Steven E. Tuttle

Radioimmunoguided surgery using monoclonal antibody

The potential proficiency of radioimmunoguided surgery in the intraoperative detection of tumors was assessed using labeled monoclonal antibody B72.3 in 66 patients with tissue-proved tumor. Monoclonal antibody B72.3 was injected 5 to 42 days preoperatively, and the hand-held gamma-detecting probe was used intraoperatively to detect the presence of tumor. Intraoperative probe counts of less than 20 every 2 seconds, or tumor-to-adjacent normal tissue ratios less than 2:1 were considered negative (system failure). Positive probe counts were detected in 5 of 6 patients with primary colon cancer (83 percent), in 31 of 39 patients with recurrent colon cancer (79 percent), in 4 of 5 patients with gastric cancer (80 percent), in 3 of 8 patients with breast cancer (37.5 percent), and in 4 of 8 patients with ovarian cancer (50 percent) undergoing second-look procedures. Additional patients in each group were scored as borderline positive. Overall, radioimmunoguided surgery using B72.3 identified tumors in 47 patients (71.2 percent), bordered on positive in 6 patients (9.1 percent), and failed to identify tumor in 13 patients (19.7 percent). Improved selection of patients for antigen-positive tumors, the use of higher affinity second-generation antibodies, alternate routes of antibody administration, alternate radionuclides, and more sophisticatedly bioengineered antibodies and antibody combinations should all lead to improvements in radioimmunoguided surgery.

Radioimmunoguided surgery using the monoclonal antibody B72.3 in colorectal tumors

The authors have developed a hand-held gamma-detecting probe (GDP) for intraoperative use that improves the sensitivity of external radioimmunodetection. Radiolabeled monoclonal antibody (MAb) B72.3 was injected in six patients with primary colorectal cancer and 31 patients with recurrent colorectal cancer an average of 16 days preoperatively. The GDP localized the MAb B72.3 in 83 percent of sites. The technique, known as a radioimmunoguided surgery (RIGSTM) system did not alter the surgical procedure in patients with primary colorectal cancer but did alter the approach in 26 percent (8/31) of patients with recurrent colorectal cancer. Two patients avoided unnecessary liver resections and two underwent extraabdominal approaches to document their disease. The RIGS system may influence the short-term morbidity and mortality of surgery for colorectal cancer. Larger series and longer follow-up are needed to determine whether the RIGS system confers a survival advantage to the patient with colorectal cancer.

Intraoperative radioimmunodetection of colorectal tumor with a hand-held radiation detector

A hand-held gamma detection probe was used intraoperatively to localize primary and recurrent colorectal tumors in 28 patients 48 to 72 hours after they received an intravenous injection of 2.2 mCi of iodine-131 labeled anticarcinoembryonic antigen polyclonal baboon antibody. Preoperative evaluation included determination of serum carcinoembryonic antigen, barium enema, colonoscopy, chest film, computerized axial tomography, liver, spleen, and bone scans, and endoscopy when indicated. Preoperative whole-body imaging correctly localized primary tumors in only 33 percent of the patients, whereas it correctly demonstrated tumor in 64 percent of those with recurrent disease. Intraoperative tumor-to-background ratios derived from the detector probe were elevated in all patients, averaging 3.97:1 in primary lesions and 4.18:1 in recurrent tumors. Postoperatively, carcinoembryonic antigen was localized in tissues with the avidin-biotin peroxidase staining technique to confirm intraoperative readings. Variations in stain uptake in a patient could be correlated with variations in radiation detector readings in the same patient. Results support our previous work in nude mice, demonstrating the improved sensitivity and specificity of the hand-held gamma detection device over whole-body imaging for intraoperative localization of immunoradiolabeled tumors.

Fibrolamellar carcinoma of the liver. Review of three cases and the presentation of a characteristic set of tumor markers defining this tumor.

This study demonstrates the unique clinical and histologic aspects of fibrolamellar hepatic carcinoma, a rare variant of hepatocellular carcinoma. Three cases are reviewed and an extensive study of immunologic and intracellular substances defining this tumor is presented. Length of survival was considerably longer than typical hepatoma. The cause of death generally is due to a lack of control of the primary tumor. Successful treatment appears to relate to the ability to perform a total excision of the primary hepatic tumor. Chemotherapy should be used only in the presence of metastatic disease. Surgical resection of metastatic disease, unlike the usual hepatocarcinoma, may have some beneficial use. Fibrinogen was found in all tumors. It is possible that this tumor produces fibrinogen to create its unique histologic appearance. Carcinoembryonic antigen is described for the first time in this tumor. Both deposits of alpha-1 antitrypsin and copper were found in most of the tissues studied. The presence and amounts of these substances differ markedly from the common type of hepatoma. This unique composition of intracellular components may both facilitate histologic diagnosis, particularly if the amount of tissue is limited, and give further insight into the etiology of this tumor.

Localization by hand-held gamma probe of tumor labeled with antibody “cocktail”

Five groups (n = 4) of congenitally athymic female nude mice bearing subcutaneous implants of CX-1 and/or SW-1116 tumor in the hind limbs received iodine-125 radio-labeled monoclonal antibodies (MoAbs) B72.3 (two groups), 17-1A (two groups), and cocktail (one group) (iodogen method, 50 microCi/10 micrograms/mouse). Daily probe counts were made in duplicate with a hand-held detector over each tumor site and the front leg (background) for 21 days. Animals were sacrificed and appropriate well counts were obtained. All the single MoAb preparations localized well in both tumor cell lines. Uptake of monoclonal antibody 17-1A was similar in the two tumor cell lines, with counts initially high and slowly decreasing over the 21-day period. Tumor/background ratios continued to increase over time, indicating that both tumor lines have similar antigenic expression for the monoclonal antibody 17-1A. This was not the case for monoclonal antibody B72.3, which showed a preferential uptake by the CX-1 tumor, with higher initial counts and prolonged binding of the antibody, giving rise to higher tumor/background ratios. The mixture of monoclonal antibodies B72.3 and 17-1A markedly improved the uptake by the CX-1 tumor cell line but not that by the SW-1116 cell line, where the effect was negative when compared to the uptake of the single MoAb preparations. The use of a monoclonal antibody mixture can enhance targeting of some tumor sites. Due to the heterogeneity of tumor cell lines, even within the same animal, different mixtures of monoclonal antibodies are needed to increase the targeting of tumor.

Glomerular Basement Membrane Splitting and Microaneurysm Formation Associated with Nitrosourea Therapy

A patient who developed renal insufficiency following nitrosourea therapy is reported. Light, immunohistochemical, and electron microscopic studies of the renal biopsy disclosed an unusual glomerular basement membrane injury. Light microscopy showed extensive basement membrane splitting and capillary aneurysm formation. Electron microscopic examination revealed an extensive subendothelial accumulation of electron-lucent granular material. The glomerular basement membrane was separated from the mesangium and showed splitting of the lamina densa. Immunofluorescent and immunoperoxidase staining of the glomeruli was negative for immunoglobulin, complement, and fibrinogen. This form of nitrosourea-associated glomerular injury has not been described previously.