Injection therapies for lateral epicondylalgia: a systematic review and Bayesian network meta-analysis.

BACKGROUND: There are many injection therapies for lateral epicondylalgia but there has been no previous comprehensive comparison, based on the Bayesian method. METHODS: The MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for appropriate literature. The outcome measurement was the pain score. Direct comparisons were performed using the pairwise meta-analysis, and network meta-analysis, based on a Bayesian model, was used to calculate the results of all of the potentially possible comparisons and rank probabilities. A sensitivity analysis was performed by excluding low-quality studies. The inconsistency of the model was assessed by means of the node-splitting method. Metaregression was used to assess the relationship between the sample size and the treatment effect. RESULTS: All of the injection treatments showed a trend towards better effects than placebo. Additionally, the peppering technique did not add additional benefits when combined with other treatments. No significant changes were observed by excluding low-quality studies in the sensitivity analysis. No significant inconsistencies were found according to the inconsistency analysis, and metaregression revealed that the sample size was not associated with the treatment effects. CONCLUSIONS: Some commonly used injection therapies can be considered treatment candidates for lateral epicondylalgia, such as botulinum toxin, platelet-rich plasma and autologous blood injection, but corticosteroid is not recommended. Hyaluronate injection and prolotherapy might be more effective, but their superiority must be confirmed by more research. The peppering technique is not helpful in injection therapies.

Automated synthesis of 18F-fluoropropoxytryptophan for amino acid transporter system imaging.

OBJECTIVE: This study was to develop a cGMP grade of [(18)F]fluoropropoxytryptophan ((18)F-FTP) to assess tryptophan transporters using an automated synthesizer. METHODS: Tosylpropoxytryptophan (Ts-TP) was reacted with K(18)F/kryptofix complex. After column purification, solvent evaporation, and hydrolysis, the identity and purity of the product were validated by radio-TLC (1M-ammonium acetate : methanol = 4 : 1) and HPLC (C-18 column, methanol : water = 7 : 3) analyses. In vitro cellular uptake of (18)F-FTP and (18)F-FDG was performed in human prostate cancer cells. PET imaging studies were performed with (18)F-FTP and (18)F-FDG in prostate and small cell lung tumor-bearing mice (3.7 MBq/mouse, iv). RESULTS: Radio-TLC and HPLC analyses of (18)F-FTP showed that the Rf and Rt values were 0.9 and 9 min, respectively. Radiochemical purity was >99%. The radiochemical yield was 37.7% (EOS 90 min, decay corrected). Cellular uptake of (18)F-FTP and (18)F-FDG showed enhanced uptake as a function of incubation time. PET imaging studies showed that (18)F-FTP had less tumor uptake than (18)F-FDG in prostate cancer model. However, (18)F-FTP had more uptake than (18)F-FDG in small cell lung cancer model. CONCLUSION: (18)F-FTP could be synthesized with high radiochemical yield. Assessment of upregulated transporters activity by (18)F-FTP may provide potential applications in differential diagnosis and prediction of early treatment response.

Evaluation of inhibitory effect of recreational drugs on dopaminergic terminal neuron by PET and whole-body autoradiography.

There is little investigation for the functional roles of peripheral dopamine. [(18)F]FDOPA has been used in cancer imaging (i.e., neuroendocrine and tumors pancreatic tumors) and neuroimaging (i.e., Parkinson's disease and Huntington's disease). Here, we accessed side effects of recreational drugs such as ketamine, cocaine, and methamphetamine on dopamine neurons in peripheral organs by using positron emission tomography (PET) imaging and quantitative whole-body autoradiography (QWBAR) with [(18)F]FDOPA. The images were applied for the measurement of specific binding ratios (SBRs) of striatum with the cerebellum as the reference region. Clear striatal [(18)F]FDOPA-derived radioactivity was observed. Moderate level of radiotracer accumulation was presented in the mucosal layers of the stomach and small intestine. The medulla layers of kidney had higher radioactivity than that of the cortex. Blocking images markedly eliminated the specific binding of [(18)F]FDOPA in the striatum and in peripheral organs such as stomachs, intestines, and kidney. Ketamine showed the highest inhibitory effect on striatal [(18)F]FDOPA-derived radioactivity followed by cocaine and methamphetamine. The current results demonstrated a useful crossing-validating tool that enhances the capability of [(18)F]FDOPA for further investigations of the alteration of dopaminergic neurons in the brain disorder or cancer diseases in peripheral tissues.

