Label-free reflectance hyperspectral imaging for tumor margin assessment: a pilot study on surgical specimens of cancer patients.

A label-free, hyperspectral imaging (HSI) approach has been proposed for tumor margin assessment. HSI data, i.e., hypercube (x,y,λ), consist of a series of high-resolution images of the same field of view that are acquired at different wavelengths. Every pixel on an HSI image has an optical spectrum. In this pilot clinical study, a pipeline of a machine-learning-based quantification method for HSI data was implemented and evaluated in patient specimens. Spectral features from HSI data were used for the classification of cancer and normal tissue. Surgical tissue specimens were collected from 16 human patients who underwent head and neck (H&N) cancer surgery. HSI, autofluorescence images, and fluorescence images with 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose (2-NBDG) and proflavine were acquired from each specimen. Digitized histologic slides were examined by an H&N pathologist. The HSI and classification method were able to distinguish between cancer and normal tissue from the oral cavity with an average accuracy of 90%±8%, sensitivity of 89%±9%, and specificity of 91%±6%. For tissue specimens from the thyroid, the method achieved an average accuracy of 94%±6%, sensitivity of 94%±6%, and specificity of 95%±6%. HSI outperformed autofluorescence imaging or fluorescence imaging with vital dye (2-NBDG or proflavine). This study demonstrated the feasibility of label-free, HSI for tumor margin assessment in surgical tissue specimens of H&N cancer patients. Further development of the HSI technology is warranted for its application in image-guided surgery.

Structure- and concentration-specific assessment of the physiological reactivity of α-dicarbonyl glucose degradation products in peritoneal dialysis fluids.

In peritoneal dialysis (PD), glucose degradation products (GDPs), which are formed during heat sterilization of dialysis fluids, lead to structural and functional changes in the peritoneal membrane, which eventually result in the loss of its ultrafiltration capacity. To determine the molecular mechanisms behind these processes, the present study tested the influence of the six major α-dicarbonyl GDPs in PD fluids, namely, glyoxal, methylglyoxal, 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), 3,4-dideoxyglucosone-3-ene (3,4-DGE), and glucosone with respect to their potential to impair the enzymatic activity of RNase A as well as their effects on cell viability. For comprehensive risk assessment, the α-dicarbonyl GDPs were applied separately and in concentrations as present in conventional PD fluids. Thus, it was shown that after 5 days, glucosone impaired RNase A activity most distinctly (58% remaining activity, p < 0.001 compared to that of the control), followed by 3,4-DGE (62%, p < 0.001), 3-DGal (66%, p < 0.001), and 3-DG (76%, p < 0.01). Methylglyoxal and glyoxal caused weaker inactivation with significant effects only after 10 days of incubation (79%, 81%, p < 0.001). Profiling of the advanced glycation end products formed during the incubation of RNase A with methylglyoxal revealed predominant formation of the arginine modifications imidazolinone, CEA/dihydroxyimidazoline, and tetrahydropyrimidine at Arg10, Arg33, Arg39, and Arg85. Particularly, modification at Arg39 may severely affect the active site of the enzyme. Additionally, structure- and concentration-specific assessment of the cytotoxicity of the α-dicarbonyl GDPs was performed. Although present at very low concentration, the cytotoxic effect of PD fluids after 2 days of incubation was exclusively caused by 3,4-DGE (14% cell viability, p < 0.001). After 4 days of incubation, 3-DGal (13% cell viability, p < 0.001), 3-DG (24%, p < 0.001), and, to a lower extent, glyoxal and methylglyoxal (both 57%, p < 0.01) also reduced cell viability significantly. In conclusion, 3,4-DGE, 3-DGal, and glucosone appear to be the most relevant parameters for the biocompatibility of PD fluids.

Dexamethasone-induced insulin resistance: kinetic modeling using novel PET radiopharmaceutical 6-deoxy-6-[(18)F]fluoro-D-glucose.

