PET Molecular Imaging: A Holistic Review of Current Practice and Emerging Perspectives for Diagnosis, Therapeutic Evaluation and Prognosis in Clinical Oncology.

PET/CT molecular imaging has been imposed in clinical oncological practice over the past 20 years, driven by its two well-grounded foundations: quantification and radiolabeled molecular probe vectorization. From basic visual interpretation to more sophisticated full kinetic modeling, PET technology provides a unique opportunity to characterize various biological processes with different levels of analysis. In clinical practice, many efforts have been made during the last two decades to standardize image analyses at the international level, but advanced metrics are still under use in practice. In parallel, the integration of PET imaging with radionuclide therapy, also known as radiolabeled theranostics, has paved the way towards highly sensitive radionuclide-based precision medicine, with major breakthroughs emerging in neuroendocrine tumors and prostate cancer. PET imaging of tumor immunity and beyond is also emerging, emphasizing the unique capabilities of PET molecular imaging to constantly adapt to emerging oncological challenges. However, these new horizons face the growing complexity of multidimensional data. In the era of precision medicine, statistical and computer sciences are currently revolutionizing image-based decision making, paving the way for more holistic cancer molecular imaging analyses at the whole-body level.

Nuclear Medicine Imaging Procedures in Oncology.

Nuclear medicine radionuclide imaging is a quantitative imaging modality based on radioisotope-labeled tracers which emit radiation in the form of photons used for image reconstruction. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are the two noninvasive tomographic three-dimensional radionuclide imaging procedures for both clinical and preclinical settings. In this review on nuclear medicine imaging procedures in oncology, a variety of standard SPECT and PET tracers including radioiodine, 18Fluorine fluorodeoxyglucose (18F-FDG), and 68Gallium-labeled small proteins like Prostate Specific Membrane Antigen (PSMA) or somatostatin analogues and their application as targeted molecular imaging probes for improved tumor diagnosis and tumor phenotype characterization are described. Absolute and semiquantitative approaches for calculation of tracer uptake in tumors during the course of disease and during treatment allow further insight into tumor biology, and the combination of SPECT and PET with anatomical imaging procedures like computed tomography (CT) or magnetic resonance imaging (MRI) by hybrid SPECT/CT, PET/CT, and PET/MRI scanners provides both anatomical information and tumor functional characterization within one imaging session. With the recent establishment of novel molecular radiolabeled probes for specific tumor diagnosis, prognosis, and treatment monitoring, nuclear medicine has been able to establish itself as a distinct imaging modality with increased sensitivity and specificity.

[Current Possibilities of Using Radiopharmaceuticals to Evaluate Cerebral Blood Flow].

A comparison of the possibilities of using various neurotropic radiopharmaceuticals for scintigraphic evaluation of cerebral perfusion. In the whole range of radiopharmaceuticals used to diagnose cerebral blood flow disorders, there are Ceretec (99mTc-hexamethylpropyleneamine) and Neurolite (N,N-1,2-ethylenediylbis-L-cysteine-diethyl ether), which are the most optimal agents. Due to their high cost and related radiation exposure, the radiopharmaceuticals 123І-IMP (123I-isopropyl-iodoamphetamine) and 201Tl-DDC (diethyldithiocarbamate) labeled with thallium-201 virtually minimize the possibilities of being used in daily clinical practice. Fixation of 99mTc-DDC in the brain proves to be short-term, which is insufficient for tomoscintigraphy studies. Literature has been sought in the Scopus, Web of Scince, Pubmed, EMBASE, and Russian Science Citation Index databases.

Alternative chromatographic system for the quality control of lipophilic technetium-99m radiopharmaceuticals such as [(99m)Tc(MIBI)6].

