Cell Therapy for Parkinson's Disease: A Translational Approach to Assess the Role of Local and Systemic Immunosuppression.

Neural transplantation is a promising therapeutic approach for neurodegenerative diseases; however, many patients receiving intracerebral fetal allografts exhibit signs of immunization to donor antigens that could compromise the graft. In this context, we intracerebrally transplanted mesencephalic pig xenografts into primates to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Parkinsonian primates received WT or CTLA4-Ig transgenic porcine xenografts and different durations of peripheral immunosuppression to test whether systemic plus graft-mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in primates receiving systemic plus local immunosuppression for 6 mo. Recovery was associated with restoration of dopaminergic activity detected both by positron emission tomography imaging and histological examination. Local infiltration by T cells and CD80/86+ microglial cells expressing indoleamine 2,3-dioxigenase were observed only in CTLA4-Ig recipients. Results suggest that in this primate neurotransplantation model, peripheral immunosuppression is indispensable to achieve the long-term survival of porcine neuronal xenografts that is required to study the beneficial immunomodulatory effect of local blockade of T cell costimulation.

Aliskiren improves blood pressure control and prevents cardiac damage in high-risk hypertensive subjects.

AIM: Longitudinal study aimed to evaluate the antihypertensive efficacy, safety and the effect on cardiac damage of Aliskiren, administered to a group of high-risk hypertensive patients with mild impairment of renal function and uncontrolled blood pressure (BP) despite a two-drug antihypertensive treatment. METHODS: One hundred and six patients (56 men and 50 females) aged 61.9±12.7 years, were assigned to receive Aliskiren 150-300 mg once-daily for 12 months. Clinic BP measurements were taken at every follow-up visit (1st, 6th and 12th month), while biochemical tests, estimated glomerular filtration rate (eGFR), 24-hours ambulatory BP measurements (ABMP) and echocardiography were evaluated at baseline and at the end of follow-up. Analysis of variance for repeated measures compared BP, left ventricular mass index (LVMI) and eGFR values changes. RESULTS: A significant reduction (all P<0.0001) of clinic systolic (-28.6 mmHg) and diastolic (-12.8 mmHg) BP values, mean 24h-systolic (-12.3 mmHg) and 24h-diastolic (-6.5 mmHg), day-time systolic (-11.5 mmHg) and diastolic (-6.4 mmHg), night-time systolic (-11.9 mmHg) and diastolic (-7 mmHg) ABPM values and in the use of antihypertensive drugs was observed (3.0±0.9 vs. 2.0±0.7, p=0.01). LVMI was significantly reduced (130.2±36.1 vs. 115.9±33.4 g/m2, P<0.0001); eGFR was steady (75.3±17.3 vs. 73.1±21.5 ml/min/1.73m2, P>0.05). Putative adverse events caused withdrawal of 7 subjects (6 for gastrointestinal disturbances, 1 for alopecia). CONCLUSION: Aliskiren was effective in decreasing both clinical and ABPM values and in reducing LVMI in both genders without any influence on eGFR. The treatment resulted safe, even in combination with ACE-inhibitors and angiotensin II receptor blockers. A significant reduction in the use of concomitant antihypertensive drugs was observed.

Contemporary nuclear medicine imaging of neuroendocrine tumours.

Neuroendocrine tumours (NETs) are rare, heterogeneous, and often hormonally active neoplasms. Nuclear medicine (NM) imaging using single photon- and positron-emitting radiopharmaceuticals allows sensitive and highly specific molecular imaging of NETs, complementary to anatomy-based techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI). Somatostatin-receptor scintigraphy is a whole-body imaging technique widely used for diagnosis, staging and restaging of NETs. The increasing availability of hybrid single-photon emission CT (SPECT)/CT cameras now offers superior accuracy for localization and functional characterization of NETs compared to traditional planar and SPECT imaging. The potential role of positron-emission tomography (PET) tracers in the functional imaging of NETs is also being increasingly recognized. In addition to 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG), newer positron-emitting radiopharmaceuticals such as (18)F-dihydroxyphenylalanine (DOPA) and (68)Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) peptides, show promise for the future. This article will summarize the role of current and emerging radiopharmaceuticals in NM imaging of this rare but important group of tumours.

