99mTc-3SPboroxime: A neutral 99mTc(III) radiotracer with high heart uptake and long myocardial retention.

BACKGROUND: 99mTc-3SPboroxime is a 99mTc(III) complex with high initial heart uptake comparable to that of 99mTc-Teboroxime, but with significantly longer myocardial retention in Sprague-Dawley rats. This study was performed to demonstrate its feasibility on myocardial perfusion imaging and myocardial blood flow quantification in swine models. METHODS: Dynamic single-photon emission computed tomography (SPECT) studies with 99mTc-3SPboroxime were performed in normal (with/without dipyridamole, n = 9) and acute myocardial infarction (AMI) swine (n = 3) in comparison with 99mTc-Teboroxime and 99mTc-Sestamibi. List-mode acquisitions were immediately started after injection and continued for 15 minutes. Regions of interest were drawn on heart (infarct and remote areas of AMI swine) and liver to generate time activity curves. Heart/liver and infarct/remote radioactivity ratios were calculated. One-tissue compartment model was implemented to obtain K1 and K2 values. RESULTS: The initial heart uptake of 99mTc-3SPboroxime was close to that of 99mTc-Teboroxime, but higher than that of 99mTc-Sestamibi. 99mTc-3SPboroxime had a myocardial retention longer than that of 99mTc-Teboroxime. The heart/liver ratio of 99mTc-3SPboroxime was higher than that of 99mTc-Teboroxime at later stage (13-15 minutes post-injection). The K1 value of 99mTc-3SPboroxime was much higher than that of 99mTc-Sestamibi, and the K2 value was significantly lower than that of 99mTc-Teboroxime both at rest and dipyridamole stress (rest K1: 0.63 ± 0.11 vs 0.40 ± 0.04 mL·min-1·g-1, P = 0.027; stress K1: 0.89 ± 0.05 vs 0.54 ± 0.08 mL·min-1·g-1, P = 0.031; rest K2: 0.22 ± 0.04 vs 0.33 ± 0.11 mL·min-1·g-1, P = 0.003; stress K2: 0.31 ± 0.03 vs 0.60 ± 0.30 mL·min-1·g-1, P = 0.047). High quality SPECT images could be obtained in any of the 5 minutes windows over the first 15 minutes after injection of 99mTc-3SPboroxime in normal and AMI swine models. Apical and anterior perfusion defects were clearly visualized in AMI swine. CONCLUSION: 99mTc-3SPboroxime is a promising radiotracer for future clinical translation considering its heart uptake, heart/liver ratio and SPECT image quality, as well as the advantage over 99mTc-Sestamibi in the definition of stress flow.

Association of use of proton pump inhibitors and H2 antagonists with stomach wall uptake in 99mTc-methoxy-isobutyl-isonitrile (MIBI) myocardial perfusion imaging.

BACKGROUND: Stomach wall uptake (SWU) of tracer in 99mTc-MIBI myocardial perfusion imaging (MPI) occasionally leads to imaging artifacts, thereby lowering the diagnostic accuracy. It is less-studied phenomenon for possible link with proton pump inhibitors (PPIs) intake. This prospective work looked for association of SWU with PPI intake and compared its incidence with H2 antagonists (H2A) users and patients not on either gastroprotective medication. METHODS: One hundred fifty-six patients undergoing one day stress/rest 99mTc-MIBI SPECT-MPI were distributed into four groups: control group (n = 48, not on any gastroprotective medication), PPI group (n = 47, on PPI treatment), H2A group (n = 19, on H2A therapy), and intervention group (N = 42, PPI discontinued for 3 days before MPI). Poststress planar images were analyzed for clinically relevant SWU. RESULTS: Clinically relevant SWU was seen in 36% of PPI group patients compared to 8% in the control group, 10.5% in the H2A group, and 9.5% in the intervention group, respectively, with statistically significant difference. Only 1/40 patients undergoing exercise stress showed clinically relevant SWU compared to 26/116 patients undergoing adenosine stress (P = .020). CONCLUSION: Patients on PPIs scheduled for vasodilator stress MPI may discontinue PPIs for 3 days, or replace with H2A to reduce the incidence of clinically relevant SWU associated with PPI therapy.

