Methionine Positron Emission Tomography Research Articles

Real-world experience with 11C-methionine positron emission tomography in the management of acromegaly.

L-[methyl-11C]-methionine-positron emission tomography (Met-PET) is a potentially important imaging adjunct in the diagnostic workup of pituitary adenomas, including somatotroph tumors. Met-PET can identify residual or occult disease and make definitive therapies accessible to a subgroup of patients who would otherwise require lifelong medical therapy. However, existing data on its use are still limited to small case series. Here, we report the largest single-center experience (n = 61) in acromegaly. A total of 189 cases of acromegaly were referred to our national Met-PET service in the last 12 years. For this analysis, we have reviewed outcomes in those 61 patients managed exclusively by our multidisciplinary team (single center, single surgeon). Referral indications were as follows: indeterminate magnetic resonance imaging (MRI; n = 38, 62.3%), occult residual (n = 14, 23.0%), (radio-)surgical planning (n = 6, 9.8%), and occult de novo tumor (n = 3, 4.9%). A total of 33/61 patients (54.1%) underwent PET-guided surgery. Twenty-four of 33 patients (72.7%) achieved complete biochemical remission following (re-)surgery. Insulin-like growth factor 1 levels were reduced to <2 × upper limit of normal (ULN) in 6 of the remaining 9 cases, 3 of whom achieved levels of <1.1 × ULN compared with mean preoperative levels of 2.4 × ULN (SD 0.8) for n = 9. Only 3 patients developed single new hormonal deficits (gonadotropic/thyrotropic insufficiency). There were no neurovascular complications after surgery. In patients with persistent/recurrent acromegaly or occult tumors, Met-PET can facilitate further targeted intervention (surgery/radiosurgery). This led to complete remission in most cases (24/33) or significant improvement with comparatively low risk of complications. L-[methyl-11C]-methionine-positron emission tomography should therefore be considered in all patients who are potential candidates for further surgical intervention but present no clear target on MRI.

Impact of [11C]methionine PET with Bayesian penalized likelihood reconstruction on glioma grades based on new WHO 2021 classification.

The uptake of [11C]methionine in positron emission tomography (PET) imaging overlapped in earlier images of tumors. Bayesian penalized likelihood (BPL) reconstruction increases the quantitative values of tumors compared with conventional ordered subset-expectation maximization (OSEM). The present study aimed to grade glioma malignancy based on the new WHO 2021 classification using [11C]methionine PET images reconstructed using BPL. We categorized 32 gliomas in 28 patients as grades 2/3 (n = 15) and 4 (n = 17) based on the WHO 2021 classification. All [11C]methionine images were reconstructed using OSEM + time-of-flight (TOF) and BPL + TOF (β = 200). Maximum standardized uptake value (SUVmax) and tumor-to-normal tissue ratio (T/Nmax) were measured at each lesion. The mean SUVmax was 4.65 and 4.93 in grade 2/3 and 6.38 and 7.11 in grade 4, and the mean T/Nmax was 7.08 and 7.22 in grade 2/3 and 9.30 and 10.19 in grade 4 for OSEM and BPL, respectively. The BPL significantly increased these values in grade 4 gliomas. The area under the receiver operator characteristic (ROC) curve (AUC) for SUVmax was the highest (0.792) using BPL. The BPL increased mean SUVmax and mean T/Nmax in lesions with higher contrast such as grade 4 glioma. The discrimination power between grades 2/3 and 4 in SUVmax was also increased using [11C]methionine PET images reconstructed with BPL.

Radiomics for residual tumour detection and prognosis in newly diagnosed glioblastoma based on postoperative [11C] methionine PET and T1c-w MRI

Personalized treatment strategies based on non-invasive biomarkers have potential to improve patient management in patients with newly diagnosed glioblastoma (GBM). The residual tumour burden after surgery in GBM patients is a prognostic imaging biomarker. However, in clinical patient management, its assessment is a manual and time-consuming process that is at risk of inter-rater variability. Furthermore, the prediction of patient outcome prior to radiotherapy may identify patient subgroups that could benefit from escalated radiotherapy doses. Therefore, in this study, we investigate the capabilities of traditional radiomics and 3D convolutional neural networks for automatic detection of the residual tumour status and to prognosticate time-to-recurrence (TTR) and overall survival (OS) in GBM using postoperative [11C] methionine positron emission tomography (MET-PET) and gadolinium-enhanced T1-w magnetic resonance imaging (MRI). On the independent test data, the 3D-DenseNet model based on MET-PET achieved the best performance for residual tumour detection, while the logistic regression model with conventional radiomics features performed best for T1c-w MRI (AUC: MET-PET 0.95, T1c-w MRI 0.78). For the prognosis of TTR and OS, the 3D-DenseNet model based on MET-PET integrated with age and MGMT status achieved the best performance (Concordance-Index: TTR 0.68, OS 0.65). In conclusion, we showed that both deep-learning and conventional radiomics have potential value for supporting image-based assessment and prognosis in GBM. After prospective validation, these models may be considered for treatment personalization.

