Metastases are the major cause of cancer-related deaths in patients with solid epithelial malignancies, such as breast, colorectal and prostate carcinomas. Hematogenous spreading of tumor cells from a primary tumor can be considered as a crucial step in the metastasis cascade leading eventually to the formation of clinically manifest metastases. Consequently, as shown in recent studies, the detection of disseminated tumor cells in peripheral blood might be of clinical relevance with respect to individual patient prognosis and staging or monitoring of therapy. However, the rarity of disseminated tumor cells in peripheral blood renders the application of sensitive techniques mandatory for their detection. The emergence of highly sophisticated reverse transciptase-polymerase chain reaction (RT-PCR) assays, combining a preanalytical enrichment step with the assessment of multiple molecular tumor markers expressed in disseminated tumor cells, provides a powerful tool in detecting disseminated tumor cells with high sensitivity and specificity. This review will discuss currently used tumor markers as well as experimental means to enhance the sensitivity and specificity of RT-PCR assays to detect disseminated tumor cells in the peripheral blood of patients with breast, colorectal, and prostate cancers, and their clinical relevance assessed in recent studies.

Background: Microalbuminuria is an early sign of kidney disease in diabetes and indicates cardiovascular risk. We tested if a prespecified urinary proteomic risk classifier (CKD273) was associated with development of microalbuminuria and if progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone. Methods: Prospective multicentre study in people with type 2 diabetes, normal urinary albumin excretion and preserved renal function in 15 European specialist centres. High-risk individuals determined by CKD273 were randomised 1:1 (interactive web response system) in a double-blind randomised controlled trial comparing spironolactone 25 mg o.d. to placebo. Primary endpoint was development of confirmed microalbuminuria in all individuals with available data. Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone and association between CKD273 and impaired renal function defined as a glomerular filtration rate < 60 ml/min per 1•73 m 2. This study is registered with ClinicalTrials.gov: NCT02040441 and is completed. Findings: From March 25, 2014 to September 30, 2018 we followed 1775 participants, 12% (n=216) had high-risk urinary proteomic pattern of which 209 were included in the trial and assigned spironolactone (n=102) or placebo (n=107). Median follow-up time was 2•51 years (IQR 2•0-3•0). Progression to microalbuminuria was seen in 28•2% of high-risk and 8•9% of low-risk people (P< 0•001) (hazard ratio (HR), 2•48; 95% confidence interval [CI], 1•80 to 3•42 P<0•001, independent of baseline clinical characteristics). A 30% decline in eGFR from baseline was seen in 42 (19•4 %) high-risk participants compared to 62 (3•9 %) low-risk participants, HR 5•15; 95 % CI (3•41 to 7•76; p<0.0001). Development of microalbuminuria was seen in 35 (33%) randomised to placebo and 26 (25%) randomised to spironolactone treatment (HR 0•81, 95% CI, 0•49 to 1•34, P=0•41). Harms: hyperkalaemia was seen in 13 versus 4, and gynaecomastia in 3 versus 0 subjects on spironolactone and placebo, respectively. Interpretation: In people with type 2 diabetes and normoalbuminuria, the urinary proteomic classifier CKD273 was associated with a 2•5 times increased risk for progression to microalbuminuria over a median of 2•5 years, independent of clinical characteristics. Spironolactone did not prevent progression to microalbuminuria in high-risk subjects.

BackgroundAfter total knee replacement, overall blood loss is often underestimated, although it exceeds the visible blood loss caused by bleeding into the tissues or into the joint. The use of fibrin sealants during surgery has been suggested to reduce perioperative blood loss and transfusion rates and may be beneficial for patient recovery and the postoperative function of the joint.Methods/DesignThis will be a single-centre, single-blinded, randomised controlled trial with a parallel design, for which 68 patients undergoing total knee replacement will be recruited and followed up at 3, 6 and 12 months; 34 will be control patients who will receive the standard orthopaedic surgery treatment (electrocoagulation), and the other 34 will receive the same treatment plus 5 ml EVICEL™ applied during surgery and used according to the manufacturer’s instructions. The primary objective is to test the null hypothesis that the effect of EVICEL™ for controlling haemostasis and reducing postoperative blood loss in patients undergoing total knee replacement is not superior to the use of electrocoagulation alone. The secondary objective is to show that EVICEL™ reduces the need for transfusion, increases range of motion, improves clinical outcome and wound healing, and reduces the need for analgesics. The tertiary objective is to show that EVICEL™ reduces the costs of total knee replacement treatment.DiscussionSo far, studies on the effect of fibrin sealants in total knee replacement have delivered inconsistent and ambivalent results, indicating that there is still a need for high-evidence studies as proposed in the presented study protocol.Trial registrationGerman registration number DRKS00007564; date of registration: 26 November 2014.

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