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G Paganelli

Publications and source records attributed to G Paganelli.

126 records · Page 7Linked to original sources
PubMed1988

Antibody-guided diagnosis: an Italian experience on CEA-expressing tumours.

Within the Italian CNR Biomedical Technology programmes a large multicentre clinical trial on CEA-expressing carcinomas has been carried out. F(ab')2 fragments of anti-CEA monoclonal antibody (MAb) FO23C5, radiolabelled with either 131I or 111In, were supplied to 10 different Italian nuclear medicine departments. Over 500 patients with gastrointestinal, lung, breast, and other carcinomas have been investigated. The results obtained in our nuclear medicine department are reported here. In GI cancer group, the 131I compound showed better results except in liver metastases detected only in 28/57 patients. In the lung cancer group, very satisfactory results were achieved in primary tumours and local or systemic recurrences: 111In tracer was preferentially used. In the breast cancer group immunoscintigraphy proved to be helpful in differential diagnosis of neoplastic and benign bone lesions. Significant improvements of diagnostic sensitivity were achieved in GI cancer patients by means of i.p. administration. Finally, 12 patients with advanced disease were given different 131I radioiodinated MAbs (100 mCi average dose). Administration route was either i.v. (3 cases) or i.p. (9 cases). Clinical and instrumental evidence of complete (1) or partial (7) response was observed in 8 patients.

Antibodies, Monoclonal↗
PubMed1988

In vivo labelling of biotinylated monoclonal antibodies by radioactive avidin: a strategy to increase tumor radiolocalization.

Several monoclonal antibodies (MAbs), reactive with tumor-associated antigens, selectively persist on tumor sites in vivo for many days. If biotinylated, such highly specific tags on tumor cells could become targets for radioactive avidin, administered after suitable intervals. The proposed strategy is based on a number of assumptions concerning the ability of avidin to preserve its biological properties in heterologous in vivo environments, on its lack of toxicity and on its biodistribution. A preliminary study has been carried out in rabbits, using biotinylated nitrocellulose and polystyrene targets. The results of this study indicate that in rabbits 1) avidin can be administered i.v. and i.p. without adverse reactions, 2) it does not show any preferential localization, 3) it is eliminated with a biological half-life of 24 hr, 4) its biological properties are not impaired by in vivo conditions, since it accumulates at biotinylated targets only, 5) CEA-bearing targets can be biotinylated in vivo by biotin-labelled anti-CEA MAbs and 6) the biotin-avidin chain can be further extended in vivo since bound avidin is still able to bind biotinylated radioactive proteins.

Animals↗
PubMed1988

Localization of biotinylated monoclonal antibody in nude mice bearing subcutaneous and intraperitoneal human tumour xenografts.

To demonstrate the precise distribution and binding of in vivo injected monoclonal antibodies on histological tumour sections, we have biotinylated our primary antibody AUA1. Biotinylated antibody was injected into nude mice bearing simultaneous subcutaneous and intraperitoneal xenografts of the human tumour LoVo. Twenty-four hours after injection, the animals were killed, tumours and control organs were removed. Antibody was demonstrated on frozen sections by incubating sections with avidin biotin peroxidase complex. We compared the in vivo penetration and binding of this antibody on intraperitoneal and subcutaneous xenografts. The antibody penetration was mainly restricted to a thin layer of tumour cells adjacent to the vascularized stroma in large solid subcutaneous and intraperitoneal tumours, whereas in very small intraperitoneal tumours, antibody penetration was complete. These findings were similar to our autoradiographic results. This study demonstrates that employing the biotinylated antibodies for in vivo localization studies provides superior resolution of antibody binding for morphological assessment compared to autoradiography. Localization of a biotin label is more precise and will permit ultra-structural studies.

Animals↗
PubMed1988

Immunoscintigraphy of adenocarcinomas by means of 111In-labelled F(ab')2 fragments of anti-CEA monoclonal antibody F023C5.

