Maximum Lesion-To-Contralateral Normal Brain Tissue Ratio of 11C-Methionine PET as a Prognostic Imaging Biomarker for Newly Diagnosed and Untreated Astrocytic Glioma

Purpose: This study aimed whether the uptake of amino tracer positron emissiontomography (PET) can be used as an additional imaging biomarker to estimatethe prognosis of glioma.Methods: Participants comprised 56 adult patients with newly diagnosed and untreated World Health Organization (WHO) gradeⅡ-Ⅳ astrocytic glioma who underwent surgical excision and were evaluated by 11C-methionine PET prior to the surgical excision at Osaka City University Hospital from July 2011 to March 2018. Clinical and imaging studies were retrospectively reviewed based on medical records at our institution.Results: Preoperative Karnofsky Performance Status (KPS) only influenced progression-free survival (PFS) (hazard ratio [HR] 0.20; 95% confidence interval [CI] 0.10-0.41, p<0.0001), whereas histology (anaplastic astrocytoma: HR 5.30, 95%CI 1.23-22.8, p=0.025; glioblastoma: HR 11.52, 95%CI 2.27-58.47, p=0.0032), preoperative KPS≥80 (HR 0.23, 95%CI 0.09-0.62, p=0.004), maximum lesion-to-contralateral normal brain tissue (LN max)≥4.03 (HR 0.24, 95%CI 0.08-0.71, p=0.01), and isocitrate dehydrogenase (IDH) status (HR 14.06, 95%CI 1.81-109.2, p=0.011) were factors influencing overall survival (OS) in multivariate Cox regression. OS was shorter in patients with LN max≥ 4.03 (29.3 months) than in patients with LN max<4.03 (not reached; p=0.03). OS differed significantly between patients with IDH mutant/LN max<4.03 and patients with IDH mutant/LN max ≥4.03.Conclusions: LN max using 11C-methionine PET may be used in prognostic markers for newly identified and untreated WHO gradeⅡ-Ⅳ astrocytic glioma.

Maximum Lesion-to-contralateral Normal Brain Tissue Ration of 11C-methionine PET as a Prognostic Imaging Biomarker for Newly Diagnosed and Untreated Astrocytic Glioma

Purpose: This study aimed whether the uptake of amino tracer positron emission tomography (PET) can be used as an additional imaging biomarker to estimate the prognosis of glioma.Methods: Participants comprised 56 adult patients with newly diagnosed and untreated World Health Organization (WHO) gradeⅡ-Ⅳ astrocytic glioma who underwent surgical excision and were evaluated by 11C-methionine PET prior to the surgical excision at Osaka City University Hospital from July 2011 to March 2018. Clinical and imaging studies were retrospectively reviewed based on medical records at our institution.Results: Preoperative Karnofsky Performance Status (KPS) only influenced progression-free survival (PFS) (hazard ratio [HR] 0.20; 95% confidence interval [CI] 0.10-0.41, p<0.0001), whereas histology (anaplastic astrocytoma: HR 5.30, 95%CI 1.23-22.8, p=0.025; glioblastoma: HR 11.52, 95%CI 2.27-58.47, p=0.0032), preoperative KPS≥80 (HR 0.23, 95%CI 0.09-0.62, p=0.004), maximum lesion-to-contralateral normal brain tissue (LN max)≥4.03 (HR 0.24, 95%CI 0.08-0.71, p=0.01), and isocitrate dehydrogenase (IDH) status (HR 14.06, 95%CI 1.81-109.2, p=0.011) were factors influencing overall survival (OS) in multivariate Cox regression. OS was shorter in patients with LN max≥ 4.03 (29.3 months) than in patients with LN max<4.03 (not reached; p=0.03). OS differed significantly between patients with IDH mutant/LN max<4.03 and patients with IDH mutant/LN max ≥4.03.Conclusions: LN max using 11C-methionine PET may be used in prognostic markers for newly identified and untreated WHO gradeⅡ-Ⅳ astrocytic glioma.

