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Häggström, ChristelORCID iD iconorcid.org/0000-0001-6808-4405
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Publications (10 of 51) Show all publications
Christakoudi, S., Kakourou, A., Markozannes, G., Tzoulaki, I., Weiderpass, E., Brennan, P., . . . Tsilidis, K. K. (2019). Blood pressure and risk of cancer in the European Prospective Investigation into Cancer and Nutrition. International Journal of Cancer
Open this publication in new window or tab >>Blood pressure and risk of cancer in the European Prospective Investigation into Cancer and Nutrition
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Article in journal (Refereed) Epub ahead of print
Abstract [en]

Several studies have reported associations of hypertension with cancer, but not all results were conclusive. We examined the association of systolic (SBP) and diastolic (DBP) blood pressure with the development of incident cancer at all anatomical sites in the European Prospective Investigation into Cancer and Nutrition (EPIC). Hazard ratios (HRs) (95% confidence intervals) were estimated using multivariable Cox proportional hazards models, stratified by EPIC-participating center and age at recruitment, and adjusted for sex, education, smoking, body mass index, physical activity, diabetes and dietary (in women also reproductive) factors. The study included 307,318 men and women, with an average follow-up of 13.7 (standard deviation 4.4) years and 39,298 incident cancers. We confirmed the expected positive association with renal cell carcinoma: HR = 1.12 (1.08-1.17) per 10 mm Hg higher SBP and HR = 1.23 (1.14-1.32) for DBP. We additionally found positive associations for esophageal squamous cell carcinoma (SCC): HR = 1.16 (1.07-1.26) (SBP), HR = 1.31 (1.13-1.51) (DBP), weaker for head and neck cancers: HR = 1.08 (1.04-1.12) (SBP), HR = 1.09 (1.01-1.17) (DBP) and, similarly, for skin SCC, colon cancer, postmenopausal breast cancer and uterine adenocarcinoma (AC), but not for esophageal AC, lung SCC, lung AC or uterine endometroid cancer. We observed weak inverse associations of SBP with cervical SCC: HR = 0.91 (0.82-1.00) and lymphomas: HR = 0.97 (0.93-1.00). There were no consistent associations with cancers in other locations. Our results are largely compatible with published studies and support weak associations of blood pressure with cancers in specific locations and morphologies.

Keywords
Europe, association, cancer, cohort, epidemiology, hypertension, morphology, risk factors
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-162707 (URN)10.1002/ijc.32576 (DOI)000482366600001 ()31319002 (PubMedID)
Available from: 2019-08-26 Created: 2019-08-26 Last updated: 2019-12-03
Bjørge, T., Häggström, C., Ghaderi, S., Nagel, G., Manjer, J., Tretli, S., . . . Engeland, A. (2019). BMI and weight changes and risk of obesity-related cancers: a pooled European cohort study.. International Journal of Epidemiology, Article ID dyz188.
Open this publication in new window or tab >>BMI and weight changes and risk of obesity-related cancers: a pooled European cohort study.
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2019 (English)In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, article id dyz188Article in journal (Refereed) Epub ahead of print
Abstract [en]

BACKGROUND: Obesity is an established risk factor for several cancers. Adult weight gain has been associated with increased cancer risk, but studies on timing and duration of adult weight gain are relatively scarce. We examined the impact of BMI (body mass index) and weight changes over time, as well as the timing and duration of excess weight, on obesity- and non-obesity-related cancers.

METHODS: We pooled health data from six European cohorts and included 221 274 individuals with two or more height and weight measurements during 1972-2014. Several BMI and weight measures were constructed. Cancer cases were identified through linkage with national cancer registries. Hazard ratios (HRs) of cancer with 95% confidence intervals (CIs) were derived from time-dependent Cox-regression models.

