Preparation and Evaluation of 64Cu-Radiolabled Dual-Ligand Multifunctional Gold Nanoparticles for Tumor Theragnosis.

Gold nanoparticles (AuNPs) are cutting-edge platforms for combined diagnostic and therapeutic approaches due to their exquisite physicochemical and optical properties. Using the AuNPs physically produced by femtosecond pulsed laser ablation of bulk Au in deionized water, with a capping agent-free surface, the conjugation of functional ligands onto the AuNPs can be tunable between 0% and 100% coverage. By taking advantage of this property, AuNPs functionalized by two different types of active targeting ligands with predetermined ratios were fabricated. The quantitatively controllable conjugation to construct a mixed monolayer of multiple biological molecules at a certain ratio onto the surface of AuNPs was achieved and a chelator-free 64Cu-labeling method was developed. We report here the manufacture, radiosynthesis and bioevaluation of three different types of dual-ligand AuNPs functionalized with two distinct ligands selected from glucose, arginine-glycine-aspartate (RGD) peptide, and methotrexate (MTX) for tumor theragnosis. The preclinical evaluation demonstrated that tumor uptakes and retention of two components AuNP conjugates were higher than that of single-component AuNP conjugates. Notably, the glucose/MT- modified dual-ligand AuNP conjugates showed significant improvement in tumor uptake and retention. The novel nanoconjugates prepared in this study make it possible to integrate several modalities with a single AuNP for multimodality imaging and therapy, combining the power of chemo-, thermal- and radiation therapies together.

More advantages in detecting bone and soft tissue metastases from prostate cancer using 18F-PSMA PET/CT.