PURPOSE: An insulin-resistant rat model, induced by dexamethasone, was used to evaluate a Michaelis-Menten-based kinetic model using 6-deoxy-6-[(18)F]fluoro-D-glucose (6-[(18)F]FDG) to quantify glucose transport with PET. PROCEDURES: Seventeen, male, Sprague-Dawley rats were studied in three groups: control (Ctrl), control + insulin (Ctrl + I), and dexamethasone + insulin (Dex + I). PET scans were acquired for 2 h under euglycemic conditions in the Ctrl group and under hyperinsulinemic-euglycemic conditions in the Ctrl + I and Dex + I groups. RESULTS: Glucose transport, assessed according to the 6-[(18)F]FDG concentration, was highest in skeletal muscle in the Ctrl + I, intermediate in the Dex + I, and lowest in the Ctrl group, while that in the brain was similar among the groups. Modeling analysis applied to the skeletal muscle uptake curves yielded values of parameters related to glucose transport that were greatest in the Ctrl + I group and increased to a lesser degree in the Dex + I group, compared to the Ctrl group. CONCLUSION: 6-[(18)F]FDG and the Michaelis-Menten-based model can be used to measure insulin-stimulated glucose transport under basal and an insulin resistant state in vivo.

Optical molecular imaging approach for rapid assessment of response of individual cancer cells to chemotherapy.

Predicting the response of individual patients to cytotoxic chemotherapy drugs is critical for developing individualized therapies. With this motivation, an optical molecular imaging approach was developed to detect cisplatin induced changes in the uptake and intracellular retention of choline. Intracellular uptake of choline was characterized using a click chemistry reaction between propargyl choline and Alexa-488 azide. Cisplatin induced changes in the uptake of propargyl choline in cells and tumor spheroids were compared with similar measurements using a fluorescent analogue of deoxyglucose and conventional cell viability assays. Uptake and intracellular retention of propargyl choline decreased with an increase in concentration of cisplatin. Intracellular uptake of propargyl choline was significantly reduced within 3 h of incubation with a sub-lethal dose of cisplatin. Results demonstrate that the imaging approach based on propargyl choline was more sensitive in detecting the early response of cancer cells to cisplatin as compared to the imaging based on fluorescent analogue of deoxyglucose and cell viability assays. Imaging measurements in tumor spheroids show a significant decrease in the uptake of propargyl choline following treatment with cisplatin. Overall, the results demonstrate a novel optical molecular imaging approach for rapid measurement of the response of individual cancer cells to cisplatin treatment.

In vivo assessment of cardiac insulin resistance by nuclear probes using an iodinated tracer of glucose transport.

PURPOSE: Insulin resistance, implying depressed cellular sensitivity to insulin, is a risk factor for type 2 diabetes and cardiovascular disease. This study is the first step towards the development of a technique of insulin resistance measurement in humans with a new tracer of glucose transport, [(123)I]6-deoxy-6-iodo-D-glucose (6DIG). METHODS: We investigated 6DIG kinetics in anaesthetised control rats and in three models of insulin-resistant rats: fructose fed, Zucker and ZDF. The study of myocardial 6DIG activity was performed under two conditions: first, 6DIG was injected under the baseline condition and then it was injected after a bolus injection of insulin. After each injection, radioactivity was measured over 45 min by external detection via NaI probes, in the heart and blood. A tri-compartment model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the heart. RESULTS: These coefficients were significantly increased with insulin in control rats and did not change significantly in insulin-resistant rats. The ratio of the coefficient obtained under insulin to that obtained under basal conditions gave an index of cardiac insulin resistance for each animal. The mean values of these ratios were significantly lower in insulin-resistant than in control rats: 1.16 +/- 0.06 vs 2.28 +/- 0.18 (p < 0.001) for the fructose-fed group, 0.92 +/- 0.05 vs 1.62 +/- 0.25 (p < 0.01) for the Zucker group and 1.34 +/- 0.06 vs 2.01 +/- 0.26 (p < 0.05) for the ZDF group. CONCLUSION: These results show that 6DIG could be a useful tracer to image cardiac insulin resistance.