RESULTS: During follow-up, 27 881 cancer cases were diagnosed; 9761 were obesity-related. The HR of all obesity-related cancers increased with increasing BMI at first and last measurement, maximum BMI and longer duration of overweight (men only) and obesity. Participants who were overweight before age 40 years had an HR of obesity-related cancers of 1.16 (95% CI 1.02, 1.32) and 1.15 (95% CI 1.04, 1.27) in men and women, respectively, compared with those who were not overweight. The risk increase was particularly high for endometrial (70%), male renal-cell (58%) and male colon cancer (29%). No positive associations were seen for cancers not regarded as obesity-related.

CONCLUSIONS: Adult weight gain was associated with increased risk of several major cancers. The degree, timing and duration of overweight and obesity also seemed to be important. Preventing weight gain may reduce the cancer risk.

Keywords
BMI and weight changes, Obesity-related cancers, cohort study
Identifiers
urn:nbn:se:umu:diva-165815 (URN)10.1093/ije/dyz188 (DOI)31566221 (PubMedID)
Available from: 2019-12-04 Created: 2019-12-04 Last updated: 2019-12-04
Beckmann, K., Russell, B., Josephs, D., Garmo, H., Häggström, C., Holmberg, L., . . . Adolfsson, J. (2019). Chronic inflammatory diseases, anti-inflammatory medications and risk of prostate cancer: a population-based case-control study. BMC Cancer, 19, Article ID 612.
Open this publication in new window or tab >>Chronic inflammatory diseases, anti-inflammatory medications and risk of prostate cancer: a population-based case-control study
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2019 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, article id 612Article in journal (Refereed) Published
Abstract [en]

Background: Whether chronic inflammation increases prostate cancer risk remains unclear. This study investigated whether chronic inflammatory diseases (CID) or anti-inflammatory medication use (AIM) were associated with prostate cancer risk.

Methods: Fifty-five thousand nine hundred thirty-seven cases (all prostate cancer, 2007–2012) and 279,618 age-matched controls were selected from the Prostate Cancer Database Sweden. CIDs and AIMs was determined from national patient and drug registers. Associations were investigated using conditional logistic regression, including for disease/drug subtypes and exposure length/dose.

Results: Men with a history of any CID had slightly increased risk of any prostate cancer diagnosis (OR: 1.08; 95%CI: 1.04–1.12) but not ‘unfavourable’ (high-risk or advanced) prostate cancer. Generally, risk of prostate cancer was highest for shorter exposure times. However, a positive association was observed for asthma > 5 years before prostate cancer diagnosis (OR: 1.21; 95%CI: 1.05–1.40). Risk of prostate cancer was increased with prior use of any AIMs (OR: 1.26; 95%CI: 1.24–1.29). A positive trend with increasing cumulative dose was only observed for inhaled glucocorticoids (p < 0.011).

Conclusion: Detection bias most likely explains the elevated risk of prostate cancer with prior history of CIDs or use of AIMs, given the higher risk immediately after first CID event and lack of dose response. However, findings for length of time with asthma and dose of inhaled glucocorticoids suggest that asthma may increase risk of prostate cancer through other pathways.

