Nicoletta Urbano

Evaluation of different beta-counting systems involved in 90Y-Zevalin quality control.

Background90Y-ibritumomab tiuxetan (90Y-Zevalin) is currently approved for radioimmunotherapy of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkins lymphoma. The radioimmunoconjugate may be administered to the patient only if the radiolabelling yield is higher than 95%. AimTo evaluate different methods of quality control testing for an accurate and rapid determination of radiolabelling yield in the clinical routine. MethodsFive beta-counting systems, involved in determining the yield of radiolabelled 90Y-Zevalin, were compared: an autoradiography system (AS), a thin-layer chromatography (TLC) scanner system, a dose calibrator (DC), a liquid scintillation analyser (LSA) and high-performance liquid chromatography (HPLC). These instruments were also analysed in terms of efficiency, spatial resolution, analysis time, operating procedure level, cost and availability. ResultsRadiolabelling yields were comparable among all instruments except for DC whose values were dubious. Efficiency was 1.5±0.11 MDLU·s−1 for the AS (where DLU means digital light unit), 3.5±0.2 kcps for the TLC analyser, 0.74±0.02 MBq for the DC, 15±0.12 kcps for LSA and 180±0.07 kcps for HPLC. Spatial resolution was 1 mm for AS and 5 mm for the TLC analyser. The quality control test needed 8 min with AS and DC, 15 min with TLC and LSA, and 50 min with HPLC. ConclusionsThe short analysis time, high sensitivity, simultaneous detection of multiple radioactive strips and low cost offered by AS make it a suitable tool for radioactivity analysis and quantification in a radiopharmacy laboratory.

Media Fill Test for validation of autologous leukocytes separation and labelling by 99mTc-HmPAO

OBJECTIVE Manufacturing of sterile products must be carried out in order to minimize risks of microbiological contamination. White blood cells (WBC) labelled with (99m)Tc-exametazime ((99m)Tc-hexamethylpropyleneamine oxime; (99m)Tc-HMPAO) are being successfully applied in the field of infection/inflammation scintigraphy for many years. In our radiopharmacy lab, separation and labelling of autologous leukocytes with (99m)Tc-HMPAO were performed in a laminar flow cabinet not classified and placed in a controlled area, whereas (99m)Tc-HMPAO radiolabelling procedure was carried out in a hot cell with manipulator gloves. This study was conducted to validate this process using a Media Fill simulation test. METHODS The study was performed using sterile Tryptic Soy Broth (TSB) in place of active product, reproducing as closely as possible the routine aseptic production process with all the critical steps, as described in the our internal standard operative procedures (SOP). The final vials containing the media of each processed step were then incubated for 14 days and examined for the evidence of microbial growth. RESULTS No evidence of turbidity was observed in all the steps assayed by the Media Fill. CONCLUSIONS In the separation and labelling of autologous leukocytes with (99m)Tc-HmPAO, Media-Fill test represents a reliable tool to validate the aseptic process.

Personalized medicine: a new option for nuclear medicine and molecular imaging in the third millennium

BIt’s more important to knowwhat sort of person has a disease than to know what sort of disease a person has,^ stated Hippocrates of Kos (c. 460 – c. 370 BC). This sentence of the father of modern medicine, which is based on observation of clinical signs and rational conclusions, is truly actual and it can be considered the manifesto of personalized (or precision) medicine (PM). According to the National Heart, Lung, and Blood Institute, PM is the use of diagnostic and screening methods to better manage the individual patient’s disease or predisposition toward a disease; it will enable risk assessment, diagnosis, prevention, and therapy specifically tailored to the unique characteristics of the individual, thus enhancing the quality of life and public health. It is of the utmost importance to highlight that USA President Barack Obama on January 20, 2015, in his State of the Union address, announced the PM initiative and called for

