Diagnostics of neuroendocrine tumours.

Neuroendocrine tumours (NETs) are rare pathologies which origin from neuroectodermic and endodermic cells and that can produce peptides and amino acids. About 70% of NETs derive from gastroenterohepatic (GEP) system and the other 30% from the different sites through the body. They are distinguished into single and multiple localizations and also into sporadic, familial multiple endocrine-related forms and recurrent forms. Moreover, when they produce hormones they usually are symptomatic; yet, they are characterized by the synthesis and secretion in the blood stream of several tumor-specific markers or can express somatostatin receptors in their cellular surface. The diagnosis and follow-up of NETs rely on laboratory studies, histopathology and the combination of anatomical and functional imaging, with the latter being the main method for monitoring response to therapy. In recent years, nuclear medicine has contributed to the impressive development of the knowledge of NETs in terms of biology (receptor scintigraphy), pharmacology (development of new tracers) and therapy (radiometabolic therapy). Nuclear medicine procedures for diagnosis and treatment of NETs are based on the biological properties of these tumours: the expression of somatostatin receptors. Somatostatin receptor scintigraphy not only has a crucial role in diagnosis and staging of NETs, but also in assessing suitability for treatment with cold and radiolabelled somatostatin analogues, as well as in monitoring response to treatment and detecting recurrent disease. In conventional nuclear medicine, the two most important functional imaging modalities are ¹¹¹In-octrescan and ¹²³I-MIBG. Over the last 5 years, due to the development of new tracers, such as 68Ga labelled-DOTA-peptides PET and ¹8F-DOPA, PET has also been employed with significant benefits in the diagnosis and management of NETs.

Influence of tumour size and uptake of 99mTc-octreotide on radio-guided surgery for neuroendocrine tumors.

AIM: The aim of this study was to analyze the influence of scintigraphic uptake grade and tumour size on radio-guided surgery of neuroendocrine tumours (NETs) using 99mTc-EDDA/HYNIC-TOC (99mTc-octreotide). METHODS: We investigated 21 patients with NET (F=8, M=13) for localization of 27 known lesions using a gamma probe. Three to 6 hours before surgery, 550-650 MBq of 99mTc-octreotide was injected followed by immediate imaging prior to surgery. The uptake was graded on a scale from 0-4. Localization was confirmed by endoscopic ultrasound (EUS), computed tomography (CT) and/or magnetic resonance imaging (MRI). Morphological images were used to determine size of the lesion. Local measurements of radioactivity were performed during surgery using a gamma probe. RESULTS: Twenty lesions were successfully localized intraoperatively using a gamma probe (7=grade 4, 9=grade 3, 2=grade 2 and 2=grade 0). The size of successfully localized lesions ranged between 9 and 50 mm. Seven lesions were not localized successfully of which 6 were seen on scintigraphy (2=grade 4, 1=grade 3 and 3=grade 2). The 7th lesion was not seen on preoperative scintigraphy and not localized successfully. The size of unsuccessfully localized lesions ranged between 7 and 30 mm. CONCLUSIONS: High octreotide uptake (grade 3 and 4) influence radioguided surgery. Tumour size did not influence the success of localization of lesions by gamma probe.

(99m)Tc-rituximab radiolabelled by photo-activation: a new non-Hodgkin's lymphoma imaging agent.

