Synthesis, characterization, and radiosynthesis of fluorine-18-AVT-011 as a Pgp chemoresistance imaging marker.

P-glycoprotein (Pgp) is the most studied ATP-binding cassette (ABC) efflux transporter and contributes to chemoresistance. A few tracers have been developed to detect the in-vivo status of chemoresistance using positron emission tomography (PET) imaging. In our study, we have synthesized labeled AVT-011 with fluorine-18 (18F) followed by in-vitro and in-vivo analysis. Tosylate AVT-011 precursor was synthesized and characterized by 1H-NMR and 13C-NMR. AVT-011 was labeled with 18F using the nucleophilic substitution method, and a standard set of quality control was performed. The specificity for Pgp was tested in U87MG cells with and without an inhibitor (tariquidar). The biodistribution and in-vivo stability were tested in the small animals (mice). The biodistribution data of [18F]-AVT-011 was extracted from the PET-CT imaging of breast cancer patients (n = 6). The precursor was synthesized with 36 ± 4% yield and 97 ± 2% purity. The labeling was more than 95% with a 42 ± 2% yield, as evaluated by Radio-HPLC. The cell-binding assay showed a specificity of the tracer for Pgp as the uptake increased by twice after blocking the Pgp receptors. The radiotracer showed a hepatorenal excretion pathway for clearance in an animal study. The uptake was higher in the liver, lungs, spleen, and heart at 15 min and decreased at 60 min. The patients' distribution showed similar uptake patterns as observed in the small animals. [18F]AVT-011 was characterized successfully with high radiochemical purity and yield. The in-vitro and in-vivo studies proved its specificity for Pgp and safe for patient use.

Lung clearance of inhaled aerosol of Tc-99m-methoxyisobutyl isonitrile: relationships with cigarette smoking, age and gender.

Tc-99m-methoxyisobutyl isonitrile (Tc-99m-MIBI) is a radiolabelled xenobiotic, the disappearance rate of which from lungs following inhalation as a radioaerosol correlates inversely with bronchopulmonary multidrug resistance protein 1 (MRP1) expression. Tc-99m-MIBI clearance has previously been shown to be delayed in cigarette smokers. The aim of the current study was to determine whether smoking correlates with bronchopulmonary MRP1 expression, to confirm that Tc-99m-MIBI disappearance rate from the lungs following inhalation is delayed in smokers, and to determine the effects of gender and age on disappearance rate. Participants underwent dynamic imaging for 40 min over the lungs following inhalation of Tc-99m-MIBI using a double-headed gamma camera. The half-time of clearance was obtained from geometric mean of anterior and posterior counts and averaged between the two lungs. Paraffin-embedded tissue obtained from healthy lung during surgery in 13 patients was graded immunohistochemically for MRP1 as negative (0), weak (1), moderate (2) or strong (3). In 4 non-smokers, grading was 1 in three and 0 in one. In 9 smokers, in contrast, expression was graded 2-3 in 8 and 1 in one (P<0·02). Mean clearance half-time in smokers (142 ± 29 min; n = 17) was longer than in non-smokers (91 ± 14 min; n = 18; P<0·0001). In non-smokers, half-times were not significantly different between men (96 ± 16; n = 6) min and women (88 ± 12 min; P = 0·2). Combining genders into one group, half-time correlated with participant age (P = 0·0005). We conclude that smoking upregulates MRP1 and delays clearance of inhaled Tc-99m-MIBI. There is no significant gender difference in non-smokers but ageing is associated with longer clearance half-times.

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.

Clinical Utility of SPECT/CT Imaging Post-Radioiodine Therapy: Does It Enhance Patient Management in Thyroid Cancer?

BACKGROUND: The aim of this study was to evaluate post-therapy iodine-131 single-photon emission computed tomography/computed tomography ((131)I-SPECT/CT) imaging in comparison to conventional planar (131)I whole-body imaging, and to assess its clinical impact on the management of patients. METHODS: We retrospectively reviewed planar (131)I whole-body and (131)I-SPECT/CT imaging findings in 67 patients who underwent (131)I therapy for thyroid cancer. Two nuclear medicine physicians reviewed the scans independently. The foci of increased tracer uptake were identified in the neck, thorax and elsewhere. Within the neck, the foci of (131)I-increased uptake were graded qualitatively as probable or definite uptake in thyroid remnants and probable or definite uptake in the lymph nodes. Serum thyroglobulin level, histopathology and other imaging findings served as the reference standard. RESULTS: Of the 67 patients, 57 (85%) had radioiodine avid disease and 10 (15%) demonstrated non-radioiodine avid disease. Overall, post-therapy (131)I-SPECT/CT downstaged lymph node staging in 10 patients and upstaged it in 4 patients. This translated into a change of management for 9/57 (16%) patients with radioiodine avid disease. A change of management was observed in 5/10 patients with non-radioiodine avid disease confirmed in the post-(131)I-SPECT/CT study. Additionally, clinically significant findings such as incidental lung cancer, symptomatic pleural effusion and consolidation were also diagnosed in both groups of patients. CONCLUSION: In patients with thyroid cancer, (131)I-SPECT/CT is a valuable addition to standard post-therapy planar imaging. SPECT/CT also improved diagnostic confidence and provided crucial clinical information leading to change of management for a significant number of these patients.

