Long term effect of renal transplantation on dialysis-related amyloid deposits and symptomatology.

We report the five year outcome of nine patients with dialysis-related amyloid (DRA) who underwent successful renal transplantation (RT) and six patients who remained on hemodialysis (HD). Amyloid bone cysts, a radiologic feature of DRA, and scintigraphy with 123I-labeled serum amyloid P component (SAP), a specific technique for evaluating amyloid deposits in vivo, were monitored and compared with clinical features. In all HD patients there was clinical, scintigraphic and/or radiologic evidence that DRA progressed. In contrast, eight of the RT patients experienced profound early relief of DRA symptoms following transplantation that persisted throughout follow-up, despite the reduction or withdrawal of corticosteroids. Amyloid bone cysts improved in four patients and SAP scans demonstrated regression of articular amyloid in eight out of nine cases. The modest radiographic improvement suggests that amyloid is mobilized more slowly in bone cysts than elsewhere or that cystic bone is remodeled poorly. This is the first objective evidence that DRA regresses following renal transplantation, and suggests that this may contribute to the long-term relief of DRA symptoms in transplant recipients who discontinue corticosteroids.

Cause of regional ventilation-perfusion mismatching in patients with idiopathic pulmonary fibrosis: a combined CT and scintigraphic study.

OBJECTIVE: Regional ventilation and perfusion were studied in patients with idiopathic pulmonary fibrosis (cryptogenic fibrosing alveolitis) to seek an explanation for the mismatched ventilation/perfusion (V/Q) seen on scintigrams, which may suggest pulmonary embolic disease. SUBJECTS AND METHODS: Eight patients with idiopathic pulmonary fibrosis were examined with inspiratory and expiratory CT scans. Planar and tomographic (single-photon emission computed tomography, SPECT) scintigraphy, using inhalation of krypton-81m gas (ventilation) and IV injection of 99mTc-albumin macroaggregates (perfusion), also was performed. The lungs were divided into quadrants (cranial, caudal, right, left) for analysis. RESULTS: Cystic air spaces with a "honeycomb" appearance occupied more than 33% of the cross-sectional area in 75% of all lung quadrants (n = 16), more than 66% of the area in 44% of quadrants, and less than 33% of the area in the remaining 25% of quadrants. On expiratory CT scans, the cross-sectional area of the cystic spaces diminished significantly (unlike emphysematous spaces). Sixty-seven percent of lung quadrants, corresponding to those with marked or moderate involvement with cystic spaces, showed a mismatched V/Q pattern on scintigrams (absent perfusion, normal ventilation); 27% of quadrants had matched V/Q defects, and 6% did not show defects. Two patients had, in addition, large cystic spaces typical of emphysema, but the coexistent fibrosis prevented the gross air trapping seen in bullous emphysema. CONCLUSION: The cystic air spaces that are often seen on CT scans of patients with idiopathic pulmonary fibrosis are unperfused (probably due to vascular obliteration) but are usually normally ventilated. This V/Q mismatch on scintigrams explains the large physiologic dead space seen at rest and on exercise and could suggest pulmonary embolism unless a CT scan is obtained. Conversely, the larger cystic spaces might be mistaken for emphysema unless V/Q scintigraphy is done.

Meta-iodobenzylguanidine (MIBG) scanning in the diagnosis of phaeochromocytoma.

During the period 1984-90, meta-iodobenzylguanidine (MIBG) scans were performed in 23 patients with suspected phaeochromocytoma seen at the Hammersmith Hospital. Sixteen patients had a histologically proven phaeochromocytoma and in 14 of these patients the tumour was demonstrated by abnormal uptake of MIBG. Seven patients did not have a phaeochromocytoma and in all of these the MIBG scan was negative. These findings gave the procedure a sensitivity of 87.5% with a specificity of 100%; positive and negative predictive values were 100% and 77.7%, respectively. MIBG scanning is an extremely valuable technique in the management of patients with suspected phaeochromocytoma but is best employed to localise a tumour which has been confirmed biochemically.

