Biomedical subjects

Otto Muzik

Publications and source records attributed to Otto Muzik.

At least 19 recordsLinked to original sources

PubMed2006

In vivo uptake and metabolism of alpha-[11C]methyl-L-tryptophan in human brain tumors.

Abnormal metabolism of tryptophan has been implicated in modulation of tumor cell proliferation and immunoresistance. alpha-[(11)C]Methyl-L-tryptophan (AMT) is a PET tracer to measure cerebral tryptophan metabolism in vivo. In the present study, we have measured tumor tryptophan uptake in 40 patients with primary brain tumors using AMT PET and standard uptake values (SUV). Tryptophan metabolism was further quantified in 23 patients using blood input data. Estimates of the volume of distribution (VD') and the metabolic rate constant (k(3)') were calculated and related to magnetic resonance imaging (MRI) and histology findings. All grade II to IV gliomas and glioneuronal tumors showed increased AMT SUV, including all recurrent/residual tumors. Gadolinium enhancement on MRI was associated with high VD' values, suggesting impaired blood-brain barrier, while k(3)' values were not related to contrast enhancement. Low-grade astrocytic gliomas showed increased tryptophan metabolism, as measured by k(3)'. In contrast, oligodendrogliomas showed high VD' values but lower k(3)' as compared with normal cortex. In astrocytic tumors, low grade was associated with high k(3)' and lower VD', while high-grade tumors showed the reverse pattern. The findings show high AMT uptake in primary and residual/recurrent gliomas and glioneuronal tumors. Increased AMT uptake can be due to increased metabolism of tryptophan and/or high volume of distribution, depending on tumor type and grade. High tryptophan metabolic rates in low-grade tumors may indicate activation of the kynurenine pathway, a mechanism regulating tumor cell growth. AMT PET might be a useful molecular imaging method to guide therapeutic approaches aimed at controlling tumor cell proliferation by acting on tryptophan metabolism.

Adolescent↗

PubMed2006

Use of 2-deoxy-2-[F-18]-fluoro-D-glucose positron emission tomography to monitor therapeutic response by rhabdomyosarcoma in children: report of a retrospective case study.

PURPOSE: The purpose of this study was to study the use of 2-deoxy-2-[F-18]-fluoro-D-glucose positron emission tomography (F-18 FDG PET) for monitoring therapeutic response by rhabdomyosarcoma (RMSA) in children. PATIENTS AND METHODS: A retrospective case study was performed by searching a computer database for the patients with RMSA in whom F-18 FDG PET studies were performed pre- and posttreatment. The data of the PET studies from these patients were analyzed in conjunction with clinical treatment and other imaging studies to determine whether interval changes of F-18 FDG uptake by the RMSA reflect response of RMSA to treatment. RESULTS: Four patients with RMSA who received both pretreatment and posttreatment F-18 FDG PET studies were identified from the database and included in this study. A dramatic decrease of F-18 FDG uptake by the tumor was evident in the patients who had a favorable response to the therapy and prolonged remission of the disease. In contrast, persistent abnormal FDG uptake in one patient was associated with early relapse of the RMSA. CONCLUSIONS: F-18 FDG PET may be useful for monitoring therapeutic response by RMSA in children, which needs to be verified with a prospective study in a larger patient population.

Child↗

PubMed2006

Hippocampal and thalamic diffusion abnormalities in children with temporal lobe epilepsy.

