Current status of commercial colloidal preparations for sentinel lymph node detection.
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Female↗
Biomedical subjects
M Chinol
Publications and source records attributed to M Chinol.
Improved tumor targeting of rhenium-186-labeled anti-human high-m.w. melanoma-associated antigen monoclonal antibody 763.74 following purification with anti-idiotypic monoclonal antibody MK2-23.
Because of its high-energy beta emissions and imageable gamma emissions, 186Re represents an attractive isotope to radiolabel monoclonal antibodies (MAbs) recognizing human tumor-associated antigens (TAAs) for radioimmunoscintigraphy (RIS) and radioimmunotherapy (RIT) of patients with malignant diseases. Application of 186Re, however, is hindered by the frequent denaturation of MAbs following exposure to the strong reducing conditions employed in the labeling procedures. To overcome this problem, we have utilized a direct labeling procedure and combined it with affinity chromatography over columns of immobilized anti-idiotypic (anti-id) MAbs which recognize idiotopes in the antigen-combining site of the radiolabeled MAb. The validity of the procedure was demonstrated with the anti-high-m.w. melanoma-associated antigen (HMW-MAA) MAb 763.74 and its corresponding anti-id MAb MK2-23. Utilizing this approach, MAb 763.74 was labeled to specific activities of 2.8 +/- 0.6 mCi/mg with 186Re. Furthermore, its immunoreactivity, which was reduced to about 30% following labeling with 186Re, was improved to about 50% by affinity chromatography over columns of anti-id MAb MK2-23. The improvement in immunoreactivity of 186Re MAb 763.74 resulted in a significant (p < 0.05) increase in targeting to human melanoma tumors grown in nude mice and an increase in sensitivity of RIS. Our results suggest that direct labeling of anti-TAA MAb with 186Re coupled with purification over affinity columns of anti-id MAb may facilitate the application of 186Re to RIS and RIT.
Animals↗
Intraoperative localization of the sentinel node in breast cancer: technical aspects of lymphoscintigraphic methods.
Axillary lymph node dissection is an important part of the surgical treatment of breast cancer as a staging procedure. Recent progressive advances in early detection have led to the treatment of small primary carcinomas; thus, a great number of axillary dissections show completely negative lymph nodes. The sentinel node (SN) concept, developed for melanoma patients, seems to be similarly valid in breast cancer and has the potential to change the standard surgical approach in these patients. To verify the accuracy of lymphoscintigraphic method associated with radioguided biopsy of the sentinel node in a large series of patients, we studied 382 patients with operable breast cancer. Lymphoscintigraphy (LS) was performed the day before surgery; three different-sized ranges of 99mTechnetium-labeled colloid particles were injected either by subdermal or peritumoral administration. Planar scans were registered in anterior and oblique projections, and a cutaneous marker was placed over the skin corresponding to the SN as visualized. SNs were localized and removed during surgery, using a gamma-detecting probe (GDP); total axillary dissection was then performed. In 54 patients, blue dye was also administrated in the tumor bed immediately after excision of the primary. LS identified at least one SN in 377 of 382 cases (98.7%). Axillary SN was localized in 371 cases (97.1%). The overall concordance between SN status and other axillary nodes was 96.8% (359 of 371). Localization of the SN was easier when large-size particles of colloidal albumin were injected in a volume of 0.4 ml. GDP successfully localized SN in 54/54 cases (100%), while blue dye identified SN in 37/54 patients (68.5%). In 33 of 37 cases (89%) the dye and LS identified the same node. LS and GDP-guided surgery provide accurate identification and removal of the SN, particularly when large-size radiolabeled colloids are injected in a small volume.
Axilla↗
Combined treatment of advanced oropharyngeal cancer with external radiotherapy and three-step radioimmunotherapy.
The prognosis of patients with locally advanced head and neck cancer remains grim due to poor locoregional tumour control. In the attempt to eradicate residual disease, various novel modalities have been tested, among which radioimmunotherapy (RIT) has shown some potential. We present a case of locally advanced oropharyngeal carcinoma successfully treated with a combination of various treatments including surgery, radio-chemotherapy and three-step RIT, with the avidin-biotin pretargeting system. A partial tumour response was achieved after surgery and radio-chemotherapy; persistent disease was documented at computed tomography (CT), ultrasound (US) and immunoscintigraphy (ISG) 10 weeks after the end of chemo-radiotherapy. The good correlation between the tracer localization in the scintigraphic images and residual mass visualized at CT suggested the application of three-step RIT using systemic administration of yttrium-90 (py) biotin. At present, 17 months after RIT, the patient is alive with no evidence of disease as documented by magnetic resonance imaging (MRI) and US. This is the first case of complete clinical remission of a head and neck carcinoma induced by combined treatment including pretargeted RIT with 90Y-biotin.