Synthesis and biological evaluation of O-[3-18F-fluoropropyl]-α-methyl tyrosine in mesothelioma-bearing rodents.

Radiolabeled tyrosine analogs enter cancer cells via upregulated amino acid transporter system and have been shown to be superior to (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) in differential diagnosis in cancers. In this study, we synthesized O-[3-(19)F-fluoropropyl]-α-methyl tyrosine ((19)F-FPAMT) and used manual and automated methods to synthesize O-[3-(18)F-fluoropropyl]-α-methyl tyrosine ((18)F-FPAMT) in three steps: nucleophilic substitution, deprotection of butoxycarbonyl, and deesterification. Manual and automated synthesis methods produced (18)F-FPAMT with a radiochemical purity >96%. The decay-corrected yield of (18)F-FPAMT by manual synthesis was 34% at end-of-synthesis (88 min). The decay-corrected yield of (18)F-FPAMT by automated synthesis was 15% at end-of-synthesis (110 min). (18)F-FDG and (18)F-FPAMT were used for in vitro and in vivo studies to evaluate the feasibility of (18)F-FPAMT for imaging rat mesothelioma (IL-45). In vitro studies comparing (18)F-FPAMT with (18)F-FDG revealed that (18)F-FDG had higher uptake than that of (18)F-FPAMT, and the uptake ratio of (18)F-FPAMT reached the plateau after being incubated for 60 min. Biodistribution studies revealed that the accumulation of (18)F-FPAMT in the heart, lungs, thyroid, spleen, and brain was significantly lower than that of (18)F-FDG. There was poor bone uptake in (18)F-FPAMT for up to 3 hrs suggesting its in vivo stability. The imaging studies showed good visualization of tumors with (18)F-FPAMT. Together, these results suggest that (18)F-FPAMT can be successfully synthesized and has great potential in mesothelioma imaging.

Molecular imaging of nonsmall cell lung carcinomas expressing active mutant EGFR kinase using PET with [(124)i]-morpholino-IPQA.

Mutations in the kinase domain of epidermal growth factor receptor (EGFR) have high levels of basal receptor phosphorylation and are associated with clinical responsiveness to Iressa in patients with nonsmall cell lung cancer (NSCLC). This study aimed to assess the feasibility of morpholino-[(124)I]IPQA derivative as an in vivo PET imaging tool for the expression of different EGFR mutants in NSCLC. In vitro radiotracer accumulation and washout studies demonstrated a rapid accumulation and progressive retention after washout of morpholino-[(131)I]IPQA derivative in high EGFR-expressing H1299 NSCLC derivative cell lines (L858R and E746-A750 del cell lines), but not in EGFR-transfected H1299 cell line and vector-transfected H1299 cell line. Using the morpholino-[(124)I]IPQA derivative, we obtained noninvasive microPET images of EGFR activity in L858R and E746-A750 del subcutaneous tumor xenografts, but not in subcutaneous tumor xenografts grown form control cell line. Different EGFR mutant (activity) tumors have a different morpholino-[ (∗) I]IPQA derivative uptake. However, it still needs to modify the structure of IPQA to increase its water solubility and reduce hepatobiliary clearance. Morpholino-[(124)I]IPQA derivative may be a potential probe for selection of the candidate patients suffering from NSCLC for the small molecule tyrosine kinase inhibitor therapy (e.g., Iressa) in the future.

Managing lymphoma with non-FDG radiotracers: current clinical and preclinical applications.

