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.

Differential diagnosis of adnexal masses: risk of malignancy index, ultrasonography, magnetic resonance imaging, and radioimmunoscintigraphy.

A risk of malignancy index (RMI), based on menopausal status, ultrasound (US) findings, and serum CA125, has previously been described and validated in the primary evaluation of women with adnexal masses and is widely used in selective referral of women from local cancer units to specialized cancer centers. Additional imaging modalities could be useful for further characterization of adnexal masses in this group of women. A prospective cohort study was conducted of 196 women with an adnexal mass referred to a teaching hospital for diagnosis and management. Follow-up data was obtained for 180 women; 119 women had benign and 61 women malignant adnexal masses. The sensitivity and specificity of specialist US, magnetic resonance imaging (MRI), radioimmunoscintigraphy (RS), and the RMI were determined. We identified a subgroup of women with RMI values of 25-1000 where the value of further specialist imaging was evaluated. Sensitivity and specificity for specialist US were 100% and 57%, for MRI 92% and 86%, and for RS 76% and 87%, respectively. Analysis of 123 patients managed sequentially, using RMI cutoff values of > or =25 and <1000 and then US and MRI provided a sensitivity of 94% and a specificity of 90%. Using this RMI cutoff followed by specialist US and MRI, as opposed to the traditional RMI cutoff value of 250, can increase the proportion of patients with cancer appropriately referred in to a cancer center, with no change in the proportion of patients with benign disease being managed in a local unit.

Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin's lymphoma.

PURPOSE: An open-label phase II study was conducted at two centers to establish the efficacy and safety of tositumomab and iodine I 131 tositumomab at first or second recurrence of indolent or transformed indolent B-cell lymphoma. PATIENTS AND METHODS: A single dosimetric dose was followed at 7 to 14 days by the patient-specific administered radioactivity required to deliver a total body dose of 0.75 Gy (reduced to 0.65 Gy for patients with platelets counts of 100 to 149 x 10(9)/L). Forty of 41 patients received both infusions. RESULTS: Thirty-one of 41 patients (76%) responded, with 20 patients (49%) achieving either a complete (CR) or unconfirmed complete remission [CR(u)] and 11 patients (27%) achieving a partial remission. Response rates were similar in both indolent (76%) and transformed disease (71%). The overall median duration of remission was 1.3 years. The median duration of remission has not yet been reached for those patients who achieved a CR or CR(u). Eleven patients continue in CR or CR(u) between 2.6+ and 5.2+ years after therapy. Therapy was well tolerated; hematologic toxicity was the principal adverse event. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia were observed in 5%, 45%, and 32% of patients, respectively. Secondary myelodysplasia has occurred in one patient. Four patients developed human antimouse antibodies after therapy. Five of 38 assessable patients have developed an elevated thyroid-stimulating hormone; treatment with thyroxine has been initiated in one patient. CONCLUSION: High overall and CR rates were observed after a single dose of tositumomab and iodine I 131 tositumomab in this patient group. Toxicity was modest and easily managed.

Radioimmunoscintigraphy with Tc-99m-labelled SM3 in differentiating malignant from benign adnexal masses.

OBJECTIVE: Ultrasound scanning, serum CA125 and menopausal status have previously been combined in a risk of malignancy index for the differential diagnosis of adnexal masses. Although this approach has greater accuracy than either individual tests or clinical assessment, it has a significant false positive and false negative rate. Efforts have been directed at refining differential diagnosis and this study assessed the role of radioimmunoscintigraphy using the stripped mucin 3 (SM3) antibody that has a 17-fold greater uptake in malignant than benign ovarian tumours in vitro. DESIGN: Prospective study of patients with a pelvic mass using radioimmunoscintigraphy. SETTING: Department of Nuclear Medicine of St Bartholomew's Hospital in collaboration with Cancer Network. POPULATION: A total of 93 patients with pelvic masses were recruited for this study of which 32 had ovarian cancer and 61 had benign lesions. METHODS: Radioimmunoscintigraphy was performed with Tc-99m-labelled SM3 (600 MBq), anterior and posterior pelvis imaged at 10 minutes and at 4 and 24 hours and evaluated with change detection analysis and probability mapping. MAIN OUTCOME MEASURES: Sensitivity and specificity of radioimmunoscintigraphy for ovarian cancer. RESULTS: Radioimmunoscintigraphy had a sensitivity for ovarian cancer of 84% (27 true positive and 5 false negatives) and a specificity of 87% (53 true negatives and 8 false positives) giving a negative predictive value of 91%. CONCLUSION: These results suggest that radioimmunoscintigraphy could be used to reduce the number of false positive findings in a strategy to refine differential diagnosis of the pelvic mass.

