with controls.

  • 24.
    Rosenblatt, Robert
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Stockholm South General Hospital, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Markus
    Alamdari, Farhood
    Sidiki, Alexander
    Holmström, Benny
    Hansson, Johan
    Vasko, Janos
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Marits, Per
    Gabrielsson, Susanne
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Winqvist, Ola
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Sentinel node detection in muscle-invasive urothelial bladder cancer is feasible after neoadjuvant chemotherapy in all pT stages, a prospective multicenter report2017In: World journal of urology, ISSN 0724-4983, E-ISSN 1433-8726, Vol. 35, no 6, p. 921-927Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To determine whether sentinel node detection (SNd) in muscle-invasive urothelial bladder cancer (MIBC) can be performed in patients undergoing neoadjuvant chemotherapy (NAC) and determine whether SNd is feasible in all pT stages, including pT0.

    BACKGROUND: Previous published series of SNd in MIBC have not included patients undergoing NAC, and systematic reports of pT0 patients w/wo NAC were absent. Translational immunological tumor research on MIBC focusing on SNd, in the era of NAC, requires technical feasibility. Additionally, SNd in MIBC requests further evaluations as a method for nodal staging.

    MATERIALS AND METHODS: Ninety-nine patients with suspected urothelial MIBC were prospectively selected from six urological centers. After TUR-B and primary staging, 65 MIBC patients qualified for radical cystectomy. Precystectomy staging was cT2a-T4aN0M0, including 47 NAC patients and 18 chemo-naïve patients. All 65 patients underwent intraoperative SNd by peritumoral injection of 80 Mbq Technetium and Geiger probe detection. Postcystectomy staging was pT0-T4aN0-N2M0. SNs were defined by two calculations, SNdef1 and SNdef2.

    RESULTS: Totally 1063 lymph nodes were removed (total SNs; 222-227). NAC patients with pT0 (n = 24) displayed a true positive detection in 91.7 % by either SNdef, with a median of 3.0 SNs. NACpT >0 patients had a true positive detection in 87 % (SNdef1) and 91.3 % (SNdef2). In a univariate analysis, patient group neither NAC nor tumor downstaging influenced detection rates, regardless of SN definition. In total eight patients, 4/22 metastatic nodes were SNs while 18/22 were non-SNs.

    CONCLUSIONS: Sentinel node detection in MIBC is feasible also in NAC patients, regardless of pT stage. SNd played no role in nodal staging.

  • 25.
    Rosenblatt, Robert
    et al.
    Umeå University.
    Sandström, Gabriella
    Umeå University.
    Bahar, Maryam
    Umeå University.
    Asad, Danna
    Umeå University.
    Forsman, Ramona
    Umeå University.
    Johansson, Markus
    Shareef, Marwan
    Alamdari, Farhood
    Bergh, Anders
    Winqvist, Ola
    Sherif, Amir
    Umeå University.
    Blood transfusions during neoadjuvant chemotherapy for muscle-invasive urinary bladder cancer may have a negative impact on overall survival2019In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 53, p. 35-36Article in journal (Other academic)
    Abstract [en]

    Introduction: Several studies have demonstrated a decreased overall survival for patients with muscle-invasive bladder cancer (MIBC) receiving allogenic peri- and postoperative blood transfusions at cystectomy. However, the extent and the effect of blood transfusions given during neoadjuvant chemotherapy (NAC) has never been addressed. The purpose of the present study, was to assess the impact of blood transfusions given during NAC on survival in patients with MIBC undergoing NAC and radical cystectomy.

    Materials and Methods: A cohort of 120 consecutive patients with MIBC (cT2-T4aN0M0) undergoing NAC and radical cystectomy at four Swedish centers was retrospectively evaluated. Clinical and pathoanatomical data was obtained, including data SCANDINAVIAN JOURNAL OF UROLOGY 35 on administeredallogenic blood at consecutive time-intervals. Overall survival was analyzed by Kaplan-Meier plotting and Cox regression.