F(ab')2 fragments of F023C5, an anti-CEA monoclonal antibody, were conjugated to diethylenetriamine pentaacetic acid (DTPA) and converted into a ready to use reagent for instant 111In-labelling. The resulting 111In radiopharmaceutical (2-3 mCi/0.5 mg of F(ab')2 fragments) was administered intravenously and tested for its ability to image (at 48-72 h after administration) 31 primary and 85 metastatic carcinoma lesions in 70 adenocarcinoma patients (26 gastrointestinal, 18 breast and 26 lung tumor patients) whose serum CEA was elevated in 43 cases and normal in the other 27. The results were as follows: no adverse reactions or evidence of toxicity were observed in any of the patients. positive immunoscintigraphy results were obtained in 78% CEA-seropositive and in 64% seronegative patients. the fraction of documented lesions which was imaged was 69% in CEA-seropositive patients and 39% in seronegative patients. several 'unexpected' radiolocalizations were imaged; 30/34 were confirmed as (previously occult) tumour lesions in follow-up studies. In 6 patients, the immunoscintigraphic demonstration of previously occult lesions contributed to the early detection of tumour recurrences. the major limitation of the method is the non-specific radioactivity accumulation in the liver, which prevents the detection of liver metastases. in CEA-seropositive patients the fraction of imaged extra-hepatic tumour lesions is over 80%. the major cause of negative immunoscintigraphy results is lack of CEA in the tumour lesion, as demonstrated by immunohistochemistry of surgically removed tumours.

Adenocarcinoma↗
PubMed1986

Improved immunoscintigraphy by subcutaneous injection of 99mTc or 111In labelled F(ab')2 fragments of an anti-melanoma monoclonal antibody.

Technetium-99m and/or 111In labelled F(ab')2 fragments of a melanoma associated MoAb 225.28S were injected i.v. in 80 patients affected by stage I to IV malignant melanoma. Seventy five percent of metastatic lesions already documented by other methods were detected by immunoscintigraphy, which was also capable of detecting a certain number of unknown metastases. However, we observed a lower percentage of positive scans in liver, lung and skin because of the poor tumour to background ratio. In some patients, subcutaneous (s.c.) injection allowed us to visualize documented metastases undetected by i.v. administration. An equal amount of non-specific F(ab')2 fragments (MoAb 4C4) injected s.c. as a negative control showed no positive scans. Clinical studies and chromatographic patterns of patient serum samples suggest that the s.c. route of administration offers, with respect to the i.v. route, the advantage of reducing vascular background and aspecific accumulation in liver, probably because of retention of possible contaminants by the lymphatic system.

Antibodies, Monoclonal↗
PubMedDate not supplied

MRI, antibody-guided scintigraphy, and glucose metabolism in uveal melanoma.

To evaluate the usefulness of structural and biochemical imaging techniques for the diagnosis of uveal melanoma, 12 patients with choroidal melanoma were examined. Magnetic resonance imaging was used in 11 of 12 patients, as one had a metal prosthesis. All the subjects underwent single photon planar scintigraphy (SPPS) and single photon emission computed tomography (SPECT) using the 99mTc-labeled F(ab')2 of the anti-melanoma monoclonal antibody 225.28S ([99mTc]MoAb) and positron emission tomography (PET) using [18F]fluorodeoxyglucose ([18F]FDG). Magnetic resonance identified 6 of 11 melanotic lesions (definite melanomas) and 4 of 11 hypomelanotic lesions (probable melanomas), whereas in one case it was inconclusive. [99mTc]MoAb uptake was observed in 5 of 12 lesions using SPPS and 8 of 12 lesions using SPECT. [18F]FDG uptake was observed in 3 of 12 lesions by PET. These results demonstrate that both MR and radioimmunoscintigraphy are sensitive techniques for the diagnosis of choroidal melanomas and suggest that the detection of melanomas by MR, SPPS, and SPECT is largely dependent upon their size. The validity of these conclusions was verified in four subjects in whom the diagnosis was based on MR and/or SPECT findings only and confirmed by histology. The finding that only some of the uveal melanomas of larger size are visualized based on [18F]FDG uptake suggests that melanomas can have either high or low glucose consumption.

Choroid Neoplasms↗
PubMedDate not supplied

Detection of sentinel nodes by lymphoscintigraphy and gamma probe guided surgery in vulvar neoplasia.