Aged↗
Sentinel node localization in cutaneous melanoma: lymphoscintigraphy with colloids and antibody fragments versus blue dye mapping.
In stage I cutaneous melanoma, biopsy of the first tumour-draining lymph node (sentinel node, SN) may replace routine elective lymph node dissection (ELND). The patent blue dye (PBD) technique has been shown to be an original method for the localization of the SN, but its sensitivity is sometimes unsatisfactory, depending on the basin where the SN is located. We compared three methods to locate the SN: intraoperative PBD mapping, lymphoscintigraphy (LS) with an aspecific tracer (colloid) and LS with a specific tracer (monoclonal antibody, MoAb). Fifty patients with cutaneous melanoma were enrolled in this study. The day before surgery LS was performed following an intradermal injection of 55 MBq technetium-99m-labelled HSA colloidal particles (25 patients: group A) or 220 MBq of 99mTc-F(ab')2 MoAb 225.28 S (25 patients: group B) around the site of the primary lesion. In group B an equal amount of tracer was injected, as a control, in the contralateral site. Early and delayed images were acquired with a gamma camera and SN(s) marked on the skin. In all 50 patients the PBD technique was also performed immediately before surgery. When a blue node was identified intraoperatively, its radioactivity level was measured with a gamma probe. In the absence of blue coloration, the probe alone was used to detect the SN. Lymphoscintigraphic visualization of SNs was possible in 50/50 patients (100%), a total of 73 SNs (38 in group A and 35 in group B) were found, distributed in 55 basins. Gamma probe detection (GPD) allowed the identification of SNs in 49/50 patients (98%), and 72 SNs in 54 basins were localized. By contrast, using PBD, SNs were stained only in 40/50 patients (50 SNs in 40 basins). A tumour-positive SN was histologically proven in 13 patients (26%). In group B, no increase uptake was observed in the seven positive SNs (6/25 patients) compared with the contralateral uninvolved nodes. In conclusion this study demonstrates that LS combined with GPD is a safe method for detecting SNs and is more sensitive than the PBD technique. The use of MoAb fragments did not show any advantage over the non-specific tracer.
Adolescent↗
Biochemical modifications of avidin improve pharmacokinetics and biodistribution, and reduce immunogenicity.
Pretargeting techniques using the avidin-biotin system have shown encouraging results in both diagnostic and therapeutic clinical trials. It has been shown that in cancer therapy the ideal agent to be used for pretargeting should have a plasma half-life longer than avidin and lower immunogenicity than streptavidin in order for these procedures to be applied safely and repeatedly in patients. We prepared a recombinant form of avidin with no carbohydrates and avidins, biochemically modified either by decreasing the positive charges with succinic anhydride or by linking polyethylene glycol (PEG) at three different molar ratios and evaluated their in vivo behaviour after i.p. administration in mice. The succinylation and PEGylation of avidin increased the plasma half-life proportionally to the degree of protein modification. The procedures, however, affected the biotin binding to some extent. The biodistribution studies showed that, for all six time points (ranging from 20 min to 18 h post-injection), the liver and kidney to blood ratios were lower for PEGylated avidins than native, recombinant and succinyl avidin. Recombinant and low PEGylated avidin evoked an immune response in all mice after at least three injections. Native, recombinant and succinyl avidins showed higher serum titres than PEGylated avidins. In conclusion, the conjugation of avidin to PEG chains (n = 7) originates a compound with a suitable blood clearance, low immunogenicity and concurrent low cross-reactivity with avidin.
Animals↗
The three-step pretargeting approach reduces the human anti-mouse antibody response in patients submitted to radioimmunoscintigraphy and radioimmunotherapy.
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Animals↗
Pretargeting strategies for radio-immunoguided tumour localisation and therapy.
The selective recognition of tumour cells by monoclonal antibodies, labelled with radioactive isotopes, for use in diagnosis and treatment, forms the basis of immunoscintigraphy, radio-immunoguided surgery and radio-immunotherapy. Research into the application of these systems has encountered multiple difficulties, most notably a low tumour to non-tumour ratio of radioactivity. The development of pretargeting systems, separating the individual steps of tumour cell targeting and the introduction of the radioactive label, have led to significant increments in tumour to non-tumour ratios and an improvement in diagnostic accuracy. Before pretargeting strategies are applied clinically, a thorough understanding of these systems is required and forms the backbone of this report. Clinical examples of early trials have already confirmed many of the theoretical advantages of pretargeting systems and new protocols are already being investigated.
