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Somatostatin receptors have been described on the membrane of neoplastic cells derived from the APUD system and their expression has also been demonstrated on small cell lung cancer (SCLC) in vitro and in vivo. 21 patients with SCLC were studied using 111In-octreotide (111In-OCT) scintigraphy. Scintigraphic examinations were performed following intravenous (i.v.) injection of 111 MBq 111In-OCT with whole-body scintigraphy and planar scintigraphy of the thorax as well as the SPET technique. No short-term side effects were described following 111In-OCT administration. We studied the 111In-OCT biodistribution in 3 patients with serial scintigraphies at 1, 5 and 24 h. We used the 5 h as standard scanning time for the following 18 patients. The scintigraphic results were compared with those of other conventional diagnostic procedures. 111In-OCT detected 86% (48/56) of the lesions already known at the time of scintigraphy. It was positive in all 20 SCLC patients and negative in one lung adenocarcinoma. 111In-OCT showed high sensitivity for mediastinal metastases (94%) and good sensitivity for bone metastases (75%) and abdominal lymph node metastases (71%). 111In-OCT did not detect two liver metastases. 111In-OCT detected five unknown lesions which were confirmed by other diagnostic examinations. 111In-OCT was also effective in cancer patients with low levels of NSE. Our study shows that 111In-OCT scintigraphy is a reliable, non-invasive technique to detect primary SLCL and its locoregional or distant metastases. The clinical utility of receptor status characterisation obtained with 111In-OCT scintigraphy should be evaluated by means of an appropriate prospective study.

Background. The prognosis for colorectal cancer patients is related closely to the extent of tumor at the time of diagnosis, and early detection of metastatic or recurrent disease is an important prerequisite for successful treatment. Radioimmunodetection is a relatively new technique to image colorectal cancer using radiolabelled monoclonal antibodies (MoAb). The goal of this study was to evaluate the clinical use of radioimmunodetection with the anticarcinoembryonic antigen MoAb FO23C5, radiolabelled with 131 I, in patients submitted to surgery for colorectal cancer and with suspected local recurrences

CEA determination has attained an important role in the clinical management of patients with tumors of the colorectal tract. In this paper the experience of the Istituto Tumori of Milan is reviewed and the results are discussed. Three hundred and thirty-six patients were followed after curative resection of colorectal carcinoma. The follow-up period was 15 years, from January 1975 to December 1990 (global follow-up 1358 years). In the course of follow-up 136 patients developed recurrent disease. The number of CEA determinations for each patient ranged from 1 to 37 (mean 8, total 3330). CEA levels of presurgical patients were related to the clinical stage. Among patients who developed recurrences 61% showed an increase in CEA serum levels. In 200 patients with a negative follow-up we observed only 15 cases of false-positive results.

The monoclonal antibody (Mab) 131I-MOv18 was administered to 30 patients with ovarian carcinoma intravenously (n = 20) and intraperitoneally (n = 10). After intraperitoneal administration, higher tumour uptake (mean values 1.3% vs. 0.8%) and a better tumour/background ratio (mean values 2.8 vs. 1.9) than after intravenous injection were obtained. Moreover, after intraperitoneal administration the uptake in non-affected organs, such as liver and spleen, was lower. However, occasionally the favourable results of the intraperitoneal route were cancelled by persistent pelvic non-specific accumulations of 131I-MOv18. The possibility to change the biodistribution pattern in the latter cases with peritoneal washing was evaluated. 3 patients were submitted to this procedure and an improvement in the radiotracer biodistribution was obtained in 1 case. With regard to tumour detection, the average sensitivity (73%) showed a significant difference from the sensitivities for abdominal (61%) and pelvic lesions (90%). No false positive results were noted.

Twenty-five patients treated with debulking surgery and chemotherapy for ovarian cancer were prospectively studied to evaluate the efficacy of radioimmunoscintigraphy (RIS) in detecting residual tumor before second-look surgery. RIS was performed with the monoclonal antibody OC125 F(ab')2 labelled with 1-131 without knowledge of clinical data and compared with subsequent surgical results. Second look showed tumor persistence in 12 patients, mostly characterized by small lesions. The overall diagnostic sensitivity of RIS was 50% and the specificity was 85%. In particular, RIS showed better sensitivity for pelvic tumor localizations than for abdominal sites (73% vs 33%); this was due to the inability of RIS to detect upper abdominal lesions. Therefore, our conclusion is that, at present, RIS cannot substitute surgical second-look in the management of ovarian cancer, however, considering that also ultrasonography, computer tomography and magnetic resonance are not always able to give definite diagnostic evidence in the follow-up of ovarian carcinoma, RIS could be added to these procedures to balance the limitations of each method. In this regard, the best application of RIS could be in the follow-up of patients with marker elevation without clinical evidence of disease, especially in the case of pelvic fibrosis or adhesions due to previous therapy, where the other non-invasive tools can give doubtful diagnostic results.

