Gamma Ray Detection Probe

The idea of using a hand-held probe for the localization of diseased tissue was first reported by William G. Myers in 1960 [12]. The first reported use of the probe for RIGS was in 1984 [13].

The design of the probe is based on the use of a semiconductor detector in a hand-held instrument. The probe uses a built-in 12-mm cadmium telluride detector, together with a preamplifier, and has the ability to detect gamma rays from a radioactive tracer. The gamma photons detected by the crystal are con-

counts 3

2 secom

7 10 16 31 80 422

counts 3

2 secom

7 10 16 31 80 422

Figure 1 Probe over 50 nCi node (2-second count). The count rate decreases proportionately to the square of the distance between the two. (From Ref. 14. Copyright 1999 Springer-Verlag. Reprinted by permission of Springer-Verlag GmbH & Co.)

verted into electric pulses and presented as both a digital numerical display and an auditory signal.

The efficacy of detection is the ratio between the area of the detector and the area of the sphere of radiation. The ratio between these two areas increases proportionately to the square of the distance between the two (Fig. 1) according to the inverse square law [14]. The probe serves as a homing device by directing the surgeon to the tissue with the high-count rate.

The Neoprobe 1000 and later models (Neoprobe 1500 and 2000; Neoprobe Corporation, Dublin, OH) have a special ''squelch'' mode character. This is a mathematical character of the computer that calculates the mean count of a given point (5-second count), calculates the standard deviation (square root), and starts to emit a sound only when the count is three standard deviations greater than the mean count (denoting significantly higher radiation). This feature enables the surgeon to survey an area and guide himself to the possibly diseased radioactive tissue [15].

The surgical technique is based on careful survey of the area in question. Slow scanning is mandatory. An important point in this technology is the three-point counting principle. First, an in vivo count is performed, then the tissue is excised, and an ex vivo count is performed to verify that the correct tissue was excised. Subsequently, the bed of resection is probed again to verify that no radioactive tissue is left behind. Table 1 describes several scenarios using this three-point principle.

Isotope

In RIGS, the radiolabeled MoAb is injected 3 to 4 weeks before surgery. The antibody becomes attached to the tumor while the body secretes the surplus anti-

Table 1

The Three-Point Counting Principle

Bed of

Scenario

In vivo

Ex vivo resection

1

+

+ -

Right tissue, completely excised

2

+

- +

Wrong tissue excised

3

+

+ +

Right tissue, not completely ex-

cised

4

+

- -

Technical error with resulting high

in vivo count

Source: Ref. 14. Copyright 1999 Springer-Verlag. Reprinted by permission of Springer-Verlag GmbH & Co.

Source: Ref. 14. Copyright 1999 Springer-Verlag. Reprinted by permission of Springer-Verlag GmbH & Co.

body. The concentration in the blood decreases, and a ratio builds up between the tumor and the blood, enabling the surgeon to detect the tumor when using the gamma-detecting probe (Fig. 2) [16].

Several isotopes were tested in the development of the technique: 125I, 131I, indium-111 (111In), and technetium-99m (99mTc). 125I was chosen because it combines the advantages of low Compton scattering, which obviates the need for collimation; high tissue attenuation, which improves the tumor-to-background

Counts (2 sec) Ratio

Counts (2 sec) Ratio

The Lymph Nodes Animals

Days after injection

Figure 2 Tumor and background concentration in an animal model injected with monoclonal antibody labeled with 125I. Background, continuous line;tumors;dotted line; background to tumor ratio, broken line. (From Ref. 14. Copyright 1999 Springer-Verlag. Reprinted by permission of Springer-Verlag GmbH & Co.)

Days after injection

Figure 2 Tumor and background concentration in an animal model injected with monoclonal antibody labeled with 125I. Background, continuous line;tumors;dotted line; background to tumor ratio, broken line. (From Ref. 14. Copyright 1999 Springer-Verlag. Reprinted by permission of Springer-Verlag GmbH & Co.)

What Breast Attenuation
Figure 3 Advantage of low-energy radiation with 125I: no collimation needed, tissue attenuation, and negligible Compton scattering. (From Ref. 14. Copyright 1999 Springer-Verlag. Reprinted by permission of Springer-Verlag GmbH & Co.)

ratio; a good detector efficiency; and a half-life long enough to accommodate the slow clearing of the complete antibody (Figs. 3 and 4) [17,18].