Prostate cancer (PCa) is the most common solid cancer affecting men worldwide. Serum prostate-specific antigen (PSA) is at present the most commonly used biomarker for PCa screening, as well as a reliable marker of disease recurrence after initial treatment. Bone metastases (BM) are present in advanced stages of the disease. Imaging of BM is important not only for localization and characterization, but also to evaluate their size and number, as well as to follow-up the disease during and after therapy. Bone metastases formation is triggered by cancer initiating cells in the bone marrow and is facilitated by the release of several growth factors. Although BM from PCa are very heterogenic, the majority of them are described as "osteoblastic", while pure "osteolytic" metastases are very rare. The PSA levels, along with other parameters, may determine the risk of having BM. A classification report, which is currently in use, divides patients into three categories according to the risk of having BM: low risk (PSA<10ng/mL, clinical stage T1-T2a, Gleason Score ≤6), intermediate risk (PSA 10.1-20ng/mL, clinical stage T2b-T2c, Gleason Score=7) and high risk (PSA>20ng/mL, clinical stage T3a or higher, or Gleason Score ≥8). Even though PSA remains the only biomarker of this disease in clinical practice, it is not always analogue with the severity of the disease and should be evaluated along with the clinical and diagnostic imaging findings. Detection of BM is not always easy, as there may be unexpected sites and occult metastases. The clinical importance of revealing BM in patients with PCa is to determine the overall survival of the patients and their quality of life, as BM may lead to high morbidity and mortality. There are many options of treating BM, such as chemotherapy, immunotherapy, external beam radiotherapy, bone modifying agents and recently prostate-specific membrane antigen (PSMA) targeted therapies. Another potential therapy is radioguided surgery, in patients with occult and/or focally recurrent PCa. Such a single occult metastasis causing very high levels of PSA has been presented using technetium-99m (99m Tc) labeled PSMA imaging. Diagnosis and staging of PCa mostly relies on the morphology of imaging, using computerized tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography/CT (PET/CT) using fluorine-18-fluorodeoxyglucose (18 F-FDG). The radiopharmaceuticals used in Nuclear Medicine for BM in PCa are: a) those that target lesions, such as 99m Tc-phosphonates, 18 F-sodium fluoride (18 F-NaF) and b) those that target the cancer cells, such as 18 F or carbon-11 (11 C)-choline, 18 F-FDG and 18 F or gallium-68 (68 Ga)-PSMA. Bone scan with 99mTc-phosphonates is widely used for the evaluation of bone metabolism in patients with PCa. It is a low cost, widely available radiopharmaceutical having the advantage of a whole body evaluation. Planar and single photon emission tomography (SPET) may also be applied. The sensitivity of the whole body scan (WBS) ranges from 75%-95%, while the specificity is lower, ranging from 60%-75% due to false positive findings in benign conditions (arthritis, inflammation etc) who also have increased bone metabolism. Sensitivity and specificity however, perform better (96% and 94% respectively) when SPET and SPET/CT techniques are applied. Of course, bone marrow metastases cannot be detected in a WBS. The PSA marker is used to predict the pre-test probability of BM and in case of a bone scan several retrospective analyses showed that PSA levels <20ng/mL can exclude with high probability a positive WBS, with a high negative predictive value (almost 99%). The European Association of Urology (EAU) guidelines state that a bone scan can be omitted in patients with PSA levels <20ng/mL and with a Gleason Score ≤7. Imaging with 18 F-NaF PET/CT is characterized by high and rapid bone uptake, minimal serum protein binding and rapid blood clearance which lead to a fast and high target to background ratio with a short acquisition time (30 minutes). Sensitivity and specificity for the detection of BM in high risk PCa patients is almost 100%. The main advantages provided by 18 F-NaF PET/CT are the better imaging quality along with a whole body acquisition and the fusion technique. Fluorine-18-choline and 11 C-choline PET/CT came to practice lately, reflecting the cell membrane metabolism. Choline is an essential component of phospholipids and is trapped in the cells after a phosphorylation by a choline kinase. The sensitivity and specificity of 18 F-choline PET/CT for detecting BM in patients with PCa is reported to be 79% and 97% respectively. However, the performance of choline PET/CT seems to be dependent of the levels of the PSA, in cases of biochemical recurrence and reaches about 75%% in those PCa patients with PSA levels >3ng/mL, with a poor performance when the PSA level is low. Fluorine-18-FDG is the most commonly used radiotracer in PET/CT, however has a little value in staging and restaging of PCa. Because of its low sensitivity 18 F-FDG is trapped in cancer cells through the activation of the glycolytic pathways and in case of BM is an index of increased glucose metabolism in PCa cells rather than in bone lesion per se. Osteolytic lesions show more increased metabolic activity than the osteoblastic lesions and are better revealed with 18F-FDG. Therefore, 18 F-FDG PET/CT is suggested to be performed only in selected patients with PCa, those with most aggressive tumors and high Gleason score. Fluorine-18-PSMA PET/CT The need of a more sensitive and specific agent has been evident. Prostate specific monoclonal antibody (PSMA) is a folate hydrolase cell surface glycoprotein. It is mainly expressed in four tissues of the body, including prostate epithelium, the proximal tubules of the kidney, the jejunal brush border of the small intestine and ganglia of the nervous system. So consequently may in some cases be expressed in cancers other than PCa and also in benign processes. It is localized in the cytoplasm and the apical side of the prostate epithelium that lines prostatic ducts. In case of malignant transformation, PSMA is transferred from the cytoplasm to the luminal surface of the prostatic ducts and thus becomes membrane bound. It has a unique three-parts structure, an external portion, a transmembrane portion and an internal-cytoplasmatic portion. Prostate specific monoclonal antibody is also upregulated and thus overexpressed in most PCa, but weakly expressed in normal prostatic tissue. Imaging by PSMA PET/CT has been shown to detect sites of disease recurrence at lower PSA levels than conventional imaging. The PSMA overexpression