[Radiometabolic therapy for metastatic thyroid carcinoma: overview of the literature and rational bases for the use of recombinant human TSH]. / La terapia radiometabolica del carcinoma della tiroide metastatico: overview della letteratura e basi razionali all'utilizzo del TSH umano ricombinante.

The established treatment for differentiated thyroid carcinoma (DTC) is founded on total thyroidectomy and subsequent administration of radioiodine (131I) to ablate the thyroid remnant and to treat the metastatic disease. In the case of metastatic or recurrent disease, further cycles of 131I therapy are often necessary. The condition for maximizing the effectiveness of the treatment is to have an adequate stimulation from TSH, which must be >25-30 mIU/L. This elevation is achieved either discontinuing the hormone suppression therapy for an appropriate period, or administering recombinant human TSH (rhTSH). The latter has shown good clinical efficacy in patients with residual thyroid gland and is nowadays commonly employed since it is easy to use and allows to avoid the side effects of hypothyroidism. It thus represents a good alternative to thyroid hormone withdrawal for the remnant ablation, while is still open the question if its efficacy on the management of metastatic disease is superimposable to thyroid hormone withdrawal. To this purpose, a Panel of expert reviewed the literature, assessing the advantages and disadvantages for the patient, as well as the impact in terms of cost and benefit to the National Health Service. The work of the Panel concluded with a proposal for the use of rhTSH in selected patients with metastatic DTC, in which is considered the efficacy and safety of the product and is examined its use in terms of costs; this proposal was accepted by the Italian Drug Agency resulting in an update of the indications for rhTSH.

In high risk hypertensive subjects with incidental and unilateral renal artery stenosis percutaneous revascularization with stent improves blood pressure control but not glomerular filtration rate.

AIM: In high-risk hypertensive subjects (HTs) with incidental unilateral renal artery stenosis (RAS), the effectiveness of percutaneous revascularization with stent (PR-STENT) on blood pressure (BP) and glomerular filtration rate (GFR) is not established. METHODS: Eighteen HTs aged 65.7 ± 9.2 years with angiographically diagnosed unilateral RAS (≥ 60%) were randomized to receive PR-STENT (N=9) or to NO-STENT (N=9). BP (mercury sphygmomanometer) and GFR (99mTc-DTPA clearances during renal scintigraphy) were evaluated yearly for three years. Echo-Doppler of renal arteries was performed to verify the anatomic patency and flow velocities of the reperfused artery. Analysis of variance compared BP and GFR values changes from baseline to the follow-up; differences for continuous variables were evaluated between groups with the Tukey's post hoc test after adjustment for age, change of BP between baseline and at the follow-up, GFR and body mass index (BMI). RESULTS: Baseline systolic BP and GFR values were not different between groups. The significantly greater GFR increase observed in PR-STENT than in NO-STENT at univariate analysis at the end of follow-up (62.5 ± 19.2 vs. 42.24 ± 17.6, P<0.02) disappeared after adjustment for confounding factors. However, systolic BP remained significantly lower in PR-STENT than in NO-STENT (140.1 ± 4.6 vs. 170.0 ± 8.3, P<0.0001) also after adjustment for age, GFR and BMI. CONCLUSION: PR-STENT reduces systolic BP without improving GFR. Due to the strong association between high BP and renal damage, this study raises the question on whether PR-STENT should be performed in all HTs with unilateral and incidental RAS.

Surgical therapeutic planning options in nodular goiter.

