Utility of thallium-201 and iodine-123 metaiodobenzylguanidine in the scintigraphic detection of neuroendocrine neoplasia

Metaiodobenzylguanidine (MIBG) is a specific marker for neuroendocrine tumours, such as phaeochromocytoma, neuroblastoma, medullary thyroid cancer (MTC) and paraganglioma, but it suffers in some cases (especially in MTC) from a lack of sensitivity. Thallium is a well-known marker of cellularity with a great sensitivity and a lack of specificity. In order to determine whether the association of these two markers is able to improve the detection of neuroendocrine lesions, 137 scintigraphic examinations using MIBG and thallium were performed in 101 patients referred for suspicion or follow-up of neuroendocrine tumours. Thallium chloride was first injected (1 MBq/kg), images being acquired about 20 min after injection; ¹²³I-MIBG (4 MBq/kg) was then injected and images acquired 5 and 24 h later. In patients with phaeochromocytoma or neuroblastoma, thallium scintigraphy appeared of little help since no tumoural site was discovered by thallium accumulation alone. In contrast, thallium examination seemed of interest in the detection of paraganglioma and MTC, the association of the two radiopharmaceuticals increasing the number of detected sites.     

Clinical evaluation of 99mTc(V)-dimercapto succinic acid (DMSA) for imaging medullary carcinoma of thyroid and its metastasis

^99mTc(V)-DMSA kits developed by the Radiopharmaceutical Division, Bhabha Atomic Research Centre, have been evaluated for potential use in scanning medullary carcinoma of the thyroid and its metastases. There were 15 patients with proved medullary carcinoma and 6 patients with other differentiated thyroid carcinoma. Amongst the 15 patients with medullary carcinoma, 12(80%) showed positive localisation either in the primary or one or more metastatic sites. None of the six patients with carcinoma other than medullary showed increased concentration of ^99mTc (V)-DMSA. Of the 37 known metastatic sites in 15 patients with medullary carcinoma, 24 showed concentration of ^99mTc (V)-DMSA (64.9%). In addition, ^99mTc(V)-DMSA concentration was seen in 14 sites where no evidence of metastasis was revealed. The incidence of ^99mTc (V)-DMSA concentration in soft tissue and bone metastasis was similar.Isopharm, Radiopharmaceutical Division, BARC, Bombay-400 705, India     

Preparation and evaluation of 99mTc(V)-DMSA complex: Studies in medullary carcinoma of thyroid

Consequent to the promising results reported with ^99mTc(V)-DMSA for imaging certain types of soft tissue tumors, we have developed methods to prepare this radiopharmaceutical in three ways:-(i) from freshly prepared reagents, (ii) through the use of a two component kit and (iii) use of the standard renal DMSA kit by a modified recipe. The ^99mTc(V)-DMSA complex has been subjected to paper electrophoretic and chromatographic procedures and also biodistribution studies. The distinctly different behaviour of this new product compared to that of the well known renal DMSA complex has been clearly established. Scintiimaging in a preliminary clinical trial in patients with medullary carcinoma of the thyroid has been encouraging.     

Comparison of99mTc(V)-DMSA,201Tl and99mTc-MIBI imaging in the follow-up of patients with medullary carcinoma of the thyroid

Radionuclide scanning with tumour-seeking agents such as pentavalent technetium-99m dimercaptosuccinic acid [^99mTc(V)-DMSA], thallium-201 and technetium-99m sestamibi (MIBI) has been reported to be useful in the detection of medullary thyroid carcinoma (MTC). We undertook a study in 14 MTC patients to determine the comparative imaging potential of²⁰¹Tl, MIBI and^99mTc(V)-DMSA in the detection of recurrent or metastatic MTC. All patients underwent total thyroidectomy and had persistently elevated serum calcitonin levels after the surgery. Scintigraphic studies were carried out 20 min after the injection of 111 MBq of²⁰¹Tl or 555 MBq of MIBI and 2 h following the injection of 370 MBq of^99mTc(V)-DMSA. All scintigraphic findings were correlated with contemporaneous CT or MRI studies. CT, MRI and bone scans showed 42 (26 bone, 16 soft tissue) metastatic sites in 11 of the 14 patients. In the remaining three patients no lesions were detected during diagnostic evaluation.^99mTc(V)-DMSA showed all of the soft tissue metastases but could not show two bone lesions. On the other hand, MIBI imaging was false-negative in 22 (52%) sites and²⁰¹Tl was false-negative in 34 (80%) sites. Overall, lesion detection sensitivities for^99mTc(V)-DMSA, MIBI and²⁰¹Tl were 95%, 47% and 19% respectively. We conclude that^99mTc(V)-DMSA is clearly superior to MIBI and²⁰¹Tl in the follow-up of MTC patients.     