    Results: One third of the cohort (n ¼ 40) received blood transfusions during NAC-therapy. The five-year overall survival rates were significantly lower in this group compared to the non-transfused patients (39.7% and 58.9% respectively, p ¼ 0.047). In a univariate analysis, blood transfusions, nodal status and locally advanced tumor growth (pT >2), were negative prognostic factors for survival. In multivariate analysis, only pNx and pT >2 remained significant negative prognostic factors. In subgroup analysis of localized and non-disseminated patients only (n ¼ 96), blood transfused patients showed a 18,5% absolute risk increase compared to blood naïve patients (p¼ 0.197).

    Conclusions: This is the first time that the extent and the effect of allogenic blood transfusions during NAC is examined in MIBC. Data suggest that there may be an association between blood transfusion and poor pathological and oncological outcome. Firm conclusions are difficult to draw due to the limited number of study participants and the retrospective nature of the study.

  • 26. Russell, Beth
    et al.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Häggström, Christel
    Josephs, Debra
    Kumar, Pardeep
    Malmström, Per-Uno
    Van Hemelrijck, Mieke
    Neoadjuvant chemotherapy for muscle invasive bladder cancer: a nationwide investigation on survival2019In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, p. 1-7Article in journal (Refereed)
    Abstract [en]

    Objectives: Randomised controlled trials (RCTs) have investigated the use of neoadjuvant chemotherapy (NAC) and its effect on survival patients with non-metastatic muscle-invasive bladder cancer (MIBC). However, these RCTs have limited external validity and generalisability and, therefore, the current study aims to use real world evidence in the form of observational data to identify the effect that NAC may have on survival, compared to the use of radical cystectomy (RC) alone.

    Materials and methods: The study cohort (consisting of 944 patients) was selected as a target trial from the Bladder Cancer Data Base Sweden (BladderBaSe). This study calculated 5-year survival and risk of bladder cancer (BC)-specific and overall death by Cox proportional hazard models for the study cohort and a propensity score (PS) matched cohort.

    Results: Those who had received NAC had higher 5-year survival proportions and decreased risk of both overall and BC specific death (HR = 0.71, 95% CI = 0.52-0.97 and HR = 0.67, 95% CI = 0.48-0.94), respectively, as compared to patients who did not receive NAC. The PS matched cohort showed similar estimates, but with larger statistical uncertainty (Overall death: HR = 0.76, 95% CI = 0.53-1.09 and BC-specific death: HR = 0.73, 95% CI = 0.50-1.07).

    Conclusion: Results from the current observational study found similar point estimates for 5-year survival and of relative risks as previous studies. However, the results based on real world evidence had larger statistical variability, resulting in a non-statistically significant effect of NAC on survival. Future studies with detailed validated data can be used to further investigate the effect of NAC in narrower patient groups.

  • 27.
    Shah, Carl-Henrik
    et al.
    Stockholm, Sweden.
    Viktorsson, Kristina
    Stockholm, Sweden.
    Kanter, Lena
    Stockholm, Sweden.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Asmundsson, Jurate
    Stockholm, Sweden.
    Rosenblatt, Robert
    Stockholm, Sweden.
    Lewensohn, Rolf
    Stockholm, Sweden.
    Ullén, Anders
    Stockholm, Sweden.
    Vascular endothelial growth factor receptor 2, but not S100A4 or S100A6, correlates with prolonged survival in advanced urothelial carcinoma2014In: Urologic Oncology, ISSN 1078-1439, E-ISSN 1873-2496, Vol. 32, no 8, p. 1215-1224Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: A major challenge in muscle-invasive urothelial carcinoma (UC) is to identify biomarkers that can predict disease prognosis and treatment response after cystectomy. Therefore, we analyzed the potential prognostic value of the proteins vascular endothelial growth factor receptor 2 (VEGFR2), S100A4, and S100A6 in UC.