Knowledge of the radiochemical purity of radiopharmaceuticals is mandatory and can be evaluated by several methods and techniques. Planar chromatography is the technique normally employed in nuclear medicine since it is simple, rapid and usually of low cost. There is no standard system for the chromatographic technique, but price, separation efficiency and short time for execution must be considered. We have studied an alternative system using common chromatographic stationary phase and alcohol or alcohol:chloroform mixtures as the mobile phase, using the lipophilic radiopharmaceutical [(99m)Tc(MIBI)6]⁺ as a model. Whatman 1 modified phase paper and absolute ethanol, Whatman 1 paper and methanol:chloroform (25:75), Whatman 3MM paper and ethanol:chloroform (25:75), and the more expensive ITLC-SG and 1-propanol:chloroform (10:90) were suitable systems for the direct determination of radiochemical purity of [(99m)Tc(MIBI)6]⁺ since impurities such as (99m)Tc-reduced-hydrolyzed (RH), (99m)TcO(4)(-) and [(99m)Tc(cysteine)2]⁻ complex were completely separated from the radiopharmaceutical, which moved toward the front of chromatographic systems while impurities were retained at the origin. The time required for analysis was 4 to 15 min, which is appropriate for nuclear medicine routines.

Alternative chromatographic system for the quality control of lipophilic technetium-99m radiopharmaceuticals such as [99mTc(MIBI)6]+

Knowledge of the radiochemical purity of radiopharmaceuticals is mandatory and can be evaluated by several methods and techniques. Planar chromatography is the technique normally employed in nuclear medicine since it is simple, rapid and usually of low cost. There is no standard system for the chromatographic technique, but price, separation efficiency and short time for execution must be considered. We have studied an alternative system using common chromatographic stationary phase and alcohol or alcohol:chloroform mixtures as the mobile phase, using the lipophilic radiopharmaceutical [99mTc(MIBI)6]+ as a model. Whatman 1 modified phase paper and absolute ethanol, Whatman 1 paper and methanol:chloroform (25:75), Whatman 3MM paper and ethanol:chloroform (25:75), and the more expensive ITLC-SG and 1-propanol:chloroform (10:90) were suitable systems for the direct determination of radiochemical purity of [99mTc(MIBI)6]+ since impurities such as99mTc-reduced-hydrolyzed (RH),99mTcO4- and [99mTc(cysteine)2]-complex were completely separated from the radiopharmaceutical, which moved toward the front of chromatographic systems while impurities were retained at the origin. The time required for analysis was 4 to 15 min, which is appropriate for nuclear medicine routines.

Freeware for reporting radiation dosimetry following the administration of radiopharmaceuticals.

This work describes the development of a software application for reporting patient radiation dosimetry following radiopharmaceutical administration. The resulting report may be included within the patient's medical records. The application was developed in the Visual Basic programming language. The dosimetric calculations are based on the values given by the International Commission on Radiological Protection (ICRP). The software is available in both Spanish and English and can be downloaded at no cost from www.radiopharmacy.net.

Nuclear imaging of neuroendocrine tumors with unknown primary: why, when and how?

Neuroendocrine tumors (NETs) with unknown primary (CUP-NET) are associated with a poor prognosis (10-year survival 22%), grade 1 and 2 NETs having a more favorable outcome than grade 3 (also called carcinoma). There is evidence that an effort should be made to localize the primary tumor even in the presence of metastasis because resection of the primary tumor(s) may improve disease-free and overall survival, and because the choice of chemotherapeutic agent depends on the location of the primary tumor. Localization of the tumors remains challenging and often relies on a combination of radiological, endoscopic and functional imaging. The functional imaging protocol for evaluation of these patients has historically relied on somatostatin receptor scintigraphy (SRS). However, the sensitivity and specificity of SRS may be unsatisfactory, especially for NETs of midgut origin. Newer PET radiotracers such as (68)Ga-labeled somatostatin analogs ((68)Ga-DOTA-SSTa) and (18)F-DOPA have shown promise. In direct comparisons between (68)Ga-DOTA-SSTa PET/CT and (99m)Tc-HYNIC-octreotide/(111)In-pentetreotide SPECT(/CT), (68)Ga-DOTA-SSTa performed better than other techniques, giving a compelling reason for switching from SPECT/CT to PET/CT imaging. (18)F-DOPA performs better than SRS and CT in well-differentiated NETs of the small intestine. For detecting pancreatic NETs, the high background uptake of (18)F-DOPA by the normal exocrine pancreas can be somewhat overcome by pretreatment with carbidopa. We have suggested a protocol in which SRS is replaced by one of the two agents (preferably with (68)Ga-DOTA-SSTa, alternatively (18)F-DOPA) as first-line nuclear tracer for detection of CUP-NET in patients with well-differentiated NETs and (18)F-FDG PET/CT may be an additional diagnostic test for poorly differentiated tumors and for prognostication. In the near future, it is expected that patients with CUP-NET will benefit from newly developed PET approaches (radiopharmaceuticals) and intraoperative PET imaging.