Imaging 6-Phosphogluconolactonase Activity in Brain Tumors In Vivo Using Hyperpolarized δ-[1-13C]gluconolactone

IntroductionThe pentose phosphate pathway (PPP) is essential for NADPH generation and redox homeostasis in cancer, including glioblastomas. However, the precise contribution to redox and tumor proliferation of the second PPP enzyme 6-phosphogluconolactonase (PGLS), which converts 6-phospho-δ-gluconolactone to 6-phosphogluconate (6PG), remains unclear. Furthermore, non-invasive methods of assessing PGLS activity are lacking. The goal of this study was to examine the role of PGLS in glioblastomas and assess the utility of probing PGLS activity using hyperpolarized δ-[1-13C]gluconolactone for non-invasive imaging.MethodsTo interrogate the function of PGLS in redox, PGLS expression was silenced in U87, U251 and GS2 glioblastoma cells by RNA interference and levels of NADPH and reduced glutathione (GSH) measured. Clonogenicity assays were used to assess the effect of PGLS silencing on glioblastoma proliferation. Hyperpolarized δ-[1-13C]gluconolactone metabolism to 6PG was assessed in live cells treated with the chemotherapeutic agent temozolomide (TMZ) or with vehicle control. 13C 2D echo-planar spectroscopic imaging (EPSI) studies of hyperpolarized δ-[1-13C]gluconolactone metabolism were performed on rats bearing orthotopic glioblastoma tumors or tumor-free controls on a 3T spectrometer. Longitudinal 2D EPSI studies of hyperpolarized δ-[1-13C]gluconolactone metabolism and T2-weighted magnetic resonance imaging (MRI) were performed in rats bearing orthotopic U251 tumors following treatment with TMZ to examine the ability of hyperpolarized δ-[1-13C]gluconolactone to report on treatment response.ResultsPGLS knockdown downregulated NADPH and GSH, elevated oxidative stress and inhibited clonogenicity in all models. Conversely, PGLS expression and activity and steady-state NADPH and GSH were higher in tumor tissues from rats bearing orthotopic glioblastoma xenografts relative to contralateral brain and tumor-free brain. Importantly, [1-13C]6PG production from hyperpolarized δ-[1-13C]gluconolactone was observed in live glioblastoma cells and was significantly reduced by treatment with TMZ. Furthermore, hyperpolarized δ-[1-13C]gluconolactone metabolism to [1-13C]6PG could differentiate tumor from contralateral normal brain in vivo. Notably, TMZ significantly reduced 6PG production from hyperpolarized δ-[1-13C]gluconolactone at an early timepoint prior to volumetric alterations as assessed by anatomical imaging.ConclusionsCollectively, we have, for the first time, identified a role for PGLS activity in glioblastoma proliferation and validated the utility of probing PGLS activity using hyperpolarized δ-[1-13C]gluconolactone for non-invasive in vivo imaging of glioblastomas and their response to therapy.

[18F]-Fluciclovine PET discrimination of recurrent intracranial metastatic disease from radiation necrosis

Background Stereotactic radiosurgery (SRS) is often the primary treatment modality for patients with intracranial metastatic disease. Despite advances in magnetic resonance imaging, including use of perfusion and diffusion sequences and molecular imaging, distinguishing radiation necrosis from progressive tumor remains a diagnostic and clinical challenge. We investigated the sensitivity and specificity of 18F-fluciclovine PET to accurately distinguish radiation necrosis from recurrent intracranial metastatic disease in patients who had previously undergone SRS. Methods Fluciclovine PET imaging was performed in 8 patients with a total of 15 lesions that had previously undergone SRS and had subsequent MRI and clinical features suspicious for recurrent disease. The SUVmax of each lesion and the contralateral normal brain parenchyma were summated and evaluated at 4 different time points (5 minutes, 10 minutes, 30 minutes, and 55 minutes). Lesions were characterized as either recurrent disease (11 of 15 lesions) or radiation necrosis (4 of 15 lesions) and confirmed with histopathological correlation (7 lesions) or through serial MRI studies (8 lesions). Results Time activity curve analysis found statistically greater radiotracer accumulation for all lesions, including radiation necrosis, when compared to contralateral normal brain. While the mean and median SUVmax for recurrent disease was statistically greater than that of radiation necrosis at all time points, the difference was more significant at the earlier time points (p = 0.004 at 5 min – 0.025 at 55 min). Using a SUVmax threshold of ≥1.3, fluciclovine PET demonstrated a 100% accuracy in distinguishing recurrent disease from radiation necrosis up to 30 minutes after injection and an accuracy of 87% (sensitivity = 0.91, specificity = 0.75) at the last time point of 55 minutes. However, tumor to brain ratios (TBRmax) were not significantly different between recurrent disease and radiation necrosis at any time point due to variable levels of fluciclovine uptake in the background brain parenchyma. Conclusions Fluciclovine PET may play an important role in distinguishing active intracranial metastatic lesions from radiation necrosis in patients previously treated with SRS but needs to be validated in larger studies.

