A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood.
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Biomedical subjects
Publications and source records attributed to F Crippa.
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Clinical oncologists have always shown great interest in circulating tumor markers. There are several markers that in the clinical routine are a signal of particular tumor types; some of them are strictly tissue-specific such as prostatic specific antigen (PSA) for prostatic cancer, AFP and HCG for germ cell tumors of the testis and ovary, others such as CA 15.3, CA125, CEA or cytokeratins are less specific since their elevations can be found in different varieties of cancers even if they are preferentially associated to a certain tumor type, thus are considered markers for breast, ovarian cancer and colon adenocarcinoma. The most useful clinical applications of these parameters is their determination during the follow-up of the treated patients, in order to detect the tumor recurrence early, and also to evaluate the evolution of the disease by monitoring the treatment responses. During follow-up, increasing levels of tumor markers can be observed even several months before the clinical demonstration of cancer recurrence. The association of tumor marker tests with imaging modalities can lead to several advantages: the first is to confirm the diagnosis of relapses, possibly before the appearence of the related clinical symptoms due to tumor growth; the second is to localize the sites of lesions, while tumor markers provide only a general indication of the existence of metastases; the third is to make possible a correct whole body restaging. In the assessment of cancer response tumor markers are often very reliable and their changes are faster than the morphological ones. Among all the imaging modalities, nuclear medicine plays an important role in detecting recurrences and metastatic localizations as it is able to investigate functional rather than morphological aspects of tumors, and provide different information in comparison to morphologic imaging. In addition, the scintigraphic techniques offer the possibility to evaluate treatment responses, confirming or not the information from biochemical changes. This review aims to show some examples (breast, prostate and ovarian cancer) in which the combination of nuclear medicine imaging modalities and tumor marker tests is proposed for clinical practice. The advantages and some critical aspects are discussed on the basis of the clinical findings and the most important clinical indications are described.
BACKGROUND: Surgical removal of axillary lymph node and histologic examination for metastases are used to determine whether adjuvant treatment is necessary for patients with breast cancer. Axillary lymph node dissection (ALND) is a costly procedure associated with various side effects, and 80% or more of patients with tumors of 20 mm or less are lymph node negative and might avoid ALND. In this study, we evaluated whether an alternative, noninvasive method--i.e., positron emission tomography (PET) with 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG)-- could be used to determine axillary lymph node status in patients with breast cancer. METHODS: One hundred sixty-seven consecutive patients with breast cancers of 50 mm or less (range = 5-50 mm; mean = 21 mm) scheduled for complete ALND were studied preoperatively with FDG-PET, and then PET and pathology results from ALND were compared. All statistical tests were two-sided. RESULTS: The overall sensitivity, specificity, and accuracy of lymph node staging with PET were 94.4% (PET detected 68 of 72 patients with axillary involvement; 95% confidence interval [CI] = 86.0% to 98.2%), 86.3% (82 of 95 patients without axillary involvement; 95% CI = 77.8% to 91.9%), and 89.8% (150 of 167 patients with breast cancer; 95% CI = 84.2% to 93.6%), respectively. Positive- and negative-predictive values were 84.0% (68 patients with histologically positive lymph nodes of 81 patients with positive FDG-PET scan; 95% CI = 74.2% to 90.5%) and 95.3% (82 patients with histologically negative lymph nodes of 86 patients with negative FDG-PET scan; 95% CI = 88.2% to 98.5%), respectively. When PET results for axillary metastasis were analyzed by tumor size, the diagnostic accuracy was similar for all groups (86.0%-94.2%), with higher sensitivity for tumors of 21-50 mm (98.0%) and higher specificity for tumors of 10 mm or less (87.8%), and the range was 93.5%-97.3% for negative-predictive values and 54.5%-94.1% for positive-predictive values. Among the 72 patients with axillary involvement, PET detected three or fewer metastatic lymph nodes in 27 (37.5%) patients, about 80% of whom had no clinically palpable axillary lymph nodes. CONCLUSIONS: Noninvasive FDG-PET appears to be an accurate technique to predict axillary status in patients with breast cancer and thus to identify patients who might avoid ALND. These results should be confirmed in large multicenter studies.
