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Background/aim: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. High serum levels of soluble IL-2 receptor (sIL-2R) have been reported in acute inflammations and metastatic cancers. This study evaluated the potential of high/increasing sIL-2R levels in predicting metastases., Patients and Methods: The study included a total of 1,546 sera samples of subjects from three groups: 119 healthy controls (73 subjects), 566 UM 10 year (10y) disease-free (DF) (220 patients), 861 metastatic UM (268 patients). Patients were followed-up biannually with liver ultrasound and liver function tests for the presence of metastases (Mets). Blood samples to measure the levels of sIL-2R were obtained at the time of primary diagnosis, soon after initial treatment (enucleation, brachytherapy), every 6 months, 10 years from diagnosis, at Mets confirmation by CT, and after additional treatments., Results: Significantly higher sIL-2R levels were detected in the Mets patients compared to healthy controls and 10y DF patients. Compared to the upper limit of the normal levels of sIL-2R, 1,000 U/ml, its levels in metastatic UM were 61%, 25% in 10y DF UM, and 6.25% in the controls. High levels of sIL-2R in metastatic patients, decreased significantly post treatments. Individual kinetics of markers, indicated similar trends of sIL-2R compared to osteopontin and S-Protein 100, predicting metastases, which were confirmed on liver imaging., Conclusion: Significantly higher sIL-2R levels were evident in all UM patients with Mets. Significant increases in sIL-2R levels on serial evaluations indicated and predicted UM Mets, enabling earlier treatment of Mets, to improve survival., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Prognostic factors serve as a vital tool in the treatment of patients with head and neck cancer (HNC). The aim of this study was to evaluate the clinical potential of Thymidine-kinase-1 (TK1) marker in the prognosis of HNC patients., Patients and Methods: We evaluated 366 blood samples from 278 HNC patients and 88 healthy controls, using an ELISA assay. Correlations of TK1 levels with disease stage, lymph node involvement and response to radiation therapy, were determined., Results: In HNC patients, TK1 levels were significantly higher compared to healthy controls. Significantly higher TK1 levels were demonstrated in node positive cases and in advanced disease stages compared to node negative and early disease stages. Levels were higher prior to radiation and decreased significantly thereafter, in patients responding to treatment. Increasing levels of TK1 post-radiation were indicative of recurrence or of non-response to treatment, while decreasing levels indicated a positive response., Conclusion: TK1 is a tumor marker in HNC patients with the ability to assess response to therapy. High or increasing levels correlated to a poor prognosis, whereas low levels correlated to an overall increased survival., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Mucin 13 (MUC13) is a cell surface glycoprotein aberrantly expressed in a variety of epithelial carcinomas. Thus far, the role of MUC13 in various diseases remains elusive. To the best of our knowledge, this is the first study to examine the potential of MUC13 as a serum biomarker in a variety of carcinomas and other conditions., Methods: We developed a recombinant MUC13 protein, mouse monoclonal antibodies and enzyme immunoassay (ELISA) for MUC13. We used this assay to measure MUC13 levels in the supernatants of cancer cell lines and a large cohort of serum samples from healthy and diseased individuals., Results: MUC13 is secreted from cancer cell lines, with highest levels found in ovarian cancer cell lines. MUC13 levels in human sera were significantly increased in patients with renal failure and 20%-30% of patients with ovarian, liver, lung and other cancers. MUC13 was also elevated in 70% of patients with active cutaneous melanoma, but not uveal melanoma. Furthermore, we identified significant MUC13 elevations in the serum of patients with vasculitis (ANCA-positive) autoantibodies, but not in those with inflammatory bowel disease., Conclusions: Serum MUC13 is frequently elevated not only in a variety of malignant cases but also in some benign pathologies, thus appearing to be a non-specific disease biomarker. Nonetheless, serum MUC13 is clearly highly elevated in some carcinoma patients, and its relationship with tumor progression in this context warrant further research. Future studies that examine the correlation between serum MUC13 levels to stage of cancer could elucidate prognostic potential.