is even present when the cell becomes castrate-resistant and that is the reason why it is the most favorable target for PET imaging. Prostate cancer expresses 100 to 1000 times more PSMA than normal tissue and is increasing even more in higher grade tumors as well as in increased castrate resistance. Therefore, PSMA represents an excellent target for both diagnostic imaging and endoradiotherapy of PCa. For diagnostic purposes PSMA ligands, mainly small-molecule inhibitors, are most commonly labeled either with 68 Ga or 18 F. The 18 F-PSMA-1007 (((3S,10S,14S)-1-(4-(((S)-4-carboxy-2-((S)-4-carboxy-2-(6-18 F-fluoronicotinamido) butanamido) methyl phenyl)-3- (naphthalen-2-ylmethyl)-1,4,12-trioxo-2,5,11,13-tetraazahexadecane- 10,14,16-tricarboxylic acid)) seems to be more favorable among other 18 F-PSMA ligands candidate compounds because it demonstrates high labeling yields, better tumor uptake and non-urinary background clearance. On the contrary, 68 Ga-PSMA is rapidly excreted via the urinary tract resulting in intense accumulation in the bladder, thus, obscuring the prostate. Compared to 68 Ga, 18 F has many advantages such as it is produced in larger amounts, it has a longer half life and a higher physical spatial resolution. The short half-life of 68 Ga relative to 18 F (68 vs. 110 min) makes 68 Ga-PSMA inconvenient for longer transport, so that it is almost mandatory to use local gallium generators, which have a higher cost and lower yields at the end of their first half-life. Each generator provides only one or two elutions per day and it requires separate syntheses at different times of the day in a local radiopharmacy. Furthermore, the resolution of 68 Ga-labeled tracers is physically limited because of positron range effects. In contrast, 18 F labels avoid these intrinsic difficulties and can be produced at high yields in central cyclotrons. Fluorine-18-PSMA-1007 has been recently used by us in the Nuclear Medicine Department of "Evangelismos" general hospital of Athens and our experience so far showed favorable results, with high image resolution acquisitions and lesions which showed PSMA avidity. Fluorine-18-PSMA-1007 PET/CT imaging was carried out with a dual phase protocol, consisting of two separate scans. One (early scan) at 60min post injection starting from the diaphragm to the middle of the thighs and the late scan at 180min from the dome of the skull to the knee joints. Patients were asked to urine before the examination. Images were acquired with a scan time of 3min per bed position on a General Electric PET/CT system and the image reconstruction was performed by the standard software method provided by the manufacturer. A low dose CT scan, without a contrast agent, was performed before the PET scan in order to be used for the attenuation correction. Administered activities were calculated based on the department's protocols with a suggested injected activity of 4MBq/kg. Any areas of focally increased radiotracer uptake, at both the early and late PET scans, were considered as abnormal, despite the presence or absence of morphological changes of the CT scan. The normal distribution of the radiotracer was taken underconsideration, which includes mainly the liver and the gallbladder, as it has hepatobiliary clearance rather than renal, the spleen, the pancreas, the submandibular, sublingual, lacrimal and parotid glands, the kidneys, the urinary bladder and the small intestine. The maximum standardized uptake value (SUVmax) was calculated for each lesion. A typical case of a 78 years man with PCa having PSA 7,3ng/mL and also having Paget's disease was tested by the above procedure for initial staging. The 18 F-PSMA-1007 PET/CT imaging revealed diffusely increased radiotracer uptake in the bones of the pelvis with a SUVmax 9. The CT imaging of the pelvis was consistent with Paget's disease, with diffuse mixed osteosclerotic and osteolytic lesions, accompanied with bone expansion. The primary PCa was also revealed with focally increased radiotracer uptake in the left prostatic lobe with a SUVmax 19, as well as a second small focus of pathologically increased PSMA uptake in the right prostatic lobe with a SUVmax 23. Another patient 79 years old, with PCa was studied with 18 F-choline PET/CT which showed diffuse bone metastasis in the pelvis. He had PSA level, 412ng/mL. The 18 F-PSMA-1007 PET/CT imaging showed multiple foci of increased radiotracer uptake throughout the whole skeleton, including the skull, both humerus and femoral bones with indicative SUVmax 26. Computed tomography showed rather similar BM. There were also lymph nodes metastases at the left internal mammary chain as well as the left inguinal areas, with a SUVmax 25. The first case indicated that 18 F-PSMA PET/CT could easily differentiate PCa BM from Paget's disease, however benign conditions such as Paget's disease may also show PSMA uptake and the second case that 18 F-PSMA PET/CT scan was more sensitive than the 18 F-choline PET/CT scan, with high quality images. According to other authors the SUVmax value of BM in PCa was 16.57±23.59 using the 18 F-PSMA PET/CT scan. This imaging modality in accordance to other authors is better than 68 Ga-labelled PSMA-ligands and can better differentiate BM from healing fractures. Very recently a novel PET radiopharmaceutical has been approved both in USA and Europe: 18 F-fluciclovine (trans-1-amino-3-[18 F] fluoro-cyclobutane carboxylic acid). Fluorine-18-fluciclovine is a synthetic amino acid that is transported by multiple sodium-dependent and sodium-independent channels found to be upregulated in PCa cells. The main indication of use includes the detection and localization of PCa recurrence in patients with a rising PSA following prior therapy. The main advantages of 18 F-fluciclovine are the low urinary excretion, which allows for better evaluation of prostate bed and the low uptake in inflammatory cells (e.g. macrophages). There are no studies in the literature comparing 18 F-PSMA to 18 F-fluciclovine, however two studies comparing 18 F-fluciclovine to 68 Ga-PSMA, showed better performance for 68 Ga-PSMA in PCa patients with biochemical recurrence. So, 18 F-PSMA-1007 PET/CT imaging seems to be very promising in staging and restaging patients with PCa, especially when biochemical relapse is under consideration. Although it seems to perform better than other imaging modalities like bone scan, 18 F-FDG PET/CT or 18 F-choline PET/CT, its high cost and low availability must be considered. Further large studies need to be conducted in order to evaluate the accuracy and the predictive values of this method, emphasizing on bone metastases.

