To use MIBI or not to use MIBI? That is the question when assessing tumour cells

^99mTc-sestamibi (MIBI) is a well-known tumour imaging agent. Its retention within tumour cell mitochondria is related to perfusion and to the magnitude of the electrical gradient, reflecting cell viability. Several internal cell factors modulate this uptake; for example, multidrug resistance membrane proteins (Pgp and MRP1) and anti-apoptotic BCl-2 protein of the outer mitochondrial membrane can limit retention of MIBI. At the early stage of cell apoptosis, the electrical driving forces of MIBI uptake are impaired, and influx and accumulation are reduced. It seems clear that MIBI can be used before treatment to detect drug resistance, assess anti-apoptotic status and predict treatment efficacy. Although it has been suggested that MIBI might be used to monitor tumour response to treatment, MIBI is unable to differentiate tumours with ongoing apoptosis from those developing drug resistance.     

In vivo evaluation of 111In-DTPA-N-TIMP-2 in Kaposi sarcoma associated with HIV infection.

Matrix metalloproteinases are the major agents responsible for the degradation of extracellular matrix and are produced at high levels by transformed and tumour cells, where they participate in the metastatic process by allowing local invasion. They are also more active at sites of new normal growth and angiogenesis. In the early stages of Kaposi sarcoma (KS), in vitro studies have demonstrated that vascular invasion can be inhibited by inhibitors of matrix metalloproteinases. Imaging of visceral and cutaneous KS presents a problem and therefore the potential use of a labelled inhibitor of metalloproteinases, N-TIMP-2, with indium-111 was thought to present a possible imaging tool. The biokinetics, dosimetry and potential for imaging with 111In-DTPA-N-TIMP-2 were assessed in five patients with HIV infection and KS. Between 103.1 and 108.0 MBq of this agent was injected into each patient, and the dynamic uptake over the kidneys was assessed, whole body scans were performed and blood samples were obtained. The clearance from the blood was rapid, with a first component half-time of 16.6+/-3.4 min and a second component half-time of 9.68+/-2.68 h. Two out of five patients experienced minor shivering but one of these patients was generally unwell before the study. The last three patients had no such problems. The tracer distributed predominantly to the kidneys and did not localise in other tissues. No KS lesions were clearly identified. 111In-DTPA-N-TIMP-2 can be successfully prepared and administered to patients safely, with a biodistribution and dosimetry which would allow its use as an imaging tracer. It is unlikely to be of use for imaging KS, but may have a role in other tumours that produce matrix metalloproteinases.     

Effect of steroids on [18F]fluorodeoxyglucose uptake in an experimental tumour model

BACKGROUND: It is well known that blood glucose level affects the uptake of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) in tumours. Thus, the action of steroids on glucose metabolism may alter blood glucose levels and may affect FDG uptake in tumours in patients treated with steroids. To clarify this point, we determined the effects of steroids on FDG uptake in tumours in a rat model of a malignant tumour. METHODS: Rats were inoculated with allogenic hepatoma cells (KDH-8) into the left calf muscle. They were fasted overnight and divided into three groups (n=5 in each group): (1) dexamethasone (DEX) pretreated (0.8 mg.kg(-1) body weight, i.m. injection 4 h before FDG i.v. injection); (2) prednisolone (PRE) pretreated (8 mg.kg(-1) body weight, i.m. injection 20 h before FDG i.v. injection); and (3) control (untreated) groups. Radioactivity in tissues was determined 1 h after i.v. injection of FDG. FDG uptake in the tumour was expressed as the percentage of injected dose per gram of tissue after normalization to animal's weight (%ID/g tissue/kg body weight). RESULTS: DEX and PRE pretreatments significantly increased the blood glucose levels to 128% and 145% of the control value. The levels of FDG uptake in the tumour were not significantly affected by DEX and PRE pretreatment (90% and 87% of the control value, respectively) (P=NS). CONCLUSIONS: These results demonstrate that FDG uptake in the tumour was not affected by pretreatment with steroids, in spite of a slight elevation in blood glucose level.     

An evaluation of 99mTc-HMPAO uptake in cerebral gliomas--a comparison with X-ray CT

Nineteen patients with biopsy-proven cerebral gliomas were studied with 99mTc-HMPAO single photon emission tomography (SPECT) imaging and X-ray computed tomography (CT). The uptake of 99mTc-HMPAO was correlated with tumour size and morphology as shown by X-ray CT, and overall patient survival. It appears that uptake of 99mTc-HMPAO is associated with larger, ill-defined tumours and was an adverse factor in patient survival. In those tumours with normal or increased uptake, 99mTc-HMPAO imaging is useful in distinguishing the tumour margin from surrounding oedema.     

