Methionine Positron Emission Tomography Research Articles

Role of 11C Methionine Positron Emission Tomography (11CMETPET) for Surgery and Radiation Therapy Planning in Newly Diagnosed Glioblastoma Patients Enrolled into a Phase II Clinical Study.

(1) Background: We investigated the role of [11C]-methionine PET in a cohort of newly diagnosed glioblastoma multiforme (GBM) patients to evaluate whether it could modify the extent of surgical resection and improve radiation therapy volume delineation. (2) Methods: Newly diagnosed GBM patients, ages 18–70, with a Karnofsky performance scale (KPS) ≥ 70 with available MRI and [11C]-methionine PET were included. Patients were treated with different amounts of surgical resection followed by radio-chemotherapy. The role of [11C]-methionine PET in surgical and RT planning was analyzed. A threshold of SUVmax was searched. (3) Results: From August 2013 to April 2016, 93 patients were treated and included in this analysis. Residual tumor volume was detected in 63 cases on MRI and in 78 on [11C]-methionine PET, including 15 receiving gross total resection. The location of uptake was mainly observed in FLAIR abnormalities. [11C]-methionine uptake changed RT volume in 11% of patients. The presence of [11C]-methionine uptake in patients receiving GTR proved to influence survival (p = 0.029). The threshold of the SUVmax conditioning outcome was five. (4) Conclusions: [11C]-methionine PET allowed to detect areas at higher risk of recurrence located in FLAIR abnormalities in patients affected by GBM. A challenging issue is represented by integrating morphological and functional imaging to better define the extent of surgical resection to perform.

Increased Uptake of 18F-THK5351 in Glioblastoma But Not in Primary Central Nervous System Lymphoma.

18F-THK5351 was initially developed to target tau aggregates in neurofibrillary tangles. However, it was also shown to bind to an enzyme, monoamine oxidase B, which is highly expressed in the outer mitochondrial membrane of astrocytes. In a case with glioblastoma, both l-[methyl-11C]-methionine PET and 18F-THK5351 PET showed increased uptake in the tumor. On the other hand, in another case with primary central nervous system lymphoma, l-[methyl-11C]-methionine PET showed increased uptake in the tumor, but 18F-THK5351 PET showed no abnormal uptake in the tumor. 18F-THK5351 PET might be helpful in differentiating between glioblastoma and primary central nervous system lymphoma.

Voxelwise Principal Component Analysis of Dynamic [S-Methyl-11C]Methionine PET Data in Glioma Patients.

Simple SummaryRecent works on dynamic amino acid positron emission tomography (PET) imaging of gliomas have highlighted characteristic behaviors of time-activity curves (TACs) extracted from the whole tumor w.r.t. the grade, genotype, and outcome. However, gliomas are known to be highly heterogeneous tumors. Here, we aim at highlighting similar dynamic behaviors at the voxel level within the tumor volume in [S-methyl-11C]methionine PET data of 33 glioma patients using principal component analysis (PCA). The PCA model was derived from TACs of 20 patients and subsequently applied to 13 other patients in whom our approach was shown to outperform classical pharmacokinetic modeling to this end. Our parameter-free approach provides additional parametric maps from dynamic methionine PET scans with little modification of the routine protocol and no arterial sampling. This early methodological work paves the way for various clinical studies on glioma heterogeneity with applications for treatment planning and response evaluation.Recent works have demonstrated the added value of dynamic amino acid positron emission tomography (PET) for glioma grading and genotyping, biopsy targeting, and recurrence diagnosis. However, most of these studies are based on hand-crafted qualitative or semi-quantitative features extracted from the mean time activity curve within predefined volumes. Voxelwise dynamic PET data analysis could instead provide a better insight into intra-tumor heterogeneity of gliomas. In this work, we investigate the ability of principal component analysis (PCA) to extract relevant quantitative features from a large number of motion-corrected [S-methyl-11C]methionine ([11C]MET) PET frames. We first demonstrate the robustness of our methodology to noise by means of numerical simulations. We then build a PCA model from dynamic [11C]MET acquisitions of 20 glioma patients. In a distinct cohort of 13 glioma patients, we compare the parametric maps derived from our PCA model to these provided by the classical one-compartment pharmacokinetic model (1TCM). We show that our PCA model outperforms the 1TCM to distinguish characteristic dynamic uptake behaviors within the tumor while being less computationally expensive and not requiring arterial sampling. Such methodology could be valuable to assess the tumor aggressiveness locally with applications for treatment planning and response evaluation. This work further supports the added value of dynamic over static [11C]MET PET in gliomas.