Preparation and clinical evaluation of technetium-99m dimercaptosuccinic acid for tumour scintigraphy

We describe a simple method of pentavalent technetium-99m dimercaptosuccinic acid [^99mTc(V)-DMSA] preparation for the imaging of medullary carcinoma of the thyroid using commercially available kits. ^99mTc(V)-DMSA is available at high pH (approximately 7.5) by adding NaHCO₃ solution in the presence of a small amout of reducing agent (SnCl₂). On the other hand, trivalent ^99mTc-DMSA [^99m-Tc(III)-DMSA] can be obtained at low pH (below 3) in the presence of an excess amount of reducing agent. In the clinical evaluation of a patient with a medullary carcinoma of the thyroid, only ^99mTc(V)-DMSA revealed an area of intense accumulation.     

99mTc(V)-DMSA seintigraphy in monitoring the response of bone disease to vitamin D3 therapy in renal osteodystrophy

Renal osteodystrophy (ROD) is a common and serious complication for uremic patients and patients are treated with 1,25-dihydroxyvitamin D3. The bone scanning agent 99mTc-phosphate has also been used to evaluate in ROD but it is not clear that bone scintigraphy has a role in the follow-up of treatment. In this study 99mTc(V)-DMSA scintigraphy was performed in eleven patients [age 40.7 +/- 17.3 (mean +/- SD) yr] with ROD before and after vitamin D3 therapy. Images were obtained after hemodialysis performed following tracer injection to maintain normal blood levels of the radiopharmaceutical and to reduce soft tissue activity. Lumbar vertebra-to-soft tissue uptake ratios (LUR) were quantified with the planar 99mTc(V)-DMSA images. Alkaline phosphatase and parathyroid hormone levels after treatment had significantly decreased compared with pre-therapy. In all patients there was visually decreased uptake in bone structures after treatment. After treatment the mean LUR ratio was significantly lower than those of before treatment (3.59 +/- 2.63 vs. 1.65 +/- 0.62; p = 0.01). LUR values were correlated with pre-therapy alkaline phosphatase and parathyroid hormone. These findings indicate that 99mTc(V)-DMSA scintigraphy is sensitive in evaluating the response of ROD to vitamin D3 therapy.     

Comparison of metabolic and receptor imaging in recurrent medullary thyroid carcinoma with histopathological findings

Early diagnosis of metastases of medullary thyroid carcinoma (MTC) provides the optimal condition for curative outcome. The aim of this study was to appraise the detection of metastases in patients with recurrent MTC using [¹¹¹In-DTPA-d-Phe¹]-pentetreotide and pentavalent technetium-99m dimercaptosuccinic acid [^99mTc(V)-DMSA] in comparison with histopathological findings. Eighteen MTC patients with persistently elevated tumour marker (calcitonin, carcinoembryonic antigen) levels underwent somatostatin receptor scintigraphy using [¹¹¹In-DTPA-d-Phe¹]-pentetreotide (222 MBq) with early (4 h after injection) and delayed (24 h) whole-body scans and single-photon emission tomography (SPET) imaging. Metabolic whole-body and SPET imaging using 500 MBq ^99mTc(V)-DMSA was performed 4 h after injection. Metabolic and receptor imaging revealed 51 sites of focal accumulation in the 18 patients investigated. Comparison with histological findings revealed that metabolic and receptor imaging had a sensitivity of 84% for the diagnosis of MTC. Using [¹¹¹In-DTPA-d-Phe¹]-pentetreotide, SPET discovered four lymph node metastases in two patients in whom planar views had previously identified only one lymph node metastasis, and provided no new information in the other 16 patients. In comparison, SPET studies [using ^99mTc(V)-DMSA] additionally localized eight lymph node metastases in four patients and confirmed the diagnosis of hepatic metastases (n=5) in another patient in whom conventional imaging modalities and planar views had previously detected only three liver metastases. Overall, lesion detection sensitivities for ^99mTc(V)-DMSA and [¹¹¹In-DTPA-d-Phe¹]-pentetreotide were 69% and 29%, respectively. Five surgically removed foci were adjudged false-positive with respect to MTC metastases. False-positve results were caused by lymphadenitis, an enchondroma and a pheochromocytoma (histologically proven). The smallest lesion identified by metabolic imaging was a 6 mm in diameter lymph node metastasis located in the upper mediastinum. Somatostatin receptor scintigraphy only demonstrated tumour sizes more than 1 cm in diameter. These preliminary results suggest that the combination of metabolic [^99mTc(V)-DMSA] and receptor ([¹¹¹In-DTPA-d-Phe¹]-pentetreotide) imaging is more sensitive for tumour localization in patients with recurrent MTC than the use of only one radiopharmaceutical. However, neither ^99mTc(V)-DMSA nor [¹¹¹In-DTPA-d-Phe¹]-pentetreotide is specific for MTC and false-positive scintigraphic findings have to be considered. Furthermore, somatostatin receptor scintigraphy cannot visualize small tumour sites (<1 cm). Further studies are needed to evaluate the role of combined metabolic and receptor imaging in the management of patients with recurrent MTC. Received 10 February and in revised form 20 May 1998     