A total of 493 melanoma patients were investigated by 20 European nuclear medicine departments by means of the saine99mTc-labelled immunoradiopharmaceutical and the same immunoscintigraphy (ISG) protocol. (i) No chemical or clinical toxicity was detected during or following the studies. (ii) Positive results were obtained in 287/363 (79%) patients (321 carrying known lesions and 42 carrying previously occult lesions): in 231 (80%) of them, 402/402 lesions were imaged, in the remaining 56 ISG-positive patients, 108/204 lesions were imaged; in 76 patients 0/122 lesions were imaged. (iii) The fraction of melanoma lesions visualized by ISG was 510/728 (70A%); 605 of these lesions were already documented at the time of the study, and 123 were previously occult. (iv) A total of 218 documented melanoma lesions (30%) were not visualized by ISG in 132 patients: about 70% of the ISG-negative lesions were of small size (less than 2 cm diameter). (v) The melanoma nature of 69/123 previously occult lesions was confirmed by clinical criteria and/or additional investigations in follow-up studies. The results obtained in this study are similar to those obtained in the Italian Multicentre Study which had previously been carried out with 258 melanoma patients.

Nineteen patients with clinical and mammographic diagnosis of breast cancer and 1 patient already mastectomized underwent radioimmunoscintigraphy (RIS) in order to evaluate the axillary node status before surgery. After histologic examination, ductal breast carcinomas were found in 17/19 patients and axillary metastases were found in 11 patients. RIS was performed with planar scintigraphies and SPET (Single Photon Emission Tomography) of mammary and axillary regions after intravenous injection of In-111 B72.3. Overall RIS sensitivity for breast tumors was 71% (12/17); according to the tumor site different RIS sensitivity was demonstrated (90% for lesions of external quadrants versus 43% for lesions of internal quadrants). RIS was negative in 2 patients with post-surgery diagnosis of mammary dysplasia. As regards axillary metastasis RIS sensitivity and specificity were 91% (10/11) and 78% (7/9), respectively. Human Anti-Murine Antibody (HAMA) production was shown in 16.7% (2/12) of the patients. The quantitation of In-111 B72.3 uptake (%I.D./g; mean+/-S.D.) was 0.0054+/-0.0021 in breast tumors, 0.0021+/-0.0011 in normal mammary tissue, 0.0053+/-0.0027 in axillary metastasis and 0.0032+/-0.008 in normal axillary nodes. Our data demonstrated that RIS can detect tumor spread to the axilla in patients with breast cancer. Larger pre-operative study is required to evaluate if RIS can alter the management of this disease.

Sixteen of 19 enrolled patients with minimal residual disease of ovarian cancer (macroscopic disease < 5 mm or positive blind biopsies and/or positive peritoneal washing), demonstrated by surgical second-look, underwent intraperitoneal radioimmunotherapy (RIT) with the radiolabelled monoclonal antibody I-131 MOv18 (mean dose 14 mg of MOv18 with 3700 GBq of I-131) 30–40 days after the second-look procedure. Clinical follow-up and/or third-look evaluation performed 90 days after RIT showed complete response (CR) in 5 patients, no change (NC) in 6 patients and progressive disease (PD) in 5 patients. Follow-up study showed long-term maintained CR in 1 patient (34 months) and relapses in the other 4 patients after a mean disease-free period of 10.5 months. 5 NC patients showed clinical or instrumental progression after a mean disease-free period of 13 months. The toxicity of RIT was negligible. Only 1 patient showed mild and transient bone marrow suppression (platelet count nadir 52000 mm3 after 30 days). HAMA production was demonstrated in 94% (1516) of patients. In conclusion, RIT appears to be a very promising therapeutic approach to treat minimal residual disease of ovarian cancer.