Diagnostic Performance of [11C]Methionine Positron Emission Tomography in Newly Diagnosed and Untreated Glioma Based on the Revised World Health Organization 2016 Classification

The relationship between uptake of amino acid tracer with positron emission tomography (PET) and glioma subtypes/gene status is still unclear. To assess the relationship between uptake of [11C]methionine using PET and pathology, IDH (isocitrate dehydrogenase) mutation, 1p/19q codeletion, and TERT (telomerase reverse transcriptase) promoter status in gliomas. The participants were 68 patients with newly diagnosed and untreated glioma who underwent surgical excision and preoperative [11C]methionine PET examination at Osaka City University Hospital between July 2011 and March 2018. Clinical and imaging studies were reviewed retrospectively based on the medical records at our institution. The mean lesion/contralateral normal brain tissue (L/N) ratio of diffuse astrocytomas was significantly lower than that of anaplastic astrocytomas (P= 0.00155), glioblastoma (P < 0.001), and oligodendrogliomas (P=0.0157). The mean L/N ratio of IDH mutant gliomas was significantly lower than that of IDH wild-type gliomas (median 1.75 vs. 2.61; P= 0.00162). A mean L/N ratio of 2.05 provided the best sensitivity and specificity for distinguishing between IDH mutant and IDH wild-type gliomas (69.2% and 76.2%, respectively). The mean L/N ratio of TERT promoter mutant gliomas was significantly higher than that of TERT promoter wild-type gliomas (P=0.0147). Multiple regression analysis showed that pathologic diagnosis was the only influential factor on L/N ratio. Distinguishing glioma subtypes based on the revised 2016 World Health Organization classification of the central nervous system tumors on the basis of [11C]methionine PET alone seems to be difficult. However, [11C]methionine PET might be useful for predicting the IDH mutation status in newly diagnosed and untreated gliomas noninvasively before tumor resection.

STMO-11 Supratotal resection of Glioblastoma with Methionine PET

Objective: To assess the resection of both of contrast-enhanced (CE) and methionine-uptake (MU) and the oncological outcome in newly diagnosed glioblastoma. Methods: This retrospective study included a glioblastoma cohort from Chiba University who met the two criteria, i) total resection of CE tumor, ii) preoperative evaluation with methionine positron emission tomography (Met-PET). Data regarding the pattern of recurrence and overall survival were collected. Results: Among 247 cases with glioblastoma, total resection of CE was achieved in 112. Preoperative Met-PET was performed in 30 out of 112. The median age at operation, a period of follow-up, and the preoperative tumor volume in 30 patients were 56 year-old, 17.9 months, and 18.8 cc respectively. The promoter region of the O6-methylguanine-DNA methyltransferase was methylated in 37%. Radiological comparison revealed that Met uptake was detected beyond the CE area in 13 out of 30, and the Met uptake was also resected with awake mapping technique in 7 patients (supratotal resection group; STR). The median progression-free survival (PFS) in STR was 23 months, and all the patterns of recurrence were distant recurrence. In contrast, the PFS in total resection group (TRG) was 9 months (p=0.09, Wilcoxon). Furthermore, 14 out of 17 recurrence were local in TRG subgroup. While the median OS in TRG was 18 months, it has not reached in STR (p=0.04, Wilcoxon). Conclusions: The resection of both of CE and MU was associated with better PFS and OS. This finding must be validated in a larger cohort with a multicenter study.

NI-10 T2/FLAIR mismatch sign and methionine PET uptake in grade II and III gliomas

Background: Recent study suggests that “T2/FLAIR mismatch” sign is specific MRI finding for isocitrate dehydrogenase mutated (IDH-mut) 1p19q non-codeleted gliomas (Grade II and III astrocytic tumors). T2/FLAIR mismatch sign may be useful for predicting the histological type of glioma before surgery. However, it is not known what this finding reflects. Therefore, we examined the correlation between T2/FLAIR mismatch sign and uptake of methionine with positron emission tomography (MET-PET), and molecular classification of glioma.Methods: 74 glioma patients (grade II: 30 cases, grade III: 44 cases) with preoperative MRI and MET-PET who underwent surgical resection during 2000–2019 were included in this study. MR scans were evaluated by 3 independent reviewers to assess presence/absence of T2/FLAIR mismatch sign. The tumor-to-normal (T/N) ratio of methionine uptake was calculated by dividing the maximum standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. We examined the relationship between IDH mutation, 1p/19q codeletion, mismatch, and T/N ratio of MET-PET.Results: Out of the 74 cases, astrocytic tumors (A group: IDH-mutant, 1p19q non-codeleted) were 21 (28%), oligodendroglial tumors (O group: IDH-mutant, 1p19q codeleted) were 19 (26%), and IDH wild tumors (W group) were 34 (46%). The T2/FLAIR mismatch sign was present in 16 cases (22%). The T/N ratio of MET-PET in the tumor with T2/FLAIR mismatch sign was 1.56, which was significantly lower than that in the tumor without mismatch sign (2.01, p=0.016). T2/FLAIR mismatch sign was found in 7 (33%) cases in the A group, 0 (0%) case in the O group and 9 (26%) cases in the W group, and the positive rate was significantly higher in the A group (p=0.013).Conclusions: “T2/FLAIR mismatch” sign was a specific finding for astrocytic tumor, and the cases with positive “T2/FLAIR mismatch” sign had significantly lower MET-PET uptake than that with negative cases.

