Initial tumor targeting, biodistribution, and pharmacokinetic evaluation of the monoclonal antibody PAM4 in patients with pancreatic cancer.

This pharmacokinetic study was performed to assess the potential usefulness of the murine monoclonal antibody (MoAb) PAM4-IgG1 as an immunotargeting agent for pancreatic cancer imaging or therapy. This MoAb reacts specifically with mucin purified from human pancreatic cancer. 131I-labeled PAM4-IgG1 was injected i.v. into five patients with suspected pancreatic cancer. Whole-body scans and spot views of the abdominal area were recorded with a computerized gamma camera, and specific regions of interest were drawn over the liver and spleen to define the kinetics of activity in these organs. Blood samples taken from 0.1-144 h after injection served to define the kinetics of plasma distribution and removal of activity from the body. Surgery confirmed pancreatic cancer in four of the five patients, whereas chronic pancreatitis was present in the fifth patient; in all four pancreatic cancer patients, immunostaining with the MoAb PAM4 demonstrated the presence of the specific antigen, with a cytoplasmic and endoluminal/secretory pattern of distribution. Nonspecific radioactivity accumulation in the liver, spleen, and bone marrow was low, linked essentially to the blood pool effect of circulating activity in these organs. The overall quality of scintigraphic maps recorded over the abdomen was quite satisfactory due to the low liver and spleen activity, with good scintigraphic demonstration of the pancreatic cancers (either primary or metastatic); the patient subsequently found to have pancreatitis failed to show PAM4 targeting. Except in one patient with widespread peritoneal metastases (in whom these tumor implants were detected scintigraphically already 24-48 hours after tracer injection), scintigraphic evidence of the tumor lesions was usually late, starting at about 72-96 h after tracer injection. The results obtained in this preliminary study indicate the potential usefulness of MoAb PAM4 for immunoscintigraphy in patients with either primary and/or recurrent pancreatic cancer while also suggesting that the use of the faster-clearing Fab fragments of this MoAb probably would result in improved immunoscintigraphic properties.

Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer.

PURPOSE: Dexrazoxane was found effective in reducing doxorubicin cardiotoxicity when given at a dose ratio (dexrazoxane: doxorubicin) of 20:1. Preclinical studies indicated that dexrazoxane at a dose ratio of 10 to 15:1 also protected against epirubicin-induced cardiotoxicity. The main objective of this study was to investigate the efficacy of dexrazoxane, given at a dose ratio of 10:1 against epirubicin cardiotoxicity. PATIENTS AND METHODS: One hundred sixty-two advanced breast cancer patients were randomized to receive epirubicin-based chemotherapy with or without dexrazoxane. Patients who had previously received adjuvant chemotherapy that contained anthracyclines were treated with cyclophosphamide 600 mg/m2 intravenously (IV), epirubicin 60 mg/m2 IV, and fluorouracil 600 mg/m2 IV, on day 1 every 3 weeks. The other patients were treated with epirubicin 120 mg/m2 IV on day 1 every 3 weeks. Cardiac toxicity was defined as clinical signs of congestive heart failure, a decrease in resting left ventricular ejection fraction (LVEF) to < or = 45%, or a decrease from baseline resting LVEF of > or = 20 EF units. RESULTS: One hundred sixty patients were evaluated. Cardiotoxicity was recorded in 18 of 78 patients (23.1%) in the control arm and in six of 82 (7.3%) in the dexrazoxone arm. The cumulative probability of developing cardiotoxicity was significantly lower in dexrazoxane-treated patients than in control patients (P = .006; odds ratio, 0.29; 95% confidence limit [CL], 0.09 to 0.78). Noncardiac toxicity, objective response, progression-free survival, and overall survival were similar in both arms. CONCLUSION: Dexrazoxane given at a dexrazoxane:epirubicin dose ratio of 10:1 protects against epirubicin-induced cardiotoxicity and does not affect the clinical activity and the noncardiac toxicity of epirubicin. The clinical use of dexrazoxane should be recommended in patients whose risk of developing cardiotoxicity could hamper the eventual use and possible benefit of epirubicin.

Comparison of plasma and urinary methods for the direct measurement of the thyroxine to 3,5,3' - triiodothyronine conversion rate in man.

