J. Lumbroso

A new immunoradiometric assay (IRMA) system for thyroglobulin measurement in the follow-up of thyroid cancer patients

A new commercially available kit for thyroglobulin (Tg) measurement [immunoradiometric assay (IRMA) system based on monoclonal antibodies] was used in 479 patients with thyroid carcinoma. The effective working range was 1 ng/ml, and results were strongly correlated with our homemade radioimmunoassay (RIA). This IRMA method is less susceptible to interferences of auto-antibodies than our RIA. During thyroxine (T4) treatment, the Tg level was undetectable in 98% of patients after total thyroid ablation, in 91% after total thyroidectomy and in 42% after lobectomy only. In this situation, Tg was found in all patients with large metastases and in 88% of those with small metastases. Following T4 withdrawal, Tg was detectable in all patients with neoplastic disease and in 13% of those in complete remission after total thyroid ablation. In conclusion, Tg measured with this IRMA method appears to be a reliable marker of differentiated thyroid carcinoma.

Prediction and diagnosis of bone metastases in well-differentiated gastro-entero-pancreatic endocrine cancer: a prospective comparison of whole body magnetic resonance imaging and somatostatin receptor scintigraphy.

PURPOSE Our purpose was to compare the sensitivity of whole body (WB) magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS) for the diagnosis of bone metastases (BMs) in patients with well-differentiated gastro-entero-pancreatic endocrine cancer (WD-GEP-EC) and to determine predictive factors of BM. PATIENTS AND METHODS WB-MRI and SRS were prospectively performed in 79 patients with bronchial (11), thymic (five), gastric (two), duodeno-pancreatic (24), ileal (26), colic (one), or unknown primary (10) WD-GEP-EC. RESULTS A total of 36 patients (46%) had 333 BMs involving 119 skeletal segments. WB-MRI and SRS were equally sensitive for detecting patients with BM (86 vs. 81%; P = 0.56), with 33% of the patients diagnosed with only one procedure. WB-MRI detected more BMs than SRS (80 vs. 57%; P = 0.017). Compared with SRS, WB-MRI detected more spine BMs (96 vs. 45%; P < 0.001) and tended to detect more pelvic and lower limb BMs (P = 0.054 and P = 0.06, respectively). Compared with WB-MRI, SRS detected more skull BMs (100 vs. 0%; P < 0.001) and tended to detect more rib BMs (P = 0.08). Sternal and upper-limb BMs were equally detected with WB-MRI and SRS (P = 0.32 and P = 0.46, respectively). Bone staging with SRS and spine MRI rather than WB-MRI would have detected 92% of the patients with BMs and 83% of all BMs. The extent of liver involvement and bronchial-thymic primary tumors were independent predictive factors for BM. CONCLUSIONS We recommend bone staging with SRS and spine MRI in all patients with bronchial-thymic or unknown primary WD-GEP-EC. In case of duodeno-pancreatic or ileal primary, bone imaging may be restricted to patients with liver metastases.

Follow-up of patients with differentiated thyroid carcinoma. Experience at Institut Gustave-Roussy, Villejuif

The recent introduction of sTSH assays allows for a definite control of the inhibition of TSH secretion. Clinical examination and serum thyroid hormone measurements are necessary to obviate hyperthyroidism. Relapses may occur after decades of apparent complete remission. Follow-up should be pursued throughout the patients lifetime. Two specific means allow the detection of relapses at a stage when X-rays are still normal: measurement of serum thyroglobulin and 131I total body scan. Their combined use is recommended.

Prognostic factors in patients with liver metastases from colorectal carcinoma treated with discontinuous intra-arterial hepatic chemotherapy

48 patients with colorectal cancer metastatic to the liver were implanted with a subcutaneous access system allowing hepatic intra-arterial perfusion. Regional chemotherapy used 5-fluorouracil, while 17 patients also received low-dose mitomycin at the beginning of the study. Responses to the treatment occurred in 29 patients (60%) and median survival was 14.4 months. Toxicity included gastroduodenal erosions in 12.5% of the patients, leucopenia in 20.8%, catheter thrombosis in 42% and arterial thrombosis in 50%. 2 patients died of digestive haemorrhage probably related to treatment. When individually analysed, four factors were found to significantly affect survival: presence of hepatomegaly (defined as palpable liver edge exceeding the right costal margin by more than 5 cm) (P = 0.006), percentage of hepatic replacement superior to 50% (P = 0.003), more than four metastases (P = 0.025) and hypovascularised metastases at radionuclide liver scan with 99m technetium-labelled macroaggregate albumin (MAA) (P = 0.04). The effect of the four variables on the observed survival time was analysed using a Cox regression model. Two variables were found to have simultaneously influenced survival. Presence of hepatomegaly emerged as the more significant (P = 0.0001), the other being hypovascularised metastases at 99mTc-MAA.

