Comparison of (18)F-FET and (18)F-FDG PET in brain tumors.

UNLABELLED: The purpose of this study was to compare the diagnostic value of positron emission tomography (PET) using [(18)F]-fluorodeoxyglucose ((18)F-FDG) and O-(2-[(18)F]fluoroethyl)-l-tyrosine ((18)F-FET) in patients with brain lesions suspicious of cerebral gliomas. METHODS: Fifty-two patients with suspicion of cerebral glioma were included in this study. From 30 to 50 min after injection of 180 MBq (18)F-FET, a first PET scan ((18)F-FET scan) was performed. Thereafter, 240 MBq (18)F-FDG was injected and a second PET scan was acquired from 30 to 60 min after the second injection ((18)F-FET/(18)F-FDG scan). The cerebral accumulation of (18)F-FDG was calculated by decay corrected subtraction of the (18)F-FET scan from the (18)F-FET/(18)F-FDG scan. Tracer uptake was evaluated by visual scoring and by lesion-to-background (L/B) ratios. The imaging results were compared with the histological results and prognosis. RESULTS: Histology revealed 24 low-grade gliomas (LGG) of World Health Organization (WHO) Grade II and 19 high-grade gliomas (HGG) of WHO Grade III or IV, as well as nine others, mainly benign histologies. The gliomas showed increased (18)F-FET uptake (>normal brain) in 86% and increased (18)F-FDG uptake (>white matter) in 35%. (18)F-FET PET provided diagnostically useful delineation of tumor extent while this was impractical with (18)F-FDG due to high tracer uptake in the gray matter. A local maximum in the tumor area for biopsy guidance could be identified with (18)F-FET in 76% and with (18)F-FDG in 28%. The L/B ratios showed significant differences between LGG and HGG for both tracers but considerable overlap so that reliable preoperative grading was not possible. A significant correlation of tracer uptake with overall survival was found with (18)F-FDG only. In some benign lesions like abscesses, increased uptake was observed for both tracers indicating a limited specificity of both techniques. CONCLUSIONS: (18)F-FET PET is superior to (18)F-FDG for biopsy guidance and treatment planning of cerebral gliomas. The uptake of (18)F-FDG is associated with prognosis, but the predictive value is limited and a histological evaluation of tumor tissue remains necessary. Therefore, amino acids like (18)F-FET are the preferred PET tracers for the clinical management of cerebral gliomas.

18F-FDG-PET and histopathology in 131I-lipiodol treatment for primary liver cancer.

The diagnostic accuracy of 18F-FDG-PET (fluoro-2-deoxyglucose-positron emission tomography) remains questionable for primary hepatocellular carcinoma (HCC) but seems to be more promising for restaging and therapy control. Yet, there are no data on FDG-PET in 131I-lipiodol treatment for primary liver cancer. The aim of this study was to relate baseline FDG-PET findings to histologic data and to assess, for the first time, the role of repetitive FDG-PET imaging for follow-up of 131I-lipiodol treatment. Eighteen (18) patients (16 HCC, 2 cholangiocellular carcinoma; CCC) with 36 treatment courses (up to four per patient) had 35 PET exams, including 18 post-treatment follow-up scans in 10 patients (up to three per patient, one without baseline PET; n = 17). Histopathologic results were available in 15 patients. PET results were retrospectively related to histopathologic type, grading, presence of cirrhosis, and tumor size at baseline and compared with computed tomography (CT) during follow-up. Prior to 131I-lipiodol treatment, 8 patients were PET positive and 9 PET negative. Most of the large HCCs were PET positive and most small tumors PET negative (p < 0.05), despite an overlap below 11 cm. There was no identifiable correlation between PET results and degree of tumor differentiation. Overall, 9 of 10 patients with 17 of 18 follow-up scans showed concordant results with CT. The one discrepant case became PET negative after the first treatment course, despite CT-proven tumor growth (false negative). Patient management was not changed due to PET results. In conclusion, large HCCs were significantly more often PET positive, but there was no correlation with the degree of differentiation. Follow-up PET may be useful if the tumor is first demonstrated to be FDG positive.

cis-4-[(18)F]-Fluoro-l-proline fails to detect peripheral tumors in humans.

