Nomograms including the UBC® Rapid test to detect primary bladder cancer based on a multicentre dataset.

OBJECTIVES: To evaluate the clinical utility of the urinary bladder cancer antigen test UBC® Rapid for the diagnosis of bladder cancer (BC) and to develop and validate nomograms to identify patients at high risk of primary BC. PATIENTS AND METHODS: Data from 1787 patients from 13 participating centres, who were tested between 2012 and 2020, including 763 patients with BC, were analysed. Urine samples were analysed with the UBC® Rapid test. The nomograms were developed using data from 320 patients and externally validated using data from 274 patients. The diagnostic accuracy of the UBC® Rapid test was evaluated using receiver-operating characteristic curve analysis. Brier scores and calibration curves were chosen for the validation. Biopsy-proven BC was predicted using multivariate logistic regression. RESULTS: The sensitivity, specificity, and area under the curve for the UBC® Rapid test were 46.4%, 75.5% and 0.61 (95% confidence interval [CI] 0.58-0.64) for low-grade (LG) BC, and 70.5%, 75.5% and 0.73 (95% CI 0.70-0.76) for high-grade (HG) BC, respectively. Age, UBC® Rapid test results, smoking status and haematuria were identified as independent predictors of primary BC. After external validation, nomograms based on these predictors resulted in areas under the curve of 0.79 (95% CI 0.72-0.87) and 0.95 (95% CI: 0.92-0.98) for predicting LG-BC and HG-BC, respectively, showing excellent calibration associated with a higher net benefit than the UBC® Rapid test alone for low and medium risk levels in decision curve analysis. The R Shiny app allows the results to be explored interactively and can be accessed at www.blucab-index.net. CONCLUSION: The UBC® Rapid test alone has limited clinical utility for predicting the presence of BC. However, its combined use with BC risk factors including age, smoking status and haematuria provides a fast, highly accurate and non-invasive tool for screening patients for primary LG-BC and especially primary HG-BC.

Non-invasive Detection of Bladder Cancer by UBC Rapid Test, Ultrasonography and Cytology.

BACKGROUND/AIM: There is a need to diagnose early bladder cancer by non-invasive tests. This study aimed to explore the clinical value of three non-invasive methods, UBC Rapid, ultrasound (US), and urine cytology, separately and in combination, for the primary diagnosis and surveillance of bladder-cancer. PATIENTS AND METHODS: Urine samples were obtained from 106 patients who presented with symptoms of bladder cancer and patients followed-up after transurethral resection of bladder tumors (TURB). Each patient underwent US, cystoscopy, cytology and UBC Rapid test. The sensitivity and specificity of all methods and combinations were calculated and related to cystoscopy and biopsy. RESULTS: Voided urine samples assayed with UBC Rapid and cytology yielded a sensitivity and specificity of 58.3% and 75.9%, and 57.1% and 98.0%, respectively and for US 76.2% and 98.1%. The combination of all three methods resulted in a sensitivity and specificity of 95.8% and 67.3%, and the combination of UBC Rapid and US, gave a sensitivity of 91.3%, and a specificity of 72.2%, The combination of UBC Rapid and cytology yielded a sensitivity and specificity of 84.6% and 71.2%. CONCLUSION: Combined use of UBC Rapid, US and cytology improved the sensitivity of bladder cancer detection.

Evaluation of the diagnostic accuracy of UBC® Rapid in bladder cancer: a Swedish multicentre study.

