A comprehensive overview of radioguided surgery using gamma detection probe technology.

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology.

Radiopharmaceutical management of 90Y/111In labeled antibodies: shielding and quantification during preparation and administration.

BACKGROUND: The combined application of potent beta-emitting isotopes for therapy with remitting isotopes for scintigraphy requires a profound regimen concerning team member safety and radionuclide quantification. METHODS: We have developed materials and methods for a proper and easy manipulation of 90Y during preparation and administration of 90Y/111In pharmaceuticals used for radioimmunotherapy. RESULTS: The efficacy of the shielding measures is documented. Protocols for the calibration of gamma-dose calibrators with respect to 90Y are extended to the assessment of quench-corrected liquid scintillation counting of 90Y. The contribution of 90Y backscatter to 111 In counting is quantified. Newly developed shielding equipment allows an adequate administration of relatively large volumes (100 ml) of 90Y/111In labeled pharmaceuticals to patients. CONCLUSIONS: The procedures described combine pharmaceutical (Good Manufacturing Practice) and radiation safety requirements with an accurate logging of relevant data.

Molecular imaging and radioimmunoguided surgery.

Molecular imaging comprises a series of diagnostic modalities that provide information on the physiology and molecular composition of cells and tissues. One of these modalities, radioimmunodetection, uses radiolabeled monoclonal antibodies (mAbs) to image tissues. Two radioimmunodetection modalities are described in this article: immunoscintigraphy and radioimmunoguided surgery (RIGS). In immunoscintigraphy, the radioactivity is measured with the use of an external gamma camera and used to create images. In RIGS, the radioactivity is detected intraoperatively with the use of a handheld gamma probe to help the surgeon detect foci of otherwise occult disease. Both techniques have the potential to improve the preoperative and intraoperative localization of cancer. Multiple studies have been performed on the efficacy of RIGS on different malignancies, especially colorectal cancer. Despite the good sensitivity of the technique, some concerns revolve around the high rate of false positives and the real significance of leaving RIGS-positive tissue behind in terms of long-term outcomes and survival. More studies are warranted to further develop the technique and determine the specific role it will play on the diagnosis and management of surgical disease. Surgeons should actively participate in these studies and in expanding the applications of this promising technology.

[Nuclear-medical equipment in the Research Institute for Medical Instrument-making]. / Iaderno-meditsinskaia apparatura v NII Meditsinskogo priborostroeniia.

The activity of the department for emission introscopy of the Research Institute for Medical Instrument-Making ("ZAO VNIIMP-VITA") is described in the article. A list of developed and commissioned devices and instruments for the field of nuclear medicine is presented. Methods of elaboration of some sophisticated instruments and units designed for radio-biochemical and radio-immunologic examinations as well as methods of elaboration of scintillation gamma cameras, tomograph GKS-301T, medical dosimeters and of other devices are also described.

Radioimmunodetection of cervical carcinoma xenografts with (111)In-labeled MAb Cx-99 detected by a hand-held gamma detector.

PURPOSE: To establish a radioimmunodetection (RAID) system for localization of cervical cancer by labeling 111-indium ((111)In) to a monoclonal antibody against cytokeratin 19 (MAb Cx-99), and detecting it with a hand-held gamma detector in an animal model. METHODS: MAb Cx-99 was labeled with 111-Indium by the DTPA chelating method. From the second day to the seventh day after injection of this immunoconjugate into athymic nude mice bearing cervical cancer cell line CC7T xenografts, the biodistribution ratios of tumor and non-tumor radioactivity were detected by a hand-held gamma detector. Data were also correlated with the data detected by the conventional gamma counter. RESULTS: The labeling efficiency of this (111)In-labeled MAb Cx-99 and (111)In-labeled MOPC was 91.6% and 95.5%, respectively. After injection, the liver, kidney and lung were initially noticed to have high radioactivity, but the localization of tumor/tissue ratios increased progressively as time passed, indicating the effect of delayed detection for distinguishing tumor from non-tumor tissues. Except for the spleen, the range of tumor/tissue ratios was 1.18-32.7 and 1.14-39.35 for the fourth day and the seventh day, respectively. The tumor/spleen ratio remained low until the seventh day after injection, thus indicating that the spleen might have a different excretion rate. CONCLUSION: This study indicated the feasibility of a hand-held detection system in the localization of cervical cancer after injection of (111)In-labeled MAb Cx-99. The effect of delayed detection was obvious by the decreasing high bindings in the liver, spleen and kidney, with the applicable detection time being four to seven days after injection.