Nodular goiter encompasses a spectrum of diseases from the incidental asyntomatic small solitary nodule to the large intrathoracic goiter causing pressure symptoms as well as functional complaints. The mainstay in the diagnostic evaluation is related to functional and morphological characterization with serum thyroid-stimulating hormone (TSH), ultrasound (US) and other imaging procedures and cytology by fine needle aspiration (FNA) on the basis of the different diseases. A clinical classification considering solitary cyst, adenomatous functioning nodule, follicular lesion and multinodular goiter may be proposed to consider the alternative therapies other than surgery as TSH suppressive or thyrostatic treatment, 131I therapy, percutaneous ethanol injection therapy (PEIT) or the only clinical exam in benignant lesions. Surgery should be advocated for the treatment of thyroid nodules whenever a patient presents with either pressure symptoms, hyperthyroidism or follicular/indeterminate cytology. Surgical approach, intraoperatory strategy and the extension of surgical treatment are correlated to the different clinical categories. At surgery the frozen section analysis in case of hemithyroidectomy is of aid to rule out malignancy and to prevent the reoperation. The surgical treatment of choice in case of uninodular goiter is lobectomy, total thyroidectomy or near total thyroidectomy is the correct treatment of multinodular bilateral goiter. The choice of the treatment must be condivided with the patient.

Endocrine tumors: the evolving role of positron emission tomography in diagnosis and management.

Endocrine tumors comprise a range of benign and malignant conditions that produce a spectrum of clinical symptoms and signs depending on the specific hormones they produce. The symptoms and presentations of these tumors are often independent of their size and location. Because of their expression of cell membrane receptors or production of specific types of hormones or peptides, endocrine tumors can be identified with functional radionuclide imaging much more readily compared to standard cross-sectional imaging. In recent years, 18F-fluoro-deoxy- D-glucose positron emission tomography (18F-FDG-PET) has emerged as a useful tool for diagnosing and assessing many tumors. In this review we describe how PET, using 18F-FDG and other radiopharmaceuticals can be useful in the diagnosis and management of a wide range of endocrine tumors.

Influence of tumour size and uptake of 99mTc-octreotide on radio-guided surgery for neuroendocrine tumors.

AIM: The aim of this study was to analyze the influence of scintigraphic uptake grade and tumour size on radio-guided surgery of neuroendocrine tumours (NETs) using 99mTc-EDDA/HYNIC-TOC (99mTc-octreotide). METHODS: We investigated 21 patients with NET (F=8, M=13) for localization of 27 known lesions using a gamma probe. Three to 6 hours before surgery, 550-650 MBq of 99mTc-octreotide was injected followed by immediate imaging prior to surgery. The uptake was graded on a scale from 0-4. Localization was confirmed by endoscopic ultrasound (EUS), computed tomography (CT) and/or magnetic resonance imaging (MRI). Morphological images were used to determine size of the lesion. Local measurements of radioactivity were performed during surgery using a gamma probe. RESULTS: Twenty lesions were successfully localized intraoperatively using a gamma probe (7=grade 4, 9=grade 3, 2=grade 2 and 2=grade 0). The size of successfully localized lesions ranged between 9 and 50 mm. Seven lesions were not localized successfully of which 6 were seen on scintigraphy (2=grade 4, 1=grade 3 and 3=grade 2). The 7th lesion was not seen on preoperative scintigraphy and not localized successfully. The size of unsuccessfully localized lesions ranged between 7 and 30 mm. CONCLUSIONS: High octreotide uptake (grade 3 and 4) influence radioguided surgery. Tumour size did not influence the success of localization of lesions by gamma probe.

Scintigraphic localization of adrenal tumors.

Scintigraphy has historically added much to the evaluation of adrenal dysfunction and tumor localization. The early development of radiopharmaceuticals for adrenocortical imaging provided vital clinical information well before the widespread availability of computed tomography (CT), but beginning in the early 1980's nuclear imaging became supplanted in large part by high resolution CT and more recently by magnetic resonance imaging. The parallel emergence of radiopharmaceuticals for adrenomedullary imaging also provided important functional insight in evaluating these neoplasms, but despite the clinical value of such nuclear probes they too, were relegated to a less prominent role in tumor characterization because of advances in anatomic imaging. However, with the recent introduction of dual-modality imaging platforms that directly combine CT with scintigraphy, either as single photon emission tomography (SPECT)/CT or positron emission tomography (PET)/CT, nuclear medicine studies once again play an integral role in adrenal tumor evaluation.