We identified 10 patients who developed cytomegalovirus (CMV) retinitis after HSCT during a 14-year period. The median day of diagnosis of CMV retinitis after transplantation was day 251 (range, days 106--365). CMV retinitis was associated with CMV serostatus of donor or recipient (P=0.01), CMV reactivation before day 100 (P=0.007), delayed lymphocyte engraftment (P<0.05), and chronic graft versus host disease (GVHD; P<0.001). In allogeneic recipients of HSCT who were alive at day 100 after transplantation and had chronic clinical extensive GVHD, the incidence of GVHD was 1.4% (8 of 577). Five of 10 patients had other manifestation of CMV disease before retinitis occurred (4 with gastrointestinal disease and 1 with interstitial pneumonia; median time, 70 days before onset of CMV retinitis; range, 58--279 days), and 4 others had CMV excretion. CMV retinitis was bilateral in 4 patients; 9 of 10 patients had ocular symptoms (i.e., decreased vision and floaters). Six of 7 patients responded well to ganciclovir or foscarnet systemic treatment, 1 improved only after switching to cidofovir, and 1 patient who received a transplant in 1983 did not respond to acyclovir treatment. In conclusion, CMV retinitis is an uncommon late complication after HSCT that occurs mainly in seropositive allograft recipients with previous CMV reactivation and chronic GVHD, and with delayed engraftment of lymphocytes.
Gastrointestinal (GI) cancers account for the second highest number of new tumor cases and deaths per year in the United States and Western Europe. The most frequently involved sites are, in descending order, the colorectum, stomach, pancreas, liver, bile duct, and esophagus. The most common tumor type is adenocarcinoma. Among the epithelial cancers, great attention has recently been given to the tumors of neuroendocrine origin. These concepts are relevant because nuclear medicine imaging is based on visualization by means of a particular uptake of radiolabelled tracers in cancer cells that concentrate the radioactive signal. This signal is detected and reconstructed in planar or tomographic images. Different radiopharmaceuticals have been proposed for diagnostic application in oncology (such as radiolabelled monoclonal antibodies (MAbs), receptor tracers, and positron-emitting radiopharmaceuticals), and they are currently used as tracers for tumor detection with different modalities and techniques. Most of these techniques demonstrate their clinical usefulness in the diagnosis of GI cancer. This work is not intended to be a comprehensive review of all the extensive experience and possibilities of nuclear medicine for the diagnosis of GI tumors; rather, it aims to summarize the current status of the most important approaches and their main indications in staging GI cancers.
The basis of tumour imaging with PET is a specific uptake mechanism of positron emitting radiopharmaceuticals. Among the potential tracers for breast cancer (fluorodeoxyglucose, methionine, tyrosine, fluoro-estradiol, nor-progesterone), 2-deoxy-2-fluoro-D-glucose labelled with fluorine (FDG) is the most widely used radiopharmaceutical because breast cancer is particularly avid of FDG and 18F has the advantages of a relatively long physical half-life. Mammography is the first choice examination in studying breast masses, due to its very good performances, an excellent compliance and the best value regarding the cost/effectiveness aspects. However FDG-PET revealed to be effective in the study of patients with ambiguous mammographies. The FDG uptake in tissue correlates with the histological grade and potential aggressiveness of breast cancer and this may have prognostic consequences. Besides the evaluation of breast lesions, FDG-PET shows a great efficacy in staging lymph node involvement prior surgery and this could have a great value in loco-regional staging. Whole body PET provides also information with regard to metastasis localizations both in soft tissue and bone, and plays an important clinical role mainly in detecting recurrent metastatic disease. In fact for its metabolic characteristics PET visualizes regions of enhanced metabolic activity and can complements other imaging modalities based on structural anatomic changes. Even though CT and MRI show superior resolution characteristics, it has been demonstrated that PET provides more accurate information in discriminating between viable tumour, fibrotic scar or necrosis. Several clinical evidences demonstrated that FDG-PET is also able to predict wether cancer will respond to the therapy, or, when applied at the end of the treatment, it can assess the response to the therapy. These statements are coming from the examination of more than 2000 breast cancer patients included in 88 articles or abstracts on studies in which FDG-PET was used for breast cancer detection.