A further development of a new method recently proposed for the direct measurement of the conversion ratio (CR) of T4 to T3 in man is presented. [125I]T4 and [131I]T3 are injected simultaneously, and Sephadex chromatography is performed on urine samples to determine [125I]T3 formed in vivo, while plasma samples are used to measure the injected tracers. CR is calculated with the assumption that urinary [125I]T3 closely reflects [125I]T3 appearing in plasma after the injection of precursor [125I]T4. Four normal subjects and six patients with various thyroid disorders were studied using this method. The experimental data were also analyzed by our previous method based on plasma sampling only and by two recently described methods based on urinary measurements. These comparisons were made in an attempt to ascertain whether there is any systematic difference between the conversion values derived from plasma data and those derived from urinary data. Using plasma data alone, the CR was 28.6 +/- 3.4% (mean +/- SEM) in a group of four normal subjects, 37%, in two untreated hypothyroid patients, 40.2% in one hypothyroid subject receiving T4 treatment, 30.9% in one hyperthyroid patient, 24.9% in one patient with selective hyperthyroxinemia due to amiodarone treatment, and 10.7% in one normal subject after iopanoic acid administration. These values were in excellent agreement with those obtained by the modified procedure described here, in which both urinary and plasma measurements are used. Of the methods using urinary data alone, however, one gave similar results, while the other systematically overestimated the CR, possibly due to delayed excretion of labeled T4 metabolites into the urine. We conclude that 1) the analytical procedure to separate the labeled tracers and metabolites in urine or plasma is critical for the accurate estimation of CR; 2) when an adequate separation procedure is available, plasma and urinary methods for measuring CR yield comparable results; and 3) the plasma method should be used when, in addition to CR, other kinetic (distribution and turnover) parameters of T4 and T3 metabolism are to be estimated.

Peripheral metabolism of thyroid hormones in man. I. Direct measurement of the conversion rate of thyroxine to 3,5,3'-triiodothyronine (T3) and determination of the peripheral and thyroidal production of T3.

We describe here a new method for the direct measurement of the conversion rate of T4 to T3 in man. The metabolic study was performed in 23 subjects: 13 healthy controls, 7 T4-treated hypothyroids, and 3 sick euthyroid patients. The experimental protocol involved the simultaneous iv bolus injection of [125I]T4 and [131I]T3, and the use of Sephadex G-25 column chromatography to determine the plasma concentrations of [125I]T4, [131I]T3, and [125I]T3 newly formed through 5'-monodeiodination of labeled T4 in the peripheral tissues. The T4 and T3 kinetic parameters were determined by noncompartmental analysis. The conversion rate of T4 to T3 was computed by a method based on the precursor-product relationship, using the [131I]T3 disappearance curve for correcting the concentrations of newly formed [125I]T3 (convolution method). The conversion rate of T4 to T3 was 0.2541 +/- 0.0125 (mean +/- SEM) in the control group and was significantly reduced (0.1283 +/- 0.0204; P less than 0.001) in the sick euthyroid patients, while it was slightly, though not significantly, increased in the T4-treated patients (0.2932 +/- 0.0220). A close agreement was found between the values for the conversion rate obtained by the convolution approach and those derived from the ratio between the serum concentrations of [125I]T3 and [125I]T4 at equilibrium. The conversion rates obtained by the convolution approach were also in good agreement with the values estimated from the molar ratio between the turnover rates of T3 and T4. In the control group, 72.0 +/- 3.6% of the circulating T3 was produced by 5'-monodeiodination of T4 in the peripheral tissues, and 28.0 +/- 3.6% of the circulating T3 derived from direct thyroidal secretion. The sick euthyroid patients showed a significantly smaller proportion of circulating T3 deriving from peripheral conversion of T4 (52.5 +/- 3.9%; P less than 0.025).

Chromatographic identification in serum of endogenously radioiodinated thyroid hormones after iodine-131 whole-body scintigraphy in the follow-up of patients with differentiated thyroid carcinoma.

