The development of medical infographics to raise symptom awareness and promote communication to patients with cancer: A co-creation study.

Objective: The study aims to develop medical infographics that have a potential to raise symptom awareness and promote symptom communication between patients diagnosed with cancer and healthcare professionals. Methods: This study comprised four phases: 1) development of medical infographics, 2) user testing with healthcare professionals and patients, 3) selection of specific medical infographics, and 4) interviews on these specific medical infographics with patients using the think-aloud method. Results: Design students created 22 medical infographics conveying information about six symptoms and concerns. Patients (n = 28) with cancer said that the colourful infographics evoked individual emotional responses and associations, and they facilitated their narratives of experiences with symptoms. Healthcare professionals (n = 29) thought the infographics were eye-catching and may promote dialogue on symptoms. Conclusions: The design of medical infographics must target a specific population. When introduced, the use of medical infographics may be influenced by the physical surroundings. Medical infographics can facilitate symptom communication by creating symptom awareness and providing patients with the vocabulary to describe their symptoms and concerns. Innovation: Medical infographics are engaging visual messages with the potential to help prepare cancer patients to communicate their symptom experiences and reduce the feeling of being alone in experiencing certain symptoms.

Feasibility, usability and acceptance of weekly electronic patient-reported outcomes among patients receiving pelvic CT- or online MR-guided radiotherapy - A prospective pilot study.

INTRODUCTION: The potential of patient symptoms being monitored longitudinally in radiotherapy (RT) is still unexploited. When novel technologies like online adaptive MR-guided radiotherapy (MRgRT) are evaluated, weekly electronic patient-reported outcomes (ePROs) may add knowledge about the symptom trajectory. This study aimed at evaluating feasibility, usability and acceptance of weekly ePRO among patients receiving pelvic radiotherapy. MATERIALS AND METHODS: In a mixed-methods convergent design, a prospective pilot study enrolled patients referred to pelvic radiotherapy with curative intent. Patients used their own device at home to self-report PRO weekly during and four weeks following radiotherapy and week 8, 12, and 24 (paper-questionnaire as an alternative). Feasibility was extracted from the ePRO software. The Patient Feedback Form and patient interviews were used to explore usability and patient acceptance. Patients were informed that clinicians had no access to PRO responses. RESULTS: In total, 40 patients were included; 32 patients with prostate cancer and 8 with cervical cancer (consent rate 87%), median age 68 (36-76). The majority did digital reporting (93%). 85% of patients responded to ≥80% of the weekly questionnaires with 91% average adherence to weekly completion (60% for follow-up), although lower for patients ≥age 70. Time spent on ePRO (97%) and frequency of reporting (92%) was considered appropriate. Interviews (n = 14) revealed the application was usable and the patients requested real-time feedback from the clinicians. CONCLUSION: Recruitment for ePRO during radiotherapy was feasible and adherence to weekly self-reporting high. The digital application was usable and weekly frequency and time spent acceptable. Real-time feedback from the clinicians is requested by the patients.

Development of patient-reported outcomes item set to evaluate acute treatment toxicity to pelvic online magnetic resonance-guided radiotherapy.

BACKGROUND: A new technology in cancer treatment, the MR-linac, provides online magnetic resonance-guided radiotherapy (MRgRT) that combines real-time visualization of the tumor and surrounding tissue with radiation therapy to deliver treatment more accurately. Online MRgRT makes it possible to minimize treatment volume, potentially reducing acute treatment toxicity. Patient-reported outcomes (PRO) add the patient perspective to evaluating treatment toxicity related to new technology. The objective of this mixed-methods study was to develop and explore the content validity of a set of PRO items to evaluate acute pelvic toxicity to radiotherapy including online MRgRT. METHODS: A literature review and chart audit were conducted to identify symptomatic adverse events (AEs) to be selected from the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) library and European Organisation for Research and Treatment of Cancer (EORTC) item library. To validate the content, the item set was applied in a prospective pilot cohort of patients referred for primary pelvic RT with curative intent. Patients reported symptoms weekly during RT (4-8 weeks) and the subsequent 4 weeks. Follow-up reports were collected at 8, 12, and 24 weeks after RT. To ensure symptom coverage clinician-reported toxicity and individual patient interviews were conducted. The symptomatic AEs were included in the final item set if ≥20% of patients reported them. RESULTS: Eighteen acute symptomatic AEs were selected for the initial item set. Forty patients (32 prostate cancer, 8 cervical cancer) were included in the pilot study. Patients with prostate cancer and those with cervical cancer both reported all 18 acute AEs. However, vomiting was not reported by > 20% of patients thus excluded from the item set. Adding a few diagnosis-specific AEs to the final item set was required for both prostate and cervical cancer patients. CONCLUSIONS: A PRO item set for patients with pelvic cancer treated with radiotherapy with a curative intent was developed and content validity explored. In the pilot study, the item set captured the most common acute symptomatic AEs for patients with prostate and cervical cancer related to pelvic RT including online MRgRT. Further validation of the content in broader disease sites would be needed in future studies.

