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Annals of Surgery Dec 1992Radioimmunoguided surgery (RIGS) has been employed intraoperatively in cases of colorectal cancer to assess the extent of local tumor spread and metastatic disease. This...
Radioimmunoguided surgery (RIGS) has been employed intraoperatively in cases of colorectal cancer to assess the extent of local tumor spread and metastatic disease. This technique uses radiolabeled monoclonal antibodies (MAbs) directed against tumor-associated antigens, and a hand-held gamma-detection probe to detect the radiolabel fixed to tumor tissue. Recently introduced is an MAb directed against tumor-associated glycoprotein (anti-TAG), CC49. Sixty patients were entered into the initial study. Eighteen of 21 (86%) primary tumors were localized by the CC49 MAb and the gamma-detecting probe. Twenty-nine of 30 (97%) recurrent tumors were localized. Antibody dose did not affect localization. Specimens were divided into tissue types I through IV, based on antibody localization and hematoxylin and eosin (H&E) staining: type I, RIGS (-) and histologically (-); type II, RIGS (-) and histologically (+); type III, RIGS (+) and histologically (-); type IV, RIGS (+) and histologically (+). Type IV tissue were further classified by whether they were grossly apparent, IVa, or grossly inapparent, IVb (occult). Occult tumor found by RIGS and confirmed by H&E staining (type IV) had localization ratios similar to RIGS-positive, histology-negative tissue (type III). Traditionally found cancer (type IV) had significantly higher ratios. In 12 of 24 patients (50%) with primary tumors and 14 of 30 patients (47%) with recurrent tumors, RIGS with CC49 altered the planned operative procedure. Radioimmunoguided surgery with CC49 provides useful, immediate intraoperative information not available by other techniques.
Topics: Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; Female; Humans; Intraoperative Period; Iodine Radioisotopes; Male; Middle Aged; Radioimmunodetection
PubMed: 1466615
DOI: 10.1097/00000658-199212000-00003 -
Journal of Nuclear Medicine : Official... Dec 1994One of the limitations of intraoperative tumor detection with radiolabeled monoclonal antibody (Mab), by means of a gamma-detecting probe (GDP), is the long time... (Clinical Trial)
Clinical Trial
UNLABELLED
One of the limitations of intraoperative tumor detection with radiolabeled monoclonal antibody (Mab), by means of a gamma-detecting probe (GDP), is the long time interval needed between Mab injection and surgery to obtain low blood-pool activity. Such an interval can be shortened considerably, exploiting the high affinity between avidin and biotin.
METHODS
Twenty patients with colorectal cancer were injected with 1 mg of biotinylated 125I monoclonal antibodies followed, 48 hr later, by a chase of cold avidin. During surgery, the GDP was used to detect radioactive emissions from the tumor and normal tissue. Tumor tissue samples were analyzed in vitro by immunohistochemical tests for the presence of tumor antigens and in vivo antibody localization.
RESULTS
At the time of surgery (average 7 days postinjection), the mean value of circulating radioactivity was 6% +/- 3% of the injected dose. Of 20 patients studied, tumors were localized in 13 cases (65%). Subclinical tumors were detected in 3 patients (15%).
CONCLUSION
The use of 125I-labeled biotinylated Mabs followed by avidin as a chase enhances the applicability and effectiveness of radioimmunoguided surgery technology and will allow the use of radioisotopes with a shorter half-life than 125I.