Evaluating the Diagnostic Efficacy of 99mTc-Methionine Single-Photon Emission Computed Tomography-Computed Tomography: A Head-to-Head Comparison with 11C-Methionine Positron Emission Tomography-Magnetic Resonance Imaging in Glioma Patients.

Background: Amino acid positron emission tomography (PET) imaging plays a significant role in the diagnosis of gliomas and in differentiating tumor recurrence from necrosis. In this study, the authors have evaluated the diagnostic efficacy of [99mTc]Tc-methionine single-photon emission computed tomography-computed tomography (SPECT-CT) in comparison with [11C]methionine PET-magnetic resonance imaging (MRI) in delineating tumors. Methods: Thirty-one (primary: 16 and postoperative: 15) patients of confirmed (either MRI or histopathological proven) glioma underwent both [99mTc]Tc-methionine SPECT-CT and [11C]methionine PET-MRI. A comparative analysis was performed between SPECT, PET, and MR images to calculate the concordance between the modalities and to evaluate the diagnostic efficacy of the [99mTc]Tc-methionine SPECT. Results: [99mTc]Tc-methionine SPECT showed comparable uptake in the tumor lesions in comparison to [11C]methionine PET. A significant and strong positive correlation was observed between the volume of tumor (Vt) in PET and Vt MR (p < 0.004). Likewise, a significant and strong positive correlation was found between Vt SPECT and Vt MR. [99mTc]-methionine has a sensitivity and specificity of 91% and 75%, respectively, compared with 82% and 100% for [11C]methionine in postoperative cases to differentiate the tumor recurrence from necrosis. The sensitivity and specificity of [99mTc]Tc-methionine was 92% and 100%, respectively, compared with 92% and 67% for [11C]methionine in primary tumors. Conclusion: [99mTc]Tc-methionine SPECT-CT is as equally good as [11C]methionine for diagnosing and differentiating it from necrosis especially in high-grade glioma.

The role of preoperative [11C]methionine PET in defining tumor-related epilepsy and predicting short-term postoperative seizure control in temporal lobe low-grade gliomas.

Surgery is the mainstay of treatment for low-grade glioma (LGG)-related epilepsy. However, the goal of achieving both oncological radical resection and seizure freedom can be challenging. PET with [11C]methionine (MET) has been recently introduced in clinical practice for the management of patients with LGGs, not only to monitor the response to treatments, but also as a preoperative tool to define the metabolic tumor extent and to predict tumor grading, type, and prognosis. Still, its role in defining tumor-related epilepsy and postoperative seizure outcomes is limited. The aim of this preliminary study was to investigate the role of MET PET in defining preoperative seizure characteristics and short-term postoperative seizure control in a cohort of patients with newly diagnosed temporal lobe low-grade gliomas (tLGGs). Patients with newly diagnosed and histologically proven temporal lobe grade 2/3 gliomas (2021 WHO CNS tumor classification) who underwent resection at the authors' institution between July 2011 and March 2021 were included in this retrospective study. MET PET images were acquired, fused with MRI scans, and qualitatively and semiquantitatively analyzed. Any eventual PET/MRI involvement of the temporomesial area, seizure characteristics, and 1-year seizure outcomes were reported. A total of 52 patients with tLGGs met the inclusion criteria. MET PET was positive in 41 (79%) patients, with a median metabolic tumor volume of 14.56 cm3 (interquartile range [IQR] 6.5-28.2 cm3). The median maximum and mean tumor-to-background ratio (TBRmax, TBRmean) were 2.24 (IQR 1.58-2.86) and 1.53 (IQR 1.37-1.70), respectively. The metabolic tumor volume was found to be related to the presence of seizures at disease onset, but only in noncodeleted tumors (p = 0.014). Regarding patients with uncontrolled seizures at surgery, only the temporomesial area PET involvement showed a statistical correlation both in the univariate (p = 0.058) and in the multivariate analysis (p = 0.030). At 1-year follow-up, seizure control was correlated with MET PET-derived semiquantitative data. Particularly, higher TBRmax (p = 0.0192) and TBRmean (p = 0.0128) values were statistically related to uncontrolled seizures 1 year after surgery. This preliminary study suggests that MET PET may be used as a preoperative tool to define seizure characteristics and outcomes in patients with tLGGs. These findings need to be further validated in larger series with longer epileptological follow-ups.

