Establishment and Characterization of an Empirical Biomarker SS/PV-ROC Plot Using Results of the UBC® Rapid Test in Bladder Cancer.

BACKGROUND: This investigation included both a study of potential non-invasive diagnostic approaches for the bladder cancer biomarker UBC® Rapid Test and a study including comparative methods about sensitivity-specificity characteristic (SS-ROC) and predictive receiver operating characteristic (PV-ROC) curves that used bladder cancer as a useful example. METHODS: The study included 289 urine samples from patients with tumors of the urinary bladder, patients with non-evidence of disease (NED) and healthy controls. The UBC® Rapid Test is a qualitative point of care assay. Using a photometric reader, quantitative data can also be obtained. Data for pairs of sensitivity/specificity as well as positive/negative predictive values were created by variation of threshold values for the whole patient cohort, as well as for the tumor-free control group. Based on these data, sensitivity-specificity and predictive value threshold distribution curves were constructed and transformed into SS-ROC and PV-ROC curves, which were included in a single SS/PV-ROC plot. RESULTS: The curves revealed TPP-asymmetric improper curves which cross the diagonal from above. Evaluation of the PV-ROC curve showed that two or more distinct positive predictive values (PPV) can correspond to the same value of a negative predictive value (NPV) and vice versa, indicating a complexity in PV-ROC curves which did not exist in SS-ROC curves. In contrast to the SS-ROC curve, the PV-ROC curve had neither an area under the curve (AUC) nor a range from 0% to 100%. Sensitivity of the qualitative assay was 58.5% and specificity 88.2%, PPV was 75.6% and NPV 77.3%, at a threshold value of approximately 12.5 µg/L. CONCLUSIONS: The SS/PV-ROC plot is a new diagnostic approach which can be used for direct judgement of gain and loss of predictive values, sensitivity and specificity according to varied threshold value changes, enabling characterization, comparison and evaluation of qualitative and quantitative bioassays.

Novel Tools for Single Comparative and Unified Evaluation of Qualitative and Quantitative Bioassays: SS/PV-ROC and SS-J/PV-PSI Index-ROC Curves with Integrated Concentration Distributions, and SS-J/PV-PSI Index Cut-Off Diagrams.

Background: This investigation is both a study of potential non-invasive diagnostic approaches for the bladder cancer biomarker UBC® Rapid test and a study including novel comparative methods for bioassay evaluation and comparison that uses bladder cancer as a useful example. The objective of the paper is not to investigate specific data. It is used only for demonstration, partially to compare ROC methodologies and also to show how both sensitivity/specificity and predictive values can be used in clinical diagnostics and decision making. This study includes ROC curves with integrated cut-off distribution curves for a comparison of sensitivity/specificity (SS) and positive/negative predictive values (PPV/NPV or PV), as well as SS-J index/PV-PSI index-ROC curves and SS-J/PV-PSI index cut-off diagrams (J = Youden, PSI = Predictive Summary Index) for the unified direct comparison of SS-J/PV results achieved via quantitative and/or qualitative bioassays and an identification of optimal separate or unified index cut-off points. Patients and Methods: According to the routine diagnostics, there were 91 patients with confirmed bladder cancer and 1152 patients with no evidence of bladder cancer, leading to a prevalence value of 0.073. This study performed a quantitative investigation of used-up test cassettes from the visual UBC® Rapid qualitative point-of-care assay, which had already been applied in routine diagnostics. Using a photometric reader, quantitative data could also be obtained from the test line of the used cassettes. Interrelations between SS and PV values were evaluated using cumulative distribution analysis (CAD), SS/PV-ROC curves, SS-J/PV-PSI index-ROC curves, and the SS-J/PV-PSI index cut-off diagram. The maximum unified SS-J/PV-PSI index value and its corresponding cut-off value were determined and calculated with the SS-J/PV-PSI index cut-off diagram. Results: The use of SS/PV-ROC curves with integrated cut-off concentration distribution curves provides improved diagnostic information compared to "traditional" ROC curves. The threshold distributions integrated as curves into SS/PV-ROC curves and SS-J/PV-PSI index-ROC curves run in opposite directions. In contrast to the SS-ROC curves, the PV-ROC and the novel PV-PSI index-ROC curves had neither an area under the curve (AUC) nor a range from 0% to 100%. The cut-off level of the qualitative assay was 7.5 µg/L, with a sensitivity of 65.9% and a specificity of 63.3%, and the PPV was 12.4% and the NPV was 95.9%, at a threshold value of 12.5 µg/L. Based on these set concentrations, the reader-based evaluation revealed a graphically estimated 5% increase in sensitivity and a 13% increase in specificity, as compared to the visual qualitative POC test. In the case of predictive values, there was a gain of 8% for PPV and 10% for NPV. The index values and cut-offs were as follows: visual SS-J index, 0.328 and 35 µg/L; visual PV-PSI index, 0.083 and 5.4 µg/L; maximal reader Youden index, 0.0558 and 250 µg/L; and maximal PV-PSI index, 0.459 and 250 µg/L, respectively. The maximum unified SS-J/PV-PSI index value was 0.32, and the cut-off was 43 µg/L. The reciprocal SS-J index correctly detected one out of three patients, while the reciprocal PV-PSI index gave one out of twelve patients a correct diagnosis. Conclusions: ROC curves including cut-off distribution curves supplement the information lost in "traditionally plotted" ROC curves. The novel sets of ROC and index-ROC curves and the new SS/PV index cut-off diagrams enable the simultaneous comparison of sensitivity/specificity and predictive value profiles of diagnostic tools and the identification of optimal cut-off values at maximal index values, even in a unifying SS/PV approach. Because the curves within an SS-J/PV-PSI index cut-off diagram are distributed over the complete cut-off range of a quantitative assay, this field is open for special clinical considerations, with the need to vary the mentioned clinical diagnostic parameters. Complete or partial areas over the x-axis (AOX) can be calculated for summarized quantitative or qualitative effectivity evaluations with respect to single and/or unified SS-J and PV-PSI indices and with respect to single, several, or several unified assays. The SS-J/PV-PSI index-AOX approach is a new tool providing additional joint clinical information, and the reciprocal SS-J indices can predict the number of patients with a correct diagnosis and the number of persons who need to be examined in order to correctly predict a diagnosis of the disease. These methods could be used in applications like medical or plant epidemiology, machine learning algorithms, and neural networks.