UNLABELLED: System A amino acid transport is increased in transformed and malignant cells. The amino acid 4-cis[(18)F]fluoro-l-proline (cis-[(18)F]FPro) has been shown to be a substrate of the System A amino acid carrier. In this pilot study, we investigated the diagnostic potential of cis-[(18)F]FPro in patients with various tumors in comparison with [(18)F]fluorodeoxyglucose-positron emission tomography (FDG-PET). METHODS: Eight patients (seven females, one male, age range 43-77 years) with large primary, recurrent or metastatic tumors of different histologies were included in this study. One patient had a recurrent non-Hodgkin lymphoma; two patients, metastatic colon or rectal cancer; one, a metastatic endometrial cancer; one, a multiple myeloma; one, an Ewing sarcoma; one, a metastatic breast cancer and one, a gastrointestinal stromal tumor. PET scans of the trunk were acquired at 1 h after intravenous injection of 400 MBq cis-[(18)F]FPro and compared to PET scans with [(18)F]FDG. RESULTS: None of the tumors or metastatic lesions in this series of patients demonstrated relevant uptake of cis-[(18)F]FPro. In contrast, all tumors with exception of the multiple myeloma showed an intensive uptake of [(18)F]FDG. The mean standardized uptake value of cis-[(18)F]FPro in the tumor or metastases was significantly lower than that of [(18)F]FDG uptake (1.7+/-0.6 vs. 5.7+/-3.0; n=8; P<.01). CONCLUSION: Although other System A-specific tracers have shown relevant tumor uptake, cis-[(18)F]FPro fails to detect most types of human tumors. Based on these results, we cannot recommend a further evaluation of this tracer as a tumor-seeking agent.

Prognostic value of 18F-fluoroethyl-L-tyrosine PET and MRI in small nonspecific incidental brain lesions.

UNLABELLED: Nonspecific incidental brain lesions (NILs) are being detected more frequently because of an increasing number of screening or research MRI scans of the brain, and their natural course is uncertain. METHODS: In a prospective cohort study starting in 1999, we determined the outcomes of patients with incidental, nonenhancing, supratentorial, lobar, and small-volume (<10 mL) lesions, depending on the findings of MRI and PET with the (18)F-labeled amino acid fluoroethyl-l-tyrosine ((18)F-FET). Patients with seizures, focal neurologic deficits, signs of local or systemic infection or inflammation, known brain disease, or any kind of previous cerebral treatment were excluded. Finally, 21 patients were eligible. MRI was performed in 19 of these patients because of nonspecific symptoms (such as headaches, dizziness, or sudden deafness), whereas 2 patients were healthy volunteers in MRI studies. Clinical follow-up and MRI scans were obtained at 4- to 6-mo intervals, and follow-up ranged from 3 to 8.5 y. Mean lesion-to-brain (L/B) ratios of >or=1.6 on (18)F-FET PET were rated as positive. RESULTS: Four different outcome groups were identified. In group A, 5 NILs regressed or vanished completely. All of these lesions were circumscribed on MRI, and (18)F-FET uptake was negative, with an L/B ratio of 1.2+/-0.2 (mean +/- SD). In group B, 10 NILs were stable, without growth. All of these lesions were circumscribed on MRI, and (18)F-FET uptake was negative (L/B ratio: 1.0+/-0.1). In group C, 2 NILs grew slowly over years, and an astrocytoma of World Health Organization (WHO) grade II was diagnosed after resection in each case. The lesions were circumscribed on MRI, and (18)F-FET uptake was negative (L/B ratios: 0.7 and 1.0). In group D, 4 NILs showed sudden and rapid growth, with clinical deterioration, and a high-grade glioma of WHO grade III or IV was diagnosed after resection in all cases. The lesions were diffuse on MRI, and (18)F-FET uptake was significantly increased (L/B ratio: 2.0+/-0.4) (P<0.01 for group D vs. group A or group B). CONCLUSION: For NILs, a circumscribed growth pattern on MRI and normal or low (18)F-FET uptake on PET are strong predictors for a benign course, with the eventual development of a low-grade glioma. In contrast, NILs with a diffuse growth pattern on MRI and increased (18)F-FET uptake indicate a high risk for the development of a high-grade glioma.

Differential uptake of O-(2-18F-fluoroethyl)-L-tyrosine, L-3H-methionine, and 3H-deoxyglucose in brain abscesses.