Serum amyloid P component scintigraphy and turnover studies for diagnosis and quantitative monitoring of AA amyloidosis in juvenile rheumatoid arthritis.

OBJECTIVE: To evaluate aspects of the natural history of AA amyloidosis complicating juvenile rheumatoid arthritis (JRA), and its response to therapy with chlorambucil. METHODS: Scintigraphy and 7-day turnover studies were performed in JRA patients with histologically proven (n = 35) or clinically suspected (n = 30) AA amyloidosis, following intravenous injection of 123I and 125I-labeled serum amyloid P component (SAP). Prospective monitoring studies were performed over 2-3 years in 20 patients with amyloidosis. All but 2 amyloidosis patients were treated with chlorambucil. RESULTS: Positive scanning results were obtained in all patients in whom imaging was performed within 12 years of positive biopsy findings of amyloid and in 5 patients with clinically suspected amyloidosis. Negative scanning results with normal SAP metabolism, indicating regression of amyloid, were obtained in 4 patients whose amyloidosis had been in full clinical remission for more than 12 years. Prospective monitoring studies in patients whose JRA-associated inflammatory activity was in remission demonstrated regression of amyloid in 8 patients and no substantial changes in 8 others; however, in 4 further patients with active inflammation, there was accumulation of amyloid. There was a very poor correlation between the amount of amyloid present at a particular site and the resultant organ dysfunction. CONCLUSION: Radiolabeled SAP scintigraphy and turnover studies are useful complementary tools in the diagnosis, screening, and quantitative monitoring of type AA amyloidosis in JRA. The amyloid deposits may progress and/or regress at different rates in different anatomic sites over short periods.

Scintigraphic quantification and serial monitoring of human visceral amyloid deposits provide evidence for turnover and regression.

Radiolabelled serum amyloid P component scintigraphy provides information on the diagnosis and distribution of amyloid which was not previously available. A simple reproducible method for quantifying the uptake of 123I-labelled serum amyloid P component into individual livers, spleens and kidneys was devised and evaluated in 22 patients with different types of systemic amyloidosis. Prospective studies in 10 patients were undertaken in order to monitor aspects of the natural history of visceral amyloid deposits. Although measurements of tracer uptake were not as discriminating for diagnostic purposes as the opinions of two highly experienced visual observers, the availability of objective scintigraphic parameters should facilitate interpretation of serum amyloid P component scans in centres unfamiliar with the technique. The follow-up studies demonstrated several intriguing features of amyloidogenesis. There was very rapid progression of deposits in some individuals with differential rates of accretion in different organs. The single patient with AL amyloidosis treated with cytotoxic drugs showed substantial regression of hepatic amyloid deposits whilst his splenic amyloid increased. His spleen was then removed and further regression of the hepatic amyloid was observed. It is concluded that quantitative serum amyloid P component scintigraphy is a useful method for assessing visceral amyloid and that the deposits not only progress at extremely variable rates, but can evidently also be mobilized. These findings encourage active therapeutic approaches in the management of amyloidosis.

Pulmonary granulocyte margination is increased in patients with inflammatory bowel disease.

The pulmonary granulocyte content of the lung was quantified in patients with inflammatory bowel disease (IBD) after injection of 111In-labelled granulocytes and compared with patient controls, who, on the basis of their negative white cell scans, were not considered to have active inflammation. The mean ratios of lung:liver count rates per pixel on the posterior gamma camera image in patient controls was 0.34 (S.D. 0.16, n = 8) at 1-1.5 h after injection of the cells, and 0.29 (S.D. 0.14, n = 18) at 2-4 h. This ratio was higher in patients with active IBD at both imaging times: 0.45 (0.13, n = 13, P > 0.05) and 0.44 (0.1, n = 19, P < 0.001). Patients with inactive IBD also had increased ratios at both imaging times: 0.6 (0.14, n = 7, P < 0.01) and 0.54 (0.15, n = 12, P < 0.001), respectively. In a further group of 12 patients with active IBD, there was no correlation between the lung:liver ratio and the severity of the IBD as assessed by whole-body 111In retention at 4-6 days after labelled cell injection. These patients were treated for 3 weeks with an oral, non-absorbable corticosteroid, after which there was a significant decrease in disease activity but no significant change in the lung:liver ratio. Inflammatory bowel disease appears to be associated with abnormal pulmonary granulocyte accumulation. It is not apparently related to disease activity but may be the result of an associated pulmonary abnormality.

