[en] Introduction: ¹⁷⁷Lu labeled DOTA-TATE, a somatostatin analog, is presently being considered as a promising agent for the treatment of patients suffering from inoperable neuroendocrine tumors which over-expresses somatostatin receptors. One of the challenges involved in carrying out targeted tumor therapy using ¹⁷⁷Lu-DOTA-TATE is to prepare the radiolabeled agent with adequately high specific activity in order that sufficient activity can be deposited in the cancerous lesions without saturating the limited number of receptors present in the cancerous site. As the specific activity of ¹⁷⁷Lu available at the time of preparation of the agent may vary considerably, it is crucial and poses a challenge to optimize the labeling protocol, more importantly with respect to the amount of peptide, in order that it can be prepared with high radiochemical purity using minimum amount of DOTA-TATE. The present paper describes our studies towards preparing several batches of ¹⁷⁷Lu-DOTA-TATE for clinical application in human patients using indigenously produced ¹⁷⁷Lu. Experimental: ¹⁷⁷Lu was produced by thermal neutron bombardment on enriched (64.3% to 82% in ¹⁷⁶Lu) Lu₂O₃ target at a neutron flux of 6x10¹³-1x10¹⁴ n/cm².s for 21 days in our Institute's reactor. For the preparation of a patient dose of ¹⁷⁷Lu-DOTA-TATE (typically 150-200 mCi, 5.55-7.40 GBq), first the amount of Lu required to obtain that dose was calculated from the specific activity of ¹⁷⁷Lu after the necessary decay correction. The requirement of DOTA-TATE was subsequently determined considering that DOTA-TATE: Lu molar ratio to be 4:1 (minimum requirement for achieving adequate stability post-preparation). A stock solution of the DOTA-TATE, prepared in de-ionized water with a concentration of 1 μg/μL, was used for the preparation of the agent. Required volume of DOTA-TATE solution and ''1''7''7LuCl3 were added to three times of their volume equivalent of 0.1 M ammonium acetate buffer (pH ∼5) containing 40 mg/mL gentisic acid. The pH of the reaction mixture was adjusted, if required, within 4-5. The preparation was then subsequently heated in at 90^oC (boiling water bath) for 60 min. Quality control was performed by employing paper chromatography (PC) and high performance liquid chromatography (HPLC) techniques. Finally, the preparation was subjected to Millipore filtration and administered to the patients. Considering typical specific activity of ¹⁷⁷Lu available during the preparation of the agent to be 25 Ci/mg (925 GBq/mg), a 200 mCi (7.40 GBq) patient dose requires the use of 8 μg i.e. 0.045 μM Lu. This implies that 260 μg of DOTA-TATE needs to be used for the preparation. Therefore, for the actual preparation of the agent 260 μL of DOTA-TATE stock solution was added to ∼1.4 mL of 0.1 M ammonium acetate buffer containing 56 mg of gentisic acid followed by 200 mCi (typical volume 200 μL) of ¹⁷⁷LuCl3. Results: ¹⁷⁷Lu was obtained with a specific activity range of 20-40 Ci/mg (740-1480 GBq/mg). Several batches of ¹⁷⁷Lu-DOTA-TATE were prepared using the ¹⁷⁷Lu and the amount of DOTA-TATE required to prepare a patient dose of 200 mCi varied from 175-350 μg. A patient dose is typically achieved in a total volume of 1.5-2.2 mL. In PC performed using 50% acetonitrile in water, ¹⁷⁷Lu-DOTA-TATE moved from the point of spotting (Rf >0.4) while uncomplexed ¹⁷⁷Lu remained at the point of application (Rf = 0). In HPLC carried out employing gradient elution technique using water and acetonitrile mixed with 0.1% trifluoroacetic acid as the eluting solvent, ¹⁷⁷Lu-DOTA-TATE exhibited a retention time of 900 s, while uncomplexed ¹⁷⁷Lu eluted out within 250 s. The radiochemical purity of the ¹⁷⁷Lu-DOTA-TATE complex was determined to be 98.25±1.1%. The agent was obtained with a specific activity of 0.57-1.14 Ci/mg (21.14-42.29 GBq/mg) or 0.82x10³-1.63x10³ Ci/mMole (30.23-60.46 TBq/mMole). Conclusion: An optimized protocol was developed for the preparation of injectible ¹⁷⁷Lu- DOTA-TATE with high specific activity taking into account the variable specific activity of ¹⁷⁷Lu available during the preparation of the agent. Several batches of the agent were prepared with high radiochemical purity following this protocol. ¹⁷⁷Lu-DOTA-TATE prepared following this protocol is regularly being administered to the patients suffering from neuroendocrine tumors. (author)

