Better results with rhenium-186 radiosynoviorthesis than with cortivazol in rheumatoid arthritis (RA): a two-year follow-up randomized controlled multicentre study.

OBJECTIVE: The aim of this international multicentric randomized phase 3 clinical trial was to compare prospectively radiosynoviorthesis (RSO) with rhenium-186-sulfide (186Re) to intra-articular corticotherapy in patients with clinically controlled rheumatoid arthritis (RA), but in whom one or a few medium-sized joints remained painful or swollen. METHODS: One hundred and twenty-nine joints in 81 RA patients [stratified into 2 groups: wrists (group 1, n = 78) and all the other joints (group 2, n = 51, including 18 elbows, 21 shoulders and 12 ankles)] were randomized to receive intra-articular injections of either 186Re-sulfide (64 +/- 4 MBq), or cortivazol (Altim) 3.75 mg. Clinical assessment was performed before and then at 3, 6, 12, 18 and 24 months after local therapy, using a 4-step verbal rating scale (VRS) and a 100 mm visual analog scale for pain, a 4-step VRS for joint swelling and mobility and a 2-step VRS for the radiological stage. The Mantel-Haenszel test was used for qualitative variables, analysis of variance (ANOVA) for quantitative pain analysis and Kaplan-Meyer survival test for relapse analysis. RESULTS: 186Re was observed to be statistically superior to cortivazol at 18 and 24 months while no statistical difference was seen for any criterion at 3, 6 and 12 months post injection. At 24 months, the difference in favor of 186Re was significant for pain (p = 0.024), joint swelling (p = 0.01), mobility (p = 0.05, non-wrists only), pain and swelling (p = 0.03) and pain or swelling (p = 0.02). "Survival" studies (Kaplan-Meyer) demonstrated a greater relative risk of relapse in corticoid treated joints, but only from the second year of follow-up. No serious side effect was observed in any patient, with only light and transient local pain and/or swelling occurring in 24% of cases, regardless of the treatment used. CONCLUSION: 186Re-sulfide and cortivazol had similar efficacy up to 12 months post-injection, but 186Re became clearly more effective at 18 and 24 months, for all criteria monitored and for RA outcome. Therefore, 186Re RSO can be recommended for routine clinical use.

169Erbium-citrate synoviorthesis after failure of local corticosteroid injections to treat rheumatoid arthritis-affected finger joints.

OBJECTIVES: Intra-articular injection of 169Erbium-citrate (169Er-citrate; radiosynoviorthesis or radiosynovectomy) is an effective local treatment of rheumatic joint diseases. However, its efficacy in corticosteroid-resistant rheumatoid arthritis-affected joints has not been clearly demonstrated. METHODS: A double-blind, randomised, placebo-controlled, international multicentre study was conducted in patients with rheumatoid arthritis with recent (< or = 24 months) ineffective corticosteroid injection(s) into their finger joint(s). Eighty-five finger joints of 44 patients were randomised to receive a single injection of placebo (NaCl 0.9%) or 169Er-citrate. Results of evaluation 6 months later were available for 82 joints (46 metacarpophalangeal and 36 proximal interphalangeal joints) of 42 patients: 39 169Er-citrate-injected joints and 43 placebo-injected joints. Efficacy was assessed using a rating scale for joint pain, swelling and mobility. RESULTS: Intent-to-treat analysis of the results of the 82 joints showed a significant effect of 169Er-citrate compared to placebo for the principal criteria decreased pain or swelling (95 vs 79%; p = 0.038) and decreased pain and swelling (79 vs 47%; p = 0.0024) and for the secondary criteria decreased pain (92 vs 72%; p = 0.017), decreased swelling (82 vs 53%; p = 0.0065) and increased mobility (64 vs 42%; p = 0.036). Per-protocol analysis, excluding 18 joints of patients who markedly changed their usual systemic treatment for arthritis, gave similar percentages of improvement but statistical significance was lower owing the reduced power of the statistical tests. CONCLUSION: These results confirm the clinical efficacy of 169Er-citrate synoviorthesis of rheumatoid arthritis-diseased finger joints after recent failure of intra-articular corticotherapy.