PURPOSE: Rituximab was the first chimeric monoclonal antibody to be approved for treatment of indolent B-cell non-Hodgkin's lymphoma (NHL). It is directed against the CD20 antigen, which is expressed by 95% of B-cell NHLs. The aim of this study was to explore the possibility of radiolabelling rituximab with (99m)Tc for use as an imaging agent in NHL for early detection, staging, remission assessment, monitoring for metastatic spread and tumour recurrence, and assessment of CD20 expression prior to (radio)immunotherapy. METHODS: Rituximab was purified from Mabthera solution (Roche), photo-activated at 302 nm by UV irradiation and radiolabelled with (99m)Tc. The effectiveness of the labelling method was evaluated by determination of the number of free thiol groups per photoreduced antibody, radiochemical purity and in vitro stability of (99m)Tc-rituximab. RESULTS: On average, 4.4 free thiol groups per photoreduced antibody were determined. Radiolabelling yields greater than 95% were routinely observed after storage of the photo-activated antibody at -80 degrees C for 195 days. The direct binding assay showed preserved ability of (99m)Tc-rituximab to bind to CD20, with an average immunoreactive fraction of 93.3%. The internalisation rate was proven to be low, with only 5.3% of bound (99m)Tc-rituximab being internalised over 4 h at 37 degrees C. CONCLUSION: Our results demonstrate that (99m)Tc-rituximab of high radiochemical purity and with preserved binding affinity for the antigen can be prepared by photoreduction and that the method shows good reproducibility. (99m)Tc-rituximab will be further explored as an imaging agent applicable in NHL for the purposes mentioned above.

The importance of follow-up of children with vesicoureteral reflux grade 1.

AIM: The objectives of this study were, first, to determine the probability of detecting vesicoureteral reflux (VUR) into the renal collecting system (VUR grade 2 or higher) by follow-up cyclic radionuclide cystography (CRC) in children with VUR 1 on initial examination, and in children without VUR and with the same clinical history; and secondly, to find out whether dividing VUR 1 into three subclasses, including possible reflux into the ureter, reflux into the lower ureter, and reflux into the whole length of the ureter, enhances detection of higher grade reflux in these children. METHODS: 275 children with VUR 1 found on initial CRC, and 31 children without reflux and with the same clinical history were studied. In total, 414 renal units with VUR 1 of different subclasses and 198 renal units without reflux were evaluated. RESULTS: Follow-up CRC disclosed reflux into the renal collecting system in 20% of children with VUR 1 on initial investigation, and in 23% of children with no reflux at the time of initial investigation. The probability that follow-up examination would disclose VUR 2 in 3 in renal units with different subclasses of grade 1 reflux was 8-16%, and did not differ significantly from the probability for detecting reflux in kidneys with no reflux on initial examination. CONCLUSION: In the absence of recurrent urinary tract infection, the management of children with VUR 1 identified by CRC can be the same as in children without reflux. Yet, in children with no reflux or with VUR 1 detected after urinary tract infection, the probability that reflux reaching the pylon was missed should not be underestimated. Dividing VUR 1 into subclasses does not seem to be of diagnostic value.

Contrast-enhanced ultrasound voiding cystography as a screening examination for vesicoureteral reflux in the follow-up of renal transplant recipients: a new approach.

BACKGROUND: The aim of the study was to evaluate a new diagnostic procedure, ultrasound contrast-enhanced voiding cystography (USVC), for vesicoureteral reflux (VUR) in renal transplant recipients and to compare it with radionuclide voiding cystography (RVC). METHODS: Twenty-three renal transplant recipients with recurrent urinary tract infection were investigated simultaneously by RVC and USVC. After catheterization, the empty bladder was filled with normal saline (mean 250+/-30 ml) and 30-45 mBq of (99m)Tc-labelled colloid. At the end of filling the bladder, 19.5 ml of galactose-based, microbubble-containing echo-enhancing agent, at a concentration of 200 mg/ml, was instilled. During the filling and voiding phases the movement of the radiotracer was recorded by a gamma camera and the presence of microbubbles in the urinary tract by ultrasound. RVC was used to detect and grade the degree of VUR. RESULTS: Nuclear studies identified VUR in 16 (69.6%) of 23 recipients with recurrent urinary tract infection: VUR grade I in three (13%) recipients, grade II in eight (34.8%) and grade III in five (21.7%) using a simplified grading system. USVC with contrast-enhancement detected VUR in 14 (60.9%) recipients. Overall sensitivity and specificity of contrast-enhanced USVC was 75 and 71%, respectively. Statistical analysis showed that the accuracy of this procedure increased with higher grades of VUR and its sensitivity reached 100% for detection of VUR grade III. CONCLUSION: In our preliminary study, contrast-enhanced USVC has proved to be an effective examination, with the same accuracy rate as RVC in detecting grade III VUR episodes with low diagnostic accuracy for low reflux grades.