Patient care management provided by healthcare organizations is complex, involving many different care providers. The information exchange between providers concerns a varying and considerable number of actors and a high transmission load. Based on models, used to characterize specific features of work processes, we propose a new method able to analyze and represent clinical communications inside hospitals. Software has been developed, providing tools for storing and retrieving information resulting from clinical communications. The method, together with data collected in actual situations, may constitute useful tools for health information systems developers.
UNLABELLED: The purposes of this study were to establish the diagnostic accuracy of FDG PET for lymph node metastases and to determine the smallest detectable volume of disease. METHODS: Using FDG PET, we preoperatively studied 56 lymph node basins in 38 patients with a clinical or instrumental diagnosis of lymph node metastases from melanoma. All lymph node basins underwent node dissection. The FDG PET results were compared with the postoperative histopathology results. PET images were obtained using a GE 4096 WB scanner, after injection of a mean activity of 496 MBq (range, 366-699 MBq) of FDG. RESULTS: The efficacy of FDG PET in the diagnosis of involved lymph node basins was good. Sensitivity was 95% (35/37); specificity, 84% (16/19); accuracy, 91% (51/56); positive predictive value, 92% (35/38); and negative predicative value, 89% (16/18). Metastases were shown histologically in 114 of 647 surgically removed lymph nodes. FDG PET detected 100% of metastases > or = 10 mm, 83% of metastases 6-10 mm, and 23% of metastases < or = 5 mm. Moreover, FDG PET had high sensitivity (> or = 93%) only for metastases with more than 50% lymph node involvement or with capsular infiltration. CONCLUSION: Our study shows that FDG PET has a reasonable sensitivity and specificity for detecting the presence or absence of lymph node metastases in patients with melanoma. However, even if able to detect small volumes of subclinical macroscopic disease, FDG PET cannot detect subclinical microscopic disease with acceptable sensitivity. The specificity of FDG PET is good, but some false-positive results may occur.
The state of art of artificial nutrition in depleted cancer patients is reviewed in brief. Because cancer cachexia cannot be equated to simple nutrient deficiency but is due instead to complex metabolic abnormalities, the nutritional effects of total parenteral (TPN) and enteral (EN) nutrition are more limited than in starving subjects. TPN and EN usually prevent further deterioration of the nutritional status, although they are not able to fully reverse a state of depletion. There is evidence that quantitative and qualitative modulation of certain nutrients may obtain better results because of a favorable impact on host metabolism. Research in this field is fully warranted. Moreover, the effects of some substrates on tumor metabolism and tumor growth require further investigation to define a nutritional regimen able to maintain the host metabolism with minimum stimulation of tumor growth.
Although radiography, computed tomography and magnetic resonance imaging are still the methods of choice for the study of lung cancer, they have certain limitations in the determination of the nature of suspicious lung nodules, the evaluation of mediastinal involvement, the assessment of the viability of previously treated lesions and the diagnosis of tumour relapse. There is a wide range of current oncological requirements related to lung cancer: detection of malignant lesions at the earliest stage and in the most effective way; the definition of the biological characteristics of a lesion (proliferation, aggressiveness, differentiation, etc.); the need to define the operability of the patient (function of residual lung and staging); and the need to evaluate the behaviour of the tumour (response to therapy, early detection of recurrences, metastatic spread). Most of the efforts of the nuclear medicine community have been focussed on diagnosis, staging, restaging and therapy monitoring of lung cancer. Many radiopharmaceuticals have been employed for this, including gallium, monoclonal antibodies, somatostatin analogues, lipophilic cations and positron emission tracers. There is ample evidence that nuclear medicine techniques may provide complementary information with respect to anatomical imaging, for example in the assessment of preoperative function by means of ventilation and perfusion scintigraphy, or in tumour localisation by means of specific tumour-seeking agents. However, clinical data suggest that, when properly used, nuclear medicine procedures in some cases may be not only complementary to radiology but essential for the clinical management of lung cancer. An example of such a procedure is fluorodeoxyglucose positron emission tomography (FDG PET) the introduction of which has greatly contributed to confirmation of the clinical value of nuclear medicine in this field. FDG PET has proved of great help in lung cancer management and its cost-effectiveness in lung cancer staging is firmly established. In this review the results of the most important nuclear medicine techniques are summarised and their value in clinical practice is discussed. General, updated information is provided about the epidemiology, biology and clinical management of lung cancer, and about the role of nuclear medicine in these areas.