Physical and biological dosimetry in patients undergoing radiosynoviorthesis with erbium-169 and rhenium-186.

Physical and biological dosimetry were investigated in 45 rheumatoid arthritis patients treated by radiosynoviorthesis (RSO) with 186Re-sulphide (medium-sized joints) and 169Er-citrate (digital joints). Biological dosimetry involved scoring dicentrics in lymphocytes, cultured from blood samples withdrawn just before and 6 h, 24 h and 7 days after treatment. Physical methods included repeated blood sample counts and scintigraphy data. For erbium-169 (pure beta emitter), only bremsstrahlung could be measured and solely in the injection area. For rhenium-186 (both beta and gamma emitter), whole body scans and static images of joints and locoregional lymph nodes were performed. Dosimetry calculations were in accordance with the MIRDOSE 3 software and tables. For erbium-169 (21 patients), either metacarpophalangeal (30 MBq) or proximal interphalangeal (20 MBq) joints of the hands were treated (one joint per patient); 18 patients (out of 21) were interpretable for biological dosimetry, 10 (out of 11) for physical dosimetry and six (out of 10) for both. For rhenium-186, 23 wrists, nine elbows, three shoulders and two ankles were injected in 24 patients, with a maximum of three joints per patient (70 MBq per joint); 20 patients (out of 24) and 10 (out of 10) were interpretable for biological and physical dosimetry, respectively, and eight (out of 10) for both methods. Erbium-169 biological dosimetry was negative in all interpretable patients, and physical dosimetry gave a blood dose of 15 +/- 29 microGy and an effective dose lower than 1 mSv/30 MBq. For rhenium-186, biological results were negative in 16 patients (out of 20), but showed a blood irradiation around 200 mGy in the last four. A significant cumulative increase of dicentrics 7 days after injection (16/10,000 instead of 5/10,000 prior to treatment; p < 0.04) was also noted. Gamma counts gave a blood dose of 23.9 +/- 19.8 mGy/70 MBq and the effective dose was found to be 26.7 +/- 5.1 mGy/70 MBq, i.e. about 380 microGy.MBq-1. Erbium-169 RSO is very safe from both physical and biological dosimetry standpoints. Rhenium-186 leak is greater, as demonstrated by the higher blood activity and the measurable, although limited, dicentrics induction in blood lymphocytes. However, the effective dose remains moderate, i.e. 30 times lower than in 131I therapy in benign thyroid diseases.

Could somatostatin scintigraphy be superior to MIBG scan in the staging of stage IVs neuroblastoma (Pepper's syndrome)?

A 4-month-old infant suffering from Stage IVs neuroblastoma (NB IVs; Pepper's syndrome) was repeatedly examined by I-123 MIBG and somatostatin analog in-111 pentetreotide (SMS) scintigraphy, during a 2-year period. Treatment was restricted to surgery of the primary tumor. I-123 MIBG and SMS scan results were positive in the primary tumor and liver, but I-123 MIBG yielded very poor images and failed to reliably detect bone marrow metastases in the lower limbs and skull, whereas SMS precisely visualized these lesions. Six months after diagnosis, the infant was in complete clinical remission. I-123 MIBG and SMS images had returned to normal at 1 year. The prognostic implication of positive SMS imaging, in combination with positive or negative I-123 MIBG scan results, is not known in NB IVs and requires further investigation.

Indium-111-pentetreotide scintigraphy in children with neuroblast-derived tumors.