Radiolabeled methotrexate as a diagnostic agent of inflammatory target sites: A proof-of-concept study.

Methotrexate (MTX), as a pharmaceutical, is frequently used in tumor chemotherapy and is also a part of the established treatment of a number of autoimmune inflammatory disorders. Radiolabeled MTX has been studied as a tumor­diagnostic agent in a number of published studies. In the present study, the potential use of technetium­99m­labelled MTX (99mTc­MTX) as a radiotracer was investigated for the identification of inflammatory target sites. The labelling of MTX was carried out via a 99mTc­gluconate precursor. Evaluation studies included in vitro stability, plasma protein binding assessment, partition­coefficient estimation, in vivo scintigraphic imaging and ex vivo animal experiments in an animal inflammation model. MTX was successfully labelled with 99mTc, with a radiochemical purity of >95%. Stability was assessed in plasma, where it remained intact up to 85% at 4 h post­incubation, while protein binding of the radiotracer was observed to be ~50% at 4 h. These preclinical ex vivo and in vivo studies indicated that 99mTc­MTX accumulates in inflamed tissue, as well as in the spinal cord, joints and bones; all areas with relatively high remodeling activity. The results are promising, and set the stage for further work on the development and application of 99mTc­MTX as a radiotracer for inflammation associated with rheumatoid arthritis.

Residual activities of 99mTc-labelled radiopharmaceuticals in routine nuclear medicine practice.

INTRODUCTION: In this study, we present a series of common Tc-labelled radiopharmaceuticals administrations performed in a busy nuclear medicine department within a 1-year timeframe in routine practice. The main objective is to identify the true activity administered to the patient and whether that is in compliance with the EANM guidelines, where applicable, and/or with the department's protocols. As a secondary objective, we aimed to assess whether the volume of the injected dose correlates to the percentage of residual activity measured after injection for each studied radiotracer. MATERIALS AND METHODS: A number of commonly used Tc-labelled radiopharmaceuticals including Tc-pertechnetate, Tc-methylenediphosphonic acid, Tc-hydroxymethylenediphosphonic acid, Tc-3,3-diphosphono-1,2-propanedicarboxylic acid, Tc-dimercaptosuccinic acid (DMSA), Tc-mercaptoacetyltriglycine, Tc-2-methoxyisobutylisonitrile (sestamibi), Tc-1,2-bis[bis(2-ethoxyethyl)phosphino]ethane (tetrofosmin) and Tc-HYNIC-Tyr-octreotide (Tektrotyd) were assessed. All data were collected prospectively within a 1-year period under routine medical practice and included (a) injected activity, (b) residual activity, (c) percentage of residual activity (residual activity/injected activity×100), (d) effective activity (injected activity minus the residual activity), (e) injected volume, (f) time of injection and (g) type of procedure. RESULTS: In the 1837 collected measurements, the average percentage of residual activity was 13% (95% confidence interval: 12.75-13.39%). The mean effective activities were within the recommended range by the EANM guidelines, where applicable, or did not exceed the recommended doses from the department's protocols. In cases where actual injected activity was lower than the minimum suggested by the department's protocols, the imaging quality was not compromised. There was a negative correlation and thus an inverse relationship between the percentage of residual activity and administered volume for Tc-pertechnetate, Teceos, Bonescan, HDP, generic DMSA, RENOCIS, Nephromag and Tektrotyd (Spearman's r coefficient ranging from -0.311 to -0.561). Cardiologic radiotracers presented no such correlation. CONCLUSION: It should be possible to reduce the level of administered activity for the diagnostic examinations, but with consideration of the residual activity, especially for radiopharmaceuticals with a high mean residual activity (mainly tetrofosmin and sestamibi).