To investigate the possible role of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) in the prognostic evaluation of primary breast cancer, we studied 86 patients with T1-3 (TNM classification) breast tumours before surgery and compared the tumour FDG uptake, calculated as a standardized uptake value (SUV), with postoperative histopathological findings, steroid hormone receptor status of the tumour, thymidine labelling index (LI) and tissular expression of p53. SUV was significantly higher in infiltrating ductal carcinomas (n = 68; median SUV = 5.6) than in lobular ones (n = 18; median SUV = 3.8), and in grade 3 carcinomas (n = 26; median SUV = 6.2) than in grade 1-2 ones (n = 60; median SUV = 4.9). Moreover, SUV was significantly higher in carcinomas with high levels of p53 (n = 12; median SUV = 9.5) than in those with low levels (n = 48; median SUV = 4.25). By contrast, there was no significant correlation between SUV and the steroid hormone receptor status or LI of tumours. Our data demonstrate that FDG uptake, expressed as SUV, is associated with certain prognostic factors in breast cancer, such as histopathological grading and p53 expression, which can be assessed only by means of postoperative in vitro examinations. Hence, the information provided by FDG-PET is to some extent related to relevant information on tumour biology. The clinical value of these data will have to be confirmed by analysis of the independence of SUV from other prognostic factors by means of a multivariate analysis performed on a larger series of patients with adequate follow-up. If SUV is confirmed as an independent variable, FDG-PET could assume an important role in the determination of appropriate therapeutic strategies for primary breast cancer.
METHODS: The presurgical, noninvasive staging of axillary nodes for metastases was prospectively investigated in 68 patients who were diagnosed with primary breast cancer using PET with 18F-fluorodeoxyglucose (FDG). Four patients had bilateral nodules; therefore, the total number of evaluable cases was 72. Visual analyses of attenuation-corrected PET images and standardized uptake values (SUVs) of FDG uptake in carcinomas were compared with histopathological surgical findings. The SUV distribution differences between carcinomas with and without axillary metastases were evaluated by means of statistical and receiver operating characteristics analyses. RESULTS: PET correctly classified 64 of the 72 cases; four false-positive and four false-negative PET results were found. The overall sensitivity, specificity and accuracy of PET for axillary metastases were 85%, 91% and 89%, respectively. With respect to the clinical axillary stage of the patients (TNM, or tumor-node-metastasis, classification), we obtained the following results: N0 patients, sensitivity = 70%, specificity = 92%, accuracy = 86%; N1a patients, sensitivity = 85.5%, specificity = 100%, accuracy = 95%; and N1b-2 patients, sensitivity = 100%, specificity = 67%, accuracy = 87%. The median SUV in carcinomas with axillary metastases (4.6) was significantly higher than that in carcinomas without metastases (2.9), but there was a great SUV overlap between the two groups (interquartile ranges = 2.7-7.2 and 1.9-4.5, respectively). Analysis of the receiver operating characteristics curve showed that a high sensitivity of SUV in predicting axillary metastases was associated with a very low specificity and vice versa. With the best SUV cutoff value of 2.9, the sensitivity and specificity were 74% and 56%, respectively. CONCLUSION: PET showed good overall diagnostic accuracy in the detection of axillary metastases (86%). The very high accuracy (95%) in N1a patients is of particular importance. False-negative PET findings, however, can be encountered. SUVs of breast carcinoma cannot predict the spread of the disease to the axilla, even if higher values are often associated with axillary metastases. Any decision on the use of PET in the presurgical staging of breast cancer should be incorporated into a more general debate on axillary management. In selected patients with a very low probability of axillary metastases (T1a), in whom axillary surgery can already be avoided according to data from follow-up studies, 18F-FDG PET could be proposed as a noninvasive imaging modality to improve the diagnosis of axillary relapses.
