Current Radiopharmaceuticals - Volume 11, Issue 1, 2018

Background and objective: In the last twenty years, positron emission tomography / computed tomography (PET/CT) with radiolabeled choline, represented the most powerful imaging modality for prostate cancer (PCa). However, the low positive detection rate of the technique for PSA < 1 ng/ml prompted the development of other tracers for imaging PCa. Methods: We performed a critical review of ⁶⁸Ga-PSMA, a receptor ligand tracer, which has been identified as the most promising radiopharmaceutical for imaging PCa. Results: The most promising feature of this radiopharmaceutical is the high positive detection rate for prostate specific antigen (PSA) levels < 1 ng/ml or less (i.e., PSA < 0.5 ng/ml). ⁶⁸Ga-PSMA detection rate is also sensitive to PSA kinetics, expressed either as PSA doubling time or PSA velocity. There are initial results indicating that ⁶⁸Ga-PSMA may significantly affect the clinical management of PCa patients, even though the additional advantages in comparison to radiolabeled choline need to be further supported in future perspective studies. Other clinical implications, such as whether ⁶⁸Ga-PSMA PET/CT predicts PCa-specific survival, have not yet been investigated. Numerous clinical studies have been published, some of them with histopathological verification so that despite the recent introduction in the clinical field reliable estimation of sensitivity and specificity of ⁶⁸Ga-PSMA PET/CT have been obtained through meta-analyses. Most clinical studies with PET/CT with ⁶⁸Ga-PSMA are retrospective, single-institutional studies and in many cases include heterogeneous patient cohorts. Thus, multidisciplinary, well-throughout prospective trials are needed to better define the clinical implications of ⁶⁸Ga- PSMA PET/CT in PCa patients. The increasing availability of positron emission tomography / magnetic resonance (PET/MR) hybrid devices promotes the use of this radiopharmaceutical especially at initial staging when identification of tumor localization and of extra-prostatic disease represent clinically relevant questions. PSMA cold ligands can also be labeled with beta emitters with good chemical stability so that ⁶⁸Ga-PSMA PET/CT can be used to guide radiometabolic therapy of advanced metastatic PCa patients through ¹⁷⁷Lu-labeled PSMA ligands. Conclusion: PSMA labeled ligands appear very promising for diagnosis and treatment of PCa.

Background: Childhood neuroblastoma is a heterogenous disease with varied clinical presentation and biology requiring different approaches to investigation and management. Metaiodobenzylguanidine (MIBG) is an essential component of metastatic staging for neuroblastoma and has been used as a treatment strategy for relapsed and refractory neuroblastoma. However, as 10% of children with neuroblastoma will have ¹²³I-MIBG non-avid imaging and up to 60% with relapsed and refractory neuroblastoma will require further treatment with ¹³¹I-MIBG, alternative radioisotopes have been investigated for imaging and treatment. Neuroblastoma tumors express mostly somatostatin receptor- 2 (SSTR2) that can be targeted by somatostatin analogues including DOTA-conjugated peptides e.g. DOTATATE, DOTATOC. Objectives: This review summarizes the rationale, utility and experience of DOTA-conjugated peptides in imaging and treatment of childhood neuroblastoma. Results and Conclusions: Radiolabeled DOTA-peptides are used routinely in adults to image neuroendocrine tumors and have potential to be used to image and treat neuroblastoma. ⁶⁸Ga-DOTATATE PET/CT has been shown to have better sensitivity, quicker clearance and administration times, reduced radiation exposure and limited toxicity compared to ¹²³I-MIBG. Therapeutic studies of peptide receptor radionuclides e.g. ¹⁷⁷Lu-DOTATATE in patients with relapsed neuroblastoma have used ⁶⁸Ga- DOTATATE PET/CT to determine eligibility for therapy. Further studies would need to investigate appropriate indications, timings, scoring and clinical significance of radiolabeled DOTA-peptide conjugated PET/CT imaging in childhood neuroblastoma.

Background: Positron emission tomography (PET) is an instrumental diagnostic modality developed around the positron-emitting radioisotopes of biologically important elements such as carbon, oxygen and nitrogen (¹¹C, ¹⁵O, ¹³N). Among longer-lived PET radionuclides, ¹⁸F is by far the most commonly used radiotracer, extensively used for tumour imaging with FDG ([¹⁸F]-fluorodeoxyglucose) and also frequently investigated in the development of novel radiopharmaceuticals. Many other positron- emitting radionuclides with higher atomic numbers and longer half-lives have been investigated for both imaging and therapeutic purposes, including the halogens (¹²⁴I, ¹²⁰I, ⁷⁶Br) and a number of metal radionuclides. The radio-copper has attracted considerable attention, because they include isotopes which, due to their emission properties, offer themselves as agents of both diagnostic imaging (60Cu, ⁶¹Cu, ⁶²Cu, ⁶⁴Cu) and in vivo targeted radiation therapy (⁶⁴Cu and ⁶⁷Cu). Objectives: Although the use of this radionuclide has grown exponentially over the last decade, academic institutions have largely been responsible for its production and for the development of the vast majority of radiopharmaceutical based on these nuclides. A number of compounds labelled with Cuisotopes have been proposed, not only for imaging purposes but also for therapy. The aim of the present paper is to provide an overview on the clinical results obtained in human beings with copper radionuclides. Conclusion: Several preliminary studies and clinical trials evaluated the potential clinical role of copper radioisotopes for diagnostic and therapeutic purposes. ⁶⁴Cu seems to be the most suitable radioisotope for future clinical applications due to its longer half-life (12.7 h) and its commercial availability. Future clinical applications of copper radioisotopes could be enhanced by the possibility of radioligand therapy with the beta-emitting ⁶⁷Cu, creating a new “theranostics pair”.

