[18F]FDG-PET/CT and long-term responses to everolimus in advanced neuroendocrine neoplasia.

PURPOSE: This study aims to identify in patients with neuroendocrine neoplasia (NEN) the potential correlation between FDG-PET findings and responses to everolimus therapy to identify predictors of long-term efficacy. METHODS: Retrospective analysis of patients with sporadic, advanced, progressive NEN treated with everolimus was performed based on the available data on FDG-PET patients obtained before commencing therapy. Data are expressed as the median (25-75th IQR). Risk factor analysis and survival analysis were performed by logistic regression and Cox proportional hazard regression and the determination of Kaplan-Meier curves, as appropriate. RESULTS: Sixty-six patients were evaluated (NET G1 19.7%, NET G2 75.7%, and NET G3 4.6%), including 45.4% with positive FDG-PET findings. Overall, disease stabilization and a partial response were achieved for 71.2% and 6% of patients, respectively. A long-term response (> 24 months) was observed in 33% of patients. Ki67 was the only predictor of tumor progression (p = 0.03). No significant difference in clinical outcomes was observed between patients with positive or negative FDG-PET findings (median PFS was 24 months and 18 months, respectively, p = 0.337; the disease control rate was 83.3% and 70%, respectively, p = 0.245). CONCLUSIONS: Everolimus is a valid therapeutic option for advanced, progressive, well-differentiated NEN, even in patients with positive FDG-PET findings.

A computational fluid dynamics analysis of the effects of size and shape of anterior nasal septal perforations.

BACKGROUND: Nasal septal perforations (NSPs) often cause bleeding, crusting, obstruction, and/or whistling. The objective was to analyze the impact of anterior NSP size and shape on nasal physiology using computational fluid dynamics (CFD). METHODS: A 3-dimensional model of the nasal cavity was constructed from a radiologically normal CT scan using imaging software. Anterior NSPs (ovoid (ONSP): 0.5, 1, 2, and 3 cm long anterior-to-posteriorly and round (RNSP, 0.5 and 1 cm)) were virtually created in the model and divided into ventral, dorsal, anterior, and posterior regions. Steady-state inspiratory airflow, heat, and water vapor transport were simulated using Fluent CFD software. Air crossover through the perforation, wall shear, heat flux, water vapor flux, resistance, and humidification were analyzed. RESULTS: Air crossover and wall shear increased with perforation size. Regionally, wall shear and heat and water vapor flux were highest posteriorly and lowest anteriorly, generally increasing with size in those regions. RNSPs had greater heat and water vapor flux compared to corresponding size ONSPs. Resistance decreased by 10% or more from normal only in the 3 cm ONSP. Maximum water content was achieved more posteriorly in larger NSP nasal cavities. CONCLUSIONS: High wall shear and heat and water vapor flux in posterior perforation regions may explain the crusting most commonly noted on posterior NSP edges. This preliminary study suggests that larger NSPs have a greater effect on nasal resistance and water content. Decrease in resistance with larger NSP size may be implicated in reported symptomatic improvement following enlargement of NSPs for treatment.

Clinical indications, image acquisition and data interpretation for white blood cells and anti-granulocyte monoclonal antibody scintigraphy: an EANM procedural guideline.

INTRODUCTION: Radiolabelled autologous white blood cells (WBC) scintigraphy is being standardized all over the world to ensure high quality, specificity and reproducibility. Similarly, in many European countries radiolabelled anti-granulocyte antibodies (anti-G-mAb) are used instead of WBC with high diagnostic accuracy. The EANM Inflammation & Infection Committee is deeply involved in this process of standardization as a primary goal of the group. AIM: The main aim of this guideline is to support and promote good clinical practice despite the complex environment of a national health care system with its ethical, economic and legal aspects that must also be taken into consideration. METHOD: After the standardization of the WBC labelling procedure (already published), a group of experts from the EANM Infection & Inflammation Committee developed and validated these guidelines based on published evidences. RESULTS: Here we describe image acquisition protocols, image display procedures and image analyses as well as image interpretation criteria for the use of radiolabelled WBC and monoclonal antigranulocyte antibodies. Clinical application for WBC and anti-G-mAb scintigraphy is also described. CONCLUSIONS: These guidelines should be applied by all nuclear medicine centers in favor of a highly reproducible standardized practice.

