Clinical evidence of efficient tumor targeting based on single-chain Fv antibody selected from a combinatorial library.

We present a system for cancer targeting based on single-chain Fv (scFv) antibodies selected from combinatorial libraries, produced in bacteria and purified by using an engineered tag. Combinatorial libraries of scFv genes contain great diversity, and scFv antibodies with characteristics optimized for a particular task can be selected from them using filamentous bacteriophage. We illustrate the benefits of this system by imaging patients with carcinoembryonic antigen (CEA)-producing cancers using an iodine-123 labeled scFv anti-CEA selected for high affinity. All known tumor deposits were located, and advantages over current imaging technology are illustrated. ScFvs are produced in a cloned form and can be readily engineered to have localizing and therapeutic functions that will be applicable in cancer and other diseases.

Training of staff for the delivery of PET/CT services in the UK.

Evidence for the cost effectiveness of PET/CT imaging is now driving the widespread introduction of PET/CT services throughout the UK. The provision of PET/CT facilities will require a workforce of medical, scientific, technical and engineering staff who are adequately trained and fit for purpose. Suitably trained staff in this speciality are scarce. The development and accreditation of training courses and other educational resources for training programmes in all disciplines will therefore be required at a national and regional level. The implementation of PET/CT training can be achieved more cost-effectively by developing multi-professional learning resources whenever possible. It is intended that the recommendations would be implemented by close co-operation of both public and private healthcare providers together with educational establishments.

Radioimmunoguided surgery in colorectal cancer using a genetically engineered anti-CEA single-chain Fv antibody.

In radioimmunoguided surgery (RIGS), a radiolabeled antibody is given i.v. before surgery and a hand-held gamma-detecting probe is used to locate tumor in the operative field. The rapid blood clearance and good tumor penetration of single-chain Fv antibodies (scFv) offer potential advantages over larger antibody molecules used previously for RIGS. A Phase I clinical trial is reported on RIGS with scFv (MFE-23-his) to carcinoembryonic antigen (CEA). Thirty-four patients undergoing surgery for colorectal carcinoma (17 primary tumors, 16 liver metastases, and 1 anastomotic recurrence) and 1 patient with liver metastases of pancreatic carcinoma received 125I-labeled MFE-23-his scFv (125I-MFE-23-his) 24, 48, 72, or 96 h before operation. 125I-MFE-23-his showed biexponential blood clearance with alpha and beta half-lives of 0.32 and 10.95 h, respectively. The abdomen was scanned during surgery with a hand-held gamma detecting probe (Neoprobe Corp.). 125I-MFE-23-his showed good tumor localization; comparison with histology showed overall accuracy of 84%. Highest median ratios for tumor:normal tissue and tumor:blood were recorded 72 or 96 h after scFv injection for patients undergoing resection of liver metastases. High levels of radioactivity were found in the kidneys. Five patients had grade 1 fever, and three had a grade 1 rise in blood pressure according to the Common Toxicity Criteria. There was a significant correlation between these ratios and those measured in excised tissues using a laboratory gamma counter (P < 0.001). MFE-23-his scFv antibody localizes in CEA-producing carcinomas. The short interval between injection and operation, the lack of significant toxicity, and the relatively simple production in bacteria make MFE-23-his scFv suitable for RIGS.

Prediction of the usefulness of combined mammography and scintimammography in suspected primary breast cancer using ROC curves.