A preliminary PET radiomics study of brain metastases using a fully automatic segmentation method

BackgroundPositron Emission Tomography (PET) is increasingly utilized in radiomics studies for treatment evaluation purposes. Nevertheless, lesion volume identification in PET images is a critical and still challenging step in the process of radiomics, due to the low spatial resolution and high noise level of PET images. Currently, the biological target volume (BTV) is manually contoured by nuclear physicians, with a time expensive and operator-dependent procedure.This study aims to obtain BTVs from cerebral metastases in patients who underwent L-[11C]methionine (11C-MET) PET, using a fully automatic procedure and to use these BTVs to extract radiomics features to stratify between patients who respond to treatment or not. For these purposes, 31 brain metastases, for predictive evaluation, and 25 ones, for follow-up evaluation after treatment, were delineated using the proposed method. Successively, 11C-MET PET studies and related volumetric segmentations were used to extract 108 features to investigate the potential application of radiomics analysis in patients with brain metastases. A novel statistical system has been implemented for feature reduction and selection, while discriminant analysis was used as a method for feature classification.ResultsFor predictive evaluation, 3 features (asphericity, low-intensity run emphasis, and complexity) were able to discriminate between responder and non-responder patients, after feature reduction and selection. Best performance in patient discrimination was obtained using the combination of the three selected features (sensitivity 81.23%, specificity 73.97%, and accuracy 78.27%) compared to the use of all features. Secondly, for follow-up evaluation, 8 features (SUVmean, SULpeak, SUVmin, SULpeak prod-surface-area, SUVmean prod-sphericity, surface mean SUV 3, SULpeak prod-sphericity, and second angular moment) were selected with optimal performance in discriminant analysis classification (sensitivity 86.28%, specificity 87.75%, and accuracy 86.57%) outperforming the use of all features.ConclusionsThe proposed system is able i) to extract 108 features for each automatically segmented lesion and ii) to select a sub-panel of 11C-MET PET features (3 and 8 in the case of predictive and follow-up evaluation), with valuable association with patient outcome. We believe that our model can be useful to improve treatment response and prognosis evaluation, potentially allowing the personalization of cancer treatment plans.

Preliminary clinical assessment of dynamic carbon-11 methionine positron-emission tomography/computed tomography for the diagnosis of the pathologies in patients with musculoskeletal lesions: a prospective study

BackgroundThis study prospectively assessed the diagnostic capacity of dynamic carbon-11 methionine (C-11 MET) positron-emission tomography (PET)/computed tomography for the diagnosis of pathologies in patients with primary unknown musculoskeletal lesions (MSLs). In total, 13 patients with MSLs underwent dynamic scans (5–10 [phase 1], 10–15 [phase 2], 15–20 [phase 3], 20–25 [phase 4], 25–30 [phase 5], and 30–35 [phase 6] min post-injection of C-11 MET). We statistically compared the maximum standardised uptake values (SUVmax) and corresponding retention index for dynamic scans (RI-SUV) for five benign MSLs (BMSLs), five primary malignant musculoskeletal tumours (PMMSTs), four metastatic musculoskeletal tumours (MMSTs), and three malignant lymphoma (ML) cases and explored their diagnostic capacities using receiver operating characteristic (ROC) curve analyses.ResultsSUVmax gradually decreased or remained similar with minimal fluctuations in all BMSL cases and four of five PMMST cases. In contrast, SUVmax increased over time in one case of PMMST and in all cases of MMST and ML. Significant differences were observed in SUVmax for all time phases and RI-SUV between BMSLs and MMSLs, in SUVmax for all time phases between PMMSTs and BMSLs, in SUVmax for all time phases and RI-SUV between non-PMMST-malignant tumours and BMSL, and in RI-SUV between non-PMMST-malignant tumours and PMMST. In ROC analyses, the areas under the curve yielded the highest values at 1.00 for differentiating most intergroup comparisons.ConclusionsDynamic C-11 MET PET scans have the potential to be good predictors of discriminating MSLs in patients with primary unknown MSLs in clinical practice.

