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Molecular mechanisms of hypoxia in cancer

Amarnath Challapalli, Laurence Carroll, Eric O. Aboagye

Clinical and Translational Imaging · 2017 · Review

doi:10.1007/s40336-017-0231-1

Abstract

Purpose. Hypoxia is a condition of insufficient oxygen to support metabolism which occurs when the vascular supply is interrupted, or when a tumour outgrows its vascular supply. It is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. This review provides an overview of hypoxia imaging with Positron emission tomography (PET), with an emphasis on the biological relevance, mechanism of action, highlighting advantages, and limitations of the currently available hypoxia radiotracers.

Methods. A comprehensive PubMed literature search was performed, identifying articles relating to biological significance and measurement of hypoxia, MRI methods, and PET imaging of hypoxia in preclinical and clinical settings, up to December 2016.

Results. A variety of approaches have been explored over the years for detecting and monitoring changes in tumour hypoxia, including regional measurements with oxygen electrodes placed under CT guidance, MRI methods that measure either oxygenation or lactate production consequent to hypoxia, different nuclear medicine approaches that utilise imaging agents the accumulation of which is inversely related to oxygen tension, and optical methods. The advantages and disadvantages of these approaches are reviewed, along with individual strategies for validating different imaging methods. PET is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels.

Conclusion. Even though hypoxia could have significant prognostic and predictive value in the clinic, the best method for hypoxia assessment has in our opinion not been realised.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 26, 2026. Paragraph numbers are ours, so an answer can point at one.

What is hypoxia?

Hypoxia generally refers to sub-physiologic tissue oxygen levels (<5–10 mmHg). Tumour hypoxia, a hallmark of malignancy, is a common and important feature of the tumour microenvironment. It is the consequence of an oxygen delivery versus consumption mismatch that occurs when cell proliferation outstrips neoangiogenesis during tumour growth. This results in very low oxygen levels (<5 mmHg) in tumours versus 40–60 mmHg in healthy tissues. Hypoxia can generally be classified as (1) perfusion-related (acute) hypoxia due to insufficient blood flow, (2) diffusion-related (chronic) hypoxia caused by an increase in diffusion distances with tumour expansion, and (3) anaemic hypoxia caused by a decrease in oxygen transport capacity. The latter two are considered relatively stable, whereas the degree of acute hypoxia may change in a short time. Cancer cells respond differently to decreased oxygen tension by eliciting cell death or cell survival, which partially depends on the time of exposure to hypoxia.

The origin of chronic hypoxia in human tumours was postulated by Thomlinson and Gray in 1955. Chronic hypoxia, also referred to as diffusion-limited hypoxia (DLH), is caused by consumption of oxygen by cells close to vessels, leaving inadequate oxygen for the cells further away from the vessels (>100 µm of capillary blood vessels), as demonstrated by means of phosphorescence lifetime imaging of R3230AC tumours in dorsal flap window chambers. Chronic hypoxic changes are exacerbated in larger tumours and contribute to long-term cellular changes such as high frequency of DNA breaks, accumulation of DNA replication errors, potentially leading to genetic instability and mutagenesis.

Brown and colleagues were the first to present a second form of hypoxia: acute hypoxia. Acute hypoxia is an abrupt and brief exposure to short-term hypoxia (between a few minutes and up to 72 h) which occurs consequent to fluctuations in tumour perfusion accompanying functionally and structurally defective vascular network in tumour (overdilated, hyperpermeable, tortuous, and disrupted), and associated with high-interstitial pressure of the extracellular matrix. This leads to periods of better or worse oxygenation promulgating the lexicon—cycling hypoxia. Temporal occlusion of blood vessels caused by blood clots or tumour emboli can also cause acute hypoxia. Acute hypoxia can lead to generation of high levels of reactive oxygen species (ROS) that can damage cells. Cellular adaptations to these conditions have been enumerated and include decreasing oxidative metabolism and activating autophagy. Increased radio-resistance of cancer cells, induction of spontaneous metastasis, and genomic instability due to delayed DNA damage response and rapid p53-dependent apoptosis can also result from hypoxia, leading to an aggressive tumour phenotype.

Hypoxia represents a unique tumour vulnerability to be exploited in the context of newly emerging personalised medicine strategies. Undoubtedly, both chronic and acute tumour hypoxia directly affect clinical responses to therapy by influencing tumour growth, ability to metastasize, and resistance to cell death.

Methods

A comprehensive PubMed literature search was performed, identifying articles relating to types of hypoxia, biological significance of hypoxia, measurement of hypoxia, MRI methods, and PET imaging of hypoxia in preclinical and clinical settings, up to December 2016. Search terms that were used to identify such articles were “hypoxia imaging,” “MRI,” “FMISO”, “FAZA”, “FETNIM”, “EF5”, “HX4”, “RP-170”, “Cu-ATSM”, and “PET” or “positron emission tomography.” Original publications in English were selected for inclusion in this review.

Biology and clinical significance of hypoxia

Tumour hypoxia is frequently seen in solid tumours, and tumour cells survive by activating different signalling pathways leading to a plethora of temporally or spatially heterogeneous changes in tumours (Table 1), elicited at different thresholds of oxygen tension. In fact, during malignant growth, hypoxic regions are associated with increased genetic instability and more aggressive phenotype which correlate with tumour metastasis risk. Likewise, hypoxia causes unequivocal resistance to cancer treatments, such as reduced drug penetration, intrinsic chemoresistance (by mechanisms including loss of sensitivity to p53-mediated apoptosis or diminution of cell proliferation by metabolic stress), and resistance to ionizing radiation (reduced ability of oxygen to fix DNA lesions).