UNLABELLED: The amino acid O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) has been shown to be a useful tracer for brain tumor imaging. Experimental studies demonstrated no uptake of (18)F-FET in inflammatory cells but increased uptake has been reported in single cases of human brain abscesses. To explore this inconsistency, we investigated the uptake of (18)F-FET in comparison with that of L-[methyl-(3)H]methionine ((3)H-MET) and D-(3)H-deoxyglucose ((3)H-DG) in brain and calf abscesses in rats. METHODS: Abscesses were induced in the brain (n = 9) and calf (n = 5) of Fisher CDF rats after inoculation of Staphylococcus aureus. Five days later, (18)F-FET and (3)H-MET (n = 10) or (18)F-FET and (3)H-DG (n = 4) were injected intravenously. One hour after injection the rats were sacrificed, and the brain or calf muscle was investigated using dual-tracer autoradiography. Lesion-to-background ratios (L/B) and standardized uptake values (SUVs) were calculated. The autoradiograms were compared with histology and immunostaining for glial fibrillary acidic protein (GFAP), CD68 for macrophages, and CD11b for microglia. RESULTS: (18)F-FET uptake in the area of macrophage infiltration and activated microglia at the rim of the brain abscesses was low (L/B, 1.5 +/- 0.4). In contrast, high uptake was observed for (3)H-MET as well as for (3)H-DG (L/B, 4.1 +/- 1.1 for (3)H-MET vs. 3.1 +/- 1.5 for (3)H-DG; P < 0.01 vs. (18)F-FET). Results for calf abscesses were similar. In the vicinity of the brain abscesses, slightly increased uptake was noted for (18)F-FET (L/B, 1.8 +/- 0.3) and (3)H-MET (L/B, 1.8 +/- 0.4), whereas (3)H-DG distribution was normal (L/B, 1.2 +/- 0.2). Anti-GFAP immunofluorescence showed a diffuse astrocytosis in those areas. CONCLUSION: Our results demonstrate that there is no accumulation of (18)F-FET in macrophages and activated microglia in experimental brain abscesses, whereas (3)H-MET and (3)H-DG exhibit high uptake in these cells. Thus, the specificity of (18)F-FET for gliomas may be superior to that (3)H-MET and (3)H-DG. Increased (18)F-FET uptake in human brain abscesses appears to be related to reactive astrocytosis.

Detection of secondary thalamic degeneration after cortical infarction using cis-4-18F-fluoro-D-proline.

UNLABELLED: The amino acid cis-4-(18)F-fluoro-D-proline (D-cis-(18)F-FPro) exhibits preferential uptake in the brain compared with its L-isomer, but the clinical potential of the tracer is as yet unknown. In this study we explored the cerebral uptake of D-cis-(18)F-FPro in rats with focal cortical infarctions. METHODS: Focal cortical infarctions were induced in different areas of the cortex of 20 Fisher CDF rats by photothrombosis (PT). At variable time points after PT (1 d to 4 wk), the rats were injected intravenously with D-cis-(18)F-FPro. For comparison, 12 rats were injected simultaneously with (3)H-deoxyglucose ((3)H-DG), 3 rats were injected with (3)H-methyl-L-methionine ((3)H-MET), and 2 rats were injected with (3)H-PK11195. Within 2 h after injection of the tracers, coronal cryosections of the brains were produced and evaluated by dual-tracer autoradiography. Lesion-to-brain ratios (L/B ratios) were calculated by dividing the maximal uptake in areas with increased tracer uptake by the mean uptake in normal brain tissue. Histologic slices were stained by toluidine blue and by immunostainings for glial fibrillary acidic protein (GFAP), CD68 for macrophages, and CD11b for microglia. RESULTS: Prominent uptake of D-cis-(18)F-FPro was found in ipsilateral thalamic nuclei (TN) and partially in the corpus striatum starting at 3 d after infarction with increasing L/B ratios up to 4 wk (mean L/B ratio +/- SD, 6.7 +/- 3.5). The involved TN varied with the site of the cortical lesion corresponding to their thalamocortical projections connecting them with their specific target region in the cerebral cortex. The TN were positive for CD11b and GFAP from day 7 onward, whereas uptake of (3)H-DG, (3)H-MET, and (3)H-PK11195 and immunostaining for CD68 were similar to that of normal brain. Furthermore, increased uptake of D-cis-(18)F-FPro was found in the area of the cortical infarctions (mean L/B ratio +/- SD, 12.1 +/- 8.1). From day 5 onward, the pattern of uptake was congruent with that of immunostaining for CD11b and CD68 but was different from that of GFAP. CONCLUSION: D-cis-(18)F-FPro appears to be a sensitive PET tracer for detection of secondary degeneration of TN after cortical injury. The uptake mechanisms of D-cis-(18)F-FPro remain to be elucidated, but the relationship to microglial activation suggests a diagnostic potential in various brain diseases.

Prognostic value of O-(2-18F-fluoroethyl)-L-tyrosine PET and MRI in low-grade glioma.