[en] Radiopharmaceuticals have been used to treat cancer for over 70 years. Molecular radiotherapy (MRT) is currently a major growth area with an increasing number of compounds entering the clinic and a rapidly expanding interest in the scientific aspects of radiation delivery. Whilst radiopharmaceuticals have generally been administered according to similar protocols defined for non-radioactive drug delivery, primarily with fixed activities or sometimes based on patient weight or body surface area, recent scientific advances in quantitative imaging and internal dosimetry are now causing a shift toward administrations that take into account individual dosimetry, as is routinely the case for external beam radiotherapy (EBRT). The relative lack of progress in MRT belies the fact that this area does not require the significant resources that are required for EBRT. At a basic level, dosimetry can be considered separately for the whole-body, which requires external measurements of the activity retained in the patient following administration, or tumour or normal organ dosimetry, for which absorbed dose calculations are based on image data. Whole-body dosimetry can be performed with relative ease and accuracy. An external measurement obtained immediately following administration of a radiopharmaceutical provides a baseline count relating to activity in vivo. Subsequent measurements can then be related to this baseline to provide an accurate calculation of the activity retained at any time. This is useful for radiation protection purposes but can also be used to calculate whole-body absorbed doses which have been shown to correlate with haematological toxicity. This is the basis for treatment with I-131 tositumomab for non-Hodgkins lymphoma, where patients are prescribed an activity that will deliver a 0.75 Gy whole-body absorbed dose and for an international study using I-131 mIBG to treat neuroblastoma, where the protocol is designed to deliver a total of 4 Gy whole-body absorbed dose in 2 fractions. The I-131 mIBG is given concomitantly with topotecan which is a topoisomerase inhibitor that can act as a radiosensitiser, indicating the potential for multi-modality therapy that is currently being explored. The accuracy of whole-body dosimetry can be calculated and is dependent in turn on the accuracy of measurements, which for example should be obtained immediately after patient voiding, and on the number of measurements acquired for each effective decay phase. Image-based tumour or normal organ dosimetry can offer more detailed information regarding the localisation of uptake and retention of an administered radiopharmaceutical. Time-sequential images are acquired following administration and by application of suitable calibration factors activity-time curves are used to estimate the cumulated activities in user- defined regions of interest. Image-based dosimetry is prone to large errors and uncertainties if not performed correctly although can yield clinically useful information. It is essential that routine quality control (for example to correct for uniformity and centre-of-rotation misalignment) is performed to ensure that the camera is operating correctly and initial measurements should include characterisation of deadtime, as the large activities encountered in MRT can cause erratic response. For the quantitative imaging required for absorbed dose calculations image corrections are essential although can be performed with relative ease. Scatter correction is particularly relevant for high energy beta emitters such as I-131 and can be performed by acquiring counts in energy windows adjacent to the peak window. For SPECT imaging, attenuation correction should be performed using measured attenuation coefficients for the radionuclide used. The optimal SPECT image reconstruction method or parameters to use for any given radionuclide have not been defined. These must be considered carefully and are dependent on the localisation of activity and count rate. As with whole-body dosimetry, the accuracy of dosimetry calculations is dependent on the number of measurements (i.e. scans) obtained although in practice a total of 3-4 scans are usually sufficient as the effective decay in any given organ, or tumour, is frequently mono- exponential. An increasing number of studies are now demonstrating that the effect of treatment, both in terms of response and toxicity, is dependent on the absorbed doses delivered to target and to normal tissues. This raises the prospect of personalised treatment planning, whereby the level and frequency of administrations are tailored to the individual patient. Patient-specific treatments promise a significant increase in the effectiveness of molecular radiotherapy and offer a significant improvement on current population-based treatments. As only a small number of patients are treated at individual centres it is essential that prospective data collection is performed in multi-centre studies. However the variation in methods employed at different centres to perform dosimetry hinder direct comparisons of absorbed dose calculations. To address this, the EANM dosimetry committee are undertaking a program (DOSITEST) to assess the current range of methodologies employed and their relative accuracies to harmonise practice