Positron emission tomography/computed tomography and radioimmunotherapy of prostate cancer.

PURPOSE OF REVIEW: Traditional morphologically based imaging modalities are now being complemented by positron emission tomography (PET)/computed tomography (CT) in prostate cancer. Metastatic prostate cancer is an attractive target for radioimmunotherapy (RIT) as no effective therapies are available. This review highlights the most important achievements within the last year in PET/CT and RIT of prostate cancer. RECENT FINDINGS: Conflicting results exist on the use of choline for detection of malignant disease in the prostate gland. The role of PET/CT in N-staging remains to be elucidated further. However, F-choline and C-choline PET/CT have been demonstrated to be useful for detection of recurrence. F-choline and F-fluoride PET/CT are useful for detection of bone metastases. Prostate tumor antigens may be used as targets for RIT. Prostate-specific membrane antigen is currently under focus of a number of diagnostic and therapeutic strategies. J591, a monoclonal antibody, which targets the extracellular domain of prostate-specific membrane antigen, shows promising results. HER2 receptors may also have a potential as target for PET/CT imaging and RIT of advanced prostate cancer. SUMMARY: PET/CT in prostate cancer has proven to play a significant role, in particular for detection of prostate cancer recurrence and bone metastases. RIT of metastatic prostate cancer warrants further investigations.

Recent developments in urologic oncology: positron emission tomography molecular imaging.

PURPOSE OF REVIEW: Traditional morphologically based imaging modalities in uro-oncology are now being complemented by the functional and molecular imaging technique positron emission tomography (PET). This review highlights the most important recent developments. RECENT FINDINGS: Prostate cancer: PET imaging with the new radiotracers 11C-choline, 18F-fluorocholine, and 11C-acetate show promising results. The role of anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid remains to be elucidated further. 18F-fluoride PET is useful for the detection of bone metastases. Bladder cancer: 18F-fluorodeoxyglucose (FDG) PET/CT with delayed images after a diuretic and oral hydration may improve detection of locally recurrent or residual bladder tumours. Both 18F-FDG PET and 11C-choline PET may be useful for staging of bladder cancer. Renal cancer: 18F-FDG PET has a role in staging and restaging of the disease. Recently, 124I-cG250 PET has shown promising results in the detection of clear-cell renal carcinoma. Testicular cancer: 18F-FDG PET is useful in staging and follow-up after treatment. There are no important recent developments with new radiopharmaceuticals in testicular cancer. SUMMARY: The utility of PET molecular imaging in uro-oncology expanded due to the new metabolic PET tracers with more favourable properties.

Positron emission tomography and positron emission tomography/computerized tomography of urological malignancies: an update review.

