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- Hemdan, Tammer, 1974-, et al.
(författare)
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Choline-phosphate cytidylyltransferase-alpha as a possible predictor of survival and response to cisplatin neoadjuvant chemotherapy in urothelial cancer of the bladder
- 2018
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Ingår i: Scandinavian journal of urology. - : TAYLOR & FRANCIS LTD. - 2168-1805 .- 2168-1813. ; 52:3, s. 200-205
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Kerzeli, Iliana Kyriaki, et al.
(författare)
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Elevated levels of MMP12 sourced from macrophages are associated with poor prognosis in urothelial bladder cancer
- 2023
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Ingår i: BMC Cancer. - : BioMed Central (BMC). - 1471-2407 .- 1471-2407. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Urothelial bladder cancer is most frequently diagnosed at the non-muscle-invasive stage (NMIBC). However, recurrences and interventions for intermediate and high-risk NMIBC patients impact the quality of life. Biomarkers for patient stratification could help to avoid unnecessary interventions whilst indicating aggressive measures when required.Methods In this study, immuno-oncology focused, multiplexed proximity extension assays were utilised to analyse plasma (n = 90) and urine (n = 40) samples from 90 newly-diagnosed and treatment-naive bladder cancer patients. Public single-cell RNA-sequencing and microarray data from patient tumour tissues and murine OH-BBN-induced urothelial carcinomas were also explored to further corroborate the proteomic findings.Results Plasma from muscle-invasive, urothelial bladder cancer patients displayed higher levels of MMP7 (p = 0.028) and CCL23 (p = 0.03) compared to NMIBC patients, whereas urine displayed higher levels of CD27 (p = 0.044) and CD40 (p = 0.04) in the NMIBC group by two-sided Wilcoxon rank-sum tests. Random forest survival and multivariable regression analyses identified increased MMP12 plasma levels as an independent marker (p < 0.001) associated with shorter overall survival (HR = 1.8, p < 0.001, 95% CI:1.3-2.5); this finding was validated in an independent patient OLINK cohort, but could not be established using a transcriptomic microarray dataset. Single-cell transcriptomics analyses indicated tumour-infiltrating macrophages as a putative source of MMP12.Conclusions The measurable levels of tumour-localised, immune-cell-derived MMP12 in blood suggest MMP12 as an important biomarker that could complement histopathology-based risk stratification.As MMP12 stems from infiltrating immune cells rather than the tumor cells themselves, analyses performed on tissue biopsy material risk a biased selection of biomarkers produced by the tumour, while ignoring the surrounding microenvironment.
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| 3. |
- Kerzeli, Iliana Kyriaki, et al.
(författare)
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Proximity Extension Assay reveals MMP12 in plasma as a predictor of outcome in urothelial bladder cancer
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background Urothelial bladder cancer (UBC) is most-frequently diagnosed at the non-muscle-invasive stage (NMIBC). However, recurrences and interventions for intermediate and high-risk NMIBC patients impact quality of life. Biomarkers for patient stratification can help to avoid unnecessary interventions whilst indicating aggressive measures when required.Methods Proximity Extension Assay (PEA) was utilised to analyse plasma (n=90) and urine (n=40) samples from 90 newly-diagnosed and treatment-naïve UBC patients with an immuno-oncology protein panel. Public single-cell and bulk RNA sequencing data from patient tumour tissues and a murine OH-BBN induced UBC model were also explored. Results Plasma samples from muscle-invasive UBC patients displayed higher levels of MMP7 and CCL23 compared to NMIBC patients, whereas urine samples displayed higher levels of CD27 and CD40 in the NMIBC group. Increased MMP12 plasma levels were identified as an independent marker of poor survival outcome and this finding was further validated in an independent cohort. Moreover, scRNA-seq data analysis indicated tumour infiltrating macrophages as a putative source of MMP12. Conclusion The local production, but systemic diffusion of MMP12, suggests that MMP12 could be an important biomarker to complement histopathology-based risk stratification. Additionally, it may represent a pharmacological target in bladder cancer.