MON-LB58 The Use of 11C Methionine PET CT In Localization of ACTH Dependent Cushing’s Disease

Background and objective: Hypercortisolism is the hall mark of ACTH Cushing’s syndrome, which is a benign ACTH secreting tumor resulting in high morbidity and mortality. The diagnosis is based on an elevated serum ACTH, elevated 24h urinary cortisol or a non-suppressible ACTH after dexamethasone suppression test. Confirmation of ACTH hypersecretion is followed by localization of the adenoma which can be pituitary in origin or peripheral. Dynamic MRI of the pituitary gland is the gold standard for diagnosis of pituitary tumors, and contrast enhanced CT scan is the gold standard for ectopic lesions which are usually lung tumors. The localization of the lesion is often a challenge because conventional MRI fail to show pituitary lesions and sometimes requiring inferior petrosal sinus sampling to confirm pituitary origin. Transsphenoidal surgery is the treatment of choice for Cushing’s disease, even without MRI evidence of pituitary tumors, if pituitary origin is confirmed by inferior petrosal sinus sampling. This causes increase in the incidence of treatment failure and complications. Thus, the diagnosis of Cushing’s disease urges exploring new diagnostic modalities. In our study we test the sensitivity of 11C methionine PET CT together with dynamic pituitary MRI in localization of ACTH dependent Cushing’s disease. Materials and methods This is an interventional, prospective study, forty-one subjects: newly diagnosed ACTH dependent Cushing’s Syndrome (n=29). (indicated by non-suppressible ACTH on dexamethasone suppression test) or persistent hypercortisolism following transsphenoidal surgery (n=12). 11C methionine PET CT was done in all cases in addition to dynamic pituitary MRI. All patients underwent 11 C-methionine PET-CT in addition to dynamic pituitary MRI This allowed us to determine whether suspected adenomas seen on structural imaging exhibited focal tracer uptake on functional imaging.Inclusion Criteria:• Aged 18 years old or over• Patient with a diagnosed Cushing’s disease confirmed by non-suppressible ACTH on dexamethasone suppression test.• Patient with persistent ACTH dependent Cushing’s disease following transsphenoidal surgery.• Patient not enrolled in other interventional studies.Exclusion Criteria:• Contraindication to MRI• Pregnant woman, breastfeeding RESULTS: Patients with newly diagnosed ACTH dependent Cushing: 24 out of 29 of the cases showed adenoma on dynamic MRI of the pituitary; 5 out of 29 cases failed to showed any lesions on dynamic MRI of the pituitary; Inferior petrosal sampling was done and confirmed pituitary origin in 4 out of 5 and 1 out of 5 was found to have ectopic ACTH secretion. In patients with persistent hypercortisolism following transsphenoidal surgery; 3 out of 12 of the cases showed adenoma on dynamic MRI of the pituitary and 7 out of 12 cases failed to showed any lesions on dynamic MRI of the pituitary and inferior petrosal sampling was done and confirmed pituitary origin in all 12 cases. All 41 cases underwent 11C methionine PET CT scan; 39 patients showed tracer uptake on 11c methionine PET CT scan in the pituitary area, 36 of which had unilateral asymmetrical tracer uptake. All 40 subjects with suspected pituitary lesions were confirmed to be of pituitary origin by histopathological examination of biopsies taken intraoperatively. CONCLUSIONS 11C methionine PET CT has proven to be of very high sensitivity in detecting ACTH secreting adenomas, further studies should be done on a larger scale as this modality can address the pitfalls in localization of ACTH secreting lesions.

NI-05 CLINICOPATHOLOGICAL ANALYSIS AND METHIONINE PET ANALYSIS IN PATIENTS WITH GLIOMATOSIS CEREBRI

OBJECTIVEGliomatosis cerebri (GC) was defined as the tumor infiltrating into more than three lobes in WHO2007, but was deleted in WHO2016 because they include genetically heterogeneous tissues. However, we often encounter the cases with strongly invasive glioma. Then, we clinically analyzed the cases of GC.PATIENTS AND METHODSSeven cases (five men, median age: 57 years (23-89y)) diagnosed as GC in our hospital were included. Data of methionine-positron emission tomography (Met-PET), IDH and p53 mutation, MIB1-labeling index (LI) by immunohistochemistry were searched. We compared the accumulation areas of the Met-PET with the hyperintensity area (T2/FLAIR-high) and gadolinium-enhanced area on the MRI. We also examined a biopsy method, sites and a treatment regimen and analyzed overall survival (OS) and progression-free survival (PFS).RESULTSThe primary symptoms were disorientation in five, epileptic seizure and abnormal vision were two, respectively. The largest lesion area with the image was T2/FLAIR-high, followed by Met-PET and Gd in all. The surgical methods were stereotactic biopsy (2), navigation-guided biopsy (2), endoscopic biopsy (1), and craniotomy (2), The average of tumor/normal ratio in Met-PET was 2.92 (1.97–5.0). The pathological grade was diagnosed as Grade III in 4 and Grade II in 3. IDH1R132H was negative in all, p53 was positive in 5, and an average of MIB-1LI was 12% (2–35). The radiotherapy was performed in 6 cases, and, temozolomide was given to all, and bevacizumab was in 3. Six patients died of a tumor. Median PFS and OS were 8mos and 16.5mos, respectively.CONCLUSIONBecause the GC cannot expect improvement by surgery, it is necessary to obtain the pathological diagnosis by a quick and correct biopsy, and the neurologic deterioration by the biopsy technique should be avoided. The Met-PET suggesting the highest grade site was useful for the plan of the biopsy site.