99mTc-Radiolabeled TPGS Nanomicelles Outperform 99mTc-Sestamibi as Breast Cancer Imaging Agent.

D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) is a Food and Drug Administration (FDA) approved biomaterial that can form nanosized micelles in aqueous solution. TPGS micelles stand as an interesting system to perform drug delivery as they can carry lipophilic drugs and overcome P glycoprotein efflux as well. Therefore, TPGS micelles combined with other copolymers have been reported in many cancer research studies as a carrier for therapeutic drugs. Their ability to reach tumoral tissue can also be exploited to develop imaging agents with diagnostic application. A radiolabeling method with 99mTc for TPGS nanosized micelles and their biodistribution in a healthy animal model as well as their pharmacokinetics and radiolabeling stability in vivo was previously reported. The aim of this work was to evaluate the performance of this radioactive probe as a diagnostic imaging agent compared to routinely available SPECT radiopharmaceutical, 99mTc-sestamibi. A small field of view gamma camera was used for scintigraphy studies using radiolabeled TPGS micelles in two animal models of breast cancer: syngeneic 4T1 murine cell line (injected in BALB/c mice) and chemically NMU-induced (Sprague-Dawley rats). Ex vivo radioactivity accumulation in organs of interest was measured by a solid scintillation counter, and a semiquantitative analysis was performed over acquired images as well. Results showed an absence of tumoral visualization in 4T1 model for both radioactive probes by gamma camera imaging. On the contrary, NMU-induced tumors had a clear tumor visualization by scintigraphy. A higher tumor/background ratio and more homogeneous uptake were found for radiolabeled TPGS micelles compared to 99mTc-sestamibi. In conclusion, 99mTc-radiolabeled TPGS micelles might be a potential SPECT imaging probe for diagnostic purposes.

Feasibility of Hyperfunctioning Parathyroid Gland Localization Using [18F]fluciclovine PET/CT.

PURPOSE: To evaluate the ability of anti-1-amino-3-anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid ([18F]fluciclovine) positron emission tomography/X-ray computed tomography (PET/CT) in comparison to Technetium-99m 2-methoxy isobutyl isonitrile ([99mTc]sestamibi) single-photon emission computed tomography/CT (SPECT/CT) for the localization of hyperfunctioning parathyroid glands in patients with hyperparathyroidism. PROCEDURES: Four patients with hyperparathyroidism underwent 60-minutes sequential neck and thorax PET/CT after [18F]fluciclovine (352 ± 28 MBq) injection. Lesion uptake and target-to-background ratios (TBR) were compared with [99mTc]sestamibi (798 ± 27 MBq) SPECT/CT in the same patient. RESULTS: Both techniques detected 4/5 hyperfunctioning parathyroid glands identified at surgery. The highest [18F]fluciclovine uptake and TBRs were at 5-9 min with rapid washout. [99mTc]sestamibi had significantly higher TBRs compared with [18F]fluciclovine (5-9 min) for blood pool (10.9 ± 4.7 vs 1.3 ± 0.6; p < 0.01) and reference muscle backgrounds (5.8 ± 3.0 vs 1.7 ± 0.6; p < 0.01), with non-significant trend for thyroid tissue background (1.3 ± 0.5 vs 1.1 ± 0.5; p = 0.73). CONCLUSION: Hyperfunctioning parathyroid glands can be detected on [18F]fluciclovine PET/CT at early imaging, but conspicuity (TBR) is better with [99mTc]sestamibi. [18F]fluciclovine PET/CT does not seem promising in the detection of hyperfunctioning parathyroid glands.

99mTc-MIBI single photon emission computed tomography/computed tomography for the incidental detection of rare parathyroid carcinoma.

