The significance of intraoperative periportal lymph node metastasis identification in patients with colorectal carcinoma.

BACKGROUND: Nine patients who underwent Radioimmunoguided Surgery (RIGS) (Neoprobe Corporation, Dublin, OH) procedures for colorectal cancer were found to have disease recurrence in the periportal area. This led to a retrospective study to determine whether periportal lymph node involvement could have been predicted intraoperatively for these patients. METHODS: One hundred twenty-four patients underwent second-look RIGS for recurrent colon and rectal cancer from 1986 to 1992. The monoclonal antibody (MAb) B72.3 was administered as the carrier agent to 87 patients and the CC49 second-generation MAb was administered to 37 patients. Both MAbs were radiolabeled with Iodine-125. RESULTS: Periportal lymph nodes with RIGS-positive tissue were found in 47 (38%) patients, hematoxylin and eosin-positive lymph nodes were found in 13 of 47, and in further immunohistochemical studies performed for 31 of the remaining 34 patients, positive lymph nodes were found in 8, resulting in an incidence of 48% (21/44). A critical review of the nine patients' charts who later presented with a tumor mass in the periportal area demonstrated intraoperative gamma-detecting probe counts in ratios three to five times that of the normal adjacent tissues in the periportal area at the time of first exploration. Probe-directed biopsy was reported to be histologically negative for tumor in these patients, and, thus, the surgeon proceeded assuming the periportal area to be negative. A retrospective study of the periportal lymph nodes of these patients using cytokeratin immunohistochemical analysis identified tumor in five (56%). CONCLUSIONS: These findings suggest that the RIGS system may be a valuable method of intraoperative prediction and detection of periportal lymph node metastasis.

Intraoperative localization of neuroendocrine tumors with 125I-TYR(3)-octreotide and a hand-held gamma-detecting probe.

BACKGROUND: This study evaluates a novel method of intraoperative localization of endocrine gastroenteropancreatic tumors with a hand-held gamma-detecting probe to detect in situ tumor binding of the radioiodinated somatostatin analog 125I-TYR(3)-octreotide. METHODS: Seven patients with biochemical and radiologic evidence of a specific endocrine tumor, one patient with biochemical evidence of gastrinoma but no tumor localized by conventional imaging techniques, and four patients with equivocal preoperative biochemical or radiologic study results but suspected of harboring a neuroendocrine tumor underwent abdominal exploration with intraoperative injection of 125I-TYR(3)-octreotide. 298 +/- 63 microCi. A hand-held gamma-detecting probe was used during operation to determine whether gross tumor accumulated the radiolabeled analog and occult tumor could be detected. Positive uptake was defined as tumor/background ratios exceeding 2:1. RESULTS: The tumor in all seven patients with gross disease accumulated 125I-TYR(3)-octreotide. Occult tumor beyond that appreciated with preoperative imaging or by routine operative exploration was detected in a patient with carcinoid tumor. In the patient with the occult gastrinoma the probe detected the lesion within the duodenal bulb before duodenotomy and also predicted what proved histologically to be positive peripancreatic adenopathy. There was a single false-positive reading from the stomach in a patient with suspected carcinoid tumor in whom no tumor could be found grossly or histologically. A pancreatic mass that probed negative proved to be an adenocarcinoma of ductal origin. CONCLUSIONS: Tumor-specific peptide-receptor binding can be detected in situ with 125J-TYR(3)-octreotide and a hand-held gamma-detecting probe. This technique may facilitate neuroendocrine tumor localization and operative cytoreduction.

Radioimmunoguided radical prostatectomy and lymphadenectomy.

BACKGROUND: The feasibility of using radioimmunoguided surgery (RIGS) (Neoprobe Corp., Columbus, OH) for intraoperative detection of prostate cancer was examined in a pre-Phase I clinical study involving 10 patients having radical prostatectomy and lymphadenectomy. METHODS: Patients were injected with iodine 125-radiolabeled B72.3 monoclonal antibody, which has been shown previously to bind to TAG-72, a pancarcinoma and oncofetal antigen. At a mean of 26 days after injection, RIGS was performed with a specially designed intraoperative gamma-detecting probe. RESULTS: By comparing probe counts with counts of appropriate background tissues, the RIGS system successfully localized tumor to the prostate of all 10 patients. Clinically occult and histologically confirmed bilateral intraprostatic tumor was identified in three patients. One additional patient had bilateral positive intraprostatic probe count ratios with the RIGS technique; on histologic examination, tumor was identified unilaterally, and extensive high-grade prostatic intraepithelial neoplasia was found on the contralateral side. Probe count ratios were positive in the lymph nodes of three patients; two had tumor confirmed histologically. CONCLUSIONS: The current investigation supports the feasibility of the RIGS technique and the need for additional studies.

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.

Intraoperative radioimmunolocalization of colorectal carcinoma with a hand-held gamma probe and MAb B72.3: comparison of in vivo gamma probe counts with in vitro MAb radiolocalization.

