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Zare, R., Grabe, M., Hermann, G. G. & Malmström, P.-U. (2018). Can routine outpatient follow-up of patients with bladder cancer be improved?: A multicenter prospective observational assessment of blue light flexible cystoscopy and fulguration. Research and Reports in Urology, 10, 151-157
Open this publication in new window or tab >>Can routine outpatient follow-up of patients with bladder cancer be improved?: A multicenter prospective observational assessment of blue light flexible cystoscopy and fulguration
2018 (English)In: Research and Reports in Urology, ISSN 2253-2447, E-ISSN 1179-1551, Vol. 10, p. 151-157Article in journal (Refereed) Published
Abstract [en]

Background: The aim of this prospective cohort study was to determine the feasibility of incorporating blue light flexible cystoscopy (BLFC) and biopsy/fulguration into routine outpatient follow-up of non-muscle invasive bladder cancer patients.

Methods: The study included patients with non-muscle-invasive bladder cancer (NMIBC) who were scheduled for routine follow-up. Hexaminolevulinate was instilled in the outpatient department, and the bladder was examined under white light and then with BLFC. Biopsies were taken from all suspicious lesions. Small tumors and suspicious lesions were fulgurated on site; patients with larger lesions were referred to the operating room for resection.

Results: The study included 69 patients, with a mean age of 70 years (range 33 -89 years) and a mean duration since NMIBC diagnosis of 8 years. Most patients had high-grade cancer at initial diagnosis (52/69) and were at high risk of recurrence (48/69). Two patients per hour could be assessed using outpatient BLFC. Preparation and instillation of hexaminolevulinate took less than 10 minutes per patient, and patients had an additional waiting time of 45 60 minutes following instillation, while the hexaminolevulinate solution was retained in the bladder before examination. Eleven patients had histologically confirmed tumors that were identified using both white light flexible cystoscopy and BLFC. An additional three patients had tumors that were identified by BLFC only: two with Ta tumors and one with carcinoma in situ. Of the 14 patients with confirmed tumors, 11 could be managed on site with fulguration, whereas three were referred to the operating room. No adverse events attributable to BLFC were reported.

Conclusion: Routine outpatient management of patients with NMIBC using BLFC and onsite biopsy/fulguration is feasible, despite the additional time required for hexaminolevulinate instillation, and appears to allow early detection of recurrent lesions, which can be fulgurated without the need for hospitalization.

Place, publisher, year, edition, pages
DOVE MEDICAL PRESS LTD, 2018
Keywords
bladder cancer, blue light, diagnosis, flexible cystoscopy, hexaminolevulinate, outpatients
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-368771 (URN)10.2147/RRU.S141314 (DOI)000447216900001 ()30349812 (PubMedID)
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2018-12-10Bibliographically approved
Hemdan, T., Turker, P., Malmström, P.-U. & Segersten, U. (2018). Choline-phosphate cytidylyltransferase-alpha as a possible predictor of survival and response to cisplatin neoadjuvant chemotherapy in urothelial cancer of the bladder. Scandinavian journal of urology, 52(3), 200-205
Open this publication in new window or tab >>Choline-phosphate cytidylyltransferase-alpha as a possible predictor of survival and response to cisplatin neoadjuvant chemotherapy in urothelial cancer of the bladder
2018 (English)In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 52, no 3, p. 200-205Article in journal (Refereed) Published
Abstract [en]