This study aimed to evaluate the characteristics of parathyroid carcinoma and to validate the diagnostic value of Tc-methoxyisobutylisonitrile (MIBI) single photon emission computed tomography/x-ray computed tomography (SPECT/CT) for differentiating between parathyroid carcinoma and hyperparathyroidism. Four consecutive patients with suspected primary hyperparathyroidism were enrolled in this study and underwent Tc-MIBI SPECT/CT, ultrasonography, enhanced CT, and MRI. Serum parathyroid hormone (PTH) and calcium were measured. All primary and recurrent lesions showed high focal uptake on Tc-MIBI image, whereas metastatic lymph nodes gave false negative results. The serum PTH was 165.14 ±â€Š90.26 pmol/L, which declined rapidly after surgery. One patient with a persistently high PTH (147.5 pmol/L) after surgery presented with multiple lymphadenopathy in the neck. Higher expression of chromogranin A (CgA) further confirmed parathyroid carcinoma as a rare endocrine tumor. Parathyroid carcinoma is thus usually diagnosed incidentally based on nonspecific multiorgan symptoms of hypercalcemia and hyperparathyroidism. Tc-MIBI SPECT/CT may help to localize the parathyroid carcinoma, while MRI is valuable for detecting metastasis. Serum PTH and CgA serve as circulating biomarkers in parathyroid carcinoma, and raised levels of PTH and CgA together with locoregional lymphadenopathy may indicate parathyroid carcinoma. Further studies are needed.

Evaluation of the Effect of Resveratrol and Doxorubicin on 99mTc-MIBI Uptake in Breast Cancer Cell Xenografts in Mice.

BACKGROUND AND OBJECTIVE: Doxorubicin (DOX), despite having antitumor properties, also exhibits cardiotoxicity. Resveratrol has antitumor property for breast cancer cells. 99mTc-MIBI has higher absorption rate in human breast cancer cell line MCF-7. In the present study, the authors intend to investigate the effect of DOX and resveratrol on the absorption of 99mTc-MIBI in breast cancer cell xenografts in mice. MATERIALS AND METHODS: Sixteen xenograft models in nude mice were divided into four groups. Group I (S, control) received 2% DMSO in 0.9% saline, group II (D) 2.5 mg/kg DOX, group III (D + R) 20 mg/kg/d resveratrol with 2.5 mg/kg DOX (total dose of 15 mg/kg in six injections), and group IV (R) 20 mg/kg/d resveratrol for 2 weeks. Single-photon emission computed tomography (SPECT) images were taken for the determination of 99mTc-MIBI absorption. Mice were sacrificed, and the percentage of injected dose per gram (%ID/g) of the heart, liver, tumor, and muscle was measured using a gamma counter. Hematoxylin-eosin staining and Masson's trichrome staining were used for investigation of histopathological changes. RESULTS: The %ID/g of tumor was lowest in group D + R. The severity of tumor necrosis or apoptosis was highest in group D + R, but there is no significant difference in pathological injuries and %ID/g of tumor between the group D + R and group D. In addition to the results of the %ID/g, the severity of pathological injuries to the liver and heart cells in group D + R was higher compared with group D. There is a significant difference in the %ID/g of the liver between the group D + R and group D. SPECT images showed that the lowest amount of %ID/g was observed in the tumor of group D + R. CONCLUSIONS: According to the results of pathology, biodistribution study, and imaging, the combination of DOX and resveratrol has shown higher antitumor effect; hence, 99mTc-MIBI can be used to evaluate their antitumor effect.

Complementary role of parathormone washout test to 99mTc-MIBI parathyroid scintigraphy and histopathologic analysis of cell types in parathyroid adenomas. / Gammagrafía paratiroidea con 99mTc-MIBI: valor complementario de la paratohormona en el aspirado y análisis histopatológico de los tipos de células en los adenomas paratiroideos.