[11C]-methionine positron emission tomography in the evaluation of pediatric low-grade gliomas.

[11C]-Methionine positron emission tomography (PET; [11C]-MET-PET) is principally used for the evaluation of brain tumors in adults. Although amino acid PET tracers are more commonly used in the evaluation of pediatric brain tumors, data on [11C]-MET-PET imaging of pediatric low-grade gliomas (pLGG) is scarce. This study aimed to investigate the roles of [11C]-MET-PET in the evaluation of pLGGs. Eighteen patients with newly diagnosed pLGG and 26 previously treated pLGG patients underwent [11C]-MET-PET met the inclusion and exclusion criteria. Tumor-to-brain uptake ratio (TBR) and metabolic tumor volumes were assessed for diagnostic performances (newly diagnosed, 15; previously treated 26), change with therapy (newly diagnosed, 9; previously treated 7), and variability among different histology (n = 12) and molecular markers (n = 7) of pLGGs. The sensitivity of [11C]-MET-PET for diagnosing pLGG, newly diagnosed, and previously treated combined was 93% for both TBRmax and TBRpeak, 76% for TBRmean, and 95% for qualitative evaluation. TBRmax showed a statistically significant reduction after treatment, while other PET parameters showed a tendency to decrease. Median TBRmax, TBRpeak, and TBRmean values were slightly higher in the BRAFV600E mutated tumors compared to the BRAF fused tumors. Median TBRmax, and TBRpeak in diffuse astrocytomas were higher compared to pilocytic astrocytomas, but median TBRmean, was slightly higher in pilocytic astrocytomas. However, formal statistical analysis was not done due to the small sample size. Our study shows that [11C]-MET-PET reliably characterizes new and previously treated pLGGs. Our study also shows that quantitative parameters tend to decrease with treatment, and differences may exist between various pLGG types.

Extensive Shrinkage and Long-term Stable Disease in a Teenage Female Patient With High-grade Glioma Treated With Temozolomide and Radiation in Combination With Oral Recombinant Methioninase and a Low-methionine Diet.

Gliomas are the most common and recalcitrant malignant primary brain tumors. All cancer types are addicted to methionine, which is a fundamental and general hallmark of cancer known as the Hoffman effect. Particularly glioma cells exhibit methionine addiction. Because of methionine addiction, [11C]-methionine positron emission tomography (MET-PET) is widely used for glioma imaging in clinical practice, which can monitor the extent of methionine addiction. Methionine restriction including recombinant methioninase (rMETase) and a low-methionine diet, has shown high efficacy in preclinical models of gliomas, especially in combination with chemotherapy. The aim of the present study was to determine the efficacy of methionine restriction with oral rMETase (o-rMETase) and a low-methionine diet, combined with radiation and temozolomide (TMZ), on a teenage female patient with high-grade glioma. A 16-year-old girl was diagnosed with high-grade glioma. Magnetic resonance imaging (MRI) showed a left temporal-lobe tumor with compression to the left lateral ventricle and narrowing of sulci in the left temporal lobe. After the start of methionine restriction with o-rMETase and a low-methionine diet, along with TMZ combined with radiotherapy, the tumor size shrunk at least 60%, with improvement in the left lateral ventricle and sulci. The patient's condition remains stable for 19 months without severe adverse effects. Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with radiation and TMZ as first-line chemotherapy, were highly effective in a patient with high-grade glioma.

[11C] Methionine-PET Imaging as a Cancer Biomarker for Methionine Addiction and Sensitivity to Methionine-restriction-based Combination Chemotherapy.

Methionine addiction is a fundamental and universal hallmark of cancer, termed the Hoffman effect. Methionine addiction of cancer is greater than glucose addiction, termed the Warburg effect, as shown by the comparison of PET imaging with [11C]methionine and [18F]fluorodeoxyglucose. The aim of the present study was to determine whether [11C]methionine PET (MET-PET) images could be a biomarker of methionine addiction of cancer and potential response to methionine-restriction-based combination chemotherapy. In the present study a patient with invasive lobular carcinoma of the breast metastatic to axillary lymph nodes was imaged by both MET-PET and [18F]fluorodeoxyglucose PET (FDG-PET) before and after combination treatment with methionine restriction, comprising a low-methionine diet and methioninase, along with first-line chemotherapy. MET-PET gave a much stronger and precise image of the patient's metastatic axillary lymph nodes than FDG-PET. The patient had a complete response to methionine restriction-based chemotherapy as shown by MET-PET. MET-PET imaging is a biomarker of methionine-addicted cancer and potential response to methionine-restriction-based chemotherapy.

Individualized discrimination of tumor progression from treatment-related changes in different types of adult-type diffuse gliomas using [11C]methionine PET.