Multifunctional radiolabeled nanoparticles: strategies and novel classification of radiopharmaceuticals for cancer treatment.

In this review, we emphasize the efforts on the development of radiolabeled nanoparticles (NPs) for cancer treatment, i.e. theranostic tools based on nanotechnology and nuclear medicine. Currently, radionuclide therapy remains to be an important treatment option. The ionizing radiation from radionuclides (not provided by drugs) can kill cells or inhibit the growth in the periphery and the inaccessible center of cancerous lesions. Sites of damage comprise all cellular levels, especially DNA in the nucleus of cells. In addition, recent developments in nanotechnology have made it possible to conjugate NPs to biological moieties for targeted therapy. This enables the more specific radiation dose delivery, preventing damage to healthy tissues. Before the introduction of these NPs-based radionuclide therapies in clinical practice, it is necessary perform investigations to demonstrate dosage-accurate radiation delivery, biocompatibility, pharmacokinetic/pharmacodynamic parameters and risk/benefit evaluations. Because of these issues, a transition to clinical trials is difficult. The properties of NPs make it possible to build theranostic devices with targeting and regulatory mechanisms offered by biological effectors against cancer.

[Differential diagnosis of brain gliomas by positron emission tomography using various radiopharmaceuticals].

OBJECTIVE: To comparatively study the diagnostic capabilities of positron emission tomography (PET) with various tumorotropic radiopharmaceuticals (TRPs) in detecting malignant brain gliomas (BG) and estimating their degree. MATERIAL AND METHODS: One hundred and fourteen patients, including 47 with histologically verified glioblastoma multiforme (GBM), 27 with anaplastic astrocytoma (AA), 23 with benign astrocytoma (BA), and 17 with postoperative cysts, were examined. PET was performed using TRPs: 18F-fluorodesoxyglucose (18F-FDG), 11C-sodium butyrate (11C-SB), 11C-L-methionine (11C-MET), and 11C-choline (11C-COL). RESULTS: Malignant gliomas (GBM and AA) were clearly visualized by PET using 11C-MET, 11C-CHOL, and 11C-SB. 18F-FDG PET visualization of tumors was difficult because of increased RP accumulation in the cerebral cortex. WHO grades II-III gliomas were completely visualized by 11C-MET PET. Only some tumors were clearly displayed by PET with 11C-CHOL and 11C-SB. The accumulation indices (AI) obtained by 11C-CHOL PET in patients with malignant gliomas were, on average, 4.0- and 5.5-fold higher than those by 11C-MET and 11C-SB PET, respectively. Significant differences (p < 0.001) in AI obtained by "C-CHOL ("C-CHOL-AI) PET were first established between the patients with GBM (WHO grade IV) and those with AA (WHO grade III). CONCLUSION: 11C-CHOL PET is the most sensitive method to identify gliomas and estimate their grade. The advantage of 11C-MET PET is the possible imaging of the entire volume of viable tumor tissue.

Obligations, precautions and pending issues in regulatory development for radiopharmaceuticals in Brazil

Radiopharmaceuticals are compounds that have a radionuclide and may be gamma-radiation emitter (γ) or positrons emitter (β+), linked to a molecule with specific diagnostic and therapeutic purposes. The progress in the use of radiopharmaceuticals has culminated to a sector in common with other types of drugs: regulation and surveillance. From 2006 on, production, marketing and use of these drugs were open to the Brazilian market granting much more freedom due to the Constitutional Amendment 49, resulting from the previous Constitutional Amendment 199/03 which removes the Union monopoly for this kind of manipulation and granted this production to other nuclear medicine. From this date on, the amount of this type of sold product have been greatly increased, and the nucleus of surveillance and regulation in Brazil have also advanced in the legislative processes, creating documents that are now more focused on radiopharmaceuticals in the national territory (Resolutions No. 63 and No. 64). In international overview, there is too much to be done in regulatory terms in Brazil, such as adding mainly issues of drugs surveillance to pharmacovigilance practice in radiopharmaceuticals drugs.