OBJECTIVE: Parathyroid scintigraphy (PS) can be negative or equivocal (N/E) in a considerable number of cases with highly suspicious clinical findings and biochemical results for parathyroid adenoma (PA). The aims of this study were to investigate the complementary role of parathormone washout test (PWT) to PS in patients with primary hyperparathyroidism (PHPT) and evaluate histopathologic aspects of PAs in comparison with PS results. MATERIAL AND METHODS: Thirty-eight patients with PHPT referred for PS were included in the study. Seventeen patients had both scintigraphic and ultrasonographic findings concordant with PA (Group A). Twenty-one patients having N/E PS, but suspected lesions for PA on ultrasonography (US) formed Group B. PWT was performed for all patients and they underwent the surgical intervention. An adenoma was removed in all patients and the histopathologic cell characteristics were established. RESULTS: The tumor size on US was larger in those patients whose adenomas were seen on the PS (P<.001). The percentages of chief (or principal), oxyphilic and clear cells in PAs were not statistically different between the groups. Serum parathormone level and PWT were not statistically significant between Group A and Group B (P=.095 and P=.04, respectively). CONCLUSION: Although there is not a definitive threshold value, the sensitivity of PS increases with lesion size. While chief cell and oxyphilic cell content of PAs tend to deplete in N/E PS, clear cell rate increases substantially. Combining PS with both US and PWT increases the sensitivity of detection and localization of PAs.

Cystic parathyroid adenoma: Primary hyperparathyroidism without 99mTc-MIBI uptake. / Adenoma quístico paratiroideo: hiperparatiroidismo primario sin captación de 99mTc-MIBI.

Cystic parathyroid adenoma is a rare disease (<0.01% of all cervical masses) that associates primary hyperparathyroidism in 9% of cases. Parathyroid scintigraphy is essential for its diagnosis with uncommon false negative results. Hybrid SPECT/CT equipments allow a more accurate diagnosis. Functional cystic parathyroid adenomas are surgically treated. A case of a 64-year-old woman with diagnoses of hyperparathyroidism and a cystic parathyroid adenoma without uptake in scintigraphy is described.

Contribution of early SPECT/CT to 99mTc-MIBI double phase scintigraphy in primary hyperparathyroidism: Diagnostic value and correlation between uptake and biological parameters.

AIM: To evaluate the value of 99mTc-MIBI double-phase scintigraphy (DPS) and early SPECT/CT in the pre-surgical assessment of patients with primary hyperparathyroidism (PHPT). Also, to calculate the correlation between uptake and some biological parameters. MATERIAL AND METHODS: Forty patients with PHPT were included: 37 solitary adenomas, 1 hyperplasia, and 2 double adenomas. Fifteen patients had ectopic glands. DPS and early SPECT/CT were acquired in all patients. Ultrasound was performed in 31/40. All patients underwent surgery, intra-operative iPTH measurements, and histopathological examinations. Qualitative DPS uptake was assessed and correlated to pre-surgical calcium, iPTH levels, gland weight, and maximum diameter. RESULTS: In the planar study, there were 23 positive cases, 8 doubtful, and 9 negatives. With the SPECT/CT, 8/9 negatives cases were located. All doubtful cases were confirmed as positives. Gland location improved in 16 cases (12 ectopic). DPS+SPECT/CT failed to detect a solitary adenoma and at least one gland in three cases of multiglandular disease (MGD). The sensitivity by patient was: DPS 72.5%, DPS+SPECT/CT 90%, and ultrasound 42%. Ultrasound and scintigraphy (DPS+SPECT/CT) were concordant in 16/31 patients. For the rest of them, scintigraphy proved correct in 14/15, and both techniques failed in one case. There was a significant correlation between level of uptake and iPTH level, gland weight, and maximum diameter. CONCLUSION: Early SPECT/CT improves sensitivity and the locating of parathyroid pathological glands and increases diagnostic confidence. iPTH level, glandular size, and weight are related to the qualitative assessment of 99mTc-MIBI uptake in early DPS.

Comparison of the radiotoxicity of the 99mTc-labeled compounds 99mTc-pertechnetate, 99mTc-HMPAO and 99mTc-MIBI.