Background: Knowledge of radiobiology is of paramount importance to be able to grasp and have an in-depth understanding of the consequences of ionizing radiation. One of the most important effects of this physical stressor's interaction to targeted and non-targeted cells, tissues and organs is on the late effects on the development of primary and secondary cancers. Thus, an in-depth understanding of the mechanisms of radiation carcinogenesis remains to be elucidated, and some studies have demonstrated or proposed a role of non-targeted effect in excess risk of cancer incidence. The non-targeted effect in radiobiology refers to a dynamic complex response in non-irradiated tissues caused by the release of presumably of clastogenic factors from irradiated cells. Although, most of these responses in non-targeted tissues have marked similarities to irradiated tissues, other studies have shown some differences. Also, the non-targeted effect has shown sex and tissue specificity that are seen in irradiated tissues too. So far, several studies have been conducted to depict mechanisms that may be involved in this phenomenon. Epigenetic dysfunctions, DNA damage and cell death are responsible for initiation of several signaling pathways that finally result in secretion of clastogenic factors. Moreover, studies have shown that damage to both nucleus and mitochondrial DNA, membrane and some organelles is involved. Oxidized DNA associated with other cell death factors stimulates secretion of inflammatory as well as some anti-inflammatory cytokines from irradiated area. Additionally, oxidative stress that results in damage to cellular structures to include cell membranes can affect secretion of exosomes and miRNAs. These bystander effect exogenous mediators migrate to distant tissues and stimulate various signaling pathways which can lead to changes in immune responses, epigenetic modulations and radiation carcinogenesis. Conclusion: In this review, we focus on descriptive and hierarchical events with emphasis on the molecular and functional interactions of ionizing radiation with cells to the mechanisms involved in cancer induction in non-targeted tissues.

Background: The Italian Tailored Assessment of Lung Indeterminate Accidental Nodule (ITALIAN) is a retrospective, multicenter trial designed to compare the diagnostic information provided by segmental positron emission tomography (PET)/computed tomography (CT) (s-PET/CT) with those of whole body (wb)-PET/CT in patients with single pulmonary nodules (SPN). This report describes the details and implications of the ITALIAN trial design. Methods and Results: Between September 2016 and May 2017, 502 consecutive patients (302 men, mean age 67±12 years) with SPN undergoing 18F-fluorodeoxyglucose (FDG) PET/CT were enrolled. PET/CT images will be visually and semiquantitatively evaluated. For visual analysis, a 4-point scoring system (1=absent; 2=mild; 3=moderate and 4=intense) will be used; for semiquantitative analysis, maximum standardized uptake value (SUV) in the SPN and mean SUV in the mediastinal blood pool and in the liver will be computed. Conclusion: The results of this trial might help to define the role of s-PET/CT in patients with SPN. This trial will also evaluate the impact on radiobiology and costs subsequent the introduction of this alternative imaging acquisition modality.

Purpose: To assess the capability of 18F-FAZA PET/CT in identifying intratumoral hypoxic areas in early and locally advanced non-small cell lung cancer (NSCLC) patients and to compare 18FFAZA PET/CT with 18F-FDG PET/CT and histopathological biomarkers and to investigate whether the assessment of tumour to blood (T/B) and tumour to muscle (T/M) ratios provide comparable information regarding the hypoxic fractions of the tumour. Materials and Methods: Seven patients with NSCLC were prospectively enrolled (3 men, 4 women; median age: 71 years; range 63-80). All patients underwent to 18F-FDG PET/CT and 18F-FAZA PET/CT before surgery. Maximum standardized uptake value (SUVmax) was used to evaluate 18FFDG PET/CT images, while 18F-FAZA PET/CT images have been interpreted by using tumour-toblood (T/B) and tumour-to-muscle (T/M) ratio. Surgery was performed in all patients; immunohistochemical analysis for hypoxia biomarkers was performed on histologic tumor samples. Results: All lung lesions showed intense 18F-FDG uptake (mean SUVmax: 7.35; range: 2.35-25.20). A faint 18F-FAZA uptake was observed in 6/7 patients (T/B < 1.2) while significant uptake was present in the remaining 1/7 (T/B and T/M=2.24). On both 2 and 4 h imaging after injection, no differences were observed between T/M and T/B (p=0.5), suggesting that both blood and muscle are equivalent in estimating the background activity for image analysis. Immunohisotchemical analysis showed low or absent staining for hypoxia biomarkers in 3 patients (CA-IX and GLUT-1: 0%; HIF-1α: mean 3.3%; range 0-10). Two patients showed staining for HIF-1α of 5%, with CA-IX being 60% and 30%, respectively and GLUT-1 being 30% and 80%, respectively; in 1/7 HIF-1α was 10%, CA-IX was 50% and GLUT-1 was 90%. In one patient a higher percentage of HIF-1α and CA-IX (20% and 70%, respectively) positive cells was present, with GLUT-1 being 30%. Conclusions: To the best of our knowledge, this is the first paper assessing hypoxia and glucose metabolism in comparison with immunohistochemistry in patients candidate to surgery for NSCLC. Although including a small number of patients, useful insight regarding correlation between imaging and immunohistochemistry are reported along with methodological suggestions for clinical practice.