Higher Cho/NAA Ratio in Postoperative Peritumoral Edema Zone Is Associated With Earlier Recurrence of Glioblastoma

Objective: To explore the prognostic significance of metabolic parameters in postoperative peritumoral edema zone (PEZ) of patients with glioblastoma (GBM) based on proton magnetic resonance spectroscopy (MRS).Methods: The postoperative MRS data of 67 patients with GBM from Beijing Tiantan Hospital were retrospectively reviewed. Metabolite ratios including Cho/NAA, Cho/Cr, and NAA/Cr in both postoperative PEZ and contralateral normal brain region were recorded. Log-rank analysis and Cox regression model were used to identify parameters correlated with progression-free survival (PFS) and overall survival (OS).Results: Compared with the contralateral normal brain region, postoperative PEZ showed a lower ratio of NAA/Cr (1.20 ± 0.42 vs. 1.81 ± 0.48, P &lt; 0.001), and higher ratios of Cho/Cr and Cho/NAA (1.36 ± 0.44 vs. 1.02 ± 0.27, P &lt; 0.001 and 1.32 ± 0.59 vs. 0.57 ± 0.14, P &lt; 0.001). Both the ratios of Cho/NAA and NAA/Cr were identified as prognostic factors in univariate analysis (P &lt; 0.05), while only Cho/NAA ≥ 1.31 was further confirmed as an independent risk factor for early recurrence in the Cox regression model (P &lt; 0.01). According to the factors of MGMT promoter unmethylation, without radiotherapy and Cho/NAA ≥ 1.31, a prognostic scoring scale for GBM was established, which could divide patients into low-risk, moderate-risk, and high-risk groups. There was a significant difference of survival rate between the three groups (P &lt; 0.001).Conclusions: Higher Cho/NAA ratio in the postoperative PEZ of GBM predicts earlier recurrence and is associated with poor prognosis. The prognostic scoring scale based on clinical, molecular and metabolic parameters of patients with GBM can help doctors to make more precise prediction of survival time and to adjust therapeutic regimens.

[18F]-Fluciclovine PET discrimination of recurrent intracranial metastatic disease from radiation necrosis

Background Stereotactic radiosurgery (SRS) is often the primary treatment modality for patients with intracranial metastatic disease. Despite advances in magnetic resonance imaging, including use of perfusion and diffusion sequences and molecular imaging, distinguishing radiation necrosis from progressive tumor remains a diagnostic and clinical challenge. We investigated the sensitivity and specificity of 18F-fluciclovine PET to accurately distinguish radiation necrosis from recurrent intracranial metastatic disease in patients who had previously undergone SRS. Methods Fluciclovine PET imaging was performed in 8 patients with a total of 15 lesions that had previously undergone SRS and had subsequent MRI and clinical features suspicious for recurrent disease. The SUVmax of each lesion and the contralateral normal brain parenchyma were summated and evaluated at four different time points (5 min, 10 min, 30 min, and 55 min). Lesions were characterized as either recurrent disease (11 of 15 lesions) or radiation necrosis (4 of 15 lesions) and confirmed with histopathological correlation (7 lesions) or through serial MRI studies (8 lesions). Results Time activity curve analysis found statistically greater radiotracer accumulation for all lesions, including radiation necrosis, when compared to contralateral normal brain. While the mean and median SUVmax for recurrent disease were statistically greater than those of radiation necrosis at all time points, the difference was more significant at the earlier time points (p = 0.004 at 5 min–0.025 at 55 min). Using a SUVmax threshold of ≥ 1.3, fluciclovine PET demonstrated a 100% accuracy in distinguishing recurrent disease from radiation necrosis up to 30 min after injection and an accuracy of 87% (sensitivity = 0.91, specificity = 0.75) at the last time point of 55 min. However, tumor-to-background ratios (TBRmax) were not significantly different between recurrent disease and radiation necrosis at any time point due to variable levels of fluciclovine uptake in the background brain parenchyma. Conclusions Fluciclovine PET may play an important role in distinguishing active intracranial metastatic lesions from radiation necrosis in patients previously treated with SRS but needs to be validated in larger studies.

