Radioimmunodetection of medullary thyroid carcinoma using indium-111 bivalent hapten and anti-CEA x anti-DTPA-indium bispecific antibody.

UNLABELLED: Pretargeting labeled bivalent hapten with bispecific antibodies has proven feasible in the clinic, and our earlier results have suggested the technique may be very sensitive for detecting small recurrences and metastases. Medullary thyroid carcinoma (MTC) is an example where this technique may be the most useful since local recurrences and isolated metastases are removed surgically when detected, and thyrocalcitonin provides a specific and sensitive tumor marker. In our current study, we evaluated pretargeted immunoscintigraphy in a larger number of MTC patients. METHODS: Anti-carcinoembryonic antigen (CEA) x anti-diethylenetriaminepentaacetic acid (DTPA) indium bispecific antibody and 111In-labeled bivalent DTPA hapten were administered sequentially (4-5 days apart) to 44 patients with elevated circulating calcitonin after resection of primary MTC. Immunoscintigraphy was performed 2, 5 and 24 hr after hapten injection and, when necessary, at longer time intervals. When available, a handheld gamma probe was used during surgery. RESULTS: Fifteen patients had known tumor sites before immunoscintigraphy. Tumors were imaged in 12 (80%) of these patients, including 3 with liver metastases. Five unknown tumor sites were detected. For the 29 patients with occult disease, immunoscintigraphy detected high-activity uptake sites in 21 patients (72%), including 5 in the liver. Twelve were confirmed by surgery, 1 by guided morphologic imaging and 1 by venous catheterization. There were 2 false-positive patients. The other 5 patients have not yet been confirmed. All detected liver metastases were high-activity uptake areas. Radioimmunoguided surgery was used in 14 patients. It was considered helpful by the surgeon in 12 patients, including 4 patients where it determined the resection of small, not palpable nor visible, tumor-involved lymph nodes. Surgical resection resulted in a significant decrease (8 patients) or normalization (1 patient) of circulating calcitonin and CEA. CONCLUSION: This technique affords high sensitivity and specificity for detecting small tumor lesions including liver metastases. Its use for immunoscintigraphy and guided surgery should improve the therapeutic management of recurrent MTC.

Two-step immunoscintigraphy for non-small-cell lung cancer staging using a bispecific anti-CEA/anti-indium-DTPA antibody and an indium-111-labeled DTPA dimer.

UNLABELLED: Immunoscintigraphy (IS) using anti-CEA F(ab')2 monoclonal antibody (MAb) is useful for improving mediastinal staging of nonsmall cell lung cancer (NSCLC), but the technique was limited because of an insufficient contrast between tumor and normal tissues. The aim of this study was to determine if the method could be improved by a two-step method which uses a bispecific anti-CEA/anti-di-DTPA antibody (Bs-MAb) and 111In-labeled di-DTPA-tyrosyl-lysine bivalent hapten. METHODS: Twelve patients were intravenously given a 30 min Bs-MAb infusion (0.1 mg/kg). Four days later, they were injected intravenously with 0.1 microgram/kg hapten labeled with 185 MBq 111In (5 mCi). Images were recorded immediately and 6 and 24 hr after hapten injection. A pharmacokinetic analysis was performed. Surgery was performed 3 days after 111In-hapten injection, and samples of tumor and normal tissues were collected for immunohistochemical and biodistribution studies. IS results were classified as true-positive (TP), false-positive (FP), true-negative (TN) or false-negative (FN) according to the surgical data. RESULTS: Primary tumors were visualized in nine patients. The contrast was excellent, generally higher than that obtained with direct labeling of anti-CEA. In the mediastinum, IS results were (after surgery) five TN, two TP and one FP. One case remains undetermined. The FP result was due to a Bs-MAb uptake in intrapulmonary lymph nodes. IS was in agreement with preoperative staging in six of these nine patients and discordant in three. CONCLUSION: Our study confirmed that the two-step method with a bispecific antibody could greatly improve the performances of IS for lung cancer staging.

Bispecific antibody and iodine-131-labeled bivalent hapten dosimetry in patients with medullary thyroid or small-cell lung cancer.

