The Future of Molecular Radiotherapy Services in the UK.

The delivery of molecular radiotherapy has, except for the use of I-131 in differentiated thyroid cancer, been somewhat haphazard. The provision of other molecular radiotherapy services has depended on the enthusiasm of individuals who have driven the development of services locally, but this has meant that provision within the UK is uneven. In addition, molecular radiotherapy to an increasing degree cannot be practised without theragnostics and is linked to high-quality molecular imaging based on a holistic physiological model not a systems-based anatomical model. The proposal to set up radiotherapy networks in England provides a logical framework for the development of a comprehensive molecular radiotherapy service with further services planned for Scotland, Wales and Northern Ireland. The development of these networked molecular radiotherapy hubs should allow both provision of present services and the ability to introduce new molecular radiotherapy techniques as they become available.

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.

Prospective study evaluating the relative sensitivity of 18F-NaF PET/CT for detecting skeletal metastases from renal cell carcinoma in comparison to multidetector CT and 99mTc-MDP bone scintigraphy, using an adaptive trial design.

BACKGROUND: The detection of occult bone metastases is a key factor in determining the management of patients with renal cell carcinoma (RCC), especially when curative surgery is considered. This prospective study assessed the sensitivity of (18)F-labelled sodium fluoride in conjunction with positron emission tomography/computed tomography ((18)F-NaF PET/CT) for detecting RCC bone metastases, compared with conventional imaging by bone scintigraphy or CT. PATIENTS AND METHODS: An adaptive two-stage trial design was utilized, which was stopped after the first stage due to statistical efficacy. Ten patients with stage IV RCC and bone metastases were imaged with (18)F-NaF PET/CT and (99m)Tc-labelled methylene diphosphonate ((99m)Tc-MDP) bone scintigraphy including pelvic single photon emission computed tomography (SPECT). Images were reported independently by experienced radiologists and nuclear medicine physicians using a 5-point scoring system. RESULTS: Seventy-seven lesions were diagnosed as malignant: 100% were identified by (18)F-NaF PET/CT, 46% by CT and 29% by bone scintigraphy/SPECT. Standard-of-care imaging with CT and bone scintigraphy identified 65% of the metastases reported by (18)F-NaF PET/CT. On an individual patient basis, (18)F-NaF PET/CT detected more RCC metastases than (99m)Tc-MDP bone scintigraphy/SPECT or CT alone (P = 0.007). The metabolic volumes, mean and maximum standardized uptake values (SUV mean and SUV max) of the malignant lesions were significantly greater than those of the benign lesions (P < 0.001). CONCLUSIONS: (18)F-NaF PET/CT is significantly more sensitive at detecting RCC skeletal metastases than conventional bone scintigraphy or CT. The detection of occult bone metastases could greatly alter patient management, particularly in the context when standard-of-care imaging is negative for skeletal metastases.

Exploring the nature of atheroma and cardiovascular inflammation in vivo using positron emission tomography (PET).

Positron emission tomography (PET) has become widely established in oncology. Subsequently, a whole new "toolbox" of tracers have become available to look at different aspects of cancer cell function and dysfunction, including cell protein production, DNA synthesis, hypoxia and angiogenesis. In the past 5 years, these tools have been used increasingly to look at the other great killer of the developed world: cardiovascular disease. For example, inflammation of the unstable plaque can be imaged with 18-fludeoxyglucose (18F-FDG), and this uptake can be quantified to show the effect that statins have in reducing inflammation and explains how these drugs can reduce the risk of stroke. 18F-FDG has also become established in diagnosing and monitoring large-vessel vasculitis and has now entered routine practice. Other agents such as gallium-68 (68Ga) octreotide have been shown to identify vascular inflammation possibly more specifically than 18FFDG.Hypoxia within the plaque can be imaged with 18F-fluoromisonidazole and resulting angiogenesis with 18F-RGD peptides. Active calcification such as that found in unstable atheromatous plaques can be imaged with 18F-NaF. PET imaging enables us to understand the mechanisms by which cardiovascular disease, including atheroma, leads tomorbidity and death and thus increases the chance of finding new and effective treatments.

The imaging of neuroendocrine tumors using single photon emission computed tomography/computed tomography.

