In this study, we demonstrated that a high Ins/Cho ratio on MR spectroscopy was associated with a better prognosis than a low Ins/Cho ratio according to KaplanMeier curves. The Ins/Cho ratio was significantly associated with PFS by KaplanMeier and multivariate analysis. Of the three cases in which the Ins/Cho ratios exceeded 1.0 and that started the Stupp regimen soon after maximum safe resection, the PFS durations were 26, 17, and ≥ 39 months (Cases 7, 8, and 26, respectively). Given that total choline in MR spectroscopy reveals cell density [9], low myoinositol levels are considered associated with poor prognosis. Indeed, a recent cohort study of recurrent glioblastoma treated with bevacizumab reported that a high myoinositol value on MR spectroscopy was associated with a good prognosis [24]. Given all these results, we considered that myoinositol affects as a second messenger and has antitumor effects. Myoinositols are located in glial cells, especially in astrocytes [25], and regulate intracranial osmotic pressure [13]. Phosphatidylinositol 3-phosphate, which contains myoinositols in its structure, is produced by intracellular membrane metabolism [10] and activates the PI3K-Akt pathway as a second messenger [26]. Activation of this pathway may cause a poorer prognosis in patients with a low Ins/Cho ratio by prompting cell proliferation and myoinositol consumption. As shown in a previous study, oral administration of myoinositols can inhibit malignant transformation of tumor cells in patients suffering non-small-cell lung cancer, in which the PI3K-Akt pathway is important [27]. Other researchers also reported that myoinositols have antitumor effects that result from their phosphorylated metabolites, such as inositol 1,3,4,5,6-pentaphosphate and inositol hexaphosphate, which can induce tumor cell apoptosis [28, 29]. These previous studies suggest that malignancy in IDH wild-type gliomas with low Ins/Cho ratios is associated with a simple reduction in antitumor effects.
However, multivariate analysis only showed that the Ins/Cho ratio was significantly associated with PFS and not OS (Fig. 1, Table 3). We assumed that the therapeutic strategies used after recurrence affected these results in the multivariate analyses. Indeed, some patients chose both surgical resection and additional chemotherapy (13%), whereas other patients opted for no additional therapy after recurrence (23%), potentially affecting outcomes. Notably, all patients younger than 50 years at diagnosis were in the group with a low Ins/Cho ratio, and 60% of these chose surgical resection and chemotherapy (Table 1). Two of these patients (cases 1 and 3) survived for approximately 2 years despite having low Ins/Cho ratios (0.57 and 0.51, respectively). By contrast, 20% of patients older than 60 years at diagnosis underwent surgical resection, and only 4% of these chose additional chemotherapy. Patients who opted for no therapy after recurrence had short survival time (e.g., cases 15 and 27) despite having relatively high Ins/Cho ratios (0.85 and 0.69, respectively).
Copy number analysis by next generation sequencing revealed no significant correlations between the Ins/Cho ratio and chromosomal areas, despite the association of specific copy number aberrations with glioblastoma (Table 4). Previous studies have shown that such copy number aberrations are an early stage of tumorigenesis in glioblastoma [15, 30, 31], and our results suggest that low myoinositol levels are less likely to be caused by decreased myoinositol synthesis due to chromosomal change and gene expression. Rather, the low myoinositol levels can be considered to result from consumption due to tumor growth.
This study is limited by its retrospective cohort design and lack of control of therapeutic strategies (e.g., resection extent by tumor location, postoperative bevacizumab use, and radiological dosages) or postoperative complications (e.g., delayed wound healing or high-fever affected the start of adjuvant therapy). These factors could have significantly affected the clinical courses and outcomes. We must now investigate more cases to clarify the putative correlations between the Ins/Cho ratio and patient prognosis.