Background/aim: Head and neck cancer (HNC) patients are usually diagnosed with advanced disease and multimodality therapies are required, as well as prognostic biomarkers to predict their response and assess survival. In this study, we aimed to evaluate the ability and clinical significance of the immune biomarker sIL-2R in HNC patients, to assess therapy response and prognosis., Materials and Methods: We evaluated 328 blood samples from 145 head and neck cancer patients (HNC) from several subgroups: 84 larynx carcinomas pre- and 39 post-therapy, 46 oral cavity carcinomas pre- and 29 post-therapy, 12 nasopharynx carcinomas, 16 parotid and other salivary gland carcinoma patients. The control group included 45 healthy subjects. Serum sIL-2R levels were evaluated by ELISA assays and correlated to disease stage, lymph nodes, response to therapy, survival and cancer differentiation., Results: Significantly higher sIL-2R levels were recorded in all HNC patients, as opposed to controls, in advanced versus early-stage disease that decreased following therapy. sIL-2R distinguished best, in comparison to other tumor markers, between HNC patients and controls. Survival was strongly associated to lower sIL-2R levels in patients entering the study., Conclusion: sIL-2R is a sensitive immune marker for HNC patients. Its levels correlate to disease stage, assess response to therapy and are predictive of recurrence or better survival. We suggest, therefore, using sIL-2R as a reliable prognostic marker in HNC patients as a single marker, or in a combined panel of biomarkers., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: Malignant melanoma incidence is increasing over the last years, while mortality is strongly decreasing due to improved early detection, close monitoring of patients including disease biomarkers as well as introduction of new therapies. The aim of the present study was to evaluate biomarkers, mainly S-100β in melanoma patients, regarding its ability to assess treatment response, especially to new immunotherapies (anti-BRAF, ipilimumab, anti-PD-1) and evaluation of prognosis of those patients., Patients and Methods: We evaluated both retrospectively and prospectively 137 malignant melanoma patients. Blood biomarker levels were evaluated by conventional ELISA assays. Correlations of marker levels to disease stage, metastases, response to new immunotherapies and survival, were performed., Results: Serum levels of biomarkers, mainly S-100β, were significantly higher in all patients before various therapies were applied (5.1+0.7 μg/L) and decreased thereafter (1.3+0.4 μg/L). Significantly higher levels of S-100β were demonstrated in advanced disease including metastases, (5.95+0.62 μg/L) as opposed to early disease (0.32+0.06 μg/L) and NED patients (0.18+0.03 μg/L). When comparing melanoma deceased patients who had extremely high levels of S-100β, (2.2+0.45 μg/L) we showed significantly lower levels in alive patients (0.26+0.02 μg/L) and certainly in normal controls (0.07+0.02 μg/L). In individual patients, kinetic evaluations showed earlier response to therapy, or recurrence and non-response, as shown only later by CT evaluations., Conclusion: S-100β can serve as a useful biomarker for the assessment of treatment response and prognosis, especially after using new immunological treatments, such as anti-BRAF, ipilimumab or anti-PD1 in malignant melanoma patients. Additional biomarkers, such as LDH, β2M and TK may also serve as part of a biomarkers panel, for improved detection of recurrence and metastasis of melanoma patients., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: Establishing prognostic factors is very important in the management of cancer patients. Our aim was to evaluate the clinical significance of a panel of tumor markers, including CEA (Carcino Embryonic Antigen), SCC (Squamous Cell Carcinoma Antigen), TPS (Tissue Polypeptide Specific Antigen) and CYFRA 21-1 in head and neck cancer patients, for assessing treatment response and prognosis of patients., Patients and Methods: We evaluated 312 blood samples from 143 head and neck cancer patients, from several sub-groups: 82 Larynx Carcinoma pre- and 38 post-therapy, 46 Oral Cavity pre and 29 post-therapy, 12 nasopharynx, 16 parotid and other salivary gland patients. Blood tumor markers levels were evaluated by conventional ELISA assays. Correlations of marker levels to stage of disease, lymph node involvement and therapy, were performed., Results: Serum levels of all four tumor markers were higher before therapy and decreased thereafter in all patients. The decrease in TPS level following therapy was significant (p=0.03). Significantly higher levels of TPS and similarly higher levels of the other tumor markers were demonstrated in advanced disease (stages III and IV) patients, as opposed to early disease (stages I and II) patients (p=0.012). Node positive patients had significantly higher TPS levels as compared to node negative (p=0.02). The same trend was shown by the other markers as well, but did not reach statistical significance. TPS was best correlated to survival of patients; those having low levels had the best clinical outcome and longer survival., Conclusion: CEA, SCC, TPS and CYFRA 21-1 can all serve as useful tumor markers in HNC patients. They assessed response to therapy and were prognostic for recurrence. TPS proved to be the most sensitive predictor of advanced disease and poor prognosis., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Biomarkers are playing increasingly important roles in the detection and management of patients with cancer. Despite an enormous number of publications on cancer biomarkers, few of these biomarkers are in widespread clinical use., Content: In this review, we discuss the key steps in advancing a newly discovered cancer candidate biomarker from pilot studies to clinical application. Four main steps are necessary for a biomarker to reach the clinic: analytical validation of the biomarker assay, clinical validation of the biomarker test, demonstration of clinical value from performance of the biomarker test, and regulatory approval. In addition to these 4 steps, all biomarker studies should be reported in a detailed and transparent manner, using previously published checklists and guidelines. Finally, all biomarker studies relating to demonstration of clinical value should be registered before initiation of the study., Summary: Application of the methodology outlined above should result in a more efficient and effective approach to the development of cancer biomarkers as well as the reporting of cancer biomarker studies. With rigorous application, all stakeholders, and especially patients, would be expected to benefit., (© 2015 American Association for Clinical Chemistry.)