BACKGROUND: Pathologic lymph node status is the most important prognostic factor in vulvar cancer; however, complete inguinofemoral node dissection is associated with significant morbidity. Intraoperative lymphoscintigraphy associated with gamma detecting probe-guided surgery has proved to be reliable in the detection of sentinel node (SN) involvement in melanoma and breast cancer patients. The present study evaluates the feasibility of the surgical identification of inguinal sentinel nodes using lymphoscintigraphy and a gamma detecting probe in patients with early vulvar cancer. METHODS: Technetium-99-labeled colloid human albumin was administered perilesionally in 44 patients. Twenty patients had T1 and 23 had T2 invasive epidermoid vulvar cancer; one patient had a lower-third vaginal cancer. An intraoperative gamma detecting probe was used to identify SNs during surgery. Complete inguinofemoral node dissection was subsequently performed. SNs underwent separate pathologic evaluation. RESULTS: A total of 77 groins were dissected in 44 patients. SNs were identified in all the studied groins. Thirteen cases had positive nodes: the SN was positive in all of them; in 10 cases the SN was the only positive node. Thirty-one patients showed negative SNs: all of them were negative for lymph node metastasis. CONCLUSIONS: Lymphoscintigraphy and SN biopsy under gamma detecting probe guidance proved to be an easy and reliable method for detection of SNs in early vulvar cancer. If these preliminary data will be confirmed, the technique would represent a real progress towards less aggressive treatment in patients with vulvar cancer.

Adult↗
PubMedDate not supplied

Pretargeting of carcinomas with the avidin-biotin system.

Diagnosis and experimental therapy of cancer have been performed with encouraging results using radiolabelled monoclonal antibodies. However, the high background due to non-specific uptake by normal tissue and blood is a major drawback in antibody-guided tumor detection. Various strategies have been proposed to overcome this problem, such as computed background subtraction, use of a second antibody, and local delivery. An antibody is a slow "bullet" for tumor targeting, since in many lesions it requires two or three days to accumulate. The use of fragments such as F(ab')2 or Fab, which display a faster blood clearance than whole antibody, improves tumor localization to a sufficient extent (hours) to allow the use of the most suitable radionuclides, e.g. 99m-Tc. In therapeutic applications we are still far away from the optimal condition in terms of the absolute amount of radioactivity delivered to the tumor. The high specificity of antibodies could be exploited at its best by delaying the delivery of the label to a time when the ratio tumor-bound to non-tumor-bound antibody has reached its maximum value. To obtain this goal, the label should display a fast clearance and should be captured by the antibody already targeted onto tumor cells. These considerations have led to strategies of tumor pretargeting where antibody and label are administered separately. One of these strategies, based on the avidin-biotin system, has already been used extensively for several years in immunohistochemistry and in ELISA. Due to the flexibility of this system, several alternative protocols are possible.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMedDate not supplied

Radiolocalization of 99mTc-labeled fragments in a melanoma xenografted model.

A xenograft model of human malignant melanoma was used to compare, in terms of tumor localization, the specific antimelanoma monoclonal antibody (MoAb) 225.28S with an irrelevant antibody (4C4). Both specific and non-specific 99mTc-labeled fragments were injected in 12 nude mice bearing subcutaneous tumor. The animals were then sacrificed at 6 and 24 hours post-injection and immediately dissected. Radioactivity of the tumor and normal tissues was measured in a well scintillation counter and autoradiography of tumor, liver and kidneys was also obtained. Tumor localization of 99mTc-labeled MoAb 225.28S fragments was highly specific compared with 99mTc-labeled irrelevant antibody 4C4. With the exception of the kidneys, already at six hours there was a satisfactory tumor-to-normal tissue ratio, which improved at 24 hours. However, the percentage of injected dose per gram of tumor decreased with time, probably due to the weaker bond of radiolabeled Fab' fragments to tumor cells. These results would indicate 99mTc-fragments of the antimelanoma MoAb 225.28S as a suitable radiotracer in clinical nuclear medicine.

Animals↗
PubMedDate not supplied

A new method for faster blood clearance in radioimmuno-guided surgery.

A major inconvenience of intraoperative tumor detection with radiolabeled monoclonal antibody (MoAb) by means of a probe is the long interval needed between the injection of MoAb and surgery (at least 20 days). We describe a new method which entails injection of 125I-labeled biotinylated monoclonal antibodies and cold avidin in order to obtain a rapid blood clearance of the radiotracer. The first clinical application of this protocol has been carried out in a colon cancer patient operated on six days after the administration of 125I-labeled biotinylated MoAb and cold avidin, with an optimal tumor-to-normal tissue ratio and with 90% of the circulating radioactivity cleared in two days.