Radiolabelled white blood cell scintigraphy in the work-up of dermal filler complications.

PURPOSE: Scintigraphy with radiolabelled autologous white blood cells (WBC) is a widely used method for the detection of sites of infection. In this study we evaluated the role of WBC scintigraphy in the diagnosis and follow-up of patients with suspected soft tissue infection caused by dermal fillers in the face. We compared several qualitative and quantitative interpretation criteria and the results obtained with MRI and high-frequency US (HFUS). METHODS: Between 2007 and 2011, ten consecutive patients (all women) aged between 25 and 65 years showing a reaction to dermal fillers were enrolled in the study. In five of these patients WBC scintigraphy was repeated at the end of therapy. Scintigraphy with (99m)Tc-HMPAO-labelled WBC was performed in each patient acquiring planar and SPECT images at 3 h and 20 h as well as HFUS with Doppler analysis and MRI with Gd-DTPA. The final diagnosis was determined by fine-needle aspiration and microbiological analysis of lesions in eight patients (before therapy in six and after therapy in two) and by clinical data and follow-up (at least 1 year) in seven patients (before therapy in four and after therapy in three). Two patients were treated with steroids, and the others were treated with antibiotics for 3 weeks. Several qualitative and semiquantitative interpretation criteria were applied to define the best strategy for accurate diagnosis of infections, implemented by SPECT images in patients with doubtful planar scans. The WBC scintigraphy results were also compared with the MRI and HFUS results. RESULTS: Sensitivity, specificity and accuracy were respectively 90 %, 100 % and 93.3 % for WBC scintigraphy with qualitative and semiquantitative interpretation of planar images and 100 %, 100 % and 100 % with qualitative analysis of SPECT images. Sensitivity, specificity and accuracy for HFUS were 44 %, 66 % and 50 %, and for MRI were 50 %, 100 % and 67.6 %, respectively. Scans performed after therapy in five patients were negative in three and still positive in two (all true results). CONCLUSION: In conclusion, scintigraphy with radiolabelled WBC was found to be the most accurate method for diagnosing infection in patients with long-term dermal filler complications, particularly using qualitative analysis of SPECT images. No differences were observed with planar images using either qualitative or semiquantitative analysis. HFUS and MRI may provide additional important information for defining the nature of the filler and for surgery, but are not accurate enough for diagnosing infection.

High sensitive thyroglobulin assay on thyroxine therapy: can it avoid stimulation test in low and high risk differentiated thyroid carcinoma patients?

Thyroglobulin (Tg) is a key marker in the follow-up of differentiated thyroid cancer (DTC). Diagnostic accuracy of serum Tg is higher after TSH stimulation than during thyroxine treatment. However, some studies suggest that TSH stimulation could be not necessary in a large part of patients, if Tg is measured by high sensitive assay under replacement therapy. The aim of this study was to evaluate the need of Tg stimulation test in DTC followed-up by sensitive Tg assay. In a prospective multicenter explorative study, 68 low or high risk patients underwent Tg measurement on thyroxine (ON-LT4-Tg) and after LT4 withdrawal (OFF-LT4-Tg). Undetectable ON-LT4-Tg and OFF-LT4-Tg values (i. e.,<0.15 ng/ml) were found in 56/68 patients, all with negative imaging workup. Twelve subjects had skewed OFF-LT4-Tg: 8 cases had increased ON-LT4-Tg and local recurrence (n=6), distant metastasis (n=1), or benign thyroglossal duct (n=1); the remaining 4 patients had undetectable ON-T4-Tg but detectable OFF-LT4-Tg and neck metastasis was recorded in one of these. By ROC analysis, the most accurate cutoff for ON-LT4-Tg and OFF-LT4-Tg were set at 0.23 ng/ml and 0.70 ng/ml, respectively. A positive ON-LT4-Tg value accurately predicts a positive stimulation test and confers an Odds Ratio of 464 (95% CI from 26.3 to 8 173.2, p<0.0001) to have persistent/recurrent disease. This study shows that DTC patients with ON-LT4-Tg below 0.23 ng/ml by our high sensitive assay should be considered disease free and they can avoid Tg stimulation test. High sensitive Tg assays should be used to better manage DTC patients.

