Mathematical Model for Evaluation of Tumor Response in Targeted Radionuclide Therapy with 211At Using Implanted Mouse Tumor.

Recent introduction of alpha-emitting radionuclides in targeted radionuclide therapy has stimulated the development of new radiopharmaceuticals. Preclinical evaluation using an animal experiment with an implanted tumor model is frequently used to examine the efficiency of the treatment method and to predict the treatment response before clinical trials. Here, we propose a mathematical model for evaluation of the tumor response in an implanted tumor model and apply it to the data obtained from the previous experiment of 211At treatment in a thyroid cancer mouse model. The proposed model is based on the set of differential equations, describing the kinetics of radiopharmaceuticals, the tumor growth, and the treatment response. First, the tumor growth rate was estimated from the control data without injection of 211At. The kinetic behavior of the injected radionuclide was used to estimate the radiation dose profile to the target tumor, which can suppress the tumor growth in a dose-dependent manner. An additional two factors, including the time delay for the reduction of tumor volume and the impaired recovery of tumor regrowth after the treatment, were needed to simulate the temporal changes of tumor size after treatment. Finally, the parameters obtained from the simulated tumor growth curve were able to predict the tumor response in other experimental settings. The model can provide valuable information for planning the administration dose of radiopharmaceuticals in clinical trials, especially to determine the starting dose at which efficacy can be expected with a sufficient safety margin.

Prediction of outcomes in MCI with (123)I-IMP-CBF SPECT: a multicenter prospective cohort study.

OBJECTIVE: The multicenter prospective cohort study (Japan Cooperative SPECT Study on Assessment of Mild Impairment of Cognitive Function: J-COSMIC) aimed to examine the value of (123)I-N-isopropyl-4-iodoamphetamine cerebral blood flow (IMP-CBF) SPECT in regards to early diagnosis of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). METHODS: Three hundred and nineteen patients with amnestic MCI at 41 participating institutions each underwent clinical and neuropsychological examinations and (123)I-IMP-CBF SPECT at baseline. Subjects were followed up periodically for 3 years, and progression to dementia was evaluated. SPECT images were classified as AD/DLB (dementia with Lewy bodies) pattern and non-AD/DLB pattern by central image interpretation and automated region of interest (ROI) analysis, respectively. Logistic regression analyses were used to assess whether baseline (123)I-IMP-CBF SPECT was predictive of longitudinal clinical outcome. RESULTS: Ninety-nine of 216 amnestic MCI patients (excluding 3 cases with epilepsy (n = 2) or hydrocephalus (n = 1) and 100 cases with incomplete follow-up) converted to AD within the observation period. Central image interpretation and automated ROI analysis predicted conversion to AD with 56 and 58 % overall diagnostic accuracy (sensitivity, 76 and 81 %; specificity, 39 and 37 %), respectively. Multivariate logistic regression analysis identified SPECT as a predictor, which distinguished AD converters from non-converters. The odds ratio for a positive SPECT to predict conversion to AD with automated ROI analysis was 2.5 and combining SPECT data with gender and mini-mental state examination (MMSE) further improved classification (joint odds ratio 20.08). CONCLUSIONS: (123)I-IMP-CBF SPECT with both automated ROI analysis and central image interpretation was sensitive but relatively nonspecific for prediction of clinical outcome during the 3-year follow-up in individual amnestic MCI patients. A combination of statistically significant predictors, both SPECT with automated ROI analysis and neuropsychological evaluation, may increase predictive utility.

Radiological protection issues arising during and after the Fukushima nuclear reactor accident.

