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Giovanni Paganelli

Publications and source records attributed to Giovanni Paganelli.

At least 19 recordsLinked to original sources
PubMed2007

Oligometastatic non-small cell lung cancer: a multidisciplinary approach in the positron emission tomographic scan era.

BACKGROUND: We have assessed the survival rate of patients with non-small cell lung cancer and synchronous hematogenous solitary metastasis identified with complete staging workup, including total body [18F]fluorodeoxyglucose positron emission tomography scan, and treated with a multidisciplinary approach. METHODS: We examined the database of all patients who underwent surgery for primary non-small cell lung cancer in our institute. The criteria required for inclusion in this analysis were diagnosis of non-small cell lung cancer with synchronous hematogenous solitary metastasis by staging workup with total body computed tomography scan and brain magnetic resonance if indicated, total body positron emission tomography scan, radical surgery for the primary tumors, local treatment of the solitary metastasis, and systemic chemotherapy administration. RESULTS: We analyzed the data from 1,509 patients treated from January 2000 to December 2005: 10 patients (0.7%) satisfied the selection criteria. The median overall survival was 26 months, and the median time to progression was 20 months; 6 patients were alive at the time of analysis, with a median follow-up of 30 months. Four patients were tumor progression-free after 9, 18, 23, and 32 months from the start of their treatment. CONCLUSIONS: The presentation of non-small cell lung cancer with a synchronous hematogenous solitary metastasis identified by [18F]fluorodeoxyglucose positron emission tomography containing complete staging workup is extremely rare. This subset of patients can achieve long-term survival after a multidisciplinary treatment approach.

Adult↗
PubMed2006

IART: intraoperative avidination for radionuclide treatment. A new way of partial breast irradiation.

A new procedure, known as Intraoperative Avidination for Radionuclide Therapy (IART), is described in breast cancer patients. In this paper, we provide proof of the principle that intraoperative injection of avidin in the tumour bed after quadrantectomy allows homing in of intravenously (IV) administered radioactive biotin to the target site. This approach of targeted therapy consists of two steps: (i) "avidination" of the anatomical area of the tumour with avidin injected by the surgeon, into and around the tumour bed; (ii) targeting the anatomical area of the tumour by IV injection of radiolabelled biotin. The scintigraphic images demonstrated fast and stable uptake of labelled biotin at the site of operated breast. The radiation dose released to the index quadrant was more than 5 Gy/GBq, consistent with a boost of 20 Gy for an activity of 3.7 GBq 90Y-biotin (100mCi). A further large clinical trial facing IART in combination with reduced external-beam radiotherapy is, in our opinion, fully justified.

Adult↗
PubMed2006

Radiation protection in radionuclide therapies with (90)Y-conjugates: risks and safety.

PURPOSE: The widespread interest in (90)Y internal radionuclide treatments has drawn attention to the issue of radiation protection for staff. Our aim in this study was to identify personnel at risk and to validate the protection devices used. METHODS: (90)Y-MoAb (Zevalin, 15 cases, 1.1 GBq/patient) and (90)Y-peptide ((90)Y-DOTATOC) systemic (i.v., 50 cases, 3.0 GBq/patient) and locoregional (l.r., 50 cases, 0.4 GBq/patient) treatments were considered. Radiolabelling was carried out in a dedicated hot cell. Tele-tongs, shielded (PMMA: polymethylmethacrylate) syringes/vials and an automatic dose fractionating system were used. Operators wore anti-X-ray and anti-contamination gloves, with TLD dosimeters placed over the fingertips. For i.v. administration, activity was administered by a dedicated system; for l.r. administration, during activity infusion in the brain cavity, tongs were used and TLDs were placed over the fingertips. The air kerma-rate was measured around the patients. RESULTS: The use of devices provided a 75% dose reduction, with mean fingertip doses of 2.9 mGy (i.v. MoAbs), 0.6 mGy (i.v. peptides)/radiolabelling procedure and 0.5 mGy/l.r. administration. The mean effective dose to personnel was 5 microSv/patient. The air kerma-rate around the patients administered i.v. (90)Y-peptides were 3.5 (1 h) and 1.0 (48 h) microGy/h at 1 m. Patient hospitalisation of 6 h (l.r.)/48 h (i.v.) guaranteed that the recommended limits of 3 mSv/year to family members and 0.3 mSv/year to the general population (Council Directive 97/43/Euratom) were respected. CONCLUSIONS: When specific procedures are adopted, a substantial improvement in (90)Y manipulation is attainable, reducing doses and increasing safety. For the widespread clinical use of (90)Y-conjugates, a completely automatic labelling procedure is desirable.