[en] Monoclonal antibody ('MAB') has been developed for targeting secretory alpha-fetoprotein in hepatic tissue. We have used these MABs for radioimmunotherapy and dose planning of recurrent hepatoblastoma, a rare childhood malignancy This MAB has been labelled with In- 111 and Y-90 for clinical purposes, and can be applied for diagnosis and therapy of liver neoplasms. Physiology based pharmacokinetic (PBPK) modeling and simulation is a useful method for prediction of biodistribution of macromolecules, it can enhance our understanding of the underlying mechanisms and hence may help in rational design of diagnostic and therapeutic agents. Here we also discuss PBPK modeling and simulation of this MAB in mice without tumor and in a pediatric patient. In the clinical study, radiopharmacokinetic parameters for this MAB (¹¹¹In-DOTA-hAFP31 IgG) were calculated after serial quantitative whole body scans in a child with hepatoblastoma. A 3-D dose planning computer program was used to calculate tumor doses for In-111 and Y-90, the active tumor was delineated on PET/CT images and tumor dose calculation was done based on the In-111-MAB SPECT data using dose point kernel approach both for In-111 and Y-90. The results were compared with MIRD doses obtained for organs in SPECT imaging field, i.e. bone marrow, heart, kidneys, liver, spleen, lungs. The simulated results were fitted to experimental time series data by varying parameters which were not fixed a priori. From quantitative serial imaging based on 8 whole body images at 0-168 hrs using In-111- MAB, the half-lives of spleen, lungs, kidneys and whole body were 502 hrs, 230 hrs, 193 hrs and 490 hrs, respectively. The measured blood half-life was 132 hrs, after a total MAB dose of 50 mg and In-111 activity of 105 MBq. The presumed Y-90 dose based on this kinetic behavior was 43 MBq which should had given 0.3Gy bone marrow dose with assumption of bone marrow: blood ratio 0.4 for IgG. The calculated MIRD Y-90 doses were for cardiac wall 0.75 Gy, liver 0.62 Gy, spleen 0.51 Gy and bone marrow 0.053 Gy, and the effective whole body dose was 0.18 Gy, i.e. 4.23 mGy/MBq. The 3-D program demonstrated the mean doses in normal tissues as follows: heart 0.58 Gy, liver 0.48 Gy, spleen 0.37 Gy and bone marrow 0.34 Gy. The actual liver tumor dose according to the 3-D calculations was in average 0.51 Gy with range of 0.22-0.96 Gy. It was demonstrated that the PBPK model describes the main features of the pharmacokinetics of the studied systems. It was also shown that simulation can be used for evaluating the parameters of the system and scaling up the pharmacokinetics of MAB from mice to man. As a conclusion, according to the data, probably 5-6 fold activity could have been infused without limiting toxicity. Using current activity only minor change in the biomarker behavior was observed, but with higher activities the response could have been evaluated. This data demonstrates that radioimmunotherapy procedure may be applied in childhood solid tumors, if appropriate dosimetry software is available. It was also concluded that the transvascular permeabilities are the most important parameters and more research is needed to enable prediction of permeabilities from molecular characteristics of macromolecules. It would also be necessary to understand better and describe with a more detailed model the microstructure of the tumor and to measure or predict the antigen concentration in tumor. Non-specific, non-saturable binding in other organs/tissues should be understood better and the kinetic constants of the binding should be measured experimentally. Although the metabolism and clearance were neglected in this study they need to be included in more detailed studies. Also the intracellular trafficking of macromolecules, which was not included in this study, shall be included in the more accurate models. (author)