Following the Fukushima accident, the International Commission on Radiological Protection (ICRP) convened a task group to compile lessons learned from the nuclear reactor accident at the Fukushima Daiichi nuclear power plant in Japan, with respect to the ICRP system of radiological protection. In this memorandum the members of the task group express their personal views on issues arising during and after the accident, without explicit endorsement of or approval by the ICRP. While the affected people were largely protected against radiation exposure and no one incurred a lethal dose of radiation (or a dose sufficiently large to cause radiation sickness), many radiological protection questions were raised. The following issues were identified: inferring radiation risks (and the misunderstanding of nominal risk coefficients); attributing radiation effects from low dose exposures; quantifying radiation exposure; assessing the importance of internal exposures; managing emergency crises; protecting rescuers and volunteers; responding with medical aid; justifying necessary but disruptive protective actions; transiting from an emergency to an existing situation; rehabilitating evacuated areas; restricting individual doses of members of the public; caring for infants and children; categorising public exposures due to an accident; considering pregnant women and their foetuses and embryos; monitoring public protection; dealing with 'contamination' of territories, rubble and residues and consumer products; recognising the importance of psychological consequences; and fostering the sharing of information. Relevant ICRP Recommendations were scrutinised, lessons were collected and suggestions were compiled. It was concluded that the radiological protection community has an ethical duty to learn from the lessons of Fukushima and resolve any identified challenges. Before another large accident occurs, it should be ensured that inter alia: radiation risk coefficients of potential health effects are properly interpreted; the limitations of epidemiological studies for attributing radiation effects following low exposures are understood; any confusion on protection quantities and units is resolved; the potential hazard from the intake of radionuclides into the body is elucidated; rescuers and volunteers are protected with an ad hoc system; clear recommendations on crisis management and medical care and on recovery and rehabilitation are available; recommendations on public protection levels (including infant, children and pregnant women and their expected offspring) and associated issues are consistent and understandable; updated recommendations on public monitoring policy are available; acceptable (or tolerable) 'contamination' levels are clearly stated and defined; strategies for mitigating the serious psychological consequences arising from radiological accidents are sought; and, last but not least, failures in fostering information sharing on radiological protection policy after an accident need to be addressed with recommendations to minimise such lapses in communication.

Novel contribution of cell surface and intracellular M1-muscarinic acetylcholine receptors to synaptic plasticity in hippocampus.

Muscarinic acetylcholine receptors (mAChRs) are well known to transmit extracellular cholinergic signals into the cytoplasm from their position on the cell surface. However, we show here that M1-mAChRs are also highly expressed on intracellular membranes in neurons of the telencephalon and activate signaling cascades distinct from those of cell surface receptors, contributing uniquely to synaptic plasticity. Radioligand-binding experiments with cell-permeable and -impermeable ligands and immunohistochemical observations revealed intracellular and surface distributions of M1-mAChRs in the hippocampus and cortex of rats, mice, and humans, in contrast to the selective occurrence on the cell surface in other tissues. All intracellular muscarinic-binding sites were abolished in M1-mAChR-gene-knockout mice. Activation of cell surface M1-mAChRs in rat hippocampal neurons evoked phosphatidylinositol hydrolysis and network oscillations at theta rhythm, and transiently enhanced long-term potentiation. On the other hand, activation of intracellular M1-mAChRs phosphorylated extracellular-regulated kinase 1/2 and gradually enhanced long-term potentiation. Our data thus demonstrate that M1-mAChRs function at both surface and intracellular sites in telencephalon neurons including the hippocampus, suggesting a new mode of cholinergic transmission in the central nervous system.

Increased glucose metabolism by FDG-PET correlates with reduced tumor angiogenesis in oral squamous cell carcinoma.

Hypoxia is known to have been related with angiogenesis and glycolysis, and may have an influence on tumor treatment effect. Because glucose utilization is higher in malignant cells than that in normal cells, dynamic glucose metabolism of tumor has been evaluated by means of [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET). To investigate the significance of tumor vascularization in oral squamous cell carcinoma, we compared tumor angiogenesis with the FDG-PET findings. Twenty patients underwent FDG-PET. For the quantitative evaluation of FDG uptake in each tumor, the mean standardized uptake value (SUV) was calculated. Microvessel structures labeled with CD34 antigen were investigated in pretreatment biopsy specimens. Using an image analyzer, we calculated the following microvessel parameters: the ratio of the total number of microvessels (TN) to tumor area (TA), the ratio of the total microvessel perimeter (TP) to the TA, and the ratio of the tumor tissue area more than 150 µm distant from each microvessel (hypoxic ratio, %). The SUV was compared with the above parameters. Simple regression analysis revealed a statistical significance between the SUV and the TN:TA ratio (p = 0.046), as well as between the SUV and the TP:TA ratio (p = 0.0206). The SUV was found to be inversely related to the TN:TA and TP:TA ratios. Elevated glucose metabolism assessed by FDG-PET correlated with reduced vascularization. Higher glucose metabolism might therefore reflect a state of hypoxia.