Correction to: Quality of life in bladder cancer patients receiving medical oncological treatment; a systematic review of the literature.

The original article contains a major error whereby a main Table is omitted. Thus, the following corrections to the original article should be considered.

Quality of life in bladder cancer patients receiving medical oncological treatment; a systematic review of the literature.

BACKGROUND: Previous quality of life (QoL) literature in bladder cancer (BC) patients has focused on finding the preferred urinary diversion while little is known about the QoL of patients in medical oncological treatment (MOT). We performed a systematic review to assess the existing literature on QoL in patients with muscle-invasive BC (MIBC) undergoing MOT. METHODS: A systematic search of Pubmed and Embase was performed. Inclusion criteria were studies containing QoL data for patients undergoing chemo- and/or radiotherapy. We extracted all QoL scorings at different time intervals and on the six most prevalent domains: overall QoL, urinary, bowel sexual symptoms, pain and fatigue. The study was carried out according to PRISMA guidelines for systematic reviews and GRADE was used to rate the quality of evidence from the included studies. RESULTS: Of 208 papers reviewed, 21 papers were included. Twenty-one different QoL instruments were applied. The only data on QoL during chemotherapy was from patients in clinical trials investigating new treatments. No studies were found for patients in neoadjuvant treatment. The level of evidence at each time point was graded as very low to moderate. From the studies included the overall QoL seemed inversely related to the organ-specific impairment from sexual and urinary symptoms and increased with decreasing organ-specific symptoms for long term survivors > 6 months after treatment. CONCLUSIONS: Collection of data on QoL from patients with MIBC disease undergoing MOT has been sparse and diverse. The present data can act as a summary but prompts for more prospective collection of QoL data from BC patients.

Combined treatment with pemetrexed and vinflunine in patients with metastatic urothelial cell carcinoma after prior platinum-containing chemotherapy - results of an exploratory phase I study.

Vinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 280 mg/m2 on day 1 of a 21-day cycle. Three levels of pemetrexed were planned starting at 400 mg/m2. Four patients were enrolled with a mean age of 66 years and with a mean number of prior GC-cycles of 6,8. Two DLT's were observed at the lowest dose-level in cohort 1. One patient experienced grade 4 thrombocytopenia and a second demonstrated hepatobiliary toxicity grade 3 with an increase in alanine aminotransaminase. Most common grade 3 and 4 adverse events were anemia, thrombocytopenia and neutropenia. Three out of four patients received 3 cycles of pemetrexed and vinflunine, all had progressive disease. Based on these observations and due to protocol design, the study was interrupted at dose level 1 for safety reasons. The combined therapy of vinflunine (Javlor®, Pierre Fabre Pharma) and pemetrexed (Alimta®, Eli Lilly) is poorly tolerated in metastatic UCC patients. The combination cannot be recommended for further investigations in metastatic UCC.

Treatment with docetaxel and cisplatin in advanced adrenocortical carcinoma, a phase II study.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare disease with a poor response to chemotherapy. Cisplatin is the most widely investigated drug in the treatment of ACC and in vitro studies have indicated activity of taxanes. The objectives of this study were to evaluate the efficacy and toxicity of cisplatin combined with docetaxel as first-line treatment of advanced ACC. METHODS: Patients with advanced ACC were included in this phase II trial investigating the response to a combination of cisplatin (50 mg m(-2)) and docetaxel (60 mg m(-2)) administered with a 3-week interval. RESULTS: Nineteen patients were included in this study. The response rate was 21% (95% CI: 3-39%). No patients obtained a complete response, 32% had stable disease, and 37% progressed while on treatment. The median progression-free survival (PFS) was 3 months (95% CI: 0.7-5.3 months) and 1 year PFS was 21% (95% CI: 3-39%). Median survival was 12.5 months (95% CI: 6-19 months). The predominant grade 3/4 toxicity was neutropenia (35%); febrile neutropenia occurred in 5% of cycles. CONCLUSION: This study could not demonstrate that the combination of cisplatin and docetaxel has higher efficacy than other regimens reported in previous studies.