[en] ⁹⁰Y is increasingly accepted world wide as a radionuclide for in-vivo therapy owing to attractive decay features (T1/2 2.67 d; Eβ max 2.28 MeV) and viable production feasibility in high specific activities. ⁹⁰Y is most often recommended for treatment of large tumour lesions as the hard β rays are effective in delivering therapeutic dose to large volume. However, possibility of high radiation dose to the critical organs such as bone marrow and kidneys is an important concern that is given due weightage while designing therapy using ⁹⁰Y. The best route to avail ⁹⁰Y for therapy applications is from ⁹⁰Sr, though neutron actiation of natural ⁸⁹Y(100% abundance) is feasible. The absorption cross section σ is barely 1.38 b, resulting in low specific activity ⁹⁰Y which is useful for limited applications. The possibility of obtaining 90Y through a radionuclide generator as the daughter of a long lived parent ⁹⁰Sr (T1/2 28.9 y) is a major advantage that enables access to high specific activity ⁹⁰Y. Transporting the 90Y activity to a user institution from a centralized production facility is reasonably feasible and this facilitates its wide spread use. Several generator designs have been developed and reported to access ⁹⁰Y. Solvent extraction using a chelating molecule in an organic solvent (0.3M HDEHP/n-dodecane), column chromatography using ion exchange resins (cationic as well as anionic; Dowex-50x8; AG 50x16; Aminex-A5) or inorganic exchanger, membrane based separation using chelating ligand impregnated membranes (CMPO in electrochemical separation are some of the methods reported. Limitations such as elution of ⁹⁰Y after initial elution of ⁹⁰Sr, availability of ⁹⁰Y as a chelated complex which then has to be treated to enable labeling the molecule of interest, possibility of obtaining small quantities of ⁹⁰Y owing to radiolytic damages to the separation system components, paucity of special automation gadgets for handling the high activities remotely, have been some impediments that have delayed the availability of large scale ⁹⁰Sr/⁹⁰Y generators and consequently the wide spread use of ⁹⁰Y. Further, the bone seeking nature of the long lived ⁹⁰Sr+2 has resulted in the very low tolerance limits for ⁹⁰Sr (≤ 74 MBq life time dose), necessitating use of extremely pure ⁹⁰Y. Considering that a patient may require treatment with ∼3.7 GBq ⁹⁰Y several times in life-time, the permissible levels for ⁹⁰Sr is well below 10-4%. Hence, a very clean separation of ⁹⁰Y from ⁹⁰Sr is essential and it is also essential to ensure the quality of the ⁹⁰Y using a reliable, real-time quality control technique. Absence of γ rays in both the nuclides, makes it difficult to quantitate the nuclides, particularly when sub-ppm levels of ⁹⁰Sr has to be measured in ⁹⁰Y. Very few methods have been reported for QC of ⁹⁰Y. Measurement of ⁹⁰Sr levels after decay of ⁹⁰Y, though simple, does not enable QC before clinical use. Use of specific crown ether based resin for retention of trace levels of ⁹⁰Sr enables real-time QC, but is cumbersome and expensive. In this context, the IAEA's CRPs on 'The Development of Therapeutic Radionuclide Generators' and it's sequel 'Development of radiopharmaceuticals based on ¹⁸⁸Re and ⁹⁰Y for radionuclide therapy' have been highly impactive and heartening. Two types of novel generators, namely the 'Supported Liquid Membrane' based generators and the 'Electrochemical Generators' have been developed by us. The latter one, named as 'Kamadhenu', the mythological cow that yields milk eternally, has been developed further as an automated model and ready for deployment. QC of ⁹⁰Y for quantitative estimation of sub- ppb levels of ⁹⁰Sr using a novel simple technique of 'Extraction Paper Chromatography' has also been achieved by us, primarily as a result of the CRP. These important developments have enabled several Member States to start/augment their programs on ⁹⁰Y based radiopharmaceuticals, which is a significant achievement of a CRP, thanks to the IAEA. (author)

[en] The main goal of this study was to optimize the radioimmunoconjugation of monoclonal antivascular endothelial growth factor receptor 1(VEGFR 1) anti-CD105(Endoglin) monoclonal antibody for an angiogenesis targeting and with ¹⁷⁷Lu as a potential angiogenic molecular tracer for radioimmunotherapy (RIT). We carried out a radioimmunoconjugation using ¹⁷⁷Lu with anti-CD105 (Endoglin) and anti-VEGFR1 for developing a more useful marker to identify proliferating endothelium involved in tumor angiogenesis than panendothelial markers. We optimized the labeling of monoclonal antibody with ¹⁷⁷Lu by using cysteine derivative isothiocyanatobenzyl-DTPA(DTPA-NCS) as BFCA. Under the optimal conditions with a slight modifications on the factors such as the reaction time and molar ratio which