Antibodies, Monoclonal↗
Purification by affinity chromatography with anti-idiotypic monoclonal antibodies of immunoreactive monoclonal antibodies following labeling with 188Re.
Because of its high energy beta emissions and imageable gamma emissions, 188Re represents an attractive isotope to radiolabel monoclonal antibodies (mAb) recognizing human tumor-associated antigens for radioimaging and radioimmunotherapy in patients with malignant diseases. The application of 188Re is, however, hindered by the denaturation of a sizable proportion of antibody molecules during the labeling process. To overcome this problem, we have combined radiolabeling of mAb with 188Re with purification of immunoreactive 188Re-labeled mAb by affinity chromatography over columns of anti-idiotypic (anti-id) mAb. Utilizing the anti-high-molecular-weight melanoma-associated antigen (HMW-MAA) mAb 763.74 as a model system, we found that the immunoreactivity of mAb 763.74 labeled with 188Re to a specific activity of 1 mCi/mg increased from about 50% to at least 80% following passage over columns of immobilized anti-id mAb. Moreover, between 90-100% of immunoreactive mAb contained in radiolabeled preparations could be recovered from anti-id mAb columns. These results indicate that the procedure we have described may facilitate the application of 188Re for immunoscintigraphy and immunotherapy of malignant diseases.
Antibodies, Anti-Idiotypic↗
Biodistribution in tumour-bearing mice of two 90Y-labelled biotins using three-step tumour targeting.
Tumour pretargeting techniques based on a three-step approach with the avidin/biotin system and associated with the high-energy beta-emitter yttrium-90 (90Y) have been applied with encouraging results in cancer therapy. While in-vivo stable binding of 90Y through a chelating agent like DOTA is essential for directly labelled monoclonal antibodies in the labelling of a fast clearing molecule like biotin, this may not be so important, since the time for catabolic processes to occur is drastically reduced. In this study, the biodistribution of 90Y bound to biotin through DTPA or DOTA was evaluated. Tumour-bearing mice received biotinylated antibody on day 1, avidin on day 2 and 90Y-labelled biotin on day 3. The biodistribution was determined 4 and 24 h after the injection of radiolabelled biotin. The majority of the injected dose was recovered in the urine 4 h after injection of both radiolabelled compounds. Higher bone uptake of 90Y was observed in animals administered 90Y-DTPA-biotin. In general, all organs including tumour showed higher accumulation of activity following the injection of 90Y-DAPA-biotin. Despite the lower levels of accumulation in the tumour after injection of 90Y-DOTA-biotin, the tumour-to-liver and tumour-to-bone ratios for the DOTA ligand were higher compared to DTPA. The higher tumour uptake observed after injection of 90Y-DTPA-biotin may be attributed to the presence of two biotin molecules in its dimeric structure. Our results indicate that the ideal 90Y-labelled biotin derivative for therapy studies should be formed from a DOTA core with two non-cleavable spacers, each ending with a biotin molecule.
Adenocarcinoma↗
Acquisition protocol for breast cancer imaging with technetium-99m-labeled synthetic peptide and technetium-99m-MDP.
UNLABELLED: Technetium-99m-MDP and, recently, a 99mTc-labeled synthetic decapentapeptide have been shown to localize in breast lesions. Our goal was to develop an acquisition protocol to improve image quality, to improve detection of axillary lymph nodes with disease and to compare the utility of the new radiotracer to 99mTc-MDP. METHODS: Ninety-three patients with documented breast carcinoma were studied. Thirty-eight patients were studied in the supine position with anterior and lateral views: eight patients were injected intravenously with 600-740 MBq 99mTc-EPPT and 30 patients with the same activity of 99mTc-MDP. A second group of 55 patients was studied using the same total activity: 20 patients were injected with 99mTc-EPPT and 35 patients with 99mTc-MDP. To improve results, patients were positioned standing up with their arm raised. The breast with a marker over the nipple touched the collimator in the oblique-lateral position. Early planar images (2-5 min postinjection) were acquired with this positioning for the healthy and the tumor breast, collecting 1500 K counts in a 256 x 256 matrix. Imaging of the axillary regions was performed while the patients were positioned supine and a frontal image was obtained at 10-15 min postinjection for 1800 K counts. RESULTS: This diagnostic study produced good quality images, with the breast lesions and axilla visualized. The positions had limitations due to the overlapping of other organs and to the proximity with the chest wall. CONCLUSION: Using this protocol, all primary lesions and 50% of the axillary lymph nodes with 99mTc-MDP, and 35% with 99mTc-EPPT, were detected as documented by histology. Our protocol may represent an improvement in the diagnosis and staging of breast cancer.