A new intraoperative approach to tumor localization using radiolabelled monoclonal antibody (MAb) B72.3 involves the use of a hand-held gamma-detecting probe (GDP) by the surgeon and, subsequently, the pathologist. We report here the use of 125I-labelled MAb B72.3 IgG and a GDP to localize primary and metastatic colorectal cancer in 31 patients. The patients were administered radiolabelled MAb i.v., and all underwent surgical exploration 5 to 35 days post-injection. In vivo localization of the MAb was evaluated using a GDP, with tumor and normal tissue counts being obtained. In each case, the subsequent tumor and normal tissue that were resected were analyzed in vitro for MAb localization; this was evaluated by calculating the radiolocalization index, i.e., the ratio of the injected dose per gram localized to tumor versus that of normal tissue. When the GDP was used intraoperatively, MAb B72.3 localized tumors in 68% (21/31) of the patients; the arbitrary criterion of tumor-to-normal tissue ratios higher than or equal to 2.0:1 in vivo being taken as positive. Resected tumor radiolocalization indices ranged from 0.5 to 543, and 71% (22/31) of the patients studied had tumors with radiolocalization indices higher than or equal to 3. Of 50 carcinoma biopsies, 34 that were probe-positive were antigen-positive when B72.3 was used in immunoperoxidase assays, while 4 carcinoma biopsies that were probe-negative were also antigen-negative. Twelve of 50 biopsies were probe-negative and antigen-positive, but many of these lesions only contained a few antigen-positive cells; none of the 50 was probe-positive and antigen-negative. Tumors of all histologic grades localized injected MAb and, in general, higher in vivo probe ratios and radiolocalization indices were obtained from patients who underwent surgery 20 to 35 days following injection of the MAb. MAb B72.3 localized tumor in all sites to which colon carcinoma commonly metastasizes, including mesenteric and peri-aortic lymph nodes, liver, lung, and peri-rectal soft tissue. There was a strong statistical correlation (p = 0.001) between detecting MAb B72.3 localization to tumors using the GDP intraoperatively and subsequent in vitro analysis of cpm/g for tumor versus normal tissues. These studies thus further validate the use of 125I-labelled MAb B72.3 IgG and of a hand-held gamma probe for the intraoperative detection of carcinomatous lesions.

Limits of sensitivity for the radioimmunodetection of colon cancer by means of a hand held gamma probe.

This study was undertaken to define the limits for the radioimmunodetection of minimal deposits of colorectal cancer cells using a hand held gamma probe. 125I labeled monoclonal antibody 17-1A and its F(ab')2 fragments were reacted in vitro with cells of the human colorectal cancer line SW 1116. The limits of sensitivity of the probe were determined by injecting doubling dilutions of 125I-antibody coated SW 1116 cells ranging from 10(7) to 3.9 x 10(4) subserosally at 2 cm intervals into 60 cm segments of freshly obtained autopsy or surgical specimens of human colon. A linear relationship was observed between the number of cells injected and the number of counts obtained with either the probe or well counter. As few as 6.25 x 10(5) 125I-antibody coated cells (less than 1 mm3) were detected under experimentally defined conditions by an earlier version of the probe, and 3.9 x 10(4) coated cells (much less than 1 mm3) could be detected by the currently available model. Although the count rates were less than 5% of those obtained by well counter, nevertheless, these were 10-25 times greater than background and allowed the detection of tumor cell deposits that otherwise would not have been discernible by either palpation or external scintigraphy. These findings, in conjunction with ongoing clinical studies, suggest that the hand held gamma probe may increase the usefulness of monoclonal antibodies for the radioimmunodetection of cancer.

Radioimmunodetection of implanted tumors with gamma probe.

Tumor uptake of 125I- and 131I-radiolabeled anti-CEA antibodies was compared in female Swiss nude mice, each bearing a CEA-producing human colon adenocarcinoma xenografted in one flank. Counts from the tumor and contralateral flank were recorded with a manipulatable, cadmium-telluride crystal gamma detector at 24, 48, and 72 hours following injection. The animals were killed, and the tumors and other organs were removed, weighed, and then assessed in an automatic gamma counter. The cadmium-telluride counter was more efficient at counting 125I-labeled antibodies than 131I antibodies. The tumor to contralateral flank ratios improved with the use of a monoclonal anti-CEA and polyclonal anti-CEA in combination compared with the single antibodies. The investigation of the external counting characteristics of the portable gamma detector demonstrated the potential of the adjunctive use of intraoperative detection with external radioimmunoscintigraphy for detection and localization of gastrointestinal tumors.

Intraoperative probe-directed immunodetection using a monoclonal antibody.

To assess monoclonal antibody (MAb) 17-1A and its F(ab')2 fragment in intraoperative radioimmunodetection and to evaluate further the clinical usefulness of a hand-held gamma-detecting probe (GDP), we injected radiolabeled monoclonal antibody 17-1A three to six days preoperatively or its F(ab')2 fragment two to three days preoperatively into 18 patients with colorectal cancer. Intraoperative GDP counts with tumor-tissue ratios of 1.5:1 or greater were obtained from 15 (75%) of 20 tumor sites, with ratios averaging 2.3:1 for fragments and 3.4:1 for whole antibody. The GDP counts contributed to intraoperative decision making in three patients, either by localization of tumor not identified by inspection or palpation or by mapping margins of resection with histologic confirmation of a local/regional recurrence. These preliminary data demonstrate that probe-directed, intraoperative radioimmunodetection can assist the surgeon in detecting subclinical tumor deposits and thus better evaluate the extent of primary or recurrent colorectal cancers intraoperatively.