Probe-guided surgery for colorectal cancer.

Anti-CEA-scintigraphy turned out to be very reliable in detecting primary and recurrent colorectal cancer, its overall accuracy being more than 90%. The intraoperative application of this technology should provide similar results when focussing at extrahepatic tumor deposits, for example in lymph nodes, thus allowing accurate staging of the underlying disease. To test this hypothesis we launched the following feasibility study the results of which are compared to those reported in the recent literature. We investigated 20 patients, six with rectum and 14 with colon cancer. 24 hours before surgery they were intravenously given 1 ml of a fab'-fragment-antibody to CEA, labeled with 25 mCi of 99mTc (CEA-Scan). During surgery the radioactivity in lymph glands regional to the tumors was measured and compared to the much lower activity in healthy nodes. For this we used a scintillation probe (C-Trak, Care Wise, Inc., Morgan Hill, CA). All lymph nodes of interest were then excised and submitted to frozen section pathology. In 7 out of 20 cases scintimetry led to an up-staging of the disease. In addition we found metastatic spread to lymph nodes that were basically not regional to the primary tumor (retroperitoneum, renal hilum etc.). Scintimetry can precisely identify even very small tumor deposits. So it leads to accurate staging while surgery is still ongoing. In a further step the concept of sentinel node diagnosis, which is right now being clinically evaluated, may some day be applied in colorectal surgical oncology.

Identification of lymph node metastases in recurrent colorectal cancer.

Lymph node metastases are an important prognostic prediction factor in patients with recurrent colorectal cancer, particularly those with liver metastasis. Fifty-six patients with recurrent colorectal cancer were operated by us using the RIGS (radioimmunoguided surgery) technology. Patients were injected with 1 mg monoclonal antibody (MoAb) CC49 labeled with 2 mCi 125I. In surgery, traditional exploration was followed by survey with a gamma-detecting probe. Sixty of 151 patients enrolled in the Neo2-14 Phase III study for recurrent colorectal cancer were diagnosed with liver metastases based on preoperative CT. In 17/56 patients (30%), RIGS identified at least one tumor site confirmed by pathology (H&E). This resulted in 16 major changes in surgical plan. RIGS performance varied between lymphatic and non-lymphatic tissue, with positive predictive value (PPV) of 100% and negative predictive value (NPV) of 94% for non-lymphoid tissue, compared to PPV of 46.5% and NPV of 100% for the lymphoid tissue. Thirty-five out of 60 patients were considered resectable after traditional evaluation. RIGS identified occult tumor in 10 of these patients (28.5%). 7/10 occult patients expired (70%), while only 7/25 of the non-occult patients expired (28%) (P = 0.046). In localizing patients, no RIGS activity in lymph nodes signifies no tumor, while H&E confirmation is needed for decisions based on RIGS activity in the lymph nodes. RIGS provides important staging information, identifying patients for whom surgery may be done with curative intent.

Tracing an unhandled suspect lesion through a gamma probe.

This article describes the efforts of the authors in developing a handheld gamma detection probe and addresses a tentative surgical protocol for tracing an unhandled suspect lesion through an albumine-aggregate 99Tcm tracer operative mapping. The electronic and software design for the system is discussed as well as its electronic and nuclear calibration. A phantom model mimicking a breast was built in order to help in the calibration of the system. Earliest results in an external detection procedure using the model and a 0.3 ml tracer sample (7 MBq activity) are presented.

Intraoperative probes and imaging probes.