Role of scintigraphy with 99mTc-infliximab in predicting the response of intraarticular infliximab treatment in patients with refractory monoarthritis.

PURPOSE: The rationale for the present study was to evaluate the predictive role of (99m)Tc-infliximab scintigraphy in therapy decision-making in patients with refractory monoarthritis and also candidates for intraarticular (IA) infliximab treatment. METHODS: We studied 12 patients (5 with rheumatoid arthritis and 7 with spondyloarthropathy) with active monoarthritis (11 knees and 1 ankle) that had lasted for at least 3 months. Patients were evaluated clinically and ultrasonographically at baseline and 12 weeks after IA administration of infliximab. At the same time-points, (99m)Tc-infliximab scintigraphy was performed: planar anterior and posterior images of arthritic joints were acquired at 6 and 20 h after injection and target-to-background (T/B) ratios were calculated. RESULTS: After treatment, a significant improvement in clinical and ultrasonographic parameters was recorded in six patients. Three patients had a partial response and three did not respond. Regarding scintigraphic evaluation, the T/B ratio analysis showed a significantly higher uptake in affected than in nonaffected joints before therapy (1.78 ± 0.46 vs. 1.29 ± 0.27, p = 0.006 at 6 h; 2.05 ± 0.50 vs. 1.41 ± 0.36 at 20 h, p = 0.002), and mean uptake at 20 h was also significantly higher than at 6 h (p = 0.0004). Scintigraphy showed a significant decrease in posttherapy T/B ratios of the affected joints (p = 0.0001 at 6 h and p = 0.0001 at 20 h), indicating a reduction in TNF into the affected joints. Most importantly, responders showed a significantly higher percentage increase in pretherapy uptake from 6 h to 20 h in the affected joints than nonresponders (p = 0.00001). CONCLUSION: The results of the present investigation suggest that (99m)Tc-infliximab scintigraphy could be a useful tool to predict the clinical response to IA infliximab treatment in patients with refractory monoarthritis.

Lingual frenectomy: functional evaluation and new therapeutical approach.

AIM: When ankyloglossia is relatively severe and generates mechanical limitations and functional challenges, surgical reduction of the frenum is indicated. MATERIALS AND METHODS: Laser technique is an innovative, safe and effective therapy for frenectomy in both children and adolescents. Erbium:YAG laser (2940nm) can be useful for paediatric dentist: 1.5W at 20pps is a commonly used average power to easily, safely and quickly cut the frenum. RESULTS: Usually after laser frenectomy, the postoperative symptoms and relapse are absent. CONCLUSION: Early intervention is advisable to reduce the onset of alterations correlated to the ankyloglossia. A multidisciplinary approach to the problem is advisable, in collaboration with orthodontist, physiotherapist and speech therapist, to better resolve the problem.

Molecular imaging of rheumatoid arthritis by radiolabelled monoclonal antibodies: new imaging strategies to guide molecular therapies.