Serum levels of thymidine kinase 1 (TK1), an enzyme involved in the G1-S phase of the cell cycle, have been previously shown to correlate with the prognosis of lymphoid malignancies. We hypothesized that TK1 levels will be higher in aggressive, compared to indolent lymphoproliferative, malignancies and this may serve as a marker of transformation from an indolent to aggressive disease. We analyzed serum from 182 patients and correlated the findings with the type of malignancy and prognosis; we further compared the TK1 levels of 31 patients with a proven transformation and 34 patients with clinically suspected transformation that was eventually deferred. The mean TK1 levels of patients with indolent and aggressive disease was 18.9±3.3 and 39.8±3.3 U/l respectively (p<0.001). Among patients with aggressive disease, low TK1 levels correlated with improved survival (p=0.008). TK1 levels >16.6 U/l predicted transformation from indolent to aggressive disease (sensitivity of 95%, specificity of 76%, negative predictive value (NPV) of 96% and positive predictive value (PPV) of 69%). A regression analysis showed that only TK1 levels were significant (relative risk (RR)=1.03 for each unit, confidence interval (CI)=1-1.05; p=0.015) for diagnosing a true transformation. In conclusion, TK levels are useful in assessing prognosis, especially in aggressive lymphoproliferative diseases. Moreover, TK levels are adequate in discriminating cases of indolent lymphoma that transformed to an aggressive disease from patients with no proven transformations. This tool provides the clinician a novel method to distinguish between symptomatic patients utilizing a simple test and may lessen the need for aggressive or invasive measures of investigation., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: High expression levels of insulin-like growth factor-1 (IGF-1) receptor were associated with metastatic uveal melanoma (UM). The purpose of this study was to examine the potential of serum IGF-1 in early detection of liver metastasis., Methods: IGF-1 serum levels were analyzed using enzyme-linked immunosorbent assay for 118 subjects in three different groups: 55 disease-free (DF) UM patients who did not develop metastasis within 10 years of diagnosis; 22 metastatic patients; and 41 healthy subjects. Matched pairs univariate analysis was performed for sera of 19 metastatic patients 12 and 6 months before the diagnosis of metastasis and on the day of diagnosis, both as time groups and normalized levels per patient. IGF-1 levels were compared among groups by analysis of variance and Student t-test., Results: Mean ± SD IGF-1 serum levels for the control, DF, and metastatic groups were 152.48 ± 49.76, 119.92 ± 60.66, and 96.99 ± 56.91 ng/mL, respectively (P < 0.001). Normalized changes in IGF-1 per metastatic patient from 6 months prior to the diagnosis of metastases compared to the day of diagnosis of metastases showed a decreasing trend., Conclusions: IGF-1 levels in 10-years' disease-free UM patients were significantly lower than those in healthy subjects and were even lower in metastatic patients. IGF-1 levels decreased toward the diagnosis of metastases. Therefore, serum IGF-1 level may be used as a predictive biomarker for metastatic UM when measured repeatedly.