Nuclear medicine imaging modalities such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) have played a prominent role in lymphoma management. PET with [(18)F]Fluoro-2-deoxy-D-glucose (FDG) is the most commonly used tool for lymphoma imaging. However, FDG-PET has several limitations that give the false positive or false negative diagnosis of lymphoma. Therefore, development of new radiotracers with higher sensitivity, specificity, and different uptake mechanism is in great demand in the management of lymphoma. This paper reviews non-FDG radiopharmaceuticals that have been applied for PET and SPECT imaging in patients with different types of lymphoma, with attention to diagnosis, staging, therapy response assessment, and surveillance for disease relapse. In addition, we introduce three radiolabeled anti-CD20 antibodies for radioimmunotherapy, which is another important arm for lymphoma treatment and management. Finally, the relatively promising radiotracers that are currently under preclinical development are also discussed in this paper.

Development of (99m)Tc-EC-tyrosine for early detection of breast cancer tumor response to the anticancer drug melphalan.

RATIONALE AND OBJECTIVES: Radiolabeled tyrosine analogues that have been successfully used in tumor imaging accumulate in tumor cells via an upregulated L-type amino acid transporter system. The anticancer drug melphalan is an L-type amino acid transporter substrate. Therefore, radiolabeled tyrosine analogues may have great potential in evaluating treatment responses to melphalan. In this study, a (99m)Tc-labeled tyrosine analogue, (99m)Tc tyrosine using N,N'-ethylene-di-L-cysteine (EC) as a chelator, was developed and its potential for noninvasively assessing tumors' early response to melphalan determined. MATERIALS AND METHODS: EC-tyrosine was synthesized in a three-step procedure and labeled with (99m)Tc. To assess cellular uptake kinetics, the percentage uptake of (99m)Tc-EC-tyrosine in the rat breast cancer cell line 13762 was measured. Planar imaging was performed in rats with 13762 cell-derived tumors. To determine the transport mechanisms of (99m)Tc-EC-tyrosine, a competitive inhibition study using L-tyrosine as an inhibitor was performed in vitro and in vivo. To assess tumors' response to melphalan, tumor-bearing rats were treated with different doses of melphalan, and planar imaging was performed 0 and 3 days after treatment. Immunohistochemical analyses were conducted to determine expressions of L-type amino acid transporter 1 and cellular proliferation marker Ki-67. RESULTS: L-tyrosine significantly inhibited (99m)Tc-EC-tyrosine uptake in vitro and in vivo. Tumor volume decreased in a dose-dependent manner with melphalan, and tumor/muscle ratios of (99m)Tc-EC-tyrosine were significantly reduced in treated groups. Immunohistochemical data indicated that about 70% of tumor cells in the melphalan-treated groups underwent apoptosis, and the changes in tumor/muscle ratios reflected the decreased percentage of viable cells in treated tumors. CONCLUSIONS: These findings suggest that (99m)Tc-EC-tyrosine has great potential for monitoring tumor response to melphalan in breast tumor-bearing rats.

Amino Acid transporter-targeted radiotracers for molecular imaging in oncology.

Amino acids are required for sustenance of continuous uncontrolled growth of tumor cells, and upregulation of amino acid transporter expression has often been observed in tumor cells to facilitate their accelerated rates of amino acid uptake. Therefore, amino acid transporters have promise as ideal targets for tumor imaging. In fact, many natural and artificial amino acids have been radiolabeled for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging of tumor. In this article, we review the classification, molecular biology, and pharmacological relevance of amino acid transport systems. In addition, we discuss the chemistry, radiochemistry, current clinical applications, and future prospects for the use of radiolabeled amino acid-based probes for PET and SPECT imaging in oncology for each category of radionuclide.

Molecular imaging kits for hexosamine biosynthetic pathway in oncology.

