Identification of the tissue of origin of a tumor is vital to its management. Previous studies showed tissuespecific expression patterns of microRNA and suggested that microRNA profiling would be useful in addressing this diagnostic challenge. MicroRNAs are well preserved in formalin-fixed, paraffin-embedded (FFPE) samples, further supporting this approach. To develop a standardized assay for identification of the tissue origin of FFPE tumor samples, we used microarray data from 504 tumor samples to select a shortlist of 104 microRNA biomarker candidates. These 104 microRNAs were profiled by proprietary quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) on 356 FFPE tumor samples. A total of 48 microRNAs were chosen from this list of candidates and used to train a classifier. We developed a clinical test for the identification of the tumor tissue of origin based on a standardized protocol and defined the classification criteria. The test measures expression levels of 48 microRNAs by qRT-PCR, and predicts the tissue of origin among 25 possible classes, corresponding to 17 distinct tissues and organs. The biologically motivated classifier combines the predictions generated by a binary decision tree and K-nearest neighbors (KNN). The classifier was validated on an independent, blinded set of 204 FFPE tumor samples, including nearly 100 metastatic tumor samples. The test predictions correctly identified the reference diagnosis in 85% of the cases. In 66% of the cases the two algorithm predictions (tree and KNN) agreed on a single-tissue origin, which was identical to the reference diagnosis in 90% of cases. Thus, a qRT-PCR test based on the expression profile of 48 tissue-specific microRNAs allows accurate identification of the tumor tissue of origin.

In the diagnosis of multiple myeloma (MM), the radiological skeletal survey (RSS) was proven to be most useful for the detection of bone lesions. Since 1961, a new technique radioisotopic bone scan (RIBS), for the detection of such lesions, using ⁸⁵Sr and ^99mTc, has been shown to be highly sensitive for the detection of skeletal metastases of epithelial tumors. We have studied 30 patients with plasma cell dyscrasia (PCD) by both methods and concluded that RSS is clearly superior to RIBS in PCD. As RIBS detected less than 50% of the lesions demonstrated by RSS there seems to be no indication for a routine RIBS in the initial work-up of patients suspected to have PCD. However, due to the fact that RIBS is useful for the detection of new bone formation it has a certain value in the localization of pathological fractures in MM, mainly in vertebral compression.

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