[18F]-Fluciclovine PET discrimination of recurrent intracranial metastatic disease from radiation necrosis

Background Stereotactic radiosurgery (SRS) is often the primary treatment modality for patients with intracranial metastatic disease. Despite advances in magnetic resonance imaging, including use of perfusion and diffusion sequences and molecular imaging, distinguishing radiation necrosis from progressive tumor remains a diagnostic and clinical challenge. We investigated the sensitivity and specificity of 18F-fluciclovine PET to accurately distinguish radiation necrosis from recurrent intracranial metastatic disease in patients who had previously undergone SRS. Methods Fluciclovine PET imaging was performed in 8 patients with a total of 15 lesions that had previously undergone SRS and had subsequent MRI and clinical features suspicious for recurrent disease. The SUVmax of each lesion and the contralateral normal brain parenchyma were summated and evaluated at 4 different time points (5 minutes, 10 minutes, 30 minutes, and 55 minutes). Lesions were characterized as either recurrent disease (11 of 15 lesions) or radiation necrosis (4 of 15 lesions) and confirmed with histopathological correlation (7 lesions) or through serial MRI studies (8 lesions). Results Time activity curve analysis found statistically greater radiotracer accumulation for all lesions, including radiation necrosis, when compared to contralateral normal brain. While the mean and median SUVmax for recurrent disease was statistically greater than that of radiation necrosis at all time points, the difference was more significant at the earlier time points (p = 0.004 at 5 min – 0.025 at 55 min). Using a SUVmax threshold of ≥ 1.3, fluciclovine PET demonstrated a 100% accuracy in distinguishing recurrent disease from radiation necrosis up to 30 minutes after injection and an accuracy of 87% (sensitivity = 0.91, specificity = 0.75) at the last time point of 55 minutes. However, tumor to brain ratios (TBRmax) were not significantly different between recurrent disease and radiation necrosis at any time point due to variable levels of fluciclovine uptake in the background brain parenchyma. Conclusions Fluciclovine PET may play an important role in distinguishing active intracranial metastatic lesions from radiation necrosis in patients previously treated with SRS but needs to be validated in larger studies.

Abstract TP88: Usefulness of High and Standard B-value DWI for Analysis of Pathophysiology in Acute Stage Cerebral Infarction

Introduction: Standard b-value DWI (sDWI) and high b-value DWI (hDWI) and ADC calculation from each DWI have been widely used for diagnosis of (acute ischemic stroke) AIS. However, diagnosis of AIS subtypes by using hDWI and ADC have not been well investigated. Hypothesis: AIS has several pathophysiological subtypes such as lacunar infarction, cardio-embolism(CE), and atherothrombotic brain infarction (ATBI), and so on, and condtion of collateral circulations differ among those subtypes. Several studies have shown that hDWI is relatively dominant in intracellular diffusion, conversely, sDWI is comparatively dominant in extracellular diffusion. Therefore, our hypothesis is that calculation of ADC from sDWI and hDWI could give valuable information for differentiation among AIS subtypes. Methods: We evaluated 130 AIS patients from medical records. Pathophysiological diagnoses were made by experienced neurologists. We acquired sDWI and hDWI at 3T MRI in all patients. 321 ADC values were obtained by calculating 200 ischemic lesions sequentially. We used relative ADC (rADC) value to adjust the difference caused by location and age. The rADC values were measured by manually placing regions of interest on the ADC maps at the ischemic lesion defined by DWI high and divided by the ADC values on the contralateral normal brain. For assessment of the AIS (within 30hrs from the onset) relationship between ATBI and CE, we subtract high b-value rADC (hrADC) from standard b-value rADC (srADC) to focus on the extracellular diffusion. To analyze the subacute phase stroke relationship between ATBI and CE, we evaluated the each rADC. And at both phase we conducted Mann-Whitney U test. Results: In superacute phase, hDWI more clearly showed hyper-intense signal than sDWI. From the onset, rADC of CE was lower than that of ATBI (median srADC-hrADC: ATBI/CE =0.0699/0.0244) (P=0.0445), this might imply the poor collateral status in CE. Contrary, for subacute phase, CE rapidly underwent necrosis in the ischemic core, rADC was higher than ATBI rADC (median ATBI/CE:0.5939/0.6480) (P=0.0011). Conclusions: We found that quantitative assessment of hrADC and srADC could give valuable information for differential diagnoses of AIS subtypes.