PURPOSE: Previous studies using diffusion MRI in patients with temporal lobe epilepsy have shown abnormal water diffusion in the hippocampus. Because thalamus and lentiform nuclei are considered important for the regulation of cortical excitability and seizure propagation, we analyzed diffusion tensor imaging (DTI) abnormalities in these subcortical structures and in hippocampus of children with partial epilepsy with and without secondary generalization. METHODS: Fourteen children with partial epilepsy involving the temporal lobe underwent MRI including a DTI sequence. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained in the hippocampus, thalamus, and lentiform nucleus, and compared with DTI data of 14 control children with no epilepsy, as well as glucose positron emission tomography (PET) findings. RESULTS: Decreased FA (p < 0.001) and increased ADC (p = 0.003) values were found in the hippocampi ipsilateral to the seizure focus. Significant FA decreases (p = 0.002) also were seen in the contralateral hippocampi, despite unilateral seizure onset and excellent surgical outcome in patients who underwent surgery. ADC values showed a trend for increase in the thalami ipsilateral to the epileptic focus in the seven children with secondarily generalized seizures (p = 0.09). No group differences of ADC or FA were found in the lentiform nuclei. The DTI variables did not correlate with regional glucose metabolism in any of the structures analyzed. CONCLUSIONS: Increased ADC values in hippocampus can assist in lateralizing the seizure focus, but decreased FA in the contralateral hippocampus suggests that it too may be dysfunctional despite unilateral seizure onset. Less-robust thalamic abnormalities of water diffusion in patients with secondarily generalized seizures suggest secondary involvement of the thalamus, perhaps due to recruitment of this structure into the epileptic network; however, this must be confirmed in a larger population. DTI appears to be a sensitive method for detection abnormalities in children with partial epilepsy, even in structures without apparent changes on conventional MRI.

Adolescent↗

PubMed2006

Longitudinal changes in cortical glucose hypometabolism in children with intractable epilepsy.

In children with partial epilepsy, there is increasing evidence to suggest that not all cortical regions showing glucose hypometabolism on positron emission tomography (PET) represent epileptogenic cortex but that some hypometabolic areas might be the result of repeated seizures. Most of the supportive data, however, have come from cross-sectional imaging studies. To evaluate longitudinal changes in cortical glucose hypometabolism, we compared two sequential [(18)F]fluorodeoxyglucose (FDG) PET scans performed 7 to 44 months apart in 15 children with intractable nonlesional partial epilepsy. The extent of hypometabolic cortex on the side of the electroencephalography-verified epileptic focus and its changes between the two PET scans were measured and correlated to clinical seizure variables. The change in seizure frequency between the two PET scans correlated positively with the change in the extent of cortical glucose hypometabolism (r = .8, P <.001). Most patients with persistent or increased seizure frequency (one or more seizures per day) showed enlargement in the area of hypometabolic cortex on the second PET scan. In contrast, patients whose seizure frequency had decreased below daily seizures between the first and second PET scans showed a decrease in the size of the hypometabolic cortex. These results support the notion that the extent of cortical glucose hypometabolism on PET scanning can undergo dynamic changes, and these are, at least partly, related to the frequency of seizures. The findings have implications on how aggressively persistent seizures should be treated in children. (J Child Neurol 2006;21:26-31).

Adolescent↗

PubMed2006

Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates.

We assessed the structural and functional imaging features of cerebellar lesions and their neurobehavioral correlates in a large cohort of patients with tuberous sclerosis complex. A consecutive series of 78 patients with tuberous sclerosis complex underwent magnetic resonance imaging (MRI) and positron emission tomography (PET) studies with [(18)F]fluorodeoxyglucose (FDG) and alpha-[(11)C]methyl-l-tryptophan (AMT) as part of their evaluation for epilepsy surgery. Neurobehavioral assessment included the Gilliam Autism Rating Scales (GARS) and the Vineland Adaptive Behavior Scales (VABS). Twenty-one patients (27%) had cerebellar lesions (10 boys; mean age 9 +/- 8 years; 9 had right-sided, 10 had left-sided, and 2 had bilateral cerebellar lesions). The lesions showed decreased glucose metabolism (0.79 +/- 0.10) and increased (1.04 +/- 0.10) AMT uptake compared with the normal (nonlesional) cerebellar cortex. Comparisons between patients with (n = 20) and without (n = 57) a cerebellar lesion on neurobehavioral functioning, controlling for the number and location of cortical tubers, revealed that the cerebellar lesion group had higher overall autistic symptomatology. Within-group analyses of the cerebellar lesion group revealed that children with right-sided cerebellar lesions had higher social isolation and communicative and developmental disturbance compared with children with left-sided cerebellar lesions. The side of the cerebellar lesion was not related to adaptive behavior functioning. These findings provide additional empiric support for a role of the cerebellum in autistic symptomatology. Further investigation of the potential role of the right cerebellum in autism, particularly with regard to the dentatothalamofrontal circuit, is warranted.