Objectives: The aim of this study was to test choline-phosphate cytidylyltransferase-alpha (CCT-alpha) protein as a biomarker for neoadjuvant cisplatin chemotherapy response in a bladder tumor setting. Materials and methods: A total of 238 patients with T2-T4 bladder cancer enrolled into two prior randomized trials comparing neoadjuvant cisplatin-based chemotherapy (NAC) plus cystectomy with cystectomy only (no-NAC) were used as discovery and validation cohorts. Protein expression was determined with immunohistochemistry and assessed with Histo (H)-scoring. Results: In the discovery cohort, comprising 61 patients, the survival ratio after NAC treatment for CCT-alpha-negative patients was significantly increased (p = 0.001) while there was no survival advantage in the CCT-alpha-positive patient group. Similarly, in the validation cohort with 177 patients, NAC treatment improved survival only in the CCT-alpha-negative group (p = 0.006). Although there was a tendency for a good NAC response with negative CCT-alpha status, the interaction variable between biomarker and treatment was not significant (p = 0.24). In the cystectomy-only group, patients with positive CCT-alpha expression had a better survival than CCT-alpha-negative patients. This prognostic effect of CCT-alpha expression remained significant after adjusting for well-known prognostic factors in a multivariate analysis. In a pooled database of both patient data sets, multivariate analyses showed CCT-alpha status as an independent factor for overall survival (p = 0.018; hazard ratio = 1.80, 95% confidence interval 1.11-2.93). Conclusion: CCT-alpha status was not predictive of outcome of NAC response; however, in the control group with cystectomy only it was found to have prognostic value.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2018
Keywords
Biomarker, bladder cancer, choline-phosphate cytidylyl-transferase-alpha, predictive, prognostic
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-372683 (URN)10.1080/21681805.2018.1439527 (DOI)000452052700007 ()29475387 (PubMedID)
Funder
Swedish Cancer SocietyErik, Karin och Gösta Selanders Foundation
Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2019-01-09Bibliographically approved
van Kessel, K. E. M., van der Keur, K. A., Dyrskjot, L., Algaba, F., Welvaart, N. Y. C., Beukers, W., . . . Zwarthoff, E. C. (2018). Molecular Markers Increase Precision of the European Association of Urology Non-Muscle-Invasive Bladder Cancer Progression Risk Groups. Clinical Cancer Research, 24(7), 1586-1593
Open this publication in new window or tab >>Molecular Markers Increase Precision of the European Association of Urology Non-Muscle-Invasive Bladder Cancer Progression Risk Groups
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2018 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 24, no 7, p. 1586-1593Article in journal (Refereed) Published
Abstract [en]

Purpose: The European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathologic parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC. Experimental Design: We prospectively included 1,239 patients in follow-up for NMIBC in six European countries. Fresh-frozen tumor samples were analyzed for GATA2, TBX2, TBX3, and ZIC4 methylation and FGFR3, TERT, PIK3CA, and RAS mutation status. Cox regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR = rate of progression per 100 patient-years) was calculated for subgroups. Results: In our cohort, 276 patients had a low, 273 an intermediate, and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared with older studies is likely due to improved treatment in the past two decades. Overall, wild-type FGFR3 and methylation of GATA2 and TBX3 were significantly associated with progression (HR = 0.34, 2.53, and 2.64, respectively). The PIR for EAU high-risk patients was 4.25. On the basis of FGFR3 mutation status and methylation of GATA2, this cohort could be reclassified into a good class (PIR = 0.86, 26.2% of patients), a moderate class (PIR = 4.32, 49.7%), and a poor class (PIR = 7.66, 24.0%). Conclusions: We conclude that the addition of selected biomarkers to the EAU risk stratification increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression. (C) 2018 AACR.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2018
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-351679 (URN)10.1158/1078-0432.CCR-17-2719 (DOI)000429050000010 ()29367430 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 201663
Available from: 2018-06-05 Created: 2018-06-05 Last updated: 2018-06-05Bibliographically approved
Holfeld, A., Valdés, A., Malmström, P.-U., Segersten, U. & Bergström Lind, S. (2018). Parallel Proteomic Workflow for Mass Spectrometric Analysis of Tissue Samples Preserved by Different Methods. Analytical Chemistry, 90(9), 5841-5849
Open this publication in new window or tab >>Parallel Proteomic Workflow for Mass Spectrometric Analysis of Tissue Samples Preserved by Different Methods
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2018 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 9, p. 5841-5849Article in journal (Refereed) Published
Abstract [en]

