Localization of radioiodine conjugated to the monoclonal antibody HMFG2 in human ovarian carcinoma: assessment of intravenous and intraperitoneal routes of administration.

The localization of i.p. injected, radioiodine conjugated monoclonal antibody HMFG2 was studied in 18 patients with ovarian carcinoma. Patients were injected i.p. at time points up to 168 h before laparotomy, at which time tumor, ascites, normal tissue, and blood samples were removed and the contained radioactivity measured. In the first 10 patients, localization was compared with that of a simultaneously injected irrelevant (nonspecific) antibody (UJ13A) of the same immunoglobulin class and, in the subsequent 8 patients, with HMFG2 administered i.v. After i.p. injection, HMFG2-radioiodine was found in concentrations of 0.0001-0.0030% of the injected amount per gram in solid tumor, 0.0363-0.02560%/g in ascites, 0.0003-0.0017%/g in blood, and 0.001-0.0012%/g in normal tissue. Tumor:normal tissue ratios of 0.9-10.0 and tumor:blood ratios of 0.3-4.0 were seen up to 168 h after injection. Localization of the HMFG2 conjugate was consistently greater than that of the irrelevant antibody. For solid tumor, the i.v. route of administration resulted in consistently higher absolute levels of HMFG2 conjugate uptake but tumor:blood and tumor:normal tissue ratios were similar. On the other hand the i.p. route of administration offered consistent advantages of 4- to 71-fold over the i.v. route when HMFG2 conjugate localization on ascites cells was examined. Ascites:normal tissue and ascites:blood ratios of up to 512 and 448, respectively, were achieved. After i.p. injection, radioiodine was cleared from the body exponentially with a half-life of 50 h. Maximum circulating blood levels of 8.6 +/- 2.0% injected activity were seen at 48 h and these then decreased with a t 1/2 value of 38 h. Over 80% of injected activity was cleared in the urine as nonprotein bound iodine by 168 h.

A prospective study of 123I-labeled monoclonal antibody imaging in ovarian cancer.

Thirty patients presenting with a pelvic mass were entered into a prospective study on the use of radioimmunoscintigraphy with the 123I-labeled monoclonal antibody HMFG2. The imaging data was obtained without knowledge of the clinical data and compared with subsequent surgical findings. A false-positive diagnosis of ovarian cancer was made in five of ten patients subsequently shown not to have ovarian cancer; thus the technique cannot be used as a screening test. A true-positive diagnosis was made in 19 out of 20 patients shown subsequently to have ovarian cancer. In 18 of these patients the distribution of uptake closely fitted the surgical findings. Methods of improving these results are described. In conclusion, radioimmunoscintigraphy is of no use in determining whether a pelvic mass is due to ovarian cancer, but has benefit in the evaluation of chemotherapy and may, in the future, prevent the need for second-look operations in some circumstances.

Ocular radioimmunoscintigraphy: sensitivity and practical considerations.

Ocular radioimmunoscintigraphy was performed in 20 patients using 99mTc-labeled monoclonal antibody 225.28S, F(ab')2 fragments. Radioimmunoscintigraphy was positive in 13 patients and the diagnosis of ocular melanoma was confirmed by enucleation of the eye or clinical follow-up. Scintigraphy was positive in one patient with lymph node metastasis from an ocular melanoma. In six patients immunoscintigraphy was negative. Using this technique a sensitivity of 92.8% was achieved for detecting ocular melanomas. Single photon emission tomography helped to separate the lesions situated in the nasal quadrant of the eye from the adjacent nasopharyngeal activity. With appropriate imaging techniques small tumors of the order of 3 x 5 x 3 mm could be detected clearly.

Kinetic analysis and probability mapping applied to the detection of ovarian cancer by radioimmunoscintigraphy.

Kinetic analysis with probability mapping is an objective method of serial image analysis applicable to radioimmunoscintigraphy. The technique is described and subjected to clinical testing by comparing the prediction of biopsy histology from the probability map in patients coming to operation. In those with ovarian cancer undergoing second-look laparotomy after completing full courses of chemotherapy, the prediction of histology in 108 biopsy sites was 45 true positives and 38 true negatives, sensitivity 80%, specificity 73%, accuracy 77% p less than 0.001. In patients with tumors less than 2 cm diameter, 41 biopsy sites were predicted with a specificity of 78% and an accuracy of 76%, p less than 0.01. The technique is reducing the need for second-look laparotomy in patients with subclinical and subradiological disease. Such disease is suitable for intraperitoneal radioimmunotherapy.

Imaging prostate cancer with technetium-99m-7E11-C5.3 (CYT-351).