123I-Interleukin-2: biochemical characterization and in vivo use for imaging autoimmune diseases.

We describe in detail the labelling of interleukin-2 with I ( I-IL2), its biochemical characterization, the binding assay and its use for the detection of tissues infiltrated with mononuclear cells. Human recombinant IL2 was labelled using an enzymatic method and its biochemical characterization was performed using high performance liquid chromatography (HPLC) analysis of cyanogen bromide-cleaved protein. biological and binding assays were performed on CTLL-2 cell line and on activated peripheral blood lymphocytes. studies were performed 1 h after administration of 2-3 mCi of I-IL2 in 10 newly diagnosed type 1 diabetes patients, five pre-diabetic patients, 10 Hashimoto's thyroiditis patients, 10 coeliac disease patients and 10 normal volunteers. I-IL2 scintigraphy allowed the detection and quantification of activated mononuclear cells in several affected tissues. In detail, I-IL2 accumulation was detected in the thyroid of all patients affected by Hashimoto's thyroiditis, in the bowel of all coeliac disease patients and in the pancreas of all pre-type 1 diabetic patients. By contrast, in newly diagnosed type 1 diabetics, I-IL2 scan was positive in five of the 10 studied patients. I-IL2 scintigraphy may be useful for studying autoimmune phenomena and in diagnostic protocols to evaluate the presence of other tissue involvement in patients with an organ-specific autoimmune disease.

Neuro-otological findings in Pendred syndrome.

Pendred syndrome is an autosomal recessive inherited disorder characterized by profound hearing impairment and inappropriate iodine release by the thyroid on perchlorate challenge. Thirty-three cases comprising members of 13 families and eight isolated cases were studied, with detailed audiological and vestibular investigation and computerized tomography. A uniform, profound, symmetrical sensorineural hearing loss was identified in all cases. Approximately one-third of the group reported progressive hearing impairment, in childhood or adolescence, associated with head injury, infection, or delayed secondary hydrops. Ninety per cent of the cases scanned showed dilated vestibular aqueducts, and all cases with progression of the hearing impairment demonstrated this structural abnormality. Approximately one-third of the cases had normal vestibular function, but a further third demonstrated a unilateral peripheral deficit, while the remaining third showed bilateral vestibular hypofunction. There was no intra-familial concordance of vestibular findings, and no correlation between vestibular abnormality and presence or absence of a dilated vestibular aqueduct, with or without a Mondini malformation. In older children and adults, Pendred syndrome was associated with a profound, symmetrical, sensorineural auditory impairment, and a variety of vestibular abnormalities, which are not uniform within families, or correlated with structural labyrinthine deformities.

Imaging bacterial infection with (99m)Tc-ciprofloxacin (Infecton).

AIMS: The diagnosis of deep seated bacterial infections, such as intra-abdominal abscesses, endocarditis, and osteomyelitis, can be difficult and delayed, thereby compromising effective treatment. This study assessed the efficacy of a new radioimaging agent, Tc-99m ciprofloxacin (Infecton), in accurately detecting sites of bacterial infection. METHODS: Eight hundred and seventy nine patients with suspected bacterial infection underwent Infecton imaging and microbiological evaluation. The sensitivity and specificity of Infecton in detecting sites of bacterial infection were determined with respect to Centres of Disease Control, World Health Organisation, and Dukes's criteria. RESULTS: Five hundred and seventy four positive and 295 negative images were produced. These included 528 true positives, 46 false positives, 205 true negatives and 90 false negatives, giving an overall sensitivity of 85.4% and a specificity of 81.7% for detecting infective foci. Sensitivity was higher (87.6%) in microbiologically confirmed infections. CONCLUSIONS: Infecton is a sensitive technique, which aids in the earlier detection and treatment of a wide variety of deep seated bacterial infections. The ability to localise infective foci accurately is also important for surgical intervention, such as drainage of abscesses. In addition, serial imaging with Infecton might be useful in monitoring clinical response and optimising the duration of antimicrobial treatment.