ELISA for complexes between urokinase-type plasminogen activator and its receptor in lung cancer tissue extracts.

A sandwich-type ELISA has been developed for the assessment of complexes between urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in extracts of squamous cell lung carcinomas. The assay is based on a combination of rabbit polyclonal anti-uPA antibodies and a biotinylated mouse anti-uPAR monoclonal antibody (MAb). The detection limit of the assay is approximately 0.5 fmol/ml. A linear dose-response is obtained with up to 40 fmol/ml of uPA:uPAR complexes, while uPA and uPAR separately do not cause any response in the ELISA. A buffer which has been used previously for optimal extraction of uPAR yields the highest amounts of uPA:uPAR complexes. Absorption of tumor extracts with anti-uPA or anti-uPAR MAbs results in a complete disappearance of the ELISA signal, demonstrating the specificity of the ELISA. The recovery of chemically cross-linked uPA:uPAR complexes added to tumor extracts varies between 80% and 105%. The intra- and inter-assay variation coefficients are 5.3% and 9.8%, respectively. Furthermore, a peptide antagonist for uPAR was employed to evaluate de novo uPA:uPAR complex formation during tumor tissue extraction and the immunoassay procedure. Our results strongly indicate that de novo complex formation is a major factor to consider and that complexes analyzed in the presence of this antagonist represent original uPA:uPAR complexes present prior to tumor tissue processing. The present ELISA appears suitable for studying the potential prognostic impact of uPA:uPAR complexes in lung tumor tissue as well as other types of cancer.

Levels of plasminogen activator inhibitor type 1 and urokinase plasminogen activator receptor in non-small cell lung cancer as measured by quantitative ELISA and semiquantitative immunohistochemistry.

The components of the plasminogen activation system have been reported to have prognostic impact in several cancer types, e.g. breast-, colon-, gastric- and lung cancer. Most of these studies have used quantification by enzyme-linked immunosorbent assay (ELISA) on tumour tissue extracts. However, results in non-small cell lung cancer (NSCLC) studies obtained by quantitative ELISA and semiquantitative immunohistochemistry differ. If the prognostic value of the components of the plasminogen activation system is to be exploited clinically in the future, it is important to choose an easy and valid methodology. In the present study we investigated levels of plasminogen activator inhibitor type 1 (PAI-1) and urokinase plasminogen activator receptor (uPAR), as quantitated by ELISA in tumour extracts from 64 NSCLC patients (38 squamous cell carcinomas, 26 adenocarcinomas), and compared them to staining intensity as semiquantitated by immunohistochemistry for PAI-1 and uPAR on corresponding cryostat sections. A significant association (r = 0.49, P < 0.0001) was found between the PAI-1 levels measured by ELISA and semiquantitated by immunohistochemistry. No association was found for uPAR. When correlating levels of PAI-1 and uPAR determined by ELISA and immunohistochemistry, respectively, to survival status, no significant correlation was found for any of the subgroups. At present neither of the methods examined in the present study can be recommended as superior for quantitating PAI-1 and uPAR with the aim of predicting prognosis. In conclusion, a larger comparative study is needed to clarify the relationship between ELISA and immunohistochemical results, before a methodology for clinical use can be chosen in non-small cell lung cancer.

Elevated plasma levels of urokinase plasminogen activator receptor in non-small cell lung cancer patients.

The urokinase plasminogen activator (uPA) is involved in extracellular matrix degradation during cancer invasion. Binding of uPA to a specific cell surface receptor (uPAR) is a key step in this process. We have previously reported that high levels of uPAR in squamous cell lung cancer tissue extracts are associated with poor prognosis (Pedersen et al., Cancer Res 1994, 54, 4671-4675). Recently we found that uPAR is present in blood plasma from healthy donors as determined by enzyme-linked immunosorbent assay (ELISA) and chemical cross-linking. We now report that uPAR in plasma from 17 patients with non-small cell lung cancer (NSCLC) was significantly higher than in 30 healthy controls (P = 0.0004), while no significant increase was found in plasma from 14 patients with small cell lung cancer (SCLC). The increased levels of uPAR in the plasma from NSCLC patients is likely to be due to release of uPAR from the tumour tissue, and may, therefore, be related to prognosis.

