Role of radioimmunolocalization in the staging of gastric carcinoma.

Intraoperative radioimmunolocalization is a potentially useful technique for staging gastric neoplasms without resorting to extensive surgical intervention. Before preoperative immunohistochemical typing for the presence or absence of tumor-associated glycoprotein (TAG) 72, we performed intraoperative radioimmunodetection on three patients presenting with gastric carcinoma using a whole monoclonal antibody (B72.3) marked with Indium-111 injected 1 week before operation. The results were calculated on the number of lymph node stations and yielded a high sensitivity due to a specificity of 72% and the absence of false negatives. Intraoperative radioimmunolocalization is a promising method for noninvasive staging of both early and advanced gastric carcinoma.

Processing of IgA aggregates in a rat model of chronic liver disease.

Heavy alcohol intake and/or lipotrope-deficient diet induced hepatocellular injury and mesangial deposition of IgA and often IgG in Lewis rats. The experimental animals showing more severe urinary abnormalities and histologic damage in the glomeruli had increased levels of IgA antibodies to dietary antigens and altered intestinal permeability. Based on human studies, the prolonged circulation of IgA-containing complexes associated with the liver disease could be envisaged as important for the development of mesangial IgA deposits. In order to verify this hypothesis, four groups (G) of Lewis rats were studied: G1 received thrice a weak an intragastric infusion of 1.5 ml/100 g body wt of whiskey; G2 rats were nourished with lipotrope-deficient diet; G3 rats were given both whiskey and LD diet; G4 rats were nourished with regular chow. After 12 weeks, heat-aggregated rat monomeric IgA was labeled with 133I and intravenously injected. Three control subgroups of rats, one given whiskey, one nourished with LD diet, and one with regular chow, were injected with radiolabeled heat-aggregated rat IgG. A large field-of-view digital gamma camera, equipped with an ultra-high-resolution collimator and interfaced to a dedicated computer, was used to analyze tracer kinetics and fate. The liver was the main organ involved in clearance of both test probes. The hepatic mean transit (MTT) was 11.4 +/- 11 min in G1 (proteinuria of 6.9 +/- 1.41 mg/day and hematuria +/+2), 221 +/- 19 min in G2 (proteinuria 9.1 +/- 0.64 mg/day and hematuria +2/+3), and 230 +/- 15 min in G3 (proteinuria 9.5 +/- 0.58 mg/day and hematuria +2/+3). In each case MTT value was found to be significantly prolonged compared to G4 (85 +/- 4 min). The multiple regression analysis showed that MTT values, proteinuria, and hematuria were significantly correlated (P < 0.01). Controls had trace amount proteinuria (0.82 +/- 0.17 mg/day, significantly lower than for each study group, P < 0.08) and undetectable hematuria. Similar results were obtained in control rats injected with aggregated IgG; i.e., MTT values were more prolonged in rats given whiskey or LD diet than normally nourished rats (P < 0.01). The lipotrope-deficient diet and the chronic alcohol abuse per se seem to lead to critical changes in hepatic uptake and catabolism of both an IgA and an IgG aggregate, which could account in turn for the reported appearance of renal immunoglobulin deposits in this experimental model. Due to the comparable delay in removal of IgA and IgG probes in equally nourished animals, additional factors are likely to be involved in the prominent deposition of IgA.

Liposome-delivered 131I-labelled Zn(II)-phthalocyanine as a radiodiagnostic agent for tumours.

131I-Zn(II)-phthalocyanine (ZnPc) incorporated into unilamellar liposomes has been systemically injected to mice bearing a transplanted MS-2 fibrosarcoma. Biodistribution studies show that the pharmacokinetic behaviour of 131I-ZnPc is very similar to that defined for the parent molecule ZnPc including a serum half-life of ca. 12 h, a high recovery from liver and spleen and minimal accumulation in kidney and brain. The most important pharmacokinetic parameter is represented by the high tumour/ muscle ratio of 131I-ZnPc concentration (ca. 9 at 24 h post-injection). These results suggest the possible use of the radiolabelled derivative for a real-time non-invasive monitoring of the ZnPc concentration in the tumour and peritumoural tissue during photodynamic therapy.

