| 1. |
- Ahlén Bergman, Emma, et al.
(författare)
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Epigenetic methylation profiles of CD4 T cell signature loci from patients with urinary bladder cancer
- 2017
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Ingår i: Scandinavian Journal of Immunology. - : John Wiley & Sons. - 0300-9475 .- 1365-3083. ; 86:4, s. 264-264
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Urinary bladder cancer (UBC) is one of the most frequent cancer diseases with 380 000 new cases diagnosed worldwide and about 150 000 deaths yearly. To dissect the role of T helper (Th) cell responses in UBC we investigate the T helper cell subpopulations; Th1, Th2, Th17 and T regulatory cells (Tregs) and their lineage commitment in draining (sentinel) and non-draining lymph nodes and blood from patients subjected to transurethral resection of the bladder (TUR-B) and/or Cystectomy. By analyzing methylation in signature genes IFNG, IL13, IL17a and FOXP3 we measure the epigenetic stability of these T helper cells.In most patients IFNG is more demethylated in sentinel nodes compared to non-sentinel nodes and blood, suggesting a Th1 activation in nodes in contact with the tumor. Aside from that, the distribution of subpopulations in all tissues investigated is highly variable in between patients. All subsets are represented, although there seem to be no or little Th17 cells in nodes. After neoadjuvant treatment (given in between the TUR-B and cystectomy) a temporary increase in methylation of IFNG locus is seen in blood, which could suggest a translocation of activated Th cells from the blood to the tumor area, but also de novo synthesis of Th cells.By analyzing the intra-patient variations in distribution and relative amount of Th cell subpopulations in blood and sentinel nodes we hope to draw conclusions on differences in outcome. The long-term goal is to be able to identify which patients could respond well to immune modulatory treatments.
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| 2. |
- 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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| 3. |
- Hartana, Ciputra Adijaya, et al.
(författare)
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Detection of micrometastases by flow cytometry in sentinel lymph nodes from patients with renal tumours
- 2016
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 115:8, s. 957-966
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Stage is an important prognostic factor in renal tumours and dissemination to regional lymph nodes is associated with poor outcomes. Lymph nodes are routinely assessed by immunohistochemistry and microscopic evaluation, a time-consuming process where micrometastases might go undiagnosed. We evaluate an alternative method for detecting metastatic cells in sentinel nodes (SNs) by flow cytometry.METHODS: A total of 15 nodes from 5 patients diagnosed with renal tumours were analysed by flow cytometry. Staining for the intracellular marker cytokeratin 18 (CK18) with the surface markers carbonic anhydrase IX (CA9) and Cadherin 6 were used in flow cytometry analysis. Peripheral blood mononuclear cells (PBMCs) with the addition of known concentrations of cancer cell lines were analysed to investigate the sensitivity of micrometastasis detection.RESULTS: Stability of the assay was marked by low intra-assay variability (coefficient of variance ⩽16%) and low inter-assay variability (R(2)=0.9996-1). Eight nodes in four patients were positive for metastasis; six of them were considered being micrometastatic. These metastases were undetected by routine pathology and the patients were restaged from pN0 to pN1.CONCLUSIONS: Flow cytometry is able to detect micrometastases in lymph nodes of renal tumour patients that were undetected under H&E examination.
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| 4. |
- 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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| 5. |
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| 6. |
- 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
- 2019
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Ingår i: Scandinavian journal of urology. - : Taylor & Francis. - 2168-1805 .- 2168-1813. ; 53, s. 35-36
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Several studies have demonstrated a decreased overall survival for patients with muscle-invasive bladder cancer (MIBC) receiving allogenic peri- and postoperative blood transfusions at cystectomy. However, the extent and the effect of blood transfusions given during neoadjuvant chemotherapy (NAC) has never been addressed. The purpose of the present study, was to assess the impact of blood transfusions given during NAC on survival in patients with MIBC undergoing NAC and radical cystectomy.Materials and Methods: A cohort of 120 consecutive patients with MIBC (cT2-T4aN0M0) undergoing NAC and radical cystectomy at four Swedish centers was retrospectively evaluated. Clinical and pathoanatomical data was obtained, including data SCANDINAVIAN JOURNAL OF UROLOGY 35 on administeredallogenic blood at consecutive time-intervals. Overall survival was analyzed by Kaplan-Meier plotting and Cox regression.Results: One third of the cohort (n ¼ 40) received blood transfusions during NAC-therapy. The five-year overall survival rates were significantly lower in this group compared to the non-transfused patients (39.7% and 58.9% respectively, p ¼ 0.047). In a univariate analysis, blood transfusions, nodal status and locally advanced tumor growth (pT >2), were negative prognostic factors for survival. In multivariate analysis, only pNx and pT >2 remained significant negative prognostic factors. In subgroup analysis of localized and non-disseminated patients only (n ¼ 96), blood transfused patients showed a 18,5% absolute risk increase compared to blood naïve patients (p¼ 0.197).Conclusions: This is the first time that the extent and the effect 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 the limited number of study participants and the retrospective nature of the study.