UNLABELLED: The somatostatin analog 111In-pentetreotide was evaluated in 11 children with sympathetic embryonic cell-derived tumors. METHODS: Six neuroblastomas, four ganglioneuroblastomas and one ganglioneuroma (benign) were imaged 4 and 24 hr after injection of 111In-pentetreotide (5 MBq/kg) and 24 hr after administration of 123I-metaiodobenzylguanidine (MIBG) (3.7 MBq/kg). RESULTS: Primary tumor was detected with both tracers in four of the five patients studied before surgery (one Stage III neuroblastoma, one Stage IV neuroblastoma, one Stage IVs neuroblastoma, one ganglioneuroblastoma), but the ganglioneuroma was not localized. Detection of bone marrow metastases was clearly better with 111In-pentetreotide in two patients, similar or slightly better with MIBG in six and (true) negative with both procedures in three. The positivity rate of 111In-pentetreotide for imaging of metastases was higher in undifferentiated malignant tumors (six neuroblastomas: two very positive, three positive, one true-negative) than in histologically well-differentiated tumors (four ganglioneuroblastomas: three weakly positive, one true-negative). All patients with positive 111In-pentetreotide imaging results had elevated urinary catecholamine levels, and the two most 111In-pentetreotide-positive metastases were found in neuroblastomas from children with an aneuploid primary tumor. The 111In-pentetreotide and MIBG results were only partly correlated with bone marrow status, as assessed by immunocytological and histological studies at the time of scanning. CONCLUSION: Abnormalities detected in 111In-pentetreotide uptake were slightly different from those seen with MIBG as a first-line routine method in neuroblast-derived tumors. However, some MIBG as a first-line routine method in neuroblast-derived tumors. However, some MIBG-negative tumor sites were detected by 111In-pentetreotide in patients with neuroblastomas. Thus, 111In-pentetreotide could provide novel information on the biology and prognosis of tumors whose clinical significance remains to be defined.

Acute renal toxicity of doxorubicin (adriamycin)-loaded cyanoacrylate nanoparticles.

Acute doxorubicin-loaded nanoparticle (DXNP) renal toxicity was explored in both normal rats and rats with experimental glomerulonephritis. In normal rats, 2/6 rats given free doxorubicin (DX) (5 mg/kg) died within one week, whereas all control animals and all rats having received free NP or DXNP survived. A 3 times higher proteinuria appeared in animals treated with DXNP than in those treated with DX. Free NP did not provoke any proteinuria. Two hr post-injection, DXNP was 2.7 times more concentrated in kidneys than free DX (p < 0.025). In rats with immune experimental glomerulonephritis, 5/6 rats given DX died within 7 days, in contrast to animals treated by DXNP, NP, or untreated, which all survived. Proteinuria appeared in all series, but was 2-5 times more intense (p > 0.001) and prolonged after doxorubicin treatment (400-700 mg/day), without significant difference between DXNP and DX. Rats treated by unloaded NP behaved as controls. These results demonstrate that, in these experimental conditions, DXNP killed less animals than free DX, despite of an enhanced renal toxicity of the former. Both effects (better survival and nephrosis) are most probably related to an enhanced capture of DXNP by cells of the mononuclear phagocyte system, including mesangial cells.

A new 123I-MIBG whole body scan scoring method--application to the prediction of the response of metastases to induction chemotherapy in stage IV neuroblastoma.

A new semi-quantitative scoring system is proposed, especially designed for the comparative interpretation of sequential whole-body meta-iodo-benzyl-guanidine (MIBG) scans in stage IV neuroblastoma children. This method was applied to assess whether MIBG scan at mid-course of induction chemotherapy could predict the final response. 27 newly diagnosed children were investigated by three sequential 123I-MIBG scans performed at the beginning, at mid-course (6 weeks) and at the end of neoadjuvant chemotherapy (12 weeks). Whole body scans were divided into nine regions in which the extension of bone metastases was separately quoted (score range: 0-3). The overall absolute scores were obtained by adding the scores of the nine regions. Relative scores were calculated by dividing the absolute score at each time by the corresponding pretreatment score. The score at mid-induction correctly predicted the overall response of metastases at the end of induction (P < 0.0001) in most cases. This method is easy to use, reproducible, subject to little inter-investigator variation, and thus well adapted to multicentric trials.

Uptake of nanoparticles by rat glomerular mesangial cells in vivo and in vitro.

