Tissue hypoxia results from an inadequate supply of oxygen (O 2 ) that compromises biological functions. Structural and functional abnormalities of the tumour vasculature together with altered diffusion conditions inside the tumour seem to be the main causes of tumour hypoxia. Evidence from experimental and clinical studies points to a role for tumour hypoxia in tumour propagation, resistance to therapy and malignant progression. This has led to the development of assays for the detection of hypoxia in patients in order to predict outcome and identify patients with a worse prognosis and/or patients that would benefit from appropriate treatments. A variety of invasive and noninvasive approaches have been developed to measure tumour oxygenation including oxygen-sensitive electrodes and hypoxia marker techniques using various labels that can be detected by different methods such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), autoradiography and immunohistochemistry. This review aims to give a detailed overview of non-invasive molecular imaging modalities with radiolabelled PET and SPECT tracers that are available to measure tumour hypoxia.Keywords Hypoxia . PET . SPECT . Nitroimidazole Hypoxia in tumour biologyThe prevalence of hypoxic areas is a characteristic feature of locally advanced solid tumours and has been described in a wide range of human malignancies, including cancer of the breast, uterine cervix, vulva, head and neck, prostate, rectum, pancreas as well as in brain tumours, soft tissue sarcomas and malignant melanomas. Up to 50-60% of locally advanced solid tumours may exhibit hypoxic and/or anoxic tissue areas that are heterogeneously distributed within the tumour mass. These hypoxic areas result from an imbalance between oxygen supply and consumption which is caused by abnormal structure and function of the microvessels supplying the tumour (causing acute hypoxia), increased diffusion distances between the nutritive blood vessels and the tumour cells (causing chronic hypoxia), and reduced O 2 transport capacity of the blood due to the presence of disease-or treatment-related anaemia [1][2][3]. Recent studies have demonstrated a clear relevance of this hypoxic microenvironment to tumour-associated metabolic alterations, which are tightly linked to the biology of the tumour. In this respect, tumour hypoxia has been associated with an aggressive tumour phenotype, poor response to radiotherapy and chemotherapy, increased risk of invasion and metastasis, and worse prognosis in advanced squamous

Available literature on the differences in circulation and microcirculation of normal liver and liver metastases as well as in rheology of the different radiolabelled microspheres [(99m)Tc-labelled macroaggregates of albumin (MAA), (90)Y-TheraSpheres and (90)Y-SIR-spheres] used in selective internal radiation therapy (SIRT) are reviewed and implications thereof on the practice of SIRT discussed. As a result of axial accumulation and skimming, large microspheres are preferentially deposited in regions of high flow, whereas smaller microspheres are preferentially diverted to regions of low flow. As flow to normal liver tissue is considerably variable between segments and also within one segment, microspheres will be delivered heterogeneously within the microvasculature of normal liver tissue. This non-uniformity in microsphere distribution in normal liver tissue has a significant "liver-sparing" effect on the dose distribution of (90)Y-labelled microspheres. Arterial flow to liver metastases is most pronounced in the hypervascular rim of metastases, followed by the smaller metastases and finally by the central hypoperfused region of the larger metastases. Because of the wide variability in size of labelled MAAs and because of the skimming effect, existing differences in flow between metastatic lesions of variable size are likely exaggerated on (99m)Tc-MAA scintigraphy when compared to (90)Y-TheraSpheres and (90)Y-SIR-spheres (smaller variability in size and probably also in specific activity). Ideally, labelled MAAs would contain a size range similar to that of (90)Y-SIR-spheres or (90)Y-TheraSpheres. Furthermore, the optimal number of MAA particles to inject for the pretreatment planning scintigraphy warrants further exploration as it was shown that concentrated suspensions of microspheres produce more optimal tumour to normal liver distribution ratios. Finally, available data suggest that the flow-based heterogeneous distribution of microspheres to metastatic lesions of variable size might be optimized, that is rendered more homogeneous, through the combined use of angiotensin II and degradable starch microspheres.

In this review, data on noninvasive imaging of apoptosis in oncology are reviewed. Imaging data available are presented in order of occurrence in time of enzymatic and morphologic events occurring during apoptosis. Available studies suggest that various radiopharmaceutical probes bear great potential for apoptosis imaging by means of positron emission tomography and single-photon emission computed tomography (SPECT). However, for several of these probes, thorough toxicologic studies are required before they can be applied in clinical studies. Both preclinical and clinical studies support the notion that 99mTc-hydrazinonicotinamide-annexin A5 and SPECT allow for noninvasive, repetitive, quantitative apoptosis imaging and for assessing tumor response as early as 24 hours following treatment instigation. Bioluminescence imaging and near-infrared fluorescence imaging have shown great potential in small-animal imaging, but their usefulness for in vivo imaging in humans is limited to structures superficially located in the human body. Although preclinical tumor-based data using high-frequency-ultrasonography (US) are promising, whether or not US will become a routinely clinically useful tool in the assessment of therapy response in oncology remains to be proven. The potential of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) for imaging late apoptotic processes is currently unclear. Neither 31P MRS nor 1H MRS signals seems to be a unique identifier for apoptosis. Although MRI-measured apparent diffusion coefficients are altered in response to therapies that induce apoptosis, they are also altered by nonapoptotic cell death, including necrosis and mitotic catastrophe. In the future, rapid progress in the field of apoptosis imaging in oncology is expected.