UNLABELLED: The purpose of this study was to estimate the dose delivered to tumor targets and normal tissues after two-step injection of an anti-CEA/anti-DTPA-In (F6-734) bispecific antibody and a 131I-labeled di-DTPA in-TL bivalent hapten in patients with medullary thyroid carcinoma (MTC) and small-cell lung cancer (SCLC). METHODS: Five patients with persistent disease or recurrences of MTC and five patients with primary SCLC or relapse were studied. In a first step, 0.1 to 0.3 mg/kg of F6-734 bispecific antibody was injected intravenously. Four days later, 6 nmole (5.8 to 9.8 mCi) of 131I-labeled di-DTPA in-TL bivalent hapten were injected. Quantitative imaging was performed during one week after the second injection. RESULTS: All 5 patients with MTC showed positive immunoscintigraphy (IS). In the smallest visualized and resected tumor (0.8 g), the fraction of injected activity per gram (% ID/g) was 0.1% at Day 3. IS was positive in 4 of the 5 patients with SCLC. The volume of the smallest visualized SCLC tumor was estimated at 11 +/- 2 ml, and tumor uptake was about 0.009% ID/g. Tumor dose estimates ranged from 4.2 to 174 cGy/mCi in patients with MTC and from 1.7 to 8 cGy/mCi in patients with SCLC. CONCLUSION: High absorbed dose values were calculated for small MTC recurrences. For SCLC recurrences the values were smaller but in the same range as those obtained by other investigators with the one-step technique in lymphoma.

131I-6 beta-iodomethylnorcholesterol scintigraphy: an assessment of its role in the investigation of adrenocortical incidentalomas.

OBJECTIVE: Most incidentally discovered adrenal tumours ('incidentaloma') are benign adrenocortical adenomas. It has been suggested that 131I-6 beta-iodomethylnorcholesterol (IMC) scan could specify the degree of functional autonomy of such adenomas depending on whether they prevent contralateral adrenal tracer uptake. Our purpose was to examine this hypothesis in a correlated scintigraphic and endocrine study. DESIGN: Prospective study evaluating the prevalence of unilateral IMC uptake (tumour uptake with no visualization of the contralateral adrenal gland) and bilateral uptake (uptake in both the tumoral and the contralateral adrenal glands) in patients with unilateral incidentaloma. Comparison of adrenocortical function and of IMC scan after dexamethasone (DXM) in the two scintigraphic groups thus defined. PATIENTS: Thirty-five patients with a unilateral mass highly suggestive of benign adrenocortical adenoma on CT scan. MEASUREMENTS: The IMC scan was performed in basal conditions (baseline scan) and after DXM (suppression scan). Adrenocortical function assessment included basal measurements of 11-deoxycortisol, 17 alpha-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulphate (DHEAS), plasma cortisol and ACTH, urinary free cortisol (UFC), overnight and low-dose DXM suppression test, and CRH test. RESULTS: The baseline scan showed 16 patients (46%) with unilateral uptake (group A) and 19 (54%) with bilateral uptake (group B). Patients in group A exhibited lower ACTH values at 0800h (P = 0.05) and higher cortisol values after an overnight DXM suppression test (P = 0.02), than did patients in group B. In addition, 3 patients in group A failed the overnight and the low-dose DXM suppression tests. Adrenal masses were larger in group A than group B (P = 0.04) and an inverse correlation was found in the whole population between tumour size and ACTH value at 0800h (P = 0.05). On the suppression scan performed in 14 patients (7 in each group), patients in group A continued to exhibit unilateral tumour uptake and bilateral uptake was suppressed in 72% of patients in group B. An adrenal mass was removed in 3 patients of group A with confirmed benign adrenocortical adenomas. In the post-surgical period, the contralateral gland was again visualized in a baseline scan and the hormonal evaluation returned to the normal range. CONCLUSION: Unilateral 131I-6 beta-iodomethylnorcholesterol tumour uptake is a frequent feature in benign adrenocortical adenomas. Hormonal data and scintigraphic profiles obtained after dexamethasone, as well as hormonoscintigraphic changes observed after surgery, provide evidence that unilateral uptake is related to functioning adenomas with various degrees of autononomy and suggest that the 131I-6 beta-iodomethylnorcholesterol scan could be a valuable tool for screening 'subclinical' Cushing's adenomas.

