Imaging of neuroendocrine tumours with gamma-emitting radiopharmaceuticals.

Nuclear medicine can image some tumors by means of receptor specific radiopharmaceuticals, and offers the possibility to characterize cancer through the detection of its receptor expression. This is the case of neuroendocrine tumours (NETs), that are visualized by different radiolabelled somatostatin analogues that bind 5 distinct somatostatin receptor types (named sstr1-5) that show different tissue distribution. The subtypes sstr2 and sstr5 are the most commonly expressed in NETs. Until now the most widely used radiolabelled somatostatin analogue for planar and single photon emission computed tomography (SPECT) has been [(111)In]pentetreotide, because of its commercial availability. Other analogues labelled with gamma emitting radionuclides are [(99m)Tc]EDDA/HYNIC-TOC, [(99m)Tc]P829, [(111)In]DOTA-lanreotide, [(111)In]DOTA-NOC-ATE, [(111)In]DOTA-BOC-ATE. However, these compounds have not been successful for the routine use. Moreover, NETs express various receptors that can be depicted by different radiopharmaceuticals, such as [(123)I]VIP and [(111)In]GLP-1. Besides this, some precursors of the catecholamines metabolism, as meta-iodo-benzyl-guanidine (MIBG), labelled with (123)I or (131)I, accumulates in neuroendocrine tissues, in particular those of sympathoadrenal lineage. MIBG scintigraphy is currently indicated for neuroblastoma, paraganglioma and phaeocromocitoma. An impressive technological progress has been achieved recently with PET and, in particular, with the development of hybrid instrumentations (PET/CT) combining nuclear imaging with radiological imaging providing both functional and morphologic information. Among positron emitting tracers, the [(18)F]FDG is the most diffuse in oncology, but other more effective tracers are available for NETs, such as the analogues labelled with 68Ga. The diagnostic sensitivity and accuracy of these technology is superior to that of gamma emitting radiopharmaceuticals, but the fact that they are not still registered limits their use in the clinical practice. This overview summarizes the state of art of NETs imaging, focusing the attention mainly on gamma-emitting tracers.

(131)I-MIBG treatment of pheochromocytoma: low versus intermediate activity regimens of therapy.

AIM: Since the second half of the 1980s, (131)I-MIBG has been widely used for treatment of patients with malignant pheochromocytoma. In 1991, at the International Meeting in Rome, it was agreed that (131)I-MIBG therapy induces significant tumor responses in about 30-50% of cases, long-term stabilization of disease in several cases and significant reduction of cathecolamine-related symptoms in almost all patients. Nevertheless, more than 20 years later, its therapeutic use in malignant phaeochromocytoma has not yet been standardized. Aim of the present study was to compare the use of low versus intermediate activity of MIBG to achieve better results in a shorter time with higher activities. METHODS: Two different modalities of (131)I-MIBG therapy were performed: before 2001, 12 patients (Group 1) received a fixed activity of 5.55 GBq/session. From 2001 to 2009, 16 patients (Group 2) were treated with 9.25-12.95 GBq/session. RESULTS: As expected, the overall response rate in Group 2 are slightly better. The most important result of increasing the single session activity was the shorter median time to achieve a significant response (7 versus 19 months), which was obtained with a lower median cumulative activity (11 versus 22 GBq) in a lower median number of sessions (2 versus 7). CONCLUSIONS: We demonstrated that intermediate single session activity shortened to one third the global treatment time, with similar efficacy and a moderate increment of toxicity. Consequently, the increase of (131)I-MIBG activity, without reaching myeloablative levels, can be recommended for standard treatment of pheochromocytoma and paraganglioma patients.

Individualized dosimetry in the management of metastatic differentiated thyroid cancer.