Immunoscintigraphy of Hodgkin's disease: In vivo use of radiolabelled monoclonal antibodies derived from Hodgkin cell lines

The Hodgkin associated monoclonal antibody (Mab) HRS-1 reacts with Hodgkin and Reed-Sternberg cells (HR-S) in all HD subtypes. HRS-1 Mab was labelled with radioiodine and injected into 10 patients for immunoscintigraphy (IS). Seven patients were injected with HRS-1 Mab radiolabelled with 131I and three patients were injected with HRS-1 Mab labelled with 123I. A control anti-alpha-fetoprotein (anti-AFP) Mab was radiolabelled with another iodine isotope and was injected simultaneously in five cases. Six out of eight patients with proven HD had a true positive scan (nodal, splenic and bony involvement). Imaging was equivocal or failed in the two other patients. In the last two patients IS imaging was truly negative due to the absence of residual HD in one patient and to an erroneous histological diagnosis of HD in another patient. These results, although preliminary, demonstrate that IS with radioiodine-labelled HRS-1 Mab is feasible and may prove to be informative in the staging of HD.

Factor analysis as a means of determining response to chemotherapy in patients with osteogenic sarcoma.

The prognosis of localized osteogenic sarcoma (OS) has improved considerably since the introduction of neoadjuvant chemotherapy. However, there is a subset of patients who do not show full benefit from neoadjuvant chemotherapy because of chemoresistance. The early identification of poor responders to chemotherapy during neoadjuvant therapy remains difficult. In order to evaluate the role of bone scintigraphy we report our experience of dynamic technetium-99m hydroxymethylene diphosphonate bone scintigraphy in 19 cases of paediatric osteogenic sarcomas. Before the beginning of chemotherapy, a dynamic scan was recorded during 30 min followed by static images at 3 h. The procedure was repeated halfway through the course of chemotherapy (6th week). Histological grading of the response to chemotherapy was carried out in the 12th week, showing nine good responses and ten poor responses. Factor analysis of dynamic structures (FADS) applied to dynamic scans allowed us to identify three factors termed vascular, “soft tissue” and osseous factors. The effect of chemotherapy on each factor was evaluated. Using FADS we were able to detect all the poor histological responders with the combination of vascular and osseous factors. Six out of nine good histological responders were also classified as scintigraphic responders. FADS applied to dynamic bone scans allowed us to identify at an early stage all the poor histological responders to neoadjuvant chemotherapy. This method may have clinical relevance for the therapeutic strategy in patients with OS.

Usefulness of technetium-99m hydroxymethylene diphosphonate scans in localizing bone metastases of differentiated thyroid carcinoma

Iodine-131 is uniquely able to demonstrate iodine uptake of differentiated thyroid carcinoma (DTC), but precise localization may be difficult, especially in the thorax, due to the quality of image resolution with 1311 and the lack of anatomical landmarks. When bone metastases do not show radioiodine uptake, bone scintigraphy can be used to detect them. We studied two groups of patients. In group 1, 15 patients with known bone metastases of DTC were treated with 3.7 GBq 131I. After 4 or 5 days, technetium-99m hydroxymethylene diphosphonate (HMDP; 740 MBq) was injected and a whole-body scan with simultaneous acquisition of 131I and 99mTc-HMDP images was carried out using a large field of view gamma camera fitted with a high-energy collimator. Technetium uptake was abnormal in 47 of 63 localizations, being increased in 29 foci, decreased in 7 and heterogeneous in 11. The superimposition of 131I and 99mTc-HMDP scans permitted an accurate localization in 80% of spine metastases and in 46% of osseous thoracic localizations, even in the presence of lung metastases. In group 2, 9 patients, who had bone pain, neurological signs or elevated serum thyroglobulin, had DTC bone metastases without iodine uptake. They received a diagnostic dose of 99mTc-HMDP 3h prior to scintigraphy with a large field of view gamma camera fitted with a low-energy collimator. Technetium uptake was abnormal in 37 of 38 localizations, being increased in 34 foci and decreased in 3. One false-negative was found in a skull metastasis. In both groups of patients, 99mTc-HMDP scans were useful. The procedure allows accurate localization of bone metastases and can be used as a guide for subsequent radiological investigations.