Up to now a number of studies have been performed to determine whether the combined use of cytokines and monoclonal antibodies (MAbs) directed against tumor-associated antigens (TAA) can increase the sensitivity of radioimmunoscintigraphy (RIS). It well known that human natural and recombinant interferons can enhance the cell surface expression of HLA Class I and II antigens as well as some specific tumor antigens, but there is scanty and conflicting information about the expression and shedding of TAA. Some authors reported that alpha-IFN enhances the expression of a melanoma-associated antigen (MAA), recognized by conventional antiserum. Other authors have found no changes in the expression of MAA identified by MAbs (17, 18). In a pilot study on patients with malignant melanoma Rosenblum demonstrated an increase in tumor uptake of the anti-melanoma MAb 96.5 after IFN administration. In our study we performed immunoscintigraphy with the anti-melanoma MAb 225.28S in the same patient before and after IFN administration in different doses. We point out the difference in biodistribution in different organs and in blood clearance and discuss the possibility to improve the sensitivity of RIS.

An anti-CEA monoclonal antibody (FO23C5), belonging to the IgG1a class, was used to perform several preclinical and clinical studies on radioimmunoscintigraphy (RIS) in patients with colorectal carcinoma. Preliminary screening on different tissues showed high specificity of this antibody for gastric and colorectal carcinomas. A pilot study on 51 patients with 64 localizations of colorectal carcinoma was realized, followed by a multicenter validation study in which, among 509 patients bearing CEA secreting tumors, 254 patients had primary or relapsed colorectal tumors. High sensitivity and specificity values were obtained by these studies and many "unsuspected" localizations were recorded. In order to better define the clinical utility of this approach, a prospective trial was run on 59 patients previously submitted to surgery for colorectal carcinoma and with suspected local relapses. A comparative evaluation of RIS, CT scan, US and MRI was performed. RIS and MRI have the highest value of accuracy (86%) followed by CT scan (68%) and US (54%). No adverse reactions were noticed in any of the patients examined.

The monoclonal antibody (MAb) b12 raised against human breast cancer cell lines was found to identify an epitope of a mucinous-like carcinoma associated antigen (MCA) that is strongly represented on breast tumor cells. The b12 MAb was used to develop an enzyme immunoassay (EIA) kit. MCA levels were measured with the EIA method in the cytosol of both breast cancer and normal breast tissue as well as in the blood of 147 patients with primary breast cancer and 92 healthy subjects. MCA cytosol levels were significantly higher in carcinoma than in normal breast tissue cytosol samples. Higher MCA levels were found in the cytosol of tumor without lymph nodal involvement. The 95th percentile of the MCA value distribution in the healthy control group (11.0 U/ml) was chosen as negative/positive cut-off level. The overall positivity rate in breast cancer group was 26.5% with MCA showing a trend toward higher levels in patients with more advanced disease. Significantly higher levels were found in patients with a higher number of positive lymph nodes.

The studies on radioimmunodetection of malignant melanoma reported are based on the use of the 225.28S monoclonal antibody against a high molecular weight melanoma associated antigen, an IgG2a isolated and characterized by Ferrone et al. The strategy followed by us to check the characteristics and the behaviour of this antibody and to verify its possible use in clinical praxis, includes three groups of trials performed from 1982 to 1987. A pilot study was performed on 42 patients with 74 melanoma lesions, a multicenter study was realized, with the collaboration of 10 Italian nuclear medicine centers, on 254 patients with 539 lesions and prospective study performed on 44 patients with 54 suspected regional lymph nodes involvements. High sensitivity and specificity were obtained especially with the use of technetium compound which also allowed the attainment of very high predictive values of positive tests. No adverse reactions were noticed.

Preoperative detection of metastases in regional lymph nodes should constitute a fundamental step towards a better management of breast cancer. The National Cancer Institute of Milan has traditionally been engaed in this particular problem, that is, the search for a new imaging technique for detecting lymph nodal metastases from breast cancer. In 1984 axillary lymphoscintigraphy was performed on 26 patients with operable breast cancer by periareolar injection of 100 μCi of 99m Tc sulphur microcolloid. The regional lymph nodes were identified as spot areas and a comparison was made between the number of primary draining axillary lymph nodes and their pathological examination. In only 2 of the 26 patients have more than 3 spot areas been revealed by axillary scintiscan, but this finding did not correspond to metastatic invasion. The lymphoscintigraphy pattern of the other 24 patients did not suggest any pathological condition. From our experience the method does not appear to help either a precise diagnosis of breast disease or the definition of the extent of mammary cancer.

