The revised WHO 2016 classification of the central nervous system tumor requires the pathological diagnosis with molecular analysis to reach a diagnosis of glioma.  This molecular information has been said to correlate with prognosis, whereas there is still a matter of debate whether imaging biomarkers help estimation of prognosis. Although MRI remains the gold standard for diagnosing glioma, its role in estimating prognosis is limited.  On the other hand, 11C-methionine PET using amino tracer might be useful to detect the tumor, predict the grade or genetic status or both,[5, 11–14] and distinguish tumor recurrence from radiation necrosis [15–17] in glioma patients. However, relatively few reports have investigated the relationship between the uptake of amino tracer using PET and prognosis in glioma. Moreover, reports investigating prognosis of glioma patients in association with molecular analysis and PET in glioma have been limited. [18–22] Thus, our goal in the present study was to determine whether 11C-methionine PET can be used as an additional imaging biomarker of prognosis.
In the present study, we excluded patients with oligodendroglioma, or those with IDH mutated- TERT promoter mutated, or both because oligodendroglioma is considered to show better prognosis than astrocytoma and is often accompanied by both IDH and TERT promoter mutations. Although TERT promoter mutation is often seen in oligodendroglioma and primary glioblastoma, prognoses differ markedly between oligodendroglioma and glioblastoma. [23, 24] An argument has also been made regarding the association between uptake of 11C-methionine and oligodendroglioma. [14, 25–28] We have previously reported a positive correlation between WHO grade and the accumulation of 11C-methionine among astrocytomas, and a statistically higher uptake of 11C-methionine in oligodendroglioma than in diffuse astrocytoma.  Median survival rates in patients with diffuse astrocytoma, anaplastic astrocytoma, and glioblastoma in this study were 37.2 months, 9.6 months, and 4.7 months for PFS, and not reached, 27.1 months, and 20.5 months for OS, respectively. Reuss et al. reported that 139 of 152 patients with diffuse astrocytoma diagnosed according to the WHO 2007 classification of the central nervous system tumors showed IDH mutant diffuse astrocytoma, whereas more than half of patients with diffuse astrocytoma were IDH wild-type in our cohort.  Minniti et al. reported that IDH mutant anaplastic astrocytoma was found in 56% of their anaplastic astrocytoma patients. OS in patients with IDH wild-type was 2.8 years.  The relatively shorter PFS and OS of patients with diffuse astrocytoma and anaplastic astrocytoma in the current study were probably attributable to the fact that the present cohort included more patients with IDH wild-type astrocytoma than the previous study. On the other hand, Wakabayashi et al. reported that the median OS in patients with glioblastoma who received Stupp’s regimen was 20.3 months , similar to our result in the current study.
Brain PET imaging has recently been recommended for use in addition to MRI in the management of glioma. [3, 4] Takano et al. reported that PFS was worse with LN max ≥ 2.0 than with LN max < 2.0 using 11C-methionine PET among patients with untreated, lower-grade, non-enhancing gliomas.  Discrimination of high-grade glioma from low-grade glioma is usually difficult using MRI alone prior to tumor resection in patients with non-enhancing, lower-grade glioma, so we considered whether 11C-methionine PET can be used to predict the prognosis of glioma. However, we could not find significant differences in PFS between astrocytoma patients with LN max ≥ 4.03 and LN max < 4.03 or between those with LN mean ≥ 2.46 and LN mean < 2.46 in the current study.
Recently, some reports have investigated the relationship between prognosis from molecular analysis and uptake of PET using 18F-fluoro-ethyl-tyrosine (18F-FET) PET[18–20, 33] and 3,4-dihydroxy-6-18F-fluoro-ethyl-L-phenylalanine (18F-FDOPA) PET. Galldiks et al. in a study of photopenic IDH mutant gliomas reported that glioma with 18F-FET accumulation below the level of background healthy brain showed unfavorable outcomes, and thus should be treated more actively.  The utility of dynamic 18F-FET PET has also been reported.  Suchorska et al. reported that longer minimal time-to-peak analysis using 18F-FET PET was associated with a favorable prognosis in IDH mutant astrocytomas.  A time-to-peak analysis ≥ 25 min was associated with longer PFS and OS in patients with IDH wild-type high-grade astrocytoma according to Bauer et al.  Kunz et al. reported homogeneous decreases in intratumoral uptake of 18F-FET over time as a factor associated with poor prognosis in non-enhancing glioma.  Using continuous measures of 18F-FDOPA PET, Patel et al. reported LN max and age as prognostic factors for OS in WHO gradeⅠ-Ⅳ gliomas, and that IDH or MGMT status did not correlate with uptake of 18F-FDOPA. In this study, we concluded that patients with LN max ≥ 4.03 displayed unfavorable OS compared to patients with LN max < 4.03 among patients with WHO gradeⅡ-Ⅳ astrocytoma. We also concluded that patients with LN max ≥ 4.03 showed unfavorable OS compared those with LN max < 4.03 among patients with WHO gradeⅡ-Ⅳ IDH mutant astrocytoma, although no significant difference in OS was evident between IDH wild-type WHO gradeⅡ-Ⅳ astrocytoma with LN max ≥ 4.03 and those with LN max < 4.03. Thus, nother molecular imaging markers might be needed to estimate prognosis in IDH wild-type astrocytoma.
Some limitations need to be considered for the current study. First, the relatively small cohort of the current study might have influenced statistical analyses. For example, TERT promoter status did not influence OS in our cohort, although Arita et al. reported tthe usefulness of TERT promoter status in addition to the IDH status.  Further study with a larger cohort is thus needed to assess the correlation between prognosis and molecular/imaging biomarkers with amino-tracer PET in patients with astrocytoma. Second, we did not take volumetric analyses into consideration in the current study, although some reports have suggested that metabolic tumor volume did not correlate with survival outcomes. [18, 20, 33, 34, 36]