<Superscript>99m</Superscript>Tc-labelled HYNIC-minigastrin with reduced kidney uptake for targeting of CCK-2 receptor-positive tumours

Purpose Different attempts have been made to develop a suitable radioligand for targeting CCK-2 receptors in vivo, for staging of medullary thyroid carcinoma (MTC) and other receptor-expressing tumours. After initial successful clinical studies with [DTPA⁰,DGlu¹]minigastrin (DTPA-MG0) radiolabelled with ¹¹¹In and ⁹⁰Y, our group developed a ^99mTc-labelled radioligand, based on HYNIC-MG0. A major drawback observed with these derivatives is their high uptake by the kidneys. In this study we describe the preclinical evaluation of the optimised shortened peptide analogue, [HYNIC⁰,DGlu¹,desGlu^2–6]minigastrin (HYNIC-MG11). Methods ^99mTc labelling of HYNIC-MG11 was performed using tricine and EDDA as coligands. Stability experiments were carried out by reversed phase HPLC analysis in PBS, PBS/cysteine and plasma as well as rat liver and kidney homogenates. Receptor binding and cell uptake experiments were performed using AR4-2J rat pancreatic tumour cells. Animal biodistribution was studied in AR4-2J tumour-bearing nude mice. Results Radiolabelling was performed at high specific activities and radiochemical purity was >90%. ^99mTc-EDDA-HYNIC-MG11 showed high affinity for the CCK-2 receptor and cell internalisation comparable to that of ^99mTc-EDDA-HYNIC-MG0. Despite high stability in solution, a low metabolic stability in rat tissue homogenates was found. In a nude mouse tumour model, very low unspecific retention in most organs, rapid renal excretion with reduced renal retention and high tumour uptake were observed. Conclusion ^99mTc-EDDA-HYNIC-MG11 shows advantages over ^99mTc-EDDA-HYNIC-MG0 in terms of lower kidney retention with unchanged uptake in tumours and CCK-2 receptor-positive tissue. However, the lower metabolic stability and impurities formed in the labelling process still leave room for further improvement. Parts of this study were presented at the Annual Congress of the European Association of Nuclear Medicine, Istanbul, Turkey, October 2005 and at the 7th International Symposium on Technetium in Chemistry and Nuclear Medicine, Bressanone, Italy, September 2006.     

Diffuse Myocardial Uptake of 99mTc-HDP in Multiple Myeloma

Soft tissue uptake is a rare finding in bone scintigraphy, with an incidence of 2%. Although the mechanism has not yet been fully clarified, several causes have been reported for this unusual uptake pattern. This paper presents a case of diffuse myocardial accumulation of technetium-99m hydroxymethylene diphosphonate (^99mTc-HDP) without either solid/visceral organ or soft tissue with multiple myeloma (MM) in skeletal scintigraphy. A 93-year-old man with hypertension and chronic heart failure for 14 years underwent bone scanning due to a 2-month history of back pain within a 1-year period of MM. Three hours later, ^99mTc-HDP late static images showed diffuse myocardial radiotracer accumulation and there were no other sites of abnormal soft tissue or visceral uptake. Myocardial accumulation had disappeared on 24-h delayed static images. This accumulation was thought to be related with AL-type amyloidosis associated with MM.     