UNLABELLED: In glioma of World Health Organization (WHO) grade II (low-grade glioma), the natural course of a particular patient is not predictable and the treatment strategy is controversial. We determined prognostic factors in adult patients with untreated, nonenhancing, supratentorial low-grade glioma with special regard to PET using the amino acid O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) and MRI. METHODS: In a prospective study, baseline (18)F-FET PET and MRI analyses were performed on 33 consecutive patients with histologically confirmed low-grade glioma. None of the patients had radiation or chemotherapy. Clinical, histologic, therapeutic (initial cytoreduction vs. biopsy), (18)F-FET uptake, and MRI morphologic parameters were analyzed for their prognostic significance. Statistical endpoints were clinical or radiologic tumor progression, malignant transformation to glioma of WHO grade III or IV (high-grade glioma), and death. RESULTS: Baseline (18)F-FET uptake and a diffuse versus circumscribed tumor pattern on MRI were highly significant predictors of prognosis (P < 0.01). By the combination of these prognostically significant variables, 3 major prognostic subgroups of low-grade glioma patients could be identified. The first of these subgroups was patients with circumscribed low-grade glioma on MRI without (18)F-FET uptake (n = 11 patients, progression in 18%, no malignant transformation and no death). The second subgroup was patients with circumscribed low-grade glioma with (18)F-FET uptake (n = 13 patients, progression in 46%, malignant transformation to a high-grade glioma in 15%, and death in 8%). The third subgroup was patients with diffuse low-grade glioma with (18)F-FET uptake (n = 9 patients, progression in 100%, malignant transformation to a high-grade glioma in 78%, and death in 56%). CONCLUSION: We conclude that baseline amino acid uptake on (18)F-FET PET and a diffuse versus circumscribed tumor pattern on MRI are strong predictors for the outcome of patients with low-grade glioma.

[Improved diagnostics of cerebral gliomas using FET PET]. / Verbesserte Diagnostik von zerebralen Gliomen mit der FET PET.

Positron emission tomography (PET) using radiolabeled amino acids has shown great potential for more accurate diagnostics of cerebral gliomas. O-(2-[18F]Fluoroethyl)-L-tyrosine (FET) is a new tracer for PET which can be produced with high efficiency and distributed on a wide clinical scale in Germany. In a biopsy-controlled study, a significant improvement of the detection of true tumor extent of cerebral gliomas could be demonstrated by the combined use of FET PET and MRT in comparison with MRT alone. Advantages of FET PET are an improved guidance of biopsies, an improved planning of surgery and radiation therapy, and the differentiation of tumor recurrence from unspecific post-therapeutic tissue changes. Furthermore, FET PET appears to be particularly valuable in the prognosis of low-grade gliomas.

Differential uptake of [18F]FET and [3H]l-methionine in focal cortical ischemia.

UNLABELLED: Amino acids such as [(11)C-methyl]l-methionine are particularly useful in brain tumor diagnosis, but unspecific uptake (e.g., in cerebral ischemia) has been reported. O-(2-[(18)F]fluoroethyl)-l-tyrosine ([(18)F]FET) shows a clinical potential similar to that of l-methionine (MET) in brain tumor diagnosis but is applicable on a wider clinical scale. The aim of this study was to evaluate the uptake of [(18)F]FET and [(3)H]MET in focal cortical ischemia in rats by dual-tracer autoradiography. METHODS: Focal cortical ischemia was induced in 25 CDF rats using the photothrombosis (PT) model. At different time points up to 6 weeks after the induction of PT, [(18)F]FET and [(3)H]MET were injected intravenously. Additionally, contrast-enhanced magnetic resonance imaging (MRI) was performed in 10 animals. One hour after tracer injection, brains were cut in coronal sections and evaluated by dual-tracer autoradiography. Lesion-to-brain (L/B) ratios were calculated by dividing the maximal uptake in the lesion by the mean uptake in the brain. An L/B ratio of >2.0 was considered indicative of pathological uptake. Histological slices were stained by cresyl violet and supplemented by immunostainings for glial fibrillary acidic protein (GFAP) and CD68 in selected cases. RESULTS: A variably increased uptake of both tracers was observed in the PT lesion and its demarcation zone up to 7 days after PT for [(18)F]FET and up to 6 weeks for [(3)H]MET. The cutoff level of 2.0 was exceeded in 12/25 animals for [(18)F]FET and in 18/25 animals for [(3)H]MET. Focally increased tracer uptake matched contrast enhancement in MRI in 3/10 cases for [(18)F]FET and in 5/10 cases for [(3)H]MET. Immunohistochemical staining in lesions with differential uptake of [(18)F]FET and [(3)H]MET revealed that selective uptake of [(18)F]FET was associated with GFAP-positive astrogliosis while selective [(3)H]MET uptake correlated with CD68-positive macrophage infiltration. CONCLUSIONS: [(18)F]FET, like [(3)H]MET, may exhibit significant uptake in the periphery of cortical infarctions, which has to be considered in the differential diagnosis of unknown brain lesions. There are discrepancies between [(18)F]FET and [(3)H]MET uptake in the area of infarctions that appear to be caused by the preferential uptake of [(18)F]FET in reactive astrocytes versus the preferential uptake of [(3)H]MET in macrophages.

Hashimoto's encephalopathy and motor neuron disease: a common autoimmune pathogenesis?