AIM: This paper analyzes the available data on the dosimetric approach and describes the use of dosimetry in the Division of Nuclear Medicine of the National Cancer Institute in Milan. Dosimetry is rarely performed when planning radio-iodine activity, although most of the available guidelines do mention this possibility, without giving any well defined indication. Aim of the present research was to validate the usefulness of dosimetry in the management of metastatic thyroid cancer. Benua (1962) set the limit of blood absorbed dose at 2 Gy to avoid hematological toxicity. Maxon (1983) determined at 80 Gy the dose to achieve complete destruction of a metastatic lesion. Dorn (2003) combined red marrow and lesion dosimetry showing that high activity administrations with less that 3 Gy to the red marrow are a safe and more effective with respect to fixed activities administrations. Lee (2008) reported 50% responses with high activity administrations based on blood dosimetry, in 47 patients which were unsuccessfully previously treated with fixed activities. Sgouros (2005) and Song (2006) introduced key parameters as Biological Effective Dose and Uniform Equivalent Dose in order to describe the effects of continuous low dose rate irradiation and non uniform activity uptake, typical of nuclear medicine treatments. METHODS: Red marrow and lesion dosimetry (planar view) were performed during the treatment, without changing the fixed activity schema. RESULTS: This experience demonstrate first of all, that dosimetry is feasible in the clinical routine, and that it can provide the clinician with important information, no matter its often quoted limited numerical accuracy. A total of 17/20 lesion doses below 80 Gy have been detected. Three/17 (doses between 40 and 80 Gy) disappeared in the follow-up scintigram. Two/17 were undetectable at computed tomography or nuclear magnetic resonance. These data suggest that repetition of treatment on a lesion drastically reduces its uptake, with a loss of therapeutic efficacy along the sequence of fixed activity administrations. CONCLUSIONS: The usefulness of dosimetry should not be assessed only on the basis of patient survival or therapeutic efficacy; the possibility to avoid useless treatments should also be considered. According to the authors, individualized dosimetry could improve the management of metastatic differentiated thyroid cancer. Even post-therapeutic dosimetry, as performed at this institution, has a significant impact on clinical decision-making. The question for the future is how to include dosimetry into the patient management framework.

MIBG for diagnosis and therapy of medullary thyroid carcinoma: is there still a role?

Medullary thyroid carcinoma (MTC) is a relatively rare neuroendocrine tumour originating from the parafollicular C cells and releases calcitonin (hCt), carcinoembryonic antigen (CEA) and occasionally other substances. In 20-30% of cases MTC presents a germline mutation of the RET proto-oncogene and occurs in 3 different hereditary forms: familial MTC, multiple endocrine neoplasia (MEN) 2A and MEN 2B syndrome. Prognosis of MTC is largely related to tumour extension at disease onset. Surgery remains the most effective therapy for potential cure. Overall survival is strictly linked to the occurrence of relapse. After surgery, serum hCt remains the most sensitive test for occult disease. Diagnostic imaging work-up includes ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy, as the more frequent sites of recurrence or metastases are cervical and mediastinal lymph nodes, lungs, liver and bone. Nuclear medicine procedures include (111)In-labelled somatostatin analogs, radioiodinated metaiodobenzylguanidine (MIBG), and several PET radiopharmaceuticals. Experience with radionuclide therapy in MTC is restricted to few patients treated with (131)I-MIBG or (90)Y-DOTATOC. Since 1987, 1 027 diagnostic MIBG scans were performed in the Department Department of Diagnostic Imaging and Therapy of the Istituto Nazionale Tumori IRCCS Foundation (Milan, Italy), 85 of which for MTC, with a sensitivity of 38.7% in patients with evidence of disease and 30.7 % if all patients were considered. Since 1994, 13 MTC patients were treated with MIBG with 4 partial responses and 4 stable diseases. Patients with liver or bone involvement responded to therapy and showed long-term partial remission of disease, others showed stability of disease, which was apparently unrelated to therapy. Improvement of efficacy can be achieved through dosimetric calculation of administered activity.

Use of an artificial neural network to predict Graves' disease outcome within 2 years of drug withdrawal.

