SPECT Imaging of Muscle Injury with [99mTc]MDP in a Mouse Model of Muscular Dystrophy.

PURPOSE: Tc-99m methylene diphosphonate ([99mTc]MDP) is an in vivo bone imaging agent that also accumulates in injured skeletal muscle cells. The objective of this study was to investigate if [99mTc]MDP could be used to detect muscle injury in the mdx mouse model of Duchenne muscular dystrophy (DMD). PROCEDURES: Static whole-body single-photon emission computed tomography/computed tomography (CT) scans were acquired at 2 h post-injection of [99mTc]MDP in two cohorts of animals at different sites: one cohort of mice at 6, 15, and 19 weeks of age, and a separate cohort at 16 weeks. The second cohort was also imaged with high-resolution CT at 8 weeks. RESULTS: mdx mice had higher [99mTc]MDP uptake and significantly higher [99mTc]MDP concentrations in muscle than controls. CONCLUSIONS: Higher uptake of [99mTc]MDP in muscle of mdx mice agrees with histological reports of muscle calcification in mdx mice, and suggests the potential translational use of [99mTc]MDP imaging for tracking DMD progression and therapeutic response.

Semi-quantitative methods yield greater inter- and intraobserver agreement than subjective methods for interpreting 99m technetium-hydroxymethylene-diphosphonate uptake in equine thoracic processi spinosi.

Scintigraphy is a standard diagnostic method for evaluating horses with back pain due to suspected thoracic processus spinosus pathology. Lesion detection is based on subjective or semi-quantitative assessments of increased uptake. This retrospective, analytical study is aimed to compare semi-quantitative and subjective methods in the evaluation of scintigraphic images of the processi spinosi in the equine thoracic spine. Scintigraphic images of 20 Warmblood horses, presented for assessment of orthopedic conditions between 2014 and 2016, were included in the study. Randomized, blinded image evaluation was performed by 11 veterinarians using subjective and semi-quantitative methods. Subjective grading was performed for the analysis of red-green-blue and grayscale scintigraphic images, which were presented in full-size or as masked images. For the semi-quantitative assessment, observers placed regions of interest over each processus spinosus. The uptake ratio of each processus spinosus in comparison to a reference region of interest was determined. Subsequently, a modified semi-quantitative calculation was developed whereby only the highest counts-per-pixel for a specified number of pixels was processed. Inter- and intraobserver agreement was calculated using intraclass correlation coefficients. Inter- and intraobserver intraclass correlation coefficients were 41.65% and 71.39%, respectively, for the subjective image assessment. Additionally, a correlation between intraobserver agreement, experience, and grayscale images was identified. The inter- and intraobserver agreement was significantly increased when using semi-quantitative analysis (97.35% and 98.36%, respectively) or the modified semi-quantitative calculation (98.61% and 98.82%, respectively). The proposed modified semi-quantitative technique showed a higher inter- and intraobserver agreement when compared to other methods, which makes it a useful tool for the analysis of scintigraphic images. The association of the findings from this study with clinical and radiological examinations requires further investigation.

An Unexpected and Less Recognized Altered Distribution on Bone Scintigraphy; Possibility of 99mTc-Dextrose Complex as a Cause.

Optimal performance of diagnostic tests and correct interpretation depend on multiple factors, one of which is proper radiopharmaceutical preparation. Unwanted impurities result in altered distribution of radiopharmaceuticals and then poor-quality or uninterpretable studies. Therefore, following the reconstitution steps according to standard and validated protocols by the technologist is mandatory. Here, we present 2 cases with unexpected and less recognized distribution of Tc-methylene diphosphonate on bone scintigraphy.

Miniaturized Radiochemical Purity Testing for 99mTc-HMPAO, 99mTc-HMDP, and 99mTc-Tetrofosmin.