A robust method, based on a novel source, for performance and diagnostic capabilities assessment of the positron emission tomography system.

The aim of our work was to provide a robust method for evaluating imaging performance of positron emission tomography (PET) systems and particularly to estimate the modulation transfer function (MTF) using the line spread function (LSF) method. A novel plane source was prepared using thin layer chromatography (TLC) of a fluorine-18-fluorodeoxyglucose ((18)F-FDG) solution. The source was placed within a phantom, and imaged using the whole body (WB) two dimensional (2D) and three dimensional (3D) standard imaging protocols in a GE Discovery ST hybrid PET/CT scanner. Modulation transfer function was evaluated by determining the LSF, for various reconstruction methods and filters. The proposed MTF measurement method was validated against the conventional method, based on point spread function (PSF). Higher MTF values were obtained with 3D scanning protocol and 3D iterative reconstruction algorithm. All MTF obtained using 3D reconstruction algorithms showed better preservation of higher frequencies than the 2D algorithms. They also exhibited better contrast and resolution. MTF derived from LSF were more precise compared with those obtained from PSF since their reproducibility was better in all cases, providing a mean standard deviation of 0.0043, in contrary to the PSF method which gave 0.0405. In conclusion, the proposed method is novel and easy to implement for characterization of the signal transfer properties and image quality of PET/computed tomography (CT) systems. It provides an easy way to evaluate the frequency response of each kernel available. The proposed method requires cheap and easily accessible materials, available to the medical physicist in the nuclear medicine department. Furthermore, it is robust to aliasing and since this method is based on the LSF, is more resilient to noise due to greater data averaging than conventional PSF-integration techniques.

Does CEA and CA 19-9 combined increase the likelihood of 18F-FDG in detecting recurrence in colorectal patients with negative CeCT?

AIM: The purpose of this prospective study was to investigate the role of 2-(fluorine-18)-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET/computed tomography (CT) in the diagnosis of recurrent colorectal cancer (CRC) in patients with increased tumor markers and negative contrast-enhanced computed tomography (CeCT) results. MATERIAL AND METHODS: Forty-three patients (27 male; median age 66 years, range 31-93 years) with increasing tumor markers and negative CeCT during follow-up for treated CRC underwent (18)F-FDG PET/CT examinations. The serum values of carcinoembryonic antigen (CEA) (n=29) and CA 19-9 (n=20) were normal after completion of treatment, with subsequent increasing concentrations. RESULTS: Among the 43 patients, (18)F-FDG PET/CT was true positive in 32 (74.4%), false positive in two (4.7%), false negative in one (2.3%), and true negative in eight (1%) patients. On the patient-basis analysis, (18)F-FDG PET/CT had a sensitivity of 97% (confidence interval: 0.82-0.99), a specificity of 80% (0.44-0.96), a positive predictive value of 94% (0.78-0.98), and a negative predictive value of 88% (0.5-0.99). There was no statistically significant correlation between CRC recurrence and CEA and CA19-9 levels (P=0.561 and 0.55, respectively). Only in the group of patients (n=6) with both tumor markers increased did (18)F-FDG PET/CT have 100% accuracy in revealing recurrent disease. CONCLUSION: (18)F-FDG PET/CT is highly sensitive in the diagnosis of recurrent CRC in patients with increasing levels of tumor markers and negative CeCT regardless of the type or level of tumor marker; however, the combination of elevated CEA and CA 19-9 increases the likelihood of (18)F-FDG in detecting recurrence.

Lack of association between KRAS mutations and 18F-FDG PET/CT in Caucasian metastatic colorectal cancer patients.