Formalin-fixed and paraffin-embedded (FFPE) and optimal cutting temperature (OCT)-embedded and frozen tissue specimens in biobanks are highly valuable in clinical studies but proteomic and post-translational modification (PTM) studies using mass spectrometry (MS) have been limited due to structural arrangement of proteins and contaminations from embedding material. This study aims to develop a parallel proteomic workflow for FFPE and OCT/frozen samples that allows for large-scale, quick, reproducible, qualitative, and quantitative high-resolution MS analysis. The optimized protocol gives details on removal of embedding material, protein extraction, and multienzyme digestion using filter-aided sample preparation method. The method was evaluated by investigating the protein expression levels in nonmuscle-invasive and muscle-invasive bladder cancer samples in two cohorts and MS spectra were carefully reviewed for contaminations. More than 2000 and 3000 proteins in FFPE and OCT/frozen samples, respectively, were identified, and samples could be clustered in different tumor stages based on their protein expression. Furthermore, more than 250 and 400 phosphopeptides could be identified from specific patient samples of FFPE and OCT/frozen, respectively, using titanium dioxide enrichment. The paper presents unique data describing the similarities and differences observed in FFPE and OCT/frozen samples and shows the feasibility to detect proteins and site-specific phosphorylation even after long-term storage of clinical samples.

National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-356506 (URN)10.1021/acs.analchem.8b00379 (DOI)000431464400045 ()29624047 (PubMedID)
Funder
Åke Wiberg Foundation, M14-0127Magnus Bergvall Foundation, 2015-01200; 2016-01675Carl Tryggers foundation , CST 15:57
Available from: 2018-08-10 Created: 2018-08-10 Last updated: 2018-08-10Bibliographically approved
Soria, F., Pisano, F., Gontero, P., Palou, J., Joniau, S., Serretta, V., . . . Sylvester, R. (2018). Predictors of oncological outcomes in T1G3 patients treated with BCG who undergo radical cystectomy. World journal of urology, 36(11), 1775-1781
Open this publication in new window or tab >>Predictors of oncological outcomes in T1G3 patients treated with BCG who undergo radical cystectomy
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2018 (English)In: World journal of urology, ISSN 0724-4983, E-ISSN 1433-8726, Vol. 36, no 11, p. 1775-1781Article in journal (Refereed) Published
Abstract [en]

Purpose: To evaluate the oncological impact of postponing radical cystectomy (RC) to allow further conservative therapies prior to progression in a large multicentre retrospective cohort of T1-HG/G3 patients initially treated with BCG.

Methods: According to the time of RC, the population was divided into 3 groups: patients who did not progress to muscle-invasive disease, patients who progressed before radical cystectomy and patients who experienced progression at the time of radical cystectomy. Clinical and pathological outcomes were compared across the three groups.

Results: Of 2451 patients, 509 (20.8%) underwent RC. Patients with tumors > 3 cm or with CIS had earlier cystectomies (HR = 1.79, p = 0.001 and HR = 1.53, p = 0.02, respectively). Patients with tumors > 3 cm, multiple tumors or CIS had earlier T3/T4 or N + cystectomies. In patients who progressed, the timing of cystectomy did not affect the risk of T3/T4 or N + disease at RC. Patients with T3/T4 or N + disease at RC had a shorter disease-specific survival (HR = 4.38, p < 0.001), as did patients with CIS at cystectomy (HR = 2.39, p < 0.001). Patients who progressed prior to cystectomy had a shorter disease-specific survival than patients for whom progression was only detected at cystectomy (HR = 0.58, p = 0.024)

Conclusions: Patients treated with RC before experiencing progression to muscle-invasive disease harbor better oncological and survival outcomes compared to those who progressed before RC and to those upstaged at surgery. Tumor size and concomitant CIS at diagnosis are the main predictors of surgical treatment while tumor size, CIS and tumor multiplicity are associated with extravesical disease at surgery.