Noninvasive imaging assessment of tumor cell proliferation could be helpful in the evaluation of tumor growth potential, the degree of malignancy, and could provide an early assessment of treatment response prior to changes in tumor size determined by computed tomography (CT), magnetic resonance imaging (MRI), Positron emission tomography (PET), Single-Photon emission computed tomography (SPECT) or ultrasonography, respectfully. Understanding of tumor proliferative activity, in turn, could aid in the selection of optimal therapy by estimating patient prognosis and selecting the proper management. PET/CT imaging of (18)F-fluoro-2-deoxy-glucose (FDG) is recognized as a technology for diagnosing the presence and extent of several cancer types. Recently, radiolabeled glucosamine analogues were introduced as a promising SPECT agent to complement FDG imaging to increase specificity and improve the accuracy of lesion size in oncology applications. Radiolabeled glucosamine analogues were developed to localize in the nuclear components of cells primarily via the hexosamine biosynthetic pathway whereas glucose localizes in the cytoplasm of cells through the glycolytic/TCA pathway. This paper reviews novel kit-based radiolabeled glucosamine analogues for metabolic imaging of tumor lesions. The novel radiolabeled glucosamine analogues may increase the specificity in oncology applications and can influence patient diagnosis, planning and monitoring of cancer treatment.

Development of (99m)Tc-N4-NIM for molecular imaging of tumor hypoxia.

The nitro group of 2-nitroimidazole (NIM) enters the tumor cells and is bioreductively activated and fixed in the hypoxia cells. 1,4,8,11-tetraazacyclotetradecane (N4) has shown to be a stable chelator for (99m)Tc. The present study was aimed to develop (99m)Tc-cyclam-2-nitroimidazole ((99m)Tc-N4-NIM) for tumor hypoxia imaging. N4-NIM precursor was synthesized by reacting N4-oxalate and 1,3-dibromopropane-NIM, yielded 14% (total synthesis). Cell uptake of (99m)Tc-N4-NIM and (99m)Tc-N4 was obtained in 13762 rat mammary tumor cells and mesothelioma cells in 6-well plates. Tissue distribution of (99m)Tc-N4-NIM was evaluated in breast-tumor-bearing rats at 0.5-4 hrs. Tumor oxygen tension was measured using an oxygen probe. Planar imaging was performed in the tumor-bearing rat and rabbit models. Radiochemical purity of (99m)Tc-N4-NIM was >96% by HPLC. Cell uptake of (99m)Tc-N4-NIM was higher than (99m)Tc-N4 in both cell lines. Biodistribution of (99m)Tc-N4-NIM showed increased tumor-to-blood and tumor-to-muscle count density ratios as a function of time. Oxygen tension in tumor tissue was 6-10 mmHg compared to 40-50 mmHg in normal muscle tissue. Planar imaging studies confirmed that the tumors could be visualized clearly with (99m)Tc-N4-NIM in animal models. Efficient synthesis of N4-NIM was achieved. (99m)Tc-N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy.

Molecular imaging of mesothelioma with (99m)Tc-ECG and (68)Ga-ECG.

We have developed ethylenedicysteine-glucosamine (ECG) as an alternative to (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) for cancer imaging. ECG localizes in the nuclear components of cells via the hexosamine biosynthetic pathway. This study was to evaluate the feasibility of imaging mesothelioma with (99m)Tc-ECG and (68)Ga-ECG. ECG was synthesized from thiazolidine-4-carboxylic acid and 1,3,4,6-tetra-O-acetyl-2-amino-D-glucopyranose, followed by reduction in sodium and liquid ammonia to yield ECG (52%). ECG was chelated with (99m)Tc/tin (II) and (68)Ga/(69)Ga chloride for in vitro and in vivo studies in mesothelioma. The highest tumor uptake of (99m)Tc-ECG is 0.47 at 30 min post injection, and declined to 0.08 at 240 min post injection. Tumor uptake (%ID/g), tumor/lung, tumor/blood, and tumor/muscle count density ratios for (99m)Tc-ECG (30-240 min) were 0.47 ± 0.06 to 0.08 ± 0.01; 0.71 ± 0.07 to 0.85 ± 0.04; 0.47 ± 0.03 to 0.51 ± 0.01, and 3.49 ± 0.24 to 5.06 ± 0.25; for (68)Ga-ECG (15-60 min) were 0.70 ± 0.06 to 0.92 ± 0.08; 0.64 ± 0.05 to 1.15 ± 0.08; 0.42 ± 0.03 to 0.67 ± 0.07, and 3.84 ± 0.52 to 7.00 ± 1.42; for (18)F-FDG (30-180 min) were 1.86 ± 0.22 to 1.38 ± 0.35; 3.18 ± 0.44 to 2.92 ± 0.34, 4.19 ± 0.44 to 19.41 ± 2.05 and 5.75 ± 2.55 to 3.33 ± 0.65, respectively. Tumor could be clearly visualized with (99m)Tc-ECG and (68)Ga-ECG in mesothelioma-bearing rats. (99m)Tc-ECG and (68)Ga-ECG showed increased uptake in mesothelioma, suggesting they may be useful in diagnosing mesothelioma and also monitoring therapeutic response.