PURPOSE: In addition to gamma radiation, 99mTc emits low-energy Auger electrons with path-lengths of nanometers to micrometers that cannot be utilized for diagnostic procedures; however, they have frequently been discussed for therapeutic applications. We compared radiotoxicity of three 99mTc-labeled radiopharmaceuticals with differences in the subcellular distribution. MATERIALS AND METHODS: The intracellular radionuclide uptake and subcellular distribution of [99mTc]-pertechnetate (99mTc-pertechnetate), [99mTc]Tc-hexamethyl-propylene-aminoxime (99mTc-HMPAO) and [99mTc]Tc-hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) were quantified in rat thyroid FRTL-5 cells. Radiotoxicity was compared using late phosphorylated histone H2AX (γH2AX) foci as a marker for unrepaired DNA double-strand breaks (DNA-DSB) and clonogenic cell survival. RESULTS: 99mTc-HMPAO showed a substantially higher uptake into the nucleus and the membrane/organelles than 99mTc-pertechnetate or 99mTc-MIBI. The colony-forming assay showed that 99mTc-pertechnetate and 99mTc-HMPAO caused a similar reduction in cell survival. 99mTc-MIBI is less radiotoxic in terms of the estimated nucleus dose and induced the fewest number of γH2AX foci compared with the other 99mTc-tracers, and 99mTc-HMPAO induced a fewer number of γH2AX foci than 99mTc-pertechnetate. CONCLUSIONS: Our findings reveal that clonogenic cellular survival is not solely determined by the DNA-DSB response. This finding may suggest the involvement of extra-nuclear radiosensitive targets in cell inactivation. For example, the mitochondria or the cell membrane could be affected by 99mTc-HMPAO.

Does the Clearance of Inhaled (99m)Tc-Sestamibi Correlate with Multidrug Resistance Protein 1 Expression in the Human Lung?

Purpose To examine the relation between the lung elimination rate of inhaled technetium 99m ((99m)Tc)-sestamibi and immunohistochemical expression of bronchopulmonary multidrug resistance protein 1 (MRP1) and permeability glycoprotein (P-gp) and assess the repeatability of the inhaled (99m)Tc-sestamibi clearance technique. Materials and Methods (99m)Tc-sestamibi is a known substrate for P-gp and MRP1, which are established cellular drug efflux transporters. The elimination rate of (99m)Tc-sestamibi from the lungs after inhalation as an aerosol has been hypothesized to be regulated by expression of these transporters. Institutional ethics committee approval was received for this prospective study. Written informed consent was obtained from all participants. The clearance of inhaled (99m)Tc-sestamibi from the lungs of 13 patients due to undergo surgery for primary lung cancer (five of 13) or spontaneous pneumothorax (eight of 13) was estimated after dynamic imaging of the lungs during a period of 40 minutes. The time taken to clear 50% of inhaled sestamibi (T1/2) was compared with a semiquantitative immunohistochemical assessment (grade 0-3) of MRP1 and P-gp expression in the lung by using parametric and nonparametric tests. The study was repeated in five participants to assess the repeatability of the technique by using a Bland Altman analysis method. Results MRP1 expression was seen in 12 of 13 patients, while P-gp expression was seen in only two. The mean (99m)Tc-sestamibi elimination rate was faster in patients (n = 6) with low levels of MRP1 expression (grade 0-1) and mean T1/2 of 105 minutes ± 20 (standard deviation), compared with those with higher levels of MRP1 expression (grade 2-3, n = 7) and mean T1/2 of 149 minutes ± 28 (P = .008). Bland-Altman analysis revealed excellent agreement between test and retest values. Conclusion Inhaled (99m)Tc-sestamibi clearance study is a repeatable technique demonstrating significant correlation with MRP1 expression in the lungs. (©) RSNA, 2016.

Percutaneous microwave ablation of benign thyroid nodules. Functional imaging in comparison to nodular volume reduction at a 3-month follow-up.