There have been several advances in technology over the past decade with the advent of hybrid imaging having a large impact on nuclear medicine, first with PET/CT and then more recently with SPECT/CT. Initial SPECT/CT systems used low dose but very low quality CT and except for attenuation correction offered no great advantage over reviewing SPECT and CT images side by side. More recently hybrid machines have become available and a series of studies have shown improved accuracy compared to SPECT alone with resulting changes in patient management. This has been true not only with somatostatin analogue imaging but also for demonstrating amine uptake using MIBG. Whilst PET/CT may be seen as the ideal, this may be less accessible due to the high cost and limited availability. In this case hybrid SPECT/CT offers hope for providing high quality and accurate imaging of neuroendocrine tumors.

The role of functional dopamine-transporter SPECT imaging in parkinsonian syndromes, part 1.

SUMMARY: As we defeat infectious diseases and cancer, one of the greatest medical challenges facing us in the mid-21st century will be the increasing prevalence of degenerative disease. Those diseases, which affect movement and cognition, can be the most debilitating. Dysfunction of the extrapyramidal system results in increasing motor disability often manifest as tremor, bradykinesia, and rigidity. The common pathologic pathway of these diseases, collectively described as parkinsonian syndromes, such as Parkinson disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies, is degeneration of the presynaptic dopaminergic pathways in the basal ganglia. Conventional MR imaging is insensitive, especially in early disease, so functional imaging has become the primary method used to differentiate a true parkinsonian syndrome from vascular parkinsonism, drug-induced changes, or essential tremor. Unusually for a modern functional imaging technique, the method most widely used in European clinics depends on SPECT and not PET. This SPECT technique (described in the first of 2 parts) commonly reports dopamine-transporter function, with decreasing striatal uptake demonstrating increasingly severe disease.

The role of functional dopamine-transporter SPECT imaging in parkinsonian syndromes, part 2.

SUMMARY: The functional imaging technique most widely used in European clinics to differentiate a true parkinsonian syndrome from vascular parkinsonism, drug-induced changes, or essential tremor is dopamine-transporter SPECT. This technique commonly reports dopamine-transporter function, with decreasing striatal uptake demonstrating increasingly severe disease. The strength of dopamine-transporter SPECT is that nigrostriatal degeneration is observed in both clinically inconclusive parkinsonism and early, even premotor, disease. In this clinical review (Part 2), we present the dopamine-transporter SPECT findings in a variety of neurodegenerative diseases, including multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies. The findings in vascular parkinsonism, drug-induced parkinsonism, and essential tremor are also described. It is hoped that this technique will be the forerunner of a range of routinely used, process-specific ligands that can identify early degenerative disease and subsequently guide disease-modifying interventions.

PET imaging of inflammation.

Inflammatory diseases are common place and often chronic. Most inflammatory cells have increased uptake of glucose which is enhanced in the presence of local cytokines. Therefore, imaging glucose metabolism by the means of 18F-fluoro-deoxy-glucose (FDG) positron emission tomography (PET) holds significant promise in imaging focal inflammation. Most of the work published involved small series of patients with either vasculitis, sarcoid or rheumatoid arthritis. It would appear that FDG PET is a simple and effective technique to identify inflammatory tissue in these conditions. There is even some work to suggest that by comparing baseline and early post therapy scans clinical outcome can be predicted. This would appear to be true with vasculitis as well as retroperitoneal fibrosis. The number of patients in each study is small but the evidence is compelling enough to recommend FDG PET imaging in the routine care of these patients.

PET imaging of inflammation.

Inflammatory diseases are common place and often chronic. Most inflammatory cells have increased uptake of glucose which is enhanced in the presence of local cytokines. Therefore, imaging glucose metabolism by the means of [18] F-fluro-de-oxy glucose (FDG) positron emission tomography (PET) holds significant promise in imaging focal inflammation. Most of the work published involved small series of patients with either vasculitis, sarcoid or rheumatoid arthritis. It would appear that FDG PET is a simple and effective technique to identify inflammatory tissue in these conditions. There is even some work to suggest that by comparing baseline and early post therapy scans clinical outcome can be predicted. This would appear to be true with vasculitis as well as retroperitoneal fibrosis. The number of patients in each study is small but the evidence is compelling enough to recommend FDG PET imaging in the routine care of these patients.

Sentinel node studies in truncal melanoma: does an increased number of draining basins correlate with an increased risk of lymph metastasis?