Imaging features of primary and secondary malignant tumours of the sacrum

Malignant tumours of the sacrum may be primary or secondary. While sacral metastases are frequently encountered, a diagnostic dilemma can present when there is a single sacral bone tumour with no history or evidence of malignancy elsewhere in the body. Familiarity with the imaging features and clinical presentations of primary malignant bone tumours is helpful in narrowing the differential. This pictorial review will illustrate with both common and uncommon malignant sacral tumours CT, MRI and positron emission tomography/CT, highlighting the specific features of each.     

Technetium-99m sestamibi brain single-photon emission tomography for detection of recurrent gliomas after radiation therapy

Technetium-99m sestamibi (MIBI), an alternative radiopharmaceutical for myocardial perfusion imaging, has also been proposed for use as an imaging agent for various tumours, including breast cancer, lung cancer, lymphomas, melanomas and brain tumours. After routine radiation therapy, deteriorating clinical status or treatment failure may be due to either radiation-induced changes or recurrent tumour. Computed tomography and magnetic resonance imaging offer imperfect discrimination of tumour viability and radionecrosis. Against this background we undertook a retrospective study of 35 malignant glioma patients in whom clinical deterioration had occurred, in order to clarify the value of ^99mTc-MIBI SPET in identifying tumour recurrence. SPET was performed 15 min after intravenous injection of 1110 MBq ^99mTc-MIBI. The images were obtained with a dual-headed gamma camera using a fan-beam collimator. Transverse, coronal and sagittal views were reconstructed. Intense MIBI uptake was found in 31 patients. This uptake was correlated with tumour recurrence as proved by histology and/or rapid, fatal evolution of these cases. The statistical analysis performed on this population of patients with MIBI uptake revealed a group of patients with a long mean survival and a group with a short mean survival. Two subgroups were found within each of these groups, according to the functional index ratio (tumour uptake/pituitary gland uptake ratio). No MIBI uptake was found in four patients who are still alive and can be considered to be disease-free. In those cases showing MIBI uptake, death occurred an average of 6.69 months following brain SPET. According to our results, the specificity and sensitivity of ^99mTc-MIBI brain SPET seem to be high. Moreover, this technique is more accurate than computed tomography or magnetic resonance imaging for discriminating between tumour recurrence and radionecrosis. Received 9 April and in revised form 9 July 1998     

Comparison of the distribution of fluorine-18 fluoromisonidazole, deoxyglucose and methionine in tumour tissue.

To evaluate the tumour imaging potential of fluorine-18 fluoromisonidazole (FMISO), we studied FMISO uptake in an experimental tumour model and examined the correlation between intratumoral distributions of FMISO, 14C-2-deoxyglucose (2DG) and 14C-methionine (Met). The study was performed using control rats with the AH109A tumour and rats with the same tumour under local hypoxia. Tumour uptake of FMISO was constant between 30 min and 2 h after injection, and the tumour to muscle ratio was 2 from 2 to 4 h. A tumour study with FMISO was scheduled at 2 h. Double-tracer autoradiography of the tumour demonstrated that in the areas of high FMISO uptake, there was low uptake of Met, while areas of low FMISO uptake showed high Met uptake. FMISO showed high grain density in the rim of the tumour surrounding the necrotic area. 2DG showed a more uniform distribution over the entire section of viable cells. The mean uptake of FMISO by hypoxic, radioresistant tumours was significantly higher than that by the control tumours (P<0.05), while both 2DG and Met uptake by the control tumours was higher than uptake by hypoxic tumours. When individual tumours were examined, the uptake of FMISO was inversely correlated with that of Met (r = -0.507, P<0.02), while 2DG showed almost uniform uptake with no significant correlation to FMISO. In conclusion, hypoxic and radioresistant tumours could be identified by increased FMISO uptake in our model, consistent with findings reported by others. We found a large overlap in the distribution of FMISO and 2DG within the tumour, but only a small overlap in the distribution of FMISO and Met. A combination of FMISO and other tracers in positron emission tomography or single-photon emission tomography studies might be more helpful than single-tracer studies in predicting the response of tumour tissues to radiotherapy.     