Differentiation of Edematous, Tumoral and Normal Areas of Brain Using Diffusion Tensor and Neurite Orientation Dispersion and Density Imaging

Background: Presurigical planning for glioma tumor resection and radiotherapy treatment require proper delineation of tumoral and peritumoral areas of brain. Diffusion tensor imaging (DTI) is the most common mathematical model applied for diffusion weighted MRI data. Neurite orientation dispersion and density imaging (NODDI) is another mathematical model for DWI data modeling.Objective: We studied whether extracted parameters of DTI, and NODDI models can be used to differentiate between edematous, tumoral, and normal areas in brain white matter (WM).Material and Methods: 12 patients with peritumoral edema underwent 3T multi-shell diffusion imaging with b-values of 1000 and 2000 smm-2 in 30 and 64 gradient directions, respectively. We fitted DTI and NODDI to data in manually drawn regions of interest and used their derived parameters to characterize edematous, tumoral and normal brain areas.Results: We found that DTI parameters fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) all significantly differentiated edematous from contralateral normal brain WM (p<0.005). However, only FA was found to distinguish between edematous WM fibers and tumor invaded fibers (p = 0.001). Among NODDI parameters, the intracellular volume fraction (ficvf) had the best distinguishing power with (p = 0.001) compared with the isotropic volume fraction (fiso), the orientation dispersion index (odi), and the concentration parameter of Watson distribution (κ), while comparing fibers inside normal, tumoral, and edematous areas.Conclusion: The combination of two diffusion based methods, i.e. DTI and NODDI parameters can distinguish and characterize WM fibers involved in edematus, tumoral, and normal brain areas with reasonable confidence. Further studies will be required to improve the detectability of WM fibers inside the solid tumor if they hypothetically exist in tumoral parenchyma.

In vivo incorporation of [9,10-3H]-palmitate into a rat metastatic brain-tumor model

✓ Lipid metabolism of an intracerebrally implanted brain tumor and normal brain was investigated in awake Fischer 344 rats using intravenously injected [9, 10-3H]-palmitate as a probe. A suspension of Walker 256 carcinosarcoma cells (250 cells in 5 µl medium), with or without 1 % low-melting-point agar, was implanted into the caudate nucleus of rats 8 to 9 weeks old. Control animals received an intracerebral injection without tumor cells. Seven days after implantation, awake rats were infused intravenously for 5 minutes with [9, 10-3H]-palmitate (6.4 mCi/kg). The rats were killed 20 minutes after initiation of the infusion and coronal brain slices were obtained for quantitative autoradiography and light histological study. Tumor cell masses were histologically well demarcated from the surrounding brain tissue. Tumor tissue incorporation of [9, 10-3H]- palmitate was heterogeneous, ranging on average from 3.1- to 6.1-fold greater than in the corresponding contralateral brain. In addition, incorporation corresponded to regional tumor cell density. The incorporation rate constant of [9, 10-3H]-palmitate in tumor was significantly increased compared to control brain and was independent of tumor size. Necrotic areas within tumors showed no incorporation of radiolabeled palmitate. Brain surrounding the tumors and control injection sites showed reactive gliosis, and possessed 30% greater incorporation of [9, 10-3H]-palmitate than contralateral normal brain. These results suggest that [9, 10-3H]- palmitate can be used to image brain tumors in vivo, measuring turnover and/or synthesis of tumor and brain lipid.