OBJECTIVE: The aim of this study was to determine the diagnostic accuracy of UBC® Rapid - a urine-based marker for bladder cancer - in patients with bladder cancer and controls, and to compare the test results across risk groups. MATERIALS AND METHODS: This prospective phase II study was conducted at four Swedish hospitals. UBC Rapid was evaluated in four groups: A, newly diagnosed bladder cancer (n = 94); B, follow-up of non-muscle-invasive bladder cancer (n = 75); C, benign urinary tract diseases (n = 51); and D, healthy controls (n = 50). Tumours were divided into high risk (carcinoma in situ, TaG3, T1, T2 and T3) and low risk (low malignant potential, TaG1 and TaG2). Urine samples were quantitatively analysed by UBC Rapid. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated based on optimal cut-off (receiver operator characteristics curve analysis). A linear regression compared the UBC Rapid results in the different risk groups. RESULTS: The optimal cut-off was 8.1 µg/l. The median UBC Rapid values were 9.3 µg/l [interquartile range (IQR) 30.9] and 4.3 µg/l (IQR 7.8) in patients with positive and negative cystoscopy, respectively (p < .001). The value for group A was 15.6 µg/l (IQR 37.9), group B 5.6 µg/l (IQR 8.6), group C 5.1 µg/l (IQR 9.0) and group D 3.3 µg/l (IQR 7.1). Sensitivity was 70.8%, specificity 61.4%, PPV 71.3% and NPV 60.8%. The high-risk group had significantly higher UBC Rapid values than the low-risk group: 20.5 µg/l (IQR 42.2), sensitivity 79.2% and specificity 61.4% versus 7.0 µg/l (IQR 9.9), sensitivity 60.0% and specificity 61.4% (p = .039). CONCLUSIONS: The UBC Rapid urine-based marker for bladder cancer gave higher values in patients with positive than in those with negative cystoscopy. The diagnostic accuracy was better in patients with high-risk than in those with low-risk tumours, and was better during primary detection than during surveillance.

The brain is a source of S100B increase during endotoxemia in the pig.

BACKGROUND: Cerebral dysfunction frequently complicates septic shock. A marker of cerebral dysfunction could be of significant value in managing sedated septic patients. Plasma S100 (S100B) proteins increase in sepsis. S100B is present not only in the brain but also in other tissues. The source of this protein has not been investigated in sepsis. Our aim in this study was to determine whether the brain is an important source of S100B in an experimental sepsis model. METHODS: Twenty-seven pigs were anesthetized and randomized to either infusion of endotoxin at the rate of 1 microg x kg(-1) x h(-1) (n = 19) or saline (n = 8). Catheters were inserted into a cervical artery and the superior sagittal sinus. Blood samples were collected from both sites and physiologic data were registered before the start of the endotoxin infusion and hourly during the experiment. After 6 h, the animals were killed and brain tissue samples were taken from the left hemisphere. S100B in plasma was measured by enzyme-linked immunosorbent assay. Brain tissue samples were stained with biotinylated S100B antibodies. RESULTS: In the endotoxemic animals, the arterial S100B concentration increased to 442 +/- 33 and 421 +/- 24 ng/L at 1 and 2 h, respectively, vs 306 +/- 28 and 261 +/- 25 ng/L in controls (P = 0.018 and 0.00053, respectively). Mean superior sagittal sinus S100B concentrations were higher than mean arterial concentrations at all time points in the endotoxemic animals; however, significance was only reached at 2 h (P = 0.033). The focal glial S100B expression was more intense in the endotoxemic pigs than in controls (P = 0.0047). CONCLUSIONS: Our results support the hypothesis that the brain is an important source of S100B in endotoxemia even though there may be other sources. These findings make S100B a candidate as a marker of cerebral dysfunction in septic shock.

Serological and immunohistochemical analysis of S100 and new derivatives as markers for prognosis in patients with malignant melanoma.

The incidence of cutaneous malignant melanoma is rising, and tumour markers are attracting attention as a possible alternative to clinical examination in the follow-up situation. S100 is the preferred marker for malignant melanoma, and correlation between serum S100 and disease relapse and survival has been reported. S100 tests previously used in clinical studies were specified poorly regarding reactivity with S100A1B and S100BB. In this study, a newly designed S100 assay (designed to measure exclusively S100A1B and S100BB) and two newly developed serological assays, S100A1B, and S100BB, were investigated postoperatively in patients undergoing radical surgery for cutaneous malignant melanoma. Additionally, immunohistochemical analysis of S100A4 was performed on the primary malignant melanoma using tissue microarrays. The primary aim of the study was to investigate whether any of these assays, either singly or in combination, can contribute additional information concerning increased risk of relapse and death because of malignant melanoma. In total, 98 patients (54 males, 44 females) with malignant melanoma were included in the study. As a continuous variable, S100BB (P=0.016) was associated statistically with increased risk of relapse; this was not the case for increased values of either S100 (P=0.11) or S100A1B (P=0.92). The Kaplan-Meier overall survival as well as disease specific survival curve for the S100 serum level demonstrated a statistically significant association with better survival if the patient had a S100 level

Tumor markers in breast cancer- European Group on Tumor Markers recommendations.

Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins (CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin (trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy.

Serum thymidine kinase activity in dogs with malignant lymphoma: a potent marker for prognosis and monitoring the disease.

Serum thymidine kinase (sTK) activity was evaluated as a tumor marker for canine malignant lymphoma (ML). The objective was to investigate if sTK, as in humans, could be used as a prognostic marker for survival time in dogs with ML and if sTK could identify early signs of progression of disease in treated dogs. Serum samples from 52 dogs with ML were tested for initial TK activity. Samples from 21 normal dogs and 25 dogs with nonhematologic neoplasms were used for comparison. Forty-four dogs with ML were treated. Serum TK activity was measured in treated dogs before each treatment and every 4 weeks thereafter until relapse. Dogs with ML had 2-180 times higher TK activity (TK 5-900 U/L) than normal dogs (TK <7 U/L) based on the mean + 2 standard deviations. In the group of other neoplasms, only 2 dogs had a moderate increase (6.4 and 7.5 U/L) compared with the controls. Mean sTK activities in the dogs with ML that had gone into complete remission (CR) were not significantly different from activities in healthy controls (P = .68). Mean sTK at least 3 weeks before and at the time of relapse was significantly higher than activity measured at CR (P < .0001). Dogs with ML that initially had sTK >30 U/L had significantly shorter survival times (P < .0001). Furthermore, sTK activity reflected the clinical staging of ML. Measuring sTK can be used as a powerful objective tumor marker for prognosis and for predicting relapse before recurrence of clinically detectable disease in dogs with ML undergoing chemotherapy.

Sensitive nonradiometric method for determining thymidine kinase 1 activity.

BACKGROUND: Thymidine kinase 1 (TK1) is a cytoplasmic enzyme, produced only in the S-phase of proliferating cells, that has potential as a tumor marker. Specific determination of TK1 in serum is difficult, in part because of differences in the physical properties of serum TK1 compared with cytoplasmic TK1. METHODS: The first step in the new assay was phosphorylation of 3'-azido-2',3'-deoxythymidine (AZT) to AZT 5'-monophosphate (AZTMP) by TK1 present in patient material. The AZTMP formed was measured in a competitive immunoassay with specific anti-AZTMP antibodies and AZTMP-labeled peroxidase. Results were compared with those of a TK radioenzyme assay (REA) for 78 samples from patients suffering from hematologic diseases. RESULTS: The detection limit was 78 microIU/L, and within-run CVs <20% were seen for samples with TK1 down to 130 microIU/L. Cross-determination of the mitochondrial isoenzyme TK2 activity was <0.1%. Between-assay imprecision (CV) was 3.5-7.4%, and the within-assay imprecision was 4.1-9.1%. In studies of recovery and linearity on dilution, measured values ranged from 84% to 115% of expected at concentrations of 0.26-10.4 mIU/L. Results of the new assay (mIU/L) = 0.109 x TK REA (U/L) + 0.092. Heterophilic antibodies did not interfere in the assay. The upper 95th percentile, in 100 healthy individuals, was 0.94 mIU/L, and the median value was 0.43 mIU/L. CONCLUSION: The TK1 enzyme-labeled immunoassay uses a stable substrate, is precise, appears to be accurate, and is resistant to interferences. It may provide a practical tool in the management of hematologic malignancies.

S100 proteins as cancer biomarkers with focus on S100B in malignant melanoma.

Although histochemical staining of the S100 protein family has been used for many years in the diagnosis of malignant melanoma, recent studies suggest one of the proteins comprising the S100 family, S100B, has particular utility in many aspects of the clinical management of malignant melanoma. This protein has been shown to be of use in staging malignant melanoma, in establishing prognosis, in evaluating treatment success and in predicting relapse. S100B is an independent prognostic factor and pretreatment circulating S100B concentrations predict duration of survival in melanoma patients. Survival is significantly longer in melanoma patients with normal S100B levels compared to those with elevated levels. Circulating S100B levels very sensitively detect metastatic growth of malignant melanoma, particularly in stage IV disease where S100B is certainly superior to other laboratory parameters. S100B concentrations reflect tumor mass. Serum S100B levels predict efficacy of treatment. Decreasing S100B concentrations reflect response to therapy while increasing S100B concentrations indicate tumor progression. Circulating S100B has a role to play in the decision to switch treatment regimens.