Axilla↗
Evaluation of four radiopharmaceuticals for imaging inflammation in a rabbit model of arthritis.
We compared the utility of four radiopharmaceuticals; 111In-chloride, 67Ga-citrate, 111In labeled leukocytes (WBCs) and 99mTc-MDP for assessing the inflammatory response in antigen induced arthritis in a rabbit model. A total of 20 rabbits, divided into four equal groups, were included in this study. Each group was studied twice with a single radiotracer; a baseline study and a follow-up study after induction of the arthritis. Knee to knee, knee to whole body, and knee to liver (except for the group studied with 99mTc-MDP) ratios were generated. Knee to knee ratios showed no significant change from baseline to arthritis studies in any of the four groups. Significantly increased knee to total body ratios were seen in all of the groups, except for the group studied with 99mTc-MDP. The greatest increase was seen in the group studied with 111In-chloride. Significantly increased knee to liver ratios were observed in all three groups for which these ratios were generated and again the greatest increase was observed in the group studied with 111In-chloride. In summary, based on the higher uptake observed in this group, of the four radiotracers evaluated, 111In-chloride is probably the most useful for monitoring the inflammatory response in antigen induced arthritis. The symmetry of the response suggests that it may also be useful in monitoring the response to therapy.
Animals↗
Radioimmunoguided surgery and colorectal cancer.
Radioimmunoguided surgery is a technique that aims to delineate the extent of epithelial neoplasms (primary/recurrent) and their spread (local, regional, and distant) which are not adequately visualized by conventional imaging techniques. The target lesion binds radiolabelled, tumour-associated monoclonal antibodies which are administered in the days before surgery and which bind to the target lesion. The radiotracer is detected intraoperatively using a hand-held gamma detecting probe. This identifies the extent of the tumour, involvement of lymph nodes or other organs and may allow a more complete surgical clearance of the tumour. This article provides a basic understanding of the RIGS (radioimmunoguided surgery) technique, the monoclonal antibodies which are used and outlines the advantages and limitations of this technique.
Antibodies, Monoclonal↗
In vitro and in vivo studies with no-carrier added radioiodinated MIBG.
An important drawback of radioiodinated MIBG prepared by isotopic exchange (maximum specific activity: 100 Ci/mmol) is that a considerable amount of carrier is present in the "ready to use" radiopharmaceutical, thus affecting MIBG uptake in the target cells. To improve the therapeutic utility of MIBG an interesting method was developed for the no-carrier-added (n.c.a.) radioiodination of MIBG via a halodesilylation reaction using 3-trimethylsilybenzylguanidine (TMSBG) as precursor. In order to investigate its possible clinical usefulness, n.c.a. [125I]- and [131I]MIBG was prepared according this procedure. HPLC analysis of the labeling mixture showed that the labeling yield reached values greater than 98% within 20 minutes at 70 degrees C. HPLC fraction containing [131I]MIBG was then recovered and tetrahydrofurane was removed under nitrogen stream. Biodistribution studies were performed in BALB/c normal mice and compared with those obtained using [131I]MIBG prepared by isotopic exchange. Preliminary results showed that at 4 hours myocardial uptake was significantly higher than that of c.a. MIBG (20.3 +/- 0.4 %ID/g). Adrenal uptake gradually increased over time; at 24 hours adrenal uptake was almost twofold that a 1 hour. MIBG uptake was also studied in the human neuroblastoma cell line SH-SY5Y which has a specific uptake system for MIBG. The kinetic parameters for MIBG in this line are: km = 0.27 +/- 0.03 microM, Vmax = 39.5 + 1.8 pmol/10(6) cell/10 min. Preliminary data from in vitro binding studies showed that significantly higher levels of specifically incorporated radioactivity can be achieved using n.c.a. [125I]MIBG instead of c.a. [125I]MIBG.
3-Iodobenzylguanidine↗
Effect of blood-brain barrier and blood-tumor barrier modification on central nervous system liposomal uptake.