Plasmin promotes an endothelium-dependent adhesion of neutrophils. Involvement of platelet activating factor and P-selectin.

BACKGROUND: The adhesion of leukocytes to the endothelium and the edema of vessel wall may cause vascular reocclusion after thrombolytic therapy. The aim of this study was to evaluate the role of platelet activating factor (PAF) and P-selectin on the adherence of polymorphonuclear neutrophils (PMN) to the endothelium and of PAF on the increased vascular permeability induced by tissue-type plasminogen activator, streptokinase, and plasmin. METHODS AND RESULTS: We studied (1) the adhesion of 111Inlabeled PMN to human umbilical cord vein-derived cultured endothelial cells (HUVEC), (2) the transfer of 125I-labeled albumin across HUVEC monolayers, and (3) the adhesion of PMN to isolated bovine coronary arteries under flow conditions. It was found that the adhesion of PMN, induced by tissue-type plasminogen activator, streptokinase, and plasmin, correlated with the synthesis of PAF by HUVEC and was inhibited by WEB 2170, a PAF receptor antagonist. The adhesion of PMN was also inhibited by the treatment of HUVEC with anti-P-selectin antibodies or of PMN with soluble P-selectin or with anti-CD18 monoclonal antibodies. Plasmin also increased the permeability of HUVEC monolayers, an effect that was partially prevented by WEB 2170. Moreover, plasmin promoted the synthesis of PAF from isolated bovine coronary arteries and the adherence of PMN to the endothelium under flow conditions. The pretreatment of PMN with WEB 2170 or with soluble P-selectin prevented adhesion. CONCLUSIONS: The synthesis of PAF by endothelial cells at the site of plasmin generation and the endothelial expression of P-selectin may render the endothelial cell surface proadhesive for neutrophils and may favor a local increase in vascular permeability.

Indium-111-labeled granulocyte head accumulation in patients with Wegener's granulomatosis.

Among the symptoms of systemic vasculitis, purulent rhinorrhea with painful sinusitis is thought to be relatively specific to Wegener's granulomatosis (WG). Sixteen patients with rapidly progressive glomerulonephritis (GN), arteritis and extensive crescents in renal biopsy were studied by head indium-111 (111In)-granulocyte scanning. They included 8 WG, 5 microscopic polyarteritis, 2 necrotizing and crescentic GN and 1 classic polyarteritis nodosa. Autologous granulocytes labeled with 12.3 MBq of 111In-oxine were administered intravenously. Scintigraphic studies were performed at 4 and 24 h post-injection. Compared to the non-WG cases, considered as a whole, significant accumulation of tracer in sinuses was observed in WG patients (Fisher's p = 0.02). Substantial scintigraphic amelioration was obtained in a WG case treated with methylprednisolone pulses and, in another WG case, after high doses of intravenous gamma-globulins. The complete disappearance of facial uptake was obtained after 2 months of intensive therapy (i.e., steroid, cyclophosphamide and plasma exchange) in another WG patient. 111In-oxine granulocyte imaging may be useful in clinical practice as an additional marker of disease activity and a tool of identification of upper respiratory tract involvement.

Urinary endothelin in glomerulonephritis patients with normal renal function.

