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Biomedical subjects

G Paganelli

Publications and source records attributed to G Paganelli.

At least 37 records · Page 2Linked to original sources
PubMed2003

Novel antitenascin antibody with increased tumour localisation for Pretargeted Antibody-Guided RadioImmunoTherapy (PAGRIT).

The Pretargeted Antibody-Guided RadioImmunoTherapy (PAGRIT) method is based on intravenous, sequential administration of a biotinylated antibody, avidin/streptavidin and (90)Y-labelled biotin. The hybridoma clone producing the monoclonal antitenascin antibody BC4, previously used for clinical applications, was found not suitable for further development because of the production of an additional, nonfunctional light chain. In order to solve this problem, the new cST2146 hybridoma clone was generated. The monoclonal antibody ST2146, produced by this hybridoma, having the same specificity as BC4 but lacking the nonfunctional light chain, was characterised. ST2146 was found able to bind human tenascin at an epitope strictly related, if not identical, to the antigenic epitope of BC4. It showed, compared to BC4, higher affinity and immunoreactivity and similar selectivity by immunohistochemistry. Biodistribution studies of biotinylated ST2146 and three other monoclonal antitenascin antibodies showed for ST2146 the highest and more specific tumour localisation in HT29-grafted nude mice. On the overall, ST2146 appears to be a good alternative to BC4 for further clinical development of PAGRIT.

Animals↗
PubMed2003

Peptide receptor radiotherapy: a new option for the management of aggressive fibromatosis on behalf of the Italian Sarcoma Group.

The management of aggressive fibromatosis (AF) is problematic, and few options are available to patients unsuitable for surgery and resistant to external-beam radiation therapy (EBRT). We report on two patients with fast-growing recurrences of AF resistant to EBRT who obtained protracted clinical benefits with (90)Y-DOTATOC. (90)Y-DOTATOC should be further investigated in this setting.

Adult↗
PubMed2002

Pretargeted adjuvant radioimmunotherapy with yttrium-90-biotin in malignant glioma patients: a pilot study.

In a previous study we applied a three-step avidin-biotin pretargeting approach to target 90Y-biotin to the tumour in patients with recurrent high grade glioma. The encouraging results obtained in this phase I-II study prompted us to apply the same approach in an adjuvant setting, to evaluate (i) time to relapse and (ii) overall survival. We enrolled 37 high grade glioma patients, 17 with grade III glioma and 20 with glioblastoma, in a controlled open non-randomized study. All patients received surgery and radiotherapy and were disease-free by neuroradiological examinations. Nineteen patients (treated) received adjuvant treatment with radioimmunotherapy. In the treated glioblastoma patients, median disease-free interval was 28 months (range=9-59); median survival was 33.5 months and one patient is still without evidence of disease. All 12 control glioblastoma patients died after a median survival from diagnosis of 8 months. In the treated grade III glioma patients median disease-free interval was 56 months (range=15-60) and survival cannot be calculated as only two, within this group, died. Three-step radioimmunotherapy promises to have an important role as adjuvant treatment in high grade gliomas, particularly in glioblastoma where it impedes progression, prolonging time to relapse and overall survival. A further randomized trial is justified.

Adult↗
PubMed2002

90Y-DOTA-D-Phe1-Try3-octreotide in therapy of neuroendocrine malignancies.

Somatostatin receptors type 2 (sst(2)) are expressed in high concentration on numerous neudoendocrine tumors. The successful use of radiolabeled somatostatin analogs in imaging promoted further studies in utilizing them in radiopeptide therapy. The somatostatin analog [(90)Y-DOTA-D-Phe(1)-Try3]octreotide (DOTATOC) (DOTA: 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) possesses favorable characteristic for its therapeutic use; shows high affinity for sst(2), moderately high affinity for sst(5), and intermediate affinity for sst(3); high hydrophilicity; stable and facile labeling with (111) In and (90) Y. In this article we report our experience with (90)Y-DOTATOC in neuroendocrine tumors. Eighty-seven patients with neuroendocrine tumors were treated with a cumulated activity ranging from 7.4 to 20.2 GBq. Most patients responded with stabilization of disease (48%); however, objective responses were observed in 28% of patients (5% complete response). No major acute reactions were observed up to the activity of 5.55 GBq per cycle. The dose limiting was bone marrow toxicity and the maximal tolerated dose was defined as 5.18 GBq.