改良注射核素骨显像剂的拔针方法可提高图像质量

目的 探讨改良注射核素骨显像剂的拔针方法对全身骨显像图像质量的影响。方法 静脉注射核素骨显像剂后用两种方法拔针。常规组117例,拔针方法以一根棉签按压穿刺点迅速拔出针头,按压片刻。改良组117例,拔针方法以两根棉签置于针头进皮肤及血管两点,拔出针头同时按压两个进针点5min以上。2h后行SPECT全身骨骼平面显像。结果 常规组注射部位显像剂浓聚的发生率为16.24%,改良组为2.56%。结论 改良注射核素骨显像剂的拔针方法使注射部位显像剂浓聚的发生率明显下降,可以提高全身骨显像图像质量。     

改良注射核素骨显像剂的拔针方法可提高图像质量

目的 探讨改良注射核素骨显像剂的拔针方法对全身骨显像图像质量的影响.方法 静脉注射核素骨显像剂后用两种方法拔针.常规组117例,拔针方法以一根棉签按压穿刺点迅速拔出针头,按压片刻.改良组117例,拔针方法以两根棉签置于针头进皮肤及血管两点,拔出针头同时按压两个进针点5min以上.2h后行SPECT全身骨骼平面显像.结果 常规组注射部位显像剂浓聚的发生率为16.24%,改良组为2.56%.结论 改良注射核素骨显像剂的拔针方法使注射部位显像剂浓聚的发生率明显下降,可以提高全身骨显像图像质量.     

The effect of chemotherapy on the uptake of technetium-99m sestamibi in breast cancer

Technetium-99m sestamibi scintimammography has been used primarily in the diagnosis of breast cancer. It has also been suggested that this technique could be used to monitor response to chemotherapy and possibly to predict those patients in whom no response can be expected. An initial study was performed in nine patients with primary breast cancer. All patients underwent prone lateral and anterior^99mTc-sestamibi imaging at diagnosis and 4–7 months later, after they had received cytotoxic chemotherapy. The uptake of^99mTc-sestamibi in the breast was compared with that in normal surrounding breast tissue and this ratio was expressed as the target to background ratio. In all patients treated there was a reduction in uptake of^99mTc-sestamibi after treatment, such that whilst all the tumours could be seen before treatment, only three were visible following chemotherapy. There was a significant fall in the mean target to background ratio of the patients undergoing chemotherapy: the tumour to background ratio was 2.48 before chemotherapy and 1.40 after treatment (P<0.001, paired Student'st test). This fall in tumour activity was observed both in those patients in whom a clinical response was seen and in the two patients in whom the tumour enlarged despite chemotherapy. It appears that the reduced uptake of^99mTc-sestamibi seen after chemotherapy may be a non-specific change and therefore may not be predictive of the clinical response to treatment.     

Evaluation of a technique for the intraoperative detection of a radiolabelled monoclonal antibody against colorectal cancer.

Occult tumour deposits may be localised at operation with a radiation detecting probe following the administration of a radiolabelled monoclonal antibody (MoAb) recognising a tumour-associated antigen. We have recently evaluated the clinical usefulness of this technique in detecting primary colorectal tumours targetted with an indium-111 MoAb. In the present study the physical characteristics of the two detector systems used were investigated; a sodium iodide [NaI(Tl)] scintillation detector and a cadmium telluride (CdTe) semiconductor probe. Limitations of the technique in use have been examined by testing the statistical significance of tumour detection using an abdominal phantom based on the currently available clinical biodistribution data for tumour uptake of radiolabelled MoAbs. The effect of tumour volume, antibody uptake, collimation and counting conditions was examined. Results indicate that tumours of 10 ml volume may be detected with the NaI(Tl) probe at the lowest levels of radiolabelled antibody uptake currently reported in the literature but that at higher published levels, lesions as small as 1 ml may be identified with both detector systems. Detector sensitivity and limited antibody specificity restrict the usefulness of the technique, although moderate improvements in tumour uptake may allow the detection of tumour deposits not clinically apparent. The statistical significance criterion used for this study could be an accurate and reliable indicator for tumour detection in vivo.     