Adolescent↗

PubMed2006

Abnormal brain connectivity in children after early severe socioemotional deprivation: a diffusion tensor imaging study.

OBJECTIVES: We previously reported that children who were subjected to early socioemotional deprivation in Romanian orphanages showed glucose hypometabolism in limbic and paralimbic structures, including the orbital frontal gyrus, infralimbic prefrontal cortex, hippocampus/amygdala, lateral temporal cortex, and the brainstem. The present study used diffusion tensor imaging tractography to examine the integrity of white matter tracts that connect these brain regions. METHODS: Fractional anisotropy and apparent diffusion coefficient for uncinate fasciculus, stria terminalis, fornix, and cingulum were measured in 7 right-handed children (5 girls and 2 boys; mean age: 9.7 +/- 2.6 years) with a history of early severe socioemotional deprivation in Eastern European orphanages and compared with similar measurements in 7 right-handed normal children (4 girls and 3 boys; mean age: 10.7 +/- 2.8 years). RESULTS: Neuropsychological assessment of the orphans verified the relatively mild specific cognitive impairment and impulsivity consistent with previous studies of children who were adopted from Romanian orphanages. Fractional anisotropy values in the left uncinate fasciculus were decreased significantly in the early deprivation group compared with control subjects. Apparent diffusion coefficient values for the early deprivation group tended to be greater than that in control subjects in all of the tracts measured, without reaching statistical significance. CONCLUSION: Our study demonstrates in children who experienced socioemotional deprivation a structural change in the left uncinate fasciculus that partly may underlie the cognitive, socioemotional, and behavioral difficulties that commonly are observed in these children.

Brain↗

PubMed2006

PET of human prostate cancer xenografts in mice with increased uptake of 64CuCl2.

UNLABELLED: Our objective was to determine whether human prostate cancer xenografts in mice can be localized by PET using 64CuCl2 as a probe (64Cu PET). METHODS: Athymic mice bearing human prostate cancer xenografts were subjected to 64Cu PET, followed by quantitative analysis of the tracer concentrations and immunohistochemistry study of human copper transporter 1 expression in the tumor tissues. RESULTS: Human prostate cancer xenografts expressing high levels of human copper transporter 1 were well visualized on the PET images obtained 24 h after injection but not on the images obtained 1 h after injection. PET quantitative analysis demonstrated a high concentration of 64CuCl2 in the tumors in comparison to that in the left shoulder regions (percentage injected dose per gram of tissue: 3.6 +/- 1.3 and 0.6 +/- 0.3, respectively; P = 0.004), at 24 h after injection. CONCLUSION: The data from this study suggested that locally recurrent prostate cancer might be localized with 64Cu PET using 64CuCl2 as a probe.

Animals↗

PubMed2006

Quantification of protein synthesis in the human brain using L-[1-11C]-leucine PET: incorporation of factors for large neutral amino acids in plasma and for amino acids recycled from tissue.

