| 1. |
- Alvaeus, Julia, et al.
(författare)
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Fewer tumour draining sentinel nodes in patients with progressing muscle invasive bladder cancer, after neoadjuvant chemotherapy and radical cystectomy
- 2020
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Ingår i: World journal of urology. - : Springer. - 0724-4983 .- 1433-8726. ; 38, s. 2207-2213
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To examine the relationship between the number of tumour draining sentinel nodes (SNs) and pathoanatomical outcomes, in muscle-invasive bladder cancer (MIBC), in patients undergoing neoadjuvant chemotherapy (NAC) and radical cystectomy (RC).MATERIALS AND METHODS: In an ongoing prospective multicenter study, we included 230 patients with suspected urothelial MIBC from ten Swedish urological centers. All underwent TURb and clinical staging. From the cohort, 116 patients with urothelial MIBC; cT2-cT4aN0M0, underwent radical cystectomy (RC) and lymphadenectomy with SN-detection (SNd). 83 patients received cisplatin-based NAC and 33 were NAC-naïve. The number and locations of detected SNs and non-SNs were recorded for each patient. The NAC treated patients were categorized by pathoanatomical outcomes post-RC into three groups: complete responders (CR), stable disease (SD) and progressive disease (PD). Selected covariates with possible impact on SN-yield were tested in uni -and multivariate analyses for NAC-treated patients only.RESULTS: In NAC treated patients, the mean number of SNs was significantly higher in CR patients (3.3) and SD patients (3.6) compared with PD patients (1.4) (p = 0.034). In a linear multivariate regression model, the number of harvested nodes was the only independent variable that affected the number of SNs (p = 0.0004).CONCLUSIONS: The number of tumor-draining SNs in NAC-treated patients was significantly lower in patients with progressive disease.
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| 2. |
- Eldh, Maria, et al.
(författare)
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Proteomic Profiling of Tissue Exosomes Indicates Continuous Release of Malignant Exosomes in Urinary Bladder Cancer Patients, Even with Pathologically Undetectable Tumour
- 2021
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:13
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Urinary bladder cancer (UBC) has a high recurrence rate, and biomarkers for different treatment strategies are highly needed. This study investigated the release of nanovesicles called exosomes from urinary bladder tissue from tumour-proximal sites as well as tumour-distant sites in transurethrally resected (TUR-B) patients with or without preoperative neoadjuvant chemotherapy prior to ensuing radical cystectomy-all without remaining visible tumour after TUR-B. We show that cancer-promoting exosomes were detected from both sites, suggesting that the previous tumour has altered the whole bladder tissue into a cancer-supporting milieu. The exosomes may originate from remaining pathologically undetectable cancer cells or transformed epithelial cells, and the study supports the notion of exosomes as mediators of metastatic spread and as potential biomarkers. It also supports early and radical removal of the bladder in urinary bladder cancer patients. Invasive urothelial bladder cancer (UBC) has high recurrence rates even after radical cystectomy (RC). Exosomes are membrane-bound nanovesicles, which have been shown to contribute to carcinogenesis and metastasis. We previously showed that urinary exosomes display a malignant profile in UBC patients despite the absence of detectable tumour. Here, we investigated exosomes from sampling sites close to or distant from the former tumour, aiming to understand the effect of the tumour on the local milieu. Ten patients scheduled for cystectomy after transurethral bladder resection (TUR-B), without remaining detectable tumour, were included. Exosomes were isolated from tissue explants of both the previous tumour site and distant bladder tissue. Proteins were quantified by mass spectrometry in seven patients. Exosomes from the previous tumour site were enriched in inflammatory but not cancer-related pathways compared to distant tissue. However, the 69 most abundant proteins in tissue-derived exosomes regardless of site, 20 of which were also found in urinary exosomes from our previous study, were enriched for cancer-related metabolic pathways and associated with poor prognosis in an external mRNA dataset. The enrichment of cancer-related pathways in the most abundant proteins, regardless of sampling site, confirms our hypothesis that despite the absence of detectable tumour, the entire bladder releases exosomes that contribute to metastasis and highlights the need for early RC.
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| 3. |
- Eriksson, Victoria, et al.