Abnormal uptake of technetium-99m hexakis-2-methoxyisobutylisonitrile in a primary cardiac lymphoma

Abnormally high uptake of technetium-99m hexakis-2-methoxyisobutylisonitrile (^99mTc-SESTAMIBI) in the right ventricle and in the septum was observed in a 47-year-old woman initially presenting with dysarthria and left hemiparesis. Endomyocardial biopsy demonstrated a high-grade malignant non-Hodgkin's lymphoma. Complete remission was achieved by combined cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy and radiotherapy of the heart and mediastinum. The post-remission single photon emission tomography (SPET) ^99mTc-SESTAMIBI study showed a homogeneous distribution pattern, in agreement with echocardiography computed tomography and magnetic resonance imaging. Increased uptake of ^99mTc-SESTAMIBI, a myocardial perfusion agent, has been observed in some benign and malignant tumours. It may prove to be useful in the diagnosis and follow-up of malignancies. Offprint requests to: G. Medolago     

Radio-guided surgery with the use of [<Superscript>99m</Superscript>Tc-EDDA/HYNIC]octreotate in intra-operative detection of neuroendocrine tumours of the gastrointestinal tract

Purpose Radio-guided surgery (RGS) is an intra-operative localising technique which enables identification of tissue “marked” by a specific radiotracer injected before surgery. It is mainly used for sentinel node mapping and for detection of parathyroid adenomas and other tumours, including neuroendocrine tumours of the gastrointestinal tract (GEP-NET). The aim of this study was to determine whether intra-operative radio-detection with the use of [^99mTc-EDDA/HYNIC]octreotate, a new somatostatin analogue, is able to reveal an unknown primary and secondary sites, thereby improving surgical treatment and the final outcome of GEP-NET. Methods The study group included nine patients with suspected GEP-NET (four carcinoids, five pancreatic NET) localised with somatostatin receptor scintigraphy (with [^99mTc-EDDA/HYNIC]octreotate), who had negative results on other pre-operative imaging tests. At surgery, suspected tumours were measured in situ and ex vivo and precise exploration of the abdominal cavity was performed with the intra-operative scintillation detector (Navigator). Results Intra-operative gamma counting localised three carcinoids. In one patient SRS was false positive (owing to inflammatory infiltration). Compared with SRS, RGS revealed additional lymph node metastases in one case. RGS resulted in successful localisation of all pancreatic NET (the smallest lesion was 8 mm in diameter). Conclusion [^99mTc-EDDA/HYNIC]octreotate SRS followed by RGS is a promising technique to improve the rate of detection and efficacy of treatment of GEP-NET, especially in the presence of occult endocrine tumours. The imaging properties of [^99mTc-EDDA/HYNIC]octreotate and the 1-day imaging protocol offer opportunities for more widespread application of this tracer followed by RGS in oncology.     

A micro-autoradiographical study of the localization of 99mTc(Sn)-MDP and 99mTc-MDP in undecalcified bone sections

The localization of ^99mTc(Sn)-MDP in bone tissue was compared with ^99mTc-MDP by means of microautoradiography of undecalcified bone sections. Sections of good histological quality were obtained by a rapid embedding method in methylmethacrylate. No differences were found in the localization of these radiopharmaceuticals in fetal rat calvariae after incubation in vitro or in rat femora after administration in vivo. In the incubation experiment, hydrolyzed ^99mTc was formed. The uptake was high in areas of new bone formation. No uptake was seen in cells or in resorbing areas. In compact bone ^99mTc(Sn)-MDP was predominantly taken up in the vicinity of blood vessels.     