UNLABELLED: The rate of incorporation of exogenous amino acids into brain proteins is indicative of the protein synthesis rate (PSR). The objective of this study was to assess the effect of plasma concentrations of leucine and large neutral amino acids (LNAAs) on the unidirectional uptake rate constant (Kcplx) of l-[1-(11)C]-leucine in the brain and to estimate the amino acid pool recycled from tissue. METHODS: Twenty-seven healthy adult volunteers (11 men and 16 women; age range, 20-50 y) underwent dynamic l-[1-(11)C]-leucine PET with arterial blood sampling. Data were analyzed with a standard 2-tissue-compartment model yielding the unidirectional uptake rate of plasma leucine into tissue (Kcplx = K(1)k(3)/(k(2) + k(3))) and the fraction of leucine originating from exogenous sources (lambda = k(2)/(k(2) + k(3))). PSR in brain was calculated as PSR = [Kcplx/lambda] x leucine. RESULTS: The mean plasma concentration of the sum of all LNAAs was 13% higher in men (981 +/- 86 micromol/L) than in women (850 +/- 76 micromol/L, P = 0.012), whereas the plasma leucine concentration was found to be similar in both sexes (men, 64 +/- 20 micromol/L; women, 58 +/- 21 micromol/L, P = 0.57). The whole-brain value for lambda was determined to be 0.64 +/- 0.03 and did not show a sex difference (P = 0.66). Whole-brain Kcplx values were significantly higher in women (0.0162 +/- 0.0024) than in men (0.0121 +/- 0.0031, P = 0.011); however, after normalization of the Kcplx to a standard plasma concentration of the sum of all LNAAs (Kcplx'), the Kcplx' was similar between the sexes (P = 0.21), as was the PSR' (1.24 +/- 0.49 micromol/L/min in men; 1.29 +/- 0.62 micromol/L/min in women, P = 0.87). No relationship between plasma leucine and Kcplx (r = -0.13, P = 0.63) was observed. Finally, there was a significant correlation between the PSR and the Kcplx derived using Patlak graphical analysis (rho = 0.65, P < 0.001). CONCLUSION: We conclude that both the Kcplx macroparameter and the PSR are stable indices of brain protein synthesis and are appropriate measures for testing altered protein synthesis in neurologic disorders.

Adult↗

PubMed2005

Imaging the pharmacokinetics of [F-18]FAU in patients with tumors: PET studies.

PURPOSE: FAU (1-(2'-deoxy-2'-fluoro-beta-D: -arabinofuranosyl) uracil) can be phosphorylated by thymidine kinase, methylated by thymidylate synthase, followed by DNA incorporation and thus functions as a DNA synthesis inhibitor. This first-in-human study of [F-18]FAU was conducted in cancer patients to determine its suitability for imaging and also to understand its pharmacokinetics as a potential antineoplastic agent. METHODS: Six patients with colorectal (n = 3) or breast cancer (n = 3) were imaged with [F-18]FAU. Serial blood and urine samples were analyzed using HPLC to determine the clearance and metabolites. RESULTS: Imaging showed that [F-18]FAU was concentrated in breast tumors and a lymph node metastasis (tumor-to-normal-breast-tissue-ratio 3.7-4.7). FAU retention in breast tumors was significantly higher than in normal breast tissues at 60 min and retained in tumor over 2.5 h post-injection. FAU was not retained above background in colorectal tumors. Increased activity was seen in the kidney and urinary bladder due to excretion. Decreased activity was seen in the bone marrow with a mean SUV 0.6. Over 95% of activity in the blood and urine was present as intact [F-18]FAU at the end of the study. CONCLUSIONS: Increased [F-18]FAU retention was shown in the breast tumors but not in colorectal tumors. The increased retention of FAU in the breast compared to bone marrow indicates that FAU may be useful as an unlabeled antineoplastic agent. The low retention in the marrow indicates that unlabeled FAU might lead to little marrow toxicity; however, the images were not of high contrast to consider FAU for diagnostic clinical imaging.

Arabinofuranosyluracil↗

PubMed2005

A simplified analysis of [18F]3'-deoxy-3'-fluorothymidine metabolism and retention.