Value of lateral blood pool imaging in patients with suspected stress fractures of the tibia.

AIM: To critically evaluate the use of lateral blood pool imaging in athletes with lower limb pain and with a clinical suspicion of stress fracture. METHODS: Two experienced nuclear medicine physicians evaluated 3-phase bone scans using 99mTc-methylene diphosphonate performed in 50 consecutive patients referred from a specialist sports injury clinic for suspected tibial stress fracture. The vascularity to the tibia as seen on the blood pool (second phase) images in the anterior/posterior views was compared with the lateral/medial view assessments. Stress fractures were presumed to be present when on the delayed images (third phase) there was a focal or fusiform area of increased tracer uptake involving the tibial cortex. Shin splints which are a recognized cause of lower limb pain in athletes mimicking stress fracture were diagnosed if increased tracer uptake was seen extending along the posterior tibial surface with no significant focal or fusiform area of uptake within this. Inter-reviewer agreement for the assessment of vascularity was also assessed using Cohen's Kappa scores. RESULTS: Twenty-four stress fractures in 24 patients and 66 shin splints in 40 patients were diagnosed. In 18 patients stress fracture and shin splints coexisted. In 10 patients no tibial pathology was identified. Of the 24 patients diagnosed with stress fractures, lateral/medial blood pool imaging was superior in the assessment of blood pool activity (P < 0.001) identifying increased vascularity in 21 cases compared with the anterior/posterior views positive in only 11 cases. The inter-reviewer agreement was near perfect for lateral/medial views, κ = 0.86 while very good for anterior/posterior views, κ = 0.68. CONCLUSION: In patients with suspected tibial stress fractures, lateral views of the tibia provide the optimal method for evaluation of vascularity. Prospective studies with quantitative or semi-quantitative assessment of skeletal vascularity could provide supplementary information relating to the pathophysiology of stress fractures, for example, the time scale of vascular changes after a tibial stress fracture, and potentially could have clinical relevance as to the assessment of the severity of stress fractures and their prognosis.

SPECT/CT in imaging foot and ankle pathology-the demise of other coregistration techniques.

Disorders of the ankle and foot are common and given the complex anatomy and function of the foot, they present a significant clinical challenge. Imaging plays a crucial role in the management of these patients, with multiple imaging options available to the clinician. The American College of radiology has set the appropriateness criteria for the use of the available investigating modalities in the management of foot and ankle pathologies. These are broadly classified into anatomical and functional imaging modalities. Recently, single-photon emission computed tomography and/or computed tomography scanners, which can elegantly combine functional and anatomical images have been introduced, promising an exciting and important development. This review describes our clinical experience with single-photon emission computed tomography and/or computed tomography and discusses potential applications of these techniques.

The added value of multislice SPECT/CT in patients with equivocal bony metastasis from carcinoma of the prostate.

PURPOSE: The purpose of this study was to investigate the additional value of single photon emission computed tomography/computed tomography (SPECT/CT) over whole-body planar bone scintigraphy and SPECT in prostate cancer patients in terms of diagnostic confidence, inter-reviewer agreement and the possible impact on the clinical management. METHODS: This was a retrospective review of 40 consecutive prostate cancer patients (mean age 71 years) who underwent (99m)Tc-methylene diphosphonate (MDP) whole-body planar bone scintigraphy, SPECT and SPECT/CT between April 2006 and April 2008. The images were evaluated by two independent reviewers; inter-reviewer agreement was evaluated using a weighted kappa score. Each focus of abnormal increased tracer uptake was recorded using a 4-point diagnostic confidence scale. Institutional Review Board approval was obtained. RESULTS: Fifty lesions on planar bone scintigraphy in the 40 patients were evaluated. On reporting the planar study and SPECT scans, reviewers rated 61% of lesions as equivocal. On reporting the SPECT/CT scans only 8% of lesions were rated as equivocal, 24% were rated as malignant and 68% as benign. Weighted kappa scores for inter-reviewer agreement were 0.43 for bone scintigraphy, 0.56 for SPECT and 0.87 for SPECT/CT. All were significant at p < 0.0001. Follow-up imaging confirmed the SPECT/CT diagnoses in 14 patients. CONCLUSION: The addition of SPECT/CT resulted in a significant reduction of equivocal reports; a definitive diagnosis was given in the majority of the patients due to the improved diagnostic confidence compared to planar or SPECT imaging alone in prostate cancer patients with suspected bone metastases.