AIM: Thyroid nodules represent a common clinical issue. Amongst other minimally invasive procedures, percutaneous microwave ablation (MWA) poses a promising new approach. The goal of this retrospective study is to find out if there is a correlation between volume reduction after 3 months and 99mTc-uptake reduction of treated thyroid nodules. PATIENTS, METHODS: 14 patients with 18 nodules were treated with MWA. Pre-ablative assessment included sonographical and functional imaging of the thyroid with 99mTc-pertechnetate and 99mTc-MIBI. Additionally, patients underwent thyroid scintigraphy 24 hours after ablation in order to evaluate the impact of the treatment on a functional level and to ensure sufficient ablation of the targeted area. At a 3-month follow-up, ultrasound examination was performed to assess nodular volume reduction. RESULTS: Mean relative nodular volume reduction after three months was 55.4 ± 17.9% (p < 0.05). 99mTc-uptake 24 hours after treatment was 45.2 ± 31.9% (99mTc-MIBI) and 35.7 ± 20.3% (99mTc-pertechnetate) lower than prior to ablation (p < 0.05). Correlating reduction of volume and 99mTc-uptake, Pearson's r was 0.41 (p < 0.05) for nodules imaged with 99mTc-MIBI and -0.98 (p < 0.05) for 99mTc-pertechnetate. According to scintigraphy 99.6 ± 22.6% of the determined target area could be successfully ablated. CONCLUSIONS: MWA can be considered as an efficient, low-risk and convenient new approach to the treatment of benign thyroid nodules. Furthermore, scintigraphy seems to serve as a potential prognostic tool for the later morphological outcome, allowing rapid evaluation of the targeted area in post-ablative examination.

Background 99mTc-methoxyisobutylisonitrile uptake of breast-specific gamma imaging in relation to background parenchymal enhancement in magnetic resonance imaging.

OBJECTIVES: This study investigated factors that could affect background uptake of (99m)Tc- methoxyisobutylisonitrile (MIBI) on normal breast by breast-specific gamma imaging (BSGI). In addition, the impact of background (99m)Tc-MIBI uptake on the diagnostic performance of BSGI was further investigated. METHODS: One hundred forty-five women with unilateral breast cancer who underwent BSGI, MRI, and mammography were retrospectively enrolled. Background uptake on BSGI was evaluated qualitatively and quantitatively. Patients were classified into non-dense and dense breast groups according to mammographic breast density. Background parenchymal enhancement (BPE) was rated according to BI-RADS classification. The relationship of age, menopausal status, mammographic breast density, and BPE with background (99m)Tc-MIBI uptake was analyzed. RESULTS: Heterogeneous texture and high background uptake ratio on BSGI were significantly correlated with younger age (p < 0.001, respectively), premenopausal status (p < 0.001 and p = 0.003), dense breast (p < 0.001, respectively), and marked BPE (p < 0.001, respectively). On multivariate analysis, only BPE remained a significant factor for background MIBI uptake (p < 0.001).There was a significant reduction in positive predictive value (p = 0.024 and p = 0.002) as background MIBI uptake and BPE grade increased. CONCLUSIONS: BPE on MRI was the most important factor for background MIBI uptake on BSGI. High background MIBI uptake or marked BPE can diminish the diagnostic performance of BSGI. KEY POINTS: • Age, menopause, density, and background parenchymal enhancement affect background MIBI uptake. • BPE is an independent factor for background MIBI uptake on BSGI. • Marked BPE may impair BSGI interpretation.

An efficient strategy based on an individualized selection of registration methods. Application to the coregistration of MR and SPECT images in neuro-oncology.

An efficient registration strategy is described that aims to help solve delicate medical imaging registration problems. It consists of running several registration methods for each dataset and selecting the best one for each specific dataset, according to an evaluation criterion. Finally, the quality of the registration results, obtained with the best method, is visually scored by an expert as excellent, correct or poor. The strategy was applied to coregister Technetium-99m Sestamibi SPECT and MRI data in the framework of a follow-up protocol in patients with high grade gliomas receiving antiangiogenic therapy. To adapt the strategy to this clinical context, a robust semi-automatic evaluation criterion based on the physiological uptake of the Sestamibi tracer was defined. A panel of eighteen multimodal registration algorithms issued from BrainVisa, SPM or AIR software environments was systematically applied to the clinical database composed of sixty-two datasets. According to the expert visual validation, this new strategy provides 85% excellent registrations, 12% correct ones and only 3% poor ones. These results compare favorably to the ones obtained by the globally most efficient registration method over the whole database, for which only 61% of excellent registration results have been reported. Thus the registration strategy in its current implementation proves to be suitable for clinical application.