Italy↗
PubMed2006

Evaluation of a new biotin-DOTA conjugate for pretargeted antibody-guided radioimmunotherapy (PAGRIT).

PURPOSE: A novel biotin-DOTA conjugate (r-BHD: reduced biotinamidohexylamine-DOTA) was investigated in order to provide an efficient pretargeted antibody-guided radioimmunotherapy (PAGRIT) application. Preclinical and clinical results are described. METHODS: (90)Y and (177)Lu were used to label r-BHD. The effect of pH and a wide range of specific activities were studied. Radiolabelled r-BHD was tested for affinity towards avidin and for stability in saline or in human serum with and without ascorbic acid. Pharmacokinetic data were collected and organ biodistribution evaluated in a tumour-bearing pretargeted animal model. A pilot study was performed in a metastatic melanoma patient and dosimetry was estimated. RESULTS: High radiochemical purity (>99%) was routinely achieved with (90)Y or (177)Lu in sodium acetate buffer (1.0 M, pH 5.0) at a specific activity of 2.6 MBq/nmol. Both (90)Y- and (177)Lu-r-BHD were also prepared at higher specific activities. Radiolabelled r-BHD was stable up to 96 h in human serum and saline with the addition of ascorbic acid. The structural modifications proposed for the r-BHD stabilised it against enzymatic degradation while retaining high binding affinity for avidin. Renal clearance appeared to be the main route of excretion in animals, and high tumour uptake was observed in the pretargeted animals. The patient study showed a total body clearance of approximately 85% in 24 h, with a kidney absorbed dose of 1.5 mGy/MBq. Tumour uptake was rapid and the calculated dose to a 10-mm tumour lesion was approximately 12 mGy/MBq. CONCLUSION: These results indicate that the new biotin-DOTA conjugate may be a suitable candidate for pretargeting trials.

Animals↗
PubMed2006

Low and high tenascin-expressing tumors are efficiently targeted by ST2146 monoclonal antibody.

ST2146biot is a biotinylated anti-tenascin monoclonal antibody (mAb) to be used for Pretargeted Antibody Guided Radioimmunotherapy (PAGRIT) of solid tumors. In vivo biodistribution studies of (125)I-labeled ST2146biot were done in nude mice transplanted with human HT-29 colon carcinoma and/or human U-118MG glioblastoma cells characterized for low and high tenascin expression, respectively. In vitro results show that ST2146 retains immunoreactivity upon biotinylation, in contrast to other anti-tenascin mAbs. In vivo biodistribution of ST2146 shows specific tumor accumulation up to 10 days after the i.v. injection, with no relevant differences between biotinylated and nonbiotinylated ST2146. A dose of 4 microg/mouse saturates the low tenascin-expressing human colon carcinoma HT-29, whereas the high tenascin-expressing human glioblastoma U-118MG seems to be saturated at a ST2146biot dose between 320 and 640 microg/mouse. The percentage of injected dose per gram of tumor ranges from 10% to 30%, corresponding to an amount of ST2146biot/g of tumor of approximately 400 ng/g and >200 microg/g for HT-29 and U-118MG, respectively. Tumor to normal organs uptake ratios are between 15 and 60, confirming high tumor selectivity of ST2146biot despite its cross-reactivity with the tenascin expressed at low level in the normal mouse organs. The ST2146biot localization data are substantially confirmed even when both low and high tenascin-expressing tumors are implanted in the same animal. To our knowledge, the absolute amount of ST2146biot, specifically localized in xenotransplanted human tumors, is the highest thus far described and supports the clinical use of this mAb in PAGRIT(R).

Adenocarcinoma↗
PubMed2006

Sentinel-lymph-node biopsy as a staging procedure in breast cancer: update of a randomised controlled study.