Quick methods are functional in clinical practice to ensure the fastest availability of radiopharmaceuticals. For this purpose, we investigated the radiochemical purity of the widely used 99mTc-hydroxymethylene diphosphonate, 99mTc-hexamethylpropyleneamine oxime, and 99mTc-tetrofosmin by reducing time as compared with the manufacturer's method. Methods: We applied a miniaturized chromatographic method with a reduced strip development from 18 cm to 9 cm for all 3 radiopharmaceuticals. The specific support medium and solvent system of the manufacturer's methods was kept unchanged for 99mTc-hydroxymethylene diphosphonate and 99mTc-tetrofosmin, whereas for 99mTc-hexamethylpropyleneamine oxime the instant thin-layer chromatography (ITLC) polysilicic gel (silicic acid [SA]) was replaced with a monosilicic gel (silicic gel [SG]) in the chromatographic system that uses methyl ethyl ketone as solvent. The method was applied and compared with the routine ITLC insert method in a total of 30 batches for each radiopharmaceutical. The precision of repeated tests was determined by comparison with the results of 10 replications on the same batch. Small volumes of concentrated 99mTcO4-, and 99mTc-albumin nanocolloid were used to produce potential radiochemical impurities. Correlation between the quick methods and the insert methods was analyzed using a nonparametric 2-tailed test and a 2 × 2 contingency table with the associated Fisher exact test to evaluate sensitivity and specificity. A receiver-operating-characteristic analysis was performed to evaluate the best cutoff. Results: The percentage radiochemical purity of the quick methods agreed with the standard chromatography procedures. We found that 99mTcO4 and colloidal impurities are not the only common radiochemical impurities with 99mTc-tetrofosmin, and shortening of the ITLC strip with respect to the manufacturer's method will worsen system resolution and may produce inaccuracy. Conclusion: The miniaturized methods we described represent a fast and reliable alternative for 99mTc-exametazime and 99mTc-oxidronate quality control, with the upper cutoff for acceptable radiochemical purity values being 84% and 95%, respectively. For 99mTc-tetrofosmin radiochemical purity testing, a longer strip as described in the standard method is warranted.

The bone scintigraphy in the diagnosis and management in children with febrile osteoarticular pain.

BACKGROUND: Bone and joint infections are common diseases in pediatrics. They still are a public health problem in Tunisia. The diagnosis is based on clinical, biological, radiological and skeletal scintigraphy arguments. The purpose of this study is to determine the contribution of triple phase bone scan in the exploration of musculoskeletal pain febrile child. METHODS: This was a descriptive and retrospective study. It was conducted over a period of 5 years. It has interested all children explored in nuclear medicine department with suspected acute osteomyelitis (OMA) , osteoarthritis (OA) or septic arthritis (SA) referred from Orthopaedic Infantile service. All these patients had, alongside the conventional radiologic exams, a triple phase bone scan HMDP-Tc99m. RESULTS: We collected 62 patients. Among the selected diagnoses, there were: 22 OMA, 4 OA, 4 SA. The mean age of the patients was 5.58 years with a male predominance. The main reason for consultation was pain. Fever was ≥ 38° C in 80 % of cases. The preferential localization was the lower limb (93.5 %). The quantitative and qualitative bone scan abnormalities objectified led to a correct diagnosis of: 18 OMA, 3 OA and 2 SA with a respectively estimated sensitivity and specificity of 76.6% and 90.6% in the all population. CONCLUSIONS: Bone scan demonstrates early abnormalities allowing osteoaricular infection diagnosis. It highlights the infection site, and draws a map of the lesions. Currently, imaging modalities differ in their availability, their cost, their input and diagnostic accuracy but they are complementary.

Multifocal septic osteomyelitis mimicking skeletal metastatic disease in a patient with prostate cancer.