Place, publisher, year, edition, pages
BioMed Central, 2019
Keywords
Prostate cancer, Chronic inflammatory disease, Autoimmune disease, Anti-inflammatory medication
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-161512 (URN)10.1186/s12885-019-5846-3 (DOI)000472477600005 ()31226970 (PubMedID)
Funder
Swedish Cancer Society, 2013/472
Available from: 2019-07-12 Created: 2019-07-12 Last updated: 2019-07-12Bibliographically approved
Bessa, A., Maclennan, S., Enting, D., Bryan, R., Josephs, D., Hughes, S., . . . Van Hemelrijck, M. (2019). Consensus in Bladder Cancer Research Priorities Between Patients and Healthcare Professionals Using a Four-stage Modified Delphi Method [Letter to the editor]. European Urology, 76(2), 258-259
Open this publication in new window or tab >>Consensus in Bladder Cancer Research Priorities Between Patients and Healthcare Professionals Using a Four-stage Modified Delphi Method
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2019 (English)In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 76, no 2, p. 258-259Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-158781 (URN)10.1016/j.eururo.2019.01.031 (DOI)000474574000036 ()30712969 (PubMedID)2-s2.0-85065993923 (Scopus ID)
Available from: 2019-05-08 Created: 2019-05-08 Last updated: 2019-09-06Bibliographically approved
Fritz, J., Bjorge, T., Nagel, G., Concin, H., Manjer, J., Häggström, C., . . . Ulmer, H. (2019). Insulin resistance measured by the triglyceride-glucose index and risk of obesity-related cancers: An epidemiological investigation in more than 500,000 individuals.. Paper presented at Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), MAY 31-JUN 04, 2019, Chicago, IL. Journal of Clinical Oncology, 37(15), 1552-1552
Open this publication in new window or tab >>Insulin resistance measured by the triglyceride-glucose index and risk of obesity-related cancers: An epidemiological investigation in more than 500,000 individuals.
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2019 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 37, no 15, p. 1552-1552Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: The role of insulin resistance as a mediator in the association of body mass index (BMI) with site-specific cancer risk has, to our knowledge, never been systematically quantified. We aimed to determine to what extent insulin resistance measured as the logarithmized triglyceride glucose product (TyG index) mediates the effect of BMI on risk of obesity-related cancers. Methods: A total of 510,471 individuals from six European cohorts with a mean age of 43.1 years were included in the study. We fitted Cox models, adjusted for relevant confounders, to investigate associations of TyG index with ten common obesity-related cancer sites, and quantified the proportion of the effect of BMI mediated through TyG index. Results: During a median follow-up of 17.2 years, 16 052 individuals developed obesity-related cancers. TyG index was associated with the risk of cancers of the kidney (hazard ratio (HR) per one standard deviation increase 1.13, 95% confidence interval: 1.07-1.20), liver (1.13, 1.04-1.23), pancreas (1.12, 1.06-1.19), colon (1.07, 1.03-1.10), and rectum (1.09, 1.04-1.14). Substantial proportions of the effect of BMI were mediated by TyG index for cancers of the pancreas (42%), rectum (34%), and colon (20%); smaller proportions for kidney (15%) and liver (11%); none for endometrium, ovary and breast (postmenopausal). Conclusions: In this pooled cohort study including more than 500,000 individuals, insulin resistance measured as the logarithmized triglyceride glucose product significantly mediated the effect of overweight and obesity on risk of cancers of the kidney, liver, pancreas, colon, and rectum. In contrast, insulin resistance did not mediate the risk for cancers of the endometrium, ovary and breast. Our results confirm a promoting role of insulin resistance in the pathogenesis of gastrointestinal cancers. Although often claimed, insulin resistance does not appear to connect excess body weight with cancers of the female reproductive organs.

Place, publisher, year, edition, pages
American Society of Clinical Oncology, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-164084 (URN)10.1200/JCO.2019.37.15_suppl.1552 (DOI)000487345804348 ()
Conference
Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), MAY 31-JUN 04, 2019, Chicago, IL
Note

Supplement: S (May 20, 2019)

Meeting Abstract: 1552

Available from: 2019-10-14 Created: 2019-10-14 Last updated: 2019-10-14Bibliographically approved
Häggström, C., Jonsson, H., Bjørge, T., Nagel, G., Manjer, J., Ulmer, H., . . . Stocks, T. (2019). Linear age-course effects on the associations between body mass index, triglycerides, and female breast and male liver cancer risk: An internal replication study of 800,000 individuals. International Journal of Cancer
Open this publication in new window or tab >>Linear age-course effects on the associations between body mass index, triglycerides, and female breast and male liver cancer risk: An internal replication study of 800,000 individuals
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Article in journal (Refereed) Epub ahead of print
Abstract [en]

