Simultaneous dual-isotope imaging based on an artificial neural network for evaluating myocardial perfusion and fatty acid metabolism.

BACKGROUND: We contrived a scatter correction method based on an artificial neural network (ANN) and applied it to the simultaneous evaluation of myocardial perfusion and fatty acid metabolism in single-photon emission computed tomography (SPECT). METHODS: The count data of three energy windows were used as inputs of the ANN. The count ratios of the estimated primary-to-total photons for (99m)Tc and (123)I, which were used to reconstruct (99m)Tc and (123)I images, were calculated using the ANN. In a phantom study, single- and dual-isotope imaging with (99m)Tc/(123)I and (201)Tl/(123)I was performed by means of a cardiac phantom simulating patients with and without obesity. In a human study, five normal volunteers and ten patients with myocardial infarction underwent myocardial perfusion and fatty acid metabolism imaging with single and dual SPECT with combinations of (99m)Tc-methoxyisobutylisonitrile/(123)I-beta-methyl(p-iodophenyl)pentadecanoic acid (BMIPP) and (201)Tl/(123)I-BMIPP as tracers. RESULTS: Technetium-99m yielded more homogeneous images than (201)Tl because of the lower degree of photon attenuation, especially in the condition of obese patients, resulting in clearer visualization of the perfusion-metabolism mismatch. Dual (99m)Tc/(123)I SPECT offered comparable images with single SPECT in assessing myocardial damage. CONCLUSIONS: The method effectively separated (99m)Tc and (123)I primary photons and proved applicable to (99m)Tc/(123)I dual-isotope myocardial SPECT.

Application of support vector machine classifiers to preoperative risk stratification with myocardial perfusion scintigraphy.

BACKGROUND: Myocardial perfusion single-photon emission computed tomography (SPECT) has been used for risk stratification before non-cardiac surgery. However, few authors have used mathematical models for evaluating the likelihood of perioperative cardiac events. METHODS AND RESULTS: This retrospective cohort study collected data of 1,351 patients referred for SPECT before non-cardiac surgery. We generated binary classifiers using support vector machine (SVM) and conventional linear models for predicting perioperative cardiac events. We used clinical and surgical risk, and SPECT findings as input data, and the occurrence of all and hard cardiac events as output data. The area under the receiver-operating characteristic curve (AUC) was calculated for assessing the prediction accuracy. The AUC values were 0.884 and 0.748 in the SVM and linear models, respectively in predicting all cardiac events with clinical and surgical risk, and SPECT variables. The values were 0.861 (SVM) and 0.677 (linear) when not using SPECT data as input. In hard events, the AUC values were 0.892 (SVM) and 0.864 (linear) with SPECT, and 0.867 (SVM) and 0.768 (linear) without SPECT. CONCLUSION: The SVM was superior to the linear model in risk stratification. We also found an incremental prognostic value of SPECT results over information about clinical and surgical risk.

Preoperative risk evaluation in diabetic patients without angina.

AIMS: The aim of the current study was to clarify whether stress myocardial perfusion single-photon emission computed tomography (SPECT) stratifies perioperative cardiac risk in noncardiac surgery of diabetic patients without chest pain. METHODS: This study enrolled consecutive 284 patients with diabetes mellitus (DM) without chest pain who underwent noncardiac surgery after dipyridamole stress SPECT. Myocardial perfusion and cardiac function were simultaneously evaluated in the SPECT examination. We sought clinical and imaging variables predictive of perioperative cardiac events, and estimated the prognostic value of SPECT. RESULTS: No clinical risk factors were proved to be significant predictors of perioperative cardiac events except the duration of diabetes. In contrast, myocardial perfusion imaging itself and the combination of information on perfusion and cardiac function provided significant risk stratification. The event rate in patients with normal perfusion was low regardless of surgical procedures, while that in patients with abnormal perfusion increased depending on the operation risk. CONCLUSIONS: Normal myocardial SPECT findings ensure the low likelihood of perioperative cardiac events in DM patients without chest pain. Perfusion and/or functional abnormalities are associated with the adverse outcome especially in high-risk operation.

Preoperative risk stratification with myocardial perfusion imaging in intermediate and low-risk non-cardiac surgery.