    METHODS: Retrospective outcome data and tumor specimens from 83 cystectomy patients with histologically confirmed invasive UC were included. Expression levels of VEGFR2 (also called flk-1 and KDR), S100A4, and S100A6 were analyzed in primary tumor tissue by immunohistochemistry.

    RESULTS: Immunohistochemical staining and analysis of VEGFR2, S100A4, and S100A6 showed localization mainly in tumor cell cytoplasm. High VEGFR2 expression and low tumor category were independent variables associated with longer overall survival (OS) and disease-free survival, revealed by a bivariate Cox proportional hazards regression model (both P<0.001). In addition, the univariate log-rank test and the Cox model demonstrated that OS beyond 2 years was significantly greater among patients with low S100A6 expression than in those with high S100A6 expression (P = 0.017 and 0.022, respectively). Differences in tumor expression of S100A4 were not significantly associated with outcome.

    CONCLUSION: In this study, VEGFR2 expression was significantly correlated with risk of disease relapse and OS in a defined cohort of patients with UC of the bladder treated by cystectomy.

  • 28.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    B cells in tumor draining lymph nodes act asefficient antigen presenting cells in cancer patients2015Conference paper (Other (popular science, discussion, etc.))
  • 29.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    The long perspective in emergence of neoadjuvant chemotherapy for bladder cancer in Ontario, Canada: space for improvement with regular and organized multidisciplinary team meetings2018In: Translational Andrology and Urology, ISSN 2223-4683, Vol. 7, no 3, p. 508-510Article in journal (Refereed)
  • 30.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    The risk of oversimplification in risk-stratification of neoadjuvant chemotherapy-responses in muscle invasive bladder cancer2019In: Translational Andrology and Urology, ISSN 2223-4683, Vol. 8, no Suppl 3, p. S337-S340Article in journal (Other academic)
  • 31.
    Sherif, Amir
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hasan, Mudhar N
    Radecka, Eva
    Rodriguez, Alvaro Lozano
    Shabo, Sarab
    Karlsson, Mona
    Schumacher, Martin C
    Marits, Per
    Winqvist, Ola
    Pilot study of adoptive immunotherapy with sentinel node-derived T cells in muscle-invasive urinary bladder cancer2015In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 49, no 6, p. 453-462Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study was to determine by computed tomography (CT) whether treatment with tumor-draining lymph-node-derived expanded autologous T lymphocytes results in objective responses and/or improved survival in patients with metastatic urinary bladder cancer (UBC) and to record the toxicity of the treatment.

    MATERIALS AND METHODS: Eighteen patients with metastatic UBC were prospectively selected from two centers. The preoperative staging was T2-T4bN1-2 and/or M0-M1 or MX. Tumor-draining lymph nodes were harvested at intended cystectomy for the extraction of T lymphocytes. This was followed by expansion of the T lymphocytes in a cell culture, and subsequent reinfusion of these autologous tumor-specific T lymphocytes. Responses to therapy were evaluated by CT scans according to Response Evaluation Criteria In Solid Tumors (RECIST) and clinical follow-up, according to the research protocol.

    RESULTS: Nine out of 18 patients were treated. Treatment was feasible and safe. In two out of nine immunologically treated patients, objective responses were detected in terms of diminished or obliterated nodal metastases. When excluding three patients with disseminated osseous metastases plus one with a T4b tumor left in situ, a success rate of two out of six treated patients was seen. The two responders had survival times of 35 and 11 months, respectively. No toxicity was recorded.

    CONCLUSIONS: Infusion of expanded autologous tumor-specific T lymphocytes is feasible and safe, and objective responses according to RECIST were recorded. One objective responder to immunotherapy displayed notably long overall survival.