Plasminogen activator inhibitor type 1 in cytosolic tumor extracts predicts prognosis in low-risk breast cancer patients.

We have reported previously that both urokinase-type plasminogen activator (uPA) and its type 1 inhibitor (PAI-1) are statistically significant prognostic variables in patients with high-risk breast cancer (Grondahl-Hansen et al., Cancer Res., 53:2513-2521, 1993), and we recently described that the uPA receptor (uPAR) is a prognostic marker in postmenopausal, node-positive breast cancer patients (Grondahl-Hansen et al., Clin. Cancer Res., 1:1079-1087, 1995). The present retrospective study describes the prognostic impact of uPA, its receptor uPAR, and PAI-1 in breast cancer cytosol from 111 low-risk premenopausal patients and 184 low-risk postmenopausal patients with a median follow-up of 6.0 years (range, 3.8-14.9) and 7.4 (range, 3.7-14.0) years, respectively. uPA, uPAR, and PAI-1 levels were determined by sandwich enzyme-linked immunosorbent assays, and data were dichotomized using the median value as the cutoff for calculation of recurrence-free survival and overall survival. A correlation was found between the levels of each of the three molecules. In univariate analysis, high PAI-1 was significantly associated with short overall survival in postmenopausal patients [relative risk (RR), 2.3; 95% confidence interval (CI), 1.3-4.3; P = 0.005] and shorter recurrence-free survival in both premenopausal (RR, 2.5; 95% CI, 1.3-4.7; P = 0.004) and postmenopausal (RR, 1.8; 95% CI, 1.1-2.9; P = 0.02) patients. Neither uPA nor uPAR reached statistical significance in the univariate analyses. The prognostic value of uPA, uPAR, and PAI-1 was then compared with that of other established prognostic variables by multivariate analysis. PAI-1 was an independent prognostic variable for recurrence-free survival in premenopausal patients, with a RR of 2.6 (95% CI, 1.3-5.0). For recurrence-free survival (RR, 1.9; 95% CI, 1.1-3.5) and overall survival (RR, 2.6; 95% CI, 1.2-5.7) in postmenopausal patients, PAI-1 was the only independent variable left in this group of patients. Neither uPA nor uPAR reached significance in the multivariate analysis. These data, together with previously published data on the prognostic significance of components of the urokinase plasminogen activation system in breast cancer cytosols, strongly indicate that PAI-1 is a statistically significant and independent prognostic marker in both low- and high-risk breast cancer patients.

Presence of urokinase plasminogen activator, its inhibitor and receptor in small cell lung cancer and non-small cell lung cancer.

Spreading of cancer cells is dependent on the combined action of several proteolytic enzymes, such as serine proteases, comprising the urokinase pathway of plasminogen activation. Previous studies of lung cancer indicate that expression, localization and prognostic impact of the components of the plasminogen activation system differ in the different non-small cell lung cancer (NSCLC) types, whereas the expression of the components in small cell lung cancer (SCLC) has only sparingly been investigated. In the present study we investigate the presence of the components of the plasminogen activation system, and compare the levels of uPA, PAI-1 and uPAR in extracts of NSCLC-tissue and SCLC-tissue. A statistically significant difference, P = 0.037, was found between uPA-levels in NSCLC-patients (n = 75) and SCLC-patients (n = 8), the highest levels being found in NSCLC. No such difference was found for the two other components investigated, although a trend towards increased uPAR-levels was observed in SCLC, P = 0.055. The relationship between the levels of each of the components and other known clinical parameters was also analysed. No relationship was found between any of the components and the clinical parameters. This is the first report of a study using a quantitative method to compare levels of the components of the plasminogen activation system in tissue extracts from the two major lung cancer groups. The study shows that uPA, PAI-1 and uPAR are present in SCLC-tissue, suggesting that the plasminogen activation system could play a role in this type of cancer during invasion. In addition a difference in the levels of the components of the plasminogen activation system in NSCLC and SCLC is found, which could contribute to the differences in biology.

p53 protein in non-small cell lung cancer as quantitated by enzyme-linked immunosorbent assay: relation to prognosis.