Humans↗
PubMed2002

Innovation in early breast cancer surgery: radio-guided occult lesion localization and sentinel node biopsy.

The surgical management of non-palpable breast lesions remains controversial. At the European Institute of Oncology we have introduced a new technique, radio-guided occult lesion localization (ROLL) to replace standard methods and overcome their disadvantages. Regarding axillary dissection, probe-guided biopsy of the sentinel node (SN) is easy to apply, and the whole procedure is associated to a low risk of false negatives. We suggest that the SN technique should be widely adopted to stage the axilla in patients with breast cancer with clinically negative lymph nodes. Large-scale implementation of the sentinel node technique will reduce the cost of treatment as a result of shorter hospitalization times.

Breast Neoplasms↗
PubMed2002

Internal mammary node lymphoscintigraphy and biopsy in breast cancer.

BACKGROUND: In patients with breast cancer, sentinel nodes (SNs) are detected outside the axilla in 1-2% of cases after superficial injection of radiocolloid in the breast. We investigated whether deep injection of tracer visualized internal mammary chain lymph (IMC) nodes more often, and assessed the impact of IMC status on disease staging. METHODS: A total of 400 patients were enrolled in this trial. The study group included 200 patients with T1-T2 N0 breast cancer in an inner quadrant. Radio tracer was injected superficially in 100 (group A), and deeply under the tumor in the others (group B). If an IMC took up tracer in group B patients it was biopsied. An additional 200 patients with outer quadrant lesions were also studied lymphoscintigraphically following superficial (100 patients) or deep (100 patients) injection, but IMC nodes were not biopsied as this would have required an additional surgical excision. RESULTS: An SN was visualized in the IMC in 65.6% of inner quadrant patients after deep injection and in 2.1% after superficial injection. In outer quadrant patients, deep injection visualized an SN in the IMC in 10% of cases. The IMC SN was located mainly in the 2nd and 3rd intercostal spaces. Radioguided IMC biopsy was performed in 62 patients. Node removal proved simple and risks insignificant. Stage migration occurred in 8% of cases. CONCLUSIONS: Deep injection allows SN localization in the IMC in 65% of inner quadrant breast lesions. Biopsy of the axillary plus IMC resulted in stage migration in 8% of patients. It is unclear whether this additional information can lead to better survival.

Adult↗
PubMed2002

Radioguided occult lesion localisation (ROLL) and surgical biopsy in breast cancer. Technical aspects.

BACKGROUND: The surgical management of non-palpable breast lesions remains controversial. At our Institute we have introduced a new technique, radioguided occult lesion localisation (ROLL) to replace standard methods and overcome their disadvantages. In this paper technical aspects of ROLL and results on a large series of patients are reported. METHODS: We analysed 812 consecutive patients with 816 non-palpable breast lesions detected mammographically or ultrasonically. (99m)Tc-labelled particles of human serum albumin (7-10 MBq) in 0.2 ml saline were injected into the lesion under stereotactic mammographic or ultrasonic guidance. Mammography and scintigraphy were then performed. With ultrasound guidance only scintigraphic control was necessary. The excision biopsy was carried out with the aid of a hand-held gamma-detecting probe, and entire removal of the lesion was verified by X-ray of the specimen. RESULTS: The tracer was correctly positioned initially in 772/816 (94.6%) cases and at second attempt in another 2. In 42/816 (5.1%) cases, lesion localisation had to be repeated using a traditional approach. X-ray demonstrated the lesion was entirely removed in 770/774 (99.5%) cases. Pathological examination revealed 367 (47.4%) benign lesions and 407 (52.6%) cancers. The cancers were treated by conservative breast surgery in 99.5% of cases. CONCLUSIONS: We concluded that ROLL enables the surgeon to remove occult breast lesions easily and reliably.

Adult↗
PubMed2001

IgEs targeted on tumor cells: therapeutic activity and potential in the design of tumor vaccines.