BACKGROUND: Although Kirsten rat sarcoma (KRAS) gene mutational testing is essential for the optimal design of therapeutic strategies for colorectal cancer, it is not always feasible or reliable. In this retrospective study, we examined whether (18)F-Fluorodeoxyglucose positron-emission tomography/computed tomography ((18)F-FDG PET/CT) scans can serve as a surrogate examination for KRAS mutational testing. PATIENTS AND METHODS: KRAS codon 12 and 13 mutational status was tested in 44 colorectal primary tumors and was compared with the (18)F-FDG PET/CT maximum standardized uptake value (SUVmax) values of the respective metastatic lesions. Glucose transporter-1 (GLUT1) mRNA levels were also measured in colorectal primary tumors. RESULTS: No statistically significant correlation between (18)F-FDG PET/CT SUVmax values and KRAS mutation status was found (parametric t-test: p=0.4753; non-parametric Kruskal-Wallis test: p=0.51). This result cannot be attributed to the effect of differing GLUT1 mRNA levels, as shown by multivariate analysis. CONCLUSION: Our study failed to promote (18)F-FDG PET/CT uptake as a surrogate examination for KRAS mutation testing.

(18)F-FDG-PET/CT, (123)I-MIBG and (99m)Tc-MDP whole-body scans, in detecting recurrence of an adult adrenal neuroblastoma.

Neuroblastoma is the most common extracranial solid malignancy in children, but is rare in adults. We report the case of a 33 year old man with recurrence of neuroblastoma, 2 years after the excision of the primary tumor in the right adrenal gland. The iodine-123-radioiodinated metaiodobenzylguanidine ((123)I-MIBG) and (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) bone scans and the fluorine-18-fluorodeoxyglucose-positron computed tomography ((18)F-FDG PET/CT) findings in this patient are presented. First, we applied (123)I-MIBG scintigraphy that detected increased uptake at the right adrenal gland region and probably at liver lesions and in several bones. Then, the (99m)Tc-MDP bone scan revealed also increased uptake of the radiopharmaceutical in bones, but there was a discrepancy between these two studies concerning the number and location of the lesions. Then, (18)F-FDG PET/CT scan was performed, which showed increased uptake of (18)F-FDG at the right adrenal gland region with extension to the liver and also in multiple bones. Additionally, an aortocaval lymph node was detected. In conclusion, this case indicated that (18)F-FDG PET/CT has defined the extent of the recurrence of neuroblastoma in a better way than (123)I-MIBG and (99m)Tc-MDP together.

SPECT and 18F-FDG PET/CT imaging of multiple paragangliomas and a growth hormone-producing pituitary adenoma as phenotypes from a novel succinate dehydrogenase subunit D mutation.

Mutations in the subunits B, C, D, and recently in A of the succinate dehydrogenase have been associated with the development of paragangliomas. We report the case of a 37-year-old man presented with multiple paragangliomas and a growth hormone-producing pituitary adenoma, with a novel succinate dehydrogenase subunit D mutation as the genetic analysis revealed. We present the similarities and the differences of the findings in patient imaging with either methods of SPECT (I-MIBG and In-pentetreotide) or PET/CT with F-FDG. This case revealed that F-FDG PET/CT detected more lesions and was superior compared with the other methods.

Clinical importance of [18F]fluorodeoxyglucose positron emission tomography/computed tomography in the management of patients with bronchoalveolar carcinoma: Role in the detection of recurrence.

[18F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been reported to have a low sensitivity in the initial diagnosis of bronchoalveolar carcinoma (BAC) due to BAC's low metabolic activity. The aim of this study was to assess the value of [18F]FDG-PET/CT in the detection of BAC recurrence. Between February 2007 and September 2011, the [18F]FDG-PET/CT scans that were performed on patients with known, histologically proven BAC were studied. A total of 24 [18F]FDG-PET/CT scans were performed in 22 patients, including 16 males and 6 females, with a mean age of 65±9 years. Among the scans, 15 were performed to assess for possible recurrence with equivocal findings in conventional imaging methods and 9 for restaging post-therapy. In all cases conventional imaging studies (CT and MRI) were performed 5-30 days prior to PET/CT. Among the 24 [18F]FDG-PET/CT scans, 18 were positive and 6 negative. Among the 15 [18F]FDG-PET/CT scans performed for suspected recurrence, 34 lesions were detected and the mean maximum standardized uptake value (SUVmax) was 6.8±3.26. In nine scans, upstaging was observed, while two were in agreement with the findings of the conventional modalities. A greater number of lesions were detected in two scans and fewer lesions were detected in one, with no change in staging. Only one scan was negative. By contrast, in patients examined for restaging, there were only five lesions with a mean SUVmax of 4.86±3.18. Agreement between the findings of [18F]FDG-PET/CT and the conventional modalities was observed in 8 out of 9 cases. Although [18F]FDG-PET/CT has been reported to have a low sensitivity in the initial diagnosis of BAC, the present results indicate that when there is recurrence, the lesions become [18F]FDG avid. [18F]FDG-PET/CT may provide further information in patients evaluated for recurrence and thus improve patient management.