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| 4. |
- Turker, Polat, et al.
(författare)
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Combination of biomarkers for neoadjuvant systemic chemotherapy before cystectomy in patients with urinary bladder cancer
- 2021
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Ingår i: Translational Research. - : Elsevier. - 1931-5244 .- 1878-1810. ; 235, s. 77-84
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Tidskriftsartikel (refereegranskat)abstract
- Clinical utility of cisplatin based neoadjuvant chemotherapy (NAC) prior to radical cystectomy is limited because of lack of tools that can guide for a better patient selection. We aim to explore if a combination of biomarkers is superior to a single marker. Pretreatment tumor specimens and clinical data from two randomized trials including 250 patients with T2-T4 urothelial bladder cancer, were used. The information on the expressions on tumor tissue of four biomarkers; CCTa, emmprin, survivin, and BCL-2, detected by immunohistochemistry in our previous studies, was used. Cox proportional hazard models, including treatment-by-biomarker interaction terms, were used to assess the predictive value of the biomarkers for efficacy of NAC on overall survival. CCTa provided predictive information about the efficacy of NAC (interaction P=0.009). None of the other biomarkers provided statistically significant information additional to CCTa. The adjusted hazard ratio for NAC treated versus no-NAC was 0.42 (95% CI: 0.27-0.64) for patients with negative CCTa expression, when adding information about emmprin it decreased to 0.33 (95% CI: 0.19-0.56) for patients with both negative CCTa and emmprin. This corresponds to a decrease in number needed to treat from 4 to 3 patients. The combination of CCTa with survivin or BCL-2 yielded similar results. In a group of patients with muscle invasive bladder cancer a combination of two biomarkers might improve the possibility to identify patients most likely to benefit from the use of NAC. Further studies designed to have sufficient power to detect an interaction effect are needed.
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| 5. |
- Turker, Polat, et al.
(författare)
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Is Bcl-2 a predictive marker of neoadjuvant chemotherapy response in patients with urothelial bladder cancer undergoing radical cystectomy?
- 2019
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Ingår i: Scandinavian journal of urology. - : TAYLOR & FRANCIS LTD. - 2168-1805 .- 2168-1813. ; 53:1, s. 45-50
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Tidskriftsartikel (refereegranskat)abstract
- Background: Response to neoadjuvant cisplatin treatment in bladder cancer has been linked to expression of Bcl-2 protein by cancer cells. The objective of this study was to test Bcl-2 as a predictive marker of neoadjuvant cisplatin chemotherapy response in a patient cohort from randomized cystectomy trials.Methods: Tumor samples were taken from 247 patients with T2-T4 bladder cancer enrolled in two randomized trials comparing cystectomy with or without neoadjuvant chemotherapy. Tissue microarrays from pre-intervention transurethral resection specimens were assessed for Bcl-2 protein status by immunohistochemistry. Extension of staining above 10% was regarded as positive. Downstaging and survival ratios in relation to Bcl-2 immunoreactivity and neoadjuvant chemotherapy utilization were calculated using the log rank test and multivariate Cox proportional hazards regression analyses.Results: Bcl-2 expression was positive in 38% and negative in 62% of the 236 evaluable patients. Bcl-2 negative patients receiving neoadjuvant chemotherapy had a significant increase in survival (p=0.009), while Bcl-2 positive patients showed no difference (p=0.4). However, the interaction variable between neoadjuvant chemotherapy and biomarker status was not significant (p=0.38). When the prognostic value was assessed in the no-chemotherapy group, 5-year overall survival times were significantly better among Bcl-2 positive patients than among Bcl-2 negative patients (42 months vs 33 months, p=0.04), but again Bcl-2 status did not remain independent when other factors were adjusted. Also, in a multivariate analysis with all patients, Bcl-2 was not significant.Conclusions: Bcl-2 status is not an independent predictor of neoadjuvant cisplatin chemotherapy response and is not prognostic in muscle-invasive bladder cancer.
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