M. Chinol, G. Paganelli (eds): Radionuclide peptide cancer therapy

215 million in fiscal year 2016 to support it. President Obama’ idea was that through advances in research, technology, and policies which empower patients, the PM initiative will enable a new era of medicine in which researchers, providers, and patients work together to develop individualized care [1]. The concept of PM, prevention and treatment strategies taking into account individual variability, might be strictly related to molecular imaging and nuclear medicine, through understanding the molecular basis of disease and defining molecular changes or markers associated with disease progression, response to treatment, and relapse. Moreover, PM is one of the components of the so-called P4 medicine, i.e. predictive, preventative, personalized, and participatory, where predictive medicine is the use of diagnostic tests to predict when a disease will become symptomatic, preventative is to take some action to prevent the precursor state from evolving into the symptomatic stage, and participatory is the idea of patients playing an active role in remaining in the wellness state [2]. This new vision of medicine includes systems approaches to biology and medicine: systems biology is the study of biological systems as collections of networks at multiple levels, from the molecular step, through cells, tissues, and organisms, to the population level; systems medicine is the application of systems biology to human disease [3]. In this scenario, molecular imaging can play an important role, because it enables early detection and/or identification of changes occurring in tissue and, consequently, changes in individual patient management in real time, it serves as a noninvasive diagnostic and monitoring tool, it allows researchers to explore new ways to manage and treat illnesses, and it facilitates drug development [4]. As a matter of fact, if PM is mainly based on molecular characterization using genomic and proteomic techniques, these ones are limited in oncology, because, as tumours are spatially and temporally heterogeneous, they require surgery or biopsies to extract and analyze what are generally small portions of cancer tissue that do not allow a full characterization of the neoplasm. On the contrary, imaging is able to non-invasively produce a view of the entire tumour, and it can be used on an ongoing basis and often repeated during treatment [5]. This Editorial Commentary refers to the article http://dx.doi.org/10.1007 /s00259-016-3580-5.

Breast osteoblast-like cells: a new biomarker for the management of breast cancer

This book provides an up-to-date and complete account of knowledge on the treatment of cancer by means of radiolabelled peptides. The editors are Marco Chinol and Giovanni Paganelli, who are respectively the Chief Radiochemist and the Director of Nuclear Medicine at the European Institute of Oncology in Milan, Italy. The publication (351 pages with an enclosed CD) includes a foreword by Umberto Veronesi, Scientific Director of the European Institute of Oncology, and is based on the experience of 41 authors from some of the most important institutions in the world. The book consists of 18 chapters grouped into four main sections. The first part (chapters I–VII) provides a comprehensive description of the structure and biology of peptides and receptors, the physical properties of radionuclides and the technology of radiolabelling. The second part (chapters VIII–XII) groups the results of some of the most experienced European and American centres. The third part (chapters XIII–XVI) explains the basis for dosimetric calculations, regulations and principles for effective radiation protection. Therefore it is particularly addressed to physicists and the personnel of nuclear medicine laboratories. The fourth part (chapters XVII–XVIII) focusses on the methods for increasing over time the linkage between receptor and ligand, improving the efficacy of treatment and reducing toxic effects; it also describes future perspectives with new molecules. Chapter I considers peptide conformation and structure, design methodologies and peptide synthesis by SPPS and peptide ligation. The modifications needed to make the peptide suitable for labelling by radioisotopes are also analysed. Chapter II analyses tumour receptor expression and the strategies for selecting those tumour receptors that are suitable for targeting, in particular somatostatin, CCK, gastrinreleasing peptide, neurotensin and VIP. Multi-receptor targeting is also evaluated. Starting from In-octreotide, Chapter III describes the physical properties of therapeutic radionuclides, particularly Y and Re. Moreover, it provides a complete review of somatostatin and CCK-B/gastrin analogues, bombesin, α-MSH and integrin antagonists. The role of PET is explained in Chapter IV, which provides an overview on the main positron-emitting radionuclides (F, Ga, Ga, Y, Cu and I). Technical details on radiolabelling reactions between the aforementioned nuclides and the most common peptides are reported. Chapter V examines the labelling of DOTA-peptides with Y and Lu to a high specific activity. In particular, it analyses the optimal conditions for their radiolabelling such as pH value, temperature and incubation time, and the effects of metal ions, as contaminants in the reaction vial, on incorporation of the radionuclide in DOTA-ligand. Modalities to remove free radionuclide by DTPA addition are also reported. Chapter VI reports a promising treatment modality for patients bearing sst2-positive tumours. It describes the preclinical findings in peptide receptor radionuclide therapy (PRRT) with a variety of somatostatin analogues including octreotide, lanreotide, RC-160 (vapreotide) and RGDoctreotate. Chapter VII focusses on the distribution and biochemical characterisation of several peptide receptors other than somatostatin in different tumour types, and on the clinical relevance of their pathological assessment on tissue samples. Different techniques for tumour peptide receptor Eur J Nucl Med Mol Imaging (2007) 34:1139–1140 DOI 10.1007/s00259-007-0412-7