UNLABELLED: The aim of this study was to compare the accuracy of 99mTc-methoxyisobutylisonitrile scintimammography (SMM) and conventional mammography in patients presenting with suspected primary breast cancer. Receiver-operating-characteristic (ROC) curve analysis was applied to determine if a combination of x-ray mammography (XMM) and SMM was more accurate than a single test alone. METHODS: The results of SMM, XMM, and a combination of both studies performed over a 3-y period on 374 suspicious lesions in 353 patients with no previous history of breast cancer were reviewed. Each scan report was reviewed and graded as follows: grade 1, definitely normal or benign; grade 2, probably normal or benign; grade 3, equivocal; grade 4, probably cancer; and grade 5, definitely cancer. The results were verified by pathologic examination of biopsy material obtained from each suspicious mass. ROC curves were generated from these results. RESULTS: There were 204 malignant breast tumors and 170 nonmalignant breast lesions. SMM diagnosed correctly 181 breast cancers and was true-negative in 122 benign breast lesions: sensitivity, 89%; specificity, 71%; positive predictive value (PPV), 79%; and negative predictive value (NPV), 84%. XMM diagnosed correctly 143 malignant tumors and was true-negative in 117 nonmalignant lesions. The sensitivity, specificity, PPV, and NPV for XMM were 70%, 69%, 73%, and 66%, respectively. Using a combination of the two tests, the combined sensitivity was 93%, specificity was 72%, PPV was 80%, and NPV was 90%. Using the index of the area under the ROC curve obtained by the rating method showed that the combination of XMM and SMM was significantly more accurate than either of the individual tests if performed alone (P < 0.05). CONCLUSION: This study shows that the combination of XMM and SMM produces more accurate results than either modality alone. Therefore, if there is doubt about the accuracy of XMM, SMM should be used as the second-line test in breast imaging.

Renal scintigraphy in acute scleroderma: report of three cases.

Scintigraphic findings in acute renal failure secondary to scleroderma are reported. In three patients, we have demonstrated severe reduction of renal perfusion with little or no parenchymal uptake of tracer and absent excretion. These findings are compatible with the known histological process of occlusive vasculopathy, and such scintigraphic findings at presentation may reflect a poor prognosis for renal recovery.

Dynamic renal transplant imaging with Tc-99m DTPA (Sn) supplemented by a transplant perfusion index in the management of renal transplants.

We have performed 955 studies on 152 patients with 167 renal transplants. Images were recorded following bolus injection of 12-15 mCi Tc-99m DTPA (Sn). The data were stored on a computer and analyzed by generation of region-of-interest curves from (a) the iliac artery distal to the transplant, (b) the kidney, and (c) a background area. A perfusion index was adopted: formula see text. In 276 studies the patient clearly had acute tubular necrosis (ATN), rejection, or a normal kidney on retrospective analysis. The normal perfusion index has a value below 150, and it increases with falling perfusion, such as is seen in rejection and in renal-artery stenosis. The use of this index in addition to sequential images and changes in the region-of-interest curves usually allows separation of rejection from ATN and, particularly, rejection from normals. When serial studies are performed, the separation of rejecting from nonrejecting transplants is excellent, although renal-artery stenosis may cause similar changes in perfusion.

Radionuclide studies in impotence.

Impotence may be of physiological origin with causes including vascular or neurological pathology. Alternatively, it may be of psychogenic origin. Clinicians can distinguish between psychological and organic impotence by observing nocturnal penile tumescence. Non-radionuclide investigations for organic impotence include penile plethysmography or pulse Doppler analysis for arterial supply, cavernosometry for venous drainage, and biothesiometry or evoked potentials for neurological pathology. Radionuclide studies are primarily based on the use of technetium 99m-pertechnetate, 99mTc-red blood cells, or xenon 133 to study the blood flow, with or without pharmacological intervention, commonly papaverine.

Report of the Radionuclides in Nephrourology Committee for evaluation of transplanted kidney (review of techniques).