Cost-effectiveness of 99mTc-sestamibi in predicting response to chemotherapy in patients with lung cancer: systematic review and meta-analysis.

UNLABELLED: Multidrug resistance (MDR) is a major problem in lung cancer. (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) has been demonstrated to be a noninvasive marker for the diagnosis of MDR-related P glycoprotein and MDR-associated protein expression in various solid tumors. Studies have shown that (99m)Tc-MIBI could play a significant role in the management of lung cancer; for example, it could be used in the selection of patients for chemotherapy or radiotherapy or in combined protocols before the start of treatment. Accurate selection of chemosensitive patients with (99m)Tc-MIBI would result not only in effective treatment of patients but also in significant cost savings for health care providers. There is increasing pressure on health care providers to consider costs in medical decision making, particularly in the last decade, as several economic evaluations have appeared in the medical literature. The aims of this study were to undertake a systematic review of the performance of (99m)Tc-MIBI imaging in the assessment of treatment resistance in lung cancer and to use the findings of the review in a decision tree analysis of the potential cost-effectiveness of (99m)Tc-MIBI imaging in selecting lung cancer patients for chemotherapy. METHODS: This study included a systematic review of the literature and a meta-analysis together with a cost-effectiveness analysis of studies with a decision tree analysis model. RESULTS: Analysis of the studies revealed that the overall sensitivity of (99m)Tc-MIBI in identifying responders to chemotherapy was 94%, the specificity was 90%, and the accuracy was 92%. The sensitivity analysis revealed an incremental cost-effectiveness ratio of greater than pound30,000 ( approximately $42,900) for the strategy of treating all patients to recover the small loss of life expectancy (7.5 d) associated with the use of (99m)Tc-MIBI to preselect patients for chemotherapy. CONCLUSION: (99m)Tc-MIBI SPECT can accurately predict which patients with lung cancer will respond to chemotherapy. The use of (99m)Tc-MIBI to preselect patients for chemotherapy has the potential to yield significant cost savings in the health care system without a significant loss of life expectancy for patients.

Synergistic impact of attenuation correction and gating in routine myocardial SPECT reporting: 2 year follow-up study.

AIM: To look at the combined impact of non-uniform attenuation correction (AC) and gated SPECT in the visual interpretation of myocardial SPECT imaging. This was compared to the individual benefit obtained by adding AC information and gated SPECT information to non-AC image information. MATERIALS: We retrospectively studied a group of 141 patients with a 22-26 month follow-up who underwent myocardial perfusion scintigraphy imaging. All the studies were corrected for attenuation with Gd line source transmission data and were ECG gated. In patients who had abnormal studies, follow-up coronary angiography information was also obtained in addition to medical follow-up information. METHODS: Two experienced nuclear medicine physicians interpreted the images independently and were blinded to the other person's report. Non-attenuation corrected data was first evaluated followed by attenuation corrected data and gated SPECT data. Four approaches to interpretation of images were undertaken: (1) non-AC images only, (2) non-AC+AC images, (3) non-AC+gated images, and (4) non-AC+AC+gated images. Study results were divided into four categories based on how confident the observers were of the diagnosis: (1) normal, (2) borderline normal, (3) borderline abnormal, and (4) abnormal. RESULTS: When results for sensitivity and specificity using the four different interpretation techniques were compared there was a statistically significant improvement in the specificity compared to non-AC image (48%) with the addition of AC (77%) and gating (82%) information (P<0.001). The best improvement in the specificity was noted when both AC and gated information (91%) was used along with non-AC information. The normalcy rates almost doubled following the addition of AC and gated data. There was also a decrease in the number of borderline results, showing an improvement in the reporter confidence in interpreting myocardial SPECT studies. Sensitivity, however, did not show a significant change between the four different approaches to interpretation of the study. CONCLUSION: Attenuation correction and gating when combined have a synergistic impact upon improving the specificity of myocardial SPECT reporting when compared to the use of individual techniques alone to improve the specificity.

Thyroid hormone and parathyroid hormone competing to maintain calcium levels in the presence of vitamin D deficiency.

Weight loss and bone disease in the elderly are very often attributed to malignancy. Rarely, benign treatable conditions may be overlooked. Thyrotoxicosis, a benign treatable condition, needs to be excluded in such patients. The diagnosis may be delayed, since the symptoms are often subtle, and secondary complications including bone disease (osteoporosis) are therefore more frequent at the time of presentation. The case presented here illustrates this well, and also highlights the value of measuring vitamin D levels in such patients. The most interesting aspect of this case was the reciprocal relationship between thyroxine and parathyroid hormone observed in maintaining calcium homeostasis in this thyrotoxic patient with low vitamin D levels.