Patients with differentiated thyroid cancer (DTC) are conventionally followed with serial 131I whole-body scintigraphy (WBS) and serum thyroglobulin (hTg) assay. Given the 15%-20% incidence of discordant results, we developed a sensitive and specific procedure for monitoring such patients, based on the assumption that 131I uptake, even if too low to be detected by 131I WBS, could be assayed in serum as thyroid products (hTg, T3 and T4) endogenously labeled with 131I. Our study included 125 patients routinely monitored for tumor recurrence or for the persistence of functioning thyroid tissue after complete primary treatment for DTC (surgery and 131I ablation of remnants). A plasma sample, taken 72 hr after administering 131I for WBS was fractionated on a Sephadex-G25 superfine column by first eluting all of the radioactive species except the thyroid hormones and then the radioiodothyronines. The sensitivity and specificity of chromatography in detecting functioning thyroid tissue after primary treatment for DTC were 98.4% and 100% (accuracy 99.2%), respectively, versus 90.6% and 95.1% for 131I WBS (accuracy 92.8%) and 60.9% and 100% for hTg (accuracy 80%). Combining chromatography with serum hTg gave the highest gains in diagnostic performance (100% for all parameters). This chromatographic method can be used in addition to conventional procedures in the follow-up of patients with DTC and represents a highly sensitive test for assessing the results of 131I ablation of postsurgical remnants.

Labeled metabolites appearing in human serum after 125I-triiodothyronine (T3) administration: a quantitative reappraisal.

The appearance in human serum of labeled iodothyronines arising from 3,5,3'-triiodothyronine (T3) catabolism was measured after bolus administration of 125I-T3. The use of column chromatography made it possible to separate in the plasma samples iodoproteins, iodide, T3 and a fourth peak ("pre-T3") eluting just before T3. The radioactivity associated with this pre-T3 peak was found to be 0.5% of T3 activity 30 min after injection, and reached a plateau value of 5.6% +/- 1.2 (mean +/- SD) from the 10th hr onward. From these data, we calculated that a maximal 5% underestimation in T3 metabolic clearance rate is inherent in those analytical methods that do not completely separate pre-T3 from T3 radioactivity. The MCR of 3,3'-diiodothyronine (T2) was also measured from the plasma disappearance curve after single injection of 125I-3,3'-T2. From these data and the mean disappearance curve of T3, the appearance curve of 3,3'-T2 in plasma was reconstructed by convolution under the assumption of a 100% conversion of T3 to 3,3'-T2. A plateau value of 4.6% of T3 activity was computed, very comparable to the experimentally determined 5.6%. This suggest that, if labeled 3,3'-T2 is the main component of the pre-T3 peak, the conversion into 3,3'-T2 represents a major pathway of T3 metabolism in man.

Triiodothyronine turnover studies in euthyroid patients with autonomous thyroid nodules.

Triiodothyronine (T3) kinetic studies were carried out using 126I-T3 and the single injection technique in eight clinically euthyroid patients with autonomous thyroid nodules and the metabolic results were compared to those obtained in a group of 12 healthy control subjects. Plasma labeled T3 concentration was measured by a chromatographic method based on the extraction of the hormone on Sephadex G-25 columns, followed by its elution with a specific anti-T3 antiserum. The analysis of the experimental plasma disappearance curves of the labeled hormone was performed using the noncompartmental method. The results obtained showed a significantly increased metabolic clearance rate of T3 in the patients with autonomous thyroid nodules, as compared to the control group. On the average, the T3 production rates were increased more significantly than the corresponding circulating levels of the hormone, therefore, suggesting that the significant TSH inhibition observed in the euthyroid patients with autonomous thyroid nodules could be related with an increased peripheral utilization of triiodothyronine.

Localization of [125I]endothelin-1 in injured aorta of rabbits.