The vasoconstrictor peptide endothelin-1 (ET1) has only recently been characterized and its effects are at present largely speculative. It has been hypothesized that ET1 acts on mesangial cells to cause vasoactive changes which might ultimately contribute to the development of glomerulosclerosis. Opposite to ET1, nitric oxide (NO) inhibits mesangial cell contraction and proliferation. NO activates soluble guanylic acid cyclase and the final product, cyclic GMP (cGMP), has been recently used as a marker of NO action. Urinary levels of ET1 and cGMP were detected in 58 patients with biopsy-proven glomerulonephritis (GN), including 36 IgA nephropathy (IgAGN), 30 with normal and 6 with impaired renal function, 10 patients with non-IgA mesangial GN and 12 pts with membranous GN (MGN) with normal renal function. Compared to normal controls (0.019 +/- 0.006 ng/min), urine ET1 levels were significantly higher in patients with normal renal function having IgAGN (0.035 +/- 0.017, p < 0.01), MGN (0.028 +/- 0.013, p < 0.05), non-IgA mesangial GN (0.027 +/- 0.012, p < 0.05) and those with IgAGN and renal failure (0.032 +/- 0.011, p < 0.01). However no difference was found between MGN patients and normals by deleting MGN cases with mild to moderate mesangial proliferation. The mean value of urinary cGMP in IgAGN patients with renal failure (0.186 +/- 0.117 nmol/min) was lower (p < 0.05) than that of each group with normal renal function (IgAGN: 0.378 +/- 0.010 nM/min; MGN: 0.338 +/- 0.064 nmol/min, non-IgAGN: 0.436 +/- 0.168 nmol/min). The same significant differences were obtained by correcting cGMP values for creatinine urinary excretion. Urinary ET/cGMP ratio (assumed as an index of the relative balance between vasoconstrictor and vasorelaxing factors) was found to be higher than normal (0.570 +/- 0.010 ng/nmol) both in IgAGN patients with normal renal function (0.103 +/- 0.064 ng/mol, p < 0.05), and in those with renal failure (0.203 +/- 0.108 ng/nmol, p < 0.02). Urinary cGMP values were not related to plasma levels of atrial natriuretic peptide (ANP). These data show that hyperexcretion of ET1 occurs in a number of patients with mesangial proliferative GN. In some of them, mainly those with established glomerular damage, the local production of ET1 is not counter-balanced by adequate cGMP biosynthesis.

Scintigraphic study of ureteral peristalsis using fast Fourier transforms.

Pathophysiological changes in ureteral kinetics can be monitored externally and non-invasively by means of a time-space matrix approach during the excretory phase of fast-frame routine renography. The main limitations of this method are poor space-time resolution and, in some cases, an inadequate visualization of the peristaltic waves. A new approach to the study of ureteral contractions using the power spectrum obtained from Fourier transforms of the ureteral time-activity curves was developed. The FORTRAN program was tested by an experimental simulation, and its subsequent application on fifty-one subjects indicated that the method is a useful complement to the space-time matrix technique. Moreover, evaluation of the power spectrum offers several advantages for the study of the pathophysiological parameters of peristalsis.

Angiotensin II local hyperreactivity in the progression of IgA nephropathy.

Immunologic and hemodynamic factors are likely to work in synergism in the progression of immunoglobulin A nephropathy (IgAN) toward sclerosis. The local activation of the renin-angiotensin system may be one the most relevant mechanisms. We investigated the hemodynamic effects of the acute administration of angiotensin-converting enzyme inhibitor (ACEI) (captopril 50 mg). The glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) were measured by 51Cr-EDTA and 125I hippurate clearances. The correspondent filtration fractions (FFs) in basal conditions and after administration of ACEI were calculated, then the changes in FF (delta FF and % delta FF) were determined. We studied 27 IgAN patients. Eighteen patients had normal renal function (GFR, 112 +/- 19 mL/min/1.73 m2) and nine had moderate renal impairment (GFR, 54 +/- 13 mL/min/1.73 m2). Sixteen patients had proteinuria > or = 0.5 g/d. In addition, 12 glomerulonephritis control cases and eight healthy subjects were investigated. After the administration of ACEI in healthy subjects we observed slight modifications in the GFR, a significant increase in the ERPF (P < 0.005), and a significant decrease in FF (P < 0.04). Similarly, in IgAN patients with normal renal function the GFR increased slightly, the ERPF increased significantly (P < 0.01), and there was a decrease in FF (P < 0.01). The delta FF and % delta FF values were not significantly different from those found in the controls. In patients with initial renal failure GFR remained unchanged, ERPF increased significantly (P < 0.005), and FF significantly decreased (P < 0.004). However, the changes in delta FF and % delta FF were significantly greater than those found in healthy controls (P < 0.01) and in IgAN patients with normal renal function (P < 0.001). IgAN patients with proteinuria levels > or = 0.5 g/d showed greater changes in delta FF and % delta FF after the administration of ACEI than patients with proteinuria levels lower than 0.5 g/d (P < 0.003 and P < 0.04, respectively) or proteinuric control cases (P < 0.05 and P < 0.01, respectively). This different response in proteinuric and nonproteinuric patients was evident even when the analysis was limited to the subgroup of IgAN patients with normal renal function. The decrease in FF consequent to an increase in the ERPF after the administration of ACEI suggests a local hyperactivity of the renin-angiotensin system in some cases of IgAN.(ABSTRACT TRUNCATED AT 400 WORDS)