Intraoperative probes have been employed to assist in the detection and removal of tumors for more than 50 years. For a period of about 40 years, essentially every detector type that could be miniaturized had been tested or at least suggested for use as an intraoperative probe. These detectors included basic Geiger-Müller (GM) tubes, scintillation detectors, and even state-of-the-art solid state detectors. The radiopharmaceuticals have progressed from (32)PO(4)(-) injections for brain tumors to sophisticated monoclonal antibodies labeled with iodine-125 for colorectal cancers. The early work was mostly anecdotal, primarily interdisciplinary collaborations between surgeons and physical scientists. These collaborations produced a few publications, but never seemed to result in an ongoing clinical practice. In the mid 1980s, several companies offered basic gamma-detecting intraoperative probes as products. This led to the rapid development of radioimmunoguided surgery (RIGS) and sentinel node detection as regularly practiced procedures to assist in the diagnosis and treatment of cancer. In recent years intraoperative imaging probes have been developed. These devices add the ability to see the details of the detected activity, giving the potential of using the technique in a low-contrast environment. Intraoperative probes are now established as clinical devices, they have a commercial infrastructure to support their continued use, and there is ongoing research, both commercial and academic, that would seem to ensure continued progress and renewed interest in this slowly developing field.

Clinical applications of gamma-detection probes - radioguided surgery.

Radioguided surgery (RGS) is a surgical technique that enables the surgeon to identify tissue "marked" by a radionuclide before surgery, based on the tissue characteristics, the radioactive tracer and its carrying molecule, or the affinity of both. Thus, yet another tool has been added to the inspection and palpation traditionally used by the surgeon. Current clinical applications of radioguided surgery are: radioimmunoguided surgery (RIGS) for colon cancer, sentinel-node mapping for malignant melanoma (which has become state-of-the-art), sentinel-node mapping for breast, vulvar and penile cancer, and detection of parathyroid adenoma and bone tumour (such as osteid osteoma). Although the same gamma-detecting probe (GDP) may be used for all these applications, the carrier substance and the radionuclide differ. MoAb and peptides are used for RIGS, sulphur colloid for sentinel-node mapping, iodine-125 for RIGS, technetium-99m for sentinel node, parathyroid and bone. The mode of injection also differs, but there are some common principles of gamma-guided surgery. RIGS enables the surgeon to corroborate tumour existence, find occult metastases, and assess the margins of resection; this may result in a change on the surgical plan. Sentinel lymph-node (SLN) scintigraphy for melanoma guides the surgeon to find the involved lymph nodes for lymph-node dissection. SLN for breast cancer is being investigated with promising results. This procedure has also changed the outlook of lymph-node pathology by giving the pathologist designated tissue samples for more comprehensive examination. Gamma-guided surgery will result in more accurate and less unnecessary surgery, better pathology and, hopefully, in better patient survival.

The radioimmunoguided surgery (RIGS) system as a diagnostic tool.

Radioimmunoguided surgery (RIGS) was developed to improve on the intraoperative detection of malignancy. The RIGS system uses a hand-held gamma radiation detection probe to identify radioactive tissues targeted by a preadministered tumor-associated radiolabeled targeting antibody or peptide. Clinical experience with RIGS in colorectal cancer has been favorable; better intraoperative staging has provided the surgeon more information regarding the pattern of disease and individual patients. Pancreatic, breast, ovarian, and prostate cancer have also been studied in clinical trials using RIGS and early results are encouraging. In the future, marked improvements with the RIGS system will be realized with the development of better targeting agents.

Noninvasive detection of atherosclerotic lesions by 99mTc-based immunoscintigraphic targeting of proliferating smooth muscle cells.