PURPOSE: [18F]3'-deoxy-3'-fluorothymidine (FLT) is a thymidine analog developed for imaging tumor proliferation with positron emission tomography (PET). To quantitatively assess images, the blood activities of FLT and its glucuronidated metabolite were measured and its kinetics analyzed. This study sought to limit the number of blood samples needed to measure FLT retention. METHODS: Total FLT activity was measured from 18 venous samples obtained over the first hour and dynamic imaging performed on 33 patients (average dose 350 MBq/mmol). The 5-, 10-, 30- and 60-min samples were analyzed to measure the fraction of activity in FLT and its glucuronide. HPLC analysis was compared against a two-step column (Sep-Pak) and metabolic rates measured using full and limited sampling. Probenecid (2 g, oral) was given to two patients to determine whether imaging of the liver improved. RESULTS: At 60 min, 74% of the blood activity was unmetabolized (range 57-85%). HPLC and Sep-Pak gave comparable results (r=0.97; average difference 2.1%). For kinetic analysis, eight venous samples were sufficient to accurately measure total activity; for metabolite analysis, a single sample at 60 min yielded data with mean errors of 2.2%. The metabolic rate correlated with average SUV (r2=0.85; p=0.0002). An aorta input function gave kinetic results comparable to venous blood (r2=0.82). Probenecid did not improve imaging of the liver. CONCLUSION: Dynamic measurements of FLT retention can be used to calculate metabolic rates using a limited set of samples and correction for metabolites measured in a single sample obtained at 60 min.

Computer Simulation↗

PubMed2005

Imaging DNA synthesis with [18F]FMAU and positron emission tomography in patients with cancer.

PURPOSE: FMAU (1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)thymine) is a thymidine analog that can be phosphorylated by thymidine kinase and incorporated into DNA. This first-in-human study of [18F]FMAU was conducted as a pilot in patients to determine its biodistribution and suitability for imaging DNA synthesis in tumors using positron emission tomography (PET). METHODS: Fourteen patients with diverse cancers (brain, prostate, colorectal, lung, and breast) were imaged with [18F]FMAU. We obtained dynamic PET images for 60 min and a whole-body image. Blood and urine samples were analyzed by high-performance liquid chromatography to measure metabolites and clearance. RESULTS: Active tumors in the breast, brain, lung and prostate were clearly visualized with standardized uptake values (SUVs) of 2.19, 1.28, 2.21, and 2.27-4.42, respectively. Unlike with other tracers of proliferation, low uptake of [18F]FMAU was seen in the normal bone marrow (SUV(mean) 0.7), allowing visualization of metastatic prostate cancer (SUV 3.07). Low background was also observed in the brain, pelvis, and thorax, aside from heart uptake (SUV 3.36-8.78). In the abdomen, increased physiological uptake was seen in the liver (SUV 10.07-20.88) and kidneys (SUV 7.18-15.66) due to metabolism and/or excretion, but the urinary bladder was barely visible (SUV(mean) 2.03). On average, 95% of the activity in the blood was cleared within 10 min post injection and an average of 70% of the activity in the urine was intact FMAU at 60 min post injection. CONCLUSION: Tumors in the brain, prostate, thorax, and bone can be clearly visualized with FMAU. In the upper abdomen, visualization is limited by the physiological uptake by the liver and kidneys.

Adult↗

PubMed2005

Application of an objective method for localizing bilateral cortical FDG PET abnormalities to guide the resection of epileptic foci.

PURPOSE: In order to improve the objective localization of bilateral cortical abnormalities in positron emission tomography (PET) image volumes, we developed a new three-dimensional image processing technique. The accuracy of this approach with respect to invasive subdural electroencephalography (EEG) data was assessed in a group of children with neocortical epilepsy. METHODS: Glucose PET image volumes were obtained from 12 epileptic children (mean age 5.2 +/- 4.3 years). Bilateral cortical areas of abnormal glucose metabolism were objectively determined using two conditional criteria assessed against a normal database. The normal database was derived from a group of 15 adult controls (mean age 27.6 years). The spatial relationship between seizure onset electrodes and PET abnormalities was assessed using a conventional receiver operating characteristic (ROC) analysis as well as using a newly defined spatial proximity index (SPI), which characterizes the association between adjacent, but not coincident, abnormalities. RESULTS: ROC analysis at the 2 standard deviation (SD) threshold, revealed an accuracy of 65% to detect seizure onset areas with a sensitivity of 64 +/- 17% and a specificity of 66 +/- 24%. Sensitivity decreased to 46 +/- 24% at the 3-SD threshold with a specificity of 80 +/- 21% (accuracy 75%). The average value for the SPI was determined as 3.82 +/- 1.65 which was 20% lower than the SPI value calculated using a simple in-plane two-dimensional asymmetry between homotopic cortical segments (4.52 +/- 3.82). CONCLUSION: The presented image processing technique improves localization of cortical abnormalities and provides valuable imaging clues for placement of subdural EEG grids prior to surgical resection.