NI-07 VALIDATION OF MACHINE LEARNING BASED HIGH GRADE GLIOMA MR SEGMENTATION VIA METHIONINE PET

Treatment planning and lesion-follow up are generally conducted by contrast-enhanced MRI in glioma patient care. On the other hand, there are, however, substantial concerns whether MRI actually reflects the extension or activity of this neoplasm, which information should be fundamentally important at every step when treating this disease. As a matter of fact, the authors of this investigation have already shown that there is no difference in tumor cell density within areas with and without contrast enhancement (J Neurosurg. 2016,125(5):1136–1142.) and furthermore that the geometry of MRI based-radiation treatment planning is significantly altered when methionine PET is integrated for this purpose (J Neurosurg. 2018 published on-line). Regardless of these concerns, there is great interest in the research community to construct a machine learning based fully automated brain tumor segmentation tool specific for gliomas using MRI. The authors attempted to validate this method by comparing MRI-based automated brain tumor segmentation and methionine PET. Consecutively collected 45 high-grade gliomas (GBM-26, grade3-19) were analyzed. BraTumIA, an automated brain tumor segmentation tool, was used for machine learning based lesion segmentation. At the same time, lesions were segmented using various thresholds on methionine PET. The authors observed 40% of pseudo-positive and 90% of pseudo-negative error on BraTumIA based lesion segmentation when methionine PET was considered as ground truth with a cut-off of 1.3 in T/N ratio. Pseudo-negative error was as high as 60% even if the threshold was elevated to 2.0. Although machine learning based glioma segmentation is expected to expand in both research and clinical use, the observed results caution the use of MRI as ground truth of spatial extension of glioma and researchers should be reminded that this imaging modality may obscure the true behavior of the disease within the patient in some cases.

NI-20 IS GLIOMATOSIS CEREBRI DIAGNOSED AS GRADEII IN NEUROIMAGING A POTENTIALLY GRADEII GLIOMA?

The 2007 World Health Organization (WHO) classification defined gliomatosis cerebri (GC) as a rare entity and an extensively infiltrating diffuse glioma involving three or more cerebral lobes. Although the revised 2016 WHO classification removed GC as a separate glioma entity due to the common histopathological findings shared with other gliomas, GC exhibits a distinct growth pattern and worse prognosis compared with other grade-matched gliomas. We retrospectively reviewed five patients with GC and five patients with insulo-opercular diffuse astrocytoma (IODA) who underwent both proton magnetic resonance spectroscopy (MRS) and [11C]-methionine positron emission tomography (MET-PET).The patients were diagnosed with GC or IODA by T2-weighted magnetic resonance imaging /fluid-attenuated inversion recovery from April 2014 to August 2019 at our institution. The locations of lesions where single-voxel MRS to measure the N-acetylaspartate (NAA)/choline (Cho) ratio and MET-PET to measure the tumor/normal (T/N) ratio were performed were the same in every patient.The mean age of all patients was 46.3±13.7 years. The mean ages of the GC (three males and two females) and IODA (two males and three females) groups were 54.0±14.0 and 38.6±8.7 years, respectively. The mean NAA/Cho ratios in the GC and IODA groups were 1.010±0.441 and 0.594±0.449, respectively. The mean T/N ratios in the GC and IODA groups were 1.201±0.050 and 1.169±0.009, respectively.The higher NAA/Cho ratio in the GC lesions may reflect the abundance of normal neural tissue in GC compared with IODA. Nonetheless, the T/N ratios of the two groups were comparable. The discrepancy suggests that GC cells have higher tumor metabolic activity than IODA cells. Therefore, when GC is simply classified as grade II glioma based on neuroimaging diagnosis, the possibility of underestimating its malignant potential at the single-cell level should be considered.

Feasibility study of finalizing the extended adjuvant temozolomide based on methionine positron emission tomography (Met-PET) findings in patients with glioblastoma

In the management of patients with newly diagnosed glioblastoma, there is no standard duration for adjuvant temozolomide treatment. This study aimed to assess the feasibility of finalizing adjuvant temozolomide treatment on the basis of methionine uptake in methionine positron emission tomography (Met-PET). We conducted a retrospective review of glioblastoma patients who underwent more than twelve cycles of temozolomide (extended temozolomide) treatment after resection and concomitant chemoradiotherapy with no evidence of recurrence on MRI. In addition to the methionine uptake value at the completion of extended temozolomide, local and distant recurrence and progression-free survival were also analyzed. Forty-four patients completed the extended temozolomide treatment. Among these, 18 experienced some type of tumor recurrence within one year. A Tmax/Nave value of 2.0 was the optimal cut-off value indicating progression. More than 80% of the patients with low methionine uptake completed the temozolomide treatment, and subsequent basic MRI observations showed no recurrence within one year after Met-PET. Subgroups with high uptake (≥2.0), even with continuation of temozolomide treatment, showed more frequent tumor progression than patients with low uptake (<2.0) who completed the extended temozolomide treatment (p < 0.001, odds ratio 14.7, 95% CI 3.46–62.3). The tumor recurrence rate increased in stepwise manner according to methionine uptake. Finalization of the extended temozolomide treatment on the basis of low uptake value was feasible with a low recurrence rate. Compared to MRI, Met-PET shows better ability to predict tumor progression in long-term glioblastoma survivors with extended temozolomide use.