Techniques and trouble-shooting in high spatial resolution thin slice MRI for rectal cancer

MRI is increasingly advocated as an optimal method of staging rectal cancer. The technique enables depiction of the relationship of tumour to the mesorectal fascia and may thus identify tumours at risk of positive circumferential margin involvement at surgery. Depth of extramural spread may also be accurately measured and tumour deposits within the mesorectum are shown. It is important that a high spatial resolution technique is used in order to accurately depict these features and care should be taken in ensuring that images acquired cover the entire rectal tumour and mesorectum. This paper describes the technique of high spatial resolution rectal cancer imaging and the potential technical pitfalls in acquiring good quality images. Important factors to consider include: adequate scan duration to achieve high spatial resolution images with sufficient signal to noise ratio, careful positioning of the pelvic phased array coil, use of T2 weighted turbo spin-echo rather than T1 weighted imaging and careful planning of scans to ensure that images are obtained perpendicular to the rectal wall.     

Indium-111 octreotide scintigraphy in patients with bone tumours of the extremities

Radiolabelled somatostatin analogues are of potential value in the imaging of somatostatin receptor-positive tumours. Recently, somatostatin receptors have been demonstrated in the osteoblast precursor cells. In this preliminary study, we evaluated the uptake characteristics of indium-111 octreotide in two benign and two malignant bone tumours. Tracer accumulation was observed in all four cases, and overall lesion to background ratio (mean±SD) was 2.74±0.84 and 2.98±1.49 at 4 h and 24 h, respectively. There was no clear relationship between I¹¹¹In-octreotide accumulation and the benign or malignant nature of the tumour. In one patient, tracer uptake was inhibited by unlabelled octreotide administration. These results suggest that¹¹¹In-octreotide can be taken up by benign and malignant bone tumours. The inhibition of tumour uptake by treatment with cold octreotide supports the concept that specific uptake mechanisms are responsible for¹¹¹In-octreotide deposition by bone tumours.     

An evaluation of99mTc-HMPAO uptake in cerebral gliomas —a comparison with X-ray CT

Nineteen patients with biopsy-proven cerebral gliomas were studied with^99mTc-HMPAO single photon emission tomography (SPELT) imaging and X-ray computed tomography (CT). The uptake of^99mTc-HMPAO was correlated with tumour size and morphology as shown by X-ray CT, and overall patient survival. It appears that uptake of^99mTc-HMPAO is associated with larger, ill-defined tumours and was an adverse factor in patient survival. In those tumours with normal or increased uptake,^99mTc-HMPAO imaging is useful in distinguishing the tumour margin from surrounding oedema.     

Dynamic contrast-enhanced MR imaging in cancer

Interest in new blood vessel formation in tumours (angiogenesis) has led to the development of imaging strategies for investigating the microvascular structure and function of tumours. One such technique is dynamic contrast-enhanced MRI (DCE-MRI), where gadolinium based contrast agents are injected intravenously and serial image acquisitions are performed as the contrast agent passes through the tumour vascular bed. Sophisticated analyses can then be applied in order to produce indirect measures of parameters that represent blood flow, vascular volume, capillary permeability and surface area. The technique has been used to characterise malignant disease and to evaluate the effect of therapies that target tumour blood vessels. This article reviews the important image acquisition and data analysis principles behind DCE-MRI and highlights its use in clinical and research medicine to date.     

Recent advances in magnetic resonance imaging of musculoskeletal tumours

Magnetic resonance imaging (MRI) has become the method of choice, where available, for the evaluation of musculoskeletal neoplasms. Recently, there has been interest and development in a number of areas in this field: (a) gradient-echo (fast-scan) sequences, which may often be substituted for more time-consuming T2-weighted sequences, are useful as localizing sequences and play an important role in intravenous contrast-enhanced scanning; (b) magnetic resonance contrast agents (e.g., gadolinium) improve delineation of tumours on static imaging and may help in estimating tumour aggressiveness with dynamic imaging; (c) STIR (short inversion time inversion recovery) increases lesion conspicuity; (d) spectroscopy, still an investigational area, may help in evaluating tumour response to chemotherapy and radiotherapy.     