Inhaled platelet-activating factor causes pulmonary neutrophil sequestration in normal humans.

Inhaled platelet-activating factor (PAF) causes bronchoconstriction and transient peripheral neutropenia in humans. We studied eight normal subjects to investigate whether inhaled PAF caused pulmonary neutrophil sequestration. All subjects received autologous 99mTc-red cells as a blood pool marker, seven received 111In-neutrophils, and one received 111In-platelets. Six subjects inhaled 48 micrograms of PAF. There was immediate pulmonary sequestration of 111In-neutrophils, maximal (218% baseline) at 6 min (p less than 0.001), returning to normal by 3 h. There was no change in circulating platelet count or pulmonary 111In-platelet transit. Methacholine inhalation caused equivalent bronchoconstriction to PAF, but it had no effect on neutrophil count or pulmonary 111In-neutrophil activity. We have demonstrated pulmonary neutrophil, but not platelet, sequestration after PAF. This supports a role for PAF as an inflammatory mediator in humans. This may be a useful model for exploring pulmonary neutrophil kinetics and preinflammatory processes.

Value of scintigraphic localization of obscure gastrointestinal bleeding.

A total of 51 technetium-99m (99mTc)-labelled autologous red cell (LRC) scans performed on 49 patients for the localization of obscure gastrointestinal bleeding over a 5-year period was reviewed. The sensitivity for LRC scanning was 72.7% with a positive predictive value of 84.2%. Forty patients underwent both LRC scanning and visceral angiography during the same admission; angiography had a sensitivity of 38.9% compared with 66.7% for LRC scanning and the positive predictive values were 77.8% and 85.7%, respectively. Overall, the site of bleeding was located in 22 (45%) of 49 patients, but LRC scanning alone was successful in identifying the lesion in 16 (33%) cases. In patients who continue to bleed to the point of requiring operation, a combination of scintigraphy and angiography will localize a source in 70% of patients.

Uses of labelled white cells.

In addition to an established clinical role, labelled white cells have great potential for clinical research. This review will therefore outline the clinical use of labelled white cells and briefly consider their contribution to developments in clinical science.

Platelet imaging of thromboembolism. Natural history of postoperative deep venous thrombosis and pulmonary embolism illustrated using the 111In-labelled platelet-specific monoclonal antibody, P256.

BACKGROUND: Deep venous thrombosis (DVT) and pulmonary thromboembolic disease are difficult to diagnose, particularly following surgery. This report demonstrates the use of 111In-labelled platelet-specific monoclonal antibody, P256 Fab', for the diagnosis and study of the time course of thromboembolic disease in a patient following total hip replacement. METHOD: One hundred micrograms of pentetic acid (DTPA)-P256 Fab' was labelled with 8 to 10 MBq of 111In chloride by incubation at room temperature for 15 min. After dilution in physiologic saline, the tracer was injected intravenously on the third and sixth days postoperatively. Imaging of the chest, pelvis, and legs was carried out at 24, 48 and 72 h following each injection. RESULTS: The first image four days after surgery demonstrated activity in the right heart which moved to the right pulmonary artery on the following day. Activity was seen in both femoral veins; on the left, this increased over two days, followed by a reduction on the seventh day after surgery, at which time new activity was seen in the right heart. After a further two days, this activity moved to the left pulmonary artery. The DVT was confirmed by venography and the pulmonary embolism (PE) by ventilation perfusion scan. CONCLUSIONS: 111Indium-labelled platelet-specific monoclonal antibody, P256 Fab', provides a technique for studying the natural history of thromboembolic disease and its treatment.