are known to be very critical in radiolabeling. The labeling yield was greater than 99% each respectively. Immunoactivity of the radioimmunoconjugate was investigated using combinations of radioanalytical and bioanalytical techniques (ITLC- SG,Cyclone phosphorimager, SDS-PAGE and ELISA). For the biological evaluations we carried out a cell binding assay and a biodistribution study using mice bearing Calu 6 lung cancer cell xenografts. The tumor-to-blood ratio was 11.16:1 24h post-injection. For anti- VEGFR1 monoclonal antibody, the biodistribution study showed high specificity in accumulating in tumour tissues where the tumor-to-blood ratio was 3.25:1 24h post-injection. In conclusion, the anti-CD105 monoclonal antibody for an angiogenesis targeting was effectively radioconjugated with ¹⁷⁷Lu. And the biodistribution study showed a high specificity for accumulating in tumour tissues. This radioimmunoconjugate is applicable to detect angiogenesis sites in various diseases and to treat tumors. the anti-VEGFR1 monoclonal antibody for angiogenesis targeting was effectively radioconjugated with ¹⁷⁷Lu. This radioimmunoconjugate is applicable to detect of angiogenesis sites in various diseases and treat tumour over expressed VEGFR 1. (author)

[en] This review will cover the efforts in Gothenburg to evaluate the potential of ²¹¹At radioimmunotherapy (RIT) in the treatment of small tumor deposits of ovarian cancer in the abdominal cavity. The lifetime risk of ovarian cancer is 1% - 2% in European and American women. Despite seemingly successful surgery followed by chemotherapy, most patients will relapse, most frequently in the abdominal cavity, and succumb to the disease. Despite newer systemic chemotherapy regimens, the outcome has not improved over the past decade. RIT with various β-emitters has displayed promising results, though an international Phase III study of 90Y-labeled antibody showed no improvement in time to relapse or survival. This disappointing result might be explained by the long range of β-emitters, which results in poor irradiation of tumors less than a few millimeters in size. In treating small tumors, the short range and high LET of α-emitters such as ²¹¹At offer a significant advantage by more effectively irradiating targeted small cell clusters. The PET and Cyclotron Unit at Rigshospitalet in Copenhagen has regularly since ∼10 years delivered ²¹¹At to the research group in Gothenburg led by Prof. Ragnar Hultborn and Prof. Lars Jacobsson. Astatine-211 is isolated from the irradiated target by dry distillation. The ²¹¹At-labelling method gives stable radiochemical yields of 70% - 80% with the antibody conjugate's tumor-cell binding ability essentially preserved. The activity of an antibody batch of 0.1 - 0.5 mg is approximately 300 - 500 MBq, sufficient for extensive animal experiments or for treatment of one patient. The therapeutic effect has been studied in a series of experiments in vitro and in nude mice with intraperitoneal (i.p.) growth of microscopic ovarian cancer tumors. A number of parameters related to the injected antibody conjugate and stage of tumor growth have been investigated. Studies of toxic effects for bone-marrow, kidneys, and the peritoneal membrane indicate that microscopic tumors smaller than approximately 0.1 mm are likely sterilized without any serious organ toxicity. Tumor cure probability decreases with increasing tumor size. Dosimetry, based on biokinetic modeling and a Monte Carlo program, indicates that an absorbed dose of approximately 20 Gy is needed for tumor eradication in nude mice. The tolerance level (mean absorbed dose) is estimated to be ∼0.5 Gy for bone-marrow and ∼10 Gy for kidneys. For the peritoneal membrane preliminary results indicate a tolerance level of more than ∼25 Gy. Comparisons with low-LET 60Co irradiation for tumor-growth inhibition and bone-marrow toxicity both resulted in an RBE of ∼5. Based on the promising results of the animal studies, a clinical Phase I study of 9 patients was started in 2005 (and published in 2009). Thirty to 120 MBq of ²¹¹At-MX35 F(ab')2 was administered i.p. in 1.1 - 2.2 L of fluid (Extraneal). Dosimetric calculations were mainly based on the ²¹¹At activity in samples of peritoneal fluid, blood, and urine 0 - 48 h post injection. Gamma camera imaging did not reveal uptake in any major organs except the thyroid. The thyroid uptake was reduced by potassium perchlorate or potassium iodide in the last four patients. No adverse effects of the treatment were observed subjectively or in the laboratory parameters. In conclusion, therapeutic absorbed doses of ²¹¹At in microscopic tumors in the abdominal cavity of humans are achievable without significant toxicity. (author)