Cytosolic acetyl-CoA synthetase affected tumor cell survival under hypoxia: the possible function in tumor acetyl-CoA/acetate metabolism.

Understanding tumor-specific metabolism under hypoxia is important to find novel targets for antitumor drug design. Here we found that tumor cells expressed higher levels of cytosolic acetyl-CoA synthetase (ACSS2) under hypoxia than normoxia. Knockdown of ACSS2 by RNA interference (RNAi) in tumor cells enhanced tumor cell death under long-term hypoxia in vitro. Our data also demonstrated that the ACSS2 suppression slowed tumor growth in vivo. These findings showed that ACSS2 plays a significant role in tumor cell survival under hypoxia and that ACSS2 would be a potential target for tumor treatment. Furthermore, we found that tumor cells excreted acetate and the quantity increased under hypoxia: the pattern of acetate excretion followed the expression pattern of ACSS2. Additionally, the ACSS2 knockdown led to a corresponding reduction in the acetate excretion in tumor cells. These results mean that ACSS2 can conduct the reverse reaction from acetyl-CoA to acetate in tumor cells, which indicates that ACSS2 is a bi-directional enzyme in tumor cells and that ACSS2 might play a buffering role in tumor acetyl-CoA/acetate metabolism.

11C-Acetate PET imaging for renal cell carcinoma.

PURPOSE: In this study, we investigated the effectiveness of positron emission tomography (PET) with (11)C-acetate (AC) for evaluation of renal cell carcinoma. METHODS: Enrolled in the study were 20 patients with suspected renal tumour, one of whom had three renal lesions. In all, 22 renal lesions were evaluated. Following administration of 350 MBq (10 mCi) of AC, whole-body PET images were obtained. Based on these PET findings, kidney lesions were scored as positive or negative. The PET results were correlated with the CT findings and histological diagnosis after surgery. RESULTS: In 18 patients, 20 tumours were diagnosed as renal cell carcinoma. Lesions in the remaining two patients were diagnosed as complicated cyst without malignant tissue. Of the 20 renal cell carcinomas. 14 (70%) showed positive AC PET findings; 6 were negative. The two patients with complicated cyst had negative AC PET findings. Of the 20 renal cell carcinomas, 19 were clear-cell carcinoma and 1 was a papillary cell carcinoma. This papillary cell carcinoma showed high AC uptake. CONCLUSION: AC demonstrates marked uptake in renal cell carcinoma. These preliminary data show that AC is a possible PET tracer for detection of renal cancer.

Relationship between impaired microvascular function in the non-infarct-related area and left-ventricular remodeling in patients with myocardial infarction.

BACKGROUND: Myocardial flow reserve (MFR) in the non-infarct-related area (NIRA) has been reported to be impaired after the onset of myocardial infarction (MI). The aim of this study was to determine whether microvascular dysfunction in the NIRA is related to left-ventricular remodeling after MI. METHODS: We prospectively studied 17 patients who suffered their first single-vessel MI, and who underwent successful revascularization. The MFR in the NIRA was assessed quantitatively using (13)N-ammonia positron emission tomography within 2 weeks after the onset. Peak creatinine kinase and the defect score on (99m)Tc-tetrofosmin myocardial perfusion imaging were used as an index of the severity of MI. The left-ventricular end-diastolic volume index (LVEDVI) was calculated using left ventriculography at 1 month and 6 months after the onset. RESULT: Patients with severely impaired MFR (<2.09) had higher peak creatinine kinase values (6000+/-5485 IU/L vs. 2250+/-1950 IU/L, p=0.0081), defect scores (16.3+/-5.9 vs. 7.9+/-6.5, p=0.0404), and LVEDVI at 1 month (125.6+/-34.4 mL/m2 vs. 82.8+/-17.7 mL/m2, p=0.0036) than those with mildly impaired MFR (> or =2.09). Moreover, the differences of LVEDVI between 2 groups persisted over 6 months (133.3+/-43.6 mL/m2 vs. 89.5+/-17.3 mL/m2, p=0.0078). The MFR in the NIRA correlated inversely with the LVEDVI at 1 month and 6 months (r=-0.590, p=0.0127 and r=-0.729, p=0.0031, respectively). CONCLUSIONS: These data indicate that microvascular impairment in the NIRA might have contributed to left-ventricular remodeling after MI.

