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It was with some confusion that, I read the recent article by Ried et al., (2017). The authors appear to be claiming that their methodology for detecting circulating tumour cells (CTC) is sensitive and also that the levels of CTC are highly predictive of risk of malignancy across a range of cancer diagnoses. The entire methodology for this study is problematic. The diagnosis (diagnostic criteria) of cancer is poorly explained. It appears that cancer diagnosis for prostate cancer in men with extremely high PSA (330 – 1970 ng/ml, normal range <6.5 ng/ml) based on Ga68-PMSA-PET alone (patients M9, M12, M13 and others) without conformational biopsy and histological results. As this study was undertaken as a clinical trial it could be reasonably expected that claims of CTC being able to detect cancer would be based on a thorough, best practice based diagnostic process rather than a single imaging test which is known to give false positive results for benign foci (Keidar et al., 2018). There is no description of blinding in this study. Cytology is not a quantitative process and as such is open to bias on behalf of the scientist (Branca and Longatto-Filho, 2015). It is also noted that no pathologists were involved in this study which relies heavily on cytology and cytopathology criteria of cancers. The assay used does not appear to have been verified or used with any independent controls, there is no description of how the raw data was analysed, nor is there any statistical analysis. There is no evidence on the specificity of this assay which is critical in light of the authors’ claim of 100% sensitive for cancer. Specificity for cancer detection is critical as a false diagnosis of cancer could cause physical, financial, and/or emotional harm (Hubbard et al., 2011). Additionally a false cancer diagnosis can actually be associated with increased risk of developing cancer (Henderson et al., 2015). To further explore the authors’ claim of 100% sensitivity it appears, from Table 1, that there was also a 100% concordance with cancer staging based on the CTC/ml values which is discordant with other studies (Krebs et al., 2011). Even within this manuscript there are examples of this type of discordance, with patient F1 having liver metastasis (which would classify this as Stage IV according to the authors) detected when her CTC count was only 3.5 per ml ( a low Stage II/III according to Table 1). LETTER to the EDITOR

Extraordinary Claims Don’t always Require Extraordinary Evidence, but They Do Require Good Quality Evidence