Can the estimation of ejection fraction during gated single photon emission computed tomography at rest add information to the cardiac perfusion study?

Left ventricular function is an important prognostic indicator in patients with coronary artery disease. The electrocardiogram gated, myocardial, single photon emission tomography (SPECT) program is coming into wide use. This program permits measurement of end diastolic volume, end systolic volume, and ejection fraction. This study was designed to show whether the measurement of ejection fraction by using (99c)Tc tetrofosmin gated SPECT at rest could give additional information to the interpretation of perfusion. Exercise 99mTc tetrofosmin SPECT and gated (99c)Tc tetrofosmin SPECT at rest were performed in 33 patients with or suspected of having coronary artery disease. Left ventricular ejection fraction was calculated from reconstructed gated SPECT at rest with a software quantitative gated SPECT. The results showed a poor correlation between segmental ejection fraction and segmental perfusion in stress and rest. There was an increasing probability of reversibility as the ejection fraction increased, while there was a greater chance of a fixed defect as the ejection fraction decreased. It is concluded that gated SPECT using (99c)Tc tetrofosmin provides clinically satisfactory functional data that, in combination with the perfusion information, will improve diagnostic and prognostic accuracy without an increase in cost or radiation dose to patients.

Ocular metastases secondary to carcinoid tumors: the utility of imaging with [(123)I]meta-iodobenzylguanidine and [(111)In]DTPA pentetreotide.

Ocular metastases from carcinoid tumors are considered rare. They can be the primary presentation of a carcinoid tumor or develop during the course of the disease. The extent of distant metastases from carcinoid tumors correlates with poor prognosis and survival; early detection of metastasis may change the overall management. Radiopharmaceutical-labeled imaging techniques have been widely applied for the detection and localization of such lesions based on isotope uptake by neuroendocrine tumors. Routine application of these imaging modalities may reveal previously unsuspected lesions and may also be used to help stage the disease and to identify patients who may be treated with radiopharmaceuticals. Of 40 patients with carcinoid tumors reviewed in our department since we started routine scanning, we identified 6 (15%) who demonstrated ocular metastases: 5 with obvious lesions and 1 with presumed metastasis according to the results of nucleotide scanning. All 6 were negative on screening with [(123)I]meta-iodobenzylguanidine, whereas 3 of 4 who were screened with [(111)In]octreotide showed positive uptake. All patients responded well to radiotherapy and chemotherapy and did not require surgical treatment. The orbit and its contents appear to be a common site for carcinoid metastasis, and radiopharmaceutical imaging with labeled octreotide is useful in identifying many of these lesions.

Axillary node status in breast cancer patients prior to surgery by imaging with Tc-99m humanised anti-PEM monoclonal antibody, hHMFG1.

In early breast cancer axillary nodes are usually impalpable and over 50% of such patients may have an axillary clearance when no nodes are involved. This work identifies axillary node status by imaging with a Tc-99m radiolabelled anti-Polymorphic Epithelial Mucin, humanised monoclonal antibody (human milk fat globule 1), prior to surgery in 30 patients. Change detection analysis of image data with probability mapping is undertaken. A specificity of 93% and positive predictive value of 92% (both 100% if a second cancer in the axilla with negative nodes is considered) were found. A strategy for combining negative imaging with the sentinel node procedure is presented.

The role of 123I-diagnostic imaging in the follow-up of patients with differentiated thyroid carcinoma as compared to 131I-scanning: avoidance of negative therapeutic uptake due to stunning.