This study aimed to assess the ability of [11C]methionine (MET) PET in distinguishing between tumor progression (TP) and treatment-related changes (TRCs) among different types of adult-type diffuse gliomas according to the 2021 World Health Organization classification and predict overall survival (OS). We retrospectively selected 113 patients with adult-type diffuse gliomas with suspected TP who underwent MET PET imaging. Maximum and mean tumor-to-background ratios (TBRmax, TBRmean) and metabolic tumor volume (MTV) were calculated. Diagnoses were verified by histopathology (n = 50) or by clinical/radiological follow-up (n = 63). The diagnostic performance of MET PET parameters was evaluated through receiver operating characteristic (ROC) analysis and area under the curve (AUC) calculation. Survival analysis employed the Kaplan-Meier method and Cox proportional-hazards regression. TP and TRCs were diagnosed in 76 (67%) and 37 (33%) patients, respectively. ROC analysis revealed TBRmax had the best performance in differentiating TP from TRCs with a cut-off of 1.96 in IDH-mutant astrocytoma (AUC, 0.87; sensitivity, 93%; specificity 69%), 1.80 in IDH-mutant and 1p/19q-codeleted oligodendroglioma (AUC, 0.96; sensitivity, 100%; specificity, 89%), and 2.13 in IDH wild-type glioblastoma (AUC, 0.89; sensitivity, 89%; specificity, 78%), respectively. On multivariate analysis, higher TBRmean and MTV were significantly correlated with shorter OS in all IDH-mutant gliomas, as well as in IDH-mutant astrocytoma subgroup. This work confirms that MET PET has varying diagnostic performances in distinguishing TP from TRCs within three types of adult-type diffuse gliomas, and highlights its high diagnostic accuracy in IDH-mutant and 1p/19q-codeleted oligodendroglioma and potential prognostic value for IDH-mutant gliomas, particularly IDH-mutant astrocytoma.

Head-to-head comparison of [11C]methionine PET, [11C]choline PET, and 4-dimensional CT as second-line scans for detection of parathyroid adenomas in primary hyperparathyroidism.

Accurate preoperative localization is imperative to guide surgery in primary hyperparathyroidism (pHPT). It remains unclear which second-line imaging technique is most effective after negative first-line imaging. In this study, we compare the diagnostic effectiveness of [11C]methionine PET/CT, [11C]choline PET/CT, and four dimensional (4D)-CT head-to-head in patients with pHPT, to explore which of these imaging techniques to use as a second-line scan. We conducted a powered, prospective, blinded cohort study in patients with biochemically proven pHPT and prior negative or discordant first-line imaging consisting of ultrasonography and 99mTc-sestamibi. All patients underwent [11C]methionine PET/CT, [11C]choline PET/CT, and 4D-CT. At first, all scans were interpreted by a nuclear medicine physician, and a radiologist who were blinded from patient data and all imaging results. Next, a non-blinded scan reading was performed. The scan results were correlated with surgical and histopathological findings. Serum calcium values at least 6months after surgery were used as gold standard for curation of HPT. A total of 32 patients were included in the study. With blinded evaluation, [11C]choline PET/CT was positive in 28 patients (88%), [11C]methionine PET/CT in 23 (72%), and 4D-CT in 15 patients (47%), respectively. In total, 30 patients have undergone surgery and 32 parathyroid lesions were histologically confirmed as parathyroid adenomas. Based on the blinded evaluation, lesion-based sensitivity of [11C]choline PET/CT, [11C]methionine PET/CT, and 4D-CT was respectively 85%, 67%, and 39%. The sensitivity of [11C]choline PET/CT differed significantly from that of [11C]methionine PET/CT and 4D-CT (p = 0.031 and p < 0.0005, respectively). In the setting of pHPT with negative first-line imaging, [11C]choline PET/CT is superior to [11C]methionine PET/CT and 4D-CT in localizing parathyroid adenomas, allowing correct localization in 85% of adenomas. Further studies are needed to determine cost-benefit and efficacy of these scans, including the timing of these scans as first- or second-line imaging techniques.

Dual Role for l-[Methyl-11C]-Methionine PET in Acromegaly: Confirming Remission and Detecting Recurrence.

Dual Role for l-[Methyl-11C]-Methionine PET in Acromegaly: Confirming Remission and Detecting Recurrence.