A number of biological consequences of low oxygen levels have been elegantly described by Höckel and Vaupel. At pO2 levels less than 10–15 mmHg, cells become radioresistant and gene expression of hypoxia-regulated genes under control of hypoxia-inducible factor (HIF1) increases. Decreased adenosine triphosphate (ATP) synthesis is seen at pO2 levels less than 10 mmHg and together with decreased protein synthesis leads to lower oxygen consumption by cells. Finally, pO2 levels less than 1 mmHg reduce oxidative phosphorylation and conversely enhance glycolysis to maintain adequate ATP levels.

Role of HIF1alpha

Pathological hypoxia is a common microenvironment factor in tumours that facilitates cell survival and propagation of the tumour. The cross-talk between tumour and its microenvironment is essential for tumour survival. Hypoxia-inducible changes not only affect tumour cells but also the tumour microenvironment. Hypoxia-inducible factor 1 and 2 (HIF1 and HIF2, respectively) are oxygen-sensitive, heterodimeric transcription factors that act as key mediators of the cellular adaptation to low oxygen. HIF1 regulates glycolysis and pyruvate metabolism, and HIF-2 controls fatty acid metabolism. HIF1 is a heterodimeric protein consisting of HIF1alpha (oxygen regulated) and HIF1beta (constitutively expressed) dimers. Hypoxia stabilises HIF1alpha which stimulates expression of a variety of genes controlling metabolic pathways, pH regulation, angiogenesis, metastatic potential, DNA replication, protein synthesis, and treatment resistance, which (1) enhances cell survival via growth factor signalling and inhibition of pro-apoptotic pathways, (2) contribute to tumour neovascularization via VEGF, VEGF receptors, COX-2, iNOS, (3) regulate cell detachment via down regulation of adhesion molecules such as cadherins, and (4) induce cell migration and invasion through matrix degrading enzymes (Table 1, Fig. 1).

Resistance to chemotherapy and radiotherapy mediated by HIF1 signalling

Drug resistance could potentially occur at the cellular level or secondary to changes in the tumour microenvironment. Tumours have convoluted vasculature which results in proliferating well-nourished cells closer to the functional blood vessels and regions of hypoxic cells located away from the functional blood vessels. Irregular blood flow and large distances between functional blood vessels in solid tumours lead to poor drug distribution, resulting in therapeutic resistance.

It is often difficult to discriminate between the effects of hypoxia per se and HIF1, and the literature on the effects of the hypoxic microenvironment and HIF1 on drug efflux and multidrug resistant phenotype, for instance, is controversial. Zhao and co-workers recently reported that HIF1alpha suppresses MDR1/P-glycoprotein in gastric cancer by inhibiting miR-27a expression in gastric cancer, and in colon cancer cells, inhibition of HIF1 leads to downregulation of p-glycoprotein and reversal of multidrug resistant phenotype. In contrast, pronounced hypoxia has minor effect on p-glycoprotein expression and activity, while acidosis, a feature of the hpoxic micro-environement, increases p-glycoprotein activity. In addition, regarding drug efficacy, the hypoxic environment can modify the efficacy of drugs that require molecular oxygen as part of their mechanism of action, e.g., bleomycins, or are activated by reductases under hypoxia, e.g., evofosfamide, tarloxotinib, tirapazamine, and SN30000, and is a barrier to drug delivery generally independent of HIF1. Hypoxia and HIF1 also confer treatment resistance of cancer cells by inducing cell cycle arrest (quiescence), making drugs that target cycling cells ineffective), and by supporting the highly tumourigenic stem cell niche. In glioblastoma, HIF1alpha+ quiescent stem-like are found to locate within the peri-necrotic region and confer higher tumourigenic potential. During severe or prolonged hypoxia, most of the cells undergo programmed cell death. However, some of the tumour cells adjust to environmental stress and survive by avoiding necrosis, inhibition of apoptosis, and decreasing senescence of cells, mediated by HIFalpha, resulting in an aggressive phenotype and resistance to treatment.

During fractionated radiotherapy, HIF1alpha protects the tumour microvasculature from radiation-induced endothelial apoptosis, via induction of vascular endothelial growth factor (VEGF) and other pro-angiogenic factors and facilitates tumour cell survival by increasing the antioxidant capacity of tumours to counteract radation-induced oxidative stress. Irradiation also induces changes in the tumour microenvironment such as vascular, stromal, and immunological changes which may promote radioresistance and tumour recurrence. These effects eventually lead to the resistance of tumour cells to chemotherapy and radiation.

Measurement of hypoxia

Knowledge of the hypoxia state enables prediction of treatment outcome and selection of patients for hypoxia modifying treatment. The relative prevalence of diffusion limited hypoxia (DLH), cyclic and perfusional hypoxia in human tumours or animal models is not known, and it is predicted that different hypoxia modes require different diagnostic and therapeutic approaches. Several noninvasive techniques (direct or indirect measurements) are available to obtain an absolute or relative value of the oxygenation status of tumours. The various strategies available are described in Table 2. Each of the techniques described interrogates different aspects of the hypoxic microenvironment, and they provide information on hypoxia at different locations: Oxygen electrodes and OxyLite sampling predominantly measure interstitial hypoxia. PET, SPECT, and extrinsic markers report on intracellular hypoxia and PET/SPECT images quantify data on a macroscopic scale in tumour regions. Blood oxygen level-dependent (BOLD)-MRI and Oxy-R fraction allow assessment of blood oxygenation, while indirect methods that report on hypoxia-induced molecular events (e.g., GLUT1, CA9 expression) rather than hypoxia itself have also been utilised as markers of tumour oxygenation.