Abdominal Neoplasms↗
PubMedDate not supplied

Radiolocalisation of an anti-CEA monoclonal antibody (FO23C5) and its fragments in a colon carcinoma xenograft model.

A new monoclonal antibody designated FO23C5 against a protein component of carcinoembryonic antigen (CEA) has been developed. A xenograft system of human colon cancer was used to compare the intact monoclonal IgG with its fragments (Fab')2 and Fab) and with an established anti-CEA antibody (MAb35) and the antibody AUA1 raised against the colon carcinoma cell line. We demonstrate that FO23C5 compares well with the existing anti-CEA antibody and with AUA1, and that F(ab')2 fragments perform best in achieving optimal tumour to normal tissue ratios compared with intact IgG and Fab fragment.

Adenocarcinoma↗
PubMedDate not supplied

Antigen "suicide": a preliminary study on the induction of specific anti-immunoglobulin immunological suppression in vivo, using radiolabelled immunoglobulin as "lethal" antigen.

The effectiveness of immunodiagnosis and immunotherapy is limited when xenogeneic antibodies are used, due to the host's anti-immunoglobulin response. We have attempted to specifically suppress the immune response to the immunogen (immunoglobulin) administered. The concept of antigen "suicide" was used, where the antigen (immunoglobulin) was suitably radiolabelled and administered to animals. The question asked was whether immunocompetent cells that specifically interact with the radiolabelled immunogen, would be lethally irradiated and thus become inactivated rather than stimulated. When mice where primed with 111Indium-labelled polyclonal human IgG (specific activity 15 mCi/mg), they responded 13% less than control animals (p = 0.0485). This suppression was IgG-specific, since all animals responded similarly to a control antigen (human albumin). However, a second boost of the same 111Indium-labelled preparation (specific activity 7 mCi/mg) did not show any statistically significant immunosuppression. In addition, rabbits primed with 125Iodine-labelled mouse monoclonal antibody (specific activity 180 mCi/mg) and boosted with the same unlabelled monoclonal antibody, showed a similar anti-mouse antibody response with the ones that received only unlabelled preparation twice. We conclude that the concept of antigen "suicide" may be effective for the induction of specific unresponsiveness; when immunoglobulins are radiolabelled with 111Indium at high specific activities, the desired state of specific immune suppression may be induced.

Animals↗
PubMedDate not supplied

Thymopentin increases the survival of mice after allogeneic blood transfusion, bacterial gavage, and burn injury.

OBJECTIVE: To investigate the effect of blood transfusion on mortality and the incidence of bacterial translocation in mice subjected to thermal burn or bacterial gavage, or both, and to assess the influence of thymopentin on mortality. DESIGN: Randomly controlled experiments. SETTING: University departments of surgery, immunology and nuclear medicine. MATERIAL: 235 Balb/c (H-2d) and C3H/HeJ (H-2k) mice. INTERVENTIONS: 8 groups of 20 mice each received: saline infusion (controls), blood transfusion (BT) alone, 20% burn alone, gavage with 1 x 10(10) Escherichia coli alone, BT and gavage, BT and burn, burn and gavage, or BT, burn, and gavage. A further 3 groups of 10 mice were all gavaged with 111In-biotin labelled E coli and randomised to additional BT and burn, BT alone, or burn alone. 98 mice that had had BT, burn, and gavage, were then randomised to receive thymopentin 0, 0.1, 1, or 5 mg/kg/day for 15 days. The impact of the pretreatment with thymopentin on PGE2 concentration was also evaluated in a separate group of 45 mice that received BT, burn, and gavage; or burn and gavage. MAIN OUTCOME MEASURES: Survival, degree of translocation. RESULTS: The highest mortality (75%) was in the BT, burn, and gavage group. BT alone significantly reduced survival in burned mice, whereas BT alone or associated with gavage had no effect. Thermal injury had the most influence on bacterial translocation, whereas BT did not increase it. Thymopentin significantly improved survival, particularly in the higher doses. The pretreatment with thymopentin significantly reduced PGE2 concentration after BT, burn and gavage. CONCLUSION: Burn injury significantly increased mortality in the presence of immune deficiency caused by BT. Thymopentin reduced mortality, possibly by immunomodulation.

Animals↗