Induction of anaesthesia by propofol and hepatic blood flow in the rabbit.

Effects of propofol (12.5 mg kg-1, i.v. bolus injection) or 0.9% sodium chloride on arterial blood pressure, arterial blood gases and hepatic circulation (radio-labelled microsphere technique) were studied in 15 conscious and unpremedicated rabbits. No significant changes were observed after sodium chloride. Propofol resulted in anaesthesia, respiratory depression (-49 +/- 14% decrease in PaO2; mean +/- SD) and hypotension (-49 +/- 13% decrease in mean arterial pressure; mean +/- SD) but no changes in hepatic arterial and portal venous blood flows. We conclude that propofol does not affect the liver circulation despite marked depression of mean arterial pressure and respiration.

Angiomagnetic resonance imaging of iliofemorocaval venous thrombosis.

Although magnetic resonance imaging has been proposed for the diagnosis of deep venous thrombosis (DVT), its role in diagnostic strategy remains to be defined. We compared prospectively magnetic resonance angiography (MRA) with two-dimensional time-of-flight with contrast venography (CV) and colour duplex sonography (CDS) in 25 patients with DVT of the pelvis confirmed by CV. All patients were examined by CV (gold standard) and MRA and 17 by CDS. These studies were compared for DVT diagnosis in the pelvis and inferior vena cava and analysis of thrombotic spread. MRA was positive in 25 patients whose DVT was diagnosed by CV (100% sensitivity). MRA sensitivity and negative predictive value were 100%, specificity 98.5% and positive predictive value 97.5% for the diagnosis of thrombosis at each anatomic level. There were discrepancies between MRA and CV (2 false-positive results for 2 venous segments) and between CDS and CV (2 false-positive and 3 false-negative results). CV was uninterpretable for 8.8% of segments and CDS was often technically limited to the pelvic level, whereas all venous segments explored were analysable in MRA. MRA gave excellent results for positive diagnosis and DVT spread. MRA is a potentially valuable technique for assessing iliofemorocaval venous thrombosis.

Bifunctional antibodies for radioimmunotherapy.

In two-step targeting technique using bifunctional antibodies, a nonradiolabeled immunoconjugate with slow uptake kinetics (several days) is initially injected, followed by a small radiolabeled hapten with fast kinetics (several hours) that binds to the bispecific immunoconjugate already taken up by the tumor target. In patients with colorectal or medullary thyroid cancer, clinical studies performed with an anti-CEA/anti-DTPA-indium bifunctional antibody and an indium-111-labeled di-DTPA-TL bivalent hapten showed that tumor uptake was not modified compared to results for F(ab')2 fragments of the same anti-CEA antibody directly labeled with indium-111, whereas the radioactivity of normal tissues was significantly reduced (3- to 6-fold). The fast tumor uptake kinetics (several hours) and high or very high tumor-to-normal tissue ratios obtained with the bifunctional antibody technique are favorable parameters for efficient radioimmunotherapy.

Pretargetted imaging of colorectal cancer recurrences using an 111In-labelled bivalent hapten and a bispecific antibody conjugate.

In 11 patients recurrence of colorectal cancer was suspected by a rise in serum carcinoembryonic antigen (CEA) (nine cases), by a subocclusive clinical situation (one case) or by endoscopy (on an anastomosis, one case). Two-step tumour targetting was performed by a first injection of 0.1 mg kg-1 of unlabelled bispecific antibody conjugate (an anti-CEA Fab' fragment chemically coupled to an anti-diethylene triamine pentaacetate (DTPA)-indium fragment) followed 4 to 5 days later by injection of the bivalent DTPA hapten labelled with 5 to 8 mCi 111In. Planar scintigraphy, single photon emission computed tomographic (SPECT) 360 degrees acquisitions and whole-body scans were obtained 4.5 and 24 h after injection of the radiolabelled hapten. Biodistribution was determined for eight patients at 48 h. The final diagnosis was confirmed histologically in nine patients (eight by second-look surgery, one by laparotomy). Overall, results were one true negative (1-year follow-up) and 10 true positive; however, for the three large liver metastases (3 to 6 cm), only the periphery of the metastasis had high uptake compared to normal liver. For pelvic recurrences, immunoscintigraphic (IS) contrast was better for small tumours. The highest tumour uptake was found for a 1 cm diameter pelvic recurrence (7.2% i.d. kg-1). Mean tumour-to-blood ratios were 6.4. Thus, this two-step tumour targetting technique, which uses a bispecific antibody conjugate and an 111In-labelled bivalent hapten injected sequentially without chasing the excess bispecific antibody, provided satisfactory results in this preliminary clinical trial for detection of recurrent colorectal cancers.