Thyrotropin variations may explain some positive radioiodine therapy scans in patients with negative diagnostic scans.

UNLABELLED: Thyroglobulin (Tg) is a specific marker of residual thyroid cancer or tumor recurrence. In patients with elevated Tg levels and negative diagnostic radioiodine (131I) whole-body scans (dWBS), administration of a therapy dose may reveal foci that were not initially apparent. The aim of this study was to identify factors, other than 131I activity, which might explain why a post-therapy 131I whole-body scan is sometimes positive despite a negative dWBS. PATIENTS AND METHODS: We reviewed data on all patients with elevated Tg levels and negative dWBS with 185 MBq 131I off-T4 at followup, who subsequently received an empiric therapy dose of 3700 MBq of 131I. During a 5-yr period, 22 patients met these criteria. 131I therapy could be given immediately after negative dWBS in 9 patients, with an average of 8 extra days of hypothyroidism. In the other 13 patients, therapy was given an average of 8 months later. RESULTS: The therapy scan was negative in 16 patients, while it showed uptake in the thyroid bed in 5 patients and distant metastases in two. In the latter two patients, the TSH level was suboptimal at the time of dWBS (9 and 25 microIU/ml), and had risen to 34 and 70 microIU/ml respectively at the time of therapy. Overall, a positive scan following therapy occurred in 7 patients (6/9 patients treated immediately and 1/13 patients treated in a separate setting; p<0.01). In patients with positive therapy scans, the mean TSH level was 73 microIU/ml at the time of dWBS and 103.5 microIU/ml at the time of therapy (41% increase; p<0.05). In patients with negative therapy scans the mean TSH level was 84 microIU/ml at dWBS and 86 microIU/ml at the time of the therapy scan (2% increase). CONCLUSIONS: Our study suggests that interval increase in TSH level with a longer period of stimulation may have contributed to making the whole-body scan positive at the time of therapy. Nowadays, patients with elevated Tg are directly given a therapy dose of 131I. Special care should be taken when preparing patients who have been on suppressive levothyroxine therapy for a long time, in order to avoid misclassifying the tumor as non-functioning.

Technetium-99m-labeled lapachol as an imaging probe for breast tumor identification. / Lapachol marcado con tecnecio 99m como sonda de imágenes para la identificación de tumores de mama.

OBJECTIVE: Breast cancer is a health problem worldwide with high incidence and mortality rates. It is well known that the development of more sensitive and specific diagnostic methods is of great importance since an early diagnosis is essential to successfully treat tumors. Lapachol is a natural compound, belonging to the naphthoquinone group that has been widely used in traditional medicine to treat various illnesses, including cancer. The aim of this study was to evaluate technetium-99m (99mTc) labeled lapachol as an imaging probe for breast cancer identification. METHODS: To achieve this purpose, lapachol was labeled with 99mTc, radiochemical purity and in vitro stability were determined. Blood clearance, in healthy mice, and biodistribution, in 4T1 tumor-bearing mice, were also evaluated. RESULTS: Lapachol was successfully labeled with 99mTc, with high values of radiochemical yield (95.9±3.4%). In vitro stability showed that the radiolabeled complex remained stable for up to 24h, with values above 90% for both saline and plasma (95.6±3.6% and 96.4±1.7%, respectively). The radiolabeled complex decays in a biphasic manner, with a half-life of distribution and elimination equal to 3.3 and 50.0min, respectively. Biodistribution and scintigraphic images showed high uptake in organs of excretion (kidneys, liver, and intestine). It could be also noted that tumor uptake was higher than the muscle at all time points. Tumor-to-muscle ratio reaches ∼4.5 at 24h after administration. CONCLUSION: These findings suggest that 99mTc-lapachol can be a potential diagnostic agent for breast tumors.

18F-FDG small animal PET for early detection of human anaplastic large cells lymphoma xenograft in immunocompromised mice.