(författare)
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A retrospective analysis of the de ritis ratio in muscle invasive bladder cancer, with focus on tumor response and long-term survival in patients receiving neoadjuvant chemotherapy and in chemo naïve cystectomy patients : a study of a clinical multicentre database
- 2022
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Ingår i: Journal of Personalized Medicine. - : MDPI. - 2075-4426. ; 12:11
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Tidskriftsartikel (refereegranskat)abstract
- Background: A high pre-treatment De Ritis ratio, the aspartate transaminase/alanine aminotransferase ratio, has been suggested to be of prognostic value for mortality in muscle-invasive bladder cancer (MIBC). Our purpose was to evaluate if a high ratio was associated with mortality and downstaging. Methods: A total of 347 Swedish patients with clinically staged T2-T4aN0M0, with administered neoadjuvant chemotherapy (NAC) or eligible for NAC and undergoing radical cystectomy (RC) 2009–2021, were retrospectively evaluated with a low ratio < 1.3 vs. high ratio > 1.3, by Log Rank test, Cox regression and Mann–Whitney U-test (MWU), SPSS 27. Results: Patients with a high ratio had a decrease of up to 3 years in disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) (p = 0.009, p = 0.004 and p = 0.009) and 5 years in CSS and OS (p = 0.019 and p = 0.046). A high ratio was associated with increased risk of mortality, highest in DFS (HR, 1.909; 95% CI, 1.265–2.880; p = 0.002). No significant relationship between downstaging and a high ratio existed (p = 0.564 MWU). Conclusion: A high pre-treatment De Ritis ratio is on a population level, associated with increased mortality post-RC in endpoints DFS, CSS and OS. Associations decrease over time and require further investigations to determine how strong the associations are as meaningful prognostic markers for long-term mortality in MIBC. The ratio is not suitable for downstaging-prediction.
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| 4. |
- Eriksson, Victoria, et al.
(författare)
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Adverse events during neoadjuvant chemotherapy for muscle invasive bladder cancer - a Swedish retrospective multicentre study of a clinical database
- 2022
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Ingår i: Translational Andrology and Urology. - : AME Publishing Company. - 2223-4683 .- 2223-4691. ; 11:8, s. 1105-1115
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Tidskriftsartikel (refereegranskat)abstract
- Background: Adverse events (AEs) during neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer (MIBC) are known but insufficiently reported. Clinical implications include affected cardiac, pulmonary, urinary, vascular and haematological organ systems. The main purpose was to evaluate the incidence and severity of AEs for ascertaining possible clinical significance. Further investigating possible effects of AEs on downstaging outcomes-downstaging is considered a surrogate marker for overall survival (OS).Methods: A retrospective evaluation of AEs during ongoing NAC for MIBC patients analysing individual patient data in a clinical database. We identified 687 cystectomies between 2009-2020 at four Swedish urological centres. Inclusion criteria were cT2-4aN0M0 in 261 NAC patients undergoing radical cystectomy (RC). Medical files were reviewed and AEs were assessed and graded, including detailed measurements by the Common Terminology Criteria for Adverse Events (CTCAE) v.5. Data were retrospectively analysed in SPSS statistics 27.0 with Spearman rank-order correlation coefficient and Mann-Whitney U-test (MWU).Results: A total of 251/261 patients [95% confidence interval (CI), 93-98%] experienced AEs during NAC pre-RC (mean two AEs/patient). In total, 208 (80%) patients received methotrexate, vinblastine, adriamycin (doxorubicin) and cisplatin (MVAC). In the total cohort, 200 (76.6%) received all pre-planned NAC-cycles. Most common AEs were anaemia (88.9%), thrombocytopenia (44.8%) and acute kidney injury (40.6%). Patients with prematurely terminated cycles had higher AE-grades (P=0.042 MWU). A correlation between higher AE-grades and decrease in downstaging existed, in the entire cohort (-0.133; P=0.033) and in patients undergoing all pre-planned NAC-cycles (-0.148; P=0.038). Anaemia and acute kidney injury were individually associated with decreased downstaging (-0.360, P=0.025 and -0.183, P=0.010, respectively).Conclusion: NAC in MIBC poses a significant risk for AEs before RC with clinical implications. For instance, patients terminating chemotherapy prematurely, have higher AE-grades and decreased downstaging. Further, acute kidney injury and anaemia are individually associated with decreased downstaging. We propose that early detection and prevention of AEs may increase downstaging of the primary tumour.
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| 5. |
- Erlandsson, Ann, 1968-, et al.