A major application of tumor biomarkers is in serial monitoring of cancer patients, but there are no published guidelines on how to evaluate biomarkers for this purpose. The European Group on Tumor Markers has convened a multidisciplinary panel of scientists to develop guidance on the design of such monitoring trials. The panel proposes a 4-phase model for biomarker-monitoring trials analogous to that in use for the investigation of new drugs. In phase I, biomarker kinetics and correlation with tumor burden are assessed. Phase II evaluates the ability of the biomarker to identify, exclude, and/or predict a change in disease status. In phase III, the effectiveness of tumor biomarker-guided intervention is assessed by measuring patient outcome in randomized trials. Phase IV consists of an audit of the long-term effects after biomarker monitoring has been included into standard patient care. Systematic well-designed evaluations of biomarkers for monitoring may provide a stronger evidence base that might enable their earlier use in evaluating responses to cancer therapy., (© 2012 American Association for Clinical Chemistry)

Purpose: High levels of serum VEGF have been reported in many types of cancers, especially in the metastatic stage. The aim of this study was to examine the potential of VEGF serum level as a tumor marker for metastases in uveal melanoma (UM) patients., Materials and Methods: Levels of serum VEGF were analyzed by ELISA for 23 UM patients (none of whom developed metastases within 5 years from diagnosis) at the time of diagnosis, soon after treatment, and 3 years later, and compared with serum VEGF levels of 39 metastatic patients, 58 10-year disease-free (10yDF) patients, and 23 healthy subjects. VEGF ratios were calculated per patient between diagnosis and after treatment, and between diagnosis and 3 years later. Matched pairs univariate analysis was performed for 17 metastatic patients for whom sera were available from before and after the diagnosis of metastases. Patients were followed biannually with liver ultrasonography and liver function tests for the presence of metastases., Results: The inter-patient VEGF level range was large (e.g., the range for the metastatic patients was 46-1892 pg/ml). The mean ± SD levels for the control, 10yDF, and metastatic groups were: 329.65 ± 190.0, 407.66 ± 261.9 and 453.52 ± 270.2, respectively (p = 0.2456). The mean VEGF level ratio from after treatment to diagnosis was 1.08 (p = 0. 0024), and the ratio from 3 years after diagnosis to diagnosis was 1.53 (p = 0.0009). The mean ± SE post/premetastatic levels ratio was 1.35 ± 0.21 (p = 0.0595)., Conclusions: Serum VEGF increased significantly after metastases developed. However, the wide inter-patient variance precludes the use of any cut-off level to determine the metastatic status of an individual patient based on a single VEGF serum level. An increase in VEGF on serial measurements may indicate the development of metastases. Further investigation is warranted to assess VEGF's value as a predictive marker for metastatic disease.