BACKGROUND: Mouse/human chimeric antibody Z2D3 identifies an antigen produced exclusively by proliferating smooth muscle cells of human atheroma, and also cross reacts with experimentally induced atherosclerotic lesions in rabbits. Fab' fragments of Z2D3 antibody were labeled with (99m)Tc using glucaric acid as a weak transchelator. The potential role of (99m)Tc-labeled Z2D3 scintigraphy was explored for noninvasive imaging of experimental atherosclerotic lesions. METHODS AND RESULTS: (99m)Tc-Z2D3 Fab' was utilized for noninvasive imaging in four rabbits with experimentally induced atherosclerotic lesions and in one control rabbit. In addition, (99m)Tc-labeled nonspecific 103D2 Fab' was used for comparison in four other rabbits with atherosclerotic lesions. The atherosclerotic lesions were induced by balloon de-endothelialization of the infradiaphragmatic abdominal aorta and 12 weeks of hyperlipidemic diet. An aliquot of 15 mCi (550 mBq) of (99m)Tc pertechnetate was incubated with 6.25 mg of glucaric acid for 30 min followed by incubation of (99m)Tc glucarate with 375 microg of Z2D3 Fab' or 103D2 Fab' for an additional 30 min. Instant thin-layer chromatography demonstrated almost complete radiolabeling. (99m)Tc-Z2D3 was administered IV and gamma imaging was performed at the time of injection, 3, 6, 9, and 12 h, followed by ex vivo imaging of the excised aorta, and biodistribution was performed. Unequivocal visualization of atherosclerotic lesions was possible in all four animals at 9 to 12 h with Z2D3 Fab'. Quantitative uptake, as represented by mean lesion-to-liver count density ratio, was 0.6+/-0.05. Imaging with nonspecific 103D2 Fab' did not show any localization in the abdominal aorta (lesion-to-liver ratio, 0.45+/-0.02, p=0.02). Ex vivo lesion-to-normal aortic segment ratio was 4.3+/-0.9 for Z2D3 and 1.04+/-0.08 for nonspecific 103D2 Fab' (p=0.01). Biodistribution studies demonstrated 0.03+/-0.003% injected Z2D3 dose per gram in the atherosclerotic lesions as compared with 0.01+/-0.003% in the nondenuded thoracic aorta of atherosclerotic rabbits (p=0.008). However, only 0.008+/-0.002% of the mean injected dose per gram was obtained in the atherosclerotic lesions (p=0.001) as compared with 0.005+/-0.003% in the normal aortic segments with 103D2. No Z2D3 uptake in normal rabbits was observed on either the in vivo or ex vivo images. CONCLUSIONS: The present study demonstrates that (99m)Tc-based immunoimaging of the vascular lesions may be feasible by the use of smaller antibody fragments. Earlier visualization is possible at the expense of a lower absolute antibody uptake in the lesions as compared to the use of intact antibody or larger fragments with longer circulating time.

[The development and application of an hand-held gamma detecting probe].

A new device for tumor to perform radioimmunoguided surgery (RIGS) was described, The instrument was based on the inverse square law that the sensitive and specificity of the detector increase as the distance between the source and the detector shorted. The experimental results showed that the hand-held gamma detecting probe was practical to perform radioimmuoguided surgery for tumor in vivo.

Radiolabeled monoclonal antibodies in diagnosis and therapy of cancer. Summary and perspectives.

The papers of the 4th Scandinavian Symposium on Radiolabeled Monoclonal Antibodies in Diagnosis and Therapy of Cancer are summarised. Particular emphasis is placed on quantitation, dosimetry and radionuclide therapy. Some biological aspects of radionuclide therapy are indicated.

Anti-CEA labelling kit BW 431/26. Results of the European multicenter trial.

In seven European countries a multicenter trial with the 99mTc-labelled monoclonal anti-CEA antibody BW 431/26 was conducted in 730 patients. The antibody is used for the immunoscintigraphic visualisation of CEA-expressing tumours. Investigated were in particular colorectal tumours, bladder and breast carcinoma, medullary thyroid carcinoma, adenocarcinoma of the lung and gastric carcinoma. The main area of use is the detection of recurrences and screening for foci in patients with rising serum CEA. The sensitivity amounts to at least 80% in case of primary colorectal tumours (n = 129) and their abdominal or pelvic metastases (n = 33) and to 90% for their recurrences (n = 107). HAMAs were detectable in less than 15% of patients investigated for the first time. In 17% of the patients examined, immunoscintigraphy was the only technique to visualize the lesion whereas all other diagnostic methods had failed. The procedure yielded additional information in 24-51% of cases.

Radioimmunoguided Surgery system improves survival for patients with recurrent colorectal cancer.