A proposal for phosphor imager acceptance testing procedure and routine quality controls in nuclear pharmacy practice.

BackgroundIn this study, we investigated the relationship between the expression of the main in situ markers of breast cancer and the presence of breast osteoblast-like cells (BOLCs).MethodsWe collected 100 breast biopsies. Serial paraffin sections were obtained from each biopsy to perform histological classifications and immunohistochemical analyses (RUNX2, RANKL, vimentin, TGFβ, Ki67, CD44, ER, PR and HER2).ResultsLinear regression analysis showed a positive and significant correlation between the number of BOLCs and the expression of EMT-related markers (vimentin and TGFβ), Ki67 and ER. Conversely, we observed an inverse correlation between the number of CD44-positive breast cancer cells and the BOLCs. No significant differences were observed between the number of BOLCs and the HER2 scores.ConclusionsMorphological and molecular characterisation of BOLCs can lay the foundations towards understanding the biological basis of the formation of breast microcalcifications, and breast cancer metastasis to bone. The data here reported may be useful for the identification of breast lesions with high potential to develop bone metastasis.

Reinduction of cell differentiation and 131I uptake in a poorly differentiated thyroid tumor in response to the reverse transcriptase (RT) inhibitor nevirapine

ObjectiveThe digital autoradiography system is currently used in nuclear medicine for quantitative imaging of radioactivity distribution (thin layer chromatography samples, tissue sections, and cell cultures). The aim of this study was to define a set of tests for setting up a specific acceptance testing procedure and routine quality controls for this instrument. Materials and methodsOver a 3-month period, we analyzed the active components of the instrument (phosphor screen and photometer) by using suitable self-manufactured equipment (phantoms, lead plate, lead cylinder, and photographic paper) required to realize, in a routine quality program, the following tests: integral uniformity (IU) and differential uniformity (DU) in a useful field of view (UFOV) and a central field of view (CFOV), resolution, geometric linearity, and sensitivity. ResultsScreen IU was 19.7±2.3% (UFOV) and 11.1±3.7% (CFOV). Screen DU ranged between 1.6±1.1 and 1.8±0.9% for UFOV and between 1.2±0.4 and 1.4±0.6% for CFOV. Screen resolution measured as full-width at half-maximum was 1.94±0.08 mm. Screen sensitivity was 505.1±10.4 digital light units and ranged between −3.15 and +3.49% with reference to the mean of measured values. Photometer IU was 17.4±0.2% (UFOV) and 13.7±1.1% (CFOV). Photometer DU ranged between 1.9±0.9 and 2.3±1.2% for UFOV and between 1.9±0.8 and 2.1±1.1% for CFOV. Photometer resolution was good (full-width at half-maximum =0.5±0.076 mm). ConclusionOur results suggest that the methodology we propose could be an easy, accurate, quick, and low-cost tool to guarantee the correct instrument basic function.