OBJECTIVES: To assess whether an association exists between drainage to multiple basins and lymphatic metastasis in patients with truncal melanoma. METHODS: We retrospectively reviewed 227 patients with primary malignant melanoma between January 2006 and December 2009. All patients received an intradermal injection of (99m)Tc-nanocolloid and lymphoscintigraphy followed by sentinel node biopsy. Pre-staging histology with Breslow thickness from excision biopsy was also obtained. RESULTS: 82/227 (36%) patients with primary truncal melanoma were identified. Nodal histology was positive for metastatic disease in 27/82 (32.9%) patients. Of these 27, 15 had 1 basin of drainage, 7 had 2 basins of drainage and 5 had 3 basins of drainage. Of the 55 node-negative patients, 35 had 1 basin, 18 had 2 basins and 2 had 3 basins of drainage. We found no significant correlation with sentinel node positivity and those that had ≥2 drainage basins. Breslow thickness was available in 65/82(79.2%) patients. Sentinel node biopsy was positive in 6/28 patients who had <1.5 mm thickness, 8/14 who had a 1.5-3.9 mm thickness and 9/23 who had ≥4 mm thickness. There was a significant correlation between Breslow thickness of ≥4 mm and nodal positivity (P = 0.03). CONCLUSION: This study demonstrates no association between multiple drainage basins and sentinel node histology. Sentinel lymph node status did correlate with Breslow thickness.

Correlation between serum calcium levels and dual-phase (99m)Tc-sestamibi parathyroid scintigraphy in primary hyperparathyroidism.

AIM: The goal of the study is to correlate serum calcium levels with the results of dual-phase (99m)Tc-sestamibi parathyroid scintigraphy to find the best cut-off level of the serum calcium that correlates with a positive presurgery. METHODS: In 111 patients, serum calcium and plasma parathormone (PTH) levels were compared with the results of the (99m)Tc-MIBI scintigraphy and with this data determined the level of calcium above which the (99m)Tc-MIBI scintigraphy was likely to be positive and below which the study was likely to be negative. RESULTS: In total, 11 men (18%) and 50 women (82%) had a positive (99m)Tc-MIBI study. Overall 67% of those patients with a positive (99m)Tc-MIBI study had a PTH >200 ng l(-1) compared to only 9% of those with a negative (99m)Tc-MIBI scintigraphy; however, for those with a positive study on an early (99m)Tc-MIBI scintigraphy, this rose to 85%. Overall a serum calcium of >2·70 mmol l(-1) was found in 82% of patients with a positive (99m)Tc-MIBI study but only 14% of those with a negative (99m)Tc-MIBI study, this is rose to 97% of patients with a parathyroid adenoma identified on early images. It is also shown that patients whose serum total calcium <2·51 mmol l(-1) rarely have positive (99m)Tc-MIBI scintigraphy. CONCLUSION: (99m)Tc-MIBI parathyroid scintigraphy is most likely to yield identification and localization of a parathyroid adenoma when both PTH and calcium are elevated; however, although there is no lower limit of PTH which can predict a negative study, we cannot recommend (99m)Tc-MIBI parathyroid scintigraphy if the serum calcium is <2·51 mmol l(-1).

Efficacy of radionuclide treatment DOTATATE Y-90 in patients with progressive metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs): a phase II study.

BACKGROUND: To evaluate the clinical and radiological effectiveness of [DOTA(0), D-Phe(1), Tyr(3)]-octreotate (DOTATATE) Y-90 in patients with extensive progressive gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs). MATERIALS AND METHODS: Sixty patients with histologically proven GEP-NETs were treated with DOTATATE Y-90. Clinical responses were assessed 6 weeks after completing therapy and then after each of the 3- to 6-month intervals. The radiological response was classified according to RECIST criteria. RESULTS: At 6 months after final treatment, radiological partial response (PR; at least a 30% decrease in the sum of the longest diameter of target lesions) was observed in 13 patients (23%), and the remaining patients had stable disease (SD; less than 30% decrease in the sum of the longest diameter of target lesions or less than 20% increase in the sum of the longest diameter of target lesions) (77%). Clinical PR at 6 months was in 43 patients (72%), nine patients had SD and progressive disease (PD) was noted in eight patients. Median progression-free survival (PFS) was 17 months, while the median overall survival (OS) was 22 months. In eight patients with early PD, the PFS was 4.5 and OS 9.5 months, while in those with SD or PR, PFS and OS were 19.5 and 23.5 months, respectively. After 12 months of follow-up, five patients had World Health Organization (WHO) grade 2 or 3 renal toxicity. Haematological toxicity (WHO grade 3 and 4) was noted during therapy in 10% of patients and persisted in 5%. CONCLUSIONS: DOTATATE Y-90 therapy is effective and relatively safe in patients with GEP-NET. Standard doses of DOTATATE Y-90 result in a relatively low risk of myelotoxicity. However, due to ongoing risk of renal toxicity, careful monitoring of the kidney is recommended.