Topics: Antibodies, Monoclonal; Avidin; Biotin; Colonic Neoplasms; Colorectal Neoplasms; Half-Life; Humans; Iodine Radioisotopes; Monitoring, Intraoperative; Radioimmunodetection; Rectal Neoplasms
PubMed: 7989979
DOI: No ID Found -
Disease Markers 2000Single chain Fv antibodies (sFvs) have been produced from filamentous bacteriophage libraries obtained from immunised mice. MFE-23, the most characterised of these sFvs,... (Review)
Review
Single chain Fv antibodies (sFvs) have been produced from filamentous bacteriophage libraries obtained from immunised mice. MFE-23, the most characterised of these sFvs, is reactive with carcinoembryonic antigen (CEA), a glycoprotein that is highly expressed in colorectal adenocarcinomas. MFE-23 has been expressed in bacteria and purified in our laboratory for two clinical trials; a gamma camera imaging trial using 123I-MFE-23 and a radioimmunoguided surgery trial using 125I-MFE-23, where tumour deposits are detected by a hand-held probe during surgery. Both these trials show MFE-23 is safe and effective in localising tumour deposits in patients with cancer. We are now developing fusion proteins which use MFE-23 to deliver a therapeutic moiety; MFE-23::CPG2 targets the enzyme carboxypeptidase G2 (CPG2) for use in the ADEPT (antibody directed enzyme prodrug therapy) system and MFE::TNF alpha aims to reduce sequestration and increase tumor concentrations of systemically administered TNF alpha.
Topics: Clinical Trials as Topic; Genes, Immunoglobulin; Humans; Immunoglobulin Fragments; Immunoglobulin Variable Region; Peptide Library; Recombinant Fusion Proteins
PubMed: 11360829
DOI: 10.1155/2000/672706 -
International Journal of Molecular... 2012Breast-conserving surgery involves completely excising the tumour while limiting the amount of normal tissue removed, which is technically challenging to achieve,...
Breast-conserving surgery involves completely excising the tumour while limiting the amount of normal tissue removed, which is technically challenging to achieve, especially given the limited intraoperative guidance available to the surgeon. This study evaluates the feasibility of radioimmunoguided surgery (RIGS) to guide the detection and delineation of tumours intraoperatively. The 3D point-response function of a commercial gamma-ray-detecting probe (GDP) was determined as a function of radionuclide ((131)I, (111)In,( 99m)Tc), energy-window threshold, and collimator length (0.0-3.0-cm). This function was used to calculate the minimum detectable tumour volumes (MDTVs) and the minimum tumour-to-background activity concentration ratio (T:B) for effective delineation of a breast tumour model. The GDP had larger MDTVs and a higher minimum required T:B for tumour delineation with (131)I than with (111)In or (99m)Tc. It was shown that for (111)In there was a benefit to using a collimator length of 0.5-cm. For the model used, the minimum required T:B required for effective tumour delineation was 5.2 ± 0.4. RIGS has the potential to significantly improve the accuracy of breast-conserving surgery; however, before these benefits can be realized, novel radiopharmaceuticals need to be developed that have a higher specificity for cancerous tissue in vivo than what is currently available.
PubMed: 22518303
DOI: 10.1155/2012/545034 -
International Journal of Cancer Feb 2002Biparatopic CEA, carcinoembryonic antigen (MAb) was newly designed and tested as to whether it enhanced the accuracy of tumor detection by reducing non-specific binding... (Comparative Study)
Comparative Study
Biparatopic CEA, carcinoembryonic antigen (MAb) was newly designed and tested as to whether it enhanced the accuracy of tumor detection by reducing non-specific binding in experimental radioimmunoguided surgery. Biparatopic MAb was prepared by using cross-linking of reduced Fab' fragments from PR1A3 and T84.66. Fifty-nine tumors from 2 human colorectal carcinoma cell lines with high (KM-12c) and low (Clone A) carcinoembryonic antigen (CEA) expression were successfully implanted subcutaneously on the backs of 42 nude mice. Tumors were localized using 125I-labeled MAbs: IgG, F(ab')(2) and Fab' of PR1A3, and biparatopic MAb of PR1A3 and T84.66. Radioactivity counted on a portable radioisotope detector correlated well with that counted on a gamma counter (p < 0.001). Accumulations of radioactivity in control mice without tumorigenesis were the greatest in PR1A3 IgG-pretreated mice and the least in biparatopic MAb-pretreated mice. Tumors of 2 cell lines did not differ in the distribution of radiolabeled MAbs. Localization indices of the tumor in various organs revealed 1.3 to 4.1 in PR1A3 IgG-pretreated mice, 2.4 to 6.6 in fragment MAbs of PR1A3-pretreated mice and 2 to 4.6 in biparatopic MAb-pretreated mice. Silver grains and immune staining were predominantly distributed in tumor cells of all types of MAb-pretreated mice. Sensitivity and specificity of tumor localization by radioimmunoguided surgery (RIGS) were the highest in the biparatopic MAb-pretreated mice (90.9% and 94.5%, respectively) and the least in the PR1A3 IgG-pretreated mice (50% and 72%). The biparatopic MAb using 2 anti-CEA MAbs against different epitopes achieved a great affinity and avidity with accurate localization of colorectal carcinoma in experimental radioimmunoguided surgery.
Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Antibody Specificity; Biomarkers, Tumor; Carcinoembryonic Antigen; Colorectal Neoplasms; Epitopes; Immunoglobulin Fab Fragments; Immunoglobulin G; Iodine Radioisotopes; Mice; Mice, Nude; Neoplasm Proteins; Neoplasm Transplantation; Protein Structure, Tertiary; Radioimmunodetection; Radiometry; Sensitivity and Specificity; Surgery, Computer-Assisted; Technetium; Tissue Distribution; Transplantation, Heterologous; Tumor Cells, Cultured
PubMed: 11802220
DOI: 10.1002/ijc.1630 -
Anticancer Research 2004Radioimmunoguided surgery (RIGS) appears as an efficient tool for accurate tumor detection up to the level of micrometastases by detecting radiolabeled antibody-bound...
BACKGROUND
Radioimmunoguided surgery (RIGS) appears as an efficient tool for accurate tumor detection up to the level of micrometastases by detecting radiolabeled antibody-bound tumor cells during operation. Anti-CEA-specific T84.66 fragments were examined as to whether they efficiently detected gastric cancer cells in experimental RIGS. T84.66, anti-CEA-specific antibody, has widely been used as an immune carrier in the preclinical and clinical trials of radioimmunotherapy and radioimmunoscintiscan.
MATERIALS AND METHODS
Fifty-one tumors from two human gastric carcinoma cell lines with profuse (MKN45) and low (RF48) CEA expression were successfully implanted subcutaneously in the backs of 32 nude mice. Tumors were localized after 125I-labeled T84.66 F(ab')2 and Fab' injection.
RESULTS
The radioactivity of F(ab')2-pretreated mice was greater than that of Fab'-pretreated in all organs and tumors (p<0.001-0.035). Localization indices of the tumor in various organs revealed 7.4 to 32.5 in F(ab')2-pretreated and 1 to 7.1 in Fab'-pretreated mice. Silver grains and immune staining were predominantly distributed in tumor cells regardless of fragment types and cell lines. There was no false-negative evaluation of tumor in F(ab')2-pretreated mice. Sensitivity and specificity of tumor localization by RIGS were the highest in the F(ab')2-pretreated mice (95% for MKN45- and 82% for RF46-xenografted mice) and the least in the Fab'-pretreated mice (66% for MKN45- and 67% for RF46-xenografted mice). In all organs, three quarters of the false-positive evaluations occurred from silver grains as radioimmune complex or dissociated nuclides in the circulation that can be eliminated with time.
CONCLUSION
Anti-CEA-specific T84.66 fragments achieved a great affinity and avidity with accurate localization of gastric carcinoma in experimental RIGS.
Topics: Animals; Autoradiography; Carcinoembryonic Antigen; Female; Humans; Immunoconjugates; Immunoglobulin Fragments; Iodine Radioisotopes; Mice; Mice, Nude; Radionuclide Imaging; Stomach Neoplasms; Xenograft Model Antitumor Assays
PubMed: 15161009
DOI: No ID Found -
Cancer Control : Journal of the Moffitt... Jan 1996Several therapeutic options are available for the treatment of rectal cancer. To determine the most appropriate method of treatment, Radioimmunoguided Surgery (RIGS) can...