Source of nonlinearity of the BOLD response revealed by simultaneous fMRI and NIRS.

The nonlinearity of the blood oxygenation level-dependent (BOLD) response to stimuli of different duration, particularly those of short duration, has been well studied by functional magnetic resonance imaging (fMRI). This nonlinearity is assumed to be due to neural adaptation and the nonlinearity of the response in the oxygen extraction fraction (OEF); the latter has not been examined quantitatively in humans. To evaluate how the OEF response contributes to the nonlinearity of the BOLD response to neural activity, we used simultaneous fMRI and near-infrared spectroscopy (NIRS). The responses to visual stimuli of four different durations were measured as changes in the BOLD signal and the NIRS-derived hemoglobin concentrations. The hemodynamic response nonlinearity was quantified using an impulse response function model with saturation nonlinearity scaling in the response amplitude, assuming that the unknown neural adaptation parameters varied within a physiologically feasible range. Independent of the degree of neural adaptation, the BOLD response consistently showed saturation nonlinearity similar to that of the OEF response estimated from the NIRS measures, the nonlinearity of which was greater than that of the response in the total hemoglobin concentration representing the cerebral blood volume (CBV). We also found that the contribution of the OEF response to the BOLD response was four to seven times greater than the contribution of the CBV response. Thus, we conclude that the nonlinearity of the BOLD response to neural activity originates mainly from that of the OEF response.

Diabetes mellitus impairs myocardial oxygen metabolism even in non-infarct-related areas in patients with acute myocardial infarction.

BACKGROUND: Although diabetes is associated with poor clinical outcomes after acute myocardial infarction, to date there have been no reports focusing on the myocardial oxygen metabolism in these patients. Thus, we evaluated the myocardial oxygen metabolism in patients with and without diabetes suffering from acute myocardial infarction using carbon-11 acetate positron emission tomography. METHODS: 20 patients (13 diabetic patients [group A] and 7 non-diabetic patients [group B]) underwent carbon-11 acetate positron emission tomography soon after the onset of acute myocardial infarction. The myocardial oxygen metabolism was evaluated within the infarct-related area and in the non infarct-related area. 6 healthy volunteers (group C) and 6 diabetic patients without coronary artery disease (group D) also participated as controls. RESULTS: There were no significant differences in gender, age, infarct-related artery, peak level of serum creatine phosphokinase, left-ventricular ejection fraction at onset, or the defect severity on myocardial perfusion images between group A and group B. In group A, the clearance rate (Kmono) of carbon-11 acetate in infarct-related area (0.042+/-0.010) was not significantly different from that in group B (0.049+/-0.016). In contrast, Kmono in non infarct-related area in group A (0.059+/-0.010) was significantly lower than that in group B (0.076+/-0.009; p=0.002), group C (0.072+/-0.004; p=0.026) and group D (0.078+/-0.005; p=0.001). CONCLUSIONS: These data indicate that the myocardial oxygen metabolism even in non infarct-related area in diabetic patients was impaired after the onset of acute myocardial infarction.

A comparative study of the plasma membrane permeabilization and fluidization induced by antipsychotic drugs in the rat brain.