Adolescent↗

PubMed2005

Origin and propagation of epileptic spasms delineated on electrocorticography.

PURPOSE: Ictal electrographic changes were analyzed on intracranial electrocorticography (ECoG) in children with medically refractory epileptic spasms to assess the dynamic changes of ictal discharges associated with spasms and their relation to interictal epileptiform activity and neuroimaging findings. METHODS: We studied a consecutive series of 15 children (age 0.4 to 13 years; nine girls) with clusters of epileptic spasms recorded on prolonged intracranial subdural ECoG recordings, which were being performed for subsequent cortical resection, and in total, 62 spasms were analyzed by using quantitative methods. RESULTS: Spasms were associated with either a "leading" spike followed by fast-wave bursts (type I: 42 events analyzed quantitatively) or fast-wave bursts without a "leading" spike (type II: 20 events analyzed quantitatively). Twenty-three of the 42 type I spasms but none of the 20 type II spasms were preceded by a focal seizure. A "leading" spike had a focal origin in all 42 type I spasms and involved the pre- or postcentral gyrus within 0.1 s in 37 of these spasms. A leading spike was associated with interictal spike activity >1/min in 40 of 42 type I spasms and originated within 2 cm from a positron emission tomography glucose hypometabolic region in all but two type I spasms. Failure to resect the cortex showing a leading spike was associated with poor surgical outcome (p = 0.01; Fisher's exact probability test). Fast-wave bursts associated with spasms involved neocortical regions extensively at least in two lobes within 1.28 s in all 62 spasms and involved the pre- or postcentral gyrus in 53 of 62 spasms. CONCLUSIONS: Epileptic spasms may be triggered by a focal neocortical impulse in a subset of patients, and a leading spike, if present, might be used as a marker of the trigger zone for epileptic spasms. Rapidly emerging widespread fast-wave bursts might explain the clinical semiology of epileptic spasms.

Brain Mapping↗

PubMed2005

Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha-[11C]methyl-L-tryptophan positron emission tomography (PET).

Tuberous sclerosis complex is commonly associated with medically intractable seizures. We previously demonstrated that high uptake of alpha-[11C]methyl-L-tryptophan (AMT) on positron emission tomography (PET) occurs in a subset of epileptogenic tubers consistent with the location of seizure focus. In the present study, we analyzed the surgical outcome of children with tuberous sclerosis complex in relation to AMT PET results. Seventeen children (mean age 4.7 years) underwent epilepsy surgery, guided by long-term videoelectroencephalography (EEG) (including intracranial EEG in 14 cases), magnetic resonance imaging (MRI), and AMT PET. AMT uptake values of cortical tubers were measured using regions of interest delineated on coregistered MRI and were divided by the value for normal-appearing cortex to obtain an AMT uptake ratio. Based on surgical outcome data, tubers showing increased AMT uptake (uptake ratio greater than 1.00) were classified into three categories: (1) epileptogenic (tubers within an EEG-defined epileptic focus whose resection resulted in seizure-free outcome), (2) nonepileptogenic (tubers that were not resected but the patient became seizure free), or (3) uncertain (all other tubers). Increased AMT uptake was found in 30 tubers of 16 children, and 23 of these tubers (77%) were located in an EEG-defined epileptic focus. The tuber with the highest uptake was located in an ictal EEG onset region in each patient. Increased AMT uptake indicated an epileptic region not suspected by scalp EEG in four cases. Twelve children (71%) achieved seizure-free outcome (median follow-up 15 months). Based on outcome criteria, 19 of 30 tubers (63%) with increased AMT uptake were epileptogenic, and these tubers had significantly higher AMT uptake than the nonepileptogenic ones (P = .009). Tubers with at least 10% increase of AMT uptake (in nine patients) were all epileptogenic. Using a cutoff threshold of 1.02 for AMT uptake ratio provided an optimal accuracy of 83% for detecting tubers that needed to be resected to achieve a seizure-free outcome. The findings suggest that resection of tubers with increased AMT uptake is highly desirable to achieve seizure-free surgical outcome in children with tuberous sclerosis complex and intractable epilepsy. AMT PET can provide independent complementary information regarding the localization of epileptogenic regions in tuberous sclerosis complex and enhance the confidence of patient selection for successful epilepsy surgery.