Correlation between Calcitonin Levels and [(18)F]FDG-PET/CT in the Detection of Recurrence in Patients with Sporadic and Hereditary Medullary Thyroid Cancer.

Purpose. Measurement of serum calcitonin is important in the followup of patients with medullary thyroid carcinoma (MTC) and reliably reflects the presence of the disease. This is the largest study so far in bibliography investigating the diagnostic accuracy of combined [(18)F]FDG-PET/CT in patients with MTC and elevated calcitonin levels. Methods. Between February 2007 and February 2011, 59 [(18)F]FDG-PET/CT were performed on 51 patients with MTC and elevated calcitonin levels for localization of recurrent disease. Conventional morphologic imaging methods were negative or showed equivocal findings. Results. Among the 59 [(18)F]FDG-PET/CT, 29 were positive (26 had true-positive and 3 false-positive findings) and 30 negative. The overall per-patient sensitivity of [(18)F]FDG-PET/CT was 44.1%. Using as cut-off point the calcitonin value of 1000 pg/ml, in patients with calcitonin exceeding this value, sensitivity raised to 86.7%. The overall sensitivity of [(18)F]FDG-PET/CT was lower (23%) in patients with MEN IIA syndrome. Conclusion. The findings of this paper show that [(18)F]FDG-PET/CT is valuable for the detection of recurrence in patients with highly elevated calcitonin levels, >1000 pg/mL, but in patients with lower calcitonin levels, its contribution is questionable. Also, there is evidence that the sensitivity of [(18)F]FDG-PET/CT is lower in patients with MTC as part of MEN IIA syndrome.

Role of positron emission tomography in the early prediction of response to chemotherapy in patients with non--small-cell lung cancer.

In recent years, molecular imaging with [(18)F]fluorodeoxyglucose-positron-emission tomography, [(18)F]FDG-PET, has become part of the standard of care in initial staging of patients with non-small-cell lung cancer. Currently, there is an increasing interest in the role of [(18)F]FDG-PET in the evaluation of biological characteristics of the tumor and the prediction of response to anticancer therapies at an early phase of treatment. According to the existing data, quantitative assessment of therapy-induced changes in tumor [(18)F]FDG uptake may allow the prediction of tumor response and patient outcome very early in the course of therapy. Treatment may be adjusted according to the chemosensitivity of the tumor tissue in an individual patient. Thus, [(18)F]FDG-PET has the potential to reduce the side effects and costs of ineffective therapy. This review provides an update on recent studies that evaluate the role of [(18)F]FDG-PET in the early prediction of response to chemotherapy and prognosis in patients with non-small-cell lung cancer. In addition, it discusses the application of [(18)F]FDG-PET to the monitoring of new targeted forms of anticancer therapy and particularly of epidermal growth factor receptor tyrosine kinase inhibitors. Finally, it evaluates the usefulness of [(18)F]fluorothymidine, a PET tracer for imaging tumor proliferation, in predicting response to therapy in patients with lung cancer.

[The use of 18F-fluorothymidine and 18F-fluorocholine in imaging with positron emission tomography].

Positron emission tomography (PET) with (18)F-fluorodeoxyglucose ((18)F-FDG) has proven useful for diagnosis, staging, restaging and therapy monitoring in a variety of tumors. Nevertheless there are some limitations. (18)F-FDG is not tumor selective and shows accumulation in inflammatory cells such as macrophages and fibroblasts that require glucose as their substrate for energy production. Furthermore, tissues with high background, such as brain may cause difficulties in image interpretation. Moreover, there are some tumors that are not avid for (18)F-FDG such as prostate cancer, hepatocellular carcinoma and some slow-growing tumors. This limitations motivated efforts to develop new oncologic tracers for PET imaging. Recently, (18)F-fluorothymidine ((18)F-FLT), a radiolabeled analog of thymidine, has been synthesized for imaging tumor cell proliferation. Another tracer that has been synthesized is (18)F-fluorocholine ((18)F-FCH) that can incorporate into tumor cell membranes by metabolic trapping. The purpose of this article is to report the role of these two new radiopharmaceuticals for PET imaging, (18)F-FLT and (18)F-FCH in the management of various malignancies.