Surface-bound IgE play a central role in antiparasite immunity; to exploit IgE-driven immune mechanisms in tumor prevention and control, monoclonal IgEs of irrelevant specificity were loaded through biotin-avidin bridging onto tumor cells, either by systemic administration to tumor-bearing mice or pre-loading of tumor cells before inoculation. Here we show that systemic administration of biotinylated IgEs to mice bearing tumors pre-targeted with biotinylated antibodies and avidin significantly decreased tumor growth rate. In addition, as compared with IgG-loaded control cells, inoculation of suboptimal doses of IgE-loaded tumor cells suppressed tumor formation in a fraction of animals and induced protective host immunity by eliciting tumor-specific T-cell responses. Similarly, tumor vaccination experiments showed that irradiated tumor cells (IgE loaded by biotin-avidin bridging) conferred protective immunity at doses 100-fold lower than the corresponding control cells without IgE. Finally, in vivo depletion of eosinophils or T cells abrogated IgE-driven tumor growth inhibition. These results demonstrate that IgEs targeted on tumor cells not only possess a curative potential but also confer long-term antitumor immunity and that IgE-driven antitumor activity is not restricted to the activation of innate immunity effector mechanisms but also results from eosinophil-dependent priming of a T-cell-mediated adaptive immune response. This suggests a potential role for IgEs in the design of new cell-based tumor vaccines.

Animals↗
PubMed2001

111In-labeled 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-lys(8)-vasotocin: a new powerful radioligand for oxytocin receptor-expressing tumors.

We developed a radioactive ligand for tumors expressing oxytocin receptors (OTRs) by linking the chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) to Lys(8)-vasotocin (LVT), an analogue of oxytocin with high affinity for OTRs. The new reagent (DOTA-LVT) retained high affinity for human OTRs, as proved by in vitro affinity binding to cells endogenously expressing OTRs, such as MCF7 breast carcinoma and MOG-U-V-W glioblastoma cells lines, as well as to transiently transfected COS7 cells. In in vivo experiments, DOTA-LVT carrying (111)In showed specific binding activity to OTR-positive TS/A mouse mammary tumors. The present study opens new perspectives for imaging and, possibly, therapy of OTR-positive human tumors such as breast and endometrial carcinomas, neuroblastomas, and glioblastomas.

Animals↗
PubMed2001

Receptor-mediated radiotherapy with 90Y-DOTA-D-Phe1-Tyr3-octreotide.

A newly developed somatostatin radioligand, DOTA-[D-Phe1-Tyr3]-octreotide (DOTATOC), has been synthesised for therapeutic purposes, because of its stable and easy labelling with yttrium-90. The aim of this study was to determine the dosage, safety profile and therapeutic efficacy of 90Y-DOTATOC in patients with cancers expressing somatostatin receptors. We recruited 30 patients with histologically confirmed cancer. The main inclusion criterion was the presence of somatostatin receptors as documented by 111In-DOTATOC scintigraphy. 90Y-DOTATOC was injected intravenously using a horizontal protocol: patients received equivalent-activity doses in each of three cycles over 6 months. The first six patients received 1.11 GBq per cycle and the four successive groups of six patients received doses increasing in 0.37-GBq steps. Toxicity was evaluated according to WHO criteria. No patient had acute or delayed adverse reactions up to 2.59 GBq 90Y-DOTATOC per cycle (total 7.77 GBq). After a total dose of 3.33 GBq, one patient developed grade II renal toxicity 6 months later. The maximum tolerated dose per cycle has not yet been reached, although transient lymphocytopenia has been observed. Total injectable activity is limited by the fact that the maximum dose tolerated by the kidneys has been estimated at 20-25 Gy. Complete or partial tumour mass reduction occurred in 23% of patients; 64% had stable and 13% progressive disease. It is concluded that high activities of 90Y-DOTATOC can be administered with a low risk of myelotoxicity, although the cumulative radiation dose to the kidneys is a limiting factor and requires careful evaluation. Objective therapeutic responses have been observed.

Adult↗
PubMed2001

Sentinel lymph node biopsy as an indicator for axillary dissection in early breast cancer.