The prognostic value of p53 protein in tumor extracts as measured by ELISA was studied retrospectively in 228 non-small cell lung cancer (NSCLC) patients. The assay measures both wild-type and mutated p53. The specimens on which this study was performed have been used earlier to analyze the prognostic impact of components of the plasminogen activation system, which enabled an analysis of relationships between these components and p53 protein. The median of the p53 protein values in the 228 patients was 0.10 (range, 0-0.70) ng/mg protein. Survival analysis comparing patients with p53 levels below versus above the median showed no significant difference (P = 0.67). When analyzing the histological types, adenocarcinoma (n = 106), squamous cell carcinoma (n = 84), and large cell carcinoma of the lung (n = 38) separately, similarly, no significant differences in survival between patients having low versus high tumor p53 levels were found. When comparing levels of p53 protein in the three histological types, a significant difference (P < 0.0001) was found, with adenocarcinomas having the lowest levels. There was a weak positive correlation (r = 0.22) between p53 protein and plasminogen activator inhibitor type 1 (PAI-1). Multivariate analysis proved no impact of p53 on survival; tumor size, PAI-1, and lymph node involvement were the only variables with significant influence on survival. These data indicate that p53 protein quantitated with a sandwich ELISA in tumor extracts from NSCLC has no prognostic value, but the observed statistically significant difference of p53 protein content between histological subgroups may be related to differences in etiology and biology in different NSCLC subtypes. In addition, the weak association found between p53 protein and the independent prognostic marker PAI-1 could suggest yet undefined interactions in lung cancer.

Prognostic significance of the receptor for urokinase plasminogen activator in breast cancer.

We have recently described the urokinase-type plasminogen activator (uPA) and its type 1 inhibitor (PAI-1) as strong prognostic variables in breast cancer (J. A. Foekens et al., Cancer Res., 52: 6101-6105, 1992; J. Grondahl-Hansen et al., Cancer Res., 53: 2513-2521, 1993; J. A. Foekens et al., J. Clin. Oncol., 11: 899-908, 1994). A specific cell surface receptor (uPAR) binds uPA and strongly enhances plasmin generation, and the amount of uPAR in the tumor tissue might therefore be a rate-limiting factor in the extracellular proteolysis involved in tumor invasion. Here, we report on the prognostic value of uPAR in cytosolic (uPARc) and Triton (uPARt) extracts prepared from 505 primary breast tumors. The median observation time was 54 (range: 12-125) months. uPAR levels were determined by a sandwich ELISA. Univariate analysis showed that high uPAR levels (above the median value) were significantly associated with a shorter overall survival, showing a stronger discriminatory effect for uPARc [relative hazard rate (RHR): 1.47; P = 0.012)] as compared with uPARt (RHR, 1.33; P = 0.059), while no statistically significant differences were found for relapse-free survival. Multivariate analysis including all patients showed that when including other biochemical variables (estrogen receptor, progesterone receptor, PS2, cathepsin D, uPA, and PAI-1), the only retained independent variable via backward elimination was PAI-1 for both relapse-free survival and overall survival. When analyzed separately in clinically relevant subgroups, the prognostic value of uPAR was particularly strong in a subgroup of 201 node-positive postmenopausal women, showing considerably shorter overall (RHR: 2.39; P < 0.0001) and relapse free (RHR: 1.91; P = 0.0006) survival for patients with high uPARc content. High uPARt levels were also significantly associated with shorter overall survival in this subgroup of patients (RHR: 1.5; P = 0.047), but not with relapse-free survival (P = 0.64). Multivariate analysis, including the basic model, estrogen and progesterone receptors, PS2, cathepsin D, uPA, PAI-1, uPARc, and uPARt in the subgroup of postmenopausal node-positive patients, showed that only uPARc and PAI-1 were significant independent prognostic parameters, with respect to overall survival, RHRs being 2.72 (P < 0.0001) and 1.81 (P = 0.005), respectively. In multivariate analysis of relapse-free survival, uPARc, PAI-1, and uPA were independent parameters with respective relative relapse rates of 1.91 (P = 0.002) for uPARc, 1.68 (P = 0.02) for PAI-1, and 1.6 (P = 0.03) for uPA. These data lend support to the hypothesis that uPAR is an important molecule in plasmin-mediated extracellular matrix degradation leading to cancer cell dissemination and death of the patient.