MRI methods

These include MR-based gradient-recalled echo techniques, electron paramagnetic resonance, and MR spectroscopy. MRI methods for interrogating tumour oxygenation are attractive since MRI scanners are widely available and they avoid the complication of short-lived radioactivity.

Blood oxygen level dependent (BOLD)-MRI

The most facile contrast mechanism, which depends on blood oxygenation—blood oxygen level dependent (BOLD) MRI—avoids the need for reporter molecules by imaging differences between diamagnetic oxy-haemoglobin and paramagnetic deoxy-haemoglobin. The presence of deoxy-haemoglobin in a blood vessel causes susceptibility differences between vessel and its surrounding tissue resulting in a decrease in T2* leading to darkening in tissues containing the vessel in a T2*-weighted imaging protocol. A limitation is that it is also sensitive to changes in Hb concentration (due to alterations in vascular volume and flow as well as interconversion of oxy- and deoxy-haemoglobin). Therefore, this technique provides qualitative assessment of changes in oxygenation rather than quantitative measurements. The technique is widely used for functional brain mapping, where it is thought to primarily reflect changes in flow.

Baudelet and Gallez have rigorously investigated correlations between pO2 estimated using fibre optic probes and BOLD signal changes and have found general correlations, but a given BOLD response may reflect vastly different changes in pO2. BOLD MRI has the advantage of both high spatial and temporal resolution and it can be repeated as needed; however, it can be susceptible to subtle motion artefacts. Rijpkema et al. used BOLD to evaluate patients during the ARCON trial for head and neck cancer and found significant changes in T2*-weighted MRI contrast accompanying hyperoxic gas breathing. No accompanying changes were observed by traditional T1-weighted gadolinium dynamic contrast-enhanced MRI. Preliminary analysis of 11 women being treated with chemotherapy for locally advanced breast cancer showed a significantly different BOLD response to breathing oxygen before the course of chemotherapy for tumours of women with good therapeutic outcome versus those with poor response. Indeed, three women with complete pathologic response showed a signal change greater than 7%, whereas those with poor outcome showed less than 3%. It is arguable whether the differential response reflects perfusion or oxygenation, but traditional dynamic contrast-enhanced MRI failed to provide similar discrimination.

The biologic sequelae of hypoxia are also amenable to imaging. Prolonged hypoxia can lead to increased lactate in tissues and 1H MRI can be used to image lactate. Furthermore, alteration of the redox state of nonprotein thiols, such as glutathione, adenine nucleotide redox state, NADH or NADPH in hypoxic cells can lead to accumulation of radiopharmaceuticals in hypoxia. All of these tests measure downstream consequences of hypoxia and often do not instantly return to normal values after an adequate O2 supply has been established. For more information, the reader is referred to a recent review that addressed the role of functional MRI (fMRI) methods to assess tumour oxygenation for predicting outcome.

PET imaging of hypoxia

Positron emission tomography (PET) has inherent advantages for studying hypoxia, as it can employ radiotracer probes that directly report on cellular oxygen levels, and not via hypoxia-mediated changes in phenotype, thereby permitting the non-invasive and three-dimensional assessment of intratumour oxygen levels in a more direct manner. In contrast to histologic characterisation, PET can monitor whole tumours although at low spatial resolution. PET has very high sensitivity and specificity compared to MR imaging and it enables the identification of regional hypoxia in vivo in preclinical and clinical settings.

PET tracers for hypoxia imaging and their mechanisms of action

The criteria for development of radiotracer probes includes improving relative tumour uptake by using isotopes with longer half-lives and ensuring rapid clearance of the parent compound from systemic circulation and normoxic tissue (hydrophilic compounds), while being sufficiently lipophilic to enter cells and allow uniform tissue distribution. The charcteristics of an ideal hypoxic tracer include: retention in low partial oxygen pressure (pO2) regions (hypoxia specific), pharmacokinetic profile and tissue distribution independent of confounding factors such as blood flow/tissue perfusion or pH, high stability, suitable tissue kinetics to enable imaging in a specified time frame, ease of synthesis, favourable dosimetry profile, reproducibility and effectiveness in multiple tumour types.

Radionuclide detection of hypoxia in tumours was first reported in 1981 with [14C]misonidazole autoradiography. Subsequently, two main tracer classes have been developed to specifically study regional tumour hypoxia with PET: [18F]labelled nitroimidazoles and Cu-labelled diacetyl-bis(N4-methylthiosemicarbazone) analogues. Multiple PET tracers suitable for the detection of hypoxia have been developed, validated and shown to exhibit different characteristics; some of these are discussed in Table 3. The first [18F]labelled drug to be clinically tested was fluoromisonidazole (FMISO) and it remains the most extensively tested agent.