DUAL PET IMAGING OF NEOPLASTIC AND INflAMMATORY BIOMARKERS IN HIGH GRADE GLIOMA

Abstract AIMS To characterize spatial distributions of 18kDa translocator protein (TSPO) and amino acid uptake as measured through dynamic [11C] (R)-PK11195 and [11C]-methionine PET in high-grade glioma. METHOD Twelve patients with newly diagnosed high-grade glioma underwent dual PET studies. [11C] (R)-PK11195 binding potential (BPND) maps were generated using simplified reference tissue model with grey-matter cerebellar time- activity-curve as tissue input-function. [11C]-methionine uptake was calculated as tumour-to-background ratio (TBR). Volumes of interest (VOIs) were defined on T1W post-contrast MRI as contrast-enhancing (CE) tumour and a ‘peritumoural’ region 5mm from the CE edge. Voxel-wise comparison of the tracers used Pearson’s correlation coeffcient. VOIs were furthermore subdivided into higher/lower TSPO (BPND &amp;gt; 0.17) and higher/lower methionine (TBR &amp;gt; 1.7). RESULTS Within the CE, voxel-wise comparison showed a strong correlation (r &amp;gt; 0.7) in eight subjects, moderate correlation (r &amp;gt; 0.5) in three subjects and weak correlation (r &amp;lt; 0.5) in one subject. Volume (mm3) with high BPND/high TBR accounted for 62±29% whereas high BPND/low TBR accounted for 13±16%. Within the peritumoral area, there was a small reduction in the proportion of subjects in the strong correlation group (6/12) but the pro- portion of voxels with higher TSPO binding and lower methionine uptake was substantially greater (35±16%). CONCLUSIONS Within high-grade glioma, there is a strong overall correlation between TSPO expression and amino acid uptake. However, in the peritumoural region there are areas of elevated TSPO expression without increased methionine uptake which could represent an inflammatory component or a discrete neoplastic cell population that may not be adequately defined with standard imaging biomarkers.

P15.10.A USE OF DUAL TRACERS PET AS A PREDICTIVE BIOMARKER OF THE SITE OF RECURRENCE IN HIGH GRADE GLIOMA

Abstract BACKGROUND High grade glioma has poor survival rate and tumour recurrence occurs despite current treatments. Positron emission tomography (PET) with [11C](R)PK11195 can evaluate translocator protein (TSPO) and [11C]methionine can assess amino acid transport. PET imaging might have the potential to detect tumour regions at baseline that will later develop as the site of recurrence. We compare TSPO measured using [11C](R)PK11195 and amino acid transport using [11C]methionine at baseline and investigate to what extend the two tracers can predict the site of tumour recurrence. MATERIAL AND METHODS Twelve patients with newly diagnosed high grade glioma underwent multimodal imaging studies. Preoperative MRI, [11C](R)PK11195 PET, [11C]methionine PET and postoperative (follow-up) MRI were co-registered. [11C](R)PK11195 binding potential (BPND) maps were generated using the simplified reference tissue model with grey matter cerebellar time-activity curve as tissue input function. [11C]methionine uptake was calculated as tumour to background ratio (TBR). Contrast enhancing volumes of interest (VOI) were defined on T1W post contrast. The VOI of [11C]methionine high uptake was standardized as TBR&amp;gt;1.7. For [11C](R)PK11195 VOI, the mean BPND + SD of grey matter voxels was calculated from individual maps of healthy control (HC; n = 50). Afterward, 95% confidence interval threshold (HC mean + 1.96 × SD) was used to describe high voxel activity in tumour (BPND&amp;gt;0.35). Tumour recurrence VOI was defined as contrast enhancement on the follow-up images. RESULTS The mean percentage overlap between high [11C](R)PK11195 BPND and [11C]methionine uptake was 48±17%. The mean percentage of each VOI showing exclusively high [11C](R)PK11195 BPND or exclusively high [11C]methionine was 25±21 or 27±22 respectively. The mean percentage overlap between high [11C](R)PK11195 and contrast enhancement is 36±14. The mean percentage of exclusively hight [11C](R)PK11195 or exclusively contrast enhancement were 38±18 or 26±25 respectively. The mean percentage overlap between high [11C]methionine and contrast enhancement were 47±12. The mean percentage of exclusively [11C]methionine or contrast enhancement were 36±20 or 17±17 respectively. The percentage volume overlap between contrast enhancing regions at recurrence and baseline [11C](R)PK11195 or [11C]methionine was 20±13 or 25±13 respectively. CONCLUSION The two PET tracers have high overlap although some regions are specific for high TSPO binding without high methionine uptake which could reflect an inflammatory component within the tumour microenvironment. The common regions between methionine and contrast enhancement is larger than TSPO binding which could represent that TSPO binding is less effected by disrupted blood-brain barrier. The mean percentage overlap with VOI representing tumour recurrence were similar.

The prognostic power of [11C]methionine PET in IDH-wildtype diffuse gliomas with lower-grade histological features: venturing beyond WHO classification.