[en] Phosphorus-32 (³²P) is a routinely used bone pain palliation agent at our institute due to its cost, availability and proven efficacy with mild and self limiting myelo-suppression. Vitamin D is known to de-differentiate tumors and supposed to enhance calcium deposition onto metastatic foci with a hope of reducing the marrow effects. A pilot study showing an increase in the ^99mTc-MDP uptake by skeletal metastatic foci, using single pulse dose of Vitamin D, in some of the patients preceded this study and found the basis for this study. The aim of this study was to evaluate the role of ³²P alone and in combination with vitamin D in the palliation of bone pain from osseous metastases and to look for its clinical efficacy and reduction in marrow suppression in our clinical environment. 62 patients with extensive osteoblastic bone metastases were randomly divided into 3 groups. Group A received ³²P alone, group B combination therapy of ³²P and Vitamin D and group C Vitamin D alone. All these patients were evaluated by a standard protocol on broad parameters of pain reduction, reduction in analgesic consumption, improvement in quality of life and effect on bone marrow suppression at the end of 4th and 8th week post-therapy. Favorable response (≥25%) to treatment was recorded in 55% of cases in-group A, 81% in- group B and 9% in-group C. Reduction in pain score of 50% to 100% were obtained in two cases in group A and 10 in group B. A decrease in pain of 26% to 50% and ≤ 25% was observed in 10 (45%) and 4 (18%) cases respectively in group A, and 8 (36%) and 2 (9%) cases respectively in group B. Analgesic consumption was reduced in both the groups of ³²P, comparatively more in group B. The improvement in mobility and quality of life was observed to be better in group B than A and C. A decrease of white blood cells, hemoglobin level and platelets counts was observed in both groups of ³²P but no significant difference was noted in group A and B was noted at the end of 8th week. It was concluded that ³²P is an effective agent for the palliation from osseous metastases. Vitamin D as an adjuvant to ³²P therapy increases the clinical efficacy of ³²P. ³²P alone or in combination with Vitamin D has myelo-suppressive effect that is transient and self- limiting. (author)

[en] Radiopharmaceuticals incorporating the β-emitting radionuclide Re-188 are still attracting much interest for their potential application in nuclear medicine as therapeutic agents. There are many advantages of employing this class of radioactive compounds as briefly summarized in the following. (1) Re-188 emits a high-energy β- particle (2.1 MeV) that can be efficiently used to deliver high-dose radiation to the target. (2) Re-188 concomitantly emits a 155-keV γ photon that can be conveniently employed to obtain good-quality SPECT images of the biodistribution of Re-188 radiopharmaceuticals and, ultimately, following in vivo the course of the therapy. (3) Re-188 has a relatively short half-life (17 hours) that may allow multiple treatments of the same patient's disease. (4) Re-188 is a radiometal belonging to the same group of Tc-99m in the transition metal series of the Periodic Table, and shares with its cogener similar (though not identical) chemical properties that could be useful for designing a broad class of Re-188 radiopharmaceuticals having the same biodistribution properties of the corresponding Tc-99m analogues. (5) Similarly to Tc-99m, the radionuclide Re-188 is produced in high-specific activity through the ¹⁸⁸W/¹⁸⁸Re transportable generator system. A first challenge encountered in the attempt to develop efficient labeling procedures for Re-188 was related to the low radiochemical yield usually observed in tracer-level preparations of Re-188 radiopharmaceuticals starting from generator-produced [¹⁸⁸ReO₄]-. This drawback is commonly associated with the low value of the standard reduction potential of the tetraoxo anion as compared to the corresponding Tc-99m pertechnetate anion. In recent years, we reported a simple and efficient procedure for overcoming this problem based on a general chemical principle called 'expansion of the coordination sphere' and involving the addition to the reaction vial of an ancillary ligand (usually, chelating hard-donor Lewis'bases) favoring the conversion of the tetrahedral arrangement of [¹⁸⁸ReO₄]- to a higher coordination geometry. Using this novel approach, we were able to