99mTc-3P4-RGD2 scintimammography in the assessment of breast lesions: comparative study with 99mTc-MIBI.

PURPOSE: To compare the potential application of (99m)Tc-3P-Arg-Gly-Asp ((99m)Tc-3P4-RGD2) scintimammography (SMM) and (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) SMM for the differentiation of malignant from benign breast lesions. METHOD: Thirty-six patients with breast masses on physical examination and/or suspicious mammography results that required fine needle aspiration cytology biopsy (FNAB) were included in the study. (99m)Tc-3P4-RGD2 and (99m)Tc-MIBI SMM were performed with single photon emission computed tomography (SPECT) at 60 min and 20 min respectively after intravenous injection of 738 ± 86 MBq radiotracers on a separate day. Images were evaluated by the tumor to non-tumor localization ratios (T/NT). Receiver operating characteristic (ROC) curve analysis was performed on each radiotracer to calculate the cut-off values of quantitative indices and to compare the diagnostic performance for the ability to differentiate malignant from benign diseases. RESULTS: The mean T/NT ratio of (99m)Tc-3P4-RGD2 in malignant lesions was significantly higher than that in benign lesions (3.54 ± 1.51 vs. 1.83 ± 0.98, p<0.001). The sensitivity, specificity, and accuracy of (99m)Tc-3P4-RGD2 SMM were 89.3%, 90.9% and 89.7%, respectively, with a T/NT cut-off value of 2.40. The mean T/NT ratio of (99m)Tc-MIBI in malignant lesions was also significantly higher than that in benign lesions (2.86 ± 0.99 vs. 1.51 ± 0.61, p<0.001). The sensitivity, specificity and accuracy of (99m)Tc-MIBI SMM were 87.5%, 72.7% and 82.1%, respectively, with a T/NT cut-off value of 1.45. According to the ROC analysis, the area under the curve for (99m)Tc-3P4-RGD2 SMM (area = 0.851) was higher than that for (99m)Tc-MIBI SMM (area = 0.781), but the statistical difference was not significant. CONCLUSION: (99m)Tc-3P4-RGD2 SMM does not provide any significant advantage over the established (99m)Tc-MIBI SMM for the detection of primary breast cancer. The T/NT ratio of (99m)Tc-3P4-RGD2 SMM was significantly higher than that of (99m)Tc-MIBI SMM. Both tracers could offer an alternative method for elucidating non-diagnostic mammograms.

Longitudinal time-dependent effects of irradiation on multidrug resistance in a non-small lung cancer cell line.

Multidrug resistance (MDR) in cancer is known to decrease the therapeutic efficacy of chemotherapy. The effects of irradiation on MDR in cancer cells remain unclear. Tc-99m methoxyisobutylisonitrile (MIBI) exhibits the same ATP-binding cassette (ABC) transporter kinetics as the chemotherapeutic compound doxorubicin. In this study, we investigated the synergistic effects of chemotherapeutics and irradiation [0 Gy: C (control) group; 3, 6, 9, 12 Gy: I (irradiation) group] in the human non-small lung cancer cell line H1299 exhibiting MDR, on MIBI and doxorubicin ABC transporter kinetics, in vitro and in vivo, respectively. In vitro, inhibition of H1299 cell proliferation by irradiation was found to be irradiation dose dependent. The degree and duration of MDR inhibition in vitro in H1299 were also dose dependent. In the cells of both the C group and 3-Gy I group, no significant difference of MIBI accumulation was observed. In the 6-Gy I group, a higher MIBI accumulation was observed at only 7 days after irradiation relative to the C group. A higher MIBI accumulation in the 9- and 12-Gy I groups with a significant difference from the C group was observed at 4 to 14 days after irradiation. A significant negative correlation between intracellular MIBI accumulation and cell replication was found. In vivo, high accumulation and retention of doxorubicin were observed in irradiated tumors in the H1299 xenograft mice group at 4 to 14 days after 9-Gy irradiation compared with the control mice group. These results provide evidence for a synergistic effect of concurrent chemotherapy and radiotherapy.