Hashimoto's encephalopathy is a rare complication of autoimmune thyroiditis not associated with thyroidal function decline. We report a 50-year-old man presenting with lower motor neuron symptoms evolving over 3 years and changes in behavior associated with attentive and cognitive impairment occurring in the last few months. Memory deficits, emotional instability, marked dysarthria, mild symmetric weakness of the lower extremities and fasciculations were the most striking clinical features. EEG was diffusely slow, cranial MRI revealed multiple subcortical white matter lesions, CSF protein was slightly elevated, electromyographic recordings showed acute and chronic denervation and extremely high TPO antibody titers were found in the serum. Hashimoto's encephalopathy and lower motor neuron disease were diagnosed. As repeated high-dose intravenous methylprednisolone administration followed by oral tapering improved both central nervous system and lower motor neuron symptoms, the question was raised whether there was a common autoimmune pathogenesis of both clinically distinct diseases.

O-(2-[18F]fluoroethyl)-L-tyrosine: uptake mechanisms and clinical applications.

O-(2-[18F]fluoroethyl)-L-tyrosine (FET) is a promising tracer for PET that has demonstrated convincing results especially in the diagnostics of brain tumors. In contrast to other radiolabeled amino acids, it can be produced with high efficiency and distributed in a satellite concept like the widely used 2-[18F]fluoro-2-deoxy-D-glucose. Although FET is not incorporated into proteins, it shows high uptake in cerebral gliomas and in extracranial squamous cell carcinomas owing to increased transport. The tracer exhibits high in vivo stability, low uptake in inflammatory tissue and suitable uptake kinetics for clinical imaging, which indicates that it may become a new standard tracer for PET. In this article, the present knowledge on the uptake mechanisms and the clinical applications of FET are reviewed and the clinical perspectives are discussed.

18F-FET PET differentiation of ring-enhancing brain lesions.

UNLABELLED: The aim of this study was to explore the differential diagnostic value of PET using the amino acid O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) in patients with newly diagnosed solitary intracerebral lesions showing ring enhancement on contrast-enhanced MRI. METHODS: (18)F-FET PET analyses were performed on 14 consecutive patients with intracerebral ring-enhancing lesions. Eleven of the patients were additionally studied with (18)F-FDG PET. In all patients, the main differential diagnosis after MRI was a malignant lesion, in particular glioblastoma multiforme, versus a benign lesion, in particular brain abscess. A malignant tumor was suspected for lesions showing increased (18)F-FET uptake on PET images with a mean lesion-to-brain ratio of at least 1.6 ((18)F-FET PET positive). A nonneoplastic lesion was suspected in cases of minimal or absent (18)F-FET uptake, with a mean lesion-to-brain ratio of less than 1.6 ((18)F-FET PET negative). Histologic diagnosis was obtained by serial biopsies in 13 of the 14 patients. One patient refused the biopsy, but follow-up indicated an abscess because his lesion regressed under antibiotic therapy. RESULTS: Histology and clinical follow-up showed high-grade malignant gliomas in 5 patients and nonneoplastic lesions in 9 patients. The findings of (18)F-FET PET were positive in all 5 glioma patients and in 3 of 9 patients with nonneoplastic lesions, including 2 patients with brain abscesses and 1 patient with a demyelinating lesion. The findings of (18)F-FDG PET were positive (mean lesion-to-gray matter ratio > or = 0.7) in 4 of 4 glioma patients and 3 of 7 patients with nonneoplastic lesions. CONCLUSION: Although (18)F-FET PET has been shown to be valuable for the diagnostic evaluation of brain tumors, our data indicate that, like (18)F-FDG PET, (18)F-FET PET has limited specificity in distinguishing between neoplastic and nonneoplastic ring-enhancing intracerebral lesions. Thus, histologic investigation of biopsy specimens remains mandatory to make this important differential diagnosis.

18F-FET PET compared with 18F-FDG PET and CT in patients with head and neck cancer.