The purpose of the present study was to assess if small animal PET is useful for serially monitoring the development of a human anaplastic large cell lymphoma (ALCL) murine xenograft and for the early selection of tumour bearing animals. The human ALCL Karpas 299 cell line was subcutaneously injected in 6-week-old NOD/SCID (non-obese diabetic/NCrCrl- Prkdc) mice (10(7) cells/mouce in 150 pil FBS) at the right flank level. Small animal 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) was serially performed (intravenous injected dose: 20 MBq in < 0.15 ml, uptake time: 60 min, image acquisition: 1 bed position of 15 min): early PET at 2 days after cell inoculation in 4/8 mice and at 4 days in the remainig 4/8, later PET scans were performed in all the animals at 7, 14, 21 and 28 days after inoculation. The images were evaluated visually and the tumour to background ratio (TBR) was used for semiquantitative analysis. Pathology sections were obtained in all cases. PET detected the presence of the tumour as early as seven days after inoculation in 4/8 mice and at 14 days in 2/8. Of the two remaining mice, one died after the first PET scan (thus preventing any evaluation of detection time) while the other showed a microscopic neoplastic infiltration at tracheal level at autopsy. Mean TBR progressively increased in all positive cases, particularly in the first 3 weeks, reaching a plateau afterwards. PET was positive in 6/8 (75%) animals, detecting the presence of viable tumour cells earlier than macroscopic evaluation, thus may be used for the early identification of tumour bearing animals.

The additional diagnostic value of a single-session combined scintigraphic and ultrasonographic examination in patients with thyroid and parathyroid diseases.

AIM: The aim of this study was to investigate the diagnostic efficacy and the clinical impact of scintigraphy combined with ultrasonography (USG) in the management of thyroid and parathyroid disorders in a large series of patients. METHODS: A total of 387 consecutive patients referred to the Nuclear Medicine Department of Hacettepe University in the period from January to September 2007 for investigating a thyroid (N. 339 patients: 232 females and 107 males, mean age+/-SD=48.9+/-13.6 years) or a parathyroid disease (N. 48 patients: 34 females and 14 males, mean age+/-SD=47.4+/-9.6 years) were prospectively evaluated, systematically performing both scintigraphy and USG in a single-day session. All the examinations were independently reviewed by two nuclear medicine physicians; in cases of discrepancy (3%) a final diagnosis was reached by consensus. For thyroid pathologies, USG results were considered to provide additional diagnostic information over scintigraphy: 1) if more nodules were identified; 2) if an irregular hyperactive area at scintigraphy suspicious for the presence of a nodule was clearly characterized at USG; 3) if a nodule missed at scintigraphy because of small size (<1 cm) was well depicted at USG, thus allowing an USG-guided fine needle aspiration cytology (FNAC) to reach a final diagnosis. For parathyroid pathologies, USG was considered to provide additional diagnostic information over scintigraphy if a low intensity radiotracer retention from the parathyroid suspected of being a parathyroid enlargement was clearly depicted at USG. In thyroid diseases, scintigraphy was considered to provide additional diagnostic information over USG, if the functional status of a diffuse or uni- or multi-nodular goiter were clearly defined at scintigraphy. In parathyroid diseases, scintigraphy was considered to provide additional diagnostic information over USG, if the differential diagnosis between a lymph node or a muscle or a vessel depicted at USG was clearly defined as a parathyroid enlargement at scintigraphy. Lastly, the clinical impact of the single-day combined scintigraphic/USG protocol was evaluated. RESULTS: USG. In the thyroid diseases group, USG was particularly useful: 1) to detect additional nodules in glands with suppressed thyroid tissue; 2) to disclose small thyroid nodules (<1 cm) in which it was possible to perform a USG-FNAC. In the parathyroid diseases group, USG was particularly useful for the detection of parathyroid enlargements not visualized at scintigraphy because characterized by a rapid wash-out of the radiotracer and thus by a low radioactivity intensity in the delayed scintigraphic images. Scintigraphy. In the thyroid diseases group, scintigraphy was particularly useful: 1) to diagnose a diffuse hyperfunctioning thyroid gland, and to differentiate in multinodular goiters the hyper- from the hypo-functioning nodules. In the hyperparathyroid diseases group, scintigraphy was particular useful in making a differential diagnosis between a true parathyroid enlargement vs. a lymph node or a muscle or a vessel as depicted at USG, and in cases with deeply or ectopically-positioned parathyroid glands. Combined imaging approach. Combined interpretation provided additional benefit in 225 of 339 patients (64.4%). Overall, using the combined scintigraphic/USG single-day protocol, in the thyroid diseases group the therapeutic strategy (drug therapy vs radioiodine therapy vs surgery) was changed in 176/225 patients (78.2%, P<0.001 by chi(2) of Pearson), and in the parathyroid disease group the therapeutic strategy (medical therapy vs surgery) was changed in 18/48 patients (37.5%, P<0.01 by chi2 test of Pearson). CONCLUSION: In agreement with some previous published experiences, the combined single-day scintigraphic/USG protocol systematically adopted in a large series of consecutive patients with thyroid and parathyroid diseases, enrolled in a limited period of time, proved to significantly increase the global diagnostic accuracy and to change the therapeutic strategy in more than two third of patients with a thyroid disease and in more than one third of patients with a parathyroid disease.