Keywords
Bladder cancer, High risk, T1G3, Cystectomy, Outcomes, Extravesical disease
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-369609 (URN)10.1007/s00345-018-2450-0 (DOI)000448864400010 ()30171454 (PubMedID)
Available from: 2018-12-14 Created: 2018-12-14 Last updated: 2018-12-14Bibliographically approved
Palou, J., Pisano, F., Sylvester, R., Joniau, S., Serretta, V., Larre, S., . . . Gontero, P. (2018). Recurrence, progression and cancer-specific mortality according to stage at re-TUR in T1G3 bladder cancer patients treated with BCG: not as bad as previously thought. World journal of urology, 36(10), 1621-1627
Open this publication in new window or tab >>Recurrence, progression and cancer-specific mortality according to stage at re-TUR in T1G3 bladder cancer patients treated with BCG: not as bad as previously thought
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2018 (English)In: World journal of urology, ISSN 0724-4983, E-ISSN 1433-8726, Vol. 36, no 10, p. 1621-1627Article in journal (Refereed) Published
Abstract [en]

Purpose: The goals of transurethral resection of a bladder tumor (TUR) are to completely resect the lesions and to make a correct diagnosis to adequately stage and treat the patient. Persistent disease after TUR is not uncommon and is why re-TUR is recommended in T1G3 patients. When there is T1 tumor in the re-TUR specimen, very high risks of progression (82%) have been reported. We analyze the risks of recurrence, progression to muscle-invasive disease and cancer-specific mortality (CSM) according to tumor stage at re-TUR in T1G3 patients treated with BCG.

Methods: In our retrospective cohort of 2451 T1G3 patients, 934 patients (38.1%) underwent re-TUR. 667 patients had residual disease (71.4%): Ta in 378 (40.5%), T1 in 289 (30.9%) patients. Times to recurrence, progression and CSM in the three groups were estimated using cumulative incidence functions and compared using the Cox regression model.

Results:During a median follow-up of 5.2years, 512 patients recurred. The recurrence rate was significantly higher in patients with a T1 at re-TUR (P<0.001). Progression rates differed according to the pathology at re-TUR, 25.3% in T1, 14.6% in Ta and 14.2% in case of no residual tumor (P<0.001). Similar trends were seen in both patients with and without muscle in the original TUR specimen.

Conclusions: Patients with T1G3 tumors and no residual disease or Ta at re-TUR have better recurrence, progression and CSM rates than previously reported, with a CSM rate of 13.1 and a 25.3% progression rate in re-TUR T1 disease.

Place, publisher, year, edition, pages
SPRINGER, 2018
Keywords
Non-muscle invasive bladder cancer, Re-transurethral resection of the bladder, Recurrence, Progression
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-366942 (URN)10.1007/s00345-018-2299-2 (DOI)000445121400013 ()29721611 (PubMedID)
Available from: 2018-11-28 Created: 2018-11-28 Last updated: 2018-11-28Bibliographically approved
Sjostrom, C., Thorstenson, A., Strock, V., Hosseini-Aliabad, A., Aljabery, F., Liedberg, F., . . . Jahnson, S. (2018). Treatment according to guidelines may bridge the gender gap in outcome for patients with stage T1 urinary bladder cancer. Scandinavian journal of urology, 52(3), 186-193
Open this publication in new window or tab >>Treatment according to guidelines may bridge the gender gap in outcome for patients with stage T1 urinary bladder cancer
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2018 (English)In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 52, no 3, p. 186-193Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2018
Keywords
Bladder cancer, female, gender, intravesical instillation therapy, male, population-based, survival
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-372682 (URN)10.1080/21681805.2018.1462254 (DOI)000452052700004 ()29676191 (PubMedID)
Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2019-01-09Bibliographically approved
Chan, O. T. M., Furuya, H., Pagano, I., Shimizu, Y., Hokutan, K., Dyrskjot, L., . . . Rosser, C. J. (2017). Association of MMP-2, RB and PAI-1 with decreased recurrence-free survival and overall survival in bladder cancer patients. OncoTarget, 8(59), 99707-99721
Open this publication in new window or tab >>Association of MMP-2, RB and PAI-1 with decreased recurrence-free survival and overall survival in bladder cancer patients
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 59, p. 99707-99721Article in journal (Refereed) Published
Abstract [en]