Apart from the consistently observed differential association between obesity and breast cancer risk by menopausal status, the associations between obesity and other metabolic imbalances with risks of cancers have not been systematically investigated across the age‐course. We created two random 50–50% cohorts from six European cohorts comprising 813,927 individuals. In the “discovery cohort”, we used Cox regression with attained age as time‐scale and tested interactions between body mass index (BMI), blood pressure, plasma glucose, triglycerides and cholesterol, and attained age in relation to cancer risk. Results with a p‐value below 0.05 were additionally tested in the “replication cohort” where a replicated result was considered evidence of a linear interaction with attained age. These findings were investigated by flexible parametric survival models for any age‐plateaus in their shape of associations with cancer risk across age. Consistent with other studies, BMI was negatively related to breast cancer risk (n cases = 11,723) among younger (premenopausal) women. However, the association remained negative for several years after menopause and, although gradually weakening over age, the association became positive only at 62 years of age. This linear and positive age‐interaction was also found for triglycerides and breast cancer, and for BMI and triglycerides in relation to liver cancer among men (n cases = 444). These findings are unlikely to be due to chance owing to the replication. The linear age‐interactions in breast cancer may suggest an influence by other age‐related factors than menopause; however, further investigation of age‐related effect modifiers in both breast and liver cancer is needed.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
age interaction, cancer risk, cohort study, metabolic factors, survival analysis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-157853 (URN)10.1002/ijc.32240 (DOI)30815851 (PubMedID)
Available from: 2019-04-04 Created: 2019-04-04 Last updated: 2019-04-05
Aljabery, F., Liedberg, F., Häggström, C., Ströck, V., Hosseini, A., Gårdmark, T., . . . Jahnson, S. (2019). Management and outcome of muscle-invasive bladder cancer with clinical lymph node metastases: a nationwide population-based study in the bladder cancer data base Sweden (BladderBaSe). Scandinavian journal of urology
Open this publication in new window or tab >>Management and outcome of muscle-invasive bladder cancer with clinical lymph node metastases: a nationwide population-based study in the bladder cancer data base Sweden (BladderBaSe)
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2019 (English)In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813Article in journal (Refereed) Epub ahead of print
Abstract [en]

Purpose: To investigate the clinical management and outcome of patients with muscle-invasive bladder cancer with clinical lymph node involvement, using longitudinal nationwide population-based data.

Methods: In the Bladder Cancer Data Base Sweden (BladderBaSe), treatment and survival in patients with urinary bladder cancer clinical stage T2-T4 N + M0 diagnosed between 1997 and 2014 was investigated. Patients´ characteristics were studied in relation to TNM classification, curative or palliative treatment, cancer-specific (CSS) and overall survival (OS). Age at diagnosis was categorised as ≤60, 61-70, 71-80 and >80 years, and time periods were stratified as follows: 1997-2001, 2002-2005, 2006-2010 and 2011-2014.

Results: There were 786 patients (72% males) with a median age of 71 years (interquartile range = 64-79 years). The proportion of patients with high comorbidity increased over time. Despite similar low comorbidity, curative treatment was given to 44% and to 70% of those in older (>70 years) and younger age groups, respectively. Curative treatment decreased over time, but chemotherapy and cystectomy increased to 25% during the last time period. Patients with curative treatment had better survival compared to those with palliative treatment, both regarding CSS and OS in the whole cohort and in all age groups.

Conclusions: The low proportion of older patients undergoing treatment with curative intent, despite no or limited comorbidity, indicates missed chances of treatment with curative intent. The reasons for an overall decrease in curative treatment over time need to be analysed and the challenge of coping with an increasing proportion of node-positive patients with clinically significant comorbidity needs to be met.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Bladder cancer, cohort study, lymph node metastasis, management, outcome
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-165088 (URN)10.1080/21681805.2019.1681504 (DOI)000493241700001 ()31663405 (PubMedID)
Available from: 2019-11-11 Created: 2019-11-11 Last updated: 2019-11-14
Myte, R., Gylling, B., Häggström, J., Häggström, C., Zingmark, C., Löfgren Burström, A., . . . van Guelpen, B. (2019). Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status. International Journal of Cancer, 145(2), 327-337
Open this publication in new window or tab >>Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 2, p. 327-337Article in journal (Refereed) Published
Abstract [en]