PURPOSE: Appropriate imaging in uro-oncology is a crucial component at primary diagnosis, followup and recurrence to achieve an accurate assessment of the disease and determine the most effective treatment. We summarize recent developments in positron emission tomography and positron emission tomography/computerized tomography for prostate, bladder and renal cancer. MATERIALS AND METHODS: The recent published literature on positron emission tomography and positron emission tomography/computerized tomography in uro-oncology was searched and reviewed. RESULTS: For prostate cancer 18F-fluorodeoxyglucose is not highly effective for primary diagnosis but it has a limited role in staging and recurrence detection. Promising results have been shown by 11C-choline, 18F-fluorocholine, 11C-acetate and 18F-fluoride. The role of 11C-methionine, 18F-fluoro-5-alpha-dihydrotestosterone and anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid remains to be elucidated. For bladder cancer 18F-fluorodeoxyglucose positron emission tomography is useful for identifying distant metastases but not for detecting primary tumors due to the urinary excretion of 18F-fluorodeoxyglucose. The role of 11C-choline and 11C-methionine remains to be evaluated further in clinical studies. For renal cancer 18F-fluorodeoxyglucose is of limited use for primary diagnosis but it has a role in staging and restaging of the disease. More clinical data are needed to investigate the roles of 18F-fluoromisonidazole and 18F-fluorothymidine. CONCLUSIONS: Several advances in positron emission tomography and positron emission tomography/computerized tomography for urological cancer have been made in recent years. However, larger clinical trials are needed to establish the role of this imaging method for urological malignancy. In the near future the new radiotracers and further advancement in this imaging technique are expected to improve the performance of positron emission tomography/computerized tomography in uro-oncology.

Usefulness of combined FDG-PET with CT or tumour markers in lung cancer diagnosis.

BACKGROUND: The synergy between in vitro and in vivo imaging was investigated in this study. PATIENTS AND METHODS: Comparison of fluorodeoxyglucose positron-emission tomography (FDG-PET) and computerised tomography (CT) included 62 patients (group 1), while that for comparison of FDG-PET and serum tumour markers included 26 patients (group 2). RESULTS: In group 1, FDG-PET had positive and negative predictive values of 81% and 80% respectively, compared to 73.7% and 71.4% for CT, respectively. Combined imaging showed 100% sensitivity and 100% specificity. In group 2, FDG-PET and CEA were both positive in 42.9%, and only CEA was falsely negative in all other cases. FDG-PET and TPA were both positive in 47.6%, and in 52.4% only FDG-PET was positive. NSE and SCC had 100% specificity; their sensitivity was 38% and 25%, respectively. CONCLUSION: FDG-PET diagnosis was improved by CT. Because the serum tumour markers were falsely negative in more than 50% and there were no falsely negative results for FDG-PET, combined imaging may allow reduction of cut-off values for conventional serum tumour markers.

Imaging of prostate cancer.

PURPOSE OF REVIEW: Appropriate imaging of prostate cancer is a crucial component of staging and therapy application. The purpose of this review is to highlight the most important developments in novel imaging modalities reported in the past year. RECENT FINDINGS: Transrectal ultrasound is used to guide needle biopsy and brachytherapy. Improved results are obtained with color and power Doppler transrectal ultrasound with sonographic contrast agents. The role of elastography in prostate cancer remains to be elucidated. Magnetic resonance imaging is now widely used for staging before treatment and accumulating data indicate the utility of this technique with magnetic resonance spectroscopy in staging and follow-up. Positron-emission tomography alone or especially in combination with computed tomography imaging with the new radiotracers (11)C-choline, (18)F-fluorocholine, (11)C-acetate and (18)F-fluoride have shown promising results. Further investigations in larger clinical studies are necessary to establish the role of these imaging techniques in the management of patients with prostate cancer. SUMMARY: This report provides a summary of novel types of imaging and indicates their promise in prostate cancer.

'Omics'-based imaging in cancer detection and therapy.

Genomics, proteomics and metabolomics, which can be also summarized as 'omics', have become increasingly inter-related with imaging. Gene expression profiling may be assessed using high-density microarrays for the detection of overexpression patterns, followed by the development of histochemical assays. Next, antibodies to the gene-corresponding proteins (for example, receptors) can be produced, leading to serum immunoassays for follow-up, as well as antibody-guided in vivo imaging or therapy. In vivo imaging for cancer detection and/or therapy can be performed by applying nonlabeled antibodies, by using radiolabeled antibodies for detection using single-photon tomography or positron emission tomography (PET), or by other tracers, for example, for magnetic resonance imaging tomography (MRI, MRT). Protein profiles from protein chips can be derived from mass maps obtained through mass spectrometry (MS). Electrophoretic separation of proteins has also been combined with MS to produce a two-dimensional assignment of proteins within a complex mixture. Overexpression of tumor-related proteins can be used for the development of antibodies to develop noninvasive assays that can be used in the screening of risk groups as a basis for further investigation by invasive imaging methods. Metabolomic profiling by nuclear magnetic resonance spectroscopy can be applied for the detection of biomarkers of the metabolome. Metabolite profiles in cells, tissues, and organisms can be generated with nuclear magnetic resonance spectroscopy and MS. Metabolic information provided by magnetic resonance spectroscopic imaging (MRSI) combined with the anatomical information provided by MRI can significantly improve the assessment of cancer location and extent, and cancer aggressiveness. Biomarkers found by MRSI can lead to new PET tracers. This article provides examples and discusses some of the recent achievements to bring forward novel strategies for the diagnosis and therapy of cancer.