Impaired left lower lobe ventilation in patients with cardiomegaly. An isotope study of mechanisms.

Reduced left lower lobe ventilation (V) in patients with enlarged hearts has been commonly observed on routine isotope ventilation-perfusion lung scanning, and there is evidence to show that this reduction is dependent on posture. Clinically, it may have a role in posture-dependent dyspnea and postoperative left lower lobe changes in cardiomegaly. Previous studies have shown improvement in left lower lobe V in the prone compared with the supine position. In 11 patients showing this phenomenon in krypton 81m V scanning, a mean relative reduction in V of 53 percent occurred at the left base. No significant change in perfusion or in the signal from preinjected technetium 99m macroaggregated albumin was observed between the two positions. No significant change in ventilatory turnover (measured with intravenous xenon 133) was seen either, suggesting that no air trapping takes place. By combining the data from the intravenous 133Xe (which gives the ratio, V/lung volume) and continuously inhaled 81mKr (which reflects regional V), an index of relative volume between the two sides was derived and shown to be significantly reduced at the left base on moving from the prone to supine positions (a mean reduction of 40 percent; p less than 0.02 by Wilcoxon signed rank test). Thus, the mechanism of postural left lower lobe hypoventilation in cardiomegaly is predominantly a regional loss of alveolar volume.

Indium-111 whole-body retention: a method for quantification of disease activity in inflammatory bowel disease.

Quantification of disease activity in inflammatory bowel disease (IBD) has been by measurement of fecal excretion of 111In-granulocytes. The difficulties of this method prompted us to evaluate quantification of whole-body 111In retention, expressed as a percentage of whole-body activity at 3 hr following injection, as an alternative method. The patient stood in front of the uncollimated gamma camera at a distance of 4 m and counts were collected over 2 min. The geometric mean was taken of posterior and anterior counts and compared with a 111In standard. The lower limit of the 95% confidence interval for whole-body retention in normals was 90%. Forty-five studies were performed on 33 patients with IBD. They were assessed in two groups, one to whom routine instructions for the collection of feces were given (Group A) but who did not always comply. The other group received oral and written instructions and were also monitored during the collection period (Group B) and reported full fecal collection. Although in Group A the correlation between fecal excretion and whole-body retention was good (r = 0.7, n = 32; p less than 0.001), in Group B the relationship between fecal excretion and whole-body retention was significantly better (r = 0.95, n = 18; p less than 0.001). On average, 111In whole-body retention was consistent with findings obtained during imaging: 111In excretion (100-whole-body retention) was 7.8% +/- 4.9% in 5 normal scans, 10% +/- 5.9% in 17 (+) scans, 22.3% +/- 8% in 20 (++) scans and 57% +/- 16% in 8 ( ) scans. We conclude that imaging is more sensitive than whole-body retention and fecal excretion in the detection of disease, but for quantification, whole-body retention is an accurate reliable alternative to fecal excretion.

A retrospective study of radiolabeled granulocyte kinetics in patients with systemic vasculitis.

Patients with systemic vasculitis, including Wegener's granulomatosis (WG) and microscopic polyarteritis (MP), may undergo white cell scanning for the investigation of infective complications and/or occult fever. In a retrospective study of 12 patients with systemic vasculitis (six each of WG and MP), all with renal disease, we observed increase diffuse lung radioactivity soon after the injection of 111In-labeled granulocytes or 99mTc-HMPAO-labeled leukocytes in all patients with WG and in three with MP. Lung activity was quantified by comparison with the liver or spleen. The lung:liver count rate ratio per pixel, 1-1.5 hr after injection, in patients with systemic vasculitis was 0.87 (s.d. 0.25), significantly higher (p less than 0.001) than the ratio 0.38 (0.13) in patient controls who had normal white cell scans. The majority of patients with systemic vasculitis had scintigraphic evidence of abnormal splenic function. Two had focal splenic defects, while 7 had increased labeled cell uptake. Nine of the patients with vasculitis showed cell migration into the gut, presumably as a result of vasculitis, and in 6 it was prominent. Focal nasal uptake was found in 5/7 patients with systemic vasculitis who had their heads imaged, and may be specific for WG. Although all patients had renal disease, there was scintigraphic evidence of diffuse parenchymal renal uptake of 111In-labeled granulocytes in only one (with MP). The presence of anti-neutrophil cytoplasmic antibodies did not correlate with any abnormality or with lung uptake. Systemic vasculitis is associated with abnormalities of granulocyte kinetics, particularly involving the lung and spleen.