We present an unusual case of a 59 years old patient with prostate cancer, who was referred to our hospital with pleurodenia, low back and other sites of bone ostalgia, for bone scintiscan. The patient underwent a whole body bone scanning after the intravenous administration of 740MBq (99m)Tc-methylene diphosphonate (MDP). The main findings of the study were: increased radiotracer uptake at the T5, T9-T10 vertebrae, the head of the 11th rib and the area of the left sternoclavicular joint (SCJ), which were initially attributed to skeletal metastatic lesions. Another "hot" area in the left knee, was consistent with severe arthritis. Physical examination revealed fever up to 38.7°C, tenderness and swelling of his left knee and various painful sites. Due to persistent fever and markedly raised inflammatory markers (ESR 102mm/h, CRP 73.8mg/L, WBC 16.800 cells/µ L - neutrophils 78%, lymphocytes 15%, monocytes 5%, eosinophils 1%), the patient was further referred for a magnetic resonance (MR) scan with specific interest on the thoracic spine and the SCJ. In the sagittal short-tau inversion recovery (STIR) MR image, abnormally high signal involving both T9 and T10 vertebral bodies due to bone marrow oedema and irregularity of the endplates with focal destruction areas, were observed. The T9-T10 intervertebral disc had an abnormally high signal suggestive of "hot disc" sign and also a prevertebral soft tissue mass abutting the anterior aspect of the involved vertebral bodies. The axial T1-weighted image with fat saturation post gadolinium (Gd), revealed diffuse strong enhancement in the vertebral body, the paraspinal soft tissue mass and the adjacent right rib. Circumferential epidural enhancement indicative of intra-canal spread of the infection, was also noticed. Additional MR sequences covered the level of the SCJ. Extensive subarticular and soft tissue changes with fluid collection and bone oedema of the left SCJ were shown with the typical pattern of diffuse enhancement suggestive of septic arthritis. The MR imaging findings combined with the scintigraphic findings were consistent with subacute multifocal septic arthritis involving the axial skeleton, as a pyogenic spondylodiscitis at the T9-T10 level, the left SCJ joint and the left knee joint. Subsequently, aspiration of the SCJ and the left knee joint was performed. A purulent fluid was drained and sent to microbiology. The sample revealed 96.000 cells/µL (95% neutrophils) and methicillin-resistant Staphylococcus aureus (MRSA). The patient received intravenous vancomucin (2gr. twice a day for 14 days) and subsequently the dose was adjusted to maintain the vancomucin serum levels between 17 and 20mcg/mL. The total treatment duration was 12 weeks. Four months later the patient had fully recovered and his blood tests were normal. The patient had not been referred to an oncology department yet, as the onset of the arthritis occurred about two weeks after the diagnosis of prostate cancer. In conclusion, we present a patient with known malignancy, fever, skeletal pain and multiple bone lesions in the (99m)Tc-MDP and the MRI examination, not due to metastatic disease but to septic arthritis.

Is it safe to omit baseline bone scan for newly diagnosed prostate cancer patients?

OBJECTIVES: The aim of this study is to modify and validate a novel screening tool to determine the necessity of bone scans in Chinese PCa patients at the time of diagnosis. METHODS: Five-hundred-and-one patients diagnosed with PCa between 2010 and 2013 at Zhongshan Hospital, Fudan University, were included in the study. All received bone scans using technetium 99m methylene diphosphonate (99mTc-​MDP) at the initial staging. Age, prostate-specific antigen (PSA) and alkaline phosphatase (ALP) at diagnosis, disease stage, and biopsy Gleason score were collected from all patients. Multivariate logistic regression analysis and discrimination analysis were performed. A validation analysis of this screening tool was performed by Shanghai Cancer Center, Fudan University. RESULTS: Among the 501 patients, 84 (16.7%) of them had BM. The area under the ROC curve was 0.9006 (95% CI, 0.87-0.93). The sensitivity of the cut-off point was 94.1%, and the specificity was 58.3%. The validation analysis demonstrated an area under the ROC curve of 0.846 (95% CI, 0.805-0.887). CONCLUSIONS: Study results demonstrated that a baseline bone scan can be safely omitted for cT1-T3 PCa patients who have a PSA ≤39 ng/ml and an ALP ≤88 IU/l. This novel screening tool may help determine the necessity of including a bone scan at the time of initial diagnosis of PCa.

[99mTc]cFLFLF for Early Diagnosis and Therapeutic Evaluation in a Rat Model of Acute Osteomyelitis.