UNLABELLED: Recent studies suggest a somewhat selective uptake of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) in cerebral gliomas and in squamous cell carcinoma (SCC) and a good distinction between tumor and inflammation. The aim of this study was to investigate the diagnostic potential of 18F-FET PET in patients with SCC of the head and neck region by comparing that tracer with 18F-FDG PET and CT. METHODS: Twenty-one patients with suspected head and neck tumors underwent 18F-FET PET, 18F-FDG PET, and CT within 1 wk before operation. After coregistration, the images were evaluated by 3 independent observers and an ROC analysis was performed, with the histopathologic result used as a reference. Furthermore, the maximum standardized uptake values (SUVs) in the lesions were determined. RESULTS: In 18 of 21 patients, histologic examination revealed SCC, and in 2 of these patients, a second SCC tumor was found at a different anatomic site. In 3 of 21 patients, inflammatory tissue and no tumor were identified. Eighteen of 20 SCC tumors were positive for both 18F-FDG uptake and 18F-FET uptake, one 0.3-cm SCC tumor was detected neither with 18F-FDG PET nor with 18F-FET PET, and one 0.7-cm SCC tumor in a 4.3-cm ulcer was overestimated as a 4-cm tumor on 18F-FDG PET and missed on 18F-FET PET. Inflammatory tissue was positive for 18F-FDG uptake (SUV, 3.7-4.7) but negative for 18F-FET uptake (SUV, 1.3-1.6). The SUVs of 18F-FDG in SCC were significantly higher (13.0 +/- 9.3) than those of 18F-FET (4.4 +/- 2.2). The ROC analysis showed significantly superior detection of SCC with (18)F-FET PET or 18F-FDG PET than with CT. No significant difference (P = 0.71) was found between 18F-FDG PET and 18F-FET PET. The sensitivity of 18F-FDG PET was 93%, specificity was 79%, and accuracy was 83%. 18F-FET PET yielded a lower sensitivity of 75% but a substantially higher specificity of 95% (accuracy, 90%). CONCLUSION: 18F-FET may not replace 18F-FDG in the PET diagnostics of head and neck cancer but may be a helpful additional tool in selected patients, because 18F-FET PET might better differentiate tumor tissue from inflammatory tissue. The sensitivity of 18F-FET PET in SCC, however, was inferior to that of 18F-FDG PET because of lower SUVs.

Preferred stereoselective brain uptake of d-serine--a modulator of glutamatergic neurotransmission.

Although it has long been presumed that d-amino acids are uncommon in mammalians, substantial amounts of free d-serine have been detected in the mammalian brain. d-Serine has been demonstrated to be an important modulator of glutamatergic neurotransmission and acts as an agonist at the strychnine-insensitive glycine site of N-methyl-d-aspartate receptors. The blood-to-brain transfer of d-serine is thought to be extremely low, and it is assumed that d-serine is generated by isomerization of l-serine in the brain. Stimulated by the observation of a preferred transport of the d-isomer of proline at the blood-brain barrier, we investigated the differential uptake of [3H]-d-serine and [3H]-l-serine in the rat brain 1 h after intravenous injection using quantitative autoradiography. Surprisingly, brain uptake of [3H]-d-serine was significantly higher than that of [3H]-l-serine, indicating a preferred transport of the d-enantiomer of serine at the blood-brain barrier. This finding indicates that exogenous d-serine may have a direct influence on glutamatergic neurotransmission and associated diseases.

Preferred stereoselective transport of the D-isomer of cis-4-[18F]fluoro-proline at the blood-brain barrier.

Generally, L-amino acids are preferably transported into mammalian cells compared with their D-isomers, and only L-amino acids are incorporated into proteins. Former studies, however, indicated that D-[H]proline is accumulated in the brain of mice after injection, while L-[3H]proline is not. We investigated the differential cerebral uptake of the D- and L-isomers of the PET tracer cis-4-[18F]fluoroproline (D-/L-cis-FPro) and of D-/L-[3H]proline (D-/L-Pro) in rats by dual tracer autoradiography and the uptake of D-cis-FPro in two human subjects by PET. The standardized uptake value (SUV) of D-cis-FPro in the cerebral cortex of rats 2 h p.i. was 3.05+/-1.18 (n=9) versus 0.06+/-0.01 (n=4) for L-cis-FPro (P<0.001) and 1.29+/-0.27 (n=4) for D-Pro versus 0.30+/-0.14 (n=9) for L-Pro (P<0.001). Analysis of the rat brain tissue after injection of D-cis-FPro (n=3) revealed no radioactivity in the proteins but a relevant part in the form of L-trans-FPro. The PET studies yielded a four- to five-fold higher SUV and influx rate constant in the human cortex for D-cis-FPro than for L-cis-FPro. We conclude that D-cis-FPro and D-Pro are preferably transported at the blood-brain barrier compared with their L-isomers and isomerized to the L-form within the brain. Thus, D-Pro in the plasma might be a source of intracerebral L-proline, which has been shown to act as a modulator of excitatory neurotransmission.

Multimodal metabolic imaging of cerebral gliomas: positron emission tomography with [18F]fluoroethyl-L-tyrosine and magnetic resonance spectroscopy.