Glomerular mesangial cells play a major role in the structure of capillary loops, generation of mediators of inflammation, and uptake of macromolecules. We demonstrate here that isobutylcyanoacrylate nanoparticles loaded with actinomycin D (ADNP) concentrate in rat mesangial cells in vitro and in vivo, as compared to the free drug (AD). In normal rats injected with 20 micrograms of 3H-ADNP or 3H-AD, the uptake ratios 3H-ADNP/3H-AD measured in whole kidneys at 30 and 120 min were 2.2 +/- 1.0 and 2.3 +/- 0.9, respectively. The same ratios calculated for isolated rat glomeruli and tubules, were 4.1 +/- 0.5 and 0.8 +/- 0.2 at 30 min, and 2.6 +/- 0.5 and 0.6 +/- 0.3 at 120 min, respectively. In the glomeruli, the absolute uptake of 3H-ADNP corresponded to 7.5 (30 min) and 1.8 (120 min)% I.D./100 mg of protein. In rats with experimental glomerulonephritis, the uptakes of 3H-ADNP and 3H-AD by the glomeruli were 6.9 and 4.0 times higher than in normal rats, respectively. In vitro experiments demonstrated up to 5 times higher uptake by glomerular mesangial cells than by epithelial cells. Uptake was maximum after 60 min, higher at 37 degrees C than at 4 degrees C, dependent on the presence of fresh serum and inhibited by cytochalasin-B. Drug targeting by nanoparticles is thus possible to renal cells involved in inflammatory processes, especially mesangial cells and macrophages. Nanoparticles could also be useful for lowering drug concentration in tubular cells, to reduce any tubular toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

[Immunoradionuclide localization of human neuroblastoma xenografted in nude mice using anti-GD2 labelled with I125]. / Localisation immunoscintigraphique de neuroblastomes humains greffés sur souris nude à l'aide d'anticorps anti-GD2 radio-iodés (125I).

Neuroblastoma is the most frequent tumour of the childhood under the age of 5. The staging and the follow up are achieved by MIBG scintigraphy, considered as the method of reference, but sometimes difficult to interpret . The availability of monoclonal antibodies against the ganglioside GD2, expressed on the cell membrane of neuroblastoma and neuro-endocrine cancers offers novel tools that deserve to be carefully explored. We investigated four mouse monoclonal antibodies (3 IgG3: BW704, 7A4, 60C3, and the IgG1 variant of BW704: MAK704), on nude mice xenografted with a human neuroblastoma (REM). Sixty one nude mice were included. The three former MAbs provided tumour imaging, the best results being obtained with BW704, followed by 7A4 and 60C3. MAK704 was disappointing. A control antiphosphorylcholine antibody (P51-1) did not give any tumour image in the three tested mice. Scintigraphy ratios tumour/liver and tumour/muscle reached 20 and 100 with BW704, respectively, on the 10th day. Good imaging quality was already obtained from the 24th h. The tumour uptake, calculated from radioactivity countings of resected samples, reached 22 +/- 3% of injected dose per gramme. These results let us hope that these antibodies could also provide highly contrasted images in humans and could open the way for therapeutic applications.

Strong uptake of 111In-pentetreotide by an MIBG-negative, xenografted neuroblastoma.

We investigated the distribution of 111In-pentetreotide (Octreoscan, Mallinckrodt) in nude mice xenografted with a human neuroblastoma cell line (SKLAN, derived from the LAN1 line). These cells develop into solid tumours in nude mice and can be grafted repeatedly in grafts of 10(8) cells. Animals were sequentially explored by scintigraphy 2, 4, 24 and 48 hr after i.v. injection of 2.5-4 MBq of the tracer and killed at various times up to 48 hr. 111In-pentetreotide was rapidly and strongly taken up by all tumours, with a tumour/muscle (T/M) ratio on resected samples of 20.0 +/- 5.7 at 2 hr, 23.7 +/- 3.0 at 4 hr, 75.6 +/- 12.6 at 24 hr and 78.7 +/- 12.4 at 48 hr, for tumours ranging from 0.5 to 8 g. Scintigraphy results were quantitatively in agreement. Pre-injection of a 15-20 times larger quantity of unlabelled octreotide s.c. reduced the tumour uptake by a factor of 2. For comparison, nude mice xenografted with the same cell line were also studied with 123I-MIBG (4 MBq). At 24 hr, the T/M ratio was 0.62 +/- 0.18. Two other cell lines (glioblastoma ROM and small-cell lung carcinoma SC41) which were similarly tested with 111In-pentetreotide (2.5-4 MBq) gave T/M ratios at 24 hr of 4.8 +/- 2.8 and 38.4 +/- 21.8, respectively. Pentetreotide seems to have a high affinity for this MIBG-negative neuroblastoma cell line, which exhibited a clearly higher tumour uptake than the 2 other lines. This work provides new experimental arguments in favour of the particular interest of somatostatin analogues in neuroblastoma and confirms our first clinical results.

