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This review traces the development of targeted radionuclide therapy (TRT) (the Magic Bullet) from the discovery of radioactivity in nature and the subsequent discovery of artificial radioactivity (the production of radioactive isotopes of stable elements) to the current status of TRT in the medical literature and clinical practice. With the availability of radioisotopes of iodine, initially to study thyroidal iodine kinetics, it was soon observed that sufficient amounts of radiation could control thyroid hyperfunction. Shortly thereafter, when radioiodine was administered to a patient with differentiated thyroid carcinoma whose hypermetabolism was secondary to excess thyroid hormone production, it was observed that radioiodine also had an antitumor effect. The concept of the Magic Bullet has since been extended to other disease states such as (1) 131I-meta-iodobenzylguanidine (131I-MIBG) to treat malignant and metastatic pheochromocytomas and paragangliomas; (2) 131I-tositumomab, a radioiodinated anti-CD20 IgG to treat CD20 expressing non-Hodgkins lymphoma. In recent years, other β-emitting radionuclides, Yttrium-90 (90Y) and Lutetium-177 (177Lu), have been added to this list. These radiometals have different physical properties that were thought to be possibly more effective than radioiodine. 90Y was initially used to radio-label somatostatin analogues to treat metastatic neuroendocrine tumors but has virtually been replaced by 177Lu since the physical characteristics of the latter appear to be better suited to effectively irradiate the micrometastases of neuroendocrine tumors. A similar evolution is taking place in the development of a targeted radionuclide therapeutic that recognizes prostate-specific membrane antigen (PSMA), an epitope expressed in increased amounts in prostate carcinoma. Both an anti-PSMA immunoglobulin (J591) and a small molecule glutamase ligand are currently being evaluated as targeted radionuclide therapy agents. Radionuclides that have affinity for the calcium hydroxyapatite in bone have been used to relieve bone pain due to tumor metastases based on increased deposition of the bone seeking radiometals at the osteoblastic interface of the tumor metastases and boney matrix. Most of these trials have been in patients with metastatic prostate cancer since there are few other options. In this regard, targeted radionuclide therapy has come full circles as the most recent addition to this anti-tumor arsenal is a radioisotope of Radium, 223Ra, an alpha emitter which has a greater radiobiologic effect but limited range in tissue thus adding an element of safety when treating marrow metastases. Other alpha emitting radiometals are currently being evaluated as alternative radiometals in place of 90Y and 177Lu to label targeting molecules. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a relatively rare hematologic disorder characterized by proliferation of plasma cells, primarily involving the bone marrow. Extramedullary involvement also occurs with poor prognosis. Asymptomatic plasma cell disorders, monoclonal gammopathy of uncertain significance, and smoldering MM, which do not require therapy, should be distinguished from symptomatic MM, which requires treatment. MM may present with CRAB , elevated C alcium levels, R enal insufficiency, A nemia, and B one lesions (including lytic lesions and osteopenia), as well as elevated levels of serum M protein or urine M protein or both. Nonsecretory myeloma in which serum and urine M proteins are absent occurs rarely, accounting for 1%-5% of patients with myeloma, but low levels of abnormal immunoglobulins are often present. Staging of patients with MM is done according to the Durie and Salmon criteria based on laboratory testing (determination of hemoglobin, serum calcium, and serum and urine M proteins) and conventional radiography. A variety of diagnostic imaging procedures have been employed to assess the extent of disease in MM and to evaluate the response to treatment as well as provide surveillance for the detection of recurrent disease. These include whole-body x-ray, which despite its limitations is regularly used to detect lytic bone lesions; CT radiography; MRI; and a variety of radionuclide imaging procedures, with 18 F-FDG-PET/CT emerging as the radionuclide procedure of choice. Recently, the Durie-Salmon criteria have been upgrade to the Durie-Salmon PLUS system, which includes 18 F-FDG-PET/CT and MRI of the spine and pelvis. [ABSTRACT FROM AUTHOR]

Ablation of residual thyroid tissue after total or near-total thyroidectomy is widely accepted by many practitioners and endorsed by relevant professional societies in the United States and the international community for patients with defined risk factors, including age greater than 45 years, large tumors; tumors with undesirable histopathology; lymph node involvement; positive surgical margins; gross and possibly microscopic extrathyroidal extension; and, of course, evidence or suspicion of distal metastases, including mediastinal lymphadenopathy, pulmonary or osseous metastases or involvement of other organs. (131)I therapy doses of 3.7-5.5 GBq (100-150 mCi) should be used, and additional activity should be used in the event there are additional findings on pretreatment whole-body scans. Depending upon the patient's age, general medical condition, and renal function, nuclear medicine practitioners should be prepared to perform whole body (blood or bone marrow) dosimetry in the event doses >5.5 GBq (150 mCi) are being considered to assure patient safety. Still unresolved is the role of (131)I ablation in the so-called "low risk" patient--particularly in a patient who has undergone a near-total thyroidectomy in the hands of a skilled surgeon. If an ablative dose is to be administered, 0.9-1.8 MBq (25-50 mCi) appears to be sufficient to eliminate most if not all thyroid tissue. The problem is defining the "low-risk" patient. After review of the extensive literature on this subject, it appears that the thoughtful and informed practitioner must make a patient specific decision in this setting on the basis of his/her experience and review of the details in each case and continue to review the evidence on this subject as it becomes available. [ABSTRACT FROM AUTHOR]