Assessment of insulin resistance in fructose-fed rats with 125I-6-deoxy-6-iodo-D-glucose, a new tracer of glucose transport.

PURPOSE: Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state that has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats using (125)I-6-deoxy-6-iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. METHODS: Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic-normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood was assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. RESULTS: Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p < 0.01; muscle, p<0.05; heart, p<0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p<0.001; muscle, p<0.001; heart, p<0.01) whereas no significant changes were observed in fructose-fed rats. CONCLUSION: This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging.

Assessment of insulin sensitivity in vivo in control and diabetic mice with a radioactive tracer of glucose transport: [125I]-6-deoxy-6-iodo-D-glucose.

BACKGROUND: Impairment of insulin-stimulated glucose transport is a characteristic of type 2 diabetes. A radioactive glucose analogue has been synthesized: [(125)I]-6-deoxy-6-iodo-D-glucose. Its biological behaviour in vitro is similar to that of 3-O-methyl-D-glucose, the reference tracer of glucose transport. The aim of the present study was to determine the ability of [(125)I]-6-deoxy-6-iodo-D-glucose to evaluate variations in glucose transport in vivo. METHODS: Biodistributions of [(125)I]-6-deoxy-6-iodo-D-glucose were performed with or without exogenous insulin (iv injection of 1.5 IU/kg) in db/+ non-diabetic control mice and in db/db type 2 diabetic mice, exhibiting a severe insulin resistance characterized by a lack of increase in glucose uptake in response to insulin. RESULTS: In db/+ mice, insulin increased [(125)I]-6-deoxy-6-iodo-D-glucose transport by 30% in most insulin-sensitive tissues (heart, diaphragm and skeletal muscle, p < 0.05) and had no effect in other organs. In db/db mice, [(125)I]-6-deoxy-6-iodo-D-glucose transport in these organs was not modified by insulin. CONCLUSION: [(125)I]-6-deoxy-6-iodo-D-glucose is able to trace in vivo an increase in glucose transport with insulin in non-diabetic mice and a defect of glucose transport in type 2 diabetic mice. It is the first time that an iodinated analogue of glucose has shown such promising results after in vivo injection. The use of this tracer to assess glucose transport in vivo in humans via nuclear imaging warrants further investigation.

Rapid viability assessment of yeast cells using vital staining with 2-NBDG, a fluorescent derivative of glucose.

A fluorescent glucose analogue, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose (2-NBDG), which had been developed previously for the analysis of glucose uptake activity by living cells, was investigated to evaluate its applicability for assaying the viability of yeasts. Fluorescence intensities of the yeast population were measured by fluorescence spectrophotometry upon exposure to antifungal agents after staining with 2-NBDG and were compared to the number of colony forming units (CFU). A good correlation was obtained between the yeast viability, determined by the CFU, and the accumulation of 2-NBDG by yeast cells (correlation constant: r=0.98). Susceptibility testing of amphotericin B and miconazole against yeast strains by plate count and 2-NBDG fluorescence method yielded corresponding results. In conclusion, we found that staining with 2-NBDG is a rapid and sensitive method for the assessment of yeast cell viability.

FDG SPECT in the assessment of myocardial viability. Comparison with dobutamine echo.

The use of 18F-fluorodeoxyglucose (FDG) imaging with single photon emission computed tomography (SPECT) has been introduced recently to assess myocardial viability. Several centres have now gained experience with cardiac FDG SPECT imaging, and this report is a summary of the currently available FDG SPECT data. Three studies have compared FDG SPECT with FDG positron emission tomography and demonstrated good agreement between them. Initial results in patients undergoing revascularization suggest that FDG SPECT can predict improvement in contractile function after revascularization. Although the initial results are promising, larger studies are needed to determine the precise role of FDG SPECT in the assessment of myocardial viability.

Preliminary assessment of fluorine-18 fluorodeoxyglucose positron emission tomography in patients with bladder cancer.