Endothelin-1 is a potent vasoconstrictor. This study was performed to determine whether arterial injury, induced by either hypercholesterolemia or mechanical disruption of the endothelium, is associated with increased localization of endothelin-1 in the artery. The blood clearance and tissue distribution of intravenously injected [125I]endothelin-1 was evaluated in 33 rabbits--control animals (n = 7), balloon de-endothelialized animals (n = 12), cholesterol-fed animals (n = 6) and animals that had both balloon de-endothelialization and high cholesterol diet (n = 8). The blood clearance half time was less than 10 min, with slightly slower clearance in the ballooned/cholesterol-fed animals. [125I]Endothelin-1 localized in the lung (approximately 12% injected dose (ID)/organ) and kidney (approximately 8%ID/organ). [125I]Endothelin-1 localization in the injured aorta increased from the baseline level of 0.06%kgID/g to its highest level within 5 min of balloon de-endothelialization (0.2%kgID/g) and decreased to 0.11%kgID/g within one week and remained essentially unchanged through 16 weeks. The area with increased binding of [125I]endothelin-1 corresponded to the zone of arterial injury stained with Evans blue. On the other hand, the binding in the aorta did not increase with the atherogenic diet. These findings suggest that endothelin-1 accumulates in injured vessels, attaining the highest levels immediately after mechanical injury.

Bone involvement in Gaucher's disease: 'bone crisis' or disease complication?

Bone involvement can represent the inaugural symptom of Gaucher's disease (GD). Here, we report the case of a 68-year old man diagnosed as having GD since 1963. In June 1994 the patient was referred to our Rheumatology Unit because of a long-lasting coxalgia on the left hip and progressive walking impairment following traumatic fracture of the left femur. Multicystic osseous changes at standard X-ray and hyper-gamma-globulinemia with an elevated ESR (122 mm, 1st hour) suggested the diagnosis of either osteonecrosis of the femoral head or multiple myeloma. On bone marrow biopsy examination, Gaucher's cell infiltrates were detected and an increased uptake in the distal left femur and proximal tibia were demonstrated by lipophilic tracer scan (99mTc-Sestamibi). Subsequently, the patient suffered another femoral fracture at a site of Gaucher's infiltrates previously documented by bone scan. We conclude that in patients with GD, 99mTc-Sestamibi bone scan can selectively evaluate the presence of bone lipid deposits, and could indirectly differentiate this bone condition from other serious skeletal complications of the disease.

[Chronic renal insufficiency. Low-protein diet supplemented with essential amino acids and ketoanalogues]. / Insufficienza renale cronica. Dieta ipoproteica supplementata con aminoacidi essenziali e chetoanaloghi.

Conventional conservative treatment of chronic uremia is aimed at reducing protein intake to a minimum level compatible with nitrogen balance. A great progress in this field is represented by a low protein diet associated with some essential aminoacids and ketoanalogues. A group of 20 patients with chronic renal failure at an advanced stage has been studied and good results have been obtained with a low protein diet (0.2 g/kg/24 h vegetable proteins) associated with essential aminoacids and ketoanalogues.

[Use of SPECT in the diagnosis of vertigo syndromes of vascular nature]. / Impiego della S.P.E.T. nella diagnosi delle sindromi vertiginose di natura vascolare.

Dizziness is doubtlessly one of the most common symptoms to arise in ischemia of the brainstem. In such cases the circulatory deficit can not only cause a direct lesion of the vestibular structures but it may also block the compensatory process. There are, however, significant difficulties in establishing whether such dizziness can be attributed to a brainstem insufficiency (BI). In fact, both CAT and NMR provide data only in the case of permanent CNS tissue lesions and tests such as the Doppler examination of neck blood vessels are unable to establish the true state of cerebral blood flow. In order to obtain semi-quantitative data regarding cerebral blood flow 99mTc-HMPAO-S.P.E.T. (Single Photon Emission Tomography) was used in 18 patients suffering from dizziness and for whom there was strong indication that the underlying cause could be vascular. There was a discrepancy between the Doppler and S.P.E.T. findings in 50% of the cases. CAT, however, proved negative in all but one of the cases. These data indicate that Doppler testing of the neck blood vessels can provide useful information regarding the status of the cerebral-afferent vessels but that these cannot be correlated to the level of cerebral blood flow. On the other hand, with S.P.E.T., in 15 of the 18 patients, it proved possible to identify significant alterations in cerebral blood flow in the absence of any permanent tissue lesions as those revealed by CAT and NMR. In the light of the present results cerebral S.P.E.T. appears to be a highly valid tool when, faced with dizziness for which a vascular origin is suspected, one must evaluate cerebral prognosis and therapy.