BACKGROUND: Perioperative cardiac risk in high risk surgery is often stratified with myocardial perfusion single-photon emission computed tomography (SPECT). However, little and no data are available about intermediate and low-risk surgery, respectively. METHODS AND RESULTS: A total of 1,220 consecutive patients underwent electrocardiography-gated dipyridamole stress SPECT to evaluate myocardial perfusion and cardiac function before intermediate or low risk non-cardiac surgery. Variables predictive of perioperative cardiac events were determined and the usefulness of combining pretest information and the incremental prognostic value of SPECT was estimated. The frequency of all cardiac events depended on clinical risk factors and type of surgical procedures. After sorting the patients with clinical risk factors and surgical risk, assessment of myocardial perfusion or cardiac function yielded significant risk stratification in intermediate, but not in low-risk surgery. Adding functional data to perfusion variables offered an incremental prognostic value for patients with an intermediate clinical risk and scheduled intermediate risk surgery. CONCLUSIONS: Integrating information about clinical risk factors, type of surgery, myocardial perfusion and cardiac function allows detailed preoperative risk stratification. Preoperative SPECT provides an incremental prognostic value in intermediate, but not in low-risk surgery.

Scatter correction based on an artificial neural network for 99mTc and 123I dual-isotope SPECT in myocardial and brain imaging.

UNLABELLED: The aim of this study was to elucidate the clinical usefulness of scatter correction with an artificial neural network (ANN) in 99mTc and 123I dual-isotope SPECT. METHODS: Two algorithms for ANN scatter correction were tested: ANN-10 and ANN-3 employing 10 and 3 energy windows for data acquisition, respectively. Three patients underwent myocardial or brain SPECT with one of the following combinations of radiopharmaceuticals administered: 99mTc-tetrofosmin and 123I-metaiodobenzylguanidine (MIBG), 99mTc-methoxyisobutylisonitrile (MIBI) and 123I-beta-methyl-paraiodophenyl-pentadecanoic acid (BMIPP), or 99mTc-ethyl-cistainate dimmer (ECD) and 123I-iomazenil. The patients were also referred for single-isotope imaging incorporating conventional triple-energy window (TEW) scatter correction. Crosstalk- and scatter-corrected 99mTc- and 123I-SPECT images in dual-isotope acquisition with ANN were compared with those in single-isotope acquisition. RESULTS: The ANN method well separated 123I and 99mTc primary photons. Although ANN-10 yielded images of poor quality, ANN-3 offered comparable image quality with the single-isotope scan without significant increase of acquisition time. CONCLUSION: The proposed method is clinically useful because it provides various combinations of information without anatomical misregistration with one acquisition.

Influence of ageing on perioperative cardiac risk in non-cardiac surgery.

BACKGROUND: ageing is known to augment perioperative cardiac risk in non-cardiac surgery. However, it remains unclear whether the increased risk is attributable to ageing itself or to the associated cardiac risk factors and coronary artery disease. METHODS: this retrospective study enrolled 1,351 patients who underwent non-cardiac surgery after dipyridamole stress myocardial perfusion scintigraphy. These patients were divided into the following four groups: Group 1-E (aged 75 or more, normal single photon emission computed tomography (SPECT)), Group 1-Y (aged less than 75, normal SPECT), Group 2-E (aged 75 or more, abnormal SPECT) and Group 2-Y (aged less than 75, abnormal SPECT). Clinical risk factors, scintigraphic findings and occurrence of perioperative cardiac events were analysed. RESULTS: the older cohorts had a significantly higher number of risk factors than their younger counterparts. No significant difference was observed in the degree of perfusion abnormality between Groups 2-E and 2-Y. Although the event rates were comparable in Groups 1-E and 1-Y, Group 2-E yielded a significantly higher rate than Group 2-Y. Ageing was an independent predictor of cardiac events in Group 2 in multivariate analysis. CONCLUSIONS: ageing has no influence on perioperative cardiac risk in patients without overt myocardial infarction or ischaemia. The likelihood of cardiac events is increased by ageing, independently of other variables, in patients with perfusion abnormality.

99mTc-sestamibi to monitor treatment with antisense oligodeoxynucleotide complementary to MRP mRNA in human breast cancer cells.