Usefulness of technetium-99m hydroxymethylene diphosphonate scans in localizing bone metastases of differentiated thyroid carcinoma

Iodine-131 is uniquely able to demonstrate iodine uptake of differentiated thyroid carcinoma (DTC), but precise localization may be difficult, especially in the thorax, due to the quality of image resolution with 1311 and the lack of anatomical landmarks. When bone metastases do not show radioiodine uptake, bone scintigraphy can be used to detect them. We studied two groups of patients. In group 1, 15 patients with known bone metastases of DTC were treated with 3.7 GBq ¹³¹I. After 4 or 5 days, technetium-99m hydroxymethylene diphosphonate (HMDP; 740 MBq) was injected and a whole-body scan with simultaneous acquisition of ¹³¹I and ^99mTc-HMDP images was carried out using a large field of view gamma camera fitted with a high-energy collimator. Technetium uptake was abnormal in 47 of 63 localizations, being increased in 29 foci, decreased in 7 and heterogeneous in 11. The superimposition of ¹³¹I and ^99mTc-HMDP scans permitted an accurate localization in 80% of spine metastases and in 46% of osseous thoracic localizations, even in the presence of lung metastases. In group 2, 9 patients, who had bone pain, neurological signs or elevated serum thyroglobulin, had DTC bone metastases without iodine uptake. They received a diagnostic dose of ^99mTc-HMDP 3h prior to scintigraphy with a large field of view gamma camera fitted with a low-energy collimator. Technetium uptake was abnormal in 37 of 38 localizations, being increased in 34 foci and decreased in 3. One false-negative was found in a skull metastasis. In both groups of patients, ^99mTc-HMDP scans were useful. The procedure allows accurate localization of bone metastases and can be used as a guide for subsequent radiological investigations.     

Correlation between 99mTc-(V)-DMSA uptake and constitutive level of phosphorylated focal adhesion kinase in an in vitro model of cancer cell lines

Purpose Although a number of prognostic indicators have been developed, it is still difficult to predict the biological behaviour of all cancer types. ^99mTc-(V)-DMSA (V DMSA) uptake and focal adhesion kinase (FAK) expression and activation level could be potential agents for this purpose. We hypothesised the existence of a correlation between V DMSA, whose uptake is linked to phosphate ions, essential compounds for tumour growth and cell proliferation, and the adhesion protein FAK, whose elevated expression and level of constitutive activation are implicated in cancer progression. The aim of this study was to assess the relationship between V DMSA incorporation rate and FAK expression and activation by phosphorylation on tyrosine 397 residue.Methods We determined V DMSA uptake in six different cancer cell lines and we measured FAK expression and activation by using Western Blotting analysis. Correlations with factors known to be associated with poor prognosis, such as invasive potential, resistance to chemotherapy and proliferation rate, were also investigated. Results The cell lines exhibited different V DMSA incorporation rates. In addition, these cells showed the same FAK expression, but various degrees of activation. A correlation was observed between V DMSA uptake and level of FAK phosphorylation and between V DMSA or constitutive FAK activation and proliferation rate. However, no correlation was shown between these parameters and the other factors tested, i.e. invasive potential and anticancer drug resistance.Conclusion The results of this in vitro study clearly demonstrate that phosphorylation of FAK, proliferation rate and V DMSA uptake are closely related. Because proliferation and a high level of constitutive FAK activation are linked to cancer progression, it can be assumed that in vivo V DMSA uptake reflects tumour aggressiveness.     

Search for polynuclear pentavalent technetium complex of dimercaptosuccinic acid [Tc(V)-DMS] tumour localization mechanism

To search for the tumour localization mechanism of Tc(V)-DMS, a polynuclear pentavalent technetium complex of dimercaptosuccinic acid [Tc(V)-DMS], the development of medullary thyroid carcinoma (MTC) bearing mouse model was considered. Subcutaneously transplanted tumour was allowed to grow for 2, 4 and 6 weeks, and the influence of the tumour stage on the biodistribution of Tc(V)-DMS was screened. High radioactivity uptake in the tumour tissue was observed, and this accumulation showed a direct correlation with tumour growth and calcitonin secretion, the MTC marker detectable in the blood serum. The gathered data implicated some calcitonin-related factors as the mediator in the Tc(V)-DMS localization; participation of a phosphate-like oxoanion, TcO₄ ^3–, is strongly suggested not only by the high radioactivity accumulation in the calcitonin-producing tumour but also by the accumulation in the bones of this model animal.Offprint requests to: A. Yokoyama     

Dosimetry of iodine 131 metaiodobenzylguanidine for treatment of resistant neuroblastoma: results of a UK study