11C-Methionine Integrated PET/MRI-Based Texture Analysis Features May Have a Potential Ability to Distinguish Oligodendroglioma (IDH-Mutant and 1p/19q-Codeleted) From Varied Gliomas

Different histology and gene status of gliomas results in different natural history, treatment, and prognosis in different subgroups. Low-grade gliomas (LGGs) with isocitrate dehydrogenase (IDH) mutant and 1p/19q-codeleted are kind of gliomas with the most favorable outcome, reflecting operational strategy. Less invasive method for prediction of pathological type-even gene status-is desired. This study investigates the potential ability of methionine-positron emission tomography (MET-PET) to determine LGGs with IDH-mutant and 1p/19q-codeleted through a retrospective review of information of 70 glioma patients. Patients underwent preoperative MET-PET, followed by operation and histopathological analysis including Immunohistochemistry and polymerase chain reaction analysis for IDH-mutant and fluorescence capillary electrophoresis analysis for 1p/19q codeletion. Texture analysis was performed for further data mining. The t-test and receiver operating characteristic curve analysis were conducted for statistical analysis. In the whole cohort analysis, SUVmax, SUVmean and texture features (SD and median) of oligodendroglioma, IDH-mutant and 1p/19q-codeleted patients were lower than these values of other patients. In WHO grade II subgroup analysis, no statistical difference of conventional features was observed between groups. Texture analysis displayed higher diffEntropy, diffVariance, and entropy in oligodendroglioma, IDH-mutant and 1p/19q-codeleted patients. Receiver operating characteristic analysis suggested AUCs of some conventional features and texture features ranged from 0.722 to 0.892 that are effective for diagnosis, determining LGGs with IDH-mutant and 1p/19q-codeleted in this cohort and WHO II grade glioma subgroup analysis respectively. 11C-Methionine integrated PET/MRI based texture analysis and conventional features may be a promising noninvasive predictor for differentiating the varied gliomas.

P14.39 How far should it be removal beyond the Gd-enhanced edge in Glioblastoma cases? -Preoperative removal range identification using Methionine-PET and Thallium-SPECT fusion image

Abstract BACKGROUND Mostly, the removal rate of glioblastoma has been discussed in the Gd enhanced area, but tumor cells are surely infiltrated beyond the Gd enhanced edge. Although Methionine-PET (MET) and Thallium-SPECT (Tl) are useful for preoperative tumor invasion range identification, they are off-label use in most countries, and their respective accumulation ranges do not match completely. In this study, Gd-MRI, MET, and Tl were performed, and the accumulation range was compared from the fusion images, and the prediction method of the tumor cell infiltration range was examined. MATERIAL AND METHODS The mean interval period between MET and Tl administration was 16.3 days in 21 cases of glioblastoma (12 male and 9 female, average age 59.1 ± 17.8 years). Fusion images were generated using iPlan Cranial 3.0.The MET-area, Tl-area, Overlap-area where MET and Tl overlap, and Accumulation-area where MET and Tl are maximally accumulated were measured in the same cross section as the Gd-enhanced maximum area (Gd-area, X cm2) in axial view. Each volume was also measured similarly. RESULTS Gd-area was correlated with all of MET-area, Tl-area, Overlap-area, and Accumulation-area (p ≦0.0001).Gd-volume (X’cm3) showed correlation with all of MET-volume, Tl-volume, Overlap-volume, and Accumulation-volume (p ≦0.0001). The linear approximation was calculated as follows. Overlap-area = 1.942X + 1.0208 (R = 0.937), Accumulation-area = 1.3299X + 6.098 (R = 0.889), Overlap-volume = 1.1539X ‘+ 7.0573 (R = 0.927), Accumulation-volume = 1.8668X ‘+30.06 (R = 0.893). CONCLUSION These linear approximations can be used to predict the tumor invasion range from the Gd-enhanced maximum area or Gd-enhanced volume without using off-label use drugs.