Comprehensive evaluation of renal transplants has been important in differential diagnosis of medical and surgical complications in the early post-transplantation period and in the long-term follow-up. If performed well, it yields excellent functional and good anatomic information about the graft that can be effectively used in the patient. That includes selection of patients for biopsy and for various drug regimens. This is true especially in patients with anuric acute tubular necrosis (ATN) and in patients with developing chronic rejection. Improving indices of renal function (effective renal plasma flow, uptake of tubular tracers) can indicate resolution of tubular injury (ATN) while there is still no improvement in plasma creatinine. In patients with chronic rejection, plasma creatinine increases only after approximately 30% of renal function is lost due to graft fibrosis. Early recognition of this condition could permit treatment and delay of retransplantation. The protocol recommended at the Copenhagen meeting includes a flow study, scintigram of the kidneys, prevoid and postvoid bladder image, injection site image (quality control), time/activity curves of the graft and bladder, and quantitative data of perfusion, function, and tracer transit. The flow study obtained during the initial transit of the bolus through the graft could be performed either with 99mTc mercaptoacetyltriglycine, or 99mTc diethylenetriaminepentaacetate (DTPA). Quantitative analysis of perfusion facilitates interpretation of the study during the early post-transplantation period. ATN, common in cadaver transplants, typically shows adequate perfusion. The function phase should include images and time/activity curves. Images alone are insufficient. Quantitative data such as clearance or other indices of function and indices of tracer transit are essential for correct interpretation of the results. Normal images and normal graft function reliably exclude clinically important complications. A single scintigram demonstrating prolonged tracer transit with decreased function cannot separate acute rejection and ATN. On serial studies, decline in function and poor perfusion are indicative of acute rejection. A normally appearing scintigram without cortical retention, but with low function, is consistent with chronic rejection. Pharmacological intervention to exclude obstruction (diuretic renogram) or hemodynamically significant renal artery stenosis (angiotensin converting enzyme challenge) should be used whenever indicated.

European Captopril Radionuclide Test Multicenter Study. Preliminary results. Inspective renographic analysis. The European Captopril Radionuclide Test Multicenter Study Group.

Captopril radionuclide test (CRT) has been introduced in clinical practice as a screening test for renovascular hypertension, since it allows the detection of the decrease of glomerular filtration rate that may be induced by angiotensin converting enzyme inhibition (25 mg oral captopril) in kidneys ipsilateral to a renal artery stenosis. However, due to the low prevalence of the disease, experiences in single centers may hardly satisfy the need for representative series of patients to validate the test. Nineteen centers participated in a collaborative study (CRT European Multicenter Study) that collected data from 424 patients. Here we report on the first results obtained by inspective renographic analysis. The captopril radionuclide test greatly potentiated the diagnostic performance of conventional renography and the accuracy was maximal when relying simply on postcaptopril findings alone. Specificity was 84.1% in the overall population and 91.8% in uncomplicated patients without nephropathy and renal insufficiency. Taking into account the sole arteriographic diagnosis, sensitivity was 73.2% or 90.7% for the subjects with unilateral or bilateral stenosis and an angiographic degree of stenosis greater than or equal to 70%. On the other hand, when a successful outcome of blood pressure after revascularization or nephrectomy was considered as the gold standard for the diagnosis of renovascular hypertension, a high sensitivity was obtained (92.7%). Moreover, the test became negative after intervention in the great majority (88%) of patients who had a positive preintervention CRT and a normalization of blood pressure after revascularization.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of captopril-DTPA scanning in the diagnosis of atherosclerotic renal artery stenosis in patients with impaired renal function.

We have analyzed our use of captopril-diethylene-triaminepentaacetic acid (DTPA) scanning in patients presenting to the Royal Free Hospital predominantly with renal impairment. The sensitivity was found to be as good in patients with bilateral disease or disease of a single kidney as in patients with unilateral disease. On a number of occasions, though, the scan suggested unilateral disease when bilateral disease existed. There were, however, a large number of patients for whom captopril-DTPA scanning was not performed because of severe renal impairment or the possibility of renal artery stenosis in a single functioning kidney.

Report of the Working Party Group on Determining the Radionuclide of Choice.

There are a variety of radiopharmaceuticals that can be used to perform captopril renography effectively. We examined a number of technetium and iodine compounds and the circumstances under which each radiopharmaceutical compound is the compound of choice. Considerations of cost, ease of use, reliability, dosage, and the effects of different protocols were all examined.

Uptake of Tc-99m MIBI related to tumour size and type.

The accuracy of Tc-99m MIBI scintimammography depends on the uptake in cancer cells being greater than surrounding normal tissue. The aim of this study was to determine which were the dominant factors affecting uptake of Tc-99m MIBI in breast cancer cells in vivo. The tumour to background ratio (TBR) was measured in 74 focal breast lumps occurring in 70 women, of whom 53 had breast cancer. In patients with breast cancer the TBR was compared in those under and over 45, those with tumours over and under 20 mm, those who had auxiliary disease, the histological type of the tumour and whether ductal on the Bloom Richardson scale. The only factor which appeared to have an influence on uptake of Tc-99m MIBI was the histological type of the tumour. Ductal carcinomas had a mean TBR of 2.07, significantly greater than either other types of breast cancer (TBR = 1.31) and benign tumours (TBR = 1.46). The histological type of tumour appears to be the dominant factor affecting uptake of Tc99m MIBI in vivo.