obtain the high-yield preparation of a large number of Re-188 complexes having exactly the same molecular structure of the corresponding Tc-99m analogues, and clearly demonstrate that these matched-pairs of Tc-99m and Re-188 complexes fully exhibit the same biodistribution properties. These findings opened the door to the application of a number of Re-188 radiopharmaceuticals to the treatment of different neoplastic diseases. In particular, we developed Re-188 radiopharmaceuticals for the therapy of the following tumours: (a) Re-188 labeled lipiodol for the treatment of hepatocellular carcinoma, (b) Re-188 labeled peptides for the therapy of different types of peptide-receptor expressing tumors, and (c) Re-188 labeled biotin and bivalent haptens for the adjuvant treatment of breast cancer. Recently, we devised a remotely controlled, multi-reaction, synthesis module for the preparation of different classes of Re-188 radiopharmaceuticals under conditions that dramatically decrease the radiation exposure of personnel involved in Re-188 production. (author)

[en] The conservative surgery with axillary dissection and additional radiotherapy represents the treatment of choice for patients with early breast cancer. A standard course of whole-breast external-beam radiation therapy (EBRT) followed by a boost to the tumour bed generally require 5/7 week to complete. This can represent a logistical problem for many patients, particularly the elderly and those who reside a considerable distance from a radiation treatment facility. As alternative to the traditional treatment of radiotherapy, the intraoperative radiotherapy (IORT) has been recently proposed. This technique, although valid, is limited by two major points: i) the availability of a dedicated intraopertive linear accelerator, ii) a restricted field of irradiation which limits the management of positive surgical margins. The experience developed in our Institute with the ROLL technique and the radionuclide therapy with the avidin-biotin pre-targeting system lead us to the development of a new approach named I.A.R.T. (Intraoperative Avidination for Radionuclide Therapy) capable to control recurrence as for EBRT and IORT. The I.A.R.T. procedure consists of a first step where the surgeon intraoperatively injects avidin directly into the tumour bed followed by a second step of an intravenous injection of ⁹⁰Y/ ¹⁷⁷Lu radiolabelled biotin, 1 day later. The avidin injection can be done with a syringe or with a dedicated spray-device (disposable and ready for intraoperative use) in the frame time while the surgeon is waiting for the sentinel node pathological analysis or after axillary clearance. Avidin percolate the tissue of the index quadrant as well as it is drained by locoregional lymph nodes. Due to its positive electric charge (pI 10.7) and the inflammatory reaction after surgery, avidin is retained at site of injection for several days and constitute a sort of new 'artificial receptor', only expressed in the breast area, able to homing radioactive biotin and deliver a dose as high as 50 Gy. The I.A.R.T. approach is simple, low cost and easy to perform and it might represent an alternative to IORT in early breast cancer patients. (author)

[en] This review will outline the advances made with radioimmunotherapy in solid and hematologic neoplasms. In particular, under-utilization of this molecular radiotherapy will be examined. In order for radioimmunotherapy to be utilized optimally, several issues need to be addressed. These include suitable education of public and professionals about the relative safety of systemic radiotherapy; greater interaction between treating physicians and referring hemato-oncologists; harmonization of economic imperatives, and an appropriate understanding of both immunologic and radiobiologic effects of therapy. Success of lymphoma radioimmunotherapy will provide incentive for the continuing study of antigen-binding proteins to which tailored radioactivity - alpha particle-based therapy for hematologic or minimal residual disease, beta particle-based therapy for bulkier disease - can be administered. Attempts to increase relative absorbed dose to tumor by adoption of multi-step targeting methods have proved promising, as has therapy based on radiation absorbed dose (to normal organs and, increasingly, to tumor). Molecular radiotherapy has considerable potential not only for thyroid cancer but for a variety of neoplasms, and efforts to promote the scientific and health care impact of radioimmunotherapy will result in improved cancer management. (author)