Metastasis-related events are the primary cause of cancer-related deaths, and circulating tumor cells (CTCs) have a pivotal role in metastatic relapse. CTCs include a variety of subtypes with different functional characteristics. Interestingly, the epithelial–mesenchymal transition (EMT) markers expressed in CTCs are strongly associated with poor clinical outcome and related to the acquisition of circulating tumor stem cell (CTSC) features. Recent studies have revealed the existence of CTC clusters, also called circulating tumor microemboli (CTM), which have a high metastatic potential. In this review, we present current opinions regarding the clinical significance of CTCs and CTM with a mesenchymal phenotype as clinical surrogate markers, and we summarize the therapeutic strategy according to phenotype characterization of CTCs in various types of cancers for future precision medicine.

Computed tomography-guided needle biopsy (CT-GNB) has a high diagnostic yield for lung cancer but higher complication rates compared to those of other biopsy modalities. We sought to clarify in which thoracic lesions we could achieve a quick pathological diagnosis using CT-GNB, considering the risks and benefits. We retrospectively enrolled 110 patients who underwent CT-GNB and 547 patients who underwent transbronchial biopsy (TBB) for parenchymal lung lesions in clinical practice. The diagnostic rates of CT-GNB and TBB were 87.3% and 75.3%. After failed diagnosis with other biopsy modalities, 92.3% of patients were finally diagnosed using CT-GNB and 65.8% using TBB. In cases with a negative bronchial sign, there was a statistically higher diagnostic rate with CT-GNB than with TBB (p < 0.001: 89.4% vs. 0%). Complication rates were higher with CT-GNB (50.9%) than with TBB (16.3%). However, there were lower rates of complications in cases with inhomogeneous tumors, subpleural lesions, and when more than 15 mm of the punctured needle length was within the target. We conclude that CT-GNB is an effective biopsy modality with a high diagnostic rate that is especially recommended when the bronchus sign is negative. It can be safely performed if risk factors for complications are taken into account.

Cancer cachexia is associated with poor immunotherapeutic outcomes. This prospective observational study longitudinally evaluated the role of cachexia-related circulating cytokines in predicting the risk and benefit of PD-1/PD-L1 blockade in advanced lung cancer. Forty-one circulating cytokines at baseline and after one cycle of PD-1/PD-L1 blockade treatment were measured in patients with advanced lung cancer between 2019 and 2020. The cachexia-related cytokines were identified by comparing the levels of circulating cytokines between cachectic and non-cachectic patients. Among 55 patients, 49.1% were diagnosed with cachexia at the beginning of PD-1/PD-L1 blockade therapy. Baseline levels of the circulating cytokines IL-6, IL-8, IL-10, IL-15, and IP-10 were significantly higher in cachectic patients. In contrast, the level of eotaxin-1 was lower in cachectic patients than in those without cachexia. Higher IL-6 at baseline and during treatment was associated with a greater risk of immune-related adverse events, while higher IL-10 at baseline was linked to worse overall survival. More importantly, increased eotaxin-1 after one cycle of PD-1/PD-L1 blockade treatment was associated with higher objective response and better overall survival. A blood-based, cachexia-related cytokine assay may yield potential biomarkers for the early prediction of clinical response to PD-1/PD-L1 blockade and provide clues for improving the outcomes of cachectic patients.

Noninvasive liquid biopsy for monitoring circulating tumor cells offers valuable insights for predicting therapeutic responses. We developed TelomeScan^® (OBP-401), based on the detection of telomerase activity as a universal cancer cell marker and an indicator of the presence of viable circulating tumor cells (CTCs) for patients with advanced non-small cell lung cancer (NSCLC). This system evaluated CTC subtypes characterized by programmed death ligand 1 (PD-L1), an immune checkpoint molecule, and vimentin, an epithelial–mesenchymal transition (EMT) marker, using a multi-fluorescent color microscope reader. The prognostic value and therapeutic responses were predicted by dynamically monitoring CTC counts in 79 patients with advanced NSCLC. The sensitivity and specificity values of TelomeScan^® for PD-L1⁽⁺⁾ cells (≥1 cell) were 75% and 100%, respectively, indicating high diagnostic accuracy. PD-L1⁽⁺⁾ and EMT⁽⁺⁾ in CTCs were detected in 75% and 12% of patients, respectively. Detection of PD-L1⁽⁺⁾CTCs and PD-L1⁽⁺⁾EMT⁽⁺⁾ CTCs before treatment was associated with poor prognosis (p < 0.05). Monitoring of reducing and increasing PD-L1⁽⁺⁾ CTC counts in two sequential samples (baseline, cycle 2 treatment) correlated significantly with partial response (p = 0.032) and progressive disease (p = 0.023), respectively. Monitoring PD-L1⁽⁺⁾CTCs by TelomeScan^® will aid in anticipating responses or resistance to frontline treatments, optimizing precision medicine choices in patients with NSCLC.