The purpose of this study was to assess the feasibility of imaging of bladder cancer with fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. We studied 12 patients with histologically proven bladder cancer who had undergone surgical procedures and/or radiotherapy. Retrograde irrigation of the urinary bladder with 1000-3710 ml saline was performed during nine of the studies. Dynamic and static PET images were obtained, and standardized uptake value images were reconstructed. FDG-PET scanning was true-positive in eight patients (66.7%), but false-negative in four (33.3%). Of 20 organs with tumor mass lesions confirmed pathologically or clinically, 16 (80%) were detected by FDG-PET scanning. FDG-PET scanning detected all of 17 distant metastatic lesions and two of three proven regional lymph node metastases. FDG-PET was also capable of differentiating viable recurrent bladder cancer from radiation-induced alterations in two patients. In conclusion, these preliminary data indicate the feasibility of FDG-PET imaging in patients with bladder cancer, although a major remaining pitfall is intense FDG accumulation in the urine.

A prospective study of PET-FDG imaging for the assessment of head and neck squamous cell carcinoma.

The main aim of the study was to evaluate the use of positron emission tomography using fluoro-deoxyglucose (PET-FDG) imaging for the detection of squamous cell carcinoma of the head and neck. Fifty-four consecutive patients with malignancies involving the head and neck were studied prospectively. Thirty-one patients presented with primary disease and 23 were suspected of recurrent or residual disease. All patients underwent full clinical staging, PET-FDG scans and anatomical imaging, 37 underwent computed tomography (CT), 13 magnetic resonance (MR) and four had both CT and MR. Clinical assessment, CT/MR, PET-FDG and histological examination were all evaluated independently of each other. All 31 primary head and neck malignant tumours were detected by PET-FDG. Based on 16 patients who underwent neck dissections, the sensitivity and specificity of PET-FDG for detecting nodal disease was 67% and 100% respectively, compared with clinical assessment of 58% and 75% and CT/MR of 67% and 25%. In all 12 patients, PET-FDG correctly identified the presence of absence or recurrent or residual disease. PET-FDG staged 13 post-treatment necks with an accuracy of 100% as compared to CT/MR which was accurate in 7 of 13 and clinical assessment which was accurate in eight. Three sites of abnormal tracer uptake unrelated to malignancy were recorded as incidental findings (mandibular osteomyelitis, 1: post glossectomy site, 2). PET-FDG was more accurate than CT/MR for identifying primary and recurrent tumours as well as metastatic lesions in the neck. If these diagnostic properties of PET-FDG are confirmed in further prospective studies, it could prove a valuable adjunct for the management of head and neck cancer.

[Cost effectiveness analysis of FDG-PET in the differential diagnosis and staging of lung cancer in Japan].

UNLABELLED: Several studies have shown that FDG-PET is more accurate than CT for the differential diagnosis and for the staging of lung cancer. We have analyzed potential effect of FDG-PET on the medical cost for the management of patients suspected of lung cancer. In the differential diagnosis, chest CT plus FDG-PET protocol reduced the number of bronchofiberscope (BFS) and biopsy by one fourth of that in the conventional protocol using CT alone. PET protocol reduced unnecessary examinations for the patients of benign disease, however, it increased the total cost of examinations by 25% due to the higher cost of PET than that of BFS and biopsy in Japan. In the staging of lung cancer, PET protocol improved accuracy of staging, reduced unnecessary surgery by 67%, and showed a saving of the cost of examination by 5%, and the total medical cost by 2.5% compared to that in the conventional protocol using CT, brain MRI, and bone scan. CONCLUSION: Use of FDG-PET for the staging may contribute to the improvement of patient management of lung cancer patients also to the saving of the medical cost.

Axillary lymph node metastases: screening with [F-18]2-deoxy-2-fluoro-D-glucose (FDG) PET.