Immunoscintigraphy in Hodgkin's disease and anaplastic large cell lymphomas: results in 18 patients using the iodine radiolabeled monoclonal antibody HRS-3.

Immunoscintigraphy (IS) using the HRS-3 Hodgkin associated monoclonal antibody (MoAb) was performed in 18 patients with Hodgkin's Disease (HD) at staging or restaging. Either F(ab')2 fragments (14 patients) or whole HRS-3 (4 patients) labeled with 77-260 Mbq 131-I were used. Whole body images, including anterior and posterior views, were taken from a digital gamma camera, within 4 to 8 hours after injection and then daily for 5 days. In one patient IS was discontinued due to iodine intolerance. Seventeen patients were evaluable: 14 showed a true positive result including 2 cases which were reviewed as anaplastic large cell lymphoma (ALCL). Nodal, splenic, bone marrow and muscle involvements were imaged, many of these sites were previously unsuspected. In 7 patients with true positive findings the Pressman Specificity Index, as measured from biopsied material, ranged from 1.5-3 in 4 patients and from 5 to greater than 100 in 3 patients. Imaging was equivocal or failed in 1 patient (lymph nodes). In 2 patients, IS imaging was truly negative due to the absence of active HD, and a false negative result occurred once (inguinal node). In none of the patients a false positive image was observed. In order to rule out non-specific iodine uptake a control, anti-ACE MoAb, labeled with 125-Iodine was injected simultaneously in 10 patients. The evaluation of the study gave a sensitivity of 87% and a good specificity. IS using radioiodine labeled MoAbs is feasible and represents a reliable non-invasive diagnostic method for the staging and follow-up of HD and ALCL.

[Value of CEA levels and of immunoscintigraphy (using CEA-marked antibodies) for the diagnosis and therapeutic monitoring of breast cancer: apropos of a case]. / Interêt du dosage du CEA et de l'immunoscintigraphie (par anticorps anti CEA marqués) pour le diagnostic et le monitoring thérapeutique du cancer du sein: à propos d'un cas.

A 33-year-old woman, who at 29 underwent mastectomy for a localised breast cancer (TINOMO), presented a relapse shown by a rapid rise in seric level of CEA. The classical complete work-up was negative. The location of the relapse was demonstrated by anti-CEA immunoscintigraphy. Radiotherapy, hormonotherapy and chemotherapy allowed to achieve a complete remission with normalization of CEA level and of immunoscintigraphy.

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.

[Monoclonal anti-AFP immunoscintigraphy of human hepatocellular carcinoma. Influence of biological, anatomical and vascular factors]. / Immunoscintigraphie monoclonale anti-AFP du carcinome hépatocellulaire humain. Influence des facteurs biologiques, anatomiques et vasculaires.