Radiolabelled monoclonal antibodies against alpha-fetoprotein for in vivo localization of human hepatocellular carcinoma by immunotomoscintigraphy.

Two high affinity monoclonal antibodies, designated AF01 and AF04, directed against distinct epitopes of human alpha-fetoprotein (AFP) and the Fab fragments of one of them, were labelled with 131I and injected into 18 patients with AFP producing hepatocellular carcinoma (HCC) in order to carry out imaging studies by tomoscintigraphy. Twelve patients were injected with whole antibody, only three of seven patients injected with AF01 and two of five patients injected with AF04 had a positive scan. In contrast, five out of six patients injected with labelled Fab fragments of AF04 had positive imaging. These results confirm that tumour imaging of HCC using 131I labelled monoclonal antibody against AFP is feasible. Moreover, utilization of tomoscintigraphy in place of linear scintigraphy and Fab fragments instead of whole immunoglobulin may improve the sensitivity of radioimmunolocalization. This technique provides useful information on the in vivo distribution of monoclonal antibodies directed against AFP and on the practicability of the eventual therapeutic use of anti-AFP antibodies in HCC.

Screening for adrenal medullary disease in patients with medullary thyroid carcinoma

Adrenal medullary disease (AMD) is clinically silent in most patients with medullary thyroid carcinoma (MTC). It was screened yearly by urinary measurements of catecholamines and derivates, and by abdominal ultrasonography (US) in a series of 174 patients with MTC. In cases with suspicion of AMD, abdominal computerized tomography and scintigraphy with meta-iodobenzylguanidine were also performed. AMD was discovered in 10 patients (one adrenal medullary hyperplasia and 9 pheochromocytomas). Three patients were already known to belong to a type II multiple endocrine neoplasia (MEN-2a) family and two had a MEN-2b syndrome. In 5 patients previously considered as having either a sporadic (4 cases) or a familial type of isolated MTC (one case), the occurrence of AMD led to diagnose a MEN-2a syndrome. The diagnostic values of the tests were evaluated by a case-control study. Urinary metanephrine plus normetanephrine (MN+N) had an acceptable sensitivity (0.8) and specificity (0.8). The other urinary tests had a high specificity (range: 0.8 to 1) but a poor sensitivity (range: 0.1 to 0.5). US had a high sensitivity (0.8) and a specificity of one. MN+N and US performed yearly constitute a simple and efficient strategy to screen for AMD in patients with MTC.

In-vivo-Imaging von Hodgkin-Lymphomen mit monoklonalen Antikörpern

Der mit Hodgkin- und Reed-Sternberg-Zellen assoziierte monoklonale Antikorper HRS-1 wurde mit radioaktivem Jod markiert und sechs Patienten mit Hodgkin-Lymphom injiziert. Vier von funf Patienten, die 131Jod-markierten HRS-1 erhalten hatten, hatten ein positives Immunszintigramm. Der sechste Patient erhielt 123Jod-markierten HRS-1 zur Durchfuhrung eines SPECT-Tomoszintigramms. Bei diesem Patienten lies sich ein Knochenbefall nachweisen. Diese ersten Ergebnisse zeigen, das eine Immunszintigraphie mit Jod-markiertem HRS-1 wichtige diagnostische Informationen bei Hodgkin-Lymphomen erbringen kann. Der tatsachliche klinische Stellenwert der Immunszintigraphie bei Hodgkin-Lymphomen mus in einer Studie mit groseren Patientenzahlen bestimmt werden. Technische Modifikationen wie z.B. die Verwendung von F(ab) oder F(ab)2-Fragmenten sollten zu einer weiteren Verbesserung dieses neuartigen diagnostischen Verfahrens fuhren.