PURPOSE: To evaluate [fluorine-18]2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) of the axilla as a screening test for detecting regional spread of breast cancer. MATERIALS AND METHODS: High-dose FDG PET of the axilla was successfully performed in 50 patients (age range, 36-79 years) with breast cancer before 52 axillary lymph node dissections. Two additional patients had scans that were uninterpretable because of intense myocardial activity that obscured the axilla. RESULTS: The sensitivity and negative predictive value were both 95%, the specificity was 66%, and the overall accuracy was 77%. The only false-negative PET scan was obtained in the largest patient, who had a low-quality scan. CONCLUSION: Patients with negative PET scans had such a low risk for axillary lymph node metastases that axillary dissection was not warranted. Patients with positive PET scans required dissection to confirm the presence and determine the number of positive lymph nodes. Had this algorithm been used to select patients for dissection, approximately $120,000 in charges ($2,300 per patient) would have been saved and 22 patients would have been spared the morbidity of axillary lymph node dissection. Within this study population, PET scans of the axilla were interpreted with sufficient sensitivity for PET to serve as a cost-effective screening test for axillary lymph node metastases.

Selecting patients with ischemic cardiomyopathy for medical treatment, revascularization, or heart transplantation.

Three major treatment options are available to patients with ischemic cardiomyopathy: medical therapy, coronary revascularization, or heart transplantation. Although survival rates have been enhanced with vasodilator therapy in such patients, the ultimate outcome is still poor. Coronary revascularization, although beneficial in some patients, may lead to disappointing outcomes in others. Cardiovascular specialists have searched for better criteria to predict which patients are most likely to benefit from revascularization compared with medical therapy, which is often followed by heart transplantation. An accurate noninvasive assessment of myocardial viability that can distinguish irreversible myocardial cellular injury from myocardial hibernation may be useful for clinical decision making. It permits selection of patients with ischemic cardiomyopathy who will most benefit from revascularization strategies with respect to postoperative improvement in regional and global left ventricular function and survival. In general, the greater the extent of viability in patients with left ventricular dysfunction and coronary artery disease, the better the prognosis with revascularization strategies. Radionuclide methods have emerged that can evaluate myocardial viability accurately. As hospitals face more pressure from managed-care organizations to reduce health-care costs, more practice guidelines are necessary to identify which patients are to benefit from which strategies and to identify when they are unlikely to benefit from costly interventions such as coronary bypass. Conversely, the cost-effectiveness of nuclear cardiology may be substantial if certain patients referred for transplantation are identified to have a good outcome with revascularization, even in the absence of anginal symptoms. Thus nuclear cardiology might provide valuable information that not only improves outcomes but also reduces overall costs of managing patients with ischemic cardiomyopathy.

Initial assessment of positron emission tomography for detection of nonpalpable regional lymphatic metastases in melanoma.

BACKGROUND: The purpose of this pilot study is to determine the feasibility of positron emission tomography with fluorodeoxyglucose (FDG-PET) for detection of nonpalpable regional lymph node metastases in patients with melanoma. METHODS: Adult patients with histologically proven cutaneous melanoma planned to undergo surgical lymphadenectomy for treatment of nonpalpable subclinical or residual metastatic melanoma in regional lymph node basin(s) participated. Each patient underwent attenuation-corrected PET imaging of the regional lymph node basin(s) with F18 fluorodeoxyglucose (FDG) followed by complete surgical lymphadenectomy. FDG-PET scans were interpreted prospectively by an experienced nuclear medicine physician. FDG-PET scan interpretations and histologic results were then correlated. RESULTS: Eleven patients underwent 12 FDG-PET scans followed by 12 operations to clear 14 regional lymph node basins. FDG-PET correctly predicted the presence of metastatic melanoma in seven of seven surgical specimens. FDG-PET scans correctly predicted the absence of disease in seven of seven histologically negative node basins. Sensitivity was 1.0; specificity was 1.0. CONCLUSIONS: This study suggests that increased fluorodeoxyglucose uptake in palpably unremarkable regional lymph node basins in patients with melanoma is highly suggestive of metastatic disease.

Whole-body FDG-PET imaging for staging of Hodgkin's disease and lymphoma.