PET imaging in the management of tumors of testis and ovary: current thinking and future directions.

The role of fluoro-D-deoxyglucose positron-emission tomography (FDG-PET) in testicular malignancies has been examined in various studies primarily in three specific settings: 1) differentiation of active disease from fibrosis/mature teratoma in patients with residual mass following chemotherapy and evaluation of the response to treatment; 2) initial staging and disease assessment after orchidectomy identification of suspected recurrences in the context of elevated circulating serum markers; and 3) predicting response to treatment. Of these, the area where FDG-PET imaging has been examined the most in testicular tumors is the evaluation of postchemotherapy residual mass in both seminoma and nonseminomatous germ cell tumors (NSGCT) of the testis, a critical step in determining the subsequent management approach of these tumors that vary amongst various centers. From the available data, this should be the test of choice for the assessment of a computed tomography (CT)-visualized residual mass following chemotherapy. In patients with residual masses or raised marker levels following therapy, positron-emission tomography (PET) appears sensitive and specific for detecting recurrent disease, at suspected and unsuspected sites. Fewer studies are available investigating its usefulness for staging at diagnosis and this requires further investigation to determine its eventual place as an imaging modality in this setting. Its precise role in disease prognostification is yet to be clearly defined in this malignancy but the initial results are promising. With regard to its role in ovarian carcinoma, it appears to be particularly useful for the diagnosis of recurrence when CA125 levels are rising and conventional imaging is inconclusive or negative. The role of fluoro-D-deoxyglucose (FDG)-PET/CT for the detection of recurrent ovarian cancer appears very promising and has the potential to replace the current surveillance techniques in detecting recurrent disease.

Nuclear medicine techniques for radio-guided surgery of hyperparathyroidism.

In recent years there has been a prominent change in surgical trends from extensive approaches to minimally invasive techniques in hyperparathyroidism. In contrast to classical bilateral exploration methods, minimally invasive parathyroidectomy necessitates an adequate preoperative imaging modality, in order to focus exactly the lesion in interest. (99m)Tc-MIBI, as a highly sensitive and widely available radiopharmaceutical, provides high success rates in terms of preoperative parathyroid lesion localization. Besides preoperative imaging, minimally invasive parathyroidectomy also requires an intraoperative modality which can act as a guide to surgeon. Hand-held gamma probes are simply-operated lesion localization devices which serve as successful intraoperative guides to surgeon. (99m)Tc-MIBI based minimal invasive parathyroidectomy has replaced the traditional 4 gland exploration as the procedure of choice in many institutions with comparable cure rates.

Neurological and psychiatric disorders in thyroid dysfunctions. The role of nuclear medicine: SPECT and PET imaging.