A 131I-labelled anti-CEA monoclonal antibody (MAb) (FO23C5) was used in a preclinical in vivo study in an animal model and in a clinical study in patients with colo-rectal carcinoma. Preliminary screening on different tissue was performed with immunoperoxidase staining, which showed a good specificity of the antibody for gastric and colo-rectal carcinoma. Initially immunoscintigraphy was performed as a pilot study at the National Cancer Institute of Milan on 51 patients with 64 localizations of colo-rectal cancer. Serial scans were performed after injection of 2 radioactive reagents, namely 131I and 111In. In vivo pharmacokinetics of the compound were studied. High sensitivity (80%) and high specificity were obtained in detecting local recurrences and abdominal metastases whereas a low positivity rate was obtained in detecting liver metastases. Our data were confirmed by preliminary results of the multicentric trial organized by the Italian National Research Council on 300 patients with about 700 localizations of CEA producing tumors.

Anti-CEA monoclonal antibodies (IgG1) from hybridoma F023C5 were labeled with I; I-F(ab’)2 fragments (Fabs) were also prepared, after pepsin-digestion of IgG and double chromatography purification. Labeling was done by the iodogen method (specific activities 13 to 19 mCi/mg). 131I-IgG and 131I-Fab were separately injected each into 4 patients not affected by a CEA-secreting cancer. Plasma disappearances, whole-body imaging, and liver and spleen uptakes were evaluated at daily intervals until 6 days after injection. Following similar early kinetics (about 45% of initial activity in plasma at 24 hours), Fab showed a significantly faster decay rate than IgG: terminal T½ 50.3 ± 6.2 hours versus 88.0 ± 11.7 hours (P

A prospective study to evaluate the clinical usefulness of radioimmunodetection of melanoma in clinical practice is ongoing at the National Cancer Institute of Milan, Italy. Technical conditions for the application of the method were previously reported. In this trial, 99mTc-labelled F(ab’) 2 fragments of the 225.28S monoclonal antibody were used against a high molecular weight melanoma associated antigen (HMW-MAA). Retrospective studies on radioimmunodetection of melanoma have already been made by our group and by other Centers in about 300 patients. This study concerns the evaluation of the regional extension of primary melanoma. 23 patients with 32 suspected lymphatic involvements of melanoma on the trunk and arms underwent immunoscintigraphy. No false positive results were observed; 3 false negatives, one corresponding to a micrometastasis, were noticed. Specificity corresponds to 100% and sensitivity to 78.6%.

131I-labelled anti-CEA monoclonal antibody was tested in an animal model to evaluate: influence of antibody type (whole versus F(ab’)2 fragments), administration route (i.v. versus i.p.), dose of tracer (100 μCi versus 1000 μCi), growth site (s.c. versus i.p.) and size of tumor. Athymic mice bearing CEA-producing human colon carcinoma (HT-29) or human melanoma as an irrelevant tumor (MeWo) received tracer and immunoscintigraphy and the localization ratios (LR) were compared. In HT-29 bearing animals F(ab’)2 fragments localized better than the whole antibody. The LR were higher after i.p. administration of the tracer, independently of the tumor characteristics or the injected dose. The highest values were achieved when the radioactivity remaining in the whole body was below 2% of the injected dose. The images were negative when the i.p. injected dose was low or tumor growth was i.p. but positive in the other conditions (i.v. administration, high tracer dose, s.c. tumor growth). In the animals bearing melanoma, images scored positive or negative when the tumor weight was respectively above or below 400 mg, but the LR were always low.

In this paper we summarize the investigations performed by our group utilizing an anti-CEA monoclonal antibody (F023C5) labelled with different radionuclides in humans. Since 1983 radioimmunoscintigraphy (RIS) was performed on 51 patients with 64 localizations of colorectal carcinoma (pilot study). A multicenter clinical trial in a large number of patients (509 pts of which 284 with gastrointestinal cancer) was subsequently carried out in collaboration with ten nuclear medicine centres. High sensitivity and specificity values were obtained by these studies and many unsuspected lesions were recorded. In order to better define the clinical role of RIS, a prospective study was performed on 59 patients with suspected local relapses of colorectal cancer. A comparative evaluation of RIS, CT scan, US and MRI was done. RIS and MRI had the highest accuracy (86%) followed by CT scan (68%) and US (54%).