IDH-wildtype (IDH-wt) diffuse gliomas with histological features of lower-grade gliomas (LGGs) are rare and heterogeneous primary brain tumours. [11C]Methionine (MET) positron emission tomography (PET) is commonly used to evaluate glial neoplasms at diagnosis. The present study aimed to assess the prognostic value of MET PET in newly diagnosed, treatment naïve IDH-wt gliomas with histological features of LGGs. Patients with a histological diagnosis of IDH-wt LGG who underwent preoperative (< 100days) MET PET/CT and surgery were retrospectively included. Qualitative and semi-quantitative analyses of MET PET images were performed. Progression-free survival (PFS) and overall survival (OS) were analysed by Kaplan-Meier curves. Cox proportional-hazards regression was used to test the association of imaging and clinical data to PFS and OS. We included 48 patients (M:F = 25:23; median age 55). 39 lesions were positive and 9 negative at MET PET. Positive MET PET was significantly associated with shorter median PFS (15.7months vs. not reached, p = 0.0146) and OS time (32.6months vs. not reached, p = 0.0253). Incomplete surgical resection and higher TBRmean values were independent predictors of shorter PFS on multivariate analysis (p < 0.001 for both). Higher tumour grade and incomplete surgical resection were independent predictors of OS at multivariate analysis (p = 0.027 and p = 0.01, respectively). MET PET is useful for the prognostic stratification of patients with IDH-wt glial neoplasms with histological LGGs features. Considering their huge biological heterogeneity, the combination of MET PET and molecular analyses may help to improve the prognostic accuracy in these diffuse gliomas subset and influence therapeutic choices accordingly.

AI-based Virtual Synthesis of Methionine PET from Contrast-enhanced MRI: Development and External Validation Study.

Background Carbon 11 (11C)-methionine is a useful PET radiotracer for the management of patients with glioma, but radiation exposure and lack of molecular imaging facilities limit its use. Purpose To generate synthetic methionine PET images from contrast-enhanced (CE) MRI through an artificial intelligence (AI)-based image-to-image translation model and to compare its performance for grading and prognosis of gliomas with that of real PET. Materials and Methods An AI-based model to generate synthetic methionine PET images from CE MRI was developed and validated from patients who underwent both methionine PET and CE MRI at a university hospital from January 2007 to December 2018 (institutional data set). Pearson correlation coefficients for the maximum and mean tumor to background ratio (TBRmax and TBRmean, respectively) of methionine uptake and the lesion volume between synthetic and real PET were calculated. Two additional open-source glioma databases of preoperative CE MRI without methionine PET were used as the external test set. Using the TBRs, the area under the receiver operating characteristic curve (AUC) for classifying high-grade and low-grade gliomas and overall survival were evaluated. Results The institutional data set included 362 patients (mean age, 49 years ± 19 [SD]; 195 female, 167 male; training, n = 294; validation, n = 34; test, n = 34). In the internal test set, Pearson correlation coefficients were 0.68 (95% CI: 0.47, 0.81), 0.76 (95% CI: 0.59, 0.86), and 0.92 (95% CI: 0.85, 0.95) for TBRmax, TBRmean, and lesion volume, respectively. The external test set included 344 patients with gliomas (mean age, 53 years ± 15; 192 male, 152 female; high grade, n = 269). The AUC for TBRmax was 0.81 (95% CI: 0.75, 0.86) and the overall survival analysis showed a significant difference between the high (2-year survival rate, 27%) and low (2-year survival rate, 71%; P < .001) TBRmax groups. Conclusion The AI-based model-generated synthetic methionine PET images strongly correlated with real PET images and showed good performance for glioma grading and prognostication. Published under a CC BY 4.0 license. Supplemental material is available for this article.

Differentiation of astrocytoma between grades II and III using a combination of methionine positron emission tomography and magnetic resonance spectroscopy

ObjectiveThis study aimed to establish a method for differentiating between grades II and III astrocytomas using preoperative imaging. MethodsWe retrospectively analyzed astrocytic tumors, including 18 grade II astrocytomas (isocitrate dehydrogenase (IDH)-mutant: IDH-wildtype = 8:10) and 56 grade III anaplastic astrocytomas (37:19). We recorded the maximum methionine (MET) uptake ratios (tumor-to-normal: T/N) on positron emission tomography (PET) and three MRS peak ratios: choline (Cho)/creatine (Cr), N-acetyl aspartate (NAA)/Cr, and Cho/NAA, between June 2015 and June 2020. We then evaluated the cut-off values to differentiate between grades II and III. We compared the grading results between contrast enhancement effects on MR and combinational diagnostic methods (CDM) on a scatter chart using the cutoff values of the T/N ratio and MRS parameters. ResultsThe IDH-mutant group showed significant differences in the Cho/NAA ratio between grades II and III using univariate analysis; however, multiple regression analysis results negated this. The IDH-wildtype group showed no significant differences between the groups. Contrast enhancement effects also showed no significant differences in IDH status. Accordingly, regardless of the IDH status, no statistically independent factors differentiated between grades II and III. However, CDMs showed higher sensitivity and negative predictive value in distinguishing them than MRI contrast examinations for both IDH statuses. We demonstrated a significantly higher diagnostic rate of grade III than of grade II with CDM, which was more striking in the IDH-mutant group than in the wild-type group. ConclusionsCDM could be valuable in differentiating between grade II and III astrocytic tumors.