Development of tyrosine-based radiotracer 99mTc-N4-Tyrosine for breast cancer imaging.

The purpose of this study was to develop an efficient way to synthesize (99m)Tc-O-[3-(1,4,8,11-tetraazabicyclohexadecane)-propyl]-tyrosine ((99m)Tc-N4-Tyrosine), a novel amino acid-based radiotracer, and evaluate its potential in breast cancer gamma imaging. Precursor N4-Tyrosine was synthesized using a 5-step procedure, and its total synthesis yield was 38%. It was successfully labeled with (99m)Tc with high radiochemical purity (>95%). Cellular uptake of (99m)Tc-N4-Tyrosine was much higher than that of (99m)Tc-N4 and the clinical gold standard (18)F-2-deoxy-2-fluoro-glucose ((18)F-FDG) in rat breast tumor cells in vitro. Tissue uptake and dosimetry estimation in normal rats revealed that (99m)Tc-N4-Tyrosine could be safely administered to humans. Evaluation in breast tumor-bearing rats showed that although (99m)Tc-N4-Tyrosine appeared to be inferior to (18)F-FDG in distinguishing breast tumor tissue from chemical-induced inflammatory tissue, it had high tumor-to-muscle uptake ratios and could detect breast tumors clearly by planar scintigraphic imaging. (99m)Tc-N4-Tyrosine could thus be a useful radiotracer for use in breast tumor diagnostic imaging.

Sulfonylurea receptor as a target for molecular imaging of pancreas beta cells with (99m)Tc-DTPA-glipizide.

OBJECTIVE: This study was aimed to assess pancreas beta cell activity using (99m)Tc-diethyleneaminepentaacetic acid-glipizide (DTPA-GLP), a sulfonylurea receptor agent. The effect of DTPA-GLP on the blood glucose level in rats was also evaluated. METHODS: DTPA dianhydride was conjugated with GLP in the presence of sodium amide, yielding 60%. Biodistribution and planar images were obtained at 30-120 min after injection of (99m)Tc-DTPA-GLP (1 mg/rat, 0.74 and 11.1 MBq per rat, respectively) in normal female Fischer 344 rats. The control group was given (99m)Tc-DTPA. To demonstrate pancreas beta cell uptake of (99m)Tc-DTPA-GLP via a receptor-mediated process, a group of rats was pretreated with streptozotocin (a beta cell toxin, 55 mg/kg, i.v.) and the images were acquired at immediately-65 min on day 5 post-treatment. The effect on the glucose levels after a single administration (ip) of DTPA-GLP was compared to glipizide (GLP) for up to 6 h. RESULTS: The structure of DTPA-GLP was confirmed by NMR, mass spectrometry and HPLC. Radiochemical purity assessed by ITLC was >96%. (99m)Tc-DTPA-GLP showed increased pancreas-to-muscle ratios, whereas (99m)Tc-DTPA showed decreased ratios at various time points. Pancreas could be visualized with (99m)Tc-DTPA-GLP in normal rat, however, (99m)Tc-DTPA has poor uptake suggesting the specificity of (99m)Tc-DTPA-GLP. Pancreas beta cell uptake could be blocked by pre-treatment with streptozotocin. DTPA-GLP showed an equal or better response in lowering the glucose levels compared to the existing GLP drug. CONCLUSIONS: It is feasible to use (99m)Tc-DTPA-GLP to assess pancreas beta cell receptor recognition. (99m)Tc-DTPA-GLP may be helpful in evaluating patients with diabetes, pancreatitis and pancreatic tumors.