UNLABELLED: To evaluate the performance of the 99mTc-labeled monoclonal antibody CYT-351 in visualizing prostate cancer, radioimmunoscintigraphy (RIS) was performed in 35 patients. METHODS: Antibody (0.5 mg) labeled with 600 MBq 99mTc was injected intravenously after obtaining informed consent. Planar and SPECT imaging was performed at 10 min and 6-8 and 22-24 hr postinjection. The scans were evaluated for visualization of the primary focus or local recurrence, extraprostatic invasion, lymph node involvement and uptake in bone and soft tissue metastases. RESULTS: Thirty-six studies in 35 patients were performed. In 13/14 evaluable studies with clinically localized prostate cancer, RIS had a true-positive rate of 92% (12/13). In eight patients with previous incidental carcinoma detected during transurethral resection undertaken for clinically benign disease, there were 86% true-positive results (6/7) and one true-negative result, which were confirmed by systematic needle biopsies. In six patients with evidence of local recurrence after a previous radical prostatectomy, the true-positive rate was 100% (6/6), which was confirmed by raised or rising prostate-specific antigen levels (PSA) and/or by biopsy. In the eight patients with known metastases, the disease was visualized in 4/4 with progression but not in the 3/3 with regression; one patient demonstrated regressing disease as determined by PSA levels. The overall accuracy was 92%. CONCLUSION: RIS with 99mTc CYT-351 is capable of providing good quality images and yielding clinically useful information safely. It has a potentially important clinical role for patients with rising PSA levels but negative images by conventional modalities.

Efficacy of immunoscintigraphy for detection of lymph node metastases.

The size of a lymph node is not in principle a limitation for the detection of cancer by Nuclear Medicine techniques. A radioactive pinhead is detectable if it has enough radioactivity on it. The approach of Nuclear Medicine to the demonstration of impalpable lymph nodes or to those lymph nodes detected by radiological techniques that are under 1 cm as to whether or not they contain cancer, is to increase the activity attached to cancer cells in such a lymph node as much as possible and to use sophisticated image analysis techniques to distinguish such uptake from its environment. This may be undertaken using a non specific technique such as F-18 Deoxyglucose and Positron Emission Tomography which is highly sensitive and which has been successful. The alternative approach is to use a highly specific and sensitive agent, such as a radio-labelled peptide or a radio-labelled monoclonal antibody together with image analysis. This paper describes these approaches and in particular the use of Tc-99m SM3 monoclonal antibody in the detection of impalpable axillary nodes in patients with breast cancer before surgery, using a change detection analysis providing a probability map of the significance of uptake of this radiopharmaceutical. It is a robust approach, providing the patient and the surgeon with information as to the likely need for extensive axillary surgery well prior to operation. A negative study should be followed by a sentinel node evaluation at surgery.

Radioimmunoscintigraphy of ocular melanoma with 99mTc labelled cutaneous melanoma antibody fragments.

The possibility of using radiolabelled monoclonal antibody fragments to image uveal melanomas has been assessed in a pilot study. 99mTc labelled F(ab')2 fragments of MoAb 225.28S raised against cutaneous melanomas were used. Initially 10 patients were imaged. In five patients the clinical findings were typical of uveal melanoma. Immunoscintigraphy was positive in all five cases. In a further five patients there was doubt about the diagnosis. One was though to have a choroidal haemangioma but failed to respond to treatment and immunoscintigraphy was positive, suggesting a diagnosis of melanoma. Two patients were assigned a diagnosis of choroidal haemangioma, one of melanocytoma or possible retinal pigment epithelium carcinoma, and one of metastasis. Immunoscintigraphy was negative in all these four cases. In combination with established diagnostic tests immunoscintigraphy may have a part to play in differentiating uveal melanoma from other similar tumours.

Characterisation of ocular melanoma with cutaneous melanoma antibodies.

It can be difficult to distinguish between various forms of pale intraocular tumour, and in particular between an amelanotic malignant melanoma, a choroidal haemangioma, and a solitary metastasis. If a monoclonal antibody specific for melanoma could be identified, it might be radiolabelled to provide a scanning technique which could distinguish between an ocular melanoma and a similar lesion. This pilot, in vitro study was undertaken to determine if monoclonal antibody against cutaneous melanoma recognises any antigenic similarity in ocular melanomas. Three cutaneous melanoma MoAbs 225.28S, 376.96S, and 763-24T and a non-specific MoAb HMFG2 were studied. Cell impressions were obtained from fresh ocular malignant melanomas. Standard staining techniques with immunofluorescence were used. MoAb 225.28S, 376.96S, and 763.24T were positive in melanomas with a dominant epithelioid cell type and in those with a dominant spindle cell type. It is concluded that MoAb 225.28S, 376.96S, and 763.24T may be suitable for imaging ocular melanomas after labelling with 123I, 111In, or 99mTc.

Global and regional cerebral blood flow. Noninvasive quantitation in patients with subarachnoid hemorrhage.

Since inert gas washout techniques for cerebral blood flow (CBF) measurement are not applicable to asymmetrical pathological states where assumptions about constancy of distribution, volume, and partition coefficients cannot be held to be valid, a new approach to regional and global CBF is described. Regional volume and regional mean transit time are measured independently to give regional volume flow in ml/min. In a pilot study, this noninvasive, quantitative technique has been applied to 37 patients with various clinical responses to subarachnoid hemorrhage. Global CBF and clinical grading were significantly associated. Reduction of regional CBF and spasm of the relevant arterial supply were also significantly associated in these patients.