The closing of the last century opened a wide variety of approaches for inflammation imaging and treatment of patients with rheumatoid arthritis (RA). The introduction of biological therapies for the management of RA started a revolution in the therapeutic armamentarium with the development of several novel monoclonal antibodies (mAbs), which can be murine, chimeric, humanised and fully human antibodies. Monoclonal antibodies specifically bind to their target, which could be adhesion molecules, activation markers, antigens or receptors, to interfere with specific inflammation pathways at the molecular level, leading to immune-modulation of the underlying pathogenic process. These new generation of mAbs can also be radiolabelled by using direct or indirect method, with a variety of nuclides, depending upon the specific diagnostic application. For studying rheumatoid arthritis patients, several monoclonal antibodies and their fragments, including anti-TNF-alpha, anti-CD20, anti-CD3, anti-CD4 and anti-E-selectin antibody, have been radiolabelled mainly with (99m)Tc or (111)In. Scintigraphy with these radiolabelled antibodies may offer an exciting possibility for the study of RA patients and holds two types of information: (1) it allows better staging of the disease and diagnosis of the state of activity by early detection of inflamed joints that might be difficult to assess; (2) it might provide a possibility to perform 'evidence-based biological therapy' of arthritis with a view to assessing whether an antibody will localise in an inflamed joint before using the same unlabelled antibody therapeutically. This might prove particularly important for the selection of patients to be treated since biological therapies can be associated with severe side-effects and are considerably expensive. This article reviews the use of radiolabelled mAbs in the study of RA with particular emphasis on the use of different radiolabelled monoclonal antibodies for therapy decision-making and follow-up.

Peptide receptor therapies in neuroendocrine tumors.

Neuroendocrine tumors (NETs) are relatively rare tumors, mainly originating from the digestive system, able to produce bioactive amines and hormones. NETs tend to be slow growing and are often diagnosed when metastatic. The localization of a NETs and the assessment of the extent of disease are crucial for management. Commonly used diagnostic techniques include morphological imaging (ultrasound, computerized tomography, magnetic resonance), and functional imaging (somatostatin receptor scintigraphy, positron emission tomography techniques). Treatment is multidisciplinary and should be individualized according to the tumor type, burden, and symptoms. Therapeutic tools include surgery, interventional radiology, and medical treatments such as somatostatin analogues, interferon, chemotherapy, new targeted drugs and peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues. NETs usually over-express somatostatin receptors, thus enabling the therapeutic use of somatostatin analogues, one of the basic tools, able to reduce signs and symptoms of hormone hypersecretion, improve quality of life, and slow tumor growth. PRRT with somatostatin analogues 90Y-DOTATOC and 177Lu-DOTATATE has been explored in NETs for more than a decade. Present knowledge and clinical studies indicate that it is possible to deliver high-absorbed doses to tumors expressing sst2 receptors, with partial and complete objective responses in up to 30% of patients. Side effects, involving the kidney and the bone marrow, are mild if adequate renal protection is used. Moreover, a consistent survival benefit is reported. As NETs may also express cholecystokinin 2, bombesin, neuropeptide Y or vasoactive intestinal peptide receptors even simultaneously, the potential availability and biological stability of radio-analogues will improve the multireceptor targeting of NETs.

Labelling and Clinical Performance of Human Leukocytes Labelled with 99mTc-HMPAO Using Leukokit® with Gelofusine versus Leukokit® with HES as Sedimentation Agent.