In breast cancer patients the detection of axillary lymph node involvement is a very critical issue, in view of the earlier diagnosis of the disease in recent years, and the increased frequency of very small tumors at first presentation. The size of cancer is related to the risk of axillary metastases, and this may affect the prognosis and the therapeutic strategies. Axillary lymph node involvement is generally recognized as an index of distant microdiffusion, and as it affects overall and disease-free survival, represents the basis for adoption of adjuvant chemotherapy. Routine axillary lymph node dissection (ALND) is expensive, and does not benefit about 70% of early breast cancer patients which are node negative (pN-). Today most of these patients have to sustain the potential morbidity and the economic costs of ALND. The clinical approach is known to be an unreliable diagnostic tool, and for the detection of axillary metastases, conventional X-ray techniques are also unable to solve the problem. By contrast, nuclear medicine procedures have revealed a very interesting diagnostic potential in recent years. This paper analyzes the numerous studies conducted in the field of lymph node visualization and the heterogeneity of the published experiences, taking into account the different approaches proposed in the literature: a) imaging with gamma-emitting tumor seeking agents; b) radioimmunoscintigraphy intravenous (i.v.) or by the interstitial route; c) lymphoscintigraphy with colloids and gamma probe sentinel biopsy; d) positron emission tomography (PET). Although it is very difficult to make a definitive statement about the clinical efficacy of all these methods, this paper reports the most important series of patients examined in the literature as well as the author's own experiences. This can serve as the basis for a better understanding of the potential of nuclear medicine procedures, and gives the reader the opportunity to weigh advantages and drawbacks of each method. At present, lymphoscintigraphy with gamma probe sentinel biopsy and FDG-PET are the nuclear medicine approaches with the best diagnostic performance. However, a correct comparison of the methods will not be possible, until their careful assessment in the same patients is performed. In addition, a final statement today should consider also the increasing need to carry out an economic analysis by evaluating the cost-effectiveness of the examinations.
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One approach in the treatment of ovarian cancer patients involves the infusion of autologous T lymphocytes coupled with a bispecific monoclonal antibody MOv18/anti-CD3 (biMAb OC/TR), which recognizes a 38-kDa glycoprotein expressed on ovarian carcinomas and the CD3 T cell receptor. However, little is known about the in vivo biodistribution of injected activated lymphocytes, information that could be obtained by scintigraphic imaging of radiolabelled T cells in order to visualize the migratory pattern. We compared the efficiency, stability and toxicity of technetium-99m hexamethylpropylene amine oxime (HMPAO), indium-111 oxine and fluorine-18 2-fluoro-2-deoxy-d-glucose (FDG) in radiolabelling activated lymphocytes targeted with biMAb OC/TR. The mean labelling efficiencies of 111In-oxine and 18F-FDG using 2.5x10(8) lymphocytes (68% and 64%, respectively) were more than twice that of 99mTc-HMPAO (31%). Retention of the radionuclide in the cell was highest in the case of 111In-oxine labelling (less than 25% of the initial cell-bound activity released after 240 min, as compared with 44% of the 99mTc label in the same period and 45% of 18F radionuclide released after 150 min). None of the three radiolabelling reagents induced any significant alteration in cell viability or immunophenotype. However, both 111In-oxine and 18F-FDG induced a loss of cytotoxic activity of lymphocytes against the ovarian carcinoma cell line IGROV1, and all three radiolabelling reagents caused a significant reduction in the proliferative ability of labelled lymphocytes compared to controls, with cell death occurring after 8-9 days. Radiolabelling with the more stable 111In-oxine reagent using a higher number of lymphocytes (1.4x10(9)) but the same total activity (around 55.5 MBq) resulted in improved labelled T cell viability and proliferative ability, although the mean labelling efficiency decreased (35.8%). Together the data suggest that 111In-oxine at low activity per cell is the most appropriate reagent for radiolabelling activated retargeted T lymphocytes useful for in vivo biodistribution studies.
We evaluated the clinical usefulness of single-photon emission tomography (SPET) with technetium-99m sestamibi and indium-111 pentetreotide in breast cancer staging. Fifteen patients with clinical and/or mammographic findings suggesting T1-2N0-1 breast cancer were studied. SPET images were acquired 20 min after 99mTc-sestamibi injection and 4 and 24 h after 111In-pentetreotide injection. Patients underwent surgery the day after the later 111In-pentetreotide acquisition. Pathological examination showed 16 tumours in the 15 patients, with one bilateral carcinoma. The mean tumour diameter was 18.7 mm. Metastatic axillary involvement was found in 6/16 tumours, with a mean of five metastatic nodes per axilla. Both tracers correctly identified 15/16 primary tumours and five of the six cases of metastatic axillary node involvement. No difference between the tracers was observed in breast cancer staging. 99mTc-sestamibi seems to be the better tracer in terms of physical characteristics, execution time and cost-effectiveness. Our data suggest the future possibility of using nuclear medicine imaging to avoid axillary dissection in patients with T1 breast cancer.