We compared the potency of the interaction of three antipsychotic drugs, i.e. chlorpromazine (CPZ), haloperidol (Hal) and sulpiride (Sul), with the plasma membrane in the rat brain. CPZ loading (> or = 100 microM) dose-dependently increased both membrane permeability (assessed as [18F]2-fluoro-2-deoxy-D-glucose-6-phosphate release from brain slices) and membrane fluidity (assessed as the reduction in the plasma membrane anisotropy of 1,6-diphenyl-1,3,5-hexatriene). On the other hand, a higher concentration of Hal (1 mM) was required to observe these effects. However, Sul failed to change membrane permeability and fluidity even at a high concentration (1 mM). These results indicated the following ranking of the potency to interact with the membrane: CPZ>Hal>Sul. The difference among antipsychotic drugs in the potency to interact with the plasma membrane as revealed in the present study may be partly responsible for the difference among the drugs in the probability of inducing extrapyramidal side-effects such as parkinsonism and tardive dyskinesia.

Effects of chlorpromazine on plasma membrane permeability and fluidity in the rat brain: a dynamic positron autoradiography and fluorescence polarization study.

Antipsychotic drugs have been widely used in psychiatry for the treatment of various mental disorders, but the underlying biochemical mechanisms of their actions still remain unclear. Although phenothiazine antipsychotic drugs have been reported to directly interact with the peripheral plasma membrane, it is not known whether these drugs actually affect plasma membrane integrity in the central nervous system. To clarify these issues, we investigated the effect of chlorpromazine (CPZ), a typical phenothiazine antipsychotic drug, on plasma membrane permeability in fresh rat brain slices using a dynamic positron autoradiography technique and [(18)F]2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) as a tracer. Treatment with CPZ (> or =100 microM) resulted in the leakage of [(18)F]FDG-6-phosphate, but not [(18)F]FDG, suggesting that the [(18)F]FDG-6-phosphate efflux was not mediated by glucose transporters, but rather by plasma membrane permeabilization. The leakage of [(18)F]FDG-6-phosphate was followed by slower leakage of cytoplasmic lactate dehydrogenase, suggesting that CPZ could initially induce small membrane holes that enlarged with time. Furthermore, the addition of CPZ (> or =100 microM) caused a decrease in 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy, which implies an increase in membrane fluidity. CPZ loading dose-dependently increased both membrane permeability and membrane fluidity, which suggested the involvement of a perturbation of membrane order in the mechanisms of membrane destabilization induced by antipsychotic drugs.

Can the detection of misery perfusion in chronic cerebrovascular disease be based on reductions in baseline CBF and vasoreactivity?

PURPOSE: The aim of this study was to clarify whether decreases in baseline regional cerebral blood flow (rCBF) and in residual cerebral vasoreactivity (CVR), assessed by the acetazolamide (ACZ) challenge, can detect misery perfusion in patients with chronic cerebrovascular disease (CVD). METHODS: Oxygen extraction fraction (OEF) and other haemodynamic parameters were measured in 115 patients (64+/-9 years old) with unilateral cerebrovascular steno-occlusive disease (>70% stenosis) using (15)O-gas and water PET. A significant elevation of OEF, by greater than the mean+2SD compared with healthy controls, was defined as misery perfusion. CBF, CVR determined by percent change in CBF after ACZ administration, OEF and other haemodynamic parameters in the territories of the bilateral middle cerebral arteries were analysed. Diagnostic accuracy for the detection of misery perfusion using the criteria determined by baseline CBF and CVR was evaluated in all patients and in only those patients with occlusive lesions. RESULTS: Ten of 24 patients with misery perfusion showed a significant reduction in CVR. Using criteria determined by significant decreases in CVR and baseline CBF, misery perfusion was detected with a sensitivity of 42% and a specificity of 95% in all patients. In patients with occlusive lesions (n=50), sensitivity was higher but specificity was slightly lower. The diagnostic accuracy of the threshold determined by baseline CBF alone was similar in all patients and in only those patients with occlusive lesions, and was higher than that achieved using the asymmetry index of OEF. CONCLUSION: Reductions in CVR and baseline CBF in the ACZ challenge for CVD would detect misery perfusion with high specificity. Reduction in baseline rCBF is more accurate than reduction in CVR alone for the detection of misery perfusion.

Practice makes perfect: the neural substrates of tactile discrimination by Mah-Jong experts include the primary visual cortex.