The scintigraphy with radiolabelled autologous leukocytes (WBCs) is considered the gold-standard technique for imaging infections. Leukokit® is a commercially available, disposable, sterile kit for labelling WBCs ex vivo. In this kit, WBCs isolation from red blood cells (RBCs) was performed using poly(O-2-hydroxyethyl)starch (HES) as the RBCs sedimentation agent. Due to its poor availability, HES has been recently replaced by Gelofusine as the RBC sedimentation agent. The aim of this study was to compare the labelling efficiency and the diagnostic accuracy of WBCs labelled with Leukokit® with HES vs Leukokit® with Gelofusine. WBCs were isolated using HES or Gelofusine for 45 minutes and then purified from platelets (PLTs) and labelled with 1.1 ± 0.3 GBq of freshly prepared 99mTc-HMPAO. The following parameters were evaluated: the number and type of recovered WBCs, RBCs contamination, PLTs contamination, vitality of neutrophils, and chemotactic properties of neutrophils. Clinical comparison was performed between 80 patients (33 males; age 67.5 ± 14.2) injected with 99mTc-HMPAO-WBCs, using HES as the sedimentation agent, and 92 patients (38 males; age 68.2 ± 12.8) injected with 99mTc-HMPAO-WBCs using Gelofusine as the sedimentation agent. Patients were affected by prosthetic joint infections, peripheral bone osteomyelitis, or vascular graft infection. We compared radiolabelling efficiency (LE), final recovery yield (RY), and diagnostic outcome based on microbiology or 2-year follow-up. Results showed that HES provides the lowest RBCs and PLTs contamination, but Gelofusine provides the highest WBC recovery. Both agents did not influence the chemotactic properties of WBCs, and no differences were found in terms of LE and RY. Sensitivity, specificity, and accuracy were also not significantly different for WBCs labelled with both agents (diagnostic accuracy 90.9%, CI = 74.9-96.1 vs 98.3%, CI = 90.8-100, for HES and Gelofusine, respectively). In conclusion, Gelofusine can be considered a suitable alternative of HES for WBCs separation and labelling.

99mTc-interleukin-2 scintigraphy in normal subjects and in patients with autoimmune thyroid diseases: a feasibility study.

PURPOSE: Radiolabelled interleukin-2 is a radiopharmaceutical used for the study of chronic inflammatory processes. (123)I-labelled interleukin-2 has successfully been used in a large number of patients affected by several immune-mediated diseases. (123)I, however, is expensive and not readily available. We have, therefore, developed a method for labelling interleukin-2 with (99m)Tc to high specific activity based on the use of an N(3)S bifunctional chelating agent. In this paper, we describe the results obtained with (99m)Tc-interleukin-2 in a series of eight normal subjects and of 12 patients with autoimmune thyroid diseases. METHODS: Biodistribution, pharmacokinetics, haematological and systemic toxicity, radiation absorbed dose and in vivo targeting were studied. RESULTS: Results showed rapid plasma clearance of (99m)Tc-interleukin-2 with retention mainly in the kidneys. Biodistribution and kinetics were similar to that observed for (123)I-interleukin-2. No acute systemic toxicity was found; a small decrease in peripheral blood lymphocytes was observed in the first hours only in patients, but it was mild and transient. (99m)Tc-interleukin-2 accumulated, to varying extents, in the thyroid of all patients affected by autoimmune thyroid diseases but not in the thyroid of normal subjects. The effective dose equivalent of a diagnostic activity of (99m)Tc-interleukin-2 (185 MBq) was 1.35 mSv. No correlation was observed between thyroid autoantibodies and uptake of (99m)Tc-interleukin-2. CONCLUSIONS: The use of (99m)Tc-interleukin-2 is safe and simple; the favourable dosimetry and biodistribution and the rapid clearance make it potentially useful for the study of chronic inflammatory diseases such as autoimmune thyroid disease.

Relevance of 99mTc-HYNIC-tir-octreotide scintigraphy in a patient affected by sarcoidosis with lung and joints involvement and secondary Sjogren's syndrome treated with infliximab: case report.

We report the case of a 59 years old woman affected by lung and joint sarcoidosis, secondary Sjogren's syndrome refractory to common disease-modifying antirheumatic drugs (DMARDs) that regressed with infliximab and methotrexate. 99mTc-HYNIC-TOC scintigraphy was useful in diagnosis, choice of treatment and follow-up.

Study of Binding Kinetics and Specificity of 99mTc-SSS-Complex and 99mTc-HMPAO to Blood Cells.