The aim of this study was to determine the non-extremity gamma dose received by a technician while performing an ordinary nuclear medicine procedure or a static (i.e. without blood sampling) fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) study. The dose per patient was measured by means of a commercial electronic pocket Geiger Mueller dosimeter, worn in the upper left pocket of the overalls. This was previously tested by exposure to known point sources of technetium-99m, gallium-67, iodine-131 and fluorine-18 in the air. A further test was performed with 99mTc, 131I and 18F sources inserted in a water phantom to simulate the condition of high scattering degradation of the primary radiation due to the patient's tissues. Subsequently, the dose was measured by two technicians for a total of 314 clinical cases, covering the most common nuclear medicine procedures, including 44 static, two-level FDG PET studies with repositioning of the patient on the couch between the transmission and the emission scan and seven whole-body PET studies. The dose read by the dosimeter was corrected for environmental background and for detector efficiency measured with sources in the air. For a limited subset of cases, the time spent close to patients was also measured. Doses were then estimated by a crude non-absorbing point source approximation and by using experimental dose rates. A comparison between experimental and estimated doses, as well as with previously published data, completed the work. For most of the conventional procedures, the measured dose per procedure proved to be within the range 0.2-0.4 microSv, except for equilibrium angiocardioscintigraphy (1.0+/-0.5 microSv) and 99mTc-sestamibi single-photon emission tomography (1. 7+/-1.0 microSv). Comparison with data published in the last 20 years shows that our values are generally lower. The current more favourable working conditions are a result of technological improvements (for instance two-head gamma cameras capable of whole-body studies), and safer shielding and distance from patients. Two-level PET gave 11.5+/-4.4 microSv and whole-body PET 5.9+/-1.2 microSv. In a subset of patients these values could be subdivided into the separate contributions from each phase of the procedure. They were: 0.11+/-0.04 microSv for daily quality assurance, 2.9+/-3.0 microSv for two transmission scans, 0.3+/-0.1 microSv for syringe preparation, 2.8+/-1.8 microSv for injection and escorting the patient to the waiting room, 1.7+/-1.5 microSv for a whole-body emission scan, 7.7+/-5.2 microSv for two emission scans, and 0.8+/-0. 2 microSv for patient departure. The higher value from PET by comparison with conventional procedures is attributable to the higher specific gamma constant of 18F, as well as the longer time required for accurate positioning.
The knowledge of biochemical and physiological mechanisms involved in tissue localization is important so as to understand the information given by diagnostic nuclear medicine imaging, and eventually to design new radiopharmaceuticals. The cellular mechanisms which permit a high cancer uptake involve the perfusion and metabolism around the tumour tissue, the interference with normal function, the altered perfusion and/or metabolism within the tumour. All these phenomena can contribute to a high concentration of particular radiotracers in cancer and can create a favourable tumour/background ratio uptake sufficient for cancer imaging. Those molecules might be also powerful tools for reaching an advanced understanding of neoplastic and even "normal" cell biology. During these last years, some radiotracer specifically designed for different applications proved to be promising radiopharmaceuticals for breast cancer imaging. This is the case of monoclonal antibodies (Mabs) developed in the past against membrane cancer antigens. Other tracers, originally proposed for the study of vascular perfusion (cardiovascular tracers), have also revealed a capacity to be taken up by cancer cells. The radiopharmaceuticals mostly used as tumour seeking agents today (Radiothallium, Sestamibi, Tetrophosmin) were generated with other applications in mind. In this paper we review the mechanisms of uptake of the most relevant agents currently proposed for breast cancer imaging, including 18F-fluorodeoxyglucose (FDG). The radiotracers will be examined on the basis of the available scientific evidence regarding their cellular uptake and release. Moreover, we report our preliminary studies on the cellular uptake and release of these and other compounds recently introduced in clinical trials.