OBJECTIVE: Some patients with relapsed differentiated thyroid cancer may show rising thyroglobulin (Tg) levels despite a lack of 131I uptake on routine whole body imaging. A significant proportion of these patients, after therapy doses of 131I, may demonstrate positive 131I uptake with a subsequent fall in serum Tg, implying a therapeutic effect. Attempts to identify such patients by increasing the dose of the diagnostic 131I tracer may lead to inhibition of subsequent uptake after the therapy dose, an effect referred to as 'stunning' and associated with a reduction in therapeutic effect. 123I is a short half-life gamma-emitter, thought to be unlikely to cause stunning, which may thus be more suitable than 131I for diagnostic imaging of thyroid cancer. DESIGN AND PATIENTS: The efficacy of the 123I radionuclide was determined in a longitudinal study of 12 patients who were selected only because they showed elevated serum Tg and a negative diagnostic 131I whole body study prior to therapy with 131I. RESULTS: There was almost complete concordance in uptake between 123I diagnostic imaging and the final scans carried out after 131I therapy (hereafter known as therapy studies) in 11 out of 12 patients at their first evaluation, in each of four patients receiving 123I at their second evaluation and in a single patient receiving 123I at a third evaluation. One patient had a positive 123I study but a negative 131I therapy study: following therapy Tg declined from 5.5 pg/l to undetectable levels, implying a therapeutic effect, and suggesting that the negative uptake was not the result of stunning. Two negative diagnostic 123I studies were followed by negative therapy studies, and thus there were no false negatives. 123I correctly identified disease in the nine patients with metastases in the lungs, mediastinum and bone at the first evaluation, in all four patients at the second evaluation and in the single patient at the third evaluation. At the end of the study, patients had received up to three 131I therapy doses, Tg had risen in four patients, fallen in eight and become undetectable in one patient. CONCLUSIONS: 123I is highly sensitive in diagnosing local recurrence and metastatic disease, and produces scintigraphic images which concord well with uptake following 131I therapy. It is proposed that 123I imaging, in combination with serum Tg measurements, should replace 131I tracer imaging as an indicator of the potential efficacy of 131I therapy. Stunning, with its detrimental effects on 131I therapy, may thus be avoided. The possibility of false negative images due to the stunning phenomenon must always be borne in mind if there is a discrepancy between positive 131I imaging studies and a surprisingly negative subsequent 131I therapy scan.

Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with (131)I-meta-iodobenzylguanidine [(131)I-mIBG].

OBJECTIVE: Meta-iodo-benzyl-guanidine labelled with 131-iodine [(131)I-mIBG] has been used extensively for imaging tumours originating from the neural crest but experience with its therapeutic use is limited, particularly for non-catecholamine secreting tumours. In order to assess the therapeutic response and potential adverse effects of the therapeutic administration of (131)I-mIBG, we have reviewed all patients who had received this form of treatment in our department. DESIGN: Retrospective analysis of the case notes of patients with neuroendocrine tumours who received treatment with (131)I-mIBG and were followed-up according to a defined protocol in a given time frame. PATIENTS: Thirty-seven patients (18 with metastatic carcinoid tumours, 8 metastatic phaeochromocytoma, 7 metastatic paraganglioma and 4 metastatic medullary carcinoma of the thyroid) treated with (131)I-mIBG over a 15-year period were included in this analysis. MEASUREMENTS: The symptomatic, hormonal and tumoural responses before and after (131)I-mIBG therapy over a median follow-up duration of 32 months (range 5-180 months) were recorded. Of the 37 patients (22 males; median age 51 years, range 18-81 years), 15 were treated with (131)I-mIBG alone whereas the other 22 received additional therapy. RESULTS: A total of 116 therapeutic (131)I-mIBG doses were administered [mean cumulative dose 592 mCi (21.9 GBq); range 200-1592 mCi (7.4-58.9 GBq)]. None of the patients showed a complete tumour response. However, 82% of patients treated with (131)I-mIBG alone and 84% who received additional therapy showed stable disease over the period of follow-up. Overall survival during the period of the study was 71%. The overall 5-year survival rate was 85% (95% confidence interval, 72-99%) for all patients and 78% (95% confidence interval, 55-100%) for the carcinoid group alone, according to Kaplan-Meier analysis. Symptomatic control was achieved in all the patients treated with (131)I-mIBG alone, and in 72% of those receiving additional therapy. Hormonal control was noted in 50% and 57% of patients, respectively. (131)I-mIBG therapy was safe and well tolerated. Serious side-effects necessitating the termination of (131)I-mIBG therapy were seen in only 2 of our patients. CONCLUSIONS: (131)I-mIBG therapy produces symptomatic and hormonal improvement and moderate tumour regression/stabilization in patients with metastatic neuroendocrine tumours with minimal adverse effects. It may be a valuable alternative or additional therapeutic option to the currently available conventional treatment modalities.