BACKGROUND: In women with breast cancer, sentinel-lymph-node biopsy (SLNB) provides information that allows surgeons to avoid axillary-lymph-node dissection (ALND) if the SLN does not have metastasis, and has a favourable effect on quality of life. Results of our previous trial showed that SLNB accurately screens the ALN for metastasis in breast cancers of diameter 2 mm or less. We aimed to update this trial with results from longer follow-up. METHODS: Women with breast tumours of diameter 2 cm or less were randomly assigned after breast-conserving surgery either to SLNB and total ALND (ALND group), or to SLNB followed by ALND only if the SLN was involved (SLN group). Analysis was restricted to patients whose tumour characteristics met eligibility criteria after treatment. The main endpoints were the number of axillary metastases in women in the SLN group with negative SLNs, staging power of SLNB, and disease-free and overall survival. FINDINGS: Of the 257 patients in the ALND group, 83 (32%) had a positive SLN and 174 (68%) had a negative SLN; eight of those with negative SLNs were found to have false-negative SLNs. Of the 259 patients in the SLN group, 92 (36%) had a positive SLN, and 167 (65%) had a negative SLN. One case of overt clinical axillary metastasis was seen in the follow-up of the 167 women in the SLN group who did not receive ALND (ie, one false-negative). After a median follow-up of 79 months (range 15-97), 34 events associated with breast cancer occurred: 18 in the ALND group, and 16 in the SLN group (log-rank p=0.6). The overall 5-year survival of all patients was 96.4% (95% CI 94.1-98.7) in the ALND group and 98.4% (96.9-100) in the SLN group (log-rank p=0.1). INTERPRETATION: SLNB can allow total ALND to be avoided in patients with negative SLNs, while reducing postoperative morbidity and the costs of hospital stay. The finding that only one overt axillary metastasis occurred during follow-up of patients who did not receive ALND (whereas eight cases were expected) could be explained by various hypotheses, including those from cancer-stem-cell research.

Adult↗
PubMed2006

Radioimmunotherapy of brain tumor.

Despite years of intensive research, the prognosis of high-grade gliomas (HGG) remains poor, as these tumors are highly resistant to currently available therapies. Therefore, there is a need for the development of new therapeutic strategies, such as the use of monoclonal antibodies (MoAbs) in association with radioisotopes, in order to achieve better responses and prognosis. This article describes our experience in radioimmunotherapy (RIT) with MoAbs and tumor pre-targeting with the avidin-biotin system, either in systemic or locoregional administrations. This therapy offers the exciting prospect of increasing the specificity of tumor cell irradiation with radioisotopes. We suggest that RIT, both systemic and locoregional, should be used as part of a combined modality approach: in combination with surgery, radiotherapy and chemotherapy.

Animals↗
PubMed2006

Dosimetric model for locoregional treatments of brain tumors with 90Y-conjugates: clinical application with 90Y-DOTATOC.

UNLABELLED: Locoregional (LR) administration of (90)Y-conjugates after surgical debulking is a promising therapeutic option of gliomas. Dosimetry is highly recommended, as patient-specific parameters influence the absorbed dose to target and normal tissues. After tumor resection, the absorbed dose must be carefully evaluated in the rim of tissue surrounding the resected area. The aim of this study was to calculate and provide the S values, according to the MIRD concept, for dosimetry of LR brain treatments with several (90)Y-labeled compounds. The S values thus obtained have been clinically applied in 12 patients treated with (90)Y-labeled [DOTA(0),D-Phe(1),Tyr(3)]octreotide ((90)Y-DOTATOC). METHODS: An anthropomorphic model for Monte Carlo simulations was developed to evaluate absorbed doses in brain-adjacent tissue (BAT) and in normal brain. To adapt the model to single patients, S values were evaluated taking into account (i) different surgical resection cavity (SRC) volumes, (ii) different percentages of conjugate binding to the cavity wall, and (iii) different depths of percolation of the conjugate trough the cavity wall. BAT was divided into 1-mm-thick consecutive adjacent shells to evaluate the dose distribution around the cavity. Corresponding S values were obtained to allow dosimetric evaluation in brain LR therapy with (90)Y-conjugates. In the clinical treatments, 0.4-1.1 GBq of (90)Y-DOTATOC were injected into the SRC via an appropriate catheter. The activity in the SRC was assumed to be the difference between the total injected activity and the activity in the blood plus the activity cumulatively eliminated with the urine. RESULTS: Assuming no diffusion, with a mean residence time in SRC of 60 +/- 8 h, absorbed doses to shell II were 0.25 and 0.03 Gy/MBq for SRC volumes of 7.2 and 65.4 mL, respectively. Assuming a slight diffusion of 1 mm with a 7.2-mL SRC, absorbed dose to shells I, II, and VI were consistently different: 5.32, 2.53, and 0.12 Gy/MBq, respectively. Mean doses to normal brain, red marrow, bladder wall, and total body were 0.015, 0.03, 1.22, and 0.006 MGy/MBq. CONCLUSION: The model proved to be suitable for the dosimetry of several LR therapies with (90)Y-conjugates. According to our results, LR treatment with (90)Y-DOTATOC can safely deliver very high doses to target tissue, sparing normal organs including brain.