OBJECTIVE: Technetium-99m sestamibi (MIBI) has been utilized to evaluate multi-drug resistance (MDR) phenomenon of malignant tumors and to predict chemotherapeutic effects on them. The current investigation examined the possibility of monitoring changes with respect to mRNA expression of multi-drug resistance associated protein (MRP) following antisense oligodeoxynucleotide (AS-ODN) treatment involving 99mTc-MIBI. METHODS: The human breast cancer MCF-7 cell line and its MDR-induced MCF-7/VP cell line were employed. Cell suspensions of the two cell lines at 1 x 10(4) cells/ml were inoculated in 24-well plates (0.2 ml/well) and incubated for one day. Antisense (AS) 20-mer phosphorothioate ODN complementary to the coding region of MRP mRNA and its sense (S) ODN were administered at final concentrations up to 25 microM, followed by a 5-day incubation. 99mTc-MIBI solution was added to each well and incubated for 30 min. Cellular 99mTc-MIBI uptake was corrected for protein concentration. MRP mRNA expression levels were analyzed via the reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Cellular uptake of 99mTc-MIBI in MCF-7/VP cells was only 15% of that of MCF-7 cells. Following AS-ODN treatment at 25 microM for five days, 99mTc-MIBI uptake in MCF-7/VP cells increased 2.4-fold in comparison with non-treated control cells. 99mTc-MIBI uptake in MCF-7 cells was unaffected by AS-ODN administration. Sense ODN did not alter uptake in either cell line. RT-PCR confirmed reduction of MRP mRNA in MCF-7/VP cells following AS-ODN treatment. CONCLUSION: Effects of AS-ODN administration on MRP function can be monitored via assessment of cellular uptake of 99mTc-MIBI.

Binding with serum components favorably affects cellular uptake of 111In-oligonucleotide in a leukemia cell line.

PURPOSE: The influence of serum components on the intracellular uptake of an 111In-oligonucleotide (ODN) against mdr1 mRNA was investigated in the murine leukemia cell line, P388/S, and its mdr1-overexpressed P388/R. METHODS: 111In-ODNs naked and vectorized with lipids were analyzed for binding with serum components using high-performance liquid chromatography (HPLC). 111In-ODN was incubated in albumin and transferrin solutions. 111In-DTPA and 111In-mononucleotide were incubated in serum. Degradation of naked 111In-ODN was detected in phosphate buffered saline (PBS) and serum containing endonuclease S1. Cellular uptakes of naked and vectorized 111In-ODN in the above cells were examined with and without fetal calf serum (FCS). RESULTS: Time-dependent binding of naked and vectorized 111In- ODN with serum components was observed throughout 24 hours. Transchelation of 111In to transferrin was not detected. HPLC profiles of 111In-DTPA and 111In-mononucleotide did not change in serum. Degradation of 111In-ODN by S1 was less remarkable in serum than in PBS. Specific accumulation of vectorized 111In-ODN in P388/R cells was achieved in culture with and without 10% FCS. CONCLUSIONS: This study verified the intense binding of ODN with serum components, leading to no inhibition on ODN intracellular specific uptake. Binding with serum components protects 111In-ODN from degradation by endonuclease and thus may facilitate ODN transmembrane delivery.

Influence of photon scattering and attenuation on ROI analysis in brain perfusion single-photon emission tomographic imaging of normal subjects.

OBJECTIVE: The aim of this study was to evaluate the effect of scatter and attenuation correction in region of interest (ROI) analysis in brain perfusion single-photon emission tomography (SPECT) and to assess the influence of selecting the reference area on semi-quantification. METHODS: Ten normal subjects were enrolled and injected with 123I-iodoamphetamine to undergo simultaneous emission and transmission scanning for scatter and attenuation correction. We reconstructed three SPECT images from common projection data of each subject: with scatter correction and non-uniform attenuation correction, with scatter correction and uniform attenuation correction, and with uniform attenuation correction applied to data without scatter correction. A program for automated ROI drawing was used to set ROIs on various regions in brain images. Regional count ratios were compared in images with different correction procedures by using three different reference areas. RESULTS: The effect of the combination of scatter and attenuation correction was marked in the precentral, temporal, posterior, hippocampus and especially in the cerebellum. In contrast, it was not appreciable in the central and parietal areas. When using the cerebellar ROI as the reference, the count ratio varied widely depending on the correction procedures. On the other hand, the whole brain reference offered the least variation in the count ratio. CONCLUSIONS: The influence of photon scattering and attenuation was dependent on regions. Since the count in the cerebellar ROI is greatly affected by photon scattering and attenuation, nonuniform attenuation correction combined with scatter correction deserves consideration when using the cerebellar ROI as the reference.

In vitro detection of mdr1 mRNA in murine leukemia cells with 111In-labeled oligonucleotide.