Radiofármacos são compostos que possuem um radionucleotídeo, podendo ser emissor de radiação gama (γ) ou emissor de pósitrons (β+), ligado a uma molécula específica com finalidade diagnóstica e terapêutica. O avanço no uso dos radiofármacos tem culminado a um setor em comum com outros tipos de medicamentos: a regulamentação e fiscalização. Após 2006, a produção, a comercialização e a utilização destes medicamentos foram abertas ao mercado interno brasileiro com maior liberdade, pois a Emenda Constitucional 49, vinda da Emenda Constitucional 199/03, que retira da União o monopólio deste tipo de manipulação, ofereceu a outros centros de medicina nuclear a oportunidade desta produção. A partir desta data, a quantidade comercializada deste tipo de medicamento aumentou absurdamente e os núcleos de vigilância e regulamentação do Brasil avançaram também nos processos legislativos, criando os documentos mais voltados a Radiofármacos existentes no território nacional, as Resoluções n° 63 e n° 64. Em visão internacional, há muito ainda a ser feito em termos regulatórios no Brasil somando principalmente os assuntos vigilantes dos medicamentos como a prática de Farmacovigilância em Radiofármacos.

A new classification of positive sestamibi and ultrasound scans in parathyroid localization.

BACKGROUND: Ultrasound (US) and sestamibi (MIBI) are traditionally considered positive or negative. The purpose of this study was to define and test a new scoring system for MIBI and US and to determine whether this can improve their accuracy for primary hyperparathyroidism. METHODS: This is a prospective study of 200 consecutive patients with primary hyperparathyroidism who had a single uptake on MIBI scans before bilateral neck exploration at a tertiary academic center between 2007 and 2008. These patients also had surgeon-performed neck US in the office, which was scored as "typical" or "atypical" based on how characteristic the image resembled a parathyroid gland. The MIBI uptake was scored by the nuclear medicine specialist as "weak," "moderate," or "strong" compared with the signal intensity of the thyroid. US and MIBI scoring was done preoperatively and their findings were compared with operative data. RESULTS: Of 200 patients, 71 % had a single adenoma, 12 % had double adenomas, and 17 % had four-gland hyperplasia. A weak, moderate, and strong signal on MIBI had an accuracy of 23, 47, and 72 %, respectively, in demonstrating single-gland disease. An atypical versus typical US appearance was accurate in 55 and 74 % of the time, in identifying single-gland disease. CONCLUSIONS: An appraisal of US and MIBI positivity in relation to image characteristics affects the reliability of both studies. This information should be kept in mind when selecting patients for focal neck exploration.

Management of advanced prostate cancer after first-line chemotherapy.

Hormone refractory prostate cancer (HRPC) causes substantial morbidity and mortality. There are increasing options for both first- and second-line therapy in the palliative treatment of patients with HRPC. Medications to control symptoms should first be optimized in patients with late-stage disease, and radiotherapy applied to dominant painful bone lesions. Docetaxel, mitoxantrone, satraplatin, and ixabepilone are active chemotherapeutic agents in the first- and/or second-line setting for patients with HRPC, and this may be true also of older drugs such as oral cyclophosphamide and vinorelbine. Radioisotopes such as strontium and samarium are useful for treatment of more generalized bone pain. Third-line hormonal maneuvers including glucocorticoids, ketoconazole, and estrogens can lead to further palliation in some patients, and there are provocative data that chemotherapy might restore hormonal sensitivity in a subset of patients.

The impact of radiopharmaceutical particle size on the visualization and identification of sentinel nodes in breast cancer.

OBJECTIVES: The aim of this study was to compare the success rate in lymphatic mapping and sentinel node biopsy in breast cancer using two radiopharmaceuticals. METHODS: The study included 119 breast cancer patients who underwent lymphoscintigraphy after a single intratumoral injection of 99mTc-labelled human albumin colloid with a particle size of 0.2-3 microm (Albu-Res) (large particle group) and 119 pair-matched control patients who underwent lymphoscintigraphy using 99mTc-labelled albumin colloid with a particle size of < 80 nm (Nanocoll) (small particle group). The dose of the tracer was used as the matching factor. RESULTS: Lymphoscintigraphy showed sentinel nodes in the axilla in 101 patients (85%) in the large particle group and in 104 patients (87%) in the small particle group. The mean number of visualized nodes in the axilla was 1.7 in the small particle group and 1.3 in the large particle group (P < 0.05). No radioactive nodes were found in the axilla during the operation in 22 patients (18%) in the small particle group and 11 patients (9%) in the large particle group (P < 0.06). Patients who avoided axillary clearance had a similar number of harvested radioactive nodes irrespective of the particle size of the tracer. CONCLUSIONS: It can be concluded that the success rate in the identification of axillary sentinel nodes may be higher when using the smaller particles, despite the similar visualization rate in lymphoscintigraphy. The number of harvested radioactive nodes was not affected by the particle size of the tracer in patients who avoided axillary clearance.