Adult↗
PubMed2006

Dosimetry in Peptide radionuclide receptor therapy: a review.

The potential of targeted therapy with radiolabeled peptides has been reported in several clinical trials. Although there have been many improvements in dose estimation, a general and reliable dosimetric approach in peptide receptor radionuclide therapy (PRRT) is still a matter of debate. This article reviews the methods for PRRT dosimetry and the results presented in the literature. Radiopharmaceutical characteristics, data processing, dosimetric outcomes, and methods to protect critical organs are reported. The biological effective dose, based on the linear quadratic model, is also described.

Computer Simulation↗
PubMed2005

Antibody pretargeting advances cancer radioimmunodetection and radioimmunotherapy.

This article reviews the methods of pretargeting, which involve separating the targeting antibody from the subsequent delivery of an imaging or therapeutic agent that binds to the tumor-localized antibody. This provides enhanced tumor:background ratios and the delivery of a higher therapeutic dose than when antibodies are directly conjugated with radionuclides, as currently practiced in cancer radioimmunotherapy. We describe initial promising clinical results using streptavidin-antibody constructs with biotin-radionuclide conjugates in the treatment of patients with malignant gliomas, and of bispecific antibodies with hapten-radionuclides in the therapy of tumors expressing carcinoembryonic antigen, such as medullary thyroid and small-cell lung cancers.

Antibodies, Neoplasm↗
PubMed2005

Preparation and characterization of active site protected poly(ethylene glycol)-avidin bioconjugates.

Avidin was modified with poly(ethylene glycol) in the presence of a biotin binding site protective agent synthesised by imminobiotin conjugation to branched 20 kDa PEG. Avidin was incubated with imminobiotin-PEG and reacted with high amounts of 5, 10 or 20 kDa PEG to modify the protein amino groups. Circular dichroism demonstrated that the extensive PEGylation does not alter the protein conformational structure. The affinity of avidin-PEG conjugates for biotin and biotinylated antibodies depended on the PEG size or the use of a protective agent. Avidin-PEG 10 and 20 kDa prepared in the presence of imminobiotin-PEG maintained 100% of the native affinity for biotin. The 5 kDa PEG derivative and the ones obtained without biotin site protection maintained 79-85% of the native affinity. The affinity for biotinylated antibodies decreased to 35% when the conjugation was performed without imminobiotin-PEG, while the conjugates obtained with high-molecular-weight PEGs in the presence of protective agent displayed high residual affinity. All conjugates possessed negligible antigenicity and immunogenicity. PEGylation greatly prolonged the avidin permanence in the circulation, reduced its disposition in the liver and kidneys and promoted accumulation into solid tumors. PEGylation was found to prevent the protein cell uptake, either by phagocytosis or pinocytosis.

Animals↗
PubMed2005

Improved tumor targeting by combined use of two antitenascin antibodies.