Carbon Radioisotopes↗

PubMed2005

Imaging DNA synthesis in vivo with 18F-FMAU and PET.

UNLABELLED: We imaged DNA synthesis in vivo with PET and (18)F-1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)thymine (FMAU), which is phosphorylated by thymidine kinases and incorporated into DNA. METHODS: We produced (18)F-FMAU and injected the tracer into 5 normal dogs and studied them by imaging or biodistribution for up to 2.5 h. The pharmacokinetics of FMAU in blood and urine were determined using high-performance liquid chromatography analysis. At the end of each study, selected tissues were removed to measure the total activity retained in these tissues. In addition, the selected tissues were extracted by acid precipitation, by which the macromolecules can be precipitated to determine the radioactivity of (18)F-FMAU incorporated into DNA. RESULTS: Imaging and tissue analysis showed increased activity in the lymph nodes, stomach, small intestine, and bone marrow, with mean standardized uptake values of 1.4, 1.6, 2.3, and 3.9, respectively, because of varying degrees of increased cell proliferation. In contrast, (18)F-FMAU was distributed with tissue-to-muscle ratios of approximately 1.0 in nonproliferative organs such as lung, liver, and kidneys. Analysis of the tissue extracts using acid precipitation demonstrated that 88% of activity in marrow and 65% of activity in small intestine was acid precipitated. However, more than 90% of activity in the nonproliferating tissues such as heart and lungs was in the supernatant. Increased activity was seen in the heart because of a high level of thymidine kinase 2 and in the gallbladder because of excretion. Analysis of blood and urine demonstrated that more than 95% of activity was present as intact (18)F-FMAU at the end of the studies. CONCLUSION: The results showed that (18)F-FMAU was selectively retained in DNA of the proliferating tissues and was resistant to degradation. These features indicate that (18)F-FMAU might be an alternative to (11)C-thymidine for imaging DNA synthesis in normal tissues and tumors.

Animals↗

PubMed2005

Biodistribution and radiation dosimetry estimates of 1-(2'-deoxy-2'-(18)F-Fluoro-1-beta-D-arabinofuranosyl)-5-bromouracil: PET imaging studies in dogs.