Ablation of residual thyroid tissue after total or near-total thyroidectomy is widely accepted by many practitioners and endorsed by relevant professional societies in the United States and the international community for patients with defined risk factors, including age greater than 45 years, large tumors; tumors with undesirable histopathology; lymph node involvement; positive surgical margins; gross and possibly microscopic extrathyroidal extension; and, of course, evidence or suspicion of distal metastases, including mediastinal lymphadenopathy, pulmonary or osseous metastases or involvement of other organs. 131I therapy doses of 3.7-5.5 GBq (100-150 mCi) should be used, and additional activity should be used in the event there are additional findings on pretreatment whole-body scans. Depending upon the patient''s age, general medical condition, and renal function, nuclear medicine practitioners should be prepared to perform whole body (blood or bone marrow) dosimetry in the event doses >5.5 GBq (150 mCi) are being considered to assure patient safety. Still unresolved is the role of 131I ablation in the so-called “low risk” patient—particularly in a patient who has undergone a near-total thyroidectomy in the hands of a skilled surgeon. If an ablative dose is to be administered, 0.9-1.8 MBq (25-50 mCi) appears to be sufficient to eliminate most if not all thyroid tissue. The problem is defining the “low-risk” patient. After review of the extensive literature on this subject, it appears that the thoughtful and informed practitioner must make a patient specific decision in this setting on the basis of his/her experience and review of the details in each case and continue to review the evidence on this subject as it becomes available. [Copyright &y& Elsevier]

Prostate cancer is a common cancer in men and continues to be a major health problem. Imaging plays an important role in the clinical management of patients with prostate cancer. An important goal for prostate cancer imaging is more accurate disease characterization through the synthesis of anatomic, functional, and molecular imaging information. Positron emission tomography (PET)/computed tomography (CT) in oncology is emerging as an important imaging tool. The most common radiotracer for PET/CT in oncology, 18F-fluorodeoxyglucose (FDG), is not very useful in the imaging of prostate cancer. However, in recent years other PET tracers have improved the accuracy of PET/CT imaging of prostate cancer. Among these, choline labeled with 18F or 11C, 11C-acetate, and 18F-fluoride has demonstrated promising results, and other new radiopharmaceuticals are under development and evaluation in preclinical and clinical studies. Large prospective clinical PET/CT trials are needed to establish the role of PET/CT in prostate cancer patients. Because there are only limited available therapeutic options for patients with advanced metastatic prostate cancer, there is an urgent need for the development of more effective treatment modalities that could improve outcome. Prostate cancer represents an attractive target for radioimmunotherapy (RIT) for several reasons, including pattern of metastatic spread (lymph nodes and bone marrow, sites with good access to circulating antibodies) and small volume disease (ideal for antigen access and antibody delivery). Furthermore, prostate cancer is also radiation sensitive. Prostate-specific membrane antigen is expressed by virtually all prostate cancers, and represents an attractive target for RIT. Antiprostate-specific membrane antigen RIT demonstrates antitumor activity and is well tolerated. Clinical trials are underway to further improve upon treatment efficacy and patient selection. This review focuses on the recent advances of clinical PET/CT imaging and RIT of prostate cancer. [Copyright &y& Elsevier]

Radioimmunotherapy is a form of targeted radionuclide therapy that uses a monoclonal antibody to deliver localized radiation. It is most appropriate for treatment of multiple tumor sites that cannot be readily excised surgically or irradiated using external beam radiation or brachytherapy. At present, 2 products, Bexxar (131I-tositumomab and unlabeled tositumomab, GlaxoSmithKline, Triangle Park, NC) and Zevalin (90Y-ibritumomab tiuxetan and unlabeled rituximab, Spectrum Pharmaceuticals, Irvine, CA and Cell Therapeutics, Seattle, WA) are approved for treatment of non-Hodgkin''s lymphoma in certain clinical situations in the United States and Canada. Zevalin is available also in Europe, and there are plans to make both agents more widely available. The therapeutic dose to be used depends upon a number of patient-specific variables. Both regimen achieve a complete response or partial response in approximately 3 of 4 patients, with a duration of remission lasting many years in some cases. This article reviews the basis for dose selection, the nuclear medicine procedures involved, the results obtained to date, and issues related to patient and staff safety. [Copyright &y& Elsevier]