The significance of a dipyridamole induced 99mTc-MIBI perfusion abnormality on single photon emission tomography: a quantitative validation with labelled water and positron emission tomography.

To relate technetium-99m 2-methoxy-isobutyl-isonitrile (99mTc-MIBI) uptake to regional myocardial blood flow (rMBF), 99mTc-MIBI single photon emission tomography (SPET) and H2(15)O positron emission tomography (PET) scans were obtained at rest and after dipyridamole infusion in six patients with single vessel coronary artery disease. 99mTc-MIBI and H2(15)O data sets were created for each segment perfused by the stenotic vessel and for a normal reference area, assigning regions on the SPET tomograms to comparable regions on the PET by similar transaxial image reconstructions. All patients demonstrated post-dipyridamole 99mTc-MIBI perfusion defects in the territories supplied by the stenotic arteries. Resting rMBF in these regions was slightly lower than that in the normal areas (0.82 +/- 0.05 vs 0.90 +/- 0.09 ml/g/min, P = NS). A 43% +/- 14% reduction in 99mTc-MIBI activity in the area at risk was coupled with on average a 60% +/- 9% reduction in post-dipyridamole rMBF compared with control regions (0.98 +/- 0.08 vs 2.52 +/- 0.51 ml/g/min, P < 0.001). Thus, SPET assessment of 99mTc-MIBI uptake tends to underestimate the perfusion contrast between areas with normal and areas with low coronary vasodilatory reserve when compared to PET. However, these findings may still not affect the clinical usefulness of 99mTc-MIBI and more extensive studies are required to confirm these results in the clinical environment.

Tumour localisation with a radioactively labelled reshaped human monoclonal antibody.

A genetically reshaped human IgG1 monoclonal antibody (Hu2PLAP) with anti-tumour specificity, was radiolabelled with Indium-111 by chelation with a new macrocyclic compound (DOTA) which allows the production of stable radioimmunoconjugates for in vivo application. This was used to image seven patients with malignant disease, of whom two had been previously exposed to mouse monoclonal antibodies and had developed human anti-mouse antibodies (HAMA). Successful tumour localisation was seen in the four patients with active disease and antigen positive tumours. No patient showed any antibody responses against Hu2PLAP, but three out of six patients tested showed an immune response against the macrocycle DOTA. Reshaped human monoclonal antibodies with anti-tumour specificity may facilitate repeated administrations of radioactive antibodies, thus allowing new possibilities, both in the diagnosis and treatment of cancer.

Anti-platelet monoclonal antibody P256 in the diagnosis of renal transplant rejection.

Platelets labeled in vitro with In-111 have a recognized place in the diagnosis of renal transplant rejection. Following their introduction for imaging thrombi, radio-labeled anti-platelet antibodies may also have a role in the diagnosis of transplant rejection. Four of 11 patients with recently donated transplants had biopsy-proven acute rejection episodes close to the time of administration of In-111 P256 Fab' fragment, which recognizes the IIb-IIIa fibrinogen receptor on primate platelets. The transplant-to-background count rate at 3 and 24 hours after these injections were 2.2 (SE 0.14) and 2.3 (0.23), respectively, almost identical to the ratios, 2.0 (0.1) and 2.2 (0.11), recorded at the corresponding times after 19 injections of P256 Fab' that were remote in timing from rejection episodes. P256 Fab' may have value in the detection of postoperative venous thrombosis, but it has no value for the detection of transplant rejection.