Head-to-Head Comparison of Tc-99m-sestamibi SPECT/CT and C-11-L-Methionin PET/CT in Parathyroid Scanning Before Operation for Primary Hyperparathyroidism.

The preferred nuclear medicine method for identification of hyperfunctioning parathyroid glands in hyperparathyroidism (HPT) develops continuously in relation to the technological progress. Diagnostic methods based on PET/CT have during recent years evolved with new tracer possibilities competing with traditional scintigraphic methods. This investigation is a head-to-head comparison of Tc-99m-sestamibi SPECT/CT gamma camera scintigraphy (sestamibi SPECT/CT) and C-11-L-methionin PET/CT imaging (methionine PET/CT) for preoperative identification of hyperfunctioning parathyroid glands. The study is a prospective cohort study including 27 patients diagnosed with primary hyperparathyroidism (PHPT). Two nuclear medicine physicians assessed all examinations independently and blinded. All scanning assessments were matched to the final surgical diagnosis as confirmed by histopathology. Biochemical monitoring of the therapeutical effects was performed preoperatively by PTH-measurements and followed postoperatively for up to 12 months. Comparisons were made for differences in sensitivity and positive predictive value (PPV). Twenty-seven patients (18 females, 9 males; mean age (range): 58.9 years (34.1-79)) were enrolled into the study. The 27 patients had a total of 33 identified sites of lesions of which 28 (85%) turned out to be histopathological verified hyperfunctioning parathyroid glands. The sensitivity and PPV for sestamibi SPECT/CT were 0.71 and 0.95; that of methionine PET/CT was 0.82 and 1, respectively. Both sensitivity and PPV were slightly lower for sestamibi SPECT/CT than for methionine PET PET/CT (-0.11, 95% confidence interval (95% CI): -0.29 to 0.08; -0.05, 95% CI: -0.14 to 0.04, respectively), but not to a statistically significant extent (p=0.38 and p=0.31). The sensitivity and PPV for diagnostic CT were 0.64 (95% CI: 0.44 to 0.81) and 1 (95% CI: 0.81 to 1). Methionine PET/CT performed comparable to sestamibi SPECT/CT with respect to identification and localization of hyperfunctioning parathyroid glands prior to surgery.

Ectopic sphenoidal ACTH-secreting adenoma revealed by 11C Methionine PET scan: case report

BackgroundEctopic ACTH pituitary adenomas (EAPA), located outside the sella turcica and deriving from cellular remnants of Rathke’s pouch are a very rare cause of Cushing’s syndrome (CS). The diagnosis is often difficult and delayed, even after comprehensive work-up. To our knowledge, we report for the first time an ectopic corticotroph tumor of the posterior wall of the sphenoid sinus, leading to false positive results of bilateral inferior petrosal sinus sampling (BIPPS) and which was finally localized by a co-registered11 C Methionine PET/MR imaging.Case presentationA 48-year-old woman was referred for a high clinical suspicion of ACTH-dependent CS. Biological testing comprising low dose dexamethasone suppression and CRH stimulation tests were indicative of pituitary Cushing’s disease, but comprehensive pituitary MRI did not reveal any pituitary adenoma. BIPSS confirmed however a central origin of ACTH secretion (central-to-peripheral ACTH ratio > 100) and revealed a significant right-to-left gradient (6.2), leading to a first right-sided exploratory hypophysectomy, that did not cure the patient. BIPSS images were reviewed and revealed preferential drainage of the left pituitary to the right petrosal sinus, leading us to a left sided exploratory hypophysectomy, which was again unsuccessful. A11 C Methionine PET/MRI was performed and revealed a hypermetabolic lesion adjacent to the posterior wall of the sphenoidal sinus. After surgical resection, this polypoid mass was identified as an ectopic ATCH-secreting pituitary adenoma expressing ACTH and T-Pit and complete remission of hypercortisolism was observed.ConclusionsIn conclusion, we report a case of ACTH-dependent Cushing’s syndrome, caused by an ectopic corticotroph adenoma located in the sphenoidal sinus, which perfectly mimicked the biological features of a classical pituitary ACTH adenoma on a comprehensive hormonal evaluation including BIPPS, and the features of a benign naso-sinusal polyp at MRI. We report for the first time a key role of11 C Methionine PET co-registered to high resolution MRI for localizing ectopic adenomas, efficiently guiding surgical removal and leading to complete remission of hypercortisolism.

