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Martin Lund,1 Torben B Pedersen,1 Søren Feddersen,2,3 Louise D Østergaard,1,3 Charlotte A Poulsen,1 Christian Enggaard,2 Mads HA Poulsen,1,3 Lars Lund1,3 1Department of Urology, Odense University Hospital, Odense, Denmark; 2Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark; 3Department of Clinical Research, University of Southern Denmark, Odense, DenmarkCorrespondence: Lars Lund, Department of Urology, Odense University Hospital, Sdr. Boulevard 29, Odense, 5000, Denmark, Tel +45 5140 8982, Fax +45 6541 1726, Email Lars.Lund@rsyd.dkPurpose: Serum levels of the polypeptide chemokine C-C motif ligand 2 (CCL2) have previously shown potential as a prostate cancer diagnostic and prognostic biomarker. Plasma CCL2 levels may be superior to serum levels as a biomarker because of their potentially lower signal-to-noise ratio.Materials and Methods: Before initiating a large comparative study of plasma and serum CCL2 levels, we performed a prospective, diagnostic pilot study Of 133 individuals from a clinically relevant population. CCL2 plasma levels were measured using a validated assay kit. Plasma was obtained independently of digital rectal examination.Results: In this pilot study, we found no relationship between CCL2 plasma values and risk of proven prostate cancer, whereas previous studies found a strong diagnostic relationship between CCL2 serum values and prostate cancer.Conclusion: Our contribution to the existing literature strengthens the idea that early in the pathological process, CCL2 mainly circulates in large, membrane-enclosed compartments, whereas plasma CCL2 levels increase markedly during disease progression. We conclude that whereas plasma CCL2 levels are not useful as a diagnostic measure, a ratio of CCL2 plasma to serum levels may prove useful as a marker of disease progression, which warrants further study.Keywords: diagnostics, liquid biopsy, CCL2, monocyte chemoattractant protein 1, MCP1

Diagnostic studies of accuracy targeting sensitivity and specificity are commonly done in a paired design in which all modalities are applied in each patient, whereas cost-effectiveness and cost-utility analyses are usually assessed either directly alongside to or indirectly by means of stochastic modeling based on larger randomized controlled trials (RCTs). However the conduct of RCTs is hampered in an environment such as ours, in which technology is rapidly evolving. As such, there is a relatively limited number of RCTs. Therefore, we investigated as to which extent paired diagnostic studies of accuracy can be also used to shed light on economic implications when considering a new diagnostic test. We propose a simple decision tree model-based cost-utility analysis of a diagnostic test when compared to the current standard procedure and exemplify this approach with published data from lymph node staging of prostate cancer. Average procedure costs were taken from the Danish Diagnosis Related Groups Tariff in 2013 and life expectancy was estimated for an ideal 60 year old patient based on prostate cancer stage and prostatectomy or radiation and chemotherapy. Quality-adjusted life-years (QALYs) were deduced from the literature, and an incremental cost-effectiveness ratio (ICER) was used to compare lymph node dissection with respective histopathological examination (reference standard) and (18)F-fluoromethylcholine positron emission tomography/computed tomography (FCH-PET/CT). Lower bounds of sensitivity and specificity of FCH-PET/CT were established at which the replacement of the reference standard by FCH-PET/CT comes with a trade-off between worse effectiveness and lower costs. Compared to the reference standard in a diagnostic accuracy study, any imperfections in accuracy of a diagnostic test imply that replacing the reference standard generates a loss in effectiveness and utility. We conclude that diagnostic studies of accuracy can be put to a more extensive use, over and above a mere indication of sensitivity and specificity of an imaging test, and that health economic considerations should be undertaken when planning a prospective diagnostic accuracy study. These endeavors will prove especially fruitful when comparing several imaging techniques with one another, or the same imaging technique using different tracers, with an independent reference standard for the evaluation of results.

To compare the diagnostic accuracy of the following imaging techniques in the detection of spine metastases, using magnetic resonance imaging (MRI) as a reference: whole-body bone scintigraphy (WBS) with technetium-99m-MDP, [18F]-sodium fluoride (NaF) positron emission tomography (PET)/computed tomography (CT) and [(18) F]-fluoromethylcholine (FCH) PET/CT.The study entry criteria were biopsy-proven prostate cancer, a positive WBS consistent with bone metastases, and no history of androgen deprivation. Within 30 days of informed consent, trial scans were performed in random order. Scans were interpreted blindly for the purpose of a lesion-based analysis. The primary target variable was bone lesion (malignant/benign) and the 'gold standard' was MRI.A total of 50 men were recruited between May 2009 and March 2012. Their mean age was 73 years, their median PSA level was 84 ng/mL, and the mean Gleason score of the tumours was 7.7. A total of 46 patients underwent all four scans, while four missed one PET/CT scan. A total of 526 bone lesions were found in the 50 men: 363 malignant and 163 non-malignant according to MRI. Sensitivity, specificity, positive and negative predictive values and accuracy were: WBS: 51, 82, 86, 43 and 61%; NaF-PET/CT: 93, 54, 82, 78 and 81%; and FCH-PET/CT: 85, 91, 95, 75 and 87%, respectively.We found that FCH-PET/CT and NaF-PET/CT were superior to WBS with regard to detection of prostate cancer bone metastases within the spine. The present results call into question the use of WBS as the method of choice in patients with hormone-naïve prostate cancer.