(författare)
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Infiltrating immune cells in prostate cancer tissue after androgen deprivation and radiotherapy
- 2023
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Ingår i: International journal of immunopathology and pharmacology. - : Sage Publications. - 0394-6320 .- 2058-7384. ; 37
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Androgen deprivation therapy (ADT) has long been a cornerstone in treatment of advanced prostate cancer (PCa), and is known to improve the results of radiotherapy (RT) for high-risk disease. The purpose of our study was to use a multiplexed immunohistochemical (mIHC) approach to investigate the infiltration of immune cells in PCa tissue after eight weeks of ADT and/or RT with 10 Gy.Methods: From a cohort of 48 patients divided into two treatment arms, we obtained biopsies before and after treatment and used a mIHC method with multispectral imaging to analyze the infiltration of immune cells in tumor stroma and tumor epithelium, focusing on areas with high infiltration.Results: Tumor stroma showed a significantly higher infiltration of immune cells compared to tumor epithelium. The most prominent immune cells were CD20(+) B-lymphocytes, followed by CD68(+) macrophages, CD8(+) cytotoxic T-cells, FOXP3(+) regulatory T-cells (Tregs), and T-bet(+) Th1-cells. Neoadjuvant ADT followed by RT significantly increased the infiltration of all five immune cells. Numbers of Th1-cells and Tregs significantly increased after single treatment with ADT or RT. In addition, ADT alone increased the number of cytotoxic T-cells and RT increased the number of B-cells.Conclusions: Neoadjuvant ADT in combination with RT results in a higher inflammatory response compared to RT or ADT alone. The mIHC method may be a useful tool for investigating infiltrating immune cells in PCa biopsies to understand how immunotherapeutic approaches can be combined with current PCa therapies.
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| 6. |
- Hiltbrunner, Stefanie, et al.
(författare)
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Urinary Exosomes from Bladder Cancer Patients Show a Residual Cancer Phenotype despite Complete Pathological Downstaging
- 2020
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Invasive urinary bladder cancer shows high recurrence rates after cystectomy even with apparent complete downstaging at cystectomy. Exosomes are nano-sized vesicles important in cell-cell communication, which have been hypothesized to contribute to cancer dissemination and recurrence. The aim of this study was to investigate if pro-carcinogenic exosomes could be detected in urine from histologically downstaged bladder cancer patients. 13 Patients were included in this study. Paired ureter and urine samples from nine patients underwent mass spectrometry, while samples from the remaining patients were used for exosome characterization. At cystectomy, exosomes were isolated from bladder and ureter urine, whereafter quantitative proteome profiling was performed. Urinary exosomes clustered based on whether they came from the bladder, with tumour contact, or the ureters, without tumour contact, even though all came from completely downstaged patients. Proteins overexpressed in exosomes derived from bladder urine contained several oncogenes and were mainly associated with tumour metabolism pathways. Although patients were histologically tumour-free at cystectomy, the bladder urine contained exosomes with a carcinogenic metabolic profile. This suggests a continuous release of exosomes from the bladder, which may promote recurrence at distant sites through metabolic rewiring, even after apparent complete downstaging. These exosomes, coming from either undetected cancer cells or partly transformed cells, are likely to increase the risk of metastasis and encourages cystectomy even in completely downstaged patients.
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| 7. |
- Krantz, David, et al.
(författare)
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IL-16 processing in sentinel node regulatory T cells is a factor in bladder cancer immunity
- 2020
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Ingår i: Scandinavian Journal of Immunology. - : John Wiley & Sons. - 0300-9475 .- 1365-3083. ; 92:6
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Tidskriftsartikel (refereegranskat)abstract
- In the effort of developing new immunotherapies, the sentinel node (SN) has proven a promising source from which to harness an effective antitumour T cell response. However, tumour immune escape, a process in which regulatory T cells (Tregs) play a central role, remains a major limiting factor. Therefore, there is a clear need to increase the knowledge of Treg function and signalling in sentinel nodes. Here, we set out to explore whether the proteome in SN-resident T cells is altered by the tumour and to identify key proteins in SN T cell signalling, focusing on Tregs. Five patients with muscle-invasive urothelial bladder cancer were prospectively included. Mass spectrometry was performed on two patients, with validation and functional studies being performed on three additional patients and four healthy donors. At cystectomy, SN, non-SN lymph nodes and peripheral blood samples were collected from the patients and T cell subsets isolated through flow cytometry before downstream experiments. Proteomic analysis indicated that growth and immune signalling pathways are upregulated in SN-resident Tregs. Furthermore, centrality analysis identified the cytokine IL-16 to be central in the SN-Treg signalling network. We show that tumour-released factors, through activating caspase-3, increase Treg IL-16 processing into bioactive forms, reinforcing Treg suppressive capacity. In conclusion, we provide evidence that Tregs exposed to secreted factors from bladder tumours show increased immune and growth signalling and altered IL-16 processing which translates to enhanced Treg suppressive function, indicating altered IL-16 signalling as a novel tumour immune escape mechanism.
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| 8. |
- Rosenblatt, Robert, et al.
