The role of molecular imaging for the evaluation of hypoxia in solid tumors

L'ipossia è una condizione patologica determinata da un ridotto apporto di ossigeno a livello tissutale. A partire dagli anni '60, Tomlinson e Gray hanno dimostrato la presenza di regioni di scarsa ossigenazione nel cancro del polmone e hanno osservato che questa caratteristica del microambiente tumorale è associata ad una maggiore resistenza alla radioterapia. La determinazione dell'ipossia nei tumori è pertanto della massima rilevanza clinica, in quanto l'aggressività del tumore, la deriva metastatica, il mancato controllo della neoplasia, l'aumento del rischio di recidiva e, in definitiva l'esito sfavorevole sono associati all'ipossia. Negli ultimi decenni, c'è stato un crescente interesse nello sviluppo di metodi per la valutazione dell'ossigenazione tumorale. Questi metodi possono essere invasivi, come il sensore polarografico di O2, o non invasivi, basati principalmente sulle tecniche di imaging. Le modalità di imaging sono senza dubbio le più interessanti perché garantiscono una visualizzazione onnicomprensiva del tessuto patologico e sono in grado di identificare il fenomeno anche in luoghi inaccessibili alle procedure invasive. Tra le modalità di imaging per la valutazione dell'ipossia, la tomografia ad emissione di positroni (PET) è una delle più studiate, in quanto offre: (a) ampio assortimento di radiofarmaci; (B) buona risoluzione intrinseca; (C) rappresentazione tridimensionale (3D); (D) (semi)quantificazione; (E) maggiore facilità per il paziente, e (f) riproducibilità dei dati. L'oggetto della tesi attuale è quello di studiare il ruolo dell'imaging molecolare alla PET nell'ipossia tumorale. Il testo è diviso in quattro sessioni distinte incentrate nel fornire in primis una panoramica sui radiofarmaci principali (Sessione-1), poi nella valutazione della correlazione tra l'espressione tissutale d'ipossia e l'imaging alla 18F-FDG PET/TC (Sessione-2). Le altre due sessioni analizzano l'impatto prognostico del tracciante per l'ipossia (64Cu-ATSM) nei tumori solidi (Sessione-3), seguito da una sofisticata analisi frattale di confronto fra le acquisizioni precoci e tardive alla 64Cu ATSM PET/TC nei tumori solidi (Sessione-4).Hypoxia is a pathological condition caused by a reduced oxygen supply at the tissue level. Since the 60’s, Tomlinson and Gray have demonstrated the presence of regions of poor oxygenation in lung cancer, and noted that this characteristic of tumor microenvironment is associated to increased resistance to radiotherapy. The detection of hypoxia in tumors is therefore of utmost clinical relevance, because tumor aggressiveness, metastatic drift, failure to disease control, increased risk of recurrence and ultimately poor outcome are associated with hypoxia. In recent decades, there has been an increasing interest in developing methods for the assessment of tumor oxygenation. These methods can be invasive, such as the polarographic O2-sensor, or non-invasive, mainly based on imaging techniques. Imaging modalities are undoubtedly the most appealing techniques for this purpose, because they guarantee an all-encompassing visualization of the pathological tissue and can identify the phenomenon even at sites inaccessible to invasive procedures. Among the image-based modalities for hypoxia assessment, positron emission tomography (PET) is one of the most extensively investigated, because it offers: (a) broad assortment of radiopharmaceuticals; (b) good intrinsic resolution; (c) three-dimensional (3D) tumor representation; (d) (semi)quantification of the hypoxic burden; (e) patient friendliness, and (f) reproducibility. The object of the current thesis is to investigate the role of molecular imaging with PET in cancer hypoxia. The text is divided into four different sessions focused on giving at first an insight on principal radiopharmaceuticals applied for hypoxia imaging (Session-1), then concentrating on the correlation of tissue expression of hypoxia and imaging findings on 18F-FDG PET/CT (Session-2). The next two sessions will analyze the prognostic impact of the hypoxia-specific tracer (64Cu-ATSM) in solid tumors (Session-3), followed by a sophisticated ad hoc computer-aided fractal geometry based analysis of DICOM images for early and late acquisitions on 64Cu-ATSM PET/CT in solid tumors (Session-4)

Multimodality imaging of ectopic focus in Graves’ Disease.

Herein, we report imaging findings related to an ectopic focus of thyroid tissue in a young female with Graves’ disease. The occurrence of ectopic thyroid tissue affects approximately 7% of adult population and represents commonly an occasional finding. Only rarely ectopic tissue can present with metastasis or develop a primary thyroid carcinoma. Multimodality imaging may be of help in this case to detect thyroid ectopia, although recent studies question its capability to differentiate benign from malignant tissue

[11C]-choline PET/CT in imaging locally advanced prostate cancer

PET Imaging with [11C]-choline has become a useful tool in the investigation of prostate cancer, with as main application the assessment of previously treated patients presenting with rising PSA and negative conventional imaging procedures. In this case report we describe [11C]-choline PET/CT findings in a patient with a locally advanced cancer, which could be successfully identified thanks to the early image acquisition and the delayed urinary excretion of the carbon-11 labeled tracer. Nuclear Med Rev 2011; 14, 2: 118–11