PURPOSE: In the pretargeted antibody-guided radioimmunotherapy (PAGRIT) system, the combined use of two different antibodies directed against the same tumor antigen could represent a valid approach for improving tumor targeting and therapeutic efficacy. We developed a novel monoclonal antitenascin antibody, ST2485, and studied its biochemical and functional properties by in vitro and in vivo assays. We then investigated the first of the three-step therapy combining ST2485 with another antitenascin antibody, ST2146, previously described, to increase accumulation of biotinylated antibodies at the tumor site. EXPERIMENTAL DESIGN: Studies of immunoreactivity, affinity, immunohistochemistry, and biodistribution in xenograft model were carried out on ST2485. Analysis of the ST2485 and ST2146 combination was preliminary carried out by ELISA and BiaCore tests and then by in vivo distribution studies after administration of the radiolabeled biotinylated antibodies, followed by a chase with avidin as clearing agent. RESULTS: ST2485 was found to be a suitable antibody for therapeutic applications. Indeed, for its behavior in all tests, it was comparable with ST2146 and better than BC2, an antibody already used for clinical trials. The additivity of ST2146 and ST2485 in tenascin C binding, shown by in vitro tests, was confirmed by biodistribution studies in a xenograft model where tumor localization of the antibodies was near the sum of each antibody alone, with a tumor-to-blood ratio higher than 24. CONCLUSION: The results reported in this study suggest that a monoclonal antitenascin antibody mixture can improve tumor targeting. This strategy could represent progress for therapeutic approaches such as PAGRIT.

Amino Acid Sequence↗
PubMed2005

Second biopsy of axillary sentinel lymph node for reappearing breast cancer after previous sentinel lymph node biopsy.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a safe and accurate axillary staging procedure for patients with primary operable breast cancer. An increasing proportion of these patients undergo breast-conserving surgery, and 5% to 15% will develop local relapses that necessitate reoperation. Although a previous SLNB is often considered a contraindication for a subsequent SLNB, few data support this concern. METHODS: Between January 2000 and June 2004, 79 patients who were previously treated at our institution with breast-conserving surgery and who had a negative SLNB for early breast cancer developed, during follow-up, local recurrence that was amenable to reoperation. Eighteen of these patients were offered a second SLNB because of a clinically negative axillary status an average of 26.1 months after the primary event. RESULTS: In all 18 patients (7 with ductal carcinoma-in-situ and 11 with invasive recurrences), preoperative lymphoscintigraphy showed an axillary sentinel lymph node, with a preoperative identification rate of 100%, and 1 or more SLNs (an average of 1.3 per patient) were surgically removed. Sentinel lymph node metastases were detected in two patients with invasive recurrence, and a complete axillary dissection followed. At a median follow up of 12.7 months, no axillary recurrences have occurred in patients who did not undergo axillary dissection. CONCLUSIONS: Second SLNB after previous SLNB is technically feasible and likely effective in selected breast cancer patients. A larger population and longer follow-up are necessary to confirm these preliminary data.

Adult↗
PubMed2005

Membrane IgE binds and activates Fc epsilon RI in an antigen-independent manner.

Interaction of secretory IgE with FcepsilonRI is the prerequisite for allergen-driven cellular responses, fundamental events in immediate and chronic allergic manifestations. Previous studies reported the binding of soluble FcepsilonRIalpha to membrane IgE exposed on B cells. In this study, the functional interaction between human membrane IgE and human FcepsilonRI is presented. Four different IgE versions were expressed in mouse B cell lines, namely: a truncation at the Cepsilon2-Cepsilon3 junction of membrane IgE isoform long, membrane IgE isoform long (without Igalpha/Igbeta BCR accessory proteins), and both epsilonBCRs (containing membrane IgE isoforms short and long). All membrane IgE versions activated a rat basophilic leukemia cell line transfected with human FcepsilonRI, as detected by measuring the release of both preformed and newly synthesized mediators. The interaction led also to Ca(2+) responses in the basophil cell line, while membrane IgE-FcepsilonRI complexes were detected by immunoprecipitation. FcepsilonRI activation by membrane IgE occurs in an Ag-independent manner. Noteworthily, human peripheral blood basophils and monocytes also were activated upon contact with cells bearing membrane IgE. In humans, the presence of FcepsilonRI in several cellular entities suggests a possible membrane IgE-FcepsilonRI-driven cell-cell dialogue, with likely implications for IgE homeostasis in physiology and pathology.

Animals↗
PubMed2005

Predicting the status of axillary sentinel lymph nodes in 4351 patients with invasive breast carcinoma treated in a single institution.

