学位論文内容の要旨
博士の専攻分野の名称

博士（医 学）

氏 名

豊永 拓哉

学 位 論 文 題 名In vivo hypoxia imaging of brain tumors can visualize microscopic necrosis and anaerobic glycolysis.
（脳腫瘍に対するインビボ低酸素イメージングによって腫瘍内の顕微鏡的壊死や嫌気性糖代謝を可視化する）【Introduction】
Hypoxia is well known as one of the major factors that affect tumor malignancy. Hypoxic conditions
stimulates translating many proteins concerning about the glycolytic system, cell migration, angiogenic
signaling, and cell proliferation. In addition, hypoxia is well known to induce radiation or chemotherapy
resistance. It is reasonable that tumor hypoxia causes poor prognosis by means of such treatment resistance.
Fluoromisonidazole (FMISO) is the most widely used tracer of positron emission tomography (PET) tovisualize severe hypoxia in vivo. We previously showed that FMISO accumulation related with presence ofnecrosis and allow distinguishing glioblastoma from other lower-grade gliomas. Thus, in chapter 1, we
focus on the relationship between hypoxia and necrosis not only for astrocytic glioma but also for othertypes of brain tumor. We tested the diagnostic performance of FMISO to predict pathological diagnosis interms of present/absent necrosis.
In chapter 2, we focus on the FMISO-and-fluorodeoxyglucose (FDG) double positive area, where weassume anaerobic glycolysis may be dominant for energy production. We tested whether the parametersfrom FMISO-and-FDG double positive area have a potential to predict prognosis.
Chapter 1【Materials and methods】
The chapter 1 population included 66 patients (M:F=36:30, age: 27–85 years) who had brain tumor andunderwent FMISO PET and magnetic resonance imaging (MRI) before radiation therapy, chemotherapy,
and surgical intervention. According to the pathological diagnosis, brain tumors were divided into threegroups astrocytic tumors (group 1), neuroepithelial tumors other than astrocytic tumors (group 2), and otherhistopathological tumors (group 3).
The FMISO PET of tumor-to-normal cerebellum ratio (TNR) was calculated for semi-quantitative analysis.
The average values of cerebellar cortex of the standard uptake value (SUV) were defined as normalreferences. The maximum SUV (SUVmax) of the tumor was divided by averaging the cerebellar SUV asthe TNR.
Two experienced neuropathologists assessed each specimen and evaluated the presence of necrosis inconsensus. The diagnosis and evaluation were determined by agreement of the two pathologists.
【Results】
Histopathological necroses were observed in 23/23 glioblastomas (100%), 5/5 glioblastomas with oligo(100%), 1/8 AOs (12.5%), 1/1 AE (100%), 4/7 PCNSLs (57.1%), and 1/2 metastatic brain tumors (50%),
and 1/1 atypical meningioma (100%). Necroses were found in 17/31 cases in group 1, 7/20 cases in group 2,and 6/15 cases in group 3. The TNR in group 1 was 3.45 ± 0.97 vs. 1.43 ± 0.42 (with vs. without necrosis),
the TNR in group 2 was 2.91 ± 0.83 vs. 1.44 ± 0.20, and the TNR in group 3 was 2.63 ± 1.16 vs. 1.36 ±0.22. The TNRs of cases with necrosis were significantly higher than those of cases without necrosis ineach group (group 1, 2, and 3: p < 0.00001, p < 0.005, and p < 0.05, respectively). The lowest TNR innecrosis positive cases was 1.65.
【Discussion】
Results indicated a strong correlation between the FMISO uptake status and the presence of necrosis. Thecorrelations were significant not only in astrocytic tumors, but also in various histological types of brain
tumor. It appears that both the presence of intratumoral micro-necrosis and FMISO uptake have certain
thresholds of pO2 pressure. Our results of strong agreement between necrosis and FMISO uptake suggestthat the thresholds are close to each other.
Chapter 2【Materials and methods】
The chapter 2 population consisted of 17 male and 15 female glioblastoma patients (age, 63.5±14.8 years).
All of the 32 glioblastoma patients underwent FDG PET, FMISO PET, and MRI before any treatments.
FDG and FMISO PET images and MR images were co-registered using SPM8 software. For FMISO, weaveraged cerebellar uptake for the normal reference, and for FDG we adopted contralateral cortex average
uptake for FDG normal reference. Within the tumor volume of interests (VOIs), a voxel that had an FMISO
TNR ≥1.3 or 1.65 was defined as FMISO-positive, and FDG TNR ≥1.0 was defined as FDG-positive. Fromthese parameters we calculated the hypoxia volume (HV), hypoxic metabolic tumor volume (hMTV),hypoxic total lesion glycolysis (hTLG), hypermetabolic fraction of hypoxia volume (HMF).
We tested the correlation between patients’ PFS or OS and those parameters using the Cox regression
model for univariate analysis and with the Cox proportional hazard model for multivariate analysis.
【Results】
The TNR for FDG was 1.55±0.52 (range, 1.08–3.96). All (100%) of the lesions had a higher FDG SUVmax
than the reference value (i.e., TNR≥1.0). The TNR for FMISO was 3.29±0.81 (range, 1.48–4.85). In
volumetric assessment, the hMTV1.3 and HV1.3 were 7.98±8.85ml (range, 0.12–35.27 ml) and 29.78±18.90(range, 0.84–81.95 ml), respectively. The hTLG1.3 was 41.69±37.65 (range, 0.66–126.26), and the HMF1.3
was 25.15±18.03% (range, 0.89–61.80%).
At these cutoff values, the hMTV1.3, hTLG1.3, and extent of resections (EOR) were significantly correlatedwith PFS (p=0.007, p=0.04, and p=0.01, respectively). A significantly shorter OS was also suggested byhigher HV1.3, higher hMTV1.3, higher hTLG1.3, and lower EOR (p=0.04, p=0.0028, p=0.037, and p=0.014,respectively).
The Cox proportional hazard model indicated that patients’ PFS and OS were independently influenced by
the hMTV1.3 or hTLG1.3.
【Discussion】
We conducted a study involving the independent detection of hypermetabolic and hypoxic volumes using
FDG PET and FMISO PET, respectively. We found that the patients who had a larger hMTV1.3 or larger
hTLG1.3, or had undergone a more extensive surgical procedure, survived significantly longer than the otherpatients. In addition, multivariate analysis indicated that both the hTLG1.3 and hMTV1.3 were significant
prognostic factors that were independent from the EOR. The FDG/FMISO double-positive fraction may
reflect ‘signal transmission efficiency’ initiated from hypoxia to anaerobic glycolysis.
【Summary and Conclusion】
FMISO PET could visualize intratumoral microscopic necrosis in vivo and could provide important
information for treatment decisions and surgical strategies of any type of brain tumor. The combination ofFDG and FMISO PET may allow evaluate tumoral anaerobic glycolysis.