Radioisotopic evaluation of bone repair after experimental surgical trauma

Este trabalho objetivou estudar a evolução temporal do processo de reparo ósseo em tíbia de rato, após trauma cirúrgico padronizado. A incorporação do radiofármaco 99mTc-MDP na região afetada foi tomada como medida indireta da intensidade de reação tecidual; foi feito também acompanhamento histológico do processo de reparo. Foram realizadas cirurgias nas duas tíbias de 72 animais divididos em 2 grupos, sendo sacrificados em diferentes dias pós-operatórios (1, 3, 7, 14, 21 e 28 dias p.o.). As cavidades criadas nas tíbias esquerdas foram preenchidas com osso liofilizado bovino, e as direitas serviram como controle (não preenchidas). Grupos paralelos de animais foram injetados com 99mTc para avaliar a influência do fluxo sangüíneo regional nos resultados. Duas horas após a injeção dos radiofármacos os animais foram sacrificados, a radiatividade foi contada tanto nos fragmentos das tíbias contendo os defeitos cirúrgicos como em fragmentos intactos de fêmur e de tíbias, como controle. Os resultados indicam que a maior atividade do tecido ósseo ocorreu entre 7 e 14 dias p.o. O emprego do radiofármaco mostrou ser de valor na avaliação do reparo dada sua sensibilidade. Não houve efeito significativo da presença de osso liofilizado sobre a evolução do reparo ósseo.

Radiotracer-based strategies to image angiogenesis.

Tumour-induced angiogenesis plays an important role in tumour progression. Great efforts are made to develop therapeutic strategies to interfere with this process resulting in the starvation of the tumour. However, strategies to monitor conventional therapies seems to be inappropriate to control these approaches. Thus, there is a keen interest in developing methods supplying information about the corresponding therapeutical effects. Several radiotracer-based approaches focused on different targets in the angiogenic process are currently investigated. One class of tracers is based on matrix metalloproteinases inhibitors. These compounds show promising results in in vitro assays. However, initial data from in vivo studies using murine tumour models could not confirm successful non-invasive monitoring of MMP activity yet. Another strategy uses a radiolabelled single chain fragment against the ED-B domain of fibronectin, an extracellular matrix protein. Promising results demonstrated selective accumulation of the tracer in the tumour vasculature of a murine tumour model. Most of the studies are concentrated on the development of radiolabelled antagonists of the integrin alpha(v)beta(3). This heterodimeric transmembrane glycoprotein is involved in the migration of activated endothelial cells during formation of new vessels. Different compounds have been labelled with (18F), (111)In, (99m)Tc, (90)Y and several iodine isotopes. In in vitro assays most of them revealed high alpha(v)beta(3) affinity and selectivity. Moreover, in different murine tumour models successful non-invasive determination of alpha(v)beta(3) expression has been shown. Some of these approaches indicate that tumour-induced angiogenesis can be monitored in animal studies. Nevertheless, translation of these approaches into clinical settings allowing visualisation of tumour-induced angiogenesis in patients needs still to be demonstrated.

Radiopharmaceuticals for targeting the angiogenesis marker alpha(v)beta(3).

A common feature of solid tumors is the formation of new blood vessels (angiogenesis) within the tumor. A receptor called alpha(v)beta(3) is found on endothelial cells lining newly growing blood vessels at a higher density than on mature blood vessels. This receptor may provide a target for radioligands to permit imaging of a wide variety of solid tumors. The radioligands may range from macromolecules such as native ligands or monoclonal antibodies, to small proteins to very small peptides. The differing characteristics of these bio-molecules have an affect on target delivery and clearance time.