Carrier Substance

Different antibodies have been tested before the currently used antibody CC49 was chosen, a second-generation anti-TAG-72 tumor-associated glycoprotein. TAG-72 is a pancarcinoma antigen found in colorectal tumors, breast cancer, prostate cancer, and ovarian cancer, as well as in secretory endometrium [19]. The antigen for CC49 has a molecular weight of 200 to 400 kDa2 and is purified

Figure 4 Disadvantage of high-energy radiation: collimation needed, tissue penetration, and Compton scattering. (From Ref. 14. Copyright 1999 Springer-Verlag. Reprinted by permission of Springer-Verlag GmbH & Co.)

from a human colon cancer xenograft used as an immunogen to generate a series of second-generation MoAbs [2].

Surgical Procedure

Patients enrolled in the RIGS study were all diagnosed with recurrent or meta-static colorectal cancer by clinical findings, abdominal computed tomography (CT), or elevated carcinoembryonic antigen (CEA) blood levels in patients who previously underwent surgery for colorectal cancer.

Before enrollment, all patients underwent a CT of the chest to exclude extra-abdominal disease, a CT of the abdomen and pelvis, and colonoscopy. All patients signed an informed consent form approved by the local institutional review board. All patients took a thyroid-blocking agent starting 2 hours before injection and then daily until surgery. This was either a saturated solution of potassium iodide or Thyro-block tablets (Wallace Laboratories, Cranbury, NJ). Patients were injected with 1 mg CC49 (anti-TAG-72 tumor-associated glycopro-tein MoAb) radiolabeled with 125I. The patients were taken to surgery with a precordial count rate of no more than 20 counts per 2 seconds. Such a count rate is usually obtained 3 to 4 weeks after injection and enables good intra-abdominal discrimination between the blood pool background and small tumors, based on 95% correlation between precordial counts and intra-abdominal aortic counts.

Surgery started with traditional exploration of inspection and palpation. To standardize exploration and abdominal assessment, the abdomen was divided into four zones: zone I is the liver; zone II concerns the upper abdomen and includes stomach, spleen, and periportal and celiac lymph nodes (Fig. 5); zone III concerns the midabdomen, including colon, small bowel, kidneys, and lymph nodes along the aorta and vena cava as far as the bifurcation; and zone IV contains the pelvis, including rectum, lymph nodes along both iliac artery and vein, female reproductive organs, and urinary bladder (Fig. 6). CT evaluation before surgery was also performed following the same zonal configuration. In all patients, the liver was examined with intraoperative ultrasound as part of the traditional evaluation. After exploration, the surgeon reported his findings, resectability status, and surgical plan. This was followed by survey with the gamma-detecting probe, Neoprobe 1000.

At the start of the operation, the surgeon ''squelches'' on the aortic bifurcation or any intra-abdominal major blood vessel with a count rate that correlates with the precordial count rate [20]. The blood vessel serves as a reference point ''blood pool background'' for the lymph nodes. For parenchymatous organs such as the liver, the surgeon may also squelch on an adjacent normal-appearing area as a reference point. The surgeon then surveys the abdomen with the probe, and whenever the device emits a continuous sound, he stops and takes three 2-second count readings. Readings that are twice as high as the reference point and greater

Figure 5 The gamma-ray detection probe is brought into contact with the lymph node in the periportal area. The surgeon's finger is inserted in the Winslow's foramen. (From Ref. 30. Copyright 1995 American Cancer Society. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

Suspicious Abdominal Lymph Nodes

Figure 6 Abdominal zones. (From Ref. 21. Copyright 1999 Springer-Verlag. Reprinted by permission of Springer-Verlag GmbH & Co.)

than 20 are considered to be positive. At the end of the survey, the surgeon again reports the surgical findings, resectability status of the patient, and surgical plan. Every suspicious tissue undergoes biopsy or is resected because lymph node involvement in certain cases may cause the surgeon to abandon the intended resection. As shown in previous studies [4], certain RIGS-positive lymph nodes are not always confirmed by H&E staining. Resection was not abandoned based on RIGS-positive lymph nodes without frozen H&E confirmation. Data were analyzed according to abdominal zones and H&E confirmation.

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