BACKGROUND: Advanced colorectal cancer is fatal. No systemic therapies have resulted in increased patient survival. METHODS: One hundred thirty-one patients with recurrent colorectal cancer enrolled in two prospective nonrandomized studies using Radioimmunoguided Surgery (RIGS) system from May 1986 to April 1992 have been analyzed. Eighty-six patients were injected with the anti-tumor-associated glycoprotein (TAG) antibody B72.3, and 45 patients were injected with the second-generation anti-TAG monoclonal antibody CC49. Both monoclonal antibodies were radiolabeled with iodine 125. Both traditional and RIGS explorations were used to determine resectability. Follow-up was a minimum of 28 months. RESULTS: Forty-nine (37.4%) of the 131 patients underwent a curative resection. Twenty-seven of the patients (55%) are alive 2 to 8 years after operation. The cancers of the remaining 82 patients were unresectable, and only two patients (2%) are alive. In this unresectable group alternative intraoperative therapeutic methods (intraoperative radiation therapy, intraperitoneal hyperthermic perfusion, hepatic lines, and brachytherapy) were tried in 11 patients with two survivors. There were no survivors in 18 patients whose cancers were found to be traditionally resectable but unresectable with RIGS or in the 53 patients whose cancers were clearly unresectable by traditional exploration. Patients selected for curative resection had significantly increased survival (p < 0.0001). CONCLUSIONS: As an intraoperative tool RIGS significantly improves the selection of patients for curative resection.

Fluorine-18-fluorodeoxyglucose-guided breast cancer surgery with a positron-sensitive probe: validation in preclinical studies.

UNLABELLED: In this study, the feasibility of utilizing 2-deoxy-2-fluoro-d-glucose (FDG) in conjunction with a positron-sensitive intraoperative probe to guide breast tumor excision was investigated. METHODS: The probe was constructed with a plastic scintillator tip coupled to a photomultiplier tube with fiber optic cable. Anticipated resolution degradation was evaluated by measurement of line spread functions in the presence of background radiation. Realistic photon background distributions were simulated with a human torso phantom and a cardiac insert. The relationship between resolution and energy threshold was measured to find the optimal discriminator settings. In addition, probe sensitivity as a function of energy threshold was determined for various size-simulated tumors. Finally, the ability to localize breast cancers in vivo was tested in a rodent model. Mammary rat tumors implanted in Lewis rats were examined after injection with FDG; these results were correlated with those of histologic analyses. RESULTS: Measurements of line spread functions indicated that resolution could be maximized in a realistic background photon environment by increasing the energy threshold to levels at or above the Compton continuum edge (340 keV). At this setting, the probe's sensitivity was determined to be 58 and 11 cps/muCi for 3.18- and 6.35-mm diameter simulated tumors, respectively. Probe readings correlated well with histologic results: the probe was generally able to discriminate between tumor and normal tissue. CONCLUSION: This study indicates that breast cancer surgery guided by a positron-sensitive probe warrants future evaluation in breast-conserving surgery of patients with breast cancer.

A fiber-optically coupled positron-sensitive surgical probe.

UNLABELLED: Positron-emitting radiopharmaceuticals such as 18F-labeled 2-deoxy-D-glucose (FDG) have considerable utility in the noninvasive imaging of cancers due to their rapid and excellent tumor-localizing properties. In addition, the relatively short range of positions in tissue facilitates the precise delineation of FDG-avid tumors. Therefore, FDG used in conjunction with a positron-sensitive probe may be capable of guiding surgical procedures. Many of the current probe systems, however, are sensitive to the intense flux of background photons produced by positron annihilation. We describe the design, manufacture and initial in vitro and in vivo testing of a probe well-suited to the detection of positron-emitting isotopes in a high-photon background. METHODS: The device consists of a small piece of plastic scintillator coupled by fiber-optic cable to a photomultiplier tube. Measurements of resolution and detector sensitivity were obtained. In addition, the reduction in resolution caused by the effects of various levels of background photon flux was determined. RESULTS: These measurements indicate that resolution is degraded minimally (approximately 5% with a background-to-source ratio of 2:1) due to annihilation photon background. Sensitivity for positrons is good, detecting amounts of radioactivity as low as 10.2 nCi of FDG in vitro. In rats given FDG subcutaneously, lymph nodes containing as little as 11 nCi of FDG could be detected above the background activity levels present in normal surrounding tissues. CONCLUSION: A plastic scintillator probe system has been devised which may be highly suitable for intraoperative FDG-guided (or other positron or beta emitting-tracer) surgery.