BACKGROUND: It has yet to be determined whether visual-tactile cross-modal plasticity due to visual deprivation, particularly in the primary visual cortex (V1), is solely due to visual deprivation or if it is a result of long-term tactile training. Here we conducted an fMRI study with normally-sighted participants who had undergone long-term training on the tactile shape discrimination of the two dimensional (2D) shapes on Mah-Jong tiles (Mah-Jong experts). Eight Mah-Jong experts and twelve healthy volunteers who were naïve to Mah-Jong performed a tactile shape matching task using Mah-Jong tiles with no visual input. Furthermore, seven out of eight experts performed a tactile shape matching task with unfamiliar 2D Braille characters. RESULTS: When participants performed tactile discrimination of Mah-Jong tiles, the left lateral occipital cortex (LO) and V1 were activated in the well-trained subjects. In the naïve subjects, the LO was activated but V1 was not activated. Both the LO and V1 of the well-trained subjects were activated during Braille tactile discrimination tasks. CONCLUSION: The activation of V1 in subjects trained in tactile discrimination may represent altered cross-modal responses as a result of long-term training.

Diagnosis of misery perfusion using noninvasive 15O-gas PET.

UNLABELLED: To avoid arterial blood sampling and complicated analyses in 15O-gas PET studies, we evaluated a noninvasive technique using the count-based method for measuring asymmetric increases in oxygen extraction fraction (OEF) in cerebrovascular disease. METHODS: Eighteen patients (mean age +/- SD, 61 +/- 16 y) with atherothrombotic large-cerebral-artery disease were studied for the measurement of hemodynamic parameters using the 15O-gas steady-state method with inhalation of 15O2, C15O2, and C15O. All patients also underwent H2(15)O PET with the bolus injection method. Count-based ratio images of 15O2/C15O2 and (15)O2/H2(15)O were calculated, and asymmetry indices (AIs) were obtained (cbOEF(SS)-AI and cbOEF(BO)-AI, respectively) using regions of interest drawn bilaterally on the cerebral cortices. These AIs were compared with the AIs of absolute OEF (qOEF-AI) and with those after cerebral blood volume (CBV) correction. A contribution factor for this correction was defined as a variable alpha, and the effect of the correction was evaluated. RESULTS: cbOEF(SS)-AI underestimated qOEF-AI significantly, especially with a greater AI (P < 0.05). cbOEF(BO)-AI linearly correlated well with qOEF-AI. CBV correction improved the slopes of regression lines between qOEF-AI and cbOEF(SS)-AI, and the optimal alpha was defined as 0.5. On the other hand, cbOEF(BO)-AI fairly estimated qOEF-AI without CBV correction. Correlation between qOEF-AI and cbOEF(BO)-AI was adversely affected, and the mean bias was increased, with a greater alpha. CONCLUSION: cbOEF(BO)-AI can fairly estimate the AI of OEF without CBV correction, whereas cbOEF(SS)-AI might require CBV correction for better estimation. The examination time and stress to patients would be reduced with the count-based method because it is noninvasive.

Molecular therapy of human neuroblastoma cells using Auger electrons of 111In-labeled N-myc antisense oligonucleotides.

UNLABELLED: Auger electrons can create breaks in nucleic acids, giving them possible therapeutic utility. We investigated the therapeutic effect of Auger electrons emitted by 111In-labeled phosphorothioate antisense oligonucleotides on human neuroblastoma cells in which N-myc was overexpressed. METHODS: Human SK-N-DZ neuroblastoma cells (5 x 10(6) cells) were treated with cationic reverse-phase evaporation vesicles (REVs) encapsulating 111In-labeled antisense (40 MBq/2 nmol of oligonucleotides/mumol of total phospholipids) that had an average diameter of 250 nm. Hybridization of the radiolabeled oligonucleotides with N-myc messenger RNA (mRNA), N-myc expression, and cell proliferation were investigated. The tumorigenicity of treated cells was analyzed in nude mice. Nonradiolabeled antisense, 111In-labeled sense, or empty cationic REVs were used as controls. RESULTS: 111In-Labeled antisense, which hybridized with N-myc mRNA, was detected in cells at 12 and 24 h after the initiation of treatment. Reduced N-myc expression and inhibited cell proliferation were shown in the same cells at 48 h after the completion of treatment. N-myc expression-suppressed cells produced intraperitoneal tumors in nude mice, but the average weight of the tumors was lower than that of tumors in control mice. CONCLUSION: Auger electrons emitted from 111In in close proximity to their target N-myc mRNA may prolong the time to cell proliferation in human neuroblastoma cells due to inhibition of the translation of N-myc. Auger electron therapy therefore has potential as an internally delivered molecular radiotherapy targeting the mRNA of a tumor cell.