The actual interest of immunoscintigraphy for the detection of alphafetoprotein-producing liver tumors was investigated by both visual examination and quantitative analysis in 61 patients with either hepatocellular carcinoma (39 patients, group I), secondary liver cancer (11 patients, group II), or non tumoral liver (9 cirrhosis, 2 healthy liver, group III): All patients received injections of 123I-anti-alphafoetoprotein monoclonal antibodies and planar scans were performed after 28 hours. Only 18 out of 39 hepatocellular carcinoma-bearing patients had a positive scan (46 p. 100). Such a moderate sensibility was due to a striking inhibitory influence of cirrhosis: the positivity rate was 6/24 and 12/15 respectively when hepatocellular carcinoma was and was not associated with cirrhosis (p less than 0.01). Specificity was also moderate (55 p. 100) for detection of hepatocellular carcinoma in tumor-bearing patients (group I and II). In the absence of cirrhosis, the intensity of the tumoral uptake was highly correlated with high serum alphafoetoprotein level (p less than 0.001) and tumor arterial hypervascularization (p less than 0.01). Anti-alphafoetoprotein monoclonal antibody uptake by the extratumoral liver was found to be very specific of hepatocellular carcinoma since it was high in 23 out of 39 patients of group I but in only 1 out of 22 in groups II and III (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Increased cytotoxicity of nanoparticle-carried Adriamycin in vitro and potentiation by verapamil and amiodarone.

The cytotoxicities of free cyanoacrylic nanoparticles, free Adriamycin, Adriamycin-loaded nanoparticles and a mixture of Adriamycin and nanoparticles are compared in cancer cell cultures. Increased cytotoxicity was observed in the sensitive (DC3F) subline when Adriamycin was in particulate form rather than free. In the derived pleiotropic resistant subline (DC3F AD/AZA), sensitivity to Adriamycin was completely restored with the conjugate. Addition of verapamil or amiodarone allowed an enhancement of efficiency of tenfold for free Adriamycin and between two- and fourfold for its conjugate form. Vectorization by nanoparticles and pharmacological modulation of cell membrane can act in synergy in synergy to overcome the resistance to Adriamycin in vitro.

Positive anticalcitonin immunoscintigraphy in patients with medullary thyroid carcinoma.

A cocktail of three monoclonal F(ab')2 fragments against three distinct epitopes of calcitonin or PDN 21 was labelled with either 111In or 131I. These F(ab')2 fragments, a control 125I-F(ab')2 fragment and 99mTc-pertechnetate were injected into four patients suffering from medullary thyroid carcinoma. Scintigraphy data were processed by energy factor analysis for an optimal separation of images corresponding to each isotope. The best tumor detection was obtained 1-3 days after injection of the 111In-F(ab')2 cocktail which clearly labeled the thyroid tumors in the four patients (smallest tumor detected, 0.6 cm) as well as lymph node and bone metastases. In the liver, positive detection was only successful with the 131I-labeled cocktail. These results were confirmed by counting rates of resected specimens which provided average specificity indices ranging from 3.3 to 13.1. Anticalcitonin antibodies could be particularly useful for immunoscintigraphy detection of residual or recurrent medullary thyroid carcinoma in patients with elevated calcitonin serum level.

[In vivo imaging of Hodgkin's lymphomas using monoclonal antibodies]. / In-vivo-Imaging von Hodgkin-Lymphomen mit monoklonalen Antikörpern.

The Hodgkin- and Reed-Sternberg cell associated monoclonal antibody HRS-1 was labeled with radioactive iodine and injected into 6 patients with Hodgkin's lymphoma for immunoscintigraphic imaging. Four of five patients who received 131I-labeled HRS-1 had a positive immunoscintigram. In the sixth patient, the HRS-1 Mab was labeled with 123I in order to utilize tomoscintigraphy instead of linear scintigraphy. Bony disease was demonstrated by immunoscintigraphy in this patient. These preliminary results demonstrate that immunoscintigraphy with iodine-labeled HRS-1 Mab is feasible and informative in Hodgkin's lymphoma. The real clinical value of immunoscintigraphy in Hodgkin's lymphoma must be determined in a larger series of patients. Several modifications of the technique such as the use of Fab or F(ab')2 fragments should further improve the results.

Radiolabeled monoclonal antibodies against Reed-Sternberg cells for in vivo imaging of Hodgkin's disease by immunoscintigraphy.