PURPOSE: The feasibility of intracellular mdr1 mRNA expression detection with radiolabeled antisense oligonucleotide (ODN) was investigated in the murine leukemia cell line, P388/S, and its subclonal, adriamycin-resistant cell line, P388/R. METHODS: The expression level of mdr1 mRNA was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Existence of the multidrug resistance (MDR) phenomenon was assessed via cellular uptake of 99mTc-sestamibi (MIBI), a known substrate for P-glycoprotein. A 15-mer phosphorothioate antisense ODN complementary to the sequences located at -1 to 14 of mdr1 mRNA and its corresponding sense ODN were conjugated with the cyclic anhydride of diethylene triamine penta-acetic acid (cDTPA) via an amino group linked to the terminal phosphate at the 5' end at pH 8-9. The DTPA-ODN complexes at concentrations of 0.1-17.4 microM were reacted with 111InCl3 at pH 5 for 1 h. The hybridization affinity of labeled ODN was evaluated with size-exclusion high-performance liquid chromatography following incubation with the complementary sequence. Cellular uptake of labeled ODN was examined in vitro. Furthermore, enhancing effects of synthetic lipid carriers (Transfast) on transmembrane delivery of ODN were assessed. RESULTS: P388/R cells displayed intense mdr1 mRNA expression in comparison with P388/S cells. 99mTc-MIBI uptake in P388/S cells was higher than that in P388/R cells. Specific radioactivity up to 1,634 MBq/nmol was achieved via elevation of added radioactivity relative to ODN molar amount. The hybridization affinity of antisense 111In-ODN was preserved at approximately 85% irrespective of specific activity. Cellular uptake of antisense 111In-ODN did not differ from that of sense 111In-ODN in either P388/S cells or P388/R cells. However, lipid carrier incorporation significantly increased transmembrane delivery of 111In-ODN; moreover, specific uptake of antisense 111In-ODN was demonstrated in P388/R cells. CONCLUSION: Radiolabeling of ODN at high specific radioactivity and specific uptake of antisense 111In-ODN in drug-resistant cells may facilitate future gene imaging of mdr1 mRNA.

Improved survival of mice bearing liver metastases of colon cancer cells treated with a combination of radioimmunotherapy and antiangiogenic therapy.

We attempted to determine whether the combined regimen of radioimmunotherapy (RIT) and antiangiogenic therapy would favorably affect the survival of animals bearing liver metastases of colon cancer cells. Daily antiangiogenic therapy with 2-methoxyestradiol (2-ME), 75 mg/kg, was initiated at 3 days following intrasplenic cell inoculation of LS180 colon cancer cells. RIT with 7 MBq of (131)I-A7, an IgG1 anti-colorectal monoclonal antibody, or (131)I-HPMS-1, an irrelevant IgG1, was conducted at 7 days. Production of vascular endothelial growth factor (VEGF) by LS180 cells was assessed in vitro. All nontreated mice died by 31 days following cell inoculation ( n=5). Monotherapy comprising 2-ME treatment resulted in slightly better survival of mice ( n=8) ( P<0.05). (131)I-A7 RIT displayed a marked therapeutic effect ( n=8) ( P<0.001); however, all animals eventually died due to metastases by 99 days. The combined regimen of (131)I-A7 RIT and antiangiogenic therapy demonstrated a superior therapeutic effect in comparison to monotherapy consisting of either RIT or antiangiogenic therapy ( n=10) ( P<0.05); three mice survived the entire 160-day observation period. The combination of antiangiogenic therapy and (131)I-HPMS-1 RIT failed to provide an appreciable benefit ( n=5). Treatment with 2-ME decreased VEGF production by LS180 cells in a dose-dependent fashion. In conclusion, a combination regimen comprising RIT and antiangiogenic therapy initiated at the early stage of metastasis would be of great benefit in terms of improvement of the therapeutic efficacy with respect to liver metastases.

Preliminary evaluation of image reconstruction by ordered-subset expectation maximization in thallium-201 lung scintigraphy.