Aim: To examine the kinetics of the tumor marker levels: osteopontin (OPN), S-100β, melanoma inhibitory activity (MIA) and tissue polypeptide-specific antigen (TPS), and to evaluate their potential for predicting earlier liver metastasis in patients with uveal melanoma (UM)., Patients and Methods: Forty-three UM patients who remained disease-free (DF) for at least 10 years, 32 patients with metastatic UM and 53 healthy controls were enrolled. Median and mean levels of the tumor markers OPN, S-100β, MIA and TPS at the time periods of 0-6, 6-12, 12-18, 18-24 and >24 months prior to confirmation of metastasis by liver ultrasound, CT scan and biopsy, served in a box and whiskers analysis and were compared by Students t-test. Trends of changes in marker levels of DF and metastatic UM groups were calculated and compared by ANOVA., Results: The lead-time for predicting metastasis was: 12-18 months both for OPN (p=0.005) and MIA (p=0.37), for S-100β 18-24 months first increase (p=0.5) followed by a second one 0-6 months (p=0.01) and for TPS 18-24 months (p=0.1). The gradient of the trendlines for the metastatic group was significantly steeper for MIA (p=0.02) and S-100β (p=0.018) than for the DF group and not statistically significant for OPN (p=0.168). For TPS, the trendline was negative. The overall increase in the levels of OPN and S-100β was significant, while for TPS and MIA, it was not., Conclusion: Significant increases in OPN and S-100β levels were demonstrated by a major lead time. Trendlines of the metastasis group were steeper than of the DF group predicting liver metastasis. The routine use of those markers in the follow up of UM patients, can enable earlier diagnosis of liver metastasis and effective therapeutic intervention, with an impact on survival.

As the release and amount of circulating biomarkers show considerable variations between individuals, single value determinations are often difficult to be interpreted on their diagnostic or prognostic significance on the individual level. However, changes of the biomarker levels in a specific person during the disease course are quite informative for the estimation of the efficacy of therapy or the early detection of recurrent disease because they consider only intraindividual variations. If methods for marker determination are maintained, preanalytical and analytical standard prerequistits are respected, thresholds for each marker have to be defined which exceeds the normal, intraindividual biological variation. Then continuous biomarker increases may be indicative for disease activity in terms of inefficient therapy response or tumor recurrence while decreasing values often are associated with activity reduction of cancer disease. Here, we review the current knowledge on biomarker kinetics in patients with non-small cell lung cancer (NSCLC) and discuss the conditions and pitfalls of their relevance for the estimation efficacy of therapy and the early detection of recurrent disease. Further, we suggest a scenario to reveal the power of the defined biomarker use in future and to include those markers into the individual management of NSCLC patients.

Aim: To investigate the diagnostic and prognostic significance of pro-gastrin-releasing peptide (ProGRP) in non-small cell (NSCLC) and small cell lung cancer (SCLC) and compare this marker with other known serum markers in lung cancer., Patients and Methods: Serum levels of ProGRP, neuron-specific enolase (NSE), CYFRA 21-1 and carcinoembryonic antigen (CEA) were measured in 37 patients with benign pulmonary disease (BPD), 88 with advanced NSCLC and 37 with SCLC., Results: The ProGRP assay showed a better clinical performance than that of NSE in discriminating between SCLC and BPD or NSCLC, especially at specificity higher than 90%. ProGRP and NSE sensitivity in SCLC at 95% specificity versus the BPD group was 78.4% and 48.6%, (p=0.001) and at 97.7% specificity versus NSCLC, 75.7% and 37.8%, respectively (p=0.001). A significant association of low ProGRP levels with high-grade NSCLC tumors was found (p=0.002). A univariate analysis showed a significant association of ProGRP with survival both in NSCLC and SCLC (p=0.03 and p=0.04, respectively). In multivariate analysis, performance status (PS) and CYFRA 21-1 in NSCLC, and PS, CYFRA 21-1 and serum lactic dehydrogenase in SCLC were found as significant variables with an independent impact on survival., Conclusion: ProGRP is a useful marker in SCLC, with diagnostic performance better than that of NSE and demonstrating association with survival in NSCLC and SCLC limited to univariate analysis.