Correlation between uptake of Tc-99m sestaMIBI and prognostic factors of breast cancer.

UNLABELLED: The purpose of this retrospective study was assessment of correlation between Tc-99m sestaMIBI uptake and some prognostic factors of breast cancer. The following prognostic factors have been included in this study: size of the tumour, age of the patients, axilla node involvement, oestrogen and progesterone receptor (ER, PR) status, grading system of Bloom-Richardson and Ki-67 antigen expression. METHODS: 79 patients were enrolled in this study, with 85 lesions confirmed as primary breast cancers. Mean age of patients was 53 years. Scintimammography (SMM) was performed after intravenous injection of 740MBq. At 5-10 min after injection standard planar images were obtained in prone lateral and anterior supine views. Assessment of correlation between known prognostic factors of breast cancer and uptake of MIBI (evaluated as a tumour to background ratio-TBR) was performed used non-parametric (Kendall-tau correlation) statistical analysis. RESULTS: There were 85 breast cancers (73 invasive ductal carcinomas, 11 DCIS (ductal carcinoma in situ) and 1 lobular carcinoma. There was positive correlation between TBR Tc-99m MIBI uptake and size of the tumour (t = 0.19, p = 0.01), presence of axilla node involvement (t = 0.2, p = 0.006) and also grade of the IDC tumours evaluated using Bloom-Richardson's criteria (t = 0.18, 0.03). There were negative correlation between TBR and presence of PR (t = -0.16, p = 0.02) and borderline negative correlation between TBR and age of patients (t = -0.137, p = 0.06) and also TBR and ER status (t = -0.135, p = 0.065). Patients who are younger and/or have PR or ER negative cancers have higher Tc-99m MIBI uptake. Patients who presented with high grade of malignancy (B-R) also have higher uptake of radiotracer. Also those with higher uptake of radiotracer often had axillary node involvement. This would suggest that more aggressive tumours have higher uptake of Tc-99m MIBI. Finally this study suggest correlation between in vivo uptake of MIBI and some of the known prognostic factors of breast cancer.

Serial quantitative imaging with 99Tcm-DTPA in pediatric renal transplantation.

Three hundred and fifty-eight renal imaging studies with quantitation of renal perfusion were performed following injection of 99Tcm-DTPA in 22 children aged 6--15 years with renal transplants. In 58 of 62 scans performed at the onset of a rejection episode, renal perfusion was decreased. This was the only feature of rejection in 6 episodes, in 5 of which the patient was oliguric due to post-operative acute tubular necrosis. In 4 episodes perfusion fell, but antirejection treatment was not given as a repeat scan was normal. On 18 occasions the plasma creatinine concentration (Pc) rose, but the scan was unchanged; no treatment was given and repeat Pc was normal. Three patients had a ureteric obstruction and 2 patients a lymphocoele detected from the images. There was no morbidity. Sequential renal scintigraphy was valuable in the early diagnosis of rejection and in the avoidance of unnecessary therapy.

Tc-99m MIBI in suspected recurrent breast cancer.

A prospective trial was performed to assess the accuracy of Tc-99m MIBI scintimammography in 63 women (mean age 65, range 33-85 years) with suspected recurrent breast cancer in the breast and/or loco-regional tissues. All patients had been diagnosed with breast cancer 1-23 years before the scintimammography. A total of 27 breasts had been removed by mastectomy so scintimammography was compared with mammography in the remaining 99 breasts. Pathological follow-up of patients confirmed 33 sites of recurrent disease within the breast, 26 (78%) were identified by scintimammography and 14 (42%) by mammography; 30 (90%) were positive on one test or the other. In addition Tc-99m MIBI scintimammography identified 10/16 (63%) of axillary lymph nodes with recurrent tumour and 4/6 sites of recurrent tumour present elsewhere. Tc-99m MIBI scintimammography is more accurate in identifying recurrent disease in the breast than mammography and can identify loco-regional recurrence outside of the breast.