OBJECTIVES: We observed whether clearer tumor delineation and greater tumor to non-tumor (T/N) count ratios could be obtained using an iterative ordered-subsets expectation maximization (OSEM) algorithm than conventional filtered-back projection algorithm (FBP) in the image reconstruction of thallium-201 (201Tl) lung scintigraphy. METHODS: In 29 patients with lung cancer and phantom studies, tomograms were reconstructed using FBP and OSEM algorithms, with and without a prefilter (Butterworth filter: BW), whose cut-off frequencies were 0.10 cycles/pixel for FBP and 0.10 and 0.17 cycles/pixel for OSEM. Visual interpretation and tumor to non-tumor (T/N) count ratios were obtained and compared. RESULTS: Without a prefilter, T/N ratios from OSEM and FBP were 1.89 +/- 0.31 (early) and 2.00 +/- 0.54 (late) for OSEM, 1.90 +/- 0.33 (early) and 2.05 +/- 0.59 (late) for FBP, respectively. The OSEM reconstruction without prefiltering showed clearer tumor contours than FBP without a prefilter. Incorporation of BW showed visually low-noised images but decreased T/N ratios in both reconstructions with BW (0.10 cycles/pixel). No greater T/N ratios were obtained by OSEM than FBP, with or without prefiltering. With BW with a cut-off frequency of 0.17 cycles/pixel, the same T/N ratios as those without BW were obtained. The tumor model sized 0.9 cm in the phantom study was invisible in both OSEM and FBP reconstructions without a prefilter, but visible with a prefilter. The influence of prefiltering on T/N ratios was also observed in phantom studies. CONCLUSIONS: Visually improved tumor delineation could be obtained in OSEM reconstruction without a prefilter as compared to FBP reconstruction without a prefilter for tumors greater than 2 cm. Prefiltering should be incorporated into OSEM reconstruction in diagnosing small tumors. However, the influence of prefilter (BW) setting on semi-quantitative interpretation needs further discussion.

Hypoxia-induced alteration of tracer accumulation in cultured cancer cells and xenografts in mice: implications for pre-therapeutic prediction of treatment outcomes with (99m)Tc-sestamibi, (201)Tl chloride and (99m)Tc-HL91.

Weak visualization of tumours in pre-therapeutic scintigrams with technetium-99m sestamibi (MIBI) is likely a predictive sign of unfavourable tumour response to radiotherapy and chemotherapy. However, factors relating to this scintigraphic finding are not well understood. The presence of hypoxic tumour cells is one of the major reasons for therapeutic failure; consequently, we attempted to determine whether oxygenation status affects (99m)Tc-MIBI accumulation in tumour cells. LS180 human colon cancer and T24 human bladder cancer cells were incubated in air or N(2) gas at 37 degrees C. Cellular uptake of (99m)Tc-MIBI was subsequently determined at 15, 60 and 120 min. Uptake of thallium-201 chloride was also assessed. Uptake of (99m)Tc-HL91 was assessed as a hypoxic marker. Accumulation of the tracers in LS180 xenografts was observed in mice treated with 5 mg/kg hydralazine and compared with that in untreated mice. pO(2) in the medium and tumours was measured with O(2) microelectrodes. N(2) gas flow gradually reduced pO(2) in the cell suspension to 1-2 mmHg in 60 min. Cellular uptake of (99m)Tc-MIBI in LS180 cells decreased by approximately 30% in N(2) gas in comparison to that in air throughout the study. Hypoxia had a more prominent influence on (201)Tl uptake, which displayed a reduction of approximately 60% in N(2) gas at 120 min, than on (99m)Tc-MIBI uptake. On the other hand, N(2) gas induced an increase of 170% in (99m)Tc-HL91 uptake at 120 min, indicating the hypoxic condition of cells. The results of in vitro assays employing the T24 cell line were similar to those obtained with the LS180 cell line. Hydralazine treatment markedly reduced (99m)Tc-MIBI and (201)Tl accumulation in LS180 xenografts; moreover, intratumoural pO(2) decreased from 14.5 +/- 6.6 mmHg to 7.6 +/- 6.2 mmHg. (99m)Tc-HL91 accumulation in xenografts was markedly increased by hydralazine. In conclusion, hypoxia reduced accumulation of (99m)Tc-MIBI and (201)Tl in tumour cells. Accordingly, hypoxia may be an important factor in terms of the interpretation of scintigraphic findings obtained with these tracers for pre-therapeutic prediction of tumour response to treatment. Furthermore, the enhanced (99m)Tc-HL91 accumulation in hypoxic tumour cells indicates the usefulness of this tracer in this regard.

Radionuclide cisternography in intracranial hypotension syndrome.

A 44-year-old male patient complaining of severe headache right after twisting his body during aerobic exercises in a swimming pool underwent In-111 DTPA radionuclide cisternography. Leakage of cerebrospinal fluid (CSF) was proved on the right side of T2 and T3 vertebrae. Cisternography after bed and conservative treatments demonstrated the disappearance of abnormal tracer accumulations. Radionuclide cisternography is of great value in diagnosing cerebral-spinal fluid leak and in evaluating the therapeutic effect.