Several therapeutic options are available for the treatment of rectal cancer. To determine the most appropriate method of treatment, Radioimmunoguided Surgery (RIGS) can be used as an intraoperative diagnostic tool and as an adjuvant to traditional methods for more accurate staging. RIGS employs radiolabeled monoclonal antibodies directed against tumor-associated antigens and a gamma-detection probe to discriminate between normal and abnormal tissue. Most patients with primary or recurrent rectal cancer are considered good candidates for surgery using RIGS scanning. Use of the RIGS system may result in improved patient survival through accurate assessment of extent of disease and the selection of appropriate therapy. Prospective studies are necessary to define the optimal use of this approach as an experimental and clinical tool.
PubMed: 10825275
DOI: 10.1177/107327489600300105 -
Bulletin Du Cancer Nov 2000Following 15 years of experimental studies, tumor immunotargeting using monoclonal antibodies directed against tumor associated antigens shows now important monoclonal... (Review)
Review
Following 15 years of experimental studies, tumor immunotargeting using monoclonal antibodies directed against tumor associated antigens shows now important monoclonal antibodies directed against tumor associated antigens shows now important clinical developments. This is mainly due to encouraging therapeutic results which have obtained using humanized antibodies such as the anti-CD20 rituximab in follicular B lymphomas and the anti-DrbB2 herceptin in breast carcinomas. Thanks to genetic engineering it is possible to graft variable or hypervariable regions from murine antibodies to human IgG, and even to obtain fully human antibodies by using either transgenic mice containing a large part of the human repertoire of human IgG, or selection of human antibody fragments expressed by phages. Radiolabeling of antibodies played a major role to demonstrate the tumor immunotargeting specificity and remains attractive for the diagnosis by immunoscintigraphy as well as for the treatment by radioimmunotherapy of some cancers. In this review, the current results and the prospects of diagnostic and therapeutic uses of anti-tumor antibodies and their fragments will be described. Concerning diagnosis, 123-iodine or 99m-technetium labeled Fab fragments allowed very demonstrative tumor images but this technique has a limited effect upon the therapeutic attitude. Immuno-PET (positron emission tomography) could enhance the sensitivity of this imaging method. Radio-immunoguided surgery and immunophotodetection are attractive techniques still under evaluation. Concerning therapy, 131-iodine labeled anti-CD20 antibodies gave spectacular results in non-Hodgkin's B lymphomas. In solid tumors which as less radiosensitive, radioimmunotherapy could concern small tumors and need the use of two-steps targeting and/or alpha emitters radioisotopes. Some other strategies will be described such as bispecific antibodies directed against tumors and immune effector cells, some antibody fragments expressed on T cells called T-bodies or some biological studies using intrabodies. Published data and works in progress demonstrate that immunotargeting of tumors will have a growing place in the treatments of cancer patients.
Topics: Animals; Antibodies, Bispecific; Antibodies, Monoclonal; Bacteriophages; Genetic Engineering; Humans; Immunoglobulin Fragments; Immunotoxins; Interprofessional Relations; Liposomes; Mice; Neoplasms; Radioimmunotherapy; Radiopharmaceuticals; Technology Transfer; Tomography, Emission-Computed
PubMed: 11125287
DOI: No ID Found -
Journal of Nuclear Medicine : Official... Jul 1998Previous studies of the intraoperative use of a handheld gamma probe to localize metastases and primary tumors of colorectal cancer have shown improved assessment of... (Comparative Study)
Comparative Study
UNLABELLED
Previous studies of the intraoperative use of a handheld gamma probe to localize metastases and primary tumors of colorectal cancer have shown improved assessment of tumor spread and changes in surgical management based on added information gained by radioimmunoguided surgery. We conducted a prospective study to determine whether intraoperative radiodetection is able to reveal microscopic and occult disease of neuroendocrine tumors [medullary thyroid carcinomas (MTCs), gastroenteropancreatic (GEP) tumors].
METHODS
After the injection of 180 MBq [111In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe1]pentetreotide and/or 500 MBq 99mTc-dimercaptosuccinic acid (DMSA) (both for double-nuclide scintigraphy), preoperative somatostatin receptor imaging (12 patients with GEP tumors) and double-nuclide scintigraphy (10 patients with relapsing MTCs were performed. The results were combined with the information obtained from conventional imaging modalities (CT and sonography). Intraoperative radiodetection was performed 24 hr after administration of [111In-DTPA-D-Phe1]pentetreotide or 4 hr after the injection of 99mTc-DMSA using a handheld gamma probe.