Sentinel node biopsy (SNB) is a new component of the surgical treatment of breast cancer that accurately predicts axillary status. Although the procedure is still mainly investigational, many patients are requesting SNB to avoid axillary dissection if the sentinel node (SN) is negative. From March 1996 to December 1999, 373 patients with breast carcinoma and clinically negative axillary nodes underwent breast surgery, mainly conservative, and SNB. If the SN was histologically uninvolved no further surgical treatment was given. All patients were informed in detail and signed a consent form. SNB involved injection of labelled albumin particles close to the primary tumour, lymphoscintigraphy and location of the sentinel node with a gamma probe during surgery. 379 SNBs were performed on 373 patients (6 were bilateral). In 94, the SN was positive and complete axillary dissection was performed. In 285 cases (280 patients) the SN was negative and no dissection was performed: these were carefully followed with quarterly clinical examination of the axilla. A total of 343 years at risk were available for evaluation from which seven cases of axillary metastases were expected. No cases of clinically evident axillary node metastasis have occurred. These findings provide further confirmation of the validity of SNB and prompt us to suggest that it should become the method of choice for axillary staging in small-sized breast cancer.

Adult↗
PubMed2001

Pre-targeted locoregional radioimmunotherapy with 90Y-biotin in glioma patients: phase I study and preliminary therapeutic results.

The aim of this study was to determine the maximum-tolerated dose, of a pre-targeting three-step (3-S) method employing 90Y-biotin in the locoregional radioimmunotherapy (RIT) of recurrent high grade glioma, and to investigate the antitumor efficacy of this new treatment. Twenty-four patients with recurrent glioma underwent second surgical debulking and implantation of a catheter into the surgical resection cavity (SRC), in order to introduce the radioimmunotherapeutic agents [biotinylated monoclonal antibody (MoAb), avidin and 90Y-biotin]. Eight patients with anaplastic astrocytoma (AA) and 16 patients with glioblastoma (GBM) were injected with biotinylated anti-tenascin MoAb (2 mg), then with avidin (10 mg; 24 h later) and finally 90Y-biotin (18 h later). Each patient received two of these treatments 8-10 weeks apart. The injected activity ranged from 0.555 to 1.110 GBq (15-30 mCi). Dosage was escalated by 0.185 GBq (5 mCi) in four consecutive groups. The treatment was well tolerated without acute side effects up to 0.740 GBq (20 mCi). The maximum tolerated activity was 1.110 GBq (30 mCi) limited by neurological toxicity. None of the patients developed hematologic toxicity. In three patients infection occurred around the catheter. The average absorbed dose to the normal brain was minimal compared with that received at the SRC interface. At first control (after 2 months), partial (PR) and minor (MR) responses were observed in three GBM (1 PR; 2 MR) and three AA patients (1 PR; 2 MR) with an overall objective response rate of 25%. Stable disease (SD) was achieved in seven GBM and five AA patients (50%). There was disease progression in six GBM patients (25%), but in none of the AA patients. At the dosage of 0.7-0.9 GBq per cycle, locoregional 3-S-RIT was safe and produced an objective response in 25% of patients. Based on these encouraging results, phase II studies employing 3-S-RIT soon after first debulking are justified.

Adult↗
PubMed2001

Radioguided sentinel lymph node biopsy in breast cancer surgery.

The concept of sentinel lymph node biopsy in breast cancer surgery relates to the fact that the tumor drains in a logical way through the lymphatic system, from the first to upper levels. Therefore, the first lymph node met (the sentinel node) will most likely be the first to be affected by metastasis, and a negative sentinel node makes it highly unlikely that other nodes are affected. Because axillary node dissection does not improve prognosis of patients with breast cancer (being important only to stage the axilla), sentinel lymph node biopsy might replace complete axillary dissection to stage the axilla in clinically N0 patients. Sentinel lymph node biopsy would represent a significant advantage as a minimally invasive procedure, considering that, after surgery, about 70% of patients are found to be free from metastatic disease, yet axillary node dissection can lead to significant morbidity. Furthermore, histologic sampling errors can be reduced if a single (sentinel) node is assessed extensively rather than few histologic sections in a high number of lymph nodes per patient. Although the pattern of lymph drainage from breast cancer can be variable, the mammary gland and the overlying skin can be considered as a biologic unit in which lymphatics tend to follow the vasculature. Therefore, considering that tumor lymphatics are disorganized and relatively ineffective, subdermal and peritumoral injection of small aliquots of radiotracer is preferred to intratumoral administration. (99m)Tc-labeled colloids with most of the particles in the 100- to 200-nm size range would be ideal for radioguided sentinel node biopsy in breast cancer. Lymphoscintigraphy is an essential part of radioguided sentinel lymph node biopsy because images are used to direct the surgeon to the site of the node. The sentinel lymph node should have a significantly higher count than that of background (at least 10:1 intraoperatively). After removal of the sentinel node, the axilla must be reexamined to ensure that all radioactive sites are identified and removed for analysis. The sentinel lymph node should be processed for intraoperative frozen section examination in its entirety, based on conventional histopathology and, when needed, immune staining with anticytokeratin antibody. The success rate of radioguidance in localizing the sentinel lymph node in breast cancer surgery is about 94%--97% in institutions where a high number of procedures are performed and approaches 99% when combined with the vital blue dye technique. At present, there is no definite evidence that negative sentinel lymph node biopsy is invariably correlated with negative axillary status, except perhaps for T1a-b breast cancers, with a size of < or =1 cm. Randomized clinical trials should elucidate the impact of avoiding axillary node dissection on patients with a negative sentinel lymph node on the long-term clinical outcome of patients.