Long-term results of patients with malignant carcinoid syndrome receiving octreotide LAR.

BACKGROUND: Octreotide LAR is an established treatment for malignant carcinoid syndrome. However, studies with large number of patients and long follow-up are lacking. AIM: To present long-terms results with octreotide LAR, assessing duration of clinical and objective response and treatment tolerance, in a large, homogeneous cohort of patients with malignant carcinoid syndrome. METHODS: A total of 108 patients with metastatic midgut neuroendocrine tumours were included in this 8-year study. Clinical evaluation was based on a symptom score. Radiological assessment was based on RECIST (Response Evaluation Criteria In Solid Tumours) criteria. RESULTS: Of the 108 patients, 24% had a sustained symptomatic response. In the remaining patients, loss of symptomatic response with the initial dose was noted within 3-60 months. In 17% of them, symptoms were controlled by just an increase of octreotide LAR dose, whilst the other patients required additional treatment. Overall, in 45.3% of patients, symptoms were well controlled during the study period with only octreotide LAR, and no additional treatment was required. No significant adverse effects were noted. CONCLUSIONS: Octreotide LAR treatment provides a sustained symptomatic response in about half of the patients with malignant carcinoid syndrome and contributes to disease stabilization for a longer period than previously described.

Radionuclides in the management of thyroid cancer.

Nuclear medicine imaging was born over 60 years ago with imaging of thyroid conditions. Most of our present imaging devices were developed for imaging of the thyroid and thyroid cancer. Millions of patients in over 100 countries have been diagnosed and treated for thyroid cancer using nuclear medicine techniques. It remains, however, one of the most dynamic areas of development in nuclear medicine with new roles for positron emission tomography and receptor based imaging. In addition to this is research into combinations of genetic therapy and radioisotopes and receptor based therapy using beta emitting analogues of somatostatin. Despite the use of ultrasound computed tomography and magnetic resonance, nuclear medicine techniques remain central to both imaging and therapy in thyroid disease and the field has recently become one of the most dynamic within the specialty.

The cost effectiveness of treatment modalities for thyrotoxicosis in a U.K. center.

OBJECTIVE: This study determined the cost effectiveness of treating thyrotoxicosis using thionamide therapy, radioiodine or surgery in the United Kingdom. DESIGN: One hundred thirty-five patients diagnosed with thyrotoxicosis (62% Graves' disease, 7% nodular disease, 5% thyroiditis, and 27% unknown aetiology) referred in 12 months were offered a fully informed choice of treatment modality. Thirteen patients with transient thyrotoxicosis were subsequently excluded from the analysis. Seventy-four patients (61%) received an 18-month course of thionamide therapy, 43 received radioiodine therapy (35%), and 5 had a thyroidectomy (4%) within the first year of diagnosis as their primary treatment. A successful outcome ("cure") was defined as euthyroidism 12 months after thionamide therapy or euthyroidism or hypothyroidism on thyroxine replacement at 24 months following radioiodine or thyroidectomy. Costs were calculated for outpatient attendances, laboratory tests, and initial and subsequent treatments. MAIN OUTCOME: In the thionamide group 73% were "cured" at 30 months after initiating treatment compared to 95% in the radioiodine group and 100% treated by thyroidectomy at 24 months. Cost per "cure" was calculated to be 3,763 pounds (5,644 dollars) per patient who received thionamides, 1,375 pounds (2,063 dollars) per patient given radioiodine and 6,551 pounds (9,826 dollars) per patient who underwent thyroidectomy. CONCLUSION: The most cost-effective primary treatment modality for thyrotoxicosis is radioiodine.

The future of infection imaging.

Over the past 10 years, there has been an unprecedented explosion in new agents suggested for imaging infection. These agents have been based on our understanding of the processes involved in invasive infection of the body by microorganisms and the body's response to them. Work with antibodies has traditionally yielded the most likely candidates, 3 of which have entered clinical use in Europe and the USA. However, the expense and limitations of producing antibodies have resulted in investigations into the use of cytokine and anti-microbial radiolabelled peptides. This work is very promising in that these types of tracers may be more specific for infection than labelled leukocytes. There remains a big question mark, however, as to whether or not these will progress from phase I/II trials to phase III trials and, ultimately, to clinical use. Finally, the investigation of radiolabelled anti-microbials continues and may prove to be most useful with anti-fungals especially in the immuno-suppressed host. We live in exciting times in the evolution of infection imaging; time and commercial constraints will determine which, if any of these tracers make it to the market and will they do so before PET rules all nuclear medicine?