PURPOSE: Early diagnosis and therapeutic monitoring of acute osteomyelitis (AO) is challenging. Here, we use a polyethylene glycol (PEG)ylated chemotactic peptide cinnamoyl-F-(D)L-F-(D)L-F (cFLFLF) conjugated with hydrazinonicotinamide (HYNIC) and labeled with Tc-99m ([(99m)Tc]cFLFLF) to image AO in a rat model and to validate its efficacy in early diagnosis and therapeutic evaluation of AO. PROCEDURES: Forty rats were divided into eight groups of five each. Groups A, B, C, G, and H were AO models, and D, E, and F were sham controls. Groups A and D underwent [(99m)Tc]cFLFLF scintigraphy, groups B and E underwent [(99m)Tc]methylene diphosphonate ([(99m)Tc]MDP) bone scan, and groups C and F underwent 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) positron emission tomography (PET)/computed tomography (CT) scan. [(99m)Tc]cFLFLF biodistribution was assessed in group G. The response to antibiotic therapy was evaluated using [(99m)Tc]cFLFLF scintigraphy in group H. Conventional radiographs were obtained following scintigraphy. Ratios of infected or sham-operated tibia to the opposite tibia (T/B) were calculated. Immediately after the imaging studies, infected tibias were excised and underwent histopathological analysis and immunohistochemistry staining. RESULTS: AO was present in all rats of groups A, B, C, G, and H. Total histological scores were not significantly different among groups A, B, and C (F = 0.34, p = 0.71). The biodistribution results revealed significant uptake and excellent retention of [(99m)Tc]cFLFLF in the infected tibia. [(99m)Tc]cFLFLF scintigraphy and [(99m)Tc]MDP bone scan both detected AO. The mean T/B ratio of [(99m)Tc]cFLFLF scintigraphy 1 h postinjection was 2.09-fold higher than that of [(99m)Tc]MDP bone scan (t = 13.81, p <0.001). The mean T/B ratio of [(18)F]FDG PET/CT scan was not significantly different from the control group F (t = 2.17, p = 0.062). [(99m)Tc]cFLFLF scintigraphy revealed a significant attenuation of inflammation in group H following a 3-week antibiotic treatment, which was verified by histopathological analysis and immunohistochemistry staining. CONCLUSION: Our results suggest that the specificity and image quality of [(99m)Tc]cFLFLF are superior to those of the [(99m)Tc]MDP and [(18)F]DFG imaging probes currently used for early diagnosis of AO. Furthermore, [(99m)Tc]cFLFLF was able to effectively evaluate the therapeutic response to antibiotic treatment of AO. Our data suggest that [(99m)Tc]cFLFLF is a promising imaging agent for detection of infectious diseases.

Determination of the radiochemical purity of (99m) Tc medronate injection by thin layer chromatography on iTLC-SG: effect of medronate concentration on the value measured.

BACKGROUND: When using iTLC-SG thin layer chromatography plates to measure radiochemical impurities in (99m) Tc medronate, falsely high values were obtained for (99m) Tc pertechnetate impurity. Preliminary investigations indicated that the mass of (99m) Tc medronate applied to the plate influences the value. AIM: The goal of this study was to determine if the concentration of medronate influences the value obtained for (99m) Tc pertechnetate impurity. EXPERIMENTAL: (99m) Tc medronate was prepared at two concentrations: 4 mg/mL and 0.2 mg/mL. Impurity levels were measured using three stationary phases: dried and undried iTLC-SG and 54SFC paper. Two mobile phases were used: methyl ethyl ketone to detect (99m) Tc pertechnetate and sodium acetate 136 g/L to detect hydrolysed and colloidal (99m) Tc. Sample spot drying and volume were also investigated. RESULTS: With 4 mg/mL samples, the three stationary phases measured similar impurity levels (p > 0.05). With the 0.2 mg/mL samples, higher levels of (99m) Tc pertechnetate were measured with iTLC-SG than with paper (p < 0.05). Neither sample spot drying nor volume was found to affect impurity levels measured. CONCLUSIONS: When using iTLC-SG to measure the radiochemical purity of (99m) Tc medronate, an artefactually high level of (99m) Tc pertechnetate impurity is measured when the medronate concentration in the sample is low. The iTLC-SG stationary phase may be unsatisfactory for measuring the radiochemical purity of (99m) Tc medronate.