Nuclear medicine offers several techniques and procedures to image infection, but radiolabelled autologous white blood cells (WBCs) are still the gold standard. These cells are usually labelled with 111In or 99mTc bound to a hydrophobic chelating agent that allows these isotopes to pass through the plasma membrane and enter in the cytoplasm. The most common compound in Europe is HMPAO that efficiently chelates 99mTc. However, up to 20-40% of the complex is released from the cells in the first few hours. The aim of this study was to radiolabel a new compound, (S3CPh)2 (S2CPh)-complex (SSS-complex) with 99mTc and compare its binding kinetics and specificity for WBC with HMPAO. The SSS-complex was labelled with 99mTc and analysed by iTLC and RP-HPLC. In vitro quality controls included a stability assay in serum and saline. Results showed a labelling efficiency of 95 ± 1.2% and 98 ± 1.4% for 99mTc-SSS-complex and 99mTc-HMPAO, respectively (p=ns). 99mTc-SSS-complex was stable in serum and in saline up to 24 h (94 ± 0.1%). Cell labelling experiments showed a higher incorporation of 99mTc-SSS-complex than 99mTc-HMPAO by granulocytes (62.6 ± 17.8% vs 40.5 ± 15%, p=0.05), lymphocytes (59.9 ± 22.2% vs 29.4 ± 13.5%; p=0.03), and platelets (44.4 ± 24% vs 20.5 ± 10.7%; p=ns), but the release of radiopharmaceutical from granulocytes at 1 h was lower for HMPAO than for SSS-complex (10.3 ± 1.9% vs 21.3 ± 1.8%; p=0.001). In conclusion, 99mTc-SSS-complex, although showing high labelling efficiency, radiochemical purity, and stability, is not a valid alternative to 99mTc-HMPAO, for example, in vivo white blood cells labelling because of high lymphocyte and platelet uptake and rapid washout from granulocytes.

Somatostatin receptor scintigraphy in patients with rheumatoid arthritis and secondary Sjögren's syndrome treated with Infliximab: a pilot study.

BACKGROUND: Human T lymphocytes infiltrating tissues in autoimmune diseases are known to express somatostatin receptors amongst other activation markers. In this study, we evaluated whether somatostatin receptor scintigraphy (SRS) using a radiolabelled somatostatin analogue ((99m)Tc-EDDA/tricine-HYNIC-tyr(3)-octreotide ((99m)Tc-EDDA/HYNIC-TOC)) is able to detect the presence of immune-mediated processes in patients with rheumatoid arthritis and secondary Sjögren's syndrome. We also aimed to evaluate whether positivity to SRS was predictive of therapeutic response and if SRS could be used for monitoring the efficacy of immunomodulatory treatment. METHODS: Eighteen patients with rheumatoid arthritis and secondary Sjögren's syndrome not responding to conventional treatment were recruited for treatment with infliximab, a monoclonal antibody against TNF-α. All patients had complete blood cell count, renal and liver function tests, measurements of ESR, CRP, ANA, ENA, and anti-dsDNA antibodies, functional salivary gland scintigraphy, labial biopsy, and ophthalmologic assessment with Schirmer's test and tear film break-up time (BUT). Diagnosis was made according to the revised criteria of the American-European Consensus Group. All patients underwent SRS at baseline and after 3-6 months of therapy with infliximab. Eleven out of 18 had repeat SRS images. Images of the salivary glands and major joints were acquired 3 h after injection of 370 MBq of (99m)Tc-EDDA/HYNIC-TOC. Image analysis was performed semi-quantitatively. RESULTS: All patients showed uptake of (99m)Tc-EDDA/HYNIC-TOC in the joints. Salivary glands also showed variable radiopharmaceutical uptake in 12 out of 18 patients, but all patients showed presence of lymphocytic infiltration at labial salivary gland biopsy. All patients, who repeated the study after treatment, showed significant reduction of somatostatin uptake in the joints but not in the salivary glands. CONCLUSIONS: SRS using (99m)Tc-EDDA/HYNIC-TOC may be a useful imaging tool to assess disease activity and extent in patients with rheumatoid arthritis and may help to detect secondary Sjögren's syndrome. It may also aid therapy decision-making with anti-TNFα antibodies in the joints but not in salivary glands.