UNLABELLED: This study reports on the biodistribution and radiation estimates of 1-(2'-deoxy-2'-(18)F-fluoro-1-beta-d-arabinofuranosyl)-5-bromouracil ((18)F-FBAU), a potential tracer for imaging DNA synthesis. METHODS: Three normal dogs were intravenously administered (18)F-FBAU and a dynamic PET scan was performed for 60 min over the upper abdomen followed by a whole-body scan for a total of 150 min. Blood samples were collected at stipulated time intervals to evaluate tracer clearance and metabolism. Tissue samples of various organs were analyzed for tracer uptake and DNA incorporation. Dynamic accumulation of the tracer in different organs was derived from reconstructed PET images. The radiation dosimetry of (18)F-FBAU was evaluated using the MIRD method. RESULTS: At 60 min after injection, blood analysis found >90% of the activity in unmetabolized form. At 2 h after injection, (18)F-FBAU uptake was highest in proliferating tissues (mean SUVs: marrow, 2.6; small intestine, 4.0), whereas nonproliferative tissues showed little uptake (mean SUVs: muscle, 0.75; lung, 0.70; heart, 0.85; liver, 1.28). Dynamic image analysis over 60 min showed progressive uptake of the tracer in marrow. Extraction studies demonstrated that most of the activity in proliferative tissues was in the acid-insoluble fraction (marrow, 83%; small intestine, 73%), consistent with incorporation into DNA. In nonproliferative tissue, most of the activity was not found in the acid-insoluble fraction (>84% for heart, muscle, and liver). CONCLUSION: These results demonstrate that (18)F-FBAU was resistant to metabolism, readily incorporated into DNA in proliferating tissues, and showed good contrast between organs of variable DNA synthesis. These findings indicate that (18)F-FBAU may find use in measuring DNA synthesis with PET.

Animals↗

PubMed2004

Synthesis procedure for routine production of [carbonyl-11C]desmethyl-WAY-100635.

An improved one-pot synthesis procedure for routine production of [carbonyl-(11)C]desmethyl-WAY-100635 ([(11)C]DWAY) is described. An efficient purification of the crude product has also been developed and was accomplished by C-18 reversed-phase semi-preparative HPLC using 55/45 EtOH-NaH(2)PO(4) buffer (20 mM, pH=6.5) as the eluent. The desired product fraction was collected in a 2.0-2.5 mL volume and formulated with 11 mL of 0.9% saline. The radioligand was ready for human use in 45 min (EOB). The product was obtained with a radiochemical yield of 11.1+/-1.8% (EOB, n=15) with a radiochemical purity of >99%. Specific activity was 133.2-185.0 GBq/micromol (3.6-5.0 Ci/micromol, EOS, n=2) when ca. 37.0 GBq (ca. 1.0 Ci) of starting [(11)C]CO(2) was used. Unlabeled mass of [(11)C]DWAY was found to be 0.15-0.24 microg/mL and the precursor was present in less than 50 ng/mL in final production solution.

Carbon Radioisotopes↗

PubMed2004

Quantitative visualization of ictal subdural EEG changes in children with neocortical focal seizures.

OBJECTIVE: To quantify the ictal subdural electroencephalogram (EEG) changes using spectral analysis, and to delineate the quantitatively defined ictal onset zones on high-resolution 3D MR images in children with intractable neocortical epilepsy. METHODS: Fourteen children with intractable neocortical epilepsy (age: 1-16 years) who had subsequent resective surgery were retrospectively studied. The subjects underwent a high-resolution MRI and prolonged subdural EEG recording. Spectral analysis was applied to 3 habitual focal seizures. After fast Fourier transformation of the EEG epoch at ictal onset, an amplitude spectral curve (square root of the power spectral curve) was created for each electrode. The EEG magnitude of ictal rhythmic discharges was defined as the area under the amplitude spectral curve within a preset frequency band including the ictal discharge frequency, and calculated for each electrode. The topography mapping of ictal EEG magnitude was subsequently displayed on a surface-rendered MRI. Finally, receiver operating characteristic (ROC) analysis was performed to evaluate the consistency between quantitatively and visually defined ictal onset zones. RESULTS: The electrode showing the maximum of the averaged ictal EEG magnitude was part of the visually defined ictal onset zone in all cases. ROC analyses demonstrated that electrodes showing >30% of the maximum of the averaged ictal EEG magnitude had a specificity of 0.90 and a sensitivity of 0.74 for the concordance with visually defined ictal onset zones. SIGNIFICANCE: Quantitative ictal subdural EEG analysis using spectral analysis may supplement conventional visual inspection in children with neocortical epilepsy by providing an objective definition of the onset zone and its simple visualization on the patient's MRI.

Adolescent↗