Factors related to energy metabolism and the metabolic syndrome, such as higher body mass index (BMI), blood glucose, or blood lipids, and blood pressure, are associated with an increased risk of colorectal cancer (CRC). However, CRC is a heterogeneous disease, developing through distinct pathways with differences in molecular characteristics and prognosis, and possibly also in risk factors. For subtypes defined by KRAS and BRAF mutation status, BMI is the only metabolic factor previously studied, with inconsistent findings. We investigated whether associations between BMI, blood glucose, blood lipids, and blood pressure and CRC risk differed by tumor KRAS and BRAF mutation status in 117,687 participants from two population-based cohorts within the Northern Sweden Health and Disease Study (NSHDS). Hazard ratios (HRs) for overall CRC and CRC subtypes by metabolic factors were estimated with Cox proportional hazards regression, using multiple imputation to handle missing exposure and tumor data. During a median follow-up of 15.6 years, we acquired 1,250 prospective CRC cases, of which 766 cases had complete baseline and molecular tumor data. Consistent with previous evidence, higher BMI, total cholesterol, triglyceride levels, and blood pressure were associated with an increased risk of overall CRC (HRs per 1 standard deviation increase: 1.07 to 1.12). These associations were similar regardless of CRC subtype by KRAS and BRAF mutation status (all pheterogeneity > 0.05). The same was true for subtypes based on microsatellite instability status. Poor metabolic health may therefore be a universal mechanism for colorectal cancer, acting across multiple developmental pathways.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
BRAF, KRAS, colorectal cancer, metabolic factors, microsatellite instability, risk factors
National Category
Cancer and Oncology Nutrition and Dietetics
Identifiers
urn:nbn:se:umu:diva-158782 (URN)10.1002/ijc.32104 (DOI)30613980 (PubMedID)2-s2.0-85060622510 (Scopus ID)
Note

Originally included in thesis in manuscript form with title [Metabolic factors and colorectal cancer risk by KRAS and BRAF mutation status]

Available from: 2019-05-08 Created: 2019-05-08 Last updated: 2019-06-11Bibliographically approved
Liedberg, F., Hagberg, O., Aljabery, F., Gårdmark, T., Hosseini, A., Jahnson, S., . . . Holmberg, L. (2019). Period-specific mean annual hospital volume of radical cystectomy is associated with outcome and perioperative quality of care: a nationwide population-based study. BJU International, 124(3), 449-456
Open this publication in new window or tab >>Period-specific mean annual hospital volume of radical cystectomy is associated with outcome and perioperative quality of care: a nationwide population-based study
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2019 (English)In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 124, no 3, p. 449-456Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
#BladderCancer, #blcsm, hospital volume, quality of care, radical cystectomy, survival
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-158482 (URN)10.1111/bju.14767 (DOI)000482452800019 ()30950568 (PubMedID)
Available from: 2019-04-29 Created: 2019-04-29 Last updated: 2019-11-20Bibliographically approved
Liedberg, F., Hagberg, O., Aljabery, F., Gårdmark, T., Hosseini, A., Jahnson, S., . . . Holmberg, L. (2019). Period-specific mean annual hospital volume of radical cystectomy is associated with outcome and perioperative quality of care in Sweden: a nationwide population-based study. Scandinavian journal of urology, 53, 20-20
Open this publication in new window or tab >>Period-specific mean annual hospital volume of radical cystectomy is associated with outcome and perioperative quality of care in Sweden: a nationwide population-based study
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2019 (English)In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 53, p. 20-20Article in journal, Meeting abstract (Other academic) Published
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.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-161604 (URN)10.1080/21681805.2019.1619285 (DOI)000472734500041 ()
Note

Supplement: 221

Special Issue: SI

Meeting Abstract: O3-03

Available from: 2019-07-18 Created: 2019-07-18 Last updated: 2019-07-18Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-6808-4405

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