[The imaging diagnosis of Sjögren's syndrome: echography, sialography and scintigraphy compared in the study of the salivary glands]. / Diagnostica per immagini della sindrome di Sjögren: ecografia, scialografia e scintigrafia a confronto nello studio delle ghiandole salivari.

The aim of the present study was to evaluate the sensitivity and specificity of the ultrasonography, in comparison with other methods of investigation (scintigraphy, sialography, and biopsy), in scanning morphostructural changes in the parotid gland in patient with Sjögren's syndrome. During the period June-October 1994, 34 patients (5 males and 29 females, age ranged between 20 and 88 years) with "sicca syndrome" underwent to echography, scintigraphy, sialography and biopsy. The diagnosis was confirmed or excluded using the European Community Epidemiologic Committee criteria for Sjögren's syndrome. Twenty-two patients out of 34 were affected by Sjögren's syndrome, while the others resulted as control subjects. The ultrasonographic investigation has shown 76.19% of sensitivity and 30.43% of specificity. Even if echography is a non-invasive method, which could be used as preliminary approach for studying the diffused involvement of the parotid gland, at the status of the art, it is not completely reliable for the global evaluation of the morphostructural changes in patients with Sjögren's syndrome, in comparison with the other techniques. Because of the double nature of the gland injury, it appears to be essential the diagnostic integration between echography and sialography.

Scintigraphic findings on 99mTc-MDP, 99mTc-sestamibi and 99mTc-HMPAO images in Gaucher's disease.

Gaucher s disease is an autosomal recessive lysosomal storage disease characterized by the specific deficiency of glucocerebrosidase that leads to accumulation of insoluble glucocerebroside in the reticuloendothelial system, particularly the bone marrow, liver, spleen and lymph nodes. Direct scintigraphic visualization of lipid deposits in Gaucher s disease has recently been described, based on the use of the lipid-soluble xenon-133. We report here on the use of the lipophilic cationic complex technetium-99m sestamibi (99mTc-MIBI), employed as an indicator of increased cellular density and metabolic activity, to evaluate Gaucher cell infiltrates in the bone marrow; 99mTc-hexametazime (99mTc-HMPAO) was also employed, as a pure indicator of lipidic infiltration in the bone marrow. A 67-year-old patient with known type 1 Gaucher s disease presented with a painful left hip and knee and difficulty in gait subsequent to traumatic fracture of the left femoral neck that had required implant of a fixation screw-plaque. Bone scan with 99mTc-methylene diphosphonate revealed reduced uptake at the distal metaphyseal-epiphyseal femoral region. In addition, whole-body maps and spot-view acquisitions of the thighs and legs were recorded at both 30 min and 2.5 h after the injection of 99mTc-MIBI: the scintigraphic pattern clearly showed increased uptake at several sites involved by Gaucher deposits in the bone marrow (both knees, with variable intensity in different areas), matching the bone changes detected by conventional x-ray. The target to non-target ratios slowly decreased with time, from an average value of 2.25 in the early scan to an average value of 2 in the delayed scan. The lipid-soluble agent 99mTc-HMPAO exhibited a superimposable scintigraphic pattern of accumulation at the involved sites, though with lower target to non-target ratios (1.27-1.48). The results obtained in this patient suggest a potential role of 99mTc-MIBI in the scintigraphic evaluation of Gaucher s lipid deposits in the bone marrow. If the results are confirmed in other patients, this radiopharmaceutical would offer clear advantages over 133Xe because of its wider availability and greater practicality (i.v. administration of 99mTc-MIBI versus inhalation of 133Xe, and use of a single gamma camera instead of two as with 133Xe).

Coagulation factor XIII in patients with acute and chronic renal disease.