A Methionine PET Targeting for Gamma Knife Radiosurgery used to Treat Recurrent Malignant Gliomas at Inoperable Stage

Purpose: The current study investigates the usefulness of metabolic positron emission tomography (PET) imaging (in particular with 11C-methionine (MET)), for target definition during gamma knife radiosurgery (GKRS) of locally multirecurrent malignant glioma at inoperable stage. Patients and Methods: We retrospectively evaluated the results of GKRS with MET-PET targeting for 24 adult focally recurrent inoperable malignant gliomas treated at the Erasme Gamma Knife Center between 2007 and 2018. We evaluated the type of tumour progression (local vs remote), progression-free survival (PFS), overall survival (OS) and toxicity after MET-PET targeting of GKRS for these 24 patients. Results: The median PFS after GKRS for the 24 patients with malignant gliomas was 5.5 (2-46) months and 4.5 (3-10), 4.5 (2-8) and 13.5 (2-46) months for glioblastoma, anaplastic glioma and grade II glioma patients, respectively. The median OS from the GKRS procedure for patients with recurrent glioblastomas (n=12) was 18 (6-45) months, 8 (6-184) months for anaplastic gliomas (n=6), and 22 (16-65) months for grade II gliomas (n=6). All patients with grade III and II multirecurrent gliomas (n=12) showed an early favourable local metabolic response, while this response was observed only in 6/12 of the glioblastomas. However, the majority (9/12=75%) of these grade II/III glioma patients further developed new lesions. GKRS treatment was associated with diverse chemotherapies in more than 50% (13/24) of cases. Post-GKRS radio-necrosis was observed in only one patient. Conclusion: Based on a limited series of 24 patients, our study shows, for the first time, the GKRS-induced metabolic response in focally recurrent inoperable malignant gliomas. GKRS could be part of the multidisciplinary approach for multirecurrent malignant gliomas that cannot be anymore treated by surgery.

Modified fractal analysis of methionine positron emission tomography images for predicting prognosis in newly diagnosed patients with glioma.

To assess intratumoural metabolic heterogeneity using modified fractal analysis and to determine its prognostic significance in patients with glioma. A total of 57 patients with newly diagnosed glioma who underwent methionine PET-computed tomography between August 2012 and January 2017 were enrolled. The requirement for informed consent was waived for this retrospective study. Tumour-to-normal tissue ratio, metabolic tumour volume, total lesion methionine uptake and modified fractal dimension (m-FD) were calculated for each tumour using methionine PET-computed tomography. Associations between these indices and tumour grade and overall survival were analysed. Overall, eight patients had grade II, 20 had grade III and 29 had grade IV tumours. The tumour-to-normal tissue ratios of grade III and grade IV tumours were significantly greater than that of grade II tumours. The metabolic tumour volume and total lesion methionine uptake of grade III tumours were significantly greater than those of grade II and grade IV tumours. The m-FD of grade IV tumours was significantly greater than those of grade II and grade III tumours. A total of 47 patients were followed up, and their prognoses were evaluated. Only the m-FD was significantly associated with a poor prognosis (P<0.05). Multivariate analyses identified age (>58 years) (hazard ratio: 5.73; 95.0% confidence interval: 1.4-29.9; P=0.015) and the m-FD (>0.87) (hazard ratio: 4.80; 95.0% confidence interval: 1.12-32.9; P=0.033) as independent prognostic factors for overall survival. Intratumoural metabolic heterogeneity is a useful imaging biomarker in patients with glioma.

P01.119 TSPO imaging in High Grade Glioma - a multitracer PET, MRI and neuropathology study

The translocator protein (TSPO) is an 18 kDa mitochondrial molecule (previously known as Peripheral Benzodiazepine Receptor), largely studied in neuroinflammation disorders and recently of growing interest in neuro-oncology [2,3]. The aim of our study is to investigate the uptake of [11C](R)-PK11195 (a PET radiotracer for TSPO) and [11C]Methionine and correlate with MR Imaging. Eleven patients (mean age 60 ± 16, M/F=5/6) with lesions suspicious of HGG on clinical MRI were recruited. All patients underwent contrast-enhanced structural and diffusion tensor MR imaging as well as dynamic [11C]-(R)PK11195 and [11C]Methionine PET scans before treatment. Parametric maps of [11C]-(R)PK11195 binding potential (BP) were generated using simplified reference tissue modelling with cerebellar grey matter as reference tissue. BP parametric maps were co-registered to post-contrast T1, fractional anisotropy(FA) and apparent diffusion coefficient (ADC) maps, and finally to [11C]Methionine summed image. Tumour was delineated as a T/N threshold above 1.4 on co-registered [11C]Methionine PET scans and a further regions delineating gadolinium enhancement and necrosis within the tumour were manually delineated. Co-registered MR/PET images were used to guide targeted tumour biopsies which were used to compare directly with histology. All confirmed HGG patients demonstrated a vivid uptake of [11C](R)-PK11195 (mean BP of whole tumour delineated using 1.4 [11C]Methionine threshold: 2.95 range 1.7–4.1; maximal BP: 4.12 range 2.1–6.2). [11C]Methionine uptake extended beyond gadolinium enhancement almost in all HGG cases, and regions of higher uptake did not spatially correlate to hottest [11C](R)-PK11195 areas (Figure 1). A significant correlation was found instead between increased [11C]Methionine uptake and mean diffusivity values (pairwise correlation coeficient = 0.69, p<0.01). TSPO antibody stain of hot TSPO targeted biopsies showed clearly higher values on optical density(OD) measurements, compared to cold uptake targeted areas within the tumour, confirming the correlation of [11C](R)-PK11195 PET imaging and histology (hot biopsies mean OD 4.3% vs 1.3% cold, p<0.001) (Figure 2). Further 3D histology modelling, colouring with multiple antibodies (Iba1, IDH1 and CD31) showed the localisation of TSPO in tumour hottest regions is mainly in the neoplastic cells rather than microglia or endothelium. Tumour recurrence was found to coincide with the regions of higher [11C](R)-PK11195 uptake in 2 of the patient’s clinical MR scans. [11C]-(R)PK11195 has the potential to detect early recurrence and provides information complimentary to perfusion metrics in early detection of recurrence. Methionine offers a better tumour delineation which could lead to more extensive surgical resections and better chances for survival.