Echo-enhanced ultrasound voiding cystography in children: a new approach.

The development of echo-enhancing agents has significantly improved the detection of the movement of fluid within the urinary tract by ultrasonography (US). The purpose of our study was to compare ultrasound voiding cystography (USVC) for the detection of vesicoureteric reflux (VUR) in children with direct radionuclide voiding cystography (DRVC). Ninety-nine children, aged 1.1-12.3 years, with 198 potentially refluxing units, were investigated simultaneously by DRVC and USVC. The indications for cystography were urinary tract infection, follow-up of a previously detected VUR, and screening of siblings of children with VUR. During the investigation an echo-enhancing agent (Levovist) was administered intravesically through a catheter already in place for the DRVC. The movement of both agents, radiotracer and Levovist, was registered simultaneously by a computerized gamma camera and US, respectively. The results were analyzed with DRVC representing the reference diagnostic test. The overall sensitivity and specificity of USVC for the detection of VUR were 79% and 92%, respectively. USVC may represent a reliable diagnostic tool for the detection and follow-up of VUR in children.

Analysing and improving the diagnosis of ischaemic heart disease with machine learning.

Ischaemic heart disease is one of the world's most important causes of mortality, so improvements and rationalization of diagnostic procedures would be very useful. The four diagnostic levels consist of evaluation of signs and symptoms of the disease and ECG (electrocardiogram) at rest, sequential ECG testing during the controlled exercise, myocardial scintigraphy, and finally coronary angiography (which is considered to be the reference method). Machine learning methods may enable objective interpretation of all available results for the same patient and in this way may increase the diagnostic accuracy of each step. We conducted many experiments with various learning algorithms and achieved the performance level comparable to that of clinicians. We also extended the algorithms to deal with non-uniform misclassification costs in order to perform ROC analysis and control the trade-off between sensitivity and specificity. The ROC analysis shows significant improvements of sensitivity and specificity compared to the performance of the clinicians. We further compare the predictive power of standard tests with that of machine learning techniques and show that it can be significantly improved in this way.

A follow-up study of vesico-ureteric reflux and renal scars in asymptomatic siblings of children with reflux.

The objectives of this study were to follow up children with vesico-ureteric reflux (VUR) and renal scars, to evaluate kidney growth and to determine the incidence of urinary tract infection (UTI) and elevated blood pressure in 40 asymptomatic siblings of children with VUR, in whom VUR had been detected at an early age, and to gather additional data which could help to evaluate the need for screening for VUR in asymptomatic siblings. During the follow-up period of 3-7 years, two children (5%) had UTI; 66% of VUR grade 1 and 2 disappeared. The progression of scars was only detected in two of nine children with renal scars on the initial study, both of whom had high-grade VUR. Renal ultrasound was normal in all siblings and none developed hypertension. The results indicate that low-grade sterile VUR may not play a major role in renal scarring, but this may not be the case with high-grade sterile VUR. Considering the correlations among VUR, UTI and reflux nephropathy, routine screening for VUR at an early age in asymptomatic siblings of children with VUR seems to be justified to identify those at the greatest risk of subsequent renal damage.

Study of myocardial regional wall motion parameter's accuracy by software perfusion phantom.