[Diagnosis of venous thrombosis. Evaluation of immunoscintigraphy with 99M technetium labelled antifibrin]. / Diagnostic des thromboses veineuses. Evaluation de l'immunoscintigraphie antifibrine marquée au technétium 99m.

OBJECTIVES: We evaluated the interpretation, reliability and usefulness of 99m technetium labelled antifibrin immunoscintigraphy for the diagnosis of deep vein thrombosis in the lower limbs. METHODS: The diagnostic value of 99m technetium labelled antifibrin immunoscintigraphy was assessed in 44 patients with suspected venous thrombosis. The reference examination was bilateral ascending phlebography; 40 patients had doppler ultrasonography of the veins; 0.5 mg of antibody labelled by 17.5 mCi on average of 99m technetium were injected intravenously, and serial scintigraphic images were collected 1 min, 90 min and 18 hours after injection. RESULTS: The best results were obtained by comparison between the 90 min and the immediate post-injection images, with 86 percent sensitivity, 73 percent specificity and 81 percent accuracy. Heparin therapy and past history of phlebitis had no influence on the results. The doppler ultrasonography/immunoscintigraphy combination had a 100 percent specificity. 99m Technetium labelled antifibrin immunoscintigraphy had about the same diagnostic value as 111 indium labelled antifibrin immunoscintigraphy. CONCLUSION: The introduction of 99m technetium as isotopic marker will make immunoscintigraphy easier and available in numerous nuclear medicine centres. Antifibrin immunoscintigraphy can be an additional diagnostic tool for the difficult diagnosis of deep vein thrombosis.

[Pelvic phlebitis presenting as paradoxical arterial embolism]. / Phlébite pelvienne révélée par une embolie artérielle paradoxale.

The authors report the case of a 24-year-old woman with paradoxical embolism of the right arm subsequent to childbirth. Patent foramen ovale was diagnosed by right cardiac catheterization and contrast echocardiography. On the basis of clinical, immunoscintigraphic and radiologic data, the pelvic region was the only possible origin of the embolic process. The main interest of this case is that arterial ischemic signs were indicative of an embolic process of pelvic origin diagnosed by scintigraphy using radiolabeled antifibrin antibody.

99Tcm-labelled anti-fibrin Fab' fragment for evaluating the course of venous thrombosis in the rabbit.

Immunoscintigraphy was performed using the Fab' fragment of 99Tcm-labelled T2G1s anti-fibrin monoclonal antibody in a rabbit experimental model of venous thrombosis of known and increasing age (1, 3 and 7 days). Scans were positive in 3/7 cases for 1-day thrombosis (fibrin-poor network) and in 7/7 cases for 3-day thrombosis (fibrin-rich network). In rabbits with 7-day thrombosis, the scan was positive (2/4 cases) only when connective tissue was not present in the clot. Scintigraphic results were concordant with those of biodistribution studies showing the mean percentage of injected dose per gram 99Tcm-T2G1s present in the thrombosed vein wall (0.043, 0.082 and 0.07 for thrombi at 1, 3 and 7 days, respectively). Mean thrombosed vein wall-to-blood ratios were 1.027, 2.291 and 1.301, respectively. Immunoscintigraphy with T2G1s anti-fibrin monoclonal antibody thus enabled hematological status to be evaluated.

Detection of lung and bone infection with anti-granulocyte monoclonal antibody BW 250/183 radiolabelled with 99Tcm.