Proton magnetic resonance spectroscopy differentiates tumefactive demyelinating lesions from gliomas

BackgroundIt is often difficult to accurately differentiate tumefactive demyelinating lesions (TDLs) from gliomas using MRI. ObjectiveTo investigate the utility of proton magnetic resonance spectroscopy (MRS) in differentiating TDLs from gliomas. MethodsCohort 1 included 6 patients with TDLs and 5 with gliomas (3 high-grade), as assessed using a 1.5T MR unit. Cohort 2 included 6 patients with TDLs and 17 patients with gliomas (8 high-grade), as assessed using a 3.0T MR unit. Single-voxel proton MRS was performed to compare the following metabolite area ratios: choline (Cho)/creatine (Cr), N-acetylaspartate (NAA)/Cr, and Cho/NAA in both cohorts. Correlations between the target-to-normal-tissue ratio (TNR) obtained using methionine-positron emission tomography (MET-PET) and each MRS metabolite ratio were examined in a subset of cohort 2 (4 patients with TDLs and 11 with gliomas). ResultsMean Cho/NAA ratio was significantly higher in gliomas than in TDLs or MS in cohort 1 (p < 0.05). Mean Cho/NAA ratio was significantly higher in high-grade gliomas than in TDLs in both cohorts (ps < 0.05). In the receiver operating characteristic analysis, high-grade glioma rather than TDL was indicated when the Cho/NAA ratio was >1.72 (the area under the curve was 0.958, and the maximum sensitivity and specificity were 100% and 87%, respectively). A significant positive correlation was observed between Cho/NAA ratio and the MET-PET TNR (r2 = 0.35, p < 0.05). ConclusionMRS effectively differentiates TDLs from high-grade gliomas. Therefore, the clinical use of MRS is likely to enhance patient outcomes.

The prognostic value of [123I]-vascular endothelial growth factor ([123I]-VEGF) in glioma

PurposeRecent studies have shown that tumor vascular endothelial cells and various tumor cells overexpress receptors for vascular endothelial growth factor (VEGF). The aim of this study was to investigate the prognostic value of [123I]-VEGF scintigraphy in patients with histologically verified brain tumors.Methods23 consecutive patients (9 women and 14 men aged 30–83 years, mean age 56.6 ± 14.4 years) with histopathologically-verified primary brain tumors were included in the study. All patients had undergone [123I]-VEGF scintigraphy. SPECT examinations of brain were performed 30 min and 18 h after injection. Additional [11C]-methionine PET ([11C]-MET PET) was performed in eight of the 23 patients. Both [123I]-VEGF and [11C]-MET PET were evaluated visually and semiquantitatively by tumor-to-normal brain uptake ratio (T/N ratio). Thresholds of the T/N ratio were evaluated by analysis of receiver operating characteristics (ROC). Overall survival (OS) was estimated using the Kaplan-Meier method.ResultsWorld Health Organization (WHO) grade IV glioma lesions showed [123I]-VEGF uptake 18 h after the injection, whereas other brain tumors of grade II or III showed negative results. There was no significant difference in the tumor size between VEGF positive and VEGF negative tumors. Patients with [123I]-VEGF T/N ratio threshold <1.32 showed significantly longer survival than patients with T/N ratio ≥ 1.32 (2680 days vs 295 days; P < 0.05). In the subgroup of 16 grade IV glioma patients, significant OS differences were found using a T/N ratio of 1.75 as threshold (T/N ratio < 1.75: 720 days; T/N ≥ 1.75: 183 days; P < 0.05). Significant difference (P < 0.05) was also found in [11C]-MET PET T/N ratios between the grade IV glioma (mean T/N ratio: 3.71) and the grade II or III glioma (mean T/N ratio: 1.74).ConclusionOur results suggest that [123I]-VEGF scintigraphy may be useful for visualization of tumor angiogenesis. In addition, [123I]-VEGF may provide relevant prognostic information in patients with glioma.