OBJECT: The purpose of this study was to determine the predictive value of [18F]fluoroethyl-L-tyrosine (FET)-positron emission tomography (PET) and magnetic resonance (MR) spectroscopy for tumor diagnosis in patients with suspected gliomas. METHODS: Both FET-PET and MR spectroscopy analyses were performed in 50 consecutive patients with newly diagnosed intracerebral lesions supposed to be diffuse gliomas on contrast-enhanced MR imaging. Lesion/brain ratios of FET uptake greater than 1.6 were considered positive, that is, indicative of tumor. Results of MR spectroscopy were considered positive when N-acetylaspartate (NAA) was decreased in conjunction with an absolute increase of choline (Cho) and an NAA/Cho ratio of 0.7 or less. An FET lesion/brain ratio, an NAA/Cho ratio, and signal abnormalities on MR images were compared with histological findings in neuronavigated biopsy specimens. The FET lesion/brain ratio and the NAA/Cho ratio were identified as significant independent predictors for the histological identification of tumor tissue. The accuracy in distinguishing neoplastic from nonneoplastic tissue could be increased from 68% with the use of MR imaging alone to 97% with MR imaging in conjunction with FET-PET and MR spectroscopy. Sensitivity and specificity for tumor detection were 100 and 81% for MR spectroscopy and 88 and 88% for FET-PET, respectively. Results of histological studies did not reveal tumor tissue in any of the lesions that were negative on FET-PET and MR spectroscopy. In contrast, a tumor diagnosis was made in 97% of the lesions that were positive with both methods. CONCLUSIONS: In patients with intracerebral lesions supposed to be diffuse gliomas on MR imaging, FET-PET and MR spectroscopy analyses markedly improved the diagnostic efficacy of targeted biopsies.

PET with O-(2-18F-Fluoroethyl)-L-Tyrosine in peripheral tumors: first clinical results.

UNLABELLED: O-(2-18F-Fluoroethyl)-L-Tyrosine (18F-FET) PET has shown promising results in brain tumor diagnosis. The aim of this prospective study was to evaluate 18F-FET PET in comparison with 18F-FDG PET in patients with peripheral tumors. METHODS: Forty-four consecutive patients with suspected malignant tumors underwent 18F-FET PET and 18F-FDG PET within 7 d. Whole-body PET studies were performed 1 h after intravenous injection of 370 MBq of 18F-FET or 18F-FDG. Six patients were excluded from the analysis because a malignant tumor could not be verified. In 38 patients (7 with colorectal cancer, 6 with pancreatic cancer, 9 with head-neck cancer, 4 with lymphomas, 3 with lung cancer, 3 with ovarian cancer, 4 with breast cancer, and 2 with prostatic cancer), 18F-FET PET and 18F-FDG PET were compared. RESULTS: 18F-FET was positive in only 13 of 38 patients (8 with head-neck cancer, 3 with breast cancer, and 2 with lung cancer), whereas 18F-FDG exhibited increased uptake in 37 of 38 patients. All squamous cell carcinomas were found to be 18F-FET-positive tumors (8 head-neck cancer and 2 lung cancer), whereas most adenocarcinomas were found to be 18F-FET-negative tumors. In patients with colorectal cancer, pancreatic cancer, ovarian cancer, prostatic cancer, and lymphomas, no increased 18F-FET uptake could be identified. All lesions that exhibited increased 18F-FET uptake also showed increased 18F-FDG uptake. No additional lesion was identified by 18F-FET PET but not by 18F-FDG PET. A subgroup analysis of patients with head-neck carcinomas allowed a better distinction between malignant and inflammatory tissues with 18F-FET than with 18F-FDG. CONCLUSION: 18F-FET is inferior to 18F-FDG as a PET tracer for general tumor diagnosis. Our preliminary results suggest rather selective uptake of 18F-FET in squamous cell carcinomas. Compared with 18F-FDG PET, 18F-FET PET may allow a better distinction between tumors and inflammatory tissues in patients with squamous cell carcinomas.

O-(2-[18F]fluoroethyl)-L-tyrosine PET combined with MRI improves the diagnostic assessment of cerebral gliomas.

MRI is commonly used to determine the location and extent of cerebral gliomas. We investigated whether the diagnostic accuracy of MRI could be improved by the additional use of PET with the amino acid O-(2-[18F]fluoroethyl)-l-tyrosine (FET). In a prospective study, PET with FET and MRI was performed in 31 patients with suspected cerebral gliomas. PET and MRIs were co-registered and 52 neuronavigated tissue biopsies were taken from lesions with both abnormal MRI signal and increased FET uptake (match), as well as from areas with abnormal MR signal but normal FET uptake or vice versa (mismatch). Biopsy sites were labelled by intracerebral titanium pellets. The diagnostic performance for the identification of cellular tumour tissue was analysed for either MRI alone or MRI combined with FET PET using alternative free response receiver operating characteristic curves (ROCs). Histologically, 26 biopsy samples corresponded to cellular glioma tissue and 26 to peritumoral brain tissue. The diagnostic performance, as determined by the area under the ROC curve (Az), was Az = 0.80 for MRI alone and Az = 0.98 for the combined MRI and FET PET approach (P < 0.001). MRI yielded a sensitivity of 96% for the detection of tumour tissue but a specificity of only 53%, and combined use of MRI and FET PET yielded a sensitivity of 93% and a specificity of 94%. Combined use of MRI and FET PET in patients with cerebral gliomas significantly improves the identification of cellular glioma tissue and allows definite histological tumour diagnosis. Thus, our findings may have considerable impact on target selection for diagnostic biopsies as well as therapy planning.