Twenty-four patients with suspected infection (eight bone, 16 lung) were studied using monoclonal antibody BW250/183 which recognizes epitopes present on the surface of granulocytes. Bronchofibroscopic samples (microbiological studies and alveolar cell counts) were obtained from 14/16 patients with lung disease. Bronchofibroscopy isolated a micro-organism nine times. In two other cases, the diagnosis of infection was based on clinical course data. Infection was confirmed by surgical biopsy in the eight patients with bone pathology. Scans were performed 2 and 24 h after injection of 1 mg BW 250/183 labelled with 99Tcm. For lung disease, immunoscintigraphy was positive six times (five true positive, one false positive) and negative 10 times (six false negative, four true negative). Immunoscintigraphy was false negative when the lung infection was not systematized or no granulocytes were mobilized in the infectious site. Immunoscintigraphy was falsely positive when noninfectious lung disease mobilized granulocytes. It was positive in all patients with bone infection. Images recorded at 24 h had better sensitivity (five false negative) than those at 2 h (eight false negative).

Radioimmunodetection of medullary thyroid cancer using a bispecific anti-CEA/anti-indium-DTPA antibody and an indium-111-labeled DTPA dimer.

Two-step radioimmunotargeting using a bispecific anti-CEA/anti-in-DTPA monoclonal antibody and an 111In-labeled DTPA dimer (diDTPA-TL) was evaluated nine times in eight patients with medullary thyroid cancer (MTC). Immunoscintigraphy was performed 5 and 24 hr after injection of 111In-diDTPA-TL. For five patients, radioimmunoguided surgery (RIGS) was performed using a hand-held gamma probe (sodium iodine), and a biodistribution study was performed 48 hr (four times) and 24 hr (one time) after injection of 111In-diDTPA-TL. Mean tumor uptake (%ID/kg in tumor) was 39 (range 2.75-139). In these five patients, immunoscintigraphy visualized all known tumors and detected unknown foci (US and CT were negative) in the neck (once) and neck and liver (once). Immunoscintigraphy, performed four times in search of a recurrence, detected unknown localizations in the mediastinum and neck (twice) and was negative twice. There were no false-positives. In three of five patients who had surgery, RIGS localized tumor foci not detected by the surgeon. RIGS failed to detect two small lesions (10 x 10 mm) corresponding to sites of fibrosis and microscopic cancer infiltration. Bispecific anti-CEA/anti-In-DTPA mediated targeting of 111In-diDTPA-TL provided elevated tumor uptake and tumor-to-normal tissue ratios. Radioimmunodetection of small MTC lesions is thus possible even when morphological imaging techniques prove negative.

Lung distribution and pharmacokinetics of aerosolized tobramycin.

Aminoglycosides are commonly used in the treatment of nosocomial pneumonia in association with beta-lactams. Unfortunately, penetration of intravenously administered aminoglycosides into the lung tissue remains low. In animal models, aerosolization of these drugs provides high lung concentrations and low serum levels. Three-hundred milligrams of tobramycin and 1 ml of 99mTc-DTPA were administered via a pneumatic nebulizer to five healthy volunteers and to five mechanically ventilated patients. Lung scintigraphy was then performed, and plasma and urine pharmacokinetics were studied. In a second group of patients undergoing thoracic surgery, 300 mg of tobramycin alone were administered in the same way; a fragment of healthy lung was then removed, and tobramycin was measured. In the first group, the scintigraphy showed radioactivity distribution in the whole lungs both in healthy volunteers and in ventilated patients. Urine samples contained 5.5% of the initial amount of tobramycin. The mean serum half-life of tobramycin was 8.96 h in healthy volunteers and 11.23 h in ventilated patients. In the second group, mean lung tissue concentrations were 5.5 and 3.61 micrograms/g, respectively, 4 and 12 h after nebulization, respectively. Aerosolization of tobramycin thus produced high lung concentrations and low serum levels.

Usefulness of imaging ovarian cancer recurrence with In-111-labeled monoclonal antibody (OC 125) specific for CA 125 antigen. The INSERM Research Network (Nantes, Rennes, Reims, Vuillejuif, Saclay.