  • 32.
    Sherif, Amir
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Rosenblatt, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Johansson, Markus
    Almadari, Farhood
    Sidiki, Alexander
    Holmström, Benny
    Hansson, Johan
    Vasko, Janos
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Marits, Per
    Gabrielsson, Susanne
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Winqvist, Ola
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Sentinel node detection in muscle invasive urothelial bladder cancer is feasible after neoadjuvant chemotherapy in all pT-stages2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, p. 37-37Article in journal (Other academic)
  • 33.
    Sherif, Amir
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winerdal, Malin
    Winqvist, Ola
    Immune responses to neoadjuvant chemotherapy in muscle invasive bladder cancer2018In: Bladder cancer, ISSN 2352-3727, Vol. 4, no 1, p. 1-7Article in journal (Refereed)
    Abstract [en]

    The secondary effects of chemotherapy, with bone marrow depression and risk of leukopenia, has traditionally been considered being detrimental for the immune system. However, growing evidence suggests a main role for chemotherapy in antitumor immunomodulation. With reference to cisplatin, which is the basis of neoadjuvant chemotherapy in muscle invasive bladder cancer, four different aspects of immunomodulation has thus far been described; increased MHC class I expression, recruitment and proliferation of effector cells, enhancement of tumor-lytic activity of cytotoxic effectors and downregulation of immunosuppressive actors in the microenvironment. Consequently, the role of chemotherapy in cancer is changing from a therapy solely aimed at inducing tumor cell death, to a potent inducer of immune responses and a potential future major partaker in cancer immunotherapy. This is a great opportunity for the urological community to broaden research in this field in order to increase knowledge, optimize and improve the neoadjuvant regimens of muscle invasive bladder cancer to ultimately improve patient outcome.

  • 34.
    Sherif, Amir
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winerdal, ME
    Winqvist, O
    Sentinel lymph node detection in urinary bladder cancer: a gateway to advanced translational research and cellular immunotherapy Minireview2016In: Egyptian Journal Of Urology, ISSN 1110-5712, Vol. 22, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Patients with advanced urothelial urinary bladder cancer (UBC) have a pessimistic prognosis, although modern urology can offer preoperative chemotherapy followed by radical surgery. Attempts to find additional, other than adjuvant cytotoxic treatment options need to be explored. The field of immune therapy may be of particular value in UBC since immunotherapy of superficial UBC using an unspecific immunotherapy modality, namely BCG, has been so successful. In addition, UBC is one of the most genetically unstable cancers carrying many neo-antigens as potential targets for T lymphocyte recognition. A tempting option aiming at highly individualized treatment could be autologous cell therapy based on the concepts of sentinel node detection. The sentinel nodes, representing the foremost arena for the struggle between the immune system of the patient and the tumor assault, can offer high quantities of highly specialized T lymphocytes. These T cells have evolved in response to a number of specific tumor antigens reaching the tumor draining sentinel nodes en route. Adoptive immunotherapy within this framework entails possibilities of harvesting tumor specific T cells from the sentinel nodes and allowing them to expand in vitro. Expanded and strengthened T cells can then be reinfused as a safe and non-toxic adjuvant immunotherapy. The first pilot trials have been published utilizing this method in two solid cancers, colon and UBC. Results demonstrate objective responses in some patients without any negative side effects. The future challenge is to increase the translational research in this specific field, to further improve immunobiological techniques, to optimize patient selection and to perform larger randomized controlled clinical trials.

  • 35. Sjöström, Carin
    et al.
    Thorstenson, Andreas
    Ströck, Viveka
    Hosseini-Aliabad, Abolfazl
    Aljabery, Firas
    Liedberg, Fredrik
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Malmström, Per-Uno
    Rosell, Johan
    Gårdmark, Truls
    Jahnson, Staffan
    Treatment according to guidelines may bridge the gender gap in outcome for patients with stage T1 urinary bladder cancer2018In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 52, no 3, p. 186-193Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this investigation was to study differences between male and female patients with stage T1 urinary bladder cancer (UBC) regarding intravesical instillation therapy, second resection and survival.