Clinical utility of cytokeratins as tumor markers.

Cytokeratins, belonging to the intermediate filament (IF) protein family, are particularly useful tools in oncology diagnostics. At present, more than 20 different cytokeratins have been identified, of which cytokeratins 8, 18, and 19 are the most abundant in simple epithelial cells. Upon release from proliferating or apoptotic cells, cytokeratins provide useful markers for epithelial malignancies, distinctly reflecting ongoing cell activity. It appears that motifs in certain cytokeratins make them likely substrates for caspase degradation, and their subsequent release occurs during the intermediate events in apoptosis. The clinical value of determining soluble cytokeratin protein fragments in body fluids lies in the early detection of recurrence and the fast assessment of the efficacy of therapy response in epithelial cell carcinomas. The three most applied cytokeratin markers used in the clinic are tissue polypeptide antigen (TPA), tissue polypeptide specific antigen (TPS), and CYFRA 21-1. TPA is a broad spectrum test that measures cytokeratins 8, 18, and 19. TPS and CYFRA 21-1 assays are more specific and measure cytokeratin 18 and cytokeratin 19, respectively. By following patients with repeated testing during management, the oncologist may obtain critical information regarding the growth activity in symptomatic patients. Although their main use is to monitor treatment and evaluate response to therapy, early prognostic information particularly on tumor progression and metastasis formation is also provided for several types of cancers. Cytokeratin tumor markers can accurately predict disease status before conventional methods and offer a simple, noninvasive, cheap, and reliable tool for more efficient management.

Comparative analysis of CA125, tissue polypeptide specific antigen, and soluble interleukin-2 receptor alpha levels in sera, cyst, and ascitic fluids from patients with ovarian carcinoma.

BACKGROUND: The serum markers CA125, tissue polypeptide specific antigen (TPS), and soluble interleukin-2 receptor alpha (sIL-2Ralpha) concentrations were determined in sera, cyst, and ascitic fluids from patients with malignant and benign ovarian neoplasms. METHODS: CA125, TPS, and sIL-2Ralpha concentrations were measured in sera, cyst, and ascitic fluids by immunoassays in 67 patients with carcinoma and in 32 patients with benign ovarian neoplasms. RESULTS: CA125, TPS, and sIL-2Ralpha levels were elevated significantly in sera from patients who had ovarian carcinoma compared with patients who had benign neoplasms (P < 0.001). Patients who had International Federation of Gynecology and Obstetrics (FIGO) Stage III-IV disease had significantly higher serum levels for the markers studied compared with patients who had FIGO Stage I-II disease (P < 0.001 for CA125; P = 0.02 for TPS and sIL-2Ralpha). Concurrent measurement of CA125 and sIL-2Ralpha in sera identified 100% of ovarian carcinomas in FIGO Stage I-II. All patients with carcinoma demonstrated markedly higher levels of CA125 and TPS for both cyst and ascites compared with corresponding sera (P < 0.001). The level of sIL-2Ralpha was higher statistically in ascitic fluid compared with the level in serum (P < 0.001); however, its values in sera and cyst fluids were comparable. In ascitic fluid, the CA125 level was significantly higher in patients who had FIGO Stage III-IV disease compared with patients who had FIGO Stage I-II disease (P = 0.002), whereas such correlations were not found for TPS or sIL-2Ralpha. In cyst fluids, the levels of all studied markers were independent of the FIGO stage. In cyst fluids from patients with benign ovarian neoplasms, TPS and sIL-2Ralpha levels were significantly lower compared with the levels in patients with ovarian carcinoma (P < 0.001), whereas the values of CA125 were overlapping. CA125 and TPS concentrations were higher in cyst fluids compared with corresponding sera, whereas sIL-2Ralpha levels were comparable and low in cyst fluids and in the circulation of patients with benign neoplasms. CONCLUSIONS: In patients with ovarian carcinoma, TPS and CA125 concentrations were significantly higher in the place of their generation compared with the concentrations in blood circulation. sIL-2Ralpha values were higher in ascites compared with the values in corresponding sera, and its concentrations in sera and cyst fluids were comparable. The assessment of serum sIL-2Ralpha levels showed potential complementary value to CA125 for the detection of ovarian carcinoma in early FIGO stages; however, a 9% false positive rate limited the significance of cumulative value for a combination of these circulating markers.