Can the apparent diffusion coefficient be used as a noninvasive parameter to distinguish tumor tissue from peritumoral tissue in cerebral gliomas?

PURPOSE: To determine whether the apparent diffusion coefficient (ADC) can be used to distinguish between tumor tissue and peritumoral brain tissue in cerebral gliomas. MATERIALS AND METHODS: Twenty-two patients with 44 biopsies were enrolled in this study. ADC maps calculated from a diffusion-weighted (DW) multislice EPI sequence were coregistered with conventional MR images. Neuronavigated biopsies and intraoperative markers were used for correlation with the histologic specimens. ADC values and lesion-to-brain ratios of the different sequences were calculated and compared for tumor tissue and peritumoral brain tissue. A logistic regression analysis was performed to determine the diagnostic value of the ADC maps. RESULTS: The ADC values and ratios demonstrated a large overlap between tumor tissue and peritumoral tissue. Group comparisons revealed a significantly (P=0.03) lower ADC ratio in tumor tissue (mean=1.28 +/- 0.39) compared to peritumoral tissue (mean=1.48 +/- 0.30), whereas the absolute ADC values did not differ significantly. In the logistic regression analysis, the lesion-to-brain ratio of the gadolinium (Gd)-enhanced T1-weighted sequence was the most valuable predictor of the presence of tumor tissue. The ADC value and ratio were not identified as significant predictors. CONCLUSION: The ADC is not helpful for distinguishing tumor tissue from peritumoral brain tissue in gliomas.

Comparison of O-(2-18F-fluoroethyl)-L-tyrosine PET and 3-123I-iodo-alpha-methyl-L-tyrosine SPECT in brain tumors.

UNLABELLED: The aim of this study was to compare PET with O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) and SPECT with 3-(123)I-iodo-alpha-methyl- L-tyrosine ((123)I-IMT) in patients with brain tumors. METHODS: Twenty patients with a suspected brain tumor were investigated by (18)F-FET PET, (123)I-IMT SPECT, and MRI within 3 wk. Region-of-interest analyses were performed on coregistered PET/SPECT/MRI images and the tumor-to-brain ratio (TBR), muscle-to-brain ratio (MBR), cerebellum-to-brain ratio (CerBR), and sinus-to-brain ratio (SBR) were calculated. In addition, the presence of tumor and the discrimination of anatomic structures on (18)F-FET PET and (123)I-IMT SPECT images were visually determined by 3 observers who were unaware of clinical data. RESULTS: The TBR of (18)F-FET and (123)I-IMT uptake in cerebral tumors showed a highly significant correlation (r = 0.96; P < 0.001). In the visual analysis for the presence or absence of tumors, no differences for (123)I-IMT SPECT and (18)F-FET PET were found in 19 of 20 patients; in one patient a low-grade glioma was only identified on (18)F-FET PET images but not on (123)I-IMT SPECT images. The contrast between tumor and normal brain was significantly higher in (18)F-FET PET (TBR, 2.0 +/- 0.9) than in (123)I-IMT SPECT (TBR, 1.5 +/- 0.5). The discrimination of anatomic structures yielded a significantly better score on (18)F-FET PET images (rating score, 2.6 +/- 0.9) compared with (123)I-IMT SPECT images (rating score, 1.7 +/- 0.9). The uptake of (18)F-FET in the muscles was significantly higher compared with (123)I-IMT (MBR (18)F-FET, 1.4 +/- 0.3; MBR (123)I-IMT, 0.6 +/- 0.2; P < 0.001) and (18)F-FET demonstrated a significantly higher blood-pool radioactivity than (123)I-IMT (SBR (18)F-FET, 1.3 +/- 0.2; SBR (123)I-IMT, 0.8 +/- 0.2; P < 0.001). CONCLUSION: The significant correlation of the TBRs of (18)F-FET and (123)I-IMT indicates that clinical experiences of brain tumor diagnostics with (123)I-IMT SPECT might be valid for (18)F-FET PET although substantial differences of the physiologic behavior were identified in extracerebral tissue. As (18)F-FET PET allows improved discrimination of anatomic structures and the tumor-to-brain contrast was significantly superior compared with (123)I-IMT SPECT scans, the results are encouraging for further evaluation of (18)F-FET for imaging brain tumors.