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  • br In the present study we observed that


    In the present study, we observed that Moniliformin the cfDNA levels were cor-related with metabolic tumor burden as assessed by MTV and TLG in NSCLC patients. In other words, patients with a higher metabolic tumor burden were likely to have higher cfDNA concentration. To date, only two studies have evaluated the relationship between cfDNA levels and metabolic tumor burden in NSCLC. Nygaard et al. demonstrated the relationship between cfDNA levels and MTV or TLG in 53 stage III-IV NSCLC patients [16]. They reported that the level of cfDNA did not correlate with MTV and TLG levels. Morbelli et al. also reported similar results in 37 stage III-IV NSCLC patients [17]. Quantitative analysis was used in a recent study to show that increased cfDNA correlated with the number of metastatic sites and lesions, and the sum of measurable le-sion diameters in 64 NSCLC patients with EGFR mutations [28]. Al-though both MTV and TLG are concordant with cfDNA levels, their clinical implications on NSCLC prognosis are quite different.
    Table 2
    Univariate and multivariate analysis of hazard ratios for OS in NSCLC patients.
    Univariate analysis
    Multivariate analysis without MTV or Multivariate analysis including
    Multivariate analysis including
    OS, overall survival; NSCLC, non-small cell lung cancer; MTV, metabolic tumor volume; TLG, total lesion glycolysis; HR, hazard ratio; CI, confidential interval; cfDNA, cell free DNA; ECOG, eastern cooperative oncology group; CCI, Charlson’s comorbidity index; ADC, adenocarcinoma; N/A, not available.
    Our study indicated poor OS in high-MTV or -TLG patients. Consistently, previous studies have reported that high baseline meta-bolic tumor parameters were independently associated with survival in NSCLC [29–31]. Chen et al. (105 stage I-IV NSCLC patients) and Zaizen et al. (68 stage III/IV NSCLC patients) reported that high TLG was as-sociated with poor OS [29,30]. Liao et al. also showed that the highest tertile-MTV and -TLG patients had poorer OS than those of the lowest tertile in 169 stage I-IV NSCLC patients [31].
    Furthermore, we tried to analyze the prognostic value of cfDNA levels combined with MTV and TLG for NSCLC. As anticipated, we observed poor prognosis for patients with high metabolic tumor burden irrespective of their cfDNA levels. Interestingly, our studies indicated poorer prognosis in patients with high-cfDNA than low-cfDNA in low metabolic tumor burden patients. Hence, monitoring baseline cfDNA levels to predict survival might be crucial for patients with low meta-bolic tumor burden. Lastly, high-cfDNA levels were independently as-sociated with poor OS in a multivariate cox regression test after ad-justing for MTV and TLG. Therefore, baseline metabolic tumor burden is not a significant confounder on the prognostic value of cfDNA levels.
    In summary, the results of In situ hybridization study provide initial support for the clinical implications of tumor biological behavior/aggressiveness, measured by cfDNA quantification and metabolic tumor burden ac-cording to MTV/TLG using FDG-PET/CT scans, for the survival of pa-tients with advanced NSCLC. We recommend that metabolic tumor burden should be initially considered for the therapeutic strategy for advanced NSCLC patients. High-MTV or high-TLG were associated with poor prognosis, and these patients would need more aggressive treat-ments, regardless of the biological behavior/aggressiveness of the tumor. The next consideration is tumor biologic aggressiveness/beha-vior. We identified that low-cfDNA and low-MTV or low-TLG showed a better prognosis than low-cfDNA and high-MTV or high-TLG. (Fig. 4) Therefore, our results suggest that monitoring cfDNA quantification as an early, accessible biomarker to identify patients with low metabolic tumor burden and who need more aggressive treatment strategies may be effective in informing treatment regimens.
    This study has several limitations. First, FDG uptake in a tumor le-sion by PET/CT can be biased since small lesions with low activity might be excluded. The inflammatory lesions or non-neoplastic condi-tions could also be included by chance, which might lead to 
    Fig. 4. Therapeutic strategy for advanced stage non-small cell lung cancer ac-cording to metabolic tumor burden and tumor biologic aggressiveness/beha-vior.
    Black arrows designate positive results, whereas white arrows designate nega-tive results.
    MTV, metabolic tumor volume; TLG, total lesion glycolysis; cfDNA, cell free DNA.
    overestimation of the tumor volume. Therefore, we carefully defined cut-off values for neoplastic conditions during MTV/TLG calculation by using patients’ radiologic data (other than PET/CT) and patients’ clin-icopathologic information. In addition, we quantified the MTV and TLG by visually estimating the hypermetabolic foci and confirmed the re-sults with two independent specialists who were blinded to the cfDNA data.