The behavior of coagulation factor XIII (fibrin-stabilizing factor, FSF) was studied in patients with renal disease. Specific antiserum against the active subunit (FSFA) was employed to set up a method for the direct measurement of the active fraction in plasma, according to the electroimmunodiffusion technique. The plasma FSFA levels were measured in the following patients: (I) 31 patients with chronic renal disease and serum creatinine not higher than 1.5 mg/dl; (II) 41 patients with chronic renal failure on conservative therapy; (III) 53 uremic patients on maintenance hemodialysis; (IV) 10 patients with acute renal failure. FSFA concentration (93.3 +/- 17.6% of a reference plasma in a group of 15 healthy controls) was found to be significantly higher than normal in the patients with chronic renal disease and serum creatinine lower than 1.5 mg/dl (127 +/- 39.8%, p less than 0.005). The FSFA levels were similarly increased in the 41 patients with chronic renal failure on conservative management (134.9 +/- 35.8%, p less than 0.001), and in the 53 end-stage uremics on maintenance hemodialysis (132.8 +/- 29.5%, p less than 0.001). Whereas, FSFA concentration was found to be markedly reduced in the 10 patients with acute renal failure (35.8 +/- 14.6%, p less than 0.001). In the patients with chronic renal disease (groups I, II, and III) plasmatic FSFA higher in those patients with serum triglycerides above the upper normal limit, and a significant positive correlation was found between serum triglycerides and FSFA plasma levels.

High-performance liquid chromatographic separation of iodoamino acids for tracer turnover studies of thyroid hormones in vivo.

A reversed-phase high-performance liquid chromatographic technique was developed to separate radioiodinated thyroxine (T4), 3,5,3'-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3) and two diiodothyronines (3,3'-T2 and 3',5'-T2), in extracts from either serum or urine. Chromatography was performed with 10-micron C18 silica gel, packed in a glass column (3 X 300 mm); the mobile phase was methanol-water (55:45) adjusted to pH 3 with H3PO4, at a flow-rate of 1.2 ml/min and a pressure of 2800 p.s.i. The results demonstrate the ability of the system to yield a clear-cut separation of the iodothyronines involved in in vivo turnover studies, i.e., T4, T3, rT3, and the two T2 compounds together.

Evaluation of new membranes for hemodialysis: preliminary studies with a polycarbonate membrane.

A synthetic polycarbonate (PC) membrane supplied by C.R. Bard Inc. was assessed as to its clinical usefulness and suitability to regular use with artificial kidney. The permeability of the PC membrane to 11 solutes of increasing molecular volumes (Na+, Ca++, K+, Cl-, HPO4-, urea, creatinine, uric acid, glucose, BSP, cyanocobalamine) was measured in vitro by rotating dialysis cells, as compared to that of Cuprophan PT 150. The evaluation of the PC membrane in vivo was carried out during a regular hemodialytic treatment in 5 patients using a Kiil dialyzer. The dialysance of 6 solutes (HPO4-, urea, creatinine, uric acid, hypaque, cyanocobalamine) across the PC membrane was measured at 200 ml/min blood flow rate. Both in vitro and in vivo the PC membrane showed permeability and dialysance coefficients to small molecules approximately the same than standard PT 150; the ultrafiltration rate of the PC membrane was also superimposable to that of PT 150. On the contrary, larger molecules were removed much more efficiently by the polycarbonate membrane than by PT 150. These data suggest that the membrane evaluated in this study possesses some peculiar features which could possibly result in an improvement of the quality of regular hemodialysis.

Trocar site tumor recurrences. May pneumoperitoneum be responsible?

BACKGROUND: Port site metastasis following laparoscopy for cancer is reported with increasing frequency and represents one of the most important limitations of the technique. METHODS: A scintigraphic model was utilized to evaluate a possible role of pneumoperitoneum in tumor cell dissemination. Labeled red blood cells (RBC) were injected at the level of the gallbladder bed during laparoscopic cholecystectomy (LC) performed for symptomatic cholecystolithiasis. LC was performed in two groups with standard CO2 pneumoperitoneum: in one group an endobag for retrieval of the specimen was utilized. In one group a gasless LC with endobag was performed. RESULTS: Radioactivity in the area of the trocar introduction was observed in almost all the patients who underwent standard (CO2) LC but represented a rare event in patients treated with the gasless method. The utilization of a protective bag for the extraction of the surgical specimen did not modify significantly the results. Moreover all patients treated with pneumoperitoneum demonstrated a wide intraperitoneal diffusion of the tracer not observed in gasless patients. CONCLUSIONS: The results of this study confirm that pneumoperitoneum may play an important role in the evolution of port site metastasis after laparoscopy for gastrointestinal cancer.