BACKGROUND: Reliable predictors of metastatic involvement would enable a better selection of candidate patients for sentinel lymph node biopsy (SLNB) and possibly allow identification of patients with such a low risk of axillary sentinel lymph node (SLN) involvement to be even spared SLNB. METHODS: The authors evaluated 4351 consecutive patients surgically treated for breast carcinoma who also underwent SLNB. Clinicopathologic features significantly associated with SLN metastases by univariate analysis were included in a multivariate model. RESULTS: By multivariate analysis, the prevalence of SLN metastases was associated directly with tumor size, multifocality, and with the occurrence of peritumoral vascular invasion (PVI; all P < 0.0001), and was associated inversely with a favorable histotype (P = 0.0007) and lack of progesterone receptors (P = 0.004). A predictive model based on the features more closely associated with SLN status documented that the patients with a favorable tumor type </= 1 cm in size and without PVI (n = 178 [4% of the population]) had the lowest risk of SLN metastases (9.5%) whereas patients with tumors > 2 cm and with PVI (n = 250 [5.7% of the population]) had the highest risk (77.2%) of SLN involvement. CONCLUSIONS: Tumor size and PVI emerged as the most powerful independent predictors of SLN metastases. Although no combination of features identified patients with a < 9.5% risk of SLN metastases, the current data may be used to tailor the management of patients with breast carcinoma with the aim of minimizing as much as possible the diagnostic and therapeutic procedures, thus improving the quality of life of the patients without any adverse effect on their survival rates.

Adolescent↗
PubMed2005

The sentinel lymph node biopsy under local anesthesia in breast carcinoma: experience of the European Institute of Oncology and impact on quality of life.

BACKGROUND: Sentinel lymph node biopsy performed under local anesthesia currently represents one of the main fields of investigation in breast cancer surgery because of its positive impact on the management and organisation of treatment. We previously published our preliminary experience with 115 patients; here we present an update of our experience with particular attention devoted to quality of life. PATIENTS AND METHODS: From September 2000 to April 2003 we treated 244 patients with this technique. We developed a 'questionnaire of impact on quality of life - LA' to be administered to these patients, to assess their reactions to the procedure: we administered the questionnaire to 243 patients. Our aim was to verify whether the advantages in terms of treatment planning are accompanied by an improvement in quality of life and a good degree of acceptance by the patients. RESULTS: The questionnaire was administered to the patients during follow-up and we obtained positive results; the impact of the procedure under local anesthesia was positive for 81% of patients, while the remaining 19% reported that it had 'no impact at all'. We can conclude that axillary sentinel node biopsy, when performed under local anesthesia, meets with a very high degree of acceptance by the patients and exerts an optimal impact on quality of life.

Adult↗
PubMed2005

The sentinel node biopsy after previous breast surgery: preliminary results on 543 patients treated at the European Institute of Oncology.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is an accurate alternative to complete axillary lymph node dissection (ALND) in clinically node-negative breast cancer patients. A previous breast biopsy has been considered a relative contraindication to SLNB. We examined the accuracy of SLNB by following the axillary relapses after the procedure in patients who had undergone a breast biopsy before SLNB. PATIENTS AND METHODS: Up to December 2003, 4351 patients with the diagnosis of invasive breast cancer underwent SLNB at the European Institute of Oncology. Already, 543 of these patients had undergone a breast biopsy; from June 1997 to January 2004, these patients received SLNB by lymphoscintigraphy performed on the biopsy area. We followed these patients with a clinical assessment every 6 months and instrumental examinations every year, particularly focusing on the research of axillary relapse of disease. RESULTS: In 70.4% of cases, the sentinel node was negative, and only three cases underwent further axillary dissection. The sentinel node was identified in 99% of cases and this was the only positive node in 61.5% of cases with positive axillary nodes. The median follow-up was 2 years; 4 nodal recurrences were observed: 3 axillary lymph node relapses and 1 loco-regional. CONCLUSIONS: SLNB accuracy after a previous breast biopsy is comparable with the results obtained in validation studies. SLNB after a previous breast biopsy can be considered a standard procedure. Lymphoscintigraphy identifies the sentinel node in 99% of patients.

Adult↗