Gated perfusion myocardial scintigraphy permits simultaneous evaluation of perfusion as well as regional contractile function of the left ventricle. Fourier analysis of regional myocardial spatial movement with respect to the myocardial geometric centre gives circular amplitude and phase profiles of ventricular contraction, in addition to regional maximum activity that represents an index of perfusion. To introduce such combined perfusion-contraction analysis the accuracy of the indices mentioned above should be evaluated for different doses of radioactivity typically administered to a patient. A mathematical software phantom, consisting of a half circularly profiled ring activity embedded in uniform background activity and noise generated by a Poisson-shaped random number generator, was constructed and used for this purpose. A 64 x 64 matrix and sequence of 16 frames per study was used. The maximum number of counts per pixel ranged from 10 to 100, simulating low count thallium and high count rate Tc-MIBI-gated studies. The relative standard error analysis (R.S.E.) with a 95.5% confidence level for a thallium type of 10 counts per pixel study exceeded 11%, while it reached acceptable values below 3% for studies with 60 and more counts per pixel. These results indicate that high count rate gated technetium-MIBI myocardial perfusion studies could also be used for reliable left ventricular regional wall motion evaluation.

Vesicoureteric reflux and renal scars in asymptomatic siblings of children with reflux.

The purpose of the study was to determine the incidence of vesicoureteric reflux (VUR), renal scars and hypertension in asymptomatic siblings of children with VUR. The study comprised 105 siblings of patients with VUR. Their age ranged from 4 months to 6.3 years. All had a direct radionuclide voiding cystography (DRVC) performed, and VUR was detected in 47 of 105 (45%). High grade VUR in the first year of life had an incidence of 50% compared with a 9% incidence in siblings older than 2 years, while only one of the 27 siblings with a low VUR grade was younger than 1 year. In 43 of 47 siblings with VUR, a technetium-99m dimercaptosuccinic acid (99mTc-DMSA) scan was performed and renal scars were found in 10, which presents 23% of siblings with VUR who were scanned and 10% of all siblings studied. One child had hypertension. Identifying VUR among asymptomatic siblings could possibly prevent renal damage and its consequences. Thus, the predictive value of positive family history alone in identifying VUR was 45% while 23% of siblings had renal scars. This incidence justifies the routine investigation of asymptomatic siblings, by using DRVC at an early stage.

Cyclic direct radionuclide voiding cystography: increasing reliability in detecting vesicoureteral reflux in children.

The purpose of this study was to establish the sensitivity of cyclic direct radionuclide cystography (RVC) in detecting vesicoureteral reflux (VUR) in infants and small children, and to compare it to the conventional (one cycle only) RVC. 428 patients (856 renal units) were admitted to the study from January 1991 through March 1992 and all had a cyclic RVC. The age of the patients ranged from 4 months to 7 years. The overall agreement of both cycles in detecting VUR in this study was 45%, the lowest being in detecting VUR I (36%), and the highest in detecting VUR III (86%). If we had used a conventional RVC (the first cycle only), 17 (29%) VUR I, 50 (36%) VUR II and 3 (9%) VUR III, which were detected in the second cycle only, would have been missed. We conclude that cyclic RVC detected 43% more VURs than the conventional (first cycle only) RVC, and would therefore recommend its use as a standard procedure instead of the conventional RVC.

Sarcoidosis in Arabs: the clinical profile of 20 patients and review of the literature.

Sarcoidosis is being increasingly recognised in Kuwait. Twenty patients were studied over three years and the clinical, biochemical and radiological data were analysed. The clinical profile revealed thoracic involvement in all the patients as well as constitutional symptoms (50%), arthralgia (55%), arthritis (15%), chest infection (35%), tuberculosis (10%), hypercalcaemia (5%), angina (15%) and hypertension (20%). None had central nervous system manifestations. Other clinical signs were erythema nodosum (25%), hepatomegaly (30%) splenomegaly (15%) and chest signs (25%), together with salivary gland (15%), skin (15%), eye (15%), and cardiac involvement (5%). The tuberculin test was negative in all those tested. The patients were classified radiologically into stage I (55%), stage II (40%) and stage III (5%) of the disease. The clinical profile was similar to the Western pattern of the disease, but there were several differences including an older age group, more frequent constitutional symptoms, the rarity of ocular and central nervous system involvement, and initial presentation as a chest infection. Therapy with steroids alone or steroids and azathioprine was used when appropriate and the response to therapy monitored.

Increase of tissue plasminogen activator in limbs during venous occlusion: a simple haemodynamic model.