    MATERIALS AND METHODS: This study included all patients with non-metastatic primary T1 UBC reported to the Swedish National Register of Urinary Bladder Cancer (SNRUBC) from 1997 to 2014, excluding those treated with primary cystectomy. Differences between groups were evaluated using chi-squared tests and logistic regression, and survival was investigated using Kaplan-Meier and log-rank tests and Cox proportional hazards analysis.

    RESULTS: In all, 7681 patients with T1 UBC (77% male, 23% female) were included. Females were older than males at the time of diagnosis (median age at presentation 76 and 74 years, respectively; p < .001). A larger proportion of males than females underwent intravesical instillation therapy (39% vs 33%, p < .001). Relative survival was lower in women aged ≥75 years and women with G3 tumours compared to men. However, women aged ≥75 years who had T1G3 tumours and underwent second resection followed by intravesical instillation therapy showed a relative survival equal to that observed in men.

    CONCLUSIONS: This population-based study demonstrates that women of all ages with T1 UBC undergo intravesical instillation therapy less frequently than men, and that relative survival is poorer in women aged ≥75 years than in men of the same age when intravesical instillation therapy and second resection are not used. However, these disparities may disappear with treatment according to guidelines.

  • 36.
    Styrke, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Sundsvall Hospital.
    Henriksson, Helene
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Sundsvall Hospital.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hasan, Mudhar
    Silfverberg, Ingrid
    Einarsson, Roland
    Malmström, Per-Uno
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Evaluation of the diagnostic accuracy of UBC(®) Rapid in bladder cancer: a Swedish multicentre study2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, no 4, p. 293-300Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study was to determine the diagnostic accuracy of UBC(®) Rapid - a urine-based marker for bladder cancer - in patients with bladder cancer and controls, and to compare the test results across risk groups.

    MATERIALS AND METHODS: This prospective phase II study was conducted at four Swedish hospitals. UBC Rapid was evaluated in four groups: A, newly diagnosed bladder cancer (n = 94); B, follow-up of non-muscle-invasive bladder cancer (n = 75); C, benign urinary tract diseases (n = 51); and D, healthy controls (n = 50). Tumours were divided into high risk (carcinoma in situ, TaG3, T1, T2 and T3) and low risk (low malignant potential, TaG1 and TaG2). Urine samples were quantitatively analysed by UBC Rapid. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated based on optimal cut-off (receiver operator characteristics curve analysis). A linear regression compared the UBC Rapid results in the different risk groups.

    RESULTS: The optimal cut-off was 8.1 μg/l. The median UBC Rapid values were 9.3 μg/l [interquartile range (IQR) 30.9] and 4.3 μg/l (IQR 7.8) in patients with positive and negative cystoscopy, respectively (p < .001). The value for group A was 15.6 μg/l (IQR 37.9), group B 5.6 μg/l (IQR 8.6), group C 5.1 μg/l (IQR 9.0) and group D 3.3 μg/l (IQR 7.1). Sensitivity was 70.8%, specificity 61.4%, PPV 71.3% and NPV 60.8%. The high-risk group had significantly higher UBC Rapid values than the low-risk group: 20.5 μg/l (IQR 42.2), sensitivity 79.2% and specificity 61.4% versus 7.0 μg/l (IQR 9.9), sensitivity 60.0% and specificity 61.4% (p = .039).

    CONCLUSIONS: The UBC Rapid urine-based marker for bladder cancer gave higher values in patients with positive than in those with negative cystoscopy. The diagnostic accuracy was better in patients with high-risk than in those with low-risk tumours, and was better during primary detection than during surveillance.