Thyroid dysfunctions may be accompanied by numerous neurological and psychiatric disorders. The most known is cognitive impairment and depression in hypothyroid patients, as well as an increased risk of cerebrovascular accidents. A separate, although a rare entity, is Hashimoto's encephalopathy. In hyperthyroidism there is an increased incidence of psychiatric disorders, including apathetic hyperthyroidism and hyperthyroid dementia. Functional imaging of cerebral blood flow and metabolism helped establish both global and/or regional decrease of both cerebral blood flow and metabolism in hypothyroidism, particularly in regions mediating attention, motor speed and visuospatial processing. Hypothyroid dementia may be mediated by neurocircuitry different from that in major depression. Less is known on flow/metabolism changes in hyperthyroidism. Global blood flow may be slightly increased, with regional deficits of blood flow, particular in hyperthyroid dementia. As presented above radionuclide functional imaging showed some metabolic patterns in thyroid dysfunctions, but still many issues remain unresolved. In particular little is known about the underlying pathology of cognitive impairment and depression in hypothyroidism, which may differ from ones in euthyroid patients. Also little is known about the reversibility of changes in cerebral blood flow following thyroid replacement therapy. In hyperthyroid patients functional imaging might contribute to elucidate the background of apathetic hyperthyroidism and potential different background of psychiatric complications.

Scintigraphic imaging of adrenal disease.

The nuclear medicine approach to adrenal imaging spans six decades with radiopharmaceuticals designed to take advantage of the unique characteristics of the functional divisions of the gland, substrate accumulation, hormone biosynthesis, receptor-ligand interactions and pharmacologic manipulation of mechanisms of central control. The recent introduction of hybrid imaging techniques that combine high resolution anatomy with the functional maps derived from the scintigraphic images is yet another step in the evolution of integrated imaging techniques that can be used to diagnostic advantage in the evaluation of disease of the adrenal gland.

Role of PET in medullary thyroid carcinoma.

In the diagnostic assessment of medullary thyroid carcinoma (MTC), nuclear medicine imaging provides its contribution mainly in the postoperative work-up to detect residual or recurrent tumor. With respect to scintigraphy with gamma-emitter radiopharmaceuticals, positron emission tomography (PET) offers interesting perspectives owing to its higher image quality, spatial resolution and speed. Moreover, the recent developments of hybrid machines allow to obtain images that simultaneously hold both anatomic (computed tomography) and functional (PET) information with great impact on diagnostic efficacy. (18)F-fluoro-deoxyglucose ((18)F-FDG) is the most frequently used PET tracer in oncology. Preliminary reports of FDG-PET in MTC patients show encouraging results with a higher sensitivity in detecting local recurrent and metastatic disease when compared with single photon emission tracers. However, (18)F-FDG uptake depends on lesion size and to some extent on the grade of differentiation and biologic aggressiveness of the tumor; so FDG-PET seems useful mainly in patients with very high calcitonin levels and high progression rate. Like other neuroendocrine tumors, MTC is characterized by the presence of amine uptake mechanism and/or peptide receptors at the cell membrane allowing the clinical use of specific radiopharmaceuticals that reflect the different metabolic pathways of MTC, and in particular the synthesis, storage and release of hormones ((18)F-dihydroxyphenilalanine, (18)F-DOPA and (18)F-fluorodopamine, (18)F-FDA) and the expression of receptors ((68)Ga-labeled somatostatin analogs). These tracers are currently under investigation and will further improve the diagnostic approach of MTC.

Anaplastic thyroid cancer: prevalence, diagnosis and treatment.