RESULTS
Intraoperative gamma counting localized 70 somatostatin receptor-positive lesions of GEP tumors, whereas preoperative receptor imaging visualized 74%, surgical palpation visualized 44% and radiological imaging modalities localized only 43%. In 10 patients with recurrent MTCs, the surgeon was successful in localizing and removing 30 tumor lesions using the gamma probe. Twenty-seven of 30 lesions demonstrated tumor involvement, whereas 3 lesions were false-positive (lymphadenitis). Double-nuclide scintigraphy revealed 67% (Octreoscan, 7 of 20; 99mTc-DMSA, 13 of 20), surgical palpation revealed 60% and conventional imaging methods (CT, sonography) revealed only 50% of all lesions detected intraoperatively by the handheld gamma probe. The smallest lesion identified by the handheld probe (not palpated by the surgeon) was a lymph node metastasis (5-mm diameter).
CONCLUSION
The preliminary data show that intraoperative handheld gamma probe detection of microscopic and occult endocrine tumors is feasible and more sensitive than external scintigraphy and conventional imaging.
Topics: Carcinoma, Medullary; Diagnostic Imaging; Digestive System Neoplasms; Feasibility Studies; Female; Humans; Indium Radioisotopes; Intraoperative Care; Male; Middle Aged; Neoplasm Recurrence, Local; Neuroendocrine Tumors; Prospective Studies; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin; Technetium Tc 99m Dimercaptosuccinic Acid; Thyroid Neoplasms
PubMed: 9669386
DOI: No ID Found -
Annals of Surgery Sep 1991Eighty-six colorectal cancer patients who entered the Radioimmunoguided Surgery (RIGS) protocol study were evaluated for 2-, 3-, 4-, and 5-year survival following...
Eighty-six colorectal cancer patients who entered the Radioimmunoguided Surgery (RIGS) protocol study were evaluated for 2-, 3-, 4-, and 5-year survival following second-look surgical procedures. Strict preoperative evaluation criteria eliminated patients with extra-abdominal tumor involvement. A saturated potassium iodide preparation was given before the intravenous administration of the B72.3 monoclonal antibody (1 mg) radiolabeled with 2 mCi of iodine-125 by the IODOGEN method. Precordial monitoring of the biologic clearance by the handheld, gamma-detecting probe (Neoprobe 1000 instrument) was conducted at weekly intervals until the average count was less than 20 counts in 2 seconds. Once the drug cleared from the blood, surgery was performed. The mean time interval between injection and operation was 24 days, with a range of 21 to 28 days and a median of 23 days. At surgery the abdomen was explored through the traditional methods of palpation and inspection, and the surgeon committed to a planned procedure. The abdomen was then re-explored with the handheld, gamma-detecting probe and the surgeon stated another intraoperative assessment. After using both traditional and RIGS detection methods, the surgeon stated whether his or her surgical plans changed because of the additional intraoperative information provided by the RIGS system. Fifty-three patients (62%) were deemed resectable by the traditional methods of palpation and inspection, but only 40 (47%) were specified as resectable by RIGS exploration. Two-, three-, four-, and five-year survival data could be gathered for each of the three groups: RIGS resectable (n = 40), traditional nonresectable (n = 33), and RIGS nonresectable (n = 13). At 2 years 95% of the resectable, 36% of the traditional nonresectable, and 53% of RIGS nonresectable patients survived. At 3 years 83%, 7%, and 30% of these patients survived, respectively. For the resectable patients, 74% survived at 4 years and 60% at 5 years, with no survivors from either nonresectable group. Use of the RIGS system increased accurate selection of resectable patients undergoing second-look surgery for recurrent colorectal cancer.
Topics: Antibodies, Monoclonal; Carcinoembryonic Antigen; Colorectal Neoplasms; Follow-Up Studies; Humans; Neoplasm Recurrence, Local; Preoperative Care; Reoperation; Survival Rate; Time Factors
PubMed: 1929612
DOI: 10.1097/00000658-199109000-00014