Aim: This study aimed to evaluate the accuracy of urine cytology, bladder ultrasound (US), urine cytokeratin 19 fragment assay (CYFRA 21-1) and the combination of these noninvasive modalities in the detection of recurrent bladder cancer., Patients and Methods: In a total of 154 patients that were followed with cystoscopy after endoscopic resection of non-muscle-invasive bladder cancer, we performed and analyzed results of 311 observations that included cytology, CYFRA 21-1, US. The urine concentration of CYFRA 21-1 was measured by an immunoradiometric assay., Results: Cystoscopy and biopsy revealed recurrent bladder tumors in 21 patients. Most of the tumors (77%) were less than 10 mm in their largest diameter. Urine cytology, US and urine CYFRA 21-1 resulted in overall sensitivity of 19.1, 52.4 and 71.4% and specificity of 96.6, 99.7 and 68.6%, respectively. Each of these methods used alone yielded false-negative results in patients harboring tumors at high risk of progression. The combination of all three methods had sensitivity and specificity of 90.5 and 67.2%, respectively. All three tests were negative in 197 of 311 observations (63.3%), missing only 2 low-risk tumors., Conclusion: The combined use of US, urinary CYFRA 21-1 and cytology appears to be an effective, noninvasive approach for the detection of recurrent bladder tumors.

Purpose: To develop a method to screen for serum biomarkers of early hepatic metastasis from uveal melanoma., Methods: Cytokeratin 18 (TPS) was identified from gene expression profiles as protein generated by highly invasive uveal melanoma cells. Sera were collected from two groups of 15 SCID mice 2 weeks after injection of either tissue culture medium or MUM2B human metastatic uveal melanoma cells into the mouse liver. Serum TPS levels were assayed in 53 healthy human controls, 64 uveal melanoma patients who were disease free for at least 10 years, and 37 patients with metastatic uveal melanoma., Results: After 2 weeks, small hepatic nodules (0.1-2.8 mm; mean, 0.80 mm) developed in 11 of 15 mice injected with MUM2B cells. Serum TPS levels in media-injected mice (84.7 U/L) were substantially lower than levels in MUM2B-injected mice (601 mug/L). TPS levels were significantly higher (P < 0.0001) in patients with metastatic uveal melanoma (139.63 +/- 22.20) than in healthy controls (54.23 +/- 0.01) or in patients free of disease (69.29 +/- 9.76). Significant differences were found between TPS levels before and after the development of hepatic metastases (P < 0.01), and serum TPS levels became elevated in four patients at least 6 months before the detection of hepatic metastases by abdominal ultrasonography., Conclusions: The direct-injection model of uveal melanoma in the mouse liver may be used to screen for potential serum biomarkers of metastatic uveal melanoma.

Background: Osteopontin (OPN) is overexpressed in metastatic uveal melanoma (UM). S-100beta and melanoma-inhibitory activity (MIA) serum levels are elevated in metastatic cutaneous melanoma. The ability of OPN, S-100beta and MIA serum levels to be used as non-invasive markers for detecting metastatic UM was tested., Patients and Methods: OPN, S-100beta and MIA levels were measured by ELISA assays in 18 patients with metastatic UM and in 38 patients who were disease-free (DF) for at least 10 years after treatment of the primary tumor. Paired serum samples from 8 patients before and after development of metastasis were analyzed. Forty-four healthy controls (C) were compared to the other two groups., Results: Serum OPN, MIA, and S-100beta levels were significantly higher in patients with metastatic UM as compared to patients who were DF for at least 10 years after treatment (p = 0.0001) or with age-matched controls. Serum OPN, MIA and S-100beta levels were significantly higher (p < 0.005) after metastasis formation than before the clinical detection of metastasis in the 8 patients. Receiver operator characteristic analysis was performed for metastatic patients vs. DF and vs. C, and the area under the curve was calculated for each marker and for the combination of the 3 markers, which was 91%., Conclusion: Elevated serum OPN, MIA and S-100beta levels correlate with metastatic UM to the liver. When used in combination, these markers provide a highly sensitive and specific method to detect hepatic metastases and therefore provide for earlier therapeutic intervention that can prolong survival.