Targeted nuclear imaging of breast cancer: status of radiotracer development and clinical applications.

Breast cancer is the most common cancer in women worldwide. Molecular imaging plays an important role in breast cancer diagnosis, staging, and treatment response evaluation. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are the main clinical molecular imaging modalities that are based on the detection of radiotracers. This article discusses the typical radiotracers used for breast cancer imaging by PET and SPECT. In addition, radiotracers that are currently applied for human breast cancer imaging or under clinical trials are also reviewed in compliance with the categories of tumor-specific targets to which they are aimed at.

Synthesis and evaluation of amino acid-based radiotracer 99mTc-N4-AMT for breast cancer imaging.

PURPOSE: This study was to develop an efficient synthesis of (99m)Tc-O-[3-(1,4,8,11-tetraazabicyclohexadecane)-propyl]-α-methyl tyrosine ((99m)Tc-N4-AMT) and evaluate its potential in cancer imaging. METHODS: N4-AMT was synthesized by reacting N4-oxalate and 3-bromopropyl AMT (N-BOC, ethyl ester). In vitro cellular uptake kinetics of (99m)Tc-N4-AMT was assessed in rat mammary tumor cells. Tissue distribution of the radiotracer was determined in normal rats at 0.5-4 h, while planar imaging was performed in mammary tumor-bearing rats at 30-120 min. RESULTS: The total synthesis yield of N4-AMT was 14%. Cellular uptake of (99m)Tc-N4-AMT was significantly higher than that of (99m)Tc-N4. Planar imaging revealed that (99m)Tc-N4-AMT rendered greater tumor/muscle ratios than (99m)Tc-N4. CONCLUSIONS: N4-AMT could be synthesized with a considerably high yield. Our in vitro and in vivo data suggest that (99m)Tc-N4-AMT, a novel amino acid-based radiotracer, efficiently enters breast cancer cells, effectively distinguishes mammary tumors from normal tissues, and thus holds the promise for breast cancer imaging.

Synthesis of (99m)Tc-EC-AMT as an imaging probe for amino acid transporter systems in breast cancer.

OBJECTIVE: This study was to develop a (99m)Tc-labeled alpha-methyl tyrosine (AMT) using L,L-ethylenedicysteine (EC) as a chelator and to evaluate its potential in breast tumor imaging in rodents. METHODS: EC-AMT was synthesized by reacting EC and 3-bromopropyl AMT (N-BOC, ethyl ester) in ethanol/potassium carbonate solution. EC-AMT was labeled with (99m)Tc in the presence of tin (II) chloride. Rhenium-EC-AMT (Re-EC-AMT) was synthesized as a reference standard for (99m)Tc-EC-AMT. To assess the cellular uptake kinetics of (99m)Tc-EC-AMT, 13 762 rat breast cancer cells were incubated with (99m)Tc-EC-AMT for 0-2 h. To investigate the transport mechanism, the same cell line was used to conduct the competitive inhibition study using L-tyrosine. Tissue distribution of (99m)Tc-EC-AMT was determined in normal rats at 0.5-4 h. Planar imaging of breast tumor-bearing rats was performed at 30 and 90 min. The data were compared with those of (18)F-2-fluoro-2-deoxy-glucose. Blocking uptake study using unlabeled AMT was conducted to investigate the transport mechanism of (99m)Tc-EC-AMT in vivo. RESULTS: Structures of EC-AMT and Re-EC-AMT were confirmed by nuclear magnetic resonance, high performance liquid chromatography and mass spectra. In-vitro cellular uptake of (99m)Tc-EC-AMT in 13,762 cells was increased as compared with that of (99m)Tc-EC and could be inhibited by L-tyrosine. Biodistribution in normal rats showed high in-vivo stability of (99m)Tc-EC-AMT. Planar scintigraphy at 30 and 90 min showed that (99m)Tc-EC-AMT could clearly visualize tumors. (99m)Tc-EC-AMT uptake could be significantly blocked by unlabeled AMT in vivo. CONCLUSION: The results indicate that (99m)Tc-EC-AMT, a new amino acid transporter-based radiotracer, is suitable for breast tumor imaging.