UNLABELLED: Anaplastic thyroid cancer (ATC) is a rare aggressive tumor arising from the follicular cells of the thyroid gland (as does well differentiated thyroid cancer, WDTC), but ATC cells do not retain any of the biological features of the original follicular cells, such as uptake of iodine and synthesis of thyroglobulin. Prognosis is almost invariably fatal. In this article the Authors review the pathology, epidemiology, clinical presentation, diagnosis and treatment options of ATC. ATC incidence typically peaks at the 6-7th decade of life (mean age at diagnosis 55-65 years), women representing 55-77% of all patients. ATC represents 2-5% of all thyroid tumors, with a decreasing trend with respect to the incidence of WDTC. The histologic patterns of ATC include giant-cell, spindle-cell and squamoid-cell tumors; these subtypes frequently coexist and are not predictive of patients' outcome. Immuno-cyto-chemistry for thyroglobulin is usually negative or weakly positive and some cases are also negative for keratin, particularly in the spindle-cell areas. ATC may arise de novo, but in most cases it develops from a pre-existing WDTC, especially the follicular subtype. Most ATC patients complain of local compressive symptoms, such as dysphagia, dysphonia, stridor and dyspnea in addition to neck pain and tenderness; in over 70% of the patients the tumor infiltrates surrounding tissues, such as fat, trachea, muscle, esophagus, and larynx. The clinical course of a rapidly enlarging mass that is firm and fixed to surrounding structures in an elderly patient is quite suggestive for ATC. Diagnosis can be confirmed by fine needle aspiration cytology or, in doubtful cases, by histology on core biopsy. Computed tomography (CT) scan and magnetic resonance imaging (MRI) are useful for defining the local extent of disease and for identifying distant metastases, as is also positron-emission tomography (PET) with [(18)F]FDG. Tracheoscopy and esophagoscopy should be performed every two months, or whenever patients refer the appearance or worsening of local symptoms. Bone scintigraphy may be included in the follow-up of patients with a longer survival and relatively good health. Because of its aggressive behavior, the latest American Joint Committee on Cancer Staging Manual classifies all ATCs as T4 and Stage IV tumors, regardless of their actual overall tumor burden. Treatment of ATC has not been standardized because it is not clear whether or not therapy is effective in prolonging survival; most patients die within six momths from diagnosis, primarily because of asphyxiation caused by local tumor invasion. When employed alone, surgery, radiotherapy, or chemotherapy are seldom adequate to achieve overall control of the disease, but a combination of these treatments may improve local control. Surgical treatment of local disease offers the best opportunity for prolonged survival if the tumor is intrathyroidal. When the tumor is extrathyroidal, the surgical approach to ATC is controversial. Some favourable results have recently been reported with newly developed chemotherapy agents and hyper-fractioned radiation therapy. Tracheostomy should be performed in patients with impending airway obstruction when death is not imminent from other sites of disease, and if patients are not candidates for local resection or chemoradiation. Interventional bronchoscopy, including Nd-YAG laser and airways stenting are alternatives to surgery in inoperable ATC-induced tracheal obstruction. Gene therapy is under investigation. Although very rare, ATC is a highly aggressive tumor that belongs to the group of killer tumors with median survival time not longer than 6-8 months. Surgery, chemotherapy and radiotherapy are the conventional therapeutic strategies performed in the attempt to improve survival. Unfortunately, very often they do not succeed any clinical benefit but only palliative RESULTS: New therapeutic strategies based on molecular approaches are desirable.

PET imaging in neuroendocrine tumors: current status and future prospects.

Neuroendocrine tumors (NET) are relatively rare diverse group of tumors that possess several unique characteristics and occur most commonly in the gastrointestinal tract. An important feature of these tumors is that they express somatostatin (SST) receptors, and thus can be successfully targeted with specific radiolabeled SST receptor related compounds. This has led to the introduction of multitude of single photon emission computed tomography (SPECT) and positron emission tomography (PET) tracers, which have significantly improved the ability for imaging these neoplastic lesions with high spatial resolution in the abdomen and elsewhere in the body. The introduction of Gallium-68 labeled radiopharmaceuticals as viable PET agents have added a new dimension to the management of patients with NET by providing high quality images compared with planar or SPECT with single photon emitting preparations. (18)F-labeled DOPA has demonstrated impressive results in differentiating between focal and diffuse disease in hyperinsulinism of the newborn which appears to be of crucial clinical benefit and has altered the management of these patients significantly. With regard to other types of NET, the current experience with such agents is relatively limited and therefore prospective studies are required to further define the role of PET in this complicated group of patients.