Purpose: This was a pilot study conducted to examine the expression of osteopontin in uveal melanoma and to determine whether serum osteopontin can be used in detecting metastatic uveal melanoma., Methods: Osteopontin mRNA was measured in three uveal melanoma cell lines of various invasive potential by real-time PCR. Tissue sections of primary and metastatic uveal melanomas were stained for osteopontin. Serum osteopontin levels were measured by ELISA assays in 15 patients with metastatic uveal melanoma and in 37 patients who were disease-free for at least 10 years after treatment of the primary tumor. Paired serum samples drawn from eight patients before and after development of metastasis were analyzed., Results: By real-time PCR, highly invasive primary and metastatic uveal melanoma cells expressed 6- and 250-fold excess osteopontin mRNA, respectively, compared with poorly invasive primary uveal melanoma cells. Tissue sections of primary uveal melanomas lacking looping vasculogenic mimicry patterns either did not stain for osteopontin or exhibited weak, diffuse staining. In primary melanomas containing looping vasculogenic mimicry patterns, strong osteopontin staining was detected in the tumor periphery where patterns were located. Diffuse strong expression of osteopontin was detected in eight samples of uveal melanomas metastatic to the liver. Serum osteopontin levels were significantly higher in patients with metastatic uveal melanoma than in patients who had been disease free for at least 10 years after treatment (P = 0.0001) or in age-matched control subjects. Serum osteopontin levels were significantly higher (P = 0.008) after metastasis than before the detection of metastasis in eight patients. When a cutoff of 10 ng/mL was used, the sensitivity and specificity of serum osteopontin in detecting metastatic melanoma was 87.5%, and the area under the receiver operator characteristic curve was 96%., Conclusions: Osteopontin is expressed diffusely in tissue sections of hepatic metastases from uveal melanoma, and increased serum osteopontin levels correlate with melanoma metastasis to the liver with high specificity and sensitivity.

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., (Copyright 2005 S. Karger AG, Basel.)

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.

Background: The urinary concentration of soluble cytokeratin 19 fragments, measured by the CYFRA 21-1 assay, may be used for the noninvasive, early detection of bladder carcinoma., Methods: This prospective study examined urine samples from 325 patients. The authors included 152 patients who presented with hematuria or irritative voiding symptoms (Group 1), 107 patients who were under surveillance after undergoing transurethral resection of bladder carcinoma (Group 2), 46 patients with urinary tract pathology other than bladder carcinoma (Group 3), and 20 healthy participants (Group 4). The urine concentration of CYFRA 21-1 was measured by an immunoradiometric assay. The patients in Groups 1 and 2 underwent cytoscopy and urine cytopathology. Biopsies were obtained if a tumor was seen on cytoscopy or if there was a suspicion of carcinoma in situ (CIS)., Results: The optimal cut-off concentration for the detection of primary bladder tumors, 4.9 microg/L, resulted in a sensitivity of 79.3% and a specificity of 88.6%. The optimal threshold for the detection of recurrent bladder tumors (excluding patients who had been treated with intravesical bacillus Calmette-Guerin [BCG]), 4.04 microg/L, resulted in a sensitivity of 76.2% and a specificity of 84.2%. There was no significant advantage for centrifugation of the urine samples or for determination of the creatinine concentration in the urine samples. The CYFRA 21-1 assay of urine samples provided a three-fold greater sensitivity compared with the sensitivity of cytology for detecting Grade 1 transitional cell tumors. CYFRA 21-1 detected 91.9% of Grade 3 tumors, 100% of CIS, and 92.8% of invasive bladder tumors (T2 or higher classification). The CYFRA 21-1 assay detected all tumors that had positive cytology with the exception of only one tumor. Conversely, the assay identified 71% of primary tumors and 65% of recurrent tumors that were missed by cytopathology. Urinary stones, infection, and previous intravesical BCG immunotherapy caused many false positive results., Conclusions: The urinary CYFRA 21-1 assay is a useful test for the noninvasive detection of bladder carcinoma and for surveillance of patients who were not treated previously with BCG. It may be used in combination with urine cytology and bladder ultrasound. Multi-institutional trials are required to compare the accuracy as well as the cost of this combination of tests with cystoscopy., (Copyright 2002 American Cancer Society.)