Interrogation of multidrug resistance (MDR1) P-glycoprotein (ABCB1) expression in human pancreatic carcinoma cells: correlation of 99mTc-Sestamibi uptake with western blot analysis.

Histopathological studies indicate that ∼63% of pancreatic tumors express multidrug resistance (MDR1) P-glycoprotein (Pgp) and its polymorphic variants. However, Pgp expression detected at the mRNA or protein level does not always correlate with functional transport activity. Because Pgp transport activity is affected by specific mutations and the phosphorylation state of the protein, altered or less active forms of Pgp may also be detected by PCR or immunohistochemistry, which do not accurately reflect the status of tumor cell resistance. To interrogate the status of the functional expression of MDR1 Pgp in MiaPaCa-2 and PANC-1 cells, cellular transport studies using Tc-Sestamibi were performed and correlated with western blot analysis. Biochemical transport assays in human pancreatic carcinoma MiaPaCa-2 and PANC-1 cells, human epidermal carcinoma drug-sensitive KB-3-1 cells, and human breast carcinoma MCF-7 cells (negative controls), and human epidermal carcinoma drug-resistant KB-8-5 cells, human breast carcinoma stably transfected with Pgp MCF-7/MDR1Pgp cells, and liver carcinoma HepG2 cells (positive controls) were performed. Protein levels were determined using a monoclonal antibody C219. Tc-Sestamibi demonstrates accumulation in human pancreatic carcinoma MiaPaCa-2 and PANC-1 cells. Uptake profiles are not affected by treatment with LY335979, a Pgp inhibitor, and correlate with western blot analysis. These cellular transport studies indicate an absence of Pgp at a functional level in MiaPaCa-2 and PANC-1 cells. Because major pancreatic tumors originate from the pancreatic duct and Tc-Sestamibi undergoes a dominant hepatobiliary mode of excretion, it would not be a sensitive probe for imaging pancreatic adenocarcinomas. Following interrogation of the functional status of Pgp in other pancreatic carcinoma cells, chemotherapeutic drugs that are also MDR1 substrates could offer alternative therapeutics for treating pancreatic adenocarcinomas.

Predictive value of CYP3A and ABCB1 phenotyping probes for the pharmacokinetics of sunitinib: the ClearSun study.

BACKGROUND AND OBJECTIVE: The wide inter-patient variability in drug exposure partly explains the toxicity and efficacy profile of sunitinib treatment. In this prospective study cytochrome P450 (CYP) 3A and adenosine triphosphate binding cassette (ABC) B1 phenotypes were correlated to the pharmacokinetics of sunitinib and its active metabolite N-desethylsunitinib. METHODS: A correlation analysis was performed between sunitinib pharmacokinetics and 1'OH-midazolam/midazolam ratio and parameters derived from technetium-99m-2-methoxy isobutyl isonitrile ((99m)Tc-MIBI) scans, respectively. A population pharmacokinetic model using non-linear mixed-effects modeling software NONMEM was built, which included the phenotype tests as covariate. RESULTS: In 52 patients, the mean trough concentration of sunitinib plus metabolite increased from 21.4 ng/mL at day 1 of a cycle to 88.1 ng/mL in the fourth week of treatment. A trend for a correlation was observed between (99m)Tc-MIBI elimination constant and trough concentrations of N-desethylsunitinib; however, this was not significant. Correlations were found between 1'OH-midazolam/midazolam ratio and sunitinib clearance (P = 0.008) and day 1 N-desethylsunitinib trough concentrations (P = 0.005), respectively. Moreover, patients suffering from grade 3 toxicities had significant lower clearance of sunitinib than patients without grade 3 toxicities (34.4 vs. 41.4 L/h; P = 0.025). CONCLUSIONS: Phenotype tests for ABCB1 and CYP3A4 did not explain inter-individual variability of sunitinib exposure sufficiently. However, the correlation between sunitinib clearance and the occurrence of severe toxicity suggests a direct exposure-toxicity relationship.