Combined PET/MRI: from Status Quo to Status Go. Summary Report of the Fifth International Workshop on PET/MR Imaging; February 15-19, 2016; Tübingen, Germany.

This article provides a collaborative perspective of the discussions and conclusions from the fifth international workshop of combined positron emission tomorgraphy (PET)/magnetic resonance imaging (MRI) that was held in Tübingen, Germany, from February 15 to 19, 2016. Specifically, we summarise the second part of the workshop made up of invited presentations from active researchers in the field of PET/MRI and associated fields augmented by round table discussions and dialogue boards with specific topics. This year, this included practical advice as to possible approaches to moving PET/MRI into clinical routine, the use of PET/MRI in brain receptor imaging, in assessing cardiovascular diseases, cancer, infection, and inflammatory diseases. To address perceived challenges still remaining to innovatively integrate PET and MRI system technologies, a dedicated round table session brought together key representatives from industry and academia who were engaged with either the conceptualisation or early adoption of hybrid PET/MRI systems. Discussions during the workshop highlighted that emerging unique applications of PET/MRI such as the ability to provide multi-parametric quantitative and visual information which will enable not only overall disease detection but also disease characterisation would eventually be regarded as compelling arguments for the adoption of PET/MR. However, as indicated by previous workshops, evidence in favour of this observation is only growing slowly, mainly due to the ongoing inability to pool data cohorts from independent trials as well as different systems and sites. The participants emphasised that moving from status quo to status go entails the need to adopt standardised imaging procedures and the readiness to act together prospectively across multiple PET/MRI sites and vendors.

Combination of nicotinamide and steroid versus nicotinamide in recent-onset IDDM. The IMDIAB II Study.

OBJECTIVE: The aim of this study was to compare the effect of nicotinamide (NCT) alone or in combination with a cortisone-like substance, deflazacort (DFL), on the integrated parameters of metabolic control in patients with the recent-onset of insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: Thirty-six patients who were diagnosed with diabetes between 5 and 35 years of age entered a randomized, double-blind, 1-year prospective study. Group A (n = 18) received NCT for 1 year (25 mg.kg-1.day-1) plus DFL for 3 months (0.6 mg.kg-1.day-1 in the first month, 0.3 mg.kg-1.day-1 in the other 2 months). Group B (n = 18) received NCT for 1 year (25 mg.kg-1.day-1) plus placebo for the first 3 months. All patients were treated with intensified insulin therapy. RESULTS: At 3 months after diagnosis, the insulin dose was significantly higher in group A compared with group B (P < 0.03) with similar HbA1 levels. Basal and stimulated C-peptide levels in group A of both adults and children were significantly higher compared with patients of group B (P < 0.05 and P < 0.03, respectively). At the end of a 1-year follow-up, basal C-peptide did not differ between the two groups, although stimulated C-peptide was still significantly higher in patients of group A compared with group B (P < 0.05). Finally, insulin requirement did not differ between the two groups. CONCLUSIONS: A short-term course of DFL therapy at diagnosis in addition to NCT slightly increases glucagon-stimulated but not basal beta-cell function after 1 year.

New approaches to image thyroid cancer cells and microenvironment.

Poorly differentiated thyroid cancer (PDTC) and undifferentiated thyroid cancer (UDTC) are still life-threatening pathologies, because of the lack of well-established diagnostic and therapeutic approaches. In the past, many attempts have been made to develop radiopharmaceutical to diagnose or treat radioactive iodine (RAI)-refractory metastases or recurrences, with limited results. Indeed, it was not possible to find a specific and overexpressed marker to be used as target of radiopharmaceuticals or targeted therapies. Nowadays, with novel advances in the field of tumor microenvironment, many new markers are available to be used as suitable targets for targeted therapies interfering with signalling pathways of cells involved in the mechanisms that favour tumor growth and metastatization. This opened new perspective in the use of radiopharmaceuticals targeting components of tumor microenvironment for early diagnosis, pre-operative staging or therapy planning and follow up with targeted drugs. In the present review we present the state of novel approaches to image thyroid cancer and its microenvironment, focusing on RAI-refractory thyroid cancer as a real clinical problem to be solved.