  • 37. Walker, Steven M
    et al.
    Knight, Laura A
    McCavigan, Andrena M
    Logan, Gemma E
    Berge, Viktor
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Pandha, Hardev
    Warren, Anne Y
    Davidson, Catherine
    Uprichard, Adam
    Blayney, Jaine K
    Price, Bethanie
    Jellema, Gera L
    Steele, Christopher J
    Svindland, Aud
    McDade, Simon S
    Eden, Christopher G
    Foster, Chris
    Mills, Ian G
    Neal, David E
    Mason, Malcolm D
    Kay, Elaine W
    Waugh, David J
    Harkin, D Paul
    Watson, R William
    Clarke, Noel W
    Kennedy, Richard D
    Molecular Subgroup of Primary Prostate Cancer Presenting with Metastatic Biology2017In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 72, no 4, p. 509-518Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy.

    OBJECTIVE: To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy.

    DESIGN, SETTING, AND PARTICIPANTS: Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months.

    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis.

    RESULTS AND LIMITATIONS: A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy samples. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13-2.33]; p=0.0092) and metastatic recurrence (multivariable HR=3.20 [1.76-5.80]; p=0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90-3.75]; p<0.0001 and HR=7.53 [4.13-13.73]; p<0.0001, respectively). The retrospective nature of the study is acknowledged as a potential limitation.

    CONCLUSIONS: The metastatic assay may identify a molecular subgroup of primary prostate cancers with metastatic potential.

    PATIENT SUMMARY: The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in this higher-risk population.

  • 38. Winerdal, Malin E.
    et al.
    Krantz, David
    Hartana, Ciputra A.
    Zirakzadeh, Ali A .
    Department of Medicine, Unit of Allergy and Immunology, Karolinska Institutet, Stockholm, Sweden.
    Linton, Ludvig
    Bergman, Emma A.
    Rosenblatt, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Stockholm South General Hospital, Karolinska Institutet, Stockholm, Sweden.
    Vasko, Janos
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Alamdari, Farhood
    Hansson, Johan
    Holmström, Benny
    Johansson, Markus
    Winerdal, Max
    Marits, Per
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Urinary Bladder Cancer Tregs Suppress MMP2 and Potentially Regulate Invasiveness2018In: Cancer immunology research, ISSN 2326-6074, Vol. 6, no 5, p. 528-538Article in journal (Refereed)
    Abstract [en]

    Regulatory T cells (Tregs) have long been considered one-sided suppressors of antitumor immune responses and hence associated to poor patient outcome in cancer. However, evidence is mounting of a paradoxical positive prognostic effect of Tregs on certain malignancies, including urinary bladder cancer (UBC). This discrepancy has partly been attributed to the shear misidentification of Tregs, but also to the inflammatory profile of the tumor. Our aim was to determine whether tumor-infiltrating Forkhead box P3+ (FOXP3+) cells confer a stable Treg phenotype and to investigate putative beneficial Treg functions, focusing on tumor-promoting inflammatory pathways in UBC. Patients (n = 52) with suspected UBC were prospectively included. We show, by employing a broad range of analytical approaches, that tumor-infiltrating CD4+FOXP3+ T cells in UBC phenotypically, functionally, and epigenetically represent a true Treg population. At the invasive front of UBC tumors, we found an inverse relationship between Treg frequency and expression of matrix metalloproteinase 2 (MMP2), a key pro-invasive factor induced by tumor-promoting inflammation. Correspondingly, a significant, dose-dependent Treg-mediated downregulation of MMP2 protein and mRNA expression was observed in both macrophages and urinary bladder cancer cells. Also, we found that Treg frequency specifically at the invasive front positively correlated with survival. Thus, we identify Treg-mediated suppression of MMP2 in the tumor microenvironment as a mechanism explaining the paradoxical positive prognostic impact of tumor-infiltrating Tregs in UBC.