[18F]Nitroimidazoles

2-Nitroimidazole compounds were originally developed as hypoxic cell radiosensitisers and were introduced as hypoxia markers in the 1970s (Fig. 2). Nitroimidazoles enter cells by passive diffusion and subsequently undergo reduction forming reactive intermediate species. Hypoxic conditions cause further reduction of the nitro-anion radical, which is irreversibly trapped in the cell when the oxygen tension is less than 10 mmHg. The reduction of nitroimidazoles requires the presence of ubiquitously expressed tissue reductases, which enables these compounds to accumulate within viable hypoxic cells, but not apoptotic or necrotic cells. Under normoxic conditions, nitro-anion radical is re-oxidised into the parent compound, which can diffuse out of the cell. The mechanism of of [18F]MISO intracellular trapping is shown in Fig. 3. Therefore, hypoxic tissues can be delineated as an area of high tracer uptake after allowing a sufficient period of time for the nonspecific tracer to be excreted from the cells.

FMISO uptake was closely correlated with pimonidazole immunohistochemistry and has been found to reflect hypoxia in head-and-neck cancer, glioma, colorectal cancer, breast cancer, lung cancer, and renal cell carcinoma.

In view of FMISO’s slow plasma clearance, FMISO imaging usually requires an interval of longer than 2 h (ideally 4 h) after administration to obtain good contrast with a hypoxia threshold in general defined as SUVmax of 1.5 or tumour:muscle ratio of 1.4. Although its biodistribution properties do not result in high-contrast images, the 2-h image unambiguously reflects regional pO2 in the range where it is clinically significant. However, due to perceived concerns regarding FMISO stability in vivo, metabolite formation, slow clearance properties, and failure to achieve image intensities in humans comparable to what had been achieved in animal models, alternative hypoxia PET tracers with different clearance and hydrophilicity characteristics have been developed in an attempt to overcome these limitations. These include fluoroazomycin arabinoside (FAZA), fluoroerythronitroimidazole (FETNIM), fluoroetanidazole (Fig. 4), and fluorinated etanidazole derivatives (EF3, EF5), HX4.

[18F]Fluoroazomycin-arabinofuranoside (FAZA)

[18F]Fluoroazomycin-arabinofuranoside (FAZA) is more hydrophilic than FMISO. Consequently, it has faster clearance kinetics, resulting in improved tumour-to-reference tissue ratios, and thus hypoxia-to-normoxia contrast. Head-to-head comparisons between FAZA, [124I]IAZA, and FMISO in preclinical animal studies imaged at 3 h after injection demonstrated faster vascular clearance of FAZA, resulting in an increased tumour-to-blood ratio (5.19) relative to that of [18F]fluoromisonidazole (3.98). More recently, clinical studies have successfully evaluated the feasibility of FAZA for imaging hypoxia in gliomas, lymphomas, lung, head-and-neck, cervical, and rectal tumours, and the results have been shown to compare favourably with equivalent FMISO data, especially as improved hypoxic–normoxic contrast was obtained at earlier time points. High FAZA tumour-to-reference tissue values have been associated with reduced disease-free survival and have shown prognostic potential in the detection of hypoxia in head-and-neck patients. Due to the higher tumour-to-reference tissue ratios in comparison with FMISO, FAZA is gaining popularity for PET imaging of tumour hypoxia. Despite the fact that FAZA is not widely available at present, increasing research demand may persuade more sites to produce it.

[18F]2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-Pentafluoropropyl)-acetamide (EF5)

The nitroimidazole EF5 has been extensively used for ex vivo immunohistochemical detection of bioreduced adducts, which indicate regions of tumour hypoxia. However, [18F]2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5), first investigated as a hypoxia PET tracer in 2001, has only recently appeared in the clinical setting. In contrast to many of the second-generation hypoxia tracers, EF5 is highly lipophilic, resulting in greater cell membrane permeability and slower blood clearance, thus improving rates of tumour uptake and homogeneity of tracer distribution. The main drawback of EF5 is the complex labelling chemistry in comparison to the simple nucleophilic displacement reactions used for the mono-fluorinated 2-nitroimidazoles.

[18F]3-fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)Methyl)-1H-1,2,3-triazol-1-yl)propan-1-ol (HX4)

[18F]3-fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)propan-1-ol (HX4), a next-generation 2-nitroimidazole tracer contains a 1,2,3-anti-triazole moiety (as a synthetic convenience) rendering it more hydrophilic than FMISO, specifically designed to maximize pharmacokinetic and clearance properties. Initial studies in humans demonstrate rapid renal clearance and urinary excretion of HX4, with a favourable dosimetry profile similar to that of FMISO.

Preclinical studies validated that the tracer uptake was indeed oxygen-dependent though tumour-to-background ratios appeared similar to those reported for FMISO in studies using the same tumour model; thus, it remains to be seen if HX4 provides any significant advantage over FMISO in a clinical setting. A phase I study of 6 patients (4 non-small-cell lung carcinoma, 1 thymus carcinoma, and 1 colon carcinoma) has shown a median tumour-to-muscle ratio of 1.40 at 120 min after injection, although no attempt was made to determine the optimal imaging time points. In head-and-neck tumours, HX4 produced tumour-to-reference tissue values similar to FMISO at relatively early time points post injection, indicating the potential advantage of shorter acquisition times. A more recent study in non-small cell lung cancer (NSCLC) patients suggested that later scan times (2–4 h p.i.) can further enhance the hypoxic-to-normoxic signal.