UNLABELLED: Accurate staging of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) is important for treatment management. In this study, the utility of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) whole-body PET was evaluated as an imaging modality for initial staging or restaging of 7 HD and 11 NHL patients. METHODS: Whole-body PET-based staging results were compared to the patient's clinical stage based on conventional staging studies, which included combinations of CT of the chest, abdomen and pelvis, MRI scans, gallium scans, lymphangiograms, staging laparatomies and bone scans. RESULTS: Accurate staging was performed in 17 of 18 patients using a whole-body PET-based staging algorithm compared to the conventional staging algorithm in 15 of 18 patients. In 5 of 18 patients, whole-body PET-based staging showed additional lesions not detected by conventional staging modalities, whereas conventional staging demonstrated additional lesions in 4 of 18 patients not detected by whole-body PET. The total cost of conventional staging was $66,292 for 16 CT chest scans, 16 CT abdominal/pelvis scans, three limited MRI scans, four bone scans, five gallium scans, two laparotomies and one lymphangiogram. In contrast, scans cost $36,250 for 18 whole-body PET studies and additional selected correlative studies: one plain film radiograph, one limited CT, one bone marrow scan, one upper GI and one endoscopy. CONCLUSION: A whole-body FDG-PET-based staging algorithm may be an accurate and cost-effective method for staging or restaging HD and NHL.

Metabolic myocardial viability assessment with iodine 123-16-iodo-3-methylhexadecanoic acid in recent myocardial infarction: comparison with thallium-201 and fluorine-18 fluorodeoxyglucose.

The best test presently available to ascertain residual viability within an infarct-related area involves the use of fluorine-18 fluorodeoxyglucose (FDG) to detect the persistence of some cellular metabolism. Rest reinjection of thallium-201 is a less accurate alternative but is easy to perform. Iodinated fatty acids, which are used with standard gamma cameras, are proposed as markers of cellular metabolism. This study was performed to assess the value of 16-iodo-3-methylhexadecanoic acid (MIHA) as a marker of the residual cellular metabolism by comparison with FDG in patients with a recent myocardial infarction, and to evaluate its contribution compared with the 201Tl stress-redistribution-reinjection technique. Stress-redistribution-reinjection 201Tl imaging, rest MIHA imaging and glucose-loaded FDG imaging were performed in 22 patients with recent myocardial infarction. Out of the 628 myocardial segments obtained from the left ventricular analysis, 400 were hypoperfused (relative uptake <0.75 of maximum uptake on stress 201Tl imaging), 177 of which were severely hypoperfused (relative uptake <0.50). Receiver operating characteristic (ROC) curves for predicting metabolic myocardial viability with FDG were derived from the results in respect of (a) 201Tl activity during exercise, redistribution and reinjection and (b) MIHA uptake, using the two FDG thresholds most commonly considered to define metabolic viability (0.50 and 0.60). Analysis of the 400 hypoperfused segments demonstrated that 201Tl reinjection was the most accurate test in predicting the presence of myocardial viability (area under the ROI curves=0.85 and 0.86 at the 0.50 and 0.60 FDG thresholds, respectively; P<0.05 vs other tests). The global predictive values of MIHA and 201Tl reinjection were, respectively, 0.87 and 0.89 at the 0.50 FDG threshold (NS), and 0.82 and 0.87 at the 0.60 FDG threshold (NS). When only the 177 severely hypoperfused segments were considered, 201Tl reinjection remained the most accurate test (accuracy 0.84 at the 0.50 FDG threshold and 0.82 at the 0.60 FDG threshold), while the accuracy of MIHA decreased significantly (0.78 at the 0.50 FDG threshold and 0.73 at the 0.60 FDG threshold, P<0.05 vs 201Tl reinjection). In all circumstances, MIHA was less specific than 201Tl reinjection for the detection of metabolic viability. In conclusion, in patients with recent myocardial infarction, MIHA accurately detects the persistence of metabolic viability, but is not superior to 201Tl.