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- Boman, Karolina, et al.
(författare)
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Podocalyxin-like and rna-binding motif protein 3 are prognostic biomarkers in urothelial bladder cancer : A validatory study
- 2017
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Ingår i: Biomarker research. - : Springer Science and Business Media LLC. - 2050-7771. ; 5:1, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Urothelial bladder cancer (UBC) is a disease that often is discovered when the tumour is non-muscle invasive, i.e. in Ta or T1 stage. Some patients will progress into muscle-invasive disease, a potentially deadly condition. Although there are some prognostic models, the need for prognostic and predictive biomarkers is considerate and urgent. Membranous expression of podocalyxin-like protein 1 (PODXL) and low expression of the RNA-binding motif 3 (RBM3) has previously been shown to be associated with an aggressive tumour phenotype and poor prognosis in several forms of cancer, including UBC. In this study, we sought to validate the prognostic impact of PODXL and RBM3 in an independent cohort of UBC. Methods: Using tissue microarrays and immunohistochemistry, PODXL and RBM3 expression was evaluated in 272 incident UBC cases from the prospective, population-based cohort study Malmö Diet and Cancer. Kaplan-Meier analysis and Cox proportional hazards modelling were used to evaluate the prognostic impact of these markers on 5-year overall survival (OS). Results: In line with previous studies, both membranous PODXL expression and low RBM3 expression was significantly associated with disadvantageous clinicopathological features. Membranous PODXL expression was significantly associated with a reduced 5-year overall survival in the entire cohort (univariable HR 3.28; 95% CI 1.89-5.69), but this association did not remain significant in multivariable analysis. In T1 tumours, PODXL was significantly associated with reduced survival in univariable analysis (HR = 2.83; 95% CI 1.04-7.72) and borderline significant in multivariable analysis (HR = 2.60; 95% CI 0.91-7.39). Low RBM3 expression was an independent predictor of a reduced survival in the entire cohort (univariable HR 3.19; 95% CI 2.02-5.04, and multivariable HR 1.85; 95% CI 1.11-3.09), and in T1 tumours (univariable HR 2.64; 95% CI 1.11-6.27, and multivariable HR 2.63; 95% CI 1.01-6.84). Conclusions: A link between membranous PODXL expression and clinically more aggressive tumours was further confirmed, but PODXL expression was not an independent prognostic biomarker in this study. Low RBM3 expression was validated as an independent factor of poor prognosis in UBC, including T1 disease. These findings suggest that these biomarkers could be useful in stratifying patients with non-muscle invasive disease for more aggressive first line treatment.
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| 2. |
- Granfelt Boman, Karolina
(författare)
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A valuable pair - candidate biomarkers RBM3 and PODXL in urothelial bladder cancer
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abstract: Bladder cancer is a heterogenous disease, ranging from minimally invasive, low-grade tumours with lowrecurrence rates and mortality on one end of the spectrum, and muscle invasive, high-grade disease prone torecurrence, progression and death at the other end.The aim of this thesis was to investigate the expression, clinicopathological correlates and prognostic significanceof the candidate biomarkers podocalyxin-like protein (PODXL, papers II and III) and RNA-binding motif protein 3(RBM3, papers I, III and IV) in urothelial bladder cancer (UBC). In paper IV, the potential predictive significance ofRBM3 was also examined. The candidate biomarkers were examined alongside established clinical risk factors.RBM3 expression was evaluated by immunohistochemistry in tissue microarrays (TMA) from three differentpatient cohorts (n=343 in paper I, n=272 in paper III and n=151 in paper IV). In paper I, negative RBM3 expressionwas significantly associated with unfavourable tumour characteristics and was an independent predictor of shorterdisease-specific survival (DSS) as well as 5-year overall survial (OS). Patients with Ta/T1 tumours displayingnegative RBM3 expression had a significantly reduced 24 month progression-free survival (PFS) and 5-year OS.No association was seen between RBM3 expression and recurrence. In paper 3, these associations werevalidated, although with a somewhat different cut-off. Low RBM3 expression was significantly associated withunfavourable tumour characteristics and was an independent predictor of a shorter OS in both the full cohort andin T1 disease.In paper IV, the expression of RBM3 was evaluated in tumours from 151 patients treated with cystectomy due tomuscle-invasive UBC, 45.7% of which had received neoadjuvant chemotherapy (NAC). RBM3 expression was notprognostic in the full cohort. However, when accounting for NAC, there was a significantly reduced RFS in in thegroup of patients with high RBM3 expression who had not been treated compared to those that had received NAC(p=0.044). The association between high RBM3 expression and response to chemotherapy was strengthened bythe silencing of RBM3 in UBC cell lines, rendering them less sensitive to cisplatin and gemcitabine.PODXL expressed in the cell membrane was evaluated by immunohistochemistry in TMA from three differentpatient cohorts (n=100 and n=343 in paper II and n=272 in paper III). Membranous expression of PODXL wasstrongly and significantly associated with unfavourable tumour characteristics in all three cohorts. In paper II,PODXL independently predicted a shorter DSS and OS in the full cohort, and a shorter PFS and DSS in patientswith Ta/T1 tumours. In paper III, membranous PODXL expression was significantly associated with a shorter OSin both the full cohort and T1 tumours, but not independent of other prognostic factors.The conclusions drawn from these studies are that both RBM3 and PODXL are potentially clinically usefulbiomarkers in UBC. RBM3 may have clinical implications in NMIBC for decision making in the pre-cystectomysetting and for its predictive value in patients under consideration for NAC. PODXL is associated with an adverseprognosis, making it a potentially useful prognostic biomarker. Both candidate biomarkers show great promise,although their value should be further examined in a prospective setting.
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| 3. |
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| 4. |
- Wahlin, Sara, et al.
(författare)
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Clinical impact of T cells, B cells and the PD-1/PD-L1 pathway in muscle invasive bladder cancer : a comparative study of transurethral resection and cystectomy specimens
- 2019
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Ingår i: OncoImmunology. - 2162-4011. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- In patients with muscle invasive bladder cancer (MIBC), neoadjuvant chemotherapy (NAC) prior to radical cystectomy has improved survival but there is an urgent unmet need to identify prognostic and predictive biomarkers to stratify patients who will benefit from treatment. This study aimed to examine the composition of tumor-infiltrating immune cells in MIBC, with particular reference to the clinical outcome and the potential modifying effect of NAC. To this end, the expression of CD8+ and FoxP3+ T cells, CD20+ B cells, PD-1+ and PD-L1+ immune cells and PD-L1+ tumor cells was evaluated by immunohistochemistry on tissue microarrays with paired transurethral resection (TURB) specimens, cystectomy specimens and lymph node metastases from 145 patients, 65 of whom had received NAC. Kaplan–Meier and Cox regression analyses were applied to assess the impact of investigated cell subsets on time to recurrence (TTR). In cystectomy specimens, high infiltration of the investigated immune cell populations, but not PD-L1+ tumor cells, were independently associated with a prolonged TTR, whereas in TURB specimens, this association was only seen for CD8+ lymphocytes. An additive beneficial prognostic effect of NAC was seen for the majority of the cell subsets but there was no significant interaction between any immune marker and NAC in relation to TTR. Furthermore, no differences in cell densities prior to NAC treatment were observed between complete and non-complete responders, or pre- and posttreatment in non-complete responders. In conclusion, immune cell infiltration provides important prognostic information in both pre- and postsurgical samples of MIBC, independently of NAC.
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