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| 7. |
- 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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| 8. |
- Rosenblatt, Robert, 1982-
(författare)
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Neoadjuvant chemotherapy in muscle-invasive urinary bladder cancer : studies on treatment response, tumor draining lymph nodes and blood transfusion
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Muscle-invasive urinary bladder cancer is a deadly disease. Mortality rates remained unchanged for decades despite radical surgery.After several randomized trials, we today know that cisplatin based chemotherapy given prior to cystectomy, improves survival for every tenth patient. Markers that predict responsiveness to chemotherapy would spare unnecessary treatment to the majority of patients. In the search for signs of chemosensitivity, we performed a retrospective analysis of the Nordic cystectomy trials 1 & 2: Chemo treated patients had an almost doubled increase in tumor downstaging compared to the controls. More importantly, this group presented with a reduced absolute risk of death of more than 30% compared to the rest of the patients. These results were presented in paper I.Many cancers spread through the lymphatic system. Usually, there is at least one tumor draining lymph node, referred to as the sentinel node. If this node is free of metastases, there is no lymphatic spread of the disease, and consequently, no use of excavating all neighboring lymph nodes.Sentinel node detection, is an established method in breast cancer, penile cancer and malignant melanoma. Based on the same principles, members of our group developed a similar detection technique in bladder cancer. Unfortunately, sensitivity and specificity were too low to rely on this method as a diagnostic tool for lymphatic spread. Instead, it turned out in recent years that sentinel nodes in muscle invasive bladder cancer are valuable for translational research-lines - mainly in tumor immunology. As for example, sentinel nodes contain tumor specific T cells that are useful in adoptive immunotherapy.In paper II, we set out to test whether sentinel node detection was feasible after chemotherapy and/or tumor downstaging. In a prospective cohort of patients, we saw no difference in detection rates between the groups. Thus, we concluded, neither chemotherapy nor downstaging appeared to hamper the identification of sentinel nodes.The concept was expanded in paper III. After recruiting more patients to the cohort mentioned above, the average numbers of sentinel nodes in different categories of patients were compared. We saw a pattern of decreased number of sentinel nodes in those with locally advanced tumors. It seemed that the number of sentinel nodes had prognostic implications.In the last study, published in paper IV, we wanted to widen our knowledge on the clinical effects of blood transfusion. Mounting data suggests that perioperative blood products have a negative impact on long term survival after cancer surgery. How much allogenic blood was given during the chemotherapy prior to surgery ? It turned out that one third of the bladder cancer patients received blood, and these patients demonstrated a significantly worse overall survival.Neoadjuvant chemotherapy has added a new beneficial dimension to the treatment of muscle invasive bladder cancer. In these four studies, we addressed the effects of chemotherapy on pathoanatomical outcomes, on tumor lymphatics and further; we are suggesting consequences of neoadjuvant chemotherapy in conjunction with blood transfusion. It appears that the immune system is involved in all aspects investigated above. Most likely, an improved scientific understanding of the immune system will be crucial for future bladder cancer treatment options.
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| 9. |
- Rosenblatt, Robert, et al.
(författare)
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Sentinel node detection in muscle-invasive urothelial bladder cancer is feasible after neoadjuvant chemotherapy in all pT stages, a prospective multicenter report
- 2017
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Ingår i: World journal of urology. - : Springer Science and Business Media LLC. - 0724-4983 .- 1433-8726. ; 35:6, s. 921-927
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To determine whether sentinel node detection (SNd) in muscle-invasive urothelial bladder cancer (MIBC) can be performed in patients undergoing neoadjuvant chemotherapy (NAC) and determine whether SNd is feasible in all pT stages, including pT0.BACKGROUND: Previous published series of SNd in MIBC have not included patients undergoing NAC, and systematic reports of pT0 patients w/wo NAC were absent. Translational immunological tumor research on MIBC focusing on SNd, in the era of NAC, requires technical feasibility. Additionally, SNd in MIBC requests further evaluations as a method for nodal staging.MATERIALS AND METHODS: Ninety-nine patients with suspected urothelial MIBC were prospectively selected from six urological centers. After TUR-B and primary staging, 65 MIBC patients qualified for radical cystectomy. Precystectomy staging was cT2a-T4aN0M0, including 47 NAC patients and 18 chemo-naïve patients. All 65 patients underwent intraoperative SNd by peritumoral injection of 80 Mbq Technetium and Geiger probe detection. Postcystectomy staging was pT0-T4aN0-N2M0. SNs were defined by two calculations, SNdef1 and SNdef2.RESULTS: Totally 1063 lymph nodes were removed (total SNs; 222-227). NAC patients with pT0 (n = 24) displayed a true positive detection in 91.7 % by either SNdef, with a median of 3.0 SNs. NACpT >0 patients had a true positive detection in 87 % (SNdef1) and 91.3 % (SNdef2). In a univariate analysis, patient group neither NAC nor tumor downstaging influenced detection rates, regardless of SN definition. In total eight patients, 4/22 metastatic nodes were SNs while 18/22 were non-SNs.CONCLUSIONS: Sentinel node detection in MIBC is feasible also in NAC patients, regardless of pT stage. SNd played no role in nodal staging.
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