Role of [(18)F]FDG-PET/CT in the detection of occult recurrent medullary thyroid cancer.

PURPOSE: Many patients with medullary thyroid carcinoma (MTC) have persistently elevated calcitonin levels after initial treatment, indicating disease recurrence. Conventional imaging is often negative or shows equivocal findings. In this study we report our experience with 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) in the evaluation of this specific group. METHODS: Between February 2007 and May 2009, 38 [(18)F]FDG-PET/CT scans were performed on 32 patients with MTC and elevated calcitonin levels for localization of recurrent disease. Six of these patients had a second [(18)F]FDG-PET/CT scan. RESULTS: Among the 38 [(18)F]FDG-PET/CT scans there were 18 positive and 20 negative scans. Out of the 18 positive scans, 17 were true positive and one false positive. These findings suggest that [(18)F]FDG-PET/CT provides additional information in almost half of all cases (overall per patient sensitivity of 47.4%) but using a serum calcitonin cut-off of 1000 pg/ml this rate is increased to 80%. An interesting finding of the study was that none of the six patients with multiple endocrine neoplasia type IIA syndrome had a positive [(18)F]FDG-PET/CT scan for MTC. When these patients were excluded, the overall per patient sensitivity rose to 60% and in patients with calcitonin levels >1000 pg/ml this rate increased to 100%. The mean SUV(max) of all lesions showing [(18)F]FDG uptake was 3.96 + or - 1.61 (range, 2-7). CONCLUSION: [(18)F]FDG-PET/CT seems to be valuable for the detection of recurrence in patients with highly elevated calcitonin levels and negative conventional imaging findings. In addition, it seems that the sensitivity of [(18)F]FDG-PET/CT may be higher in patients with sporadic or familial MTC than in patients with MTC as part of multiple endocrine neoplasia type IIA syndrome.

99mTc-depreotide in the evaluation of bone infection and inflammation.

BACKGROUND AND AIM: (99m)Tc-depreotide is a (99m)Tc-labelled somatostatin analogue, with high affinity for the 2, 3 and 5 subtypes of somatostatin receptors. These particular receptors are over-expressed on the surface of activated leucocytes, which mediate inflammatory response. Based on this property this study tried to investigate whether (99m)Tc-depreotide scintigraphy could be a useful complementary method in the investigation of bone infection and inflammation. METHODS: Twenty-three patients, who were investigated for probable osteomyelitis, underwent three-phase bone scintigraphy followed by (99m)Tc-depreotide scintigraphy. Clinical and laboratory findings, complementary imaging procedures, clinical follow-up and bone biopsy established the final diagnosis. (99m)Tc-depreotide scintigraphy was performed 3 h after the intravenous administration of 555-740 MBq of the radiopharmaceutical. Scintigraphic images were, at first, blindly interpreted alone and then in comparative assessment with bone scans. RESULTS: (99m)Tc-depreotide was positive in 12/12 cases of active osteomyelitis, one case of recent femoral head osteonecrosis and 6/9 rheumatoid arthritis sites. Negative (99m)Tc-depreotide scans were acquired in five cases of 'no-inflammation' (an uncomplicated fracture, an aseptic loosening of prosthesis, an old osteonecrosis, a healed and a successfully treated osteomyelitis), as well as in 14/14 total sites of degenerative arthritis-osteoarthropathy. In five cases (septic arthritis, periodontal and soft tissue infections) (99m)Tc-depreotide was positive, though spatially discordant with bone scintigraphy, delineating precisely the focus of infection. CONCLUSION: (99m)Tc-depreotide can be a useful complementary imaging method in the evaluation of bone infection and inflammation. Its combination with three-phase bone scintigraphy seems to be accurate in localizing the infection foci and determining the activity of the inflammatory processes.