Radiolabelled stripped mucin, SM3, monoclonal antibody for immunoscintigraphy of ovarian tumours.

A new monoclonal antibody, SM3, against stripped mucin core protein has been evaluated for the radioimmunoscintigraphy of ovarian cancer. It was radiolabelled with In-111, I-123 and Tc-99m and results showed a sensitivity of 95%, 100% and 100% and an accuracy of 73%, 86% and 100% for malignancy; respectively.

Radiolabelled monoclonal antibodies in oncology. II. Clinical applications in diagnosis.

The clinical applications of this approach to the management of patients with ovarian cancer and of patients with colorectal cancer are emphasized. The introduction of stable 99Tcm labelling of monoclonal antibodies means that radioimmunoscintigraphy is able to become routinely available in nuclear medicine departments.

Radiolabelled monoclonal antibodies in oncology. III. Radioimmunotherapy.

The requirements, problems and progress of radioimmunotherapy in the management of certain malignancies are described. The future prospects using a two- or three-stage approach are promising.

Radiolabelled monoclonal antibodies in oncology. I. Technical aspects.

The principles and technique of radioimmunoscintigraphy are described with particular reference to the choice of antibody and the radiolabel, the radiolabelling procedure and the patient protocols. The arguments in favour of using a short-lived high count rate radionuclide for radioimmunoscintigraphy are set out. Methods for labelling monoclonal antibodies with 111In, 123I or 99Tcm are described. The early image at 10 min after injection is essential as it acts as a template with which later images may be compared. In conclusion, many of the technical aspects of radioimmunoscintigraphy have been overcome and it is ready for wider application in oncology patients.

Cerebral blood flow in hypertensive patients with cerebrovascular disease: technique for measurement and effect of captopril.

Nineteen patients with unilateral cerebrovascular disease underwent cerebral blood flow (CBF) measurements; ten had been receiving conventional therapy and then were studied after treatment with captopril without or with a diuretic and nine on conventional therapy were studied twice as a control group. CBF (ml min-1) was measured after an intravenous injection of 99Tcm-labelled patient's red cells with a computer linked gamma camera over the vertex and a probe over the aorta. With deconvolution analysis regional CBF is given by regional cerebral volume divided by regional mean transit time. Results in the captopril group showed on average a 10% fall in mean blood pressure and a 10% rise in blood flow to the affected hemisphere. In the control group there was on average a 4% fall in pressure, together with an 11% fall in CBF to the affected hemisphere. Captopril appears to maintain autoregulation in cerebrovascular disease.

Imaging of phaeochromocytoma and adrenal medulla with 123I-meta-iodobenzyl guanidine.

A method for preparing meta-iodobenzyl guanidine (MIBG) labelled with 123I is described. This compound clearly imaged the normal adrenal medulla in seven out of eight patients with hypertension. The sites of metastases were demonstrated in two patients with malignant phaeochromocytoma.

Therapeutic considerations in the use of intraperitoneal radiolabelled monoclonal antibodies in ovarian carcinoma.

Eleven patients with ovarian cancer have been treated with a radiolabelled monoclonal antibody directed against human milk fat globule membrane (HMFG2). All patients had Stage III disease and had previously undergone debulking surgery followed by chemotherapy. Although 16 patients have been referred, 5 could not be treated. This paper discusses the criteria for patient selection and treatment, and describes the technical difficulties of this form of therapy and the complications sustained following the intraperitoneal instillation of up to 150 mCi iodine-131 labelled HMFG2. Significant complications included two ileo-cutaneous fistulae and peritonitis in one patient which prevented treatment from being given.

Radioimmunoscintigraphy of orbital metastases from ovarian carcinoma.

Radioimmunoscintigraphy with I-123 labeled monoclonal antibody HMFG1 has been used for imaging primary and metastatic ovarian neoplasms. Uptake of I-123 labeled HMFG1 is reported in a patient with an orbital metastasis from a primary ovarian adenocarcinoma. Radioimmunoscintigraphy may have a role to play in imaging metastatic orbital neoplasms.

Duodeno-gastric reflux and gastric adenomas: a scintigraphic study in patients with familial adenomatous polyposis.

To test whether the presence of gastric adenomas (dysplasia) was associated with gastric reflux of duodenal contents, six patients with familial adenomatous polyposis (FAP) who had gastric adenomas and nine matched FAP patients without gastric adenomas underwent scintigraphic duodeno-gastric reflux scanning. Reflux was graded 0-6, where 0 = no reflux, 1 = intermittent reflux into antrum only, 2 = prolonged reflux into antrum only, 3 = intermittent reflux into body, 4 = prolonged reflux into body, 5 = intermittent reflux into body and fundus, and 6 = prolonged reflux into body and fundus. FAP patients with gastric adenomas had more severe reflux (median 6, range 4-6) than did controls (median 3, range 0-6; P = 0.009, Mann-Whitney U test). These results are consistent with a role for bile in the development of gastric adenomatous polyps and suggest that bile is involved in the dysplasia-carcinoma sequence.