(författare)
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Blood transfusions during neoadjuvant chemotherapy for muscle-invasive urinary bladder cancer may have a negative impact on overall survival
- 2020
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Ingår i: Scandinavian journal of urology. - : Taylor & Francis. - 2168-1805 .- 2168-1813. ; 54:1, s. 46-51
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate the extent and plausible effects of blood transfusions given during cisplatin-based neoadjuvant chemotherapy (NAC) on overall survival in patients with muscle-invasive urothelial bladder cancer (MIBC) undergoing NAC and radical cystectomy (RC).Background: Several studies have demonstrated a decreased survival for MIBC patients receiving allogenic peri- and postoperative blood transfusions in conjunction with RC. No studies have previously investigated the effects of blood transfusions during NAC.Materials and methods: 120 patients with MIBC (cT2-T4aN0M0) undergoing NAC and RC between 2008 and 2014 at four Swedish cystectomy centers were retrospectively evaluated. Clinicopathological data were obtained, including data of allogenic blood administration. Survival data was analyzed by Kaplan–Meier plotting and Cox regression.Results: One third of the cohort received blood transfusions during the period of NAC. In univariate analysis, blood transfusions during NAC, nodal stage and advanced tumor stage (pT >2) were negative prognostic factors for survival. In multivariate analysis, only pNx and pT >2 remained significant negative prognostic factors. In a subgroup analysis consisting of patients with localized tumors without dissemination (n = 96), patients that received transfusions during NAC showed an 18.5% absolute risk increase of death at five years of observation, although without statistical significance (p = .197).Conclusions: This is the first time that the extent and plausible effects 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 few study participants and the retrospective nature of the study.
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| 9. |
- Rydell, Harriet, et al.
(författare)
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Central Venous Access and the Risk for Thromboembolic Events in Patients Undergoing Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle-Invasive Bladder Cancer
- 2022
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Ingår i: Life. - : MDPI. - 2075-1729. ; 12:8
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Tidskriftsartikel (refereegranskat)abstract
- Thromboembolic events (TEE) are high-risk complications in patients undergoing neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) for urothelial muscle-invasive bladder cancer (MIBC). The purpose of the study was to investigate any differences in TEE-incidence, comparing peripherally inserted central catheter (PICC) versus a totally implanted port (PORT) as CVA (central venous access) during NAC. We identified 947 cystectomized MIBC-patients from four Swedish medical centers in 2009-2021. Inclusion criteria were cT2-T4aN0M0 and 375 patients were finally eligible and evaluated, divided into: NAC-administered (n = 283) resp. NAC-naïve-NAC-eligible (n = 92), the latter as tentative control group. Data on TEEs and types of CVA were retrospectively collected and individually validated, from final transurethral resection of the bladder tumor (TUR-B) to 30 days post-RC. Adjusted logistic regression and log rank test were used for statistical analyses. Amongst NAC-administered, 83% (n = 235) received PICCs and 15% (n = 42) PORTs. Preoperative TEEs occurred in 38 PICC-patients (16.2%) and in one PORT-patient (2.4%), with 47 individual events registered. We found a significantly increased odds ratio of TEE in NAC-administered PICC-patients compared to in PORT-patients (OR: 8.140, p-value: 0.042, 95% CI 1.078-61.455). Our findings indicate a greater risk for pre-RC TEEs with PICCs than with PORTs, suggesting favoring the usage of PORTs for MIBC-NAC-patients.
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| 10. |
- Saudi, Aws, et al.
(författare)
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Immune-activated B cells are dominant in prostate cancer
- 2023
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 15:3
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Tidskriftsartikel (refereegranskat)abstract
- B cells are multifaceted immune cells responding robustly during immune surveillance against tumor antigens by presentation to T cells and switched immunoglobulin production. However, B cells are unstudied in prostate cancer (PCa). We used flow cytometry to analyze B-cell subpopulations in peripheral blood and lymph nodes from intermediate-high risk PCa patients. B-cell subpopulations were related to clinicopathological factors. B-cell-receptor single-cell sequencing and VDJ analysis identified clonal B-cell expansion in blood and lymph nodes. Pathological staging was pT2 in 16%, pT3a in 48%, and pT3b in 36%. Lymph node metastases occurred in 5/25 patients (20%). Compared to healthy donors, the peripheral blood CD19+ B-cell compartment was significantly decreased in PCa patients and dominated by naïve B cells. The nodal B-cell compartment had significantly increased fractions of CD19+ B cells and switched memory B cells. Plasmablasts were observed in tumor-draining sentinel lymph nodes (SNs). VDJ analysis revealed clonal expansion in lymph nodes. Thus, activated B cells are increased in SNs from PCa patients. The increased fraction of switched memory cells and plasmablasts together with the presence of clonally expanded B cells indicate tumor-specific T-cell-dependent responses from B cells, supporting an important role for B cells in the protection against tumors.
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