Cyclotron Production of (99m)Tc using (100)Mo2C targets.

An investigative study of the (100)Mo (p,2n)(99m)Tc reaction on a medical cyclotron using (100)Mo2C is reported. This is the first report of this compound being used as a target for this reaction. (100)Mo2C, a refractory carbide with high thermal conductivity, properties which underscore its use on a cyclotron, was synthesized using (100)MoO3. Its ease of oxidation back to (100)MoO3 under air at elevated temperatures facilitates the use of thermo-chromatography, a high temperature gas phase separation technique for the separation and isolation of (99m)Tc. Activity yields for (99m)Tc averaged 84% of the calculated theoretical yields. Additionally, the percent recovery of MoO3, the precursor for Mo2C, was consistently high at 85% ensuring a good life cycle for this target material. The produced (99m)Tc was radio-chemically pure and easily labeled MDP for imaging purposes.

Optical imaging of Tc-99m-based tracers: in vitro and in vivo results.

It has been recently shown that optical imaging (OI) methods can be used to image the in vivo biodistribution of several radiopharmaceuticals labeled with beta or alpha emitters. In this work particular attention has been focused on investigating the weaker optical signal induced by an almost pure gamma emitter like Tc-99m. Visible light emission measurements of a water solution containing Tc-99m were performed using a small animal OI system. A sequence of images was acquired for 24 h in order to study the decay of the luminescence signal. The difference between the luminescence decay half life and well-known Tc-99m half life was equal to 1%. in vivo imaging was performed by injecting one control nude mice with Tc-99m-MDP. Optical images obtained with equipment designed for bioluminescence imaging showed that a visible light emission was distinguishable and correctly localized in the bladder region where a higher concentration of Tc-99m-MDP was expected. The bladder to background ratio was always greater than 1. We conclude that the experimental data presented in this paper show that it is possible to detect in vivo luminescence optical photons induced by Tc-99m. This is important especially considering the large number of Tc-99m-based radiopharmaceutical currently available.

[Research of 99mTcO4- and 99mTcO2- in injectable solutions of 99mTc-HMDP by inverse phase HPTLC]. / Recherche de 99mTcO4- et de 99mTcO2- dans les solutions injectables de 99mTc-HMDP par HPTLC en phase inverse.

Bone scintigraphy allows the diagnostic of many pathologies related to bone through the intravenous administration of a phosphonate bone marker complexed to 99 metastable technetium (99mTc). The instability of these injectable solutions on contact with air can lead to a mixture of pertechnetate VII (99mTcO4-) and technetium IV (99mTcO2-, xH2O), technetium IV being the only derivative to fix bone. A qualitative control of the purity of these solutions proved to be consequently important before administration. We report here the perfecting of a new chromatographic test based on reverse phase high performance thin layer chromatography (HPTLC). This test, simple, rapid and reproductive allows without ambiguity the detection of 99mTcO4-(VII) and 99mTcO2-(IV), xH2O in hydroxymethylene diphosphonate (HMDP) injectable solutions ready to use.

Adsorption of radiopharmaceuticals to syringes leads to lower administered activity than intended.