Background: Para-¹⁸F-fluorohippuric acid (¹⁸F-PFH) and ortho-¹²⁴I-iodohippuric acid (¹²⁴IOIH) were recently identified as potential radiotracers suitable for conducting renography using positron emission tomography (PET). The aim of this work was to estimate preliminary human-equivalent internal radiation dose of ¹⁸F-PFH and ¹²⁴I-OIH using the biodistribution data reported in healthy rats. The results were compared with the absorbed dose data of technetium-99m-mercaptoacetyltriglycine (^99mTc- MAG3) as documented in the International Commission on Radiological Protection (ICRP) publication 80. Methods: The medical internal radiation dose (MIRD) formula was applied to extrapolate data from rats to human and to project the absorbed radiation dose for various organs in humans. S factor was calculated by Monte-Carlo N-particle (MCNP) simulation. Results: Our dose prediction shows that an injection of ¹⁸F-PFH or ¹²⁴I-OIH in humans would result in an estimated effective absorbed dose of 0.09 or 0.17 μSv/MBq respectively for whole body, which is about 135 or 73 times respectively lower than that obtained with an injection of ^99mTc-MAG3. All organs except kidneys would receive an estimated effective absorbed dose of <0.1 μSv/MBq for ¹⁸F-PFH or ¹²⁴I-OIH. Kidneys would receive a dose of 0.83 or 0.77 μSv/MBq respectively for ¹⁸F-PFH or ¹²⁴I-OIH. Conclusions: Our results indicate that ¹⁸F-PFH and ¹²⁴I-OIH would deliver much safer levels and lower radiation doses to the patients compared to ^99mTc-MAG3 and warrants a clinical trial to estimate the radiation doses more accurately.

Background: Sentinel lymph-node scintigraphy is a useful method for accurate staging of different tumors and a helpful tool in personalized therapy for oncological patients. The radiation exposure for surgical staff has been a concern since the sentinel lymph-node detection method was developed. Objective: The objective of the study was to determine and quantify the exposure to radiation of the non-dominant index for the surgeon performing sentinel lymph-node removal and to determine, if there is an irradiation risk imposed during the surgical procedure. Method: We performed a study over a period of one year, where we evaluated the exposure of surgeon's non-dominant index during 196 sentinel lymph-node removal procedures. The pharmaceutical was administrated via subcutaneous injection in four peritumoral or perilesional injection sites. The equipment we used consisted of EuroProbe3 for sentinel lymph-node detection and ring TLD dosimeter placed on the surgeon's non-dominant index. Results: The clinical distribution was: 104 melanomas, 84 breast carcinomas, 6 vulvar carcinomas and 2 penial carcinomas. The administered activity showed an average of 39.55 MBq (SD ± 1.96) Tc-99m nanoalbumin compound. The non-dominant index exposure ranged between 0.10 mSv and 0.13 mSv/month with a cumulative dose of 1.31 mSv/year, thus 6.69 μSv per procedure. Conclusion: The surgeon received a minimal dose for the non-dominant index. The values we recorded did not pose any additional concerns or restrictions, the exposure being under the limits and constraints established by regulations, close to the detectability limit of the dosimeter. The procedure is safe in terms of radiation protection, respecting the limitation and optimization principles.

Background: The production of radiopharmaceuticals, especially the PET ones, is a complex combination of economic and social factors. Despite the social aspects, that are essential, the economic issue must be considered and play an important parameter for the implementation and maintenance of producer centers around the world, with especial regards for countries which face economic crisis and/or belongs to aegis of under development countries. Objectives: In order to evaluate this scenario with carried out this study, comparing a well-established producer center in Brazil and a new on in Belarus. Results: The results showed that the producer center in Brazil face serious economic problems and all the production logistic must be re-done. On the other hand the new producer center in Belarus started following a new model of production and although it has not been profitable, the perspectives seem to be better than the Brazilian producer center. Conclusion: The Brazilian model for PET radiopharmaceutical productions should be revised in order to avoid waste and create a new perspective for the research area.