Breast Neoplasms↗
PubMed2001

Sentinel node biopsy in head and neck cancer.

The purpose of this study was to assess the value of sentinel node (SN) biopsy in oral cancer by means of a lymphoscintigraphic technique and intraoperative detection by blue-dye combined with gamma-ray probe to facilitate identification of the SN. Forty-one T1-T2N0 patients underwent lymphoscintigraphy, SN biopsy, and modified radical neck dissection. An SN was identified in 39 of 41 patients by the combined use of intraoperative blue dye and the probe and was removed. Complete neck dissections were performed and the histological evaluation compared. Thirty-eight SNs in 35 patients were negative at final pathology and correctly predicted the pathological status of the specimens from the full-neck dissections. Five SNs in four patients had micrometastases and were the only metastatic nodes identified. The results of this study on a homogenous series of patients show that SN biopsy is a valuable staging technique in T1 and T2 oral cancer with uninvolved neck, provided that no previous surgery or radiotherapy has altered lymphatic drainage in the oral cavity or in the neck. In a large number of patients, SN biopsy can avoid unnecessary neck dissection and its relevant morphofunctional sequelae.

Carcinoma, Squamous Cell↗
PubMed2001

The humoral immune response to macrocyclic chelating agent DOTA depends on the carrier molecule.

UNLABELLED: The chelating agent 1,4,7,10-tetraazacyclododecane-N,N', N",N"'-tetraacetic acid (DOTA) is used to label monoclonal antibodies (mAbs) and peptides with (90)Y. DOTA allows the generation of clinically useful stable metallic radioconjugates for the treatment of a variety of tumors, but its immunogenicity has remained controversial. In this study, we evaluated the immune response to DOTA in a preclinical mouse model and in patients entered in a clinical trial. METHODS: Sera were obtained from BALB/c mice injected intraperitoneally or subcutaneously with different doses and formulations of syngeneic and xenogeneic mAbs or peptide (murine mAb Mov19 [mM19]; its chimeric version; murine V/human C ChiMov19 [cM19]; or Tyr(3)-octreotide)-DOTA conjugates. Sera from patients with neuroendocrine tumors, enrolled in a protocol for somatostatin receptor-mediated radionuclide therapy with (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide (DOTATOC), were also collected before and after each treatment. Levels and specificity of antibody response to relevant (Mov19, ChiMov19, or Tyr(3)-octreotide) and nonrelevant (human serum albumin) DOTA targets were tested by enzyme-linked immunosorbent assay and competition assays. An anti-DOTA mAb (IgG1) derived from a ChiMov19-DOTA immunized mouse was used, in a competitive radioimmunoassay, to determine the efficiency of DOTA presentation on the different carriers. RESULTS: Depending on the immunogenicity and dosage of the mAb, a specific anti-DOTA response was revealed in the preclinical system. However, DOTA-peptide conjugate induced no immune-detectable response against either chelator or carrier. DOTA was poorly presented on small peptides, as determined using the anti-DOTA mAb. CONCLUSION: A humoral response against DOTA is possible, but only as a consequence of the response elicited against the carrier. Octreotide was not immunogenic. Thus, (90)Y-DOTATOC can be considered a safe and useful tool for receptor-mediated radionuclide therapy of somatostatin receptor-overexpressing tumors.

Animals↗