Double-tracer autoradiography with Cu-ATSM/FDG and immunohistochemical interpretation in four different mouse implanted tumor models.

BACKGROUND: We studied the regional characteristics within tumor masses using PET tracers and immunohistochemical methods. METHODS: The intratumoral distribution of (64)Cu-diacetyl-bis(N4-methylthiosemicarbazone) ([(64)Cu]Cu-ATSM) and [(18)F] 2-fluoro-2-deoxyglucose ((18)F]FDG) in mice with tumors of four different origins (LLC1, Meth-A, B16 and colon26) was compared with the immunohistochemical staining of proliferating cells (Ki67), blood vessels (CD34 or von Willebrand factor), and apoptotic cells (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling method). RESULTS: With all cell lines, [(64)Cu]Cu-ATSM and [(18)F]FDG were distributed with different gradation in the tumor mass. The immunohistochemical study demonstrated that the high [(64)Cu]Cu-ATSM uptake regions were hypovascular and consisted of tumor cells arrested in the cell cycle, whereas the high [(18)F]FDG uptake regions were hypervascular and consisted of proliferating cells. CONCLUSION: In our study, it was revealed that one tumor mass contained two regions with different characteristics, which could be distinguished by [(64)Cu]Cu-ATSM and [(18)F]FDG. Because hypoxia and cell cycle arrest are critical factors to reduce tumor sensitivity to radiation and conventional chemotherapy, regions with such characteristics should be treated intensively as one of the primary targets. [(64)Cu]Cu-ATSM, which can delineate hypoxic and cell cycle-arrested regions in tumors, may provide valuable information for cancer treatment as well as possibly for treating such regions directly as an internal radiotherapy reagent.

Comparative assessment of 18F-fluorodeoxyglucose PET and 99mTc-tetrofosmin SPECT for the prediction of functional recovery in patients with reperfused acute myocardial infarction.

PURPOSE: Although preserved glucose metabolism is considered to be a marker of myocardial viability in the chronic stage, it has not been fully elucidated whether this is also true with regard to reperfused acute myocardial infarction (AMI). The aim of this study was to compare the diagnostic performance of(99m)Tc-tetrofosmin SPECT and(18)F-fluorodeoxyglucose (FDG) PET for the prediction of functional recovery in reperfused AMI. METHODS: The study population comprised 28 patients. Both tetrofosmin SPECT and FDG PET were performed in all 28 patients at ca. 2 weeks and in 23 at 6 months. The tetrofosmin and FDG findings in infarct-related segments were compared with the regional wall motion score assessed by left ventriculography over 6 months to determine the predictive value for functional recovery. RESULTS: Of 120 infarct-related segments, 83 had preserved flow (tetrofosmin uptake >/=50%) and 81 had preserved glucose metabolism (FDG uptake >/=40%). The sensitivity and specificity of tetrofosmin SPECT for the prediction of functional recovery tended to be superior to those of FDG PET (90.0% and 72.5% vs 85.0% and 67.5%, respectively). Thirteen segments with preserved flow and decreased glucose metabolism demonstrated marked recovery of contractile function from 2.5+/-1.0 to 1.4+/-1.4 (p<0.01), with restoration of glucose metabolism at 6 months. In contrast, 11 segments with decreased flow and preserved glucose metabolism demonstrated incomplete functional improvement from 3.0+/-0.8 to 2.2+/-1.2. CONCLUSION: In the subacute phase, preserved myocardial blood flow is more reliable than glucose metabolism in predicting functional recovery in reperfused myocardium.