[18F]Fluoroerythronitromidazole (FETNIM)

The hydrophilic nature of [18F]Fluoroerythronitromidazole (FETNIM) accounts for its rapid renal clearance and low liver uptake, compared with FMISO. This also could explain the positive correlation between tumour blood flow and initial tumour FETNIM uptake. Recent clinical studies in head-and-neck, lung, cervical cancer, and oesophageal cancer showed that high tissue uptake of FETNIM was indicative of reduced progression-free and overall survival. However, as with HX4, it is not clear whether the use of this tracer presents any advantages over FMISO imaging protocols. Clinical studies with FETNIM have been mainly carried out at the University of Turku, Finland.

[18F]1-(2-1-(1H-methyl)ethoxy)-methyl-2-nitroimidazole (RP-170)

1-(2-1-(1H-methyl)ethoxy)-methyl-2-nitroimidazole was developed as a 2-nitroimidazole-based hypoxic radiosensitiser, which has also been labelled with fluorine-18 ([18F]RP-170). The hypoxic selectivity of RP-170 was demonstrated in glioma patients on the basis of significant correlations between uptake, oxygen tension measurements, and HIF1alpha immunostaining. Studies in brain and lung tumours indicated higher SUV (calculated at 1 h post injection), for hypoxic than normal tissues. The shorter interval before scanning, combined with improved hypoxic contrast compared with FMISO, could make it attractive for clinical imaging.

Copper (Cu)-diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM)

An alternative class of agents for the study of hypoxia with PET that has been intensively investigated in both preclinical and clinical studies is the complex of Cu with diacetyl-bis(N4-methylthiosemicarbazone) (ATSM) ligands, among which ATSM is the prototype (Fig. 5). The potential of these agents for hypoxia imaging was first reported by Fujibayashi et al.. Copper (Cu)-diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM) is a hypoxic marker that is selectively retained in hypoxic tissues. Cu-ATSM rapidly diffuses into the cells due to its high membrane permeability and low redox potential, secondary to its lipophilicity and low molecular weight. After cellular entry, Cu(II)-ATSM is reduced to an unstable Cu(I)-ATSM species, which further dissociates into the metal complex Cu(I), and ATSM, thus irreversibly trapping the Cu(I) within the cellular copper metabolic processes (Fig. 6). In normoxic conditions, the [Cu(I)-ATSM] can be re-oxidised to its parent compound, allowing efflux from the cell. One of the advantages of Cu-ATSM is that it can reveal molecular contrast within 10–15 min post injection mainly due to its rapid tracer kinetics.

However, it has been observed that high uptake in tumours may only partly be a direct consequence of hypoxia. Nevertheless, extremely high-contrast images of Cu-ATSM have been obtained in a variety of tumour sites. The lack of correlation between Cu-ATSM distribution and immunohistochemistry hypoxia markers casted some doubt on the hypoxia selectivity of Cu-ATSM. The suggested reason for the low correlation between Cu-ATSM uptake and hypoxic distribution, in some tumours, was the differing redox status of the tumour types. This has been further seen in pre-clinical experiments, where it was demonstrated that in the cell lines tested, [64Cu]Cu-ATSM and [64Cu]Cu-acetate had almost identical uptake in vivo over 2–16 h, post injection. However, up to 1 h post injection, [64Cu]Cu-acetate had a superior tumour-to-muscle ratio. Several factors could explain the phenomenon; indeed, some tumours might have a lower than-average redox potential with high concentrations of electron donors causing reduction and trapping of Cu-ATSM in both hypoxic and normoxic areas. This observation does not discount the fact that [64Cu]Cu-ATSM may still be clinically relevant as a tracer for hypoxia, perhaps HIF1 status, as suggested by some investigators. The timing of image acquisition is crucial, as the initial phase of tracer uptake can be perfusion and hypoxia-driven, whereas at later time points uptake is probably more indicative of tumour hypoxia.

Validation of MRI and PET hypoxia imaging

As discussed thus far, both MRI and PET play an important role in hypoxia imaging. However, there are few reports that compare these two imaging modalities. Preclinically, a clear correlation between [18F]FAZA PET image intensities and tumour oxygenation was demonstrated by Tran et al.. [18F]FAZA accurately showed improved uptake when rats with subcutaneous rhabdomyosarcomas were treated with air, in contrast to carbogen. This correlated well with an invasive OxyLite probe, although the probe demonstrated a relatively high heterogeneity in the oxygen value measured depending on the specific point within the tumour. Functional MRI ([19F]MRI, however, did not show any discernible difference in T1 spin–lattice relaxation time. In a more recent study, Valable et al. validated tissue saturation studied by MRI against FMISO PET wth high sensitivity and specificity in a rat glioma model.

In the clinical setting, Swanson et al. performed a detailed spatial analysis of the hypoxic tumour burden visible on the FMISO PET relative to the imaging changes associated with tumour neovasculature, necrosis, invasion, and edema seen on gadolinium-enhanced T1-weighted MRI (T1Gd) in 24 patients with glioblastoma. Hypoxic Volume (HV), defined within the tumour as sections that had a tumour-to-blood ratio of higher than 1.2, showed a consistent correlation with the MRI-defined regions within the tumour, supporting the idea that there is a definite link between the PET and MRI images of hypoxia. Furthermore, it was found that HV, and the respective surface areas of HV and T1Gd abnormality were the most significant predictors of survival. Simoncic et al., showed a strong correlation between FMISO PET and dynamic contrast enhanced MRI (DCE-MRI) kinetic parameters in 6 head and neck cancer patients.