Current status of PET imaging of differentiated thyroid cancer with second generation radiopharmaceuticals.

Although the prognosis of differentiated thyroid cancer (DTC) is favorable, some histotypes show worst clinical outcome and higher risk of recurrence. Serum thyroglobulin (Tg) levels and 131I-whole-body-scan (WBS), together with neck ultrasound (US), represent the golden standard for DTC follow-up. Nevertheless, the relatively high frequency of patients with high Tg levels and negative WBS requires further investigations by using new imaging modalities. The availability of whole body positron emission tomography (PET) methods, in parallel with the advances in radiochemistry, offer a wide substrate for many solutions. To this day ¹8F-fluoro-deoxy-glucose (¹8F-FDG) PET/CT still represents the imaging of choice in follow-up of patients with high serum Tg and negative ¹³¹I-WBS but in the last decades the research has focused on finding "second generation" radiopharmaceuticals for PET imaging, with both diagnostic and prognostic purposes, aiming to change the way to image thyroid cancer. Moreover, the use of various PET radiopharmaceuticals, that offer the possibility to explore different pathways involved in thyroid cancer, could find important applications in the near future for clinical decision making in order to program tailored treatments and follow-up. It would be desirable to use the same radiopharmaceutical for both imaging and dosimetric purpose to achieve a tailored therapy. Many efforts are focused in this direction and ¹²4I-PET/CT is now emerging as a valid tool in restaging and therapy management of DTC with promising results. Although the preliminary data available in literature require a confirmation in larger studies with longer follow-up, we think that in next future ¹²4I-PET/CT could gain an important role for management of DTC. The aim of this review was to perform a systematic analysis of literature describing the state of art of "second generation" PET-radiopharmaceuticals for imaging DTC. Discussion is focused on the utility of ¹²4I-PET/CT, but we also mention the pathways explored by 68Gallium-somatostatin analogues, ¹8F-FLT and ¹¹C-MET and their applications in this clinical setting.

Preparation and biodistribution of 99m technetium labelled oxidized LDL in man.

Radiolabelled autologous low density lipoprotein (LDL) has previously been used to study in vivo distribution and metabolism of native-LDL. Non-invasive imaging of atherosclerotic lesions using 99mTc-LDL was shown to be feasible in animal models and patients but the clinical utility remains to be assessed. Since recent reports suggest that oxidized LDL may play a major role in the pathogenesis of atherosclerosis, we developed a technique to oxidize autologous LDL and compared the biodistribution of oxidized-LDL with that of native-LDL in man. In addition, we evaluated the uptake in vivo of oxidized- and native-LDL by atherosclerotic plaques. LDL, obtained from human plasma was treated with various combinations of copper ions and H2O2 to induce oxidative modification by increasing the content of lipid peroxidation products and electrophoretic mobility. When LDL (0.3 mg/ml) was incubated with 100 microM Cu2+ and 500 microM H2O2 oxidation occurred rapidly within 1 h, and was labelled with 99mTc efficiently as native LDL. In vivo distribution studies revealed a faster plasma clearance of oxidized-LDL compared to native-LDL, and a higher uptake by the reticuloendothelial system. Tomographic scintigraphy of the neck in patients suffering from transient ischemic attacks, revealed accumulation of radiolabelled LDL preparations in the carotid artery affected by atherosclerotic lesions. We developed a technique to rapidly oxidize LDL using copper and H2O2. Biodistribution data demonstrate that oxidized-LDL is rapidly cleared from circulation, is taken up mostly by organs rich in macrophages, and can be detected at the level of carotid plaques.