Plasminogen activator inhibitor type 1 in cancer: therapeutic and prognostic implications.

Degradation of the extracellular matrix plays a crucial role in cancer invasion. This degradation is accomplished by the concerted action of several enzyme systems, including generation of the serine protease plasmin by the urokinase pathway of plasminogen activation, different types of collagenases and other metalloproteinases, and other extracellular enzymes. The degradative enzymes are involved also in tissue remodelling under non-malignant conditions, and the main difference appears to be that mechanisms which regulates these processes under normal conditions are defective in cancer. Specific inhibitors have been identified for most of the proteolytic enzymes, e.g. plasminogen activator inhibitors (PAI's) and tissue inhibitors of metalloproteinases (TIMP's). It has been contemplated that these inhibitors counteracted the proteolytic activity of the enzymes, thereby inhibiting extracellular tissue degradation which in turn should prevent tumor cell invasion. This review focuses on plasminogen inhibitor type 1 (PAI-1). It is described that PAI-1 is not produced by the epithelial cancer cell but by the stromal cells in the tumors, suggesting a concerted action between stroma and tumor cells in the processes controlling proteolysis in cancer. The specific localization of PAI-1 to the tumor stroma and in many cases to areas surrounding the tumor vessels has lead us to suggest that PAI-1 serves to protect the tumor stroma from the ongoing uPA-mediated proteolysis. This hypothesis is supported by recent clinical data showing increased levels of PAI-1 in metastases as compared to the primary tumor as well as data demonstrating that high levels of PAI-1 in tumor extracts from breast, lung, gastric and ovarian cancer is associated with a shorter overall survival.(ABSTRACT TRUNCATED AT 250 WORDS)

The plasminogen activation system and its role in lung cancer. A review.

The urokinase pathway of the plasminogen activation is involved in proteolytic degradation of various tissues, including dissolution of the extracellular matrix and basement membranes during the process of cancer cell invasion. Recent studies have demonstrated that components of the plasminogen activation system have a prognostic impact in breast-, lung-, colorectal, bladder and gastric cancer. A number of studies, reviewed here, have focused on the role of the plasminogen activation system in different lung cancer types. There seems to be an obvious difference between the expression, localization and prognostic impact of the components of the plasminogen activation system in different lung cancer types. The differences seen could be helpful in understanding the biology of different lung cancer types, and components of the plasminogen activation system may have prognostic relevance and clinical implications in some lung cancer types, even though confirmatory studies are needed.

The receptor for urokinase plasminogen activator is present in plasma from healthy donors and elevated in patients with paroxysmal nocturnal haemoglobinuria.

The urokinase plasminogen activator (uPA) is a proteolytic enzyme which converts the proenzyme plasminogen to the active serine protease plasmin. A cell surface receptor for uPA (uPAR) is attached to the cell membrane by a glycosyl-phosphatidylinositol anchor. Binding of uPA to uPAR leads to an enhanced plasmin formation and thereby an amplification of pericellular proteolysis. We have shown previously that uPAR is expressed on normal blood monocytes and granulocytes, but is deficient on affected blood monocytes and granulocytes in patients with paroxysmal nocturnal haemoglobinuria (PNH), and that uPAR is present in plasma from these patients. In this study a newly established sensitive enzyme-linked immunosorbent assay (ELISA) has been applied for quantitation of uPAR in plasma. Unexpectedly, we found that uPAR is not only present in PNH plasma but also in plasma from healthy individuals. In 39 healthy individuals the mean plasma-uPAR value +/- SD was 31 +/- 15 pM, median 28 (range 11-108), and the corresponding value for six PNH patients was 116 +/- 67 pM, median 90 (range 61-228). The elevated uPAR-level in PNH patients was highly significant (Mann-Whitney test; P < 0.0001), and may possibly contribute to the propensity for thrombosis in PNH by inhibition of the fibrinolytic system. Binding of pro-uPA by uPAR in plasma may interfere with the appropriate binding of pro-uPA to cell-bound uPAR and therefore inhibit cell-associated plasmin generation and fibrinolysis. It is likely that the uPAR in normal plasma reflects the overall level of activity of the uPAR-mediated cell surface proteolysis. The present ELISA may be used for studies of uPAR levels in plasma from patients with conditions in which this activity might be increased, such as cancer and inflammatory disorders. Future studies will determine if uPAR in plasma is a parameter of clinical importance in these diseases.