In 1987, the United Kingdom Children's Cancer Study Group (UKCCSG) set up a multi-centre study to investigate the toxicity of iodine 131 metaiodobenzyl-guanidine (mIBG) in the treatment of resistant neuroblastoma. Since December 1987, 25 children suffering from neuroblastoma have been treated with¹³¹I-mIBG at six UK centres. All centres followed standardised physics and clinical protocols to provide consistent toxicity and dosimetry data. These protocols describe the methods employed for both the tracer study using¹³¹I-mIBG and the subsequent therapy. Whole-body dosimetry calculations were performed on data from the tracer study. The activity administered for therapy was the amount predicted to deliver a predefined whole-body dose. Estimates of doses delivered to various organs during treatment are given in Table 1.On behalf of the mIBG Targetting Group of the United Kingdom Children's Cancer Study Group (UKCCSG), University of Leicester, Leicester, UK:Members of the mIBG Targetting Group: Christie Hospital, Manchester- P. Nuttall, S. Owens (Physics), H.R. Gattamaneni (Radiotherapy); Cookridge Hospital, Leeds - M. Sheppard, S. Packar (Physics), S. Cartright, R. Taylor (Radiotherapy); Newcastle General Hospital - A. Simpson, P. Bartholomew (Physics), H. Lucraft (Radiotherapy); Medical School, University of Newcastle upon Tyne - A. Pearson (Paediatric Oncology); Royal Hospital for Sick Children, Edinburgh - T. Eden (Paediatric Oncology); Royal Manchester Childrens' Hospital - P. Morris-Jones (Paediatric Oncology); Royal Marsden Hospital, Sutton - R. Ott, M. Rosenbloom (Physics), S. Meller, R. Corbett, R. Pinkerton (Paediatric Oncology); Royal South Hants Hospital, Southampton - V. Hall (Radiotherapy); Royal Victoria Infirmary, Newcastle upon Tyne - A. Craft (Paediatrics); Southampton General Hospital - G. Blake, M. Tristam (Physics), J. Kohler (Paediatric Oncology), V. Lewington (Nuclear Medicine); St Bartholomews Hospital, London - K. Britton, L. Hawkins (Nuclear Medicine), J. Kingston, J. Moyes (Paediatric Oncology), J. Malpas (Oncology), N. Plowman (Radiotherapy); Western General Hospital, Edinburgh - J. Hannan (Physics), M. Merrick (Nuclear Medicine), A. Rodger (Radiotherapy); Western Infirmary, Glasgow - T. Hilditch (Physics), A. Barrett (Radiotherapy), T. Wheldon, J. O'Donoghue (Radiobiology); Amersham International, Bucks-R. Bayly; UKCCSG Offices, Leicester-J. Barnes.     

Technetium-99m human polyclonal immunoglobulin G studies and conventional bone scans to detect active joint inflammation in chronic rheumatoid arthritis

Rheumatoid arthritis is a chronic polyarthritis in which active inflammed joints coexist with joints in remission. We performed bone scans (^99mTc-DPD) and ^99mTc human polyclonal immunoglobulin G scans (^99mTc-IgG) in 18 patients with rheumatoid arthritis to assess the uptake in actively inflamed joints and in joints in which remission after inflammation had occurred. A quantitative analysis of tracer uptake in each joint was performed on both scans. In 123 joints without current active inflammation, an increased ^99mTc-DPD uptake was observed (2.31 ± 1.27), whereas no ^99mTc-IgG uptake was noted (1.18±0.32). Some 78 joints with mild pain or swelling exhibited increased ^99mTc-DPD uptake (2.48 ± 1.14) and increased ^99mTc-IgG uptake (1.76 ± 0.50; P <0.001), while 21 joints with moderate to severe pain or swelling exhibited increased ^99mTc-DPD uptake (2.39±0.93) and increased ^99mTc-IgG uptake (1.79±0.51; P <0.001). In conclusion, ^99mTc-IgG scans distinguish between joints with and without active inflammation in chronic rheumatoid arthritis, whereas bone scans do not. Thus, ^99mTc-IgG scans may be useful in identifying joints with current active inflammation in rheumatoid arthritis.Work was supported by a research grant from Mallinckrodt Ibér-ica Offprint requests to: L. Berná     

Evaluation of the pharmacokinetics of 68Ga-DOTATOC in patients with metastatic neuroendocrine tumours scheduled for 90Y-DOTATOC therapy