Role of platelet-activating factor in polymorphonuclear neutrophil recruitment in reperfused ischemic rabbit heart.

This study investigated the role of platelet-activating factor in the recruitment of polymorphonuclear neutrophils (PMN) in a rabbit model of cardiac ischemia and reperfusion. The accumulation of PMN was evaluated 2 and 24 hours after removal of 40 minutes of coronary occlusion by morphometric analysis and 111In-labeled PMN infiltration. The administration of two structurally unrelated platelet-activating factor-receptor antagonists (SDZ 63-675, 5 mg/kg body weight, and WEB 2170, 5 mg/kg body weight) before reperfusion significantly reduced the accumulation of PMN, as well as the hemodynamic alterations and the size of necrotic area. Two hours after reperfusion, the percentage of increase of 111In-labeled PMN in transmural central ischemic zone was significantly reduced in rabbits pretreated with SDZ 63-675 (51.4 +/- 7.9) or WEB 2170 (32.4 +/- 8.8) with respect to untreated rabbits (107.6 +/- 13.5). The morphometric analysis of myocardial sections confirmed the reduction of PMN infiltration at 2 hours and demonstrated that at 24 hours the phenomenon was even more significant. In addition, SDZ 63-675 and WEB 2170 prevented early transient bradycardia and hypotension and reduced the infarct size, judged by staining with tetrazolium at 2 and 24 hours after reperfusion, and by histological examination at 24 hours. These results suggest that platelet-activating factor is involved in the accumulation of PMN in the reperfused ischemic myocardium and contributes to the evolution of myocardial injury.

Prospective study on captopril renography in hypertensive patients.

Six hundred and sixty-seven hypertensive patients were analyzed by captopril-enhanced scintigraphy. If time to reach maximal activity (Tmax) was > or = 5 min using 99mTc-diethylenetriaminepentaacetic acid (DTPA) or > or = 3 min with 123I-o-iodohippurate (OIH) and 99mTc-mercaptoacetyltriglycine (MAG3) and washout time > or = 15 min, a control study with nifedipine was performed. If the difference between Tmax under captopril and nifedipine premedication was > or = 5 min with 99mTc-DTPA or > or = 3 min with 123I-OIH and 99mTc-MAG3, the renogram was defined highly suggestive of renovascular hypertension. In the evaluation of bilateral abnormalities an additional parameter was considered, i.e. the presence of functional asymmetry of the emuntories susceptible of partial reversal in the control study under nifedipine. Based on these criteria, 58 out of 667 (8.7%) scintigrams were found to be abnormal. Thirty-five of these 58 patients and 32 of the remaining 609 scintigraphically negative cases underwent additional arteriographic examination. A renal vascular stenosis > or = 50% was found in 33 out of 35 (94.2%) patients with positive scintigraphy and in 3 out of 32 patients with negative scintigraphy. By examining results of the 67 patients undergoing arteriography, the sensitivity of captopril-enhanced scintigraphy was estimated to be 91.6%, with a specificity of 93.5%, an accuracy of 92.5%, and predictive values of a positive or negative result of 94.2 and 90.6%, respectively. By restricting analysis to bilateral stenosis, sensitivity was found to be 76.9%.(ABSTRACT TRUNCATED AT 250 WORDS)

Estimation of chromium-51 ethylene diamine tetra-acetic acid plasma clearance: a comparative assessment of simplified techniques.