These studies suggest that both MRI and PET could complement each other and provide a future direction in selecting the best modality to image hypoxia.

Clinical applications

There is evidence from numerous clinical studies across a range of tumour types to support the existence and importance of the “hypoxia driver” phenotype both in pre-clinical (Table 4) and clinical studies (Table 5).

Identification of tumour hypoxia and prediction of prognosis/response to treatment

The clinical significance of hypoxia PET imaging is to identify individuals with poor prognosis and those likely to benefit from hypoxia-targeted therapy. Several studies have shown that hypoxia PET imaging predicts outcome. High FMISO retention has been associated with higher risk of loco-regional failure and shorter progression-free survival in head-and-neck and renal cancer. Furthermore, a meta-review of the clinical data of over 300 patients concluded that FMISO is a predictor of poor treatment response and prognosis. Similarly, FETNIM uptake in lung, head-and-neck, and oesophageal cancer, were also associated with poor outcomes. Studies conducted with FAZA in squamous cell carcinomas of the head and neck and Cu-ATSM in patients with cervical, lung, and rectal cancer have shown that lower tumour-to-muscle ratio (TMR) is indicative of better prognosis.

These findings have been discussed in a recent meta-analysis of PET hypoxia studies which have demonstrated a common tendency towards predicting outcome in tumours showing higher tracer accumulation. Decreased FMISO uptake with treatment has been widely reported in brain, head-and-neck, lung, and renal tumours; although this was not seen in some tumours. Decrease in semi-quantitative imaging parameters such as tumour-to-muscle ratios (TMRs) signifying response to chemotherapy have also been demonstrated with Cu-ATSM in lung and head-and-neck tumours, and FAZA in lung cancer.

Radiotherapy planning

It is well known that tumours demonstrate temporal changes and/or heterogeneity in the spatial distribution of hypoxia. Identification of these areas with PET hypoxia scans enables image guidance and hence, radiation dose escalation to radioresistant sub-volumes. Boosting the dose to intra-tumoural areas of biological resistance (dose painting) is being pursued as a strategy to overcome radioresistance and improve outcomes. This is made possible due to the advances in imaging and radiation treatment planning. The feasibility of this strategy has been investigated in cancers of the head and neck, lung, and brain with Cu-ATSM, FMISO, and FAZA, mostly on anthrophomorphic phantoms, and further studies are required for translation into clinical benefit.

Discussion and concluding remarks

Hypoxia research has a long history; however, accurate and reproducible measurement of clinically relevant hypoxia with high sensitivity continues to evade the scientific community. Although radionuclide measurements of hypoxia started in the early 1980s we are yet to have a widely accepted method. In addition to studies with oxygen electrodes, imaging utilising exognous probes including FMISO-PET, FAZA-PET, HX4, and immunohistochemistry with pimonidazole have been the mainstay of hypoxia assessment in clinical studies; the EU-funded METOXIA consortium for example utilises HX4 for assessment of hypoxia. In the post-genome era, genetic methods are also making an important entrance—with a 26-gene signature in validation for assessing hypoxia. There have been some successes in the use of hypoxia measurements as part of clinical trials: a number of studies confirmed that hypoxia predicts locoregional failure to radiotherapy and chemoradiotherapy with hypoxia-modulated cytotoxin tirapazamine. Conversely, there have been several challenges, in particular poor sensitivity of the methods requiring long assessment periods (as pertains to nitroimidazole PET methods), invasive nature (as pertains to pimonidazole immunohistochemistry), an inability to relate measured output to oxygen tension (as pertains to MRI methods despite high spatial resolution) and wide heterogeneity within and between the tumours of the same patients and temporally with treatment (all methods).

Notably, despite design of newer nitroimidazoles with substantially different physicochemical properties—high hydrophilicity—concomitant improvements in signal-to-noise ratio and, thus, reduction in imaging times, have not been achieved, indicating that the ideal chemical design has not yet been realised. There is also paucity of studies examining heterogeneity of hypoxia using parametric imaging to detect the influence of hypoxia sub-volumes and whether this additional detail will have prognostic or predictive value. With the advent of PET-MRI scanners, it will be feasible to multiplex imaging modalities to provide addition information such as perfusion to increase accuracy of hypoxia measurements or provide complementary information with higher predictive value. Whatever selected method will require assessment of precision of measurement which is non-trivial with such a spatio-temporally evanescent phenomenon as hypoxia.

Thus, it is accepted that hypoxia could have significant prognostic and predictive value in the clinic; however, the best method for hypoxia assessment has in our opinion not been realised.

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    Not in our library10.3892/or_00001027

  14. 14.

    Rouschop KM, Ramaekers CH, Schaaf MB, Keulers TG, Savelkouls KG, Lambin P, Koritzinsky M, Wouters BG. Autophagy is required during cycling hypoxia to lower production of reactive oxygen species. Radiother Oncol. 2009;92(3):411-416.

    Not in our library10.1016/j.radonc.2009.06.029

  15. 15.

    Koritzinsky M, Wouters BG. The roles of reactive oxygen species and autophagy in mediating the tolerance of tumor cells to cycling hypoxia. Semin Radiat Oncol. 2013;23(4):252-261.

    Not in our library10.1016/j.semradonc.2013.05.006

  16. 16.