Imaging struma ovarii by means of 124I-Na PET/CT

Struma ovarii is a rare form of ovary tumour defined as the presence of ectopic thyroid tissue in the ovarian structures. Itusually presents with a benign course, although in some cases carcinoma or other malignant tumours can be found in the context of the ectopic tissue. Herein we report the case of a youngpatient affected by struma ovarii visualized by means of 124I-NaPET/CT. Thanks to the excellent target-to-background ratio ofthe tracer and the high resolution of the method, we could well identify the presence of some minimal tumour at the level of theleft ovary. To our knowledge, this is the first report of its kind

Metabolism of Stem and Progenitor Cells: Proper Methods to Answer Specific Questions

Stem cells can stay quiescent for a long period of time or proliferate and differentiate into multiple lineages. The activity of stage-specific metabolic programs allows stem cells to best adapt their functions in different microenvironments. Specific cellular phenotypes can be, therefore, defined by precise metabolic signatures. Notably, not only cellular metabolism describes a defined cellular phenotype, but experimental evidence now clearly indicate that also rewiring cells towards a particular cellular metabolism can drive their cellular phenotype and function accordingly. Cellular metabolism can be studied by both targeted and untargeted approaches. Targeted analyses focus on a subset of identified metabolites and on their metabolic fluxes. In addition, the overall assessment of the oxygen consumption rate (OCR) gives a measure of the overall cellular oxidative metabolism and mitochondrial function. Untargeted approach provides a large-scale identification and quantification of the whole metabolome with the aim to describe a metabolic fingerprinting. In this review article, we overview the methodologies currently available for the study of invitro stem cell metabolism, including metabolic fluxes, fingerprint analyses, and single-cell metabolomics. Moreover, we summarize available approaches for the study of in vivo stem cell metabolism. For all of the described methods, we highlight their specificities and limitations. In addition, we discuss practical concerns about the most threatening steps, including metabolic quenching, sample preparation and extraction. A better knowledge of the precise metabolic signature defining specific cell population is instrumental to the design of novel therapeutic strategies able to drive undifferentiated stem cells towards a selective and valuable cellular phenotype

The evidence-based role of catecholaminergic PET tracers in Neuroblastoma. A systematic review and a head-to-head comparison with mIBG scintigraphy

Background: Molecular imaging is pivotal in staging and response assessment of children with neuroblastoma (NB). [123I]-metaiodobenzylguanidine (mIBG) is the standard imaging method; however, it is characterised by low spatial resolution, time-consuming acquisition procedures and difficult interpretation. Many PET catecholaminergic radiotracers have been proposed as a replacement for [123I]-mIBG, however they have not yet made it into clinical practice. We aimed to review the available literature comparing head-to-head [123I]-mIBG with the most common PET catecholaminergic radiopharmaceuticals. Methods: We searched the PubMed database for studies performing a head-to-head comparison between [123I]-mIBG and PET radiopharmaceuticals including meta-hydroxyephedrine ([11C]C-HED), 18F-18F-3,4-dihydroxyphenylalanine ([18F]DOPA) [124I]mIBG and Meta-[18F]fluorobenzylguanidine ([18F]mFBG). Review articles, preclinical studies, small case series (< 5 subjects), case reports, and articles not in English were excluded. From each study, the following characteristics were extracted: bibliographic information, technical parameters, and the sensitivity of the procedure according to a patient-based analysis (PBA) and a lesion-based analysis (LBA). Results: Ten studies were selected: two regarding [11C]C-HED, four [18F]DOPA, one [124I]mIBG, and three [18F]mFBG. These studies included 181 patients (range 5-46). For the PBA, the superiority of the PET method was reported in two out of ten studies (both using [18F]DOPA). For LBA, PET detected significantly more lesions than scintigraphy in seven out of ten studies. Conclusions: PET/CT using catecholaminergic tracers shows superior diagnostic performance than mIBG scintigraphy. However, it is still unknown if such superiority can influence clinical decision-making. Nonetheless, the PET examination appears promising for clinical practice as it offers faster image acquisition, less need for sedation, and a single-day examination

Use of modern imaging methods to facilitate trials of metastasis-directed therapy for oligometastatic disease in prostate cancer: a consensus recommendation from the EORTC Imaging Group

Oligometastatic disease represents a clinical and anatomical manifestation between localised and polymetastatic disease. In prostate cancer, as with other cancers, recognition of oligometastatic disease enables focal, metastasisdirected therapies. These therapies potentially shorten or postpone the use of systemic treatment and can delay further metastatic progression, thus increasing overall survival. Metastasis-directed therapies require imaging methods that definitively recognise oligometastatic disease to validate their efficacy and reliably monitor response, particularly so that morbidity associated with inappropriately treating disease subsequently recognised as polymetastatic can be avoided. In this Review, we assess imaging methods used to identify metastatic prostate cancer at first diagnosis, at biochemical recurrence, or at the castration-resistant stage. Standard imaging methods recommended by guidelines have insufficient diagnostic accuracy for reliably diagnosing oligometastatic disease. Modern imaging methods that use PET-CT with tumour-specific radiotracers (choline or prostate-specific membrane antigen ligand), and increasingly whole-body MRI with diffusion-weighted imaging, allow earlier and more precise identification of metastases. The European Organisation for Research and Treatment of Cancer (EORTC) Imaging Group suggests clinical algorithms to integrate modern imaging methods into the care pathway at the various stages of prostate cancer to identify oligometastatic disease. The EORTC proposes clinical trials that use modern imaging methods to evaluate the benefits of metastasis-directed therapies