Study Type--Diagnostic (exploratory cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Staging of patients with prostate cancer is the cornerstone of treatment. However, after curative intended therapy a high portion of patients relapse with local and/or distant recurrence. Therefore, one may question whether surgical lymph node dissection (LND) is sufficiently reliable for staging of these patients. Several imaging methods for primary LN staging of patients with prostate cancer have been tested. Acceptable detection rates have not been achieved by CT or MRI or for that matter with PET/CT using the most common tracer fluoromethylcholine (FCH). Other more recent metabolic tracers like acetate and choline seem to be more sensitive for assessment of LNs in both primary staging and re-staging. However, previous studies were small. Therefore, we assessed the value of [(18) F]FCH PET/CT for primary LN staging in a prospective study of a larger sample and with a 'blinded' review. After a study period of 3 years and200 included patients, we concluded that [(18) F]FCH PET/CT did not reach an optimal detection rate compared with LND, and, therefore, it cannot replace this procedure. However, we did detect several bone metastases with [(18) F]FCH PET/CT that the normal bone scans had missed, and this might be worth pursuing.• To assess the value of [(18) F]fluoromethylcholine (FCH) positron emission tomography/computed tomography (PET/CT) for lymph node (LN) staging of prostate cancer. • To evaluate if FCH PET/CT can replace LN dissection (LND) for LN staging of prostate cancer, as about one-third of patients with prostate cancer who receive intended curative therapy will have recurrence, one reason being undetected LN involvement.• From January 2008 to December 2010, 210 intermediate- or high-risk patients had a FCH PET/CT scan before regional LND. • After dissection, the result of histological examination of the LNs (gold standard) was compared with the result of FCH PET/CT obtained by 'blinded review'. • Sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of FCH PET/CT were measured for detection of LNe metastases.• Of the 210 patients, 76 (36.2%) were in the intermediate-risk group and 134 (63.8%) were in the high-risk group. A medium (range) of 5 (1-28) LNs were removed per patient. • Histological examination of removed LNs showed metastases in 41 patients. Sensitivity, specificity, PPV, and NPV of FCH PET/CT for patient-based LN staging were 73.2%, 87.6%, 58.8% and 93.1%, respectively. • Corresponding values for LN-based analyses were 56.2%, 94.0%, 40.2%, and 96.8%, respectively. • The mean diameter of the true positive LN metastases was significantly larger than that of the false negative LNs (10.3 vs 4.6 mm; P0.001). • In addition, FCH PET/CT detected a high focal bone uptake, consistent with bone metastases, in 18 patients, 12 of which had histologically benign LNs.• Due to a relatively low sensitivity and a correspondingly rather low PPV, FCH PET/CT is not ideal for primary LN staging in patients with prostate cancer. • However, FCH PET/CT does convey important additional information otherwise not recognised, especially for bone metastases.

To evaluate prospectively [(18)F]-fluorocholine positron-emission/computed tomography (FCH PET/CT) for lymph node staging of prostate cancer before intended curative therapy, and to determine whether imaging 15 or 60 min after radiotracer injection is preferable.In all, 25 consecutive patients with newly diagnosed prostate cancer (Gleason score6, and/or a prostate-specific antigen level of10 ng/mL, and/or T3 cancer) were scanned before lymphadenectomy. Each patient was assessed twice with imaging, at 15 and 60 min after the injection with FCH. Images were compared with the results of histopathological examination of the surgically removed lymph nodes. Maximum standardized uptake values (SUV(max) ) at 15 and 60 min were also compared.Histopathologically, metastases were present in removed lymph nodes from three patients. FCH PET/CT showed a high radiotracer uptake in four patients, the former three and a fourth. The sensitivity, specificity, positive and negative predictive value of FCH PET/CT for patient based lymph node staging of prostate cancer were 100%, 95%, 75% and 100%, respectively; the corresponding 95% confidence intervals were 29.2-100%, 77.2-99.9%, 19.4-99.4% and 83.9-100%, respectively. Values of SUV(max) at early and late imaging were not significantly different.This small series supports the use of FCH PET/CT as a tool for lymph node staging of patients with prostate cancer. Values of SUV(max) at early and late imaging did not differ. However, larger prospective studies are needed to validate these findings.