Chromium-51 ethylene diamine tetra-acetic acid (51Cr-EDTA) total plasma clearance was evaluated using a multi-sample method (i.e. 12 blood samples) as the reference compared with several simplified methods which necessitated only one or few blood samples. The following 5 methods were evaluated: terminal slope-intercept method with 3 blood samples, simplified method of Bröchner-Mortensen and 3 single-sample methods (Constable, Christensen and Groth, Tauxe). Linear regression analysis was performed. Standard error of estimate, bias and imprecision of different methods were evaluated. For 51Cr-EDTA total plasma clearance greater than 30 ml.min-1, the results which most approximated the reference source were obtained by the Christensen and Groth method at a sampling time of 300 min (inaccuracy of 4.9%). For clearances between 10 and 30 ml.min-1, single-sample methods failed to give reliable results. Terminal slope-intercept and Bröchner-Mortensen methods were better, with inaccuracies of 17.7% and 16.9%, respectively. Although sampling times at 180, 240 and 300 min are time-consuming for patients, 51Cr-EDTA total plasma clearance can be accurately calculated for values greater than 10 ml.min-1 using the Bröchner-Mortensen method. In patients with clearance greater than 30 ml.min-1, single-sample techniques provide a good alternative to the multi-sample method; the choice of the method to be used depends on the degree of accuracy required.

Increased serum neopterin concentration as indicator of disease severity and poor survival in multiple myeloma.

In this study we investigated serum neopterin levels in 73 multiple myeloma (MM) patients (63 determinations at diagnosis, 58 in remission, and 35 at relapse), in 56 monoclonal gammopathies of undetermined significance (MGUS), and in 70 normal controls. Median neopterin level was 5.3 nmol/l in normal controls, 6.8 nmol/l in MGUS, and 10.7 nmol/l in MM patients. In comparison to healthy subjects, significantly higher levels were observed in MM patients (p less than 0.0001). A statistical difference was observed between MGUS and MM patients at diagnosis (p less than 0.007). Compared to diagnosis, a further increase was noticed during relapse, suggesting a correlation between neopterin and disease activity. The prognostic significance of raised neopterin levels was confirmed by a survival analysis. Median survival for patients with high values was 20 months, whereas it was 63.9 months for those with low values (log-rank test p less than 0.003). Serum neopterin concentrations also correlated to beta 2 microglobulin levels and the percentage of CD38+ circulating lymphocytes, indicating a link between neopterin and other myeloma prognostic factors.

Immunoscintigraphy of adenocarcinomas by means of radiolabeled F(ab')2 fragments of an anti-carcinoembryonic antigen monoclonal antibody: a multicenter study.