Serum albumin (SA) accumulation by bronchogenic tumours: a tracer technique may help with patient selection for SA-delivered chemotherapy

Systemic toxicity and inadequate tumour uptake of chemotherapeutic agents limit effective therapy of disseminated malignant disease. We seek to use macromolecules for improved delivery of therapeutic agents to tumours, and hope to use radiotracer procedures to identify those malignancies able to accumulate the transport molecule. A literature search identified in vitro and animal experimental data which indicated that serum albumin is taken up in malignancies. Selected cytostatic drugs can be bound to albumin, which suggests the suitability of the molecule as a potential transport vehicle. We therefore evaluated indium-111 labelled human serum albumin (HSA) to determine the frequency of its accumulation in bronchogenic tumours. Single-photon emission tomographic (SPET) images were obtained in 23 patients 48 h after intravenous injection of 1.5 mCi¹¹¹In diethylenetriamine penta-acetic acid (DTPA)-HSA. SPET imaging with technetium-99m labelled erythrocytes was included in the protocol to assess the influence which vascularity has on the HSA-based images. All patients went on to surgery. We documented the histological diagnosis, T-stage and differentiation grade. The scintigraphic examination demonstrated HSA uptake in three squamous cell carcinomas and four adenocarcinomas. Of these, six malignancies accumulating HSA had 2.2–5.4 times the tracer concentrations observed in comparable background regions. Small cell carcinoma failed to accumulate the labelled HSA during the 2-day scintigraphic evaluation. The HSA images did not appear to represent tumour vascularity. T-stage and differentiation grade failed to predict which tumours would demonstrate HSA uptake. Initial results suggest that HSA merits evaluation as a potential transport molecule for inmour-directed therapeutic agents, since approximately 35% of the examined malignancies showed HSA uptake. At the same time the relatively infrequent tumour HSA incorporation may mandate using scintigraphy and labelled HSA for selecting those individuals who may profit from HSA-delivered drug therapy. The described selection and therapy approach was tried in two patients who had an¹¹¹In-DTPA-HSA tumour to background ratio of 1.45:1 and 5.3:1 respectively. Both received experimental chemotherapy with methotrexate (MTX)-HSA.     

Modification of tumour response by calcium antagonists in the SCVII/St tumour implanted at two different sites

Dose responses for the effects of four calcium antagonists on SCCVII/St back and leg tumour sensitivity to 20 Gy X-rays, and on tumour perfusion indicated by relative uptake of 86rubidium, were determined. The effects of these agents on 86rubidium uptake in some normal tissues were also investigated. Flunarizine sensitized tumours to X-rays over the dose range 0.005-500 mg/kg given i.p., but only small increases in tumour perfusion were seen at doses of 0.05-5 mg/kg. Verapamil increased tumour radioresistance at doses of 20 mg/kg and above, and reduced tumour perfusion at 50 mg/kg. Below 10 mg/kg, verapamil sensitized the tumours to X-rays, but produced little or no increase in tumour perfusion. Nifedipine at 10 mg/kg and above produced very radioresistant tumours, with correspondingly large reductions in tumour perfusion. At doses below 0.5 mg/kg sensitization was seen, but no increased tumour perfusion. Diltiazem at 50 mg/kg also increased tumour radioresistance with a reduction in tumour perfusion, and at lower doses sensitized tumours to X-rays, with small increases in tumour perfusion. The effects of these agents on normal tissues were varied and difficult to interpret. The similarity between the tumour radiation responses to the four calcium antagonists suggests that they may be acting upon the tumour vasculature in a manner independent of the systemic circulation.     

99mTc-MIBI in the evaluation of breast cancer biology

A major area of interest in nuclear medicine is the scintigraphic in vivo evaluation of complex cellular processes involved in tumour growth, progression and response to treatment with the aim of defining the biological properties that may orient clinicians towards different adjustments of therapy in individual patients. In the last decade, (99m)Tc-labelled lipophilic cations emerged as suitable tools to trace specific cellular processes and functions in a variety of malignant tumours, including breast cancer. Among these agents, (99m)Tc-methoxyisobutylisonitrile (MIBI) is the most widely evaluated tracer and may serve as a paradigm for this class of compounds. Many clinical studies have been performed to correlate (99m)Tc-MIBI uptake or clearance with histological, molecular and biochemical markers of various cellular processes, including apoptosis, proliferation, P-glycoprotein expression and neoangiogenesis. The final picture emerging from these studies is that the early tracer uptake reflects the mitochondrial status, which is affected by both apoptosis and proliferation, whereas the tracer clearance reflects the activity of drug transporters such as P-glycoprotein. On the basis of the imaging parameter chosen for the analysis of (99m)Tc-MIBI scan in breast cancer patients, the biological information provided may be related to different cellular processes that ultimately govern tumour response to treatment.