  • 39. Witjes, J. Alfred
    et al.
    Compérat, Eva
    Cowan, Nigel C.
    De Santis, Maria
    Gakis, Georgios
    Lebret, Thierry
    Ribal, Maria J.
    Van der Heijden, Antoine G.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2013 Guidelines2014In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 65, no 4, p. 778-792Article in journal (Refereed)
    Abstract [en]

    CONTEXT: The European Association of Urology (EAU) guidelines panel on Muscle-invasive and Metastatic bladder cancer (BCa) updates its guidelines yearly. This updated summary provides a synthesis of the 2013 guidelines document, with emphasis on the latest developments.

    OBJECTIVE: To provide graded recommendations on the diagnosis and treatment of patients with muscle-invasive BCa (MIBC), linked to a level of evidence.

    EVIDENCE ACQUISITION: For each section of the guidelines, comprehensive literature searches covering the past 10 yr in several databases were conducted, scanned, reviewed, and discussed both within the panel and with external experts. The final results are reflected in the recommendations provided.

    EVIDENCE SYNTHESIS: Smoking and work-related carcinogens remain the most important risk factors for BCa. Computed tomography (CT) and magnetic resonance imaging can be used for staging, although CT is preferred for pulmonary evaluation. Open radical cystectomy with an extended lymph node dissection (LND) remains the treatment of choice for treatment failures in non-MIBC and T2-T4aN0M0 BCa. For well-informed, well-selected, and compliant patients, however, multimodality treatment could be offered as an alternative, especially if cystectomy is not an option. Comorbidity, not age, should be used when deciding on radical cystectomy. Patients should be encouraged to actively participate in the decision-making process, and a continent urinary diversion should be offered to all patients unless there are specific contraindications. For fit patients, cisplatinum-based neoadjuvant chemotherapy should always be discussed, since it improves overall survival. For patients with metastatic disease, cisplatin-containing combination chemotherapy is recommended. For unfit patients, carboplatin combination chemotherapy or single agents can be used.

    CONCLUSIONS: This 2013 EAU Muscle-invasive and Metastatic BCa guidelines updated summary aims to increase the quality of care and outcome for patients with muscle-invasive or metastatic BCa.

    PATIENT SUMMARY: In this paper we update the EAU guidelines on Muscle-invasive and Metastatic bladder cancer. We recommend that chemotherapy be administered before radical treatment and that bladder removal be the standard of care for disease confined to the bladder.

  • 40. Zhang, Lu
    et al.
    Hu, Jin
    Zirakzadeh, Ali A .
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Medicine, Immunology and Allergy Unit, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
    Rosvall, Jesper
    Hedlund, Mats
    Hu, Ping Sheng
    P A Wallin, Robert
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Detection of micro-metastases by flow cytometry in lymph nodes from patients with penile cancer2018In: BMC Urology, ISSN 1471-2490, E-ISSN 1471-2490, Vol. 18, no 1, article id 86Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The tumor draining lymph node concept was first described in penile cancer for staging. Immunohistochemistry and histopathology evaluations are routinely used in clinical practice to examine lymph nodes for metastasis. However, these methods are time-consuming with low diagnostic accuracy and micro-metastases might be missed. In this study, we aim to evaluate detection of metastatic cells in draining lymph nodes by flow cytometry.

    METHODS: To assess the sensitivity of micro-metastasis detection by FACS (Fluorescence-activated cell sorting), HeLa cells were titrated into Peripheral blood mononuclear cells (PBMCs) and expression of pan-cytokeratin AE1/AE3 was analyzed. Single cell suspensions were separately prepared from 10 regional lymph nodes obtained from 5 patients with invasive penile cancer undergoing radical surgery and lymph node dissection. Lymph node dereived cells were examined for cell surface expression of EpCAM, E-cadherin and intracellular expression of pan-cytokeratin AE1/AE3 by FACS.

    RESULTS: Ten lymph nodes from 5 penile cancer patients were investigated in a head-to-head comparison between FACS and pathology examination of sections. All metastatic lymph nodes verified by pathology examination were also identified by FACS. Two additional lymph nodes with micro-metastases were diagnosed by FACS only.