F(ab')2 fragments of anti-carcinoembryonic antigen (CEA) monoclonal antibody F023C5, determined to be more suitable than intact IgG and Fab fragments for immunoscintigraphy, were labeled with 131I or conjugated to DTPA for instant 111In-labeling, and administered i.v. (2-3 mCi/0.5 mg) to 509 patients in 11 nuclear medicine departments: 284 patients had gastrointestinal adenocarcinomas, 204 had nongastrointestinal adenocarcinomas and 21 were control; serum CEA was elevated in 169 patients, normal in 115, and not determined in 225. The following results were obtained: (a) no adverse reactions; (b) tumor imaging in 324 patients (in particular, in 81.5% CEA-seropositive and in 69.0% CEA-seronegative patients); (c) no significant difference in sensitivity among the results of the 11 departments; (d) no significant difference in overall sensitivity between 131I-and 111In-labeled immunoradiopharmaceuticals; (e) the fraction of documented lesions imaged was 73.3% in CEA-seropositive and 53.7% in CEA-seronegative patients; (f) the detection of liver metastases was hampered, particularly when using the 111In-labeled reagent, by nonspecific radioactivity uptake; (g) the major cause of negative immunoscintigraphy results was a lack of CEA in tumor lesions, as documented by immunohistochemistry; (h) lesion size is also important since the sensitivity was 64% for lesions up to 2 cm in diameter and 84% for larger lesions; (i) many "unexpected" radiolocalizations were recorded. Most were identified as occult tumor lesions. In 35 patients, this finding contributed to the early detection of tumor recurrences.

[Myocardial scintigraphy with thallium-201 in the evaluation of aortocoronary bypass patients]. / La scintigrafia miocardica con Tallio-201 nella valutazione dei pazienti operati di by-pass aorto-coronarico.

We have compared the results of 201-Thallium scintigraphy (201 TI Sc) and those of coronary angiography in 48 patients (Pts) at a mean time of 13 months after a coronary artery by-pass grafting operation (CABG). Forty-six pts were males and 2 females, with a mean age of 52 years (range 37-66). Eighteen pts (37%) had had a myocardial infarction (MI) before the operation, 4 (8%) had a perioperative and 3 (6%) a postoperative MI. Nineteen pts (40%) had angina, 9 (19%) atypical chest pain, 6 (12%) shortness of breath or easy fatigability and 14 (29%) had no symptoms. The overall CABG patency was 74% (left anterior descending: 73%, left circumflex: 71%, right coronary artery: 80%). The 201 TI was injected at peak exercise and its myocardial uptake was recorded immediately and after four hours at rest. The 201 TI Sc has shown a sensibility (SN), specificity (SP), positive predictive (PV-pos) and negative predictive value (PV-neg) of 86, 82, 64 and 94% respectively, compared to coronary angiography. In the single patient evaluation the 201 TI Sc has shown a SN, SP, PV-pos, PV-neg of 95, 85, 82 and 96% respectively versus 90, 82, 78 and 92% of the standard exercise test associated with a positive history for 1) residual angina and 2) peri or postoperative MI. The 201 TI Sc has not shown to be significantly superior to standard exercise testing and history in the evaluation of graft patency. However it allows a topographic localization of the disease which is not feasible with the latter techniques. The 201 TI Sc can better predict the patency rather than the occlusion of the grafts because there is a high number of false positives due to residual ungrafted native disease in the territory of a good functioning graft. The 201 TI scintigraphy can give a functional evaluation of borderline grafts stenoses beside the pure anatomic definition of angiography thanks to its capability to qualitatively assess the regional myocardial blood flow during stress.

[Aspects of phosphorus and carbohydrate metabolism in amyotrophic lateral sclerosis]. / Aspetti del metabolismo fosfo-glicidico nella sclerosi laterale amiotrofica

The behaviour of glycaemia, insulinaemia, phosphoraemia, somatotropinaemia,free glycerol and triglyceridaemia was studied in six patients with A.L.S. following sugar load (1 g/Kg) in fasting. The results of glycaemia and insulinaemia were in tune with published data which have pointed to reduced sugar tolerance and reduced insulin secretion in patients with A.L.S. In the present experiments, particularly significant were the phosphoraemia responses. The failure of inorganic phosphorus values to fall after glucose loading suggests that the glycidic intolerance of these patients is related above all to a reduction in functioning muscular mass rather than to insufficient insulin secretion. The reduction in nervous tissue may also be of importance in this sense. In fact, not all biohumoral parameters investigated were similar to those of diabetes because the behaviour of somatotropinaemia, free glycerol and plasma triglycerides was normal. The changed behaviour of phosphorus would thus indicate altered glucose uptake at peripheral tissue level.