Venous occlusion of a limb is an established procedure for increasing the venous plasma concentration of tissue plasminogen activator (t-PA). In this paper a simple haemodynamic model was developed to describe the venous plasma t-PA concentration as a function of haemodynamic parameters and the local release rate of t-PA during venous occlusion of the limb. The venous plasma pool of a limb was regarded as a single well-mixed compartment with a constant input rate of t-PA. The intravascular volume, blood flow and total limb volume of the upper extremity were also measured in three healthy subjects in order to characterise the haemodynamics during venous occlusion. Venous occlusion was shown to cause such an intense decrease of blood flow through the limb that the postocclusion increase in concentration of t-PA need not be explained by an increased release rate of t-PA but could be attributed merely to the diminished dilution of the venous compartment by inflowing arterial plasma. According to our model and haemodynamic measurements, the significant differences in the postocclusion concentration of t-PA between the arm and leg can be explained by different local release rates of t-PA.

Technetium-99m MAG3, a comparison with iodine-123 and iodine-131 orthoiodohippurate, in patients with renal disorders.

A Phase I study in 12 patients with renal disorders compared the simultaneous clearances of 99mTc-labeled mercaptoacetyltriglycine (MAG3) and 131I-labeled orthoiodohippurate (OIH). The ratio of MAG3 to OIH clearance was 0.61 +/- 0.08 as a result of its smaller volume of distribution, ratio 0.65 +/- 0.09, for the clearance half-lives were similar, ratio 1.09 +/- 0.12. A Phase II study performed serially in 20 patients with equal doses of [99mTc]MAG3 and [123I]OIH gave images of equal quality. The relative renal functions were highly correlated (r = 0.97, p less than 0.001) and transit time analyses gave good correlations: parenchymal transit time index r = 0.81, p less than 0.05. We conclude that [99mTc]MAG3 has some advantages over [99mTc]DTPA and is a suitable replacement for [123I]hippuran in routine renal imaging, relative function, and transit time studies, but not for the accurate estimation of the renal plasma flow.

Quantitation of iodine-123 MIBG uptake by normal adrenal medulla in hypertensive patients.

Eighteen hypertensive patients with a clinical suspicion of pheochromocytoma and raised or borderline raised plasma catecholamine and urinary vanillyl mandelic acid (VMA) levels were studied by scintigraphy using 123I-labeled metaiodobenzylguanidine (MIBG). None of these patients had any scintigraphic evidence of pheochromocytoma at the time of study or on subsequent clinical follow-up. A quantitative approach was taken to calculate the adrenal medullary uptake of [123I]MIBG in these patients. Three different methods of quantitation were evaluated using data acquired from an anthropomorphic phantom and analysed by three independent observers. In the patient studies 34 out of 35 adrenal medullas were visualized with uptake in the range of 0.01-0.22% of the administered dose 22 hr postinjection which was calculated using the preferred quantitation method. This is an appropriate control group range for comparison with patients who have proven norepinephrine and epinephrine secreting tumors. A quantitative approach to [123I]MIBG imaging provides an important tool for studying adrenomedullary pathophysiology.

Detection of electrocardiographically imperceptible ventricular pre-excitation by phase imaging.

The sequence of ventricular contraction was studied by radionuclide phase imaging in 25 patients with Wolff-Parkinson-White syndrome. The studies were performed when no signs of precontraction were present in the electrocardiogram; in these cases pre-excitation was either intermittent or suppressable by injection of ajmaline. In 11 of the 16 patients with free wall accessory pathways, precontraction could be detected in spite of electrocardiographically absent pre-excitation. Discrete precontraction was seen also in 2 of the 9 patients with paraseptal accessory pathways. We conclude that antegrade conduction through the accessory pathway does not need to be completely blocked if signs of pre-excitation are absent on the electrocardiogram, and that phase imaging is, at least in some patients (especially those with free wall accessory pathways), a more sensitive technique for detection of pre-excitation (precontraction) than the electrocardiogram.