    Kato Y, Yashiro M, Fuyuhiro Y, Kashiwagi S, Matsuoka J, Hirakawa T, Noda S, Aomatsu N, Hasegawa T, Matsuzaki T, Sawada T, Ohira M, Hirakawa K. Effects of acute and chronic hypoxia on the radiosensitivity of gastric and esophageal cancer cells. Anticancer Res. 2011;31(10):3369-3375.

    Not in our library

  17. 17.

    Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, Mazure NM. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol. 2009;29(10):2570-2581.

    Not in our library10.1128/mcb.00166-09

  18. 18.

    Rofstad EK, Gaustad JV, Egeland TA, Mathiesen B, Galappathi K. Tumors exposed to acute cyclic hypoxic stress show enhanced angiogenesis, perfusion and metastatic dissemination. Int J Cancer. 2010;127(7):1535-1546.

    Not in our library10.1002/ijc.25176

  19. 19.

    Pires I, Silva F, Queiroga FL, Rodrigues P, Henriques R, Pinto CA, Lopes C. Epithelioid hemangiosarcomas of the bovine urinary bladder: a histologic, immunohistochemical, and ultrastructural examination of four tumors. J Vet Diagn Invest. 2010;22(1):116-119.

    Not in our library10.1177/104063871002200124

  20. 20.

    Bristow RG, Berlin A, Dal Pra A. An arranged marriage for precision medicine: hypoxia and genomic assays in localized prostate cancer radiotherapy. Br J Radiol. 2014;87(1035):20130753.

    Not in our library10.1259/bjr.20130753

  21. 21.

    Meijer TW, Kaanders JH, Span PN, Bussink J. Targeting hypoxia, HIF-1, and tumor glucose metabolism to improve radiotherapy efficacy. Clin Cancer Res. 2012;18(20):5585-5594.

    Not in our library10.1158/1078-0432.ccr-12-0858

  22. 22.

    Zagzag D, Krishnamachary B, Yee H, Okuyama H, Chiriboga L, Ali MA, Melamed J, Semenza GL. Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res. 2005;65(14):6178-6188.

    Not in our library10.1158/0008-5472.can-04-4406

  23. 23.

    Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest. 2013;123(9):3664-3671.

    Not in our library10.1172/jci67230

  24. 24.

    Guo K, Searfoss G, Krolikowski D, Pagnoni M, Franks C, Clark K, Yu KT, Jaye M, Ivashchenko Y. Hypoxia induces the expression of the pro-apoptotic gene BNIP3. Cell Death Differ. 2001;8(4):367-376.

    Not in our library10.1038/sj.cdd.4400810

  25. 25.

    Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G, Iyer N, LaRusch J, Pak B, Taghavi P, Semenza GL. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res. 2003;63(5):1138-1143.

    Not in our library

  26. 26.

    Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH, Semenza GL. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res. 2006;66(5):2725-2731.

    Not in our library10.1158/0008-5472.can-05-3719

  27. 27.

    Azab AK, Hu J, Quang P, Azab F, Pitsillides C, Awwad R, Thompson B, Maiso P, Sun JD, Hart CP, Roccaro AM, Sacco A, Ngo HT, Lin CP, Kung AL, Carrasco RD, Vanderkerken K, Ghobrial IM. Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features. Blood. 2012;119(24):5782-5794.

    Not in our library10.1182/blood-2011-09-380410

  28. 28.

    Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer. 2008;8(11):851-864.

    Not in our library10.1038/nrc2501

  29. 29.
    Hypoxia stimulates migration of breast cancer cells via the PERK/ATF4/LAMP3-arm of the unfolded protein response · 2013
    No notice
  30. 30.

    Nagelkerke A, Bussink J, van der Kogel AJ, Sweep FC, Span PN. The PERK/ATF4/LAMP3-arm of the unfolded protein response affects radioresistance by interfering with the DNA damage response. Radiother Oncol. 2013;108(3):415-421.

    Not in our library10.1016/j.radonc.2013.06.037

  31. 31.

    Nagelkerke A, Sieuwerts AM, Bussink J, Sweep FC, Look MP, Foekens JA, Martens JW, Span PN. LAMP3 is involved in tamoxifen resistance in breast cancer cells through the modulation of autophagy. Endocr Relat Cancer. 2014;21(1):101-112.

    Not in our library10.1530/erc-13-0183

  32. 32.

    Nagelkerke A, Bussink J, Sweep FC. Span PN (2014) The unfolded protein response as a target for cancer therapy. Biochim Biophys Acta. 1846;2:277-284.

    Not in our library10.1016/j.bbcan.2014.07.006

  33. 33.

    Leung AK, Sharp PA. MicroRNA functions in stress responses. Mol Cell. 2010;40(2):205-215.

    Not in our library10.1016/j.molcel.2010.09.027

  34. 34.

    Tsai YP, Wu KJ. Epigenetic regulation of hypoxia-responsive gene expression: focusing on chromatin and DNA modifications. Int J Cancer. 2014;134(2):249-256.

    Not in our library10.1002/ijc.28190

  35. 35.

    Johnson AB, Barton MC. Hypoxia-induced and stress-specific changes in chromatin structure and function. Mutat Res. 2007;618(1–2):149-162.

    Not in our library10.1016/j.mrfmmm.2006.10.007

  36. 36.

    Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996;379(6560):88-91.

    Not in our library10.1038/379088a0

  37. 37.