Machine learning predictive performance evaluation of conventional and fuzzy radiomics in clinical cancer imaging cohorts

BackgroundHybrid imaging became an instrumental part of medical imaging, particularly cancer imaging processes in clinical routine. To date, several radiomic and machine learning studies investigated the feasibility of in vivo tumor characterization with variable outcomes. This study aims to investigate the effect of recently proposed fuzzy radiomics and compare its predictive performance to conventional radiomics in cancer imaging cohorts. In addition, lesion vs. lesion+surrounding fuzzy and conventional radiomic analysis was conducted.MethodsPreviously published 11C Methionine (MET) positron emission tomography (PET) glioma, 18F-FDG PET/computed tomography (CT) lung, and 68GA-PSMA-11 PET/magneto-resonance imaging (MRI) prostate cancer retrospective cohorts were included in the analysis to predict their respective clinical endpoints. Four delineation methods including manually defined reference binary (Ref-B), its smoothed, fuzzified version (Ref-F), as well as extended binary (Ext-B) and its fuzzified version (Ext-F) were incorporated to extract imaging biomarker standardization initiative (IBSI)-conform radiomic features from each cohort. Machine learning for the four delineation approaches was performed utilizing a Monte Carlo cross-validation scheme to estimate the predictive performance of the four delineation methods.ResultsReference fuzzy (Ref-F) delineation outperformed its binary delineation (Ref-B) counterpart in all cohorts within a volume range of 938–354987 mm3 with relative cross-validation area under the receiver operator characteristics curve (AUC) of  +4.7–10.4. Compared to Ref-B, the highest AUC performance difference was observed by the Ref-F delineation in the glioma cohort (Ref-F: 0.74 vs. Ref-B: 0.70) and in the prostate cohort by Ref-F and Ext-F (Ref-F: 0.84, Ext-F: 0.86 vs. Ref-B: 0.80). In addition, fuzzy radiomics decreased feature redundancy by approx. 20%.ConclusionsFuzzy radiomics has the potential to increase predictive performance particularly in small lesion sizes compared to conventional binary radiomics in PET. We hypothesize that this effect is due to the ability of fuzzy radiomics to model partial volume effects and delineation uncertainties at small lesion boundaries. In addition, we consider that the lower redundancy of fuzzy radiomic features supports the identification of imaging biomarkers in future studies. Future studies shall consider systematically analyzing lesions and their surroundings with fuzzy and binary radiomics.

Sex-specific radiomic features of L-[S-methyl-11C] methionine PET in patients with newly-diagnosed gliomas in relation to IDH1 predictability.

Amino-acid positron emission tomography (PET) is a validated metabolic imaging approach for the diagnostic work-up of gliomas. This study aimed to evaluate sex-specific radiomic characteristics of L-[S-methyl-11Cmethionine (MET)-PET images of glioma patients in consideration of the prognostically relevant biomarker isocitrate dehydrogenase (IDH) mutation status. MET-PET of 35 astrocytic gliomas (13 females, mean age 41 ± 13 yrs. and 22 males, mean age 46 ± 17 yrs.) and known IDH mutation status were included. All patients underwent radiomic analysis following imaging biomarker standardization initiative (IBSI)-conform guidelines both from standardized uptake value (SUV) and tumor-to-background ratio (TBR) PET values. Aligned Monte Carlo (MC) 100-fold split was utilized for SUV and TBR dataset pairs for both sex and IDH-specific analysis. Borderline and outlier scores were calculated for both sex and IDH-specific MC folds. Feature ranking was performed by R-squared ranking and Mann-Whitney U-test together with Bonferroni correction. Correlation of SUV and TBR radiomics in relation to IDH mutational status in male and female patients were also investigated. There were no significant features in either SUV or TBR radiomics to distinguish female and male patients. In contrast, intensity histogram coefficient of variation (ih.cov) and intensity skewness (stat.skew) were identified as significant to predict IDH +/-. In addition, IDH+ females had significant ih.cov deviation (0.031) and mean stat.skew (-0.327) differences compared to IDH+ male patients (0.068 and -0.123, respectively) with two-times higher standard deviations of the normal brain background MET uptake as well. We demonstrated that female and male glioma patients have significantly different radiomic profiles in MET PET imaging data. Future IDH prediction models shall not be built on mixed female-male cohorts, but shall rely on sex-specific cohorts and radiomic imaging biomarkers.