BACKGROUND: A progressive rise in serum CA 125 concentration during follow-up monitoring of ovarian cancer after treatment of primary tumor is suggestive of a recurrence. PATIENTS AND METHODS: A study was carried out in 19 patients with suspected recurrence of a previously treated ovarian carcinoma. All patients underwent ultrasonography (US), computed tomography (CT) and immunoscintigraphy (IS) using F(ab')2 fragments of indium-111-labeled OC 125 monoclonal antibody (specific for CA 125 antigen). The definitive diagnosis of recurrence was made on the basis of histological data obtained at surgery. RESULTS: In all 15 of the patients with recurrence, all three of the imaging methods had false negative results once. In 7 patients, only the IS method had positive results; six of these 7 benefited from a macroscopically total resection of the recurrence. IS was positive and concordant with US and/or CT in 7 further patients. Two of them benefited from a total resection of their recurrence. The usefulness of IS was more evident when serum CA 125 concentration was below 500 U/ml. The absence of recurrence was correctly indicated by IS and CT in 1 case and by IS associated with negative US and CT in 2 other cases. IS and CT were falsely positive in 1 case. CONCLUSION: Thus, immunoscintigraphy would appear to be an efficient method for detecting a recurrence early when limited involvement can make it possible for the surgeon to achieve total resection.

[The role of adrenal gland x-ray computed tomography and scintigraphy using radiolabelled norcholesterol in the etiological diagnosis of primary hyperaldosteronism]. / Place respective de la tomodensitométrie surrénalienne et de la scintigraphie au norcholestérol radiomarqué dans le diagnostic étiologique des hyperaldostéronismes primaires.

The major etiologies of primary aldosteronism are aldosterone-producing adrenal adenoma, requiring a surgical treatment, and bilateral hyperplasia, usually managed with medical therapy. We only report a retrospective study on 22 patients with primary aldosteronism diagnosed by clinical and usual biochemical tests. All the patients were explored by computed tomography scan (CT) and iodomethyl-norcholesterol scintigraphy. The purpose of this study was to compare the capacity of the two methods to differentiate adrenal adenoma and hyperplasia. The CT scan was more sensitive (sensitivity: 88%) compare to scintigraphy (sensitivity: 64%) for the diagnosis of adrenal adenoma. However, the scintigraphy was a useful tool to detect asymmetric macronodular adrenal hyperplasia. Therefore, the catheterisation of adrenal venous would be only necessary for a few cases. We conclude from this study and the literature review that CT scan and iodomethyl-norcholesterol scintigraphy are complementary and both useful to increase diagnostic reliability of primary aldosteronism.

Experimental venous thrombosis: what animal model?

A new experimental venous thrombosis model is described and its role relative to other models is defined. Previous models are not satisfactory for all types of investigation. Opposite, present model based on the three classic thrombogenic factors is suitable for venous scintigraphy and evaluation of different forms of therapy for venous thrombosis of the limbs. So this model permits research on diagnosis and therapy of thromboembolic disease.

Anti-beta HCG abdominopelvic immunoscintigraphy in patients with resistant gestational trophoblastic disease.

The clinical utility of abdominopelvic immunoscintigraphy (IS) using anti-beta HCG-labelled monoclonal antibodies was evaluated in six patients with resistant gestational trophoblastic disease and no common pathological site. Five patients with abnormal retrovesical uptake had persistence of uterine trophoblastic disease confirmed on hysterectomy. Four of these patients are now in remission. It is concluded that IS provides a useful indication for surgery when a single abnormal uptake site is found.

MIBG scintigraphy of a patient with pheochromocytoma on labetalol therapy.

A patient with pheochromocytoma was studied by MIBG scintigraphy while on labetalol therapy, which has been reported to interfere with imaging. Serial imaging was performed at 2, 18, 25, and 90 hours to obtain time/activity curves. Blood samples were taken at each imaging study to determine activity counts. Tumor activity per gram of tissue (surgery 116 hours after injection) was compared with blood activity. Tumor and blood activity decreased concurrently, whereas the decrease in peritumoral activity was faster, thus providing transiently improved contrast on 18- and 25-hour images. The diagnostic implications of these results are discussed.