    CONCLUSIONS: FACS analyses of pan-cytokeratin AE1/AE3 stained single cells from tumor draining lymph nodes can be used to detect micro-metastases in patients with penile cancer patients.

  • 41. Zhang, Lu
    et al.
    Hu, Jin
    Zirakzadeh, Ali
    Rosvall, Jesper
    Hedlund, Mats
    Hu, Pingsheng
    Wallin, Robert
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Immune responses against Human Papilloma virus in draining lymph nodes from patients with penile cancer2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 339-339Article in journal (Other academic)
  • 42. Zirakzadeh, A Ali
    et al.
    Kinn, Johan
    Krantz, David
    Rosenblatt, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Stockholm South General Hospital, Karolinska Institutet, Stockholm, Sweden.
    Winerdal, Malin E
    Hu, Jin
    Hartana, Ciputra Adijaya
    Lundgren, Christian
    Bergman, Emma Ahlén
    Johansson, Markus
    Holmström, Benny
    Hansson, Johan
    Sidikii, Alexander
    Vasko, Janos
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Marits, Per
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Doxorubicin enhances the capacity of B cells to activate T cells in urothelial urinary bladder cancer2017In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 176, p. 63-70Article in journal (Refereed)
    Abstract [en]

    Cancer is currently treated by a combination of therapies, including chemotherapy which is believed to suppress the immune system. Combination of immunotherapy and chemotherapy correlates with improved survival but needs careful planning in order to achieve a synergistic effect. In this study, we have demonstrated that doxorubicin treatment of B cells resulted in increased expression of CD86 and concordantly increased CD4(+) T cell activation in the presence of superantigen, an effect that was inhibited by the addition of a CD86 blocking antibody. Furthermore, doxorubicin resulted in decreased expression of the anti-inflammatory cytokines IL-10 and TNF-α. Finally, B cells from urinary bladder cancer patients, treated with a neoadjuvant regiment containing doxorubicin, displayed increased CD86-expression. We conclude that doxorubicin induces CD86 expression on B cells and hence enhances their antigen-presenting ability in vitro, a finding verified in patients. Development of tailored time and dose schedules may increase the effectiveness of combining chemotherapy and immunotherapy.

  • 43. Zirakzadeh, A. Ali
    et al.
    Marits, Per
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies2013In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 190, no 11, p. 5847-5855Article in journal (Refereed)
    Abstract [en]

    B lymphocytes contribute to immune surveillance, by tumor-specific Abs and Ag presentation to T lymphocytes, but are insufficiently studied in humans. In this article, we report a flow cytometric investigation of B lymphocyte subpopulations in blood, lymph nodes (LNs), and malignant tissues from 20 patients operated on because of advanced solid tumors. The CD19(+) compartment in peripheral blood was essentially unaltered in patients, as compared with healthy control subjects. In metastatic LNs, signs of B lymphocyte activation were observed, as evidenced by increased proportions of plasmablasts and CD86-expressing cells. In tumor-infiltrating B lymphocytes (TIL-B), both switched memory cells and plasmablasts were expanded, as compared with nonmalignant epithelium. Moreover, pronounced skewing of Ig lambda/Ig kappa ratio was evident among TIL-Bs. By spectratype analysis on IgH, we confirmed a monoclonal expansion of the Vh7 family in TIL-B, also present in a tumor-associated LN. Sequencing the clonally expanded Vh7 revealed signs of somatic hypermutation. In conclusion, B lymphocytes in cancer patients exhibit signs of activation in tumor-associated tissues, likely induced by recognition of tumor Ags. Increased numbers of switched memory cells and plasmablasts in combination with clonal expansion and signs of somatic hypermutation suggest a CD4(+) T lymphocyte-dependent antitumoral response, which may be exploited for immunotherapy.

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