BACKGROUND: Graves' disease (GD) is an autoimmune disorder characterized by hyperthyroidism, which can relapse in many patients after antithyroid drug treatment withdrawal. Several studies have been performed to predict the clinical course of GD in patients treated with antithyroid drugs, without conclusive results. The aim of this study was to define a set of easily achievable variables able to predict, as early as possible, the clinical outcome of GD after antithyroid therapy. METHODS: We studied 71 patients with GD treated with methimazole for 18 months: 27 of them achieved stable remission for at least 2 years after methimazole therapy withdrawal, whereas 44 patients relapsed. We used for the first time a perceptron-like artificial neural network (ANN) approach to predict remission or relapse after methimazole withdrawal. Twenty-seven variables obtained at diagnosis or during treatment were considered. RESULTS: Among different combinations, we identified an optimal set of seven variables available at the time of diagnosis, whose combination was useful to efficiently predict the outcome of the disease following therapy withdrawal in approximately 80% of cases. This set consists of the following variables: heart rate, presence of thyroid bruits, psycological symptoms requiring psychotropic drugs, serum TGAb and fT4 levels at presentation, thyroid-ultrasonography findings and cigarette smoking. CONCLUSIONS: This study reveals that perceptron-like ANN is potentially a useful approach for GD-management in choosing the most appropriate therapy schedule at the time of diagnosis.

Analytical and diagnostic accuracy of "second generation" assays for thyrotrophin receptor antibodies with radioactive and chemiluminescent tracers.

AIMS: To investigate the analytical and diagnostic accuracy of thyrotrophin (TSH) receptor antibody assays using recombinant human TSH receptors. METHODS: Sera from 68 patients with Graves' disease, 23 patients with autoimmune thyroiditis, and 119 healthy controls were evaluated in four different laboratories using both radioactive and chemiluminescent tracers. Functional sensitivity, interlaboratory precision, optimal cutoff values for Graves' disease, and the correlation between the two methods were evaluated. RESULTS: Functional sensitivity was 0.98 IU/litre for both assays. Interlaboratory precision, expressed as per cent coefficient of variation over a wide range of antibody concentrations, varied from 5.7% to 15.1% for the radioligand, and from 6.6% to 19.9% for the chemiluminescence assay. The two methods (radioactive and chemiluminescent) were closely correlated. All the sera from untreated or relapsing patients with Graves' disease gave TSH receptor antibody values above 2.1 IU/litre, whereas in none of the healthy controls did values exceed 2.5 IU/litre. Receiver operating curve analysis allowed an optimal cutoff point to be defined at 1.99 IU/litre, according to a sensitivity of 100% and specificity of 99.1%. CONCLUSIONS: These data show the high analytical and diagnostic accuracy of the human TSH receptor assays, both with radioactive and chemiluminescent tracers, when both functional sensitivity and interlaboratory reproducibility are considered. These two methods could be proposed as first line diagnostic markers for Graves' disease.

Abnormal bone scintigraphy and acute-onset severe primary hyperparathyroidism.

Acute-onset primary hyperparathyroidism in a previously asymptomatic individual is uncommon. We herein report the case of a 61-yr old woman who underwent bone scintigraphy for severe, rapidly worsening, diffuse bone pain, associated with weight loss, anxiety and confusion. The patient was asymptomatic until a few days before presentation. A marked redistribution of the tracer was observed, with poor bone uptake and relevant accumulation in liver, kidneys, lungs and spleen. Blood chemistry unequivocally allowed the diagnosis of primary hyperparathyroidism due to multiple parathyroid adenomas, as suggested by parathyroid scan. Unfortunately, the patient critically worsened and surgery was made impossible. She died despite intensive critical care. Autopsy confirmed both massive intraparenchymal calcium deposition in the kidneys, lungs, liver and spleen, as well as multiple parathyroid adenomas. One may speculate that some adaptation of the organism to progressively increasing blood calcium levels and to slowly increasing intraparenchymal calcium salt deposition occurred, until critically high concentrations were attained.