Purpose The purpose of the study was to evaluate the pharmacokinetics of ⁶⁸Ga-DOTATOC in order to ascertain which parameters have the greatest impact on the global DOTATOC standardised uptake value (SUV), defined as the mean SUV of the last frame of the dynamic study 55–60 min p.i. Methods Twenty-two patients with 74 metastatic lesions were examined with dynamic ⁶⁸Ga-DOTATOC PET studies. Standardised uptake values (SUVs) were calculated for all frames following the injection of the tracer. We defined global SUV as the mean SUV of the last frame (frame duration 5 min) of the dynamic study 55–60 min p.i. A two-tissue compartment model with a blood compartment was used for the evaluation of the rate constants k ₁ (receptor binding), k ₂ (displacement from the receptor), k ₃ (cellular internalisation), k ₄ (cellular externalisation) and fractional blood volume (V_b). Furthermore, a non-compartmental model was applied for calculation of the fractal dimension (FD) of the time-activity curves based on the box counting procedure. Results Qualitative analysis revealed increased uptake of ⁶⁸Ga-DOTATOC in 21/22 patients and in 72/74 lesions. The SUV for ⁶⁸Ga-DOTATOC was highly variable, with a range from 0.877 to 28.07 (mean 8.73). The highest uptake was measured in a patient with a NET of the pancreas and the lowest in a patient with a medullary thyroid carcinoma (MEN II). The quantitative evaluation based on the compartmental analysis revealed high receptor binding (k ₁) and internalisation (k ₃) for ⁶⁸Ga-DOTATOC, and low cellular externalisation (k ₄) as well as a relatively low fractional blood volume (V_b). The FD values varied from 1.10 to 1.45, with a mean of 1.33. No significant linear correlation was found for k ₁ and k ₃. A low, linear correlation was noted for k ₁ and V_b (r=0.25,p=0.03), and there was a significant non-linear correlation between SUV and FD (r=0.74, p<0.001). Best subset analysis demonstrated that k ₁ had the greatest impact on the global SUV, followed by V_b and k ₃. Conclusion DOTATOC uptake in NETs is mainly dependent on k ₁ (receptor binding) and V_b (fractional blood volume). Pharmacokinetic data analysis can help to separate blood background activity (V_b) from the receptor binding (k ₁), which may help to optimise planning of ⁹⁰Y-DOTATOC therapy.     

Influence of Pi3-K and PKC activity on 99mTc-(V)-DMSA uptake: correlation with tumour aggressiveness in an in vitro malignant glioblastoma cell line model

Purpose Intensive proliferation and a high degree of migration and invasion are characteristic features of malignant glioblastomas, associated with a poor prognosis. Phosphatidylinositol-3-kinase (Pi3-K) and protein kinase C (PKC) are two phosphorylated proteins involved in glioblastoma cell progression. Phosphorylated focal adhesion protein kinase (FAK) has also been reported to be involved in tumour progression. In a recent study, we demonstrated a correlation between phosphorylated FAK, proliferation rate and ^99mTc-(V)-dimercaptosuccinate [(V)-DMSA] uptake. We hypothesised that ^99mTc-(V)-DMSA could be a potential imaging agent to evaluate glioblastoma aggressiveness. The aim of the present study was to assess the relationship between ^99mTc-(V)-DMSA incorporation rate and modulation of Pi3-K and PKC activity.Methods Proliferation, migration and invasion capacities in the presence of protein kinase modulators—staurosporine (PKC inhibitor), 4-phorbol 12-myristate 13-acetate (PMA; PKC activator) and LY294002 (Pi3-K inhibitor)—were correlated with ^99mTc-(V)-DMSA cell accumulation in an in vitro model of several malignant glioma cells: G111 (grade II), U-87-MG (grade III) and G152 (grade IV).Results In all cell lines tested, LY294002 and staurosporine treatment inhibited cell proliferation, migration and invasion. In contrast, treatment with PMA stimulated tumour aggressiveness. ^99mTc-(V)-DMSA uptake was strongly correlated with the % of cellular proliferation (r=0.8462) and the % of cellular migration (r=0.9081), and to a lesser extent with the % of cellular invasion (r=0.7761).Conclusion Our results clearly demonstrated that ^99mTc-(V)-DMSA reflects Pi3-K and PKC activity and is correlated with tumour aggressiveness. ^99mTc-(V)-DMSA could be a reliable in vivo marker providing additional information on the biological status of malignant glioblastoma.