In this study we examined the delivered activity of radiopharmaceuticals injected into patients and the various factors which lead to incomplete delivery. Four commonly used 99Tcm radiopharmaceuticals were included, namely pertechnetate, methylene diphosphonate (MDP), macro-aggregated albumin (MAA) and tetrofosmin. There was no appreciable residual activity after injection of pertechnetate and MDP other than that due to the dead space in syringes (0.06 ml, 4% of measured activity). However, there was considerable residual activity following an MAA injection. This was particularly dependent on the radiopharmaceutical residence time in the syringe prior to injection. If MAA was pre-dispensed there was up to 80% of activity remaining in the syringe following injection. We have shown that this activity is not bound and can be decreased by agitating the syringe prior to the injection. For tetrofosmin, the activity remaining in the syringe was shown to be mostly due to adsorption of the tetrofosmin onto the plastic syringe (up to 30% of the activity); in particular, onto the rubber plunger. The amount of binding probably depends on the formulation of the rubber plunger and the plastic barrel, which varies between manufacturers. Of the three commonly used syringe brands (Becton-Dickinson, Sherwood, and Braun syringes) the Braun syringes were shown to have the least binding (6%) and would be most suitable for tetrofosmin injection. We recommend the use of Braun syringes for tetrofosmin. We also recommend that pre-dispensed MAA injections should be gently agitated before injection into the patient. No special precautions are necessary for pertechnetate or MDP injections.

Effects of alternative reconstitution procedures on the labelling efficiency and in vitro stability of 99Tcm-labelled radiopharmaceuticals.

Adding normal saline (NS) separately before 99Tcm-sodium pertechnetate to MDP cold kits has been shown to reduce substantially the radiation dose to the hand. A similar dose reduction will probably prove to be valid with the preparation of most other 99Tcm-labelled radiopharmaceuticals. However, it is unknown how this altered reconstitution procedure may affect the labelling efficiency and in vitro stability of the 99Tcm-labelled radiopharmaceuticals. We have evaluated the effects on the labelling efficiency and in vitro stability of 99Tcm-labelled MDP, mertiatide and sestamibi reconstituted with three different methods: adding normal saline before 99Tcm activity (NS/Tc); adding 99Tcm activity before normal saline (Tc/NS); and the standard reconstitution method of adding both 99Tcm activity and normal saline together. The labelling efficiency and in vitro stability were evaluated by measuring the radiochemical purity of each radiopharmaceutical tested at 0, 1, 3, 6, 12 (except 99Tcm-MDP) and 24 h after reconstitution. For 99Tc-mertiatide, there was a very slight difference in the labelling efficiency, mostly due to the Tc/NS method being approximately 0.29% lower across time post-reconstitution than the standard method. For 99Tcm-labelled MDP and sestamibi, there were no differences between the three methods in terms of labelling efficiency and in vitro stability. In conclusion, both alternative methods (i.e. NS/Tc and Tc/NS) appear not to have any detrimental effect on the labelling efficiency and in vitro stability of the 99Tcm-labelled radiopharmaceuticals that we tested. However, of the two alternative kit reconstitution methods, we recommend the NS/Tc method, since it may reduce the hand radiation dose.

Adsorption of some technetium-99m radiopharmaceuticals onto disposable plastic syringes.

OBJECTIVE: The purpose of this study was to determine the adsorption behavior of some widely used, commercially available 99mTc radiopharmaceuticals onto different types of plastic syringes. METHODS: Kits were reconstituted with 99mTc-pertechnetate diluted with 0.9% saline to produce maximum radioactive concentrations, as stated by the manufacturers. Aliquots of the solutions were transferred to four different brands of 2-ml syringes. The activity in the syringes was measured before and after injections or simulated injections. The amount adsorbed to the plastic syringe barrel and plunger before and after washout also was measured at different time intervals. Comparisons between products from different manufacturers were made for 99mTc succimer (DMSA) and 99mTc macroaggregated albumin (MAA). RESULTS: Some 99mTC preparations undergo significant adsorption to plastic syringes. Adsorption differs considerably between products from different manufacturers. There was significantly higher residual activity in some types of syringes. In some cases the residual was as high as 40%-50% of the initial activity, and most of the adsorption occurred within 15 min of filling the syringe. CONCLUSION: The data suggest that the extent of adsorption depends on pharmaceutical excipients in the kits and/or the type of syringe used. When inappropriate syringes are used, the reduction in the administered activity may result in poor-quality images. Therefore, the compatibility between radiopharmaceutical and syringe should be investigated under normal conditions of preparation and use every time a new brand of syringe or a new radiopharmaceutical comes into use in diagnostic nuclear medicine.