In this study of 25 central nervous system (CNS) tumor-bearing rats, the CNS biodistribution of intravenously administered, indium-labeled liposomes was investigated. In 16 animals, the blood-brain barrier and blood-tumor barrier were modified using intracarotid administration of etoposide. In control animals, analysis by autoradiography and well-counting experiments demonstrated uptake of liposomes in the tumor-bearing hemisphere (% injected dose/g tissue = 0.135) with minimal uptake in the non-tumor-bearing hemisphere (% injected dose/g tissue = 0.007), p < 0.01. Unilateral intracarotid etoposide administration enhanced liposome uptake in both hemispheres-0.215 and 0.023 (tumor-bearing and nontumor-bearing), respectively. The presence of meningeal tumor involvement in nontumor-implanted hemispheres increased liposomal uptake 10-fold. These findings may have clinical applicability in designing therapeutic protocols for the treatment of CNS tumors.
Animals↗
Chemistry and biological behavior of samarium-153 and rhenium-186-labeled hydroxyapatite particles: potential radiopharmaceuticals for radiation synovectomy.
Hydroxyapatite (HA), a natural constituent of bone, was studied as a particulate carrier for beta-emitting radionuclides in radiation synovectomy. Particles were radiolabeled with 153Sm or 186Re and their in vivo safety was investigated following intra-articular injection into knees of normal rabbits and rabbits with antigen-induced arthritis (AIA). Radiolabeling efficiency was greater than 95%; in vitro studies showed minimal (< or = 1%) loss of activity from particles over a 6-day period with 153Sm-labeled HA and about 5% loss of activity over a 5-day period with 186Re-labeled HA. The total cumulative extra-articular leakage of 153Sm over 6 days was 0.28% in normal rabbits and 0.09% in AIA rabbits. Leakage of 186Re from the joint was 3.05% over a 4-day period with 80% of extra-articular activity found in the urine. Histopathological evaluation of treated knees showed that HA particles are distributed throughout the synovium, embedded in the synovial fat pad. The ease and efficiency with which this HA carrier is labeled, coupled with observed extremely low leakage rates from the joint, make radiolabeled HA particles an attractive candidate as a radiation synovectomy agent for evaluation in rheumatoid arthritis patients.
Animals↗
In vivo stability of ferric hydroxide macroaggregates (FHMA). Is it a suitable carrier for radionuclides used in synovectomy?
Ferric hydroxide macroaggregates (FHMA) have been widely used as a carrier for several radionuclides used in radiation synovectomy. Different rates of extra-articular leakage of radioactivity have been observed with 90Y and 165Dy. In order to understand the mechanism(s) involved in the extra-articular leakage of radioactivity, the in vivo stability of FHMA carrier was studied. Following an injection of [59Fe]Fe-FHMA into the knees of normal rabbits, the cumulative leakage of [59Fe]Fe-FHMA was 2.9% at 5 days and 12.3% at 14 days. More than 60% of this activity was in the blood. But when FHMA was double labeled with 59Fe and 166Ho, the 59Fe leakage significantly increased to 18.5% at 5 days and 27% by 14 days. The instability of FHMA is accelerated when it is complexed with 166Ho and may be due to the "mass effect" of 166Ho or due to radiolysis induced by high energy beta particles from 166Ho. These results suggest that FHMA is a suitable carrier only for the short lived radionuclides used in synovectomy.
Animals↗
Radiopharmaceuticals for radiation synovectomy: evaluation of two yttrium-90 particulate agents.
Radiation synovectomy, a noninvasive therapeutic alternative to surgical synovectomy, has not gained widespread acceptance in the United States because of the lack of a suitable radiopharmaceutical. Two new radioactive particles, [90Y]Ca oxalate and [90Y]ferric hydroxide macroaggregates (FHMA), were developed in our laboratory and evaluated for size, stability, and joint leakage. More than 90% of the [90Y]Ca oxalate particles were in the optimal size range of 1-10 microns, and the unbound activity in serum and synovial fluid was 3.7% to 5.0%. Following injection in rabbit knees, leakage of [90Y]Ca oxalate was 5 +/- 2%, with localization primarily in the bone and virtually no uptake by the lymph nodes or liver. Yttrium-90 FHMA particles were larger (95% greater than 10 microns), and at least on a microscopic level, appeared to distribute homogeneously over the articular surface. Leakage of [90Y]FHMA was initially less but eventually slightly exceeded that of [90Y]Ca oxalate. Nevertheless, both radiopharmaceuticals can provide a satisfactory therapeutic dose to the knee with less than half the leakage and a marked reduction in absorbed dose to nontarget tissues compared to previously tested agents. Ease of preparation, physical characteristics of the 90Y beta ray, and apparent lack of substantial leakage from the joint make these agents extremely attractive for clinical evaluation in rheumatoid arthritis patients who are unresponsive to medical therapy.
Animals↗