Background: We previously reported an accurate urine-based bladder cancer (BCa)-associated diagnostic signature that can be used to non-invasively detect BCa. In this study, we investigated whether a component of this signature could risk stratify patients with BCa. Methods: Utilizing immunohistochemistry, we investigated angiogenin, MMP-2, p53, RB and PAI-1 expression from 939 patients with BCa. The expression levels were scored by assigning a proportion score and an intensity score to yield a total staining score for each protein. The expressions of each protein individually and as an aggregate were then correlated with progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Results: Differential expressions of these markers were noted in BCa. With multivariate analysis in non-muscle invasive bladder cancer (NMIBC) age, tumor grade portended a worse PFS, while age, tumor grade, nodal status, MMP2, RB and PAI-1 expression portended a worse OS. As for multivariate analysis in muscle invasive bladder cancer (MIBC), age MMP-2 and RB were associated with a worse PFS, while age, nodal status, MMP-2, RB and PAI-1 were associated with a worse OS. Using Kaplan-Meier survival analysis, we noted a significant reduction in OS as more of the five biomarkers were expressed in a tumor. Thus, overall, high expressions of MMP-2, RB and/or PAI-1 in bladder tumors were markers of poor prognosis. Conclusion: Individually, MMP-2, RB and PAI-1, as well as in aggregate correlated with poor survival in patients with BCa. Thus, patients whose bladder tumors express these biomarkers may benefit from early radical treatment and/or neoadjuvant or adjuvant therapies.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keywords
angiogenin, bladder cancer, IHC, MMP-2, PAI-1, survival
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-345219 (URN)10.18632/oncotarget.20686 (DOI)000419561600050 ()29245935 (PubMedID)
Available from: 2018-03-08 Created: 2018-03-08 Last updated: 2018-03-08Bibliographically approved
Häggström, C., Liedberg, F., Hagberg, O., Aljabery, F., Ströck, V., Hosseini, A., . . . Holmberg, L. (2017). Cohort profile: The Swedish National Register of Urinary Bladder Cancer (SNRUBC) and the Bladder Cancer Data Base Sweden (BladderBaSe). BMJ Open, 7(9), Article ID e016606.
Open this publication in new window or tab >>Cohort profile: The Swedish National Register of Urinary Bladder Cancer (SNRUBC) and the Bladder Cancer Data Base Sweden (BladderBaSe)
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2017 (English)In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, no 9, article id e016606Article in journal (Refereed) Published
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.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-337759 (URN)10.1136/bmjopen-2017-016606 (DOI)000412650700144 ()28963292 (PubMedID)
Funder
Swedish Cancer Society, CAN 2013/472
Available from: 2018-01-12 Created: 2018-01-12 Last updated: 2018-01-12Bibliographically approved
Malmström, P.-U. (2017). Drugs and risk of cancer. Scandinavian journal of urology, 51(3), 212-212
Open this publication in new window or tab >>Drugs and risk of cancer
2017 (English)In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, no 3, p. 212-212Article in journal, Editorial material (Other academic) Published
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-329719 (URN)10.1080/21681805.2017.1329905 (DOI)000403729400012 ()28657390 (PubMedID)
Available from: 2017-09-21 Created: 2017-09-21 Last updated: 2017-09-21Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8572-9957

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