Summary: We have determined the systemic biodistribution of the hormone leptin by PET imaging. PET imaging using 18F- and 68Ga-labeled leptin revealed that, in mouse, the hormone was rapidly taken up by megalin (gp330/LRP2), a multiligand endocytic receptor localized in renal tubules. In addition, in rhesus monkeys, 15% of labeled leptin localized to red bone marrow, which was consistent with hormone uptake in rodent tissues. These data confirm a megalin-dependent mechanism for renal uptake in vivo. The significant binding to immune cells and blood cell precursors in bone marrow is also consistent with prior evidence showing that leptin modulates immune function. These experiments set the stage for similar studies in humans to assess the extent to which alterations of leptin''s biodistribution might contribute to obesity; they also provide a general chemical strategy for 18F labeling of proteins for PET imaging of other polypeptide hormones. [Copyright &y& Elsevier]

Gallium-67 (67Ga)-citrate was initially introduced as a tumor imaging agent in the early 1970s, but it was soon recognized that it was useful in the identification of both acute and chronic inflammation. Because of its physical characteristics (multiple γ photons energy; long half life) and binding to the plasma protein transferrin (resulting in relatively high background and therefore reduced lesion-to-background contrast), it was less than ideal as an imaging agent. Several years later, it became possible to radiolabel leukocytes, which had the advantage of greater specificity for acute infections characterized by a granulocytic response, but had the disadvantage of requiring the removal of blood and isolation of the leukocyte component. Several radiolabeled antibody preparations and a radiolabeled antibacterial agent have been introduced and evaluated, but none of these have been used widely. Most recently, it has been recognized that the use of 18F-fluorodeoxyglucose can be used to identify infection/inflammation, probably based on the focal increase in anaerobic glucose metabolism associated with the cellular response. In this work, we review the features of each of these agents and discuss the issues involved in their use as radiopharmaceuticals for the identification of inflammation and/or infection. [Copyright &y& Elsevier]

Background: Extrathyroidal extension (ETE) is a risk factor for recurrence of papillary thyroid carcinoma (PTC). Although initial data supporting this was based on gross ETE noted at surgery, current treatment regimens group patients with microscopic ETE—identified only on histopathology—similarly to those with macroscopic (gross) ETE. This study was designed to assess the influence of microscopic ETE on disease recurrence. Methods: Retrospective analysis of 212 patients undergoing thyroidectomy for PTC between 1995 and 2004 with minimum 3-year follow-up was conducted. Results: Of 212 patients, 71 had ETE; 32% were macroscopic and 68% microscopic. Patient demographics, tumor variables, and adjuvant therapy were similar between both ETE groups. Recurrence rates were 52% for macroscopic ETE, 21% for microscopic ETE, and 13% without ETE. On multivariate analysis, patients with macroscopic ETE had a 6.4-fold increased relative risk of recurrence compared with patients with microscopic ETE (P < .02; 95% confidence interval, 1.6–25.9) and a significantly decreased disease-free survival (DFS). Furthermore, patients with microscopic ETE had neither a significantly increased risk of recurrence nor different DFS compared with patients without ETE. Conclusion: Macroscopic ETE has a higher incidence of disease recurrence than microscopic ETE, implying they should be considered separately when devising adjuvant treatment regimens. The significance of microscopic ETE is undetermined. [Copyright &y& Elsevier]

Abstract: The role of the base in the synthesis of 3′-deoxy-3′-[18F]fluorothymidine, [18F]FLT, via nucleophilic substitution of the nosyl group with [18F]fluoride was investigated. The rate of 18F-incorporation into the molecule dramatically changed as a function of the precursor-to-base ratio. In the presence of excess base, the precursor was consumed by elimination before substitution was complete. When the precursor-to-base ratio was optimal, an overall [18F]FLT yield of 30–40% was achieved even if the precursor amount was as small as 8–13mg. [Copyright &y& Elsevier]

Abstract: This study examines the relationship between fibrillar beta-amyloid (Aβ) deposition and reduced glucose metabolism, a proxy for neuronal dysfunction, in cognitively normal (NL) individuals with a parent affected by late-onset Alzheimer''s disease (AD). Forty-seven 40–80-year-old NL received positron emission tomography (PET) with 11C-Pittsburgh compound B (PiB) and 18F-fluoro-2-deoxy-d-glucose (FDG). These included 19 NL with a maternal history (MH), 12 NL with a paternal history (PH), and 16 NL with negative family history of AD (NH). Automated regions of interest, statistical parametric mapping, voxel-wise intermodality correlations, and logistic regressions were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. The MH group showed higher PiB retention and lower metabolism in AD regions compared with NH and PH, which were negatively correlated in posterior cingulate, frontal, and parieto-temporal regions (Pearson r ≤ −0.57, p ≤ 0.05). No correlations were observed in NH and PH. The combination of Aβ deposition and metabolism yielded accuracy ≥ 69% for MH vs. NH and ≥ 71% for MH vs. PH, with relative risk = 1.9–5.1 (p values < 0.005). NL individuals with AD-affected mothers show co-occurring Aβ increases and hypometabolism in AD-vulnerable regions, suggesting an increased risk for AD. [Copyright &y& Elsevier]