The Hodgkin Reed-Sternberg (HRS-1) monoclonal antibody (Mab) was raised against the L 428 Hodgkin's disease (HD) cell line. The HRS-1 Mab was labeled with radioactive iodine and injected into six patients with Hodgkin's disease of varied histological subtypes for immunoscintigraphic imaging. In five patients, the HRS-1 Mab was labeled with 131I; a control anti-alpha-fetoprotein (AFP) Mab was injected simultaneously in two of these five cases. Four of five patients had a positive scan (nodal, splenic and hepatic involvements), the results in the fifth patient being equivocal. In the sixth patient, the HRS-1 Mab was labeled with 123I in order to utilize tomoscintigraphy instead of linear scintigraphy. Although the immunoscintigraphy (IS) was performed secondary to effective chemotherapy, images of bony disease were demonstrated. These preliminary results demonstrate that IS with iodine-labeled HRS-1 Mab is feasible and informative in Hodgkin's lymphoma. The real clinical value and the specificity of IS deserves confirmation in a larger series of patients. Several techniques such as the use of Fab or F(ab')2 fragments should further improve the results.

Conjugates of elliptinium acetate with mouse monoclonal anti-alpha-fetoprotein antibodies or Fab fragments: in vitro cytotoxic effects upon human hepatoma cell lines.

Elliptinium acetate (EA) is a new anti-cancer compound displaying cytostatic activity against various malignancies including hepatoma. Using 3 hepatoma cell lines, we compared the in vitro activity of doxorubicin (reference drug), of EA and of conjugates made up with this latter drug and monoclonal antibodies (MAbs). The linkage was performed by a direct oxidation method. Specific immunoconjugates were prepared with an anti-alphafetoprotein (AFP) MAb (AF01) or its Fab fragment (Fab AF01). Non-specific conjugates were obtained with an anti-thyroglobulin MAb (TG01) or its Fab (Fab TG01). Direct membrane injury (51Cr-release), DNA and protein synthesis as well as AFP release were investigated for all compounds. Free EA displayed only weak activity on DNA and protein synthesis, at 10-fold higher molar concentration than doxorubicin. Conjugation of EA with whole AF01 allowed significant potentiation of protein synthesis inhibition without affecting the 3 other tests. In contrast, Fab AF01 x EA conjugates displayed a marked effect in the 4 tests; in particular, this conjugate was at least 100 times more efficient than any other compound when tested in the 51Cr-release test. Neither Fab AF01 nor free EA alone or in combination exhibited such an effect. Fab TG01 x EA conjugate was not directly cytotoxic but potentiated inhibition of DNA and protein synthesis between 2- and 10-fold. The mechanism of the direct cytotoxic effect of anti-AFP Fab x EA conjugate, which has never been described in any other immunodrug model, was investigated.

Is anti-alphafetoprotein immunoscintigraphy a promising approach for the diagnosis of hepatoma? Implications of a quantitative study in 41 patients.

The actual interest of immunoscintigraphy for the detection of liver tumours was investigated by both visual examination and quantitative analysis in 41 patients with hepatoma (HCC, 21 cases, 13 AFP-secreting), other primary or secondary liver cancer (9 cases), testicular cancer (2 cases) and cancer free cirrhosis (9 cases). All patients were injected with 123I-anti-alphafetoprotein (AFP) monoclonal antibodies (MAbs) and scans were performed after 28 +/- 2 h. In the hepatoma-bearing patients, 11 positive anti AFP scans were found; 9 of them had an enhanced serum; besides, 3 non HCC tumours were also detected. With respect to hepatoma diagnosis, sensitivity was 52.5% and specificity 66.5%. For all hepatomas, it was striking that the positivity rate was 2/10 and 9/11, respectively, when HCC was and was not associated with cirrhosis. Among 6 patients with a positive anti AFP scan who were also injected with control anti hCG 123I-MAb, 5 positive anti hCG scans were surprisingly found, with specificity indices ranging between 1.00 and 1.75. The quantitative study also highlighted the importance for hepatoma detection of specific and non specific factors such as serum AFP, tumoural vascularization, non tumoural liver uptake and intrahepatic distribution of HCC. Anti AFP immunoscintigraphy appears as a poorly sensitive and moderately specific method for hepatoma diagnosis. In contrast, non tumoural liver uptake level could be more useful for discriminating HCC from liver metastases and perhaps to detect the early extension of HCC.