99Tcm-DTPA for the measurement of glomerular filtration rate.

Comparison of the blood clearances of 51Cr-EDTA and 99Tcm-Sn-DTPA, in a series of 45 patients with a wide range of glomerular filtration rates, showed that there was a good correlation between the estimates of G.F.R. obtained using the two chelates simultaneously. The single-injection, single-exponential method of G.F.R. estimation was used, with a correction factor of 0.964 for 99Tcm-DTPA, which gave a relationship of G.F.R.Cr = 2.3+G.F.R.Tcml/min with a correlation coefficient of 0.99. 99Tcm-DTPA is a suitable agent for the estimation of glomerular filtration rate.

The appearances of renal transplant lymphocoeles during dynamic renal scintigraphy.

Eight patients are described in whom transplant lymphocoeles were drained. All had 99Tcm-DTPA dynamic renal scintigrams performed pre-operatively; five showed features of obstruction. Photon deficient areas on the scintigrams and bladder deformities were of particular value in detecting lymphocoeles.

Case report: localization of lipiodol-radioiodine in hepatic metastases from renal cell carcinoma.

Lipiodol, an iodinated derivative of poppyseed oil, is selectively retained in hepatocellular carcinoma and has been used as a vehicle to deliver localized doses of chemotherapeutic and radioactive agents to such tumours, thereby reducing the problems of external beam irradiation and the systemic toxicity of chemotherapy. We describe the first reported case where Lipiodol-targeted radiotherapy has been administered to a patient with secondary renal cell carcinoma in the liver. Localization was good and there were no complications. This case suggests that in future such patients may benefit from this therapy for unresectable lesions.

A pilot study of flaccid penile blood flow patterns in normal subjects and patients with erectile dysfunction.

Dynamic penile scintigraphy was performed using 99Tcm-labelled autologous erythrocytes in five normally potent volunteers and 22 patients with erectile dysfunction including 11 patients with psychogenic and 11 patients with vasculogenic impotence (four arteriogenic, three venogenic, three arteriogenic and venogenic, one arteriogenic and neurogenic). Penile radioactivity changes in the flaccid state were monitored by a gamma camera for 60 min after injection of the radionuclide. The penile time-activity curves of the normal controls characteristically showed secondary pulses of increased activity of variable amplitude, duration and frequency, consistent with phasic increase in penile blood pool. This normal rhythmic pattern was impaired in patients with penile arterial insufficiency whereas a blunted pattern was seen in most patients with functional impotence as well as in patients with nonarteriogenic organic impotence with a psychological overlay. This study provides new insights into the flaccid penile circulatory physiology, which may contribute to our understanding of the pathophysiology of erectile dysfunction. In arteriogenic subjects, the impaired response may be attributable to an inadequacy of penile arterial inflow as well as secondarily due to the resultant sinusoidal dysfunction subsequent to penile ultrastructural damage due to an altered nutritive environment. Increased adrenergic activity in patients with psychogenic impotence may be responsible for the observed deviation from the normal pattern.

Computer-generated attenuation correction does not improve the accuracy of myocardial perfusion scintigraphy.

A short study was performed to determine if it is possible to increase the accuracy of thallium-201 (201T1) single photon emission tomographic myocardial perfusion imaging using computer-generated ('Chang') attenuation correction. The stress and rest myocardial perfusion studies from 22 patients with suspected or known ischaemic heart disease were reconstructed with and without "Chang' attenuation correction. For all patients, the scintigraphy results were compared with those of coronary angiography. Attenuation correction improved the accuracy of 201T1 myocardial perfusion imaging for defining myocardial ischaemia or infarction in 8% of coronary artery territories (23% of patients), but it was worse in 5% of coronary artery territories (14% of patients). These changes were not significant (McNemar's test). Therefore, computer-generated 'Chang' attenuation correction does not appear to improve the accuracy of myocardial perfusion scintigraphy. It is important that all techniques suggested to improve the accuracy of clinical images should be tested on patients before being widely used.