    Gillies RJ, Gatenby RA. Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis? J Bioenerg Biomembr. 2007;39(3):251-257.

    Not in our library10.1007/s10863-007-9085-y

  38. 38.

    McFate T, Mohyeldin A, Lu H, Thakar J, Henriques J, Halim ND, Wu H, Schell MJ, Tsang TM, Teahan O, Zhou S, Califano JA, Jeoung NH, Harris RA, Verma A. Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem. 2008;283(33):22700-22708.

    Not in our library10.1074/jbc.m801765200

  39. 39.

    Bristow RG, Hill RP. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer. 2008;8(3):180-192.

    Not in our library10.1038/nrc2344

  40. 40.

    Brunelle JK, Bell EL, Quesada NM, Vercauteren K, Tiranti V, Zeviani M, Scarpulla RC, Chandel NS. Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metab. 2005;1(6):409-414.

    Not in our library10.1016/j.cmet.2005.05.002

  41. 41.

    Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2005;438(7070):932-936.

    Not in our library10.1038/nature04478

  42. 42.

    Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298-307.

    Not in our library10.1038/nature10144

  43. 43.

    de la Puente P, Muz B, Azab F, Azab AK. Cell trafficking of endothelial progenitor cells in tumor progression. Clin Cancer Res. 2013;19(13):3360-3368.

    Not in our library10.1158/1078-0432.ccr-13-0462

  44. 44.

    Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 1996;56(19):4509-4515.

    Not in our library

  45. 45.

    Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3(3):177-185.

    Not in our library10.1016/j.cmet.2006.02.002

  46. 46.

    Krock BL, Skuli N, Simon MC. Hypoxia-induced angiogenesis: good and evil. Genes Cancer. 2011;2(12):1117-1133.

    Not in our library10.1177/1947601911423654

  47. 47.

    Lou Y, McDonald PC, Oloumi A, Chia S, Ostlund C, Ahmadi A, Kyle A, Auf dem Keller U, Leung S, Huntsman D, Clarke B, Sutherland BW, Waterhouse D, Bally M, Roskelley C, Overall CM, Minchinton A, Pacchiano F, Carta F, Scozzafava A, Touisni N, Winum JY, Supuran CT, Dedhar S. Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res. 2011;71(9):3364-3376.

    Not in our library10.1158/0008-5472.can-10-4261

  48. 48.

    Lum JJ, Bui T, Gruber M, Gordan JD, DeBerardinis RJ, Covello KL, Simon MC, Thompson CB. The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev. 2007;21(9):1037-1049.

    Not in our library10.1101/gad.1529107

  49. 49.

    Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006;441(7092):437-443.

    Not in our library10.1038/nature04871

  50. 50.

    Terris DJ, Ho EY, Ibrahim HZ, Dorie MJ, Kovacs MS, Le QT, Koong AC, Pinto HA, Brown JM. Estimating DNA repair by sequential evaluation of head and neck tumor radiation sensitivity using the comet assay. Arch Otolaryngol Head Neck Surg. 2002;128(6):698-702.

    Not in our library10.1001/archotol.128.6.698

  51. 51.

    Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7(2):131-142.

    Not in our library10.1038/nrm1835

  52. 52.

    Yin J, Miyazaki K, Shaner RL, Merrill AH, Kannagi R. Altered sphingolipid metabolism induced by tumor hypoxia—new vistas in glycolipid tumor markers. FEBS Lett. 2010;584(9):1872-1878.

    Not in our library10.1016/j.febslet.2009.11.019

  53. 53.

    Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001;93(4):266-276.

    Not in our library10.1093/jnci/93.4.266

  54. 54.

    Rademakers SE, Span PN, Kaanders JH, Sweep FC, van der Kogel AJ, Bussink J. Molecular aspects of tumour hypoxia. Mol Oncol. 2008;2(1):41-53.

    Not in our library10.1016/j.molonc.2008.03.006

  55. 55.

    Sounni NE, Noel A. Targeting the tumor microenvironment for cancer therapy. Clin Chem. 2013;59(1):85-93.

    Not in our library10.1373/clinchem.2012.185363

  56. 56.

    Casazza A, Di Conza G, Wenes M, Finisguerra V, Deschoemaeker S, Mazzone M. Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment. Oncogene. 2014;33(14):1743-1754.

    Not in our library10.1038/onc.2013.121

  57. 57.

    Tafani M, Pucci B, Russo A, Schito L, Pellegrini L, Perrone GA, Villanova L, Salvatori L, Ravenna L, Petrangeli E, Russo MA. Modulators of HIF1alpha and NFkB in cancer treatment: is it a rational approach for controlling malignant progression? Front Pharmacol. 2013;4:13.

    Not in our library10.3389/fphar.2013.00013

  58. 58.

    Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl). 2015;3:83-92.

    Not in our library10.2147/hp.s93413

  59. 59.

    Zeng W, Liu P, Pan W, Singh SR, Wei Y. Hypoxia and hypoxia inducible factors in tumor metabolism. Cancer Lett. 2015;356(2 Pt A):263-267.

    Not in our library10.1016/j.canlet.2014.01.032

  60. 60.

    Tan Q, Saggar JK, Yu M, Wang M, Tannock IF. Mechanisms of drug resistance related to the microenvironment of solid tumors and possible strategies to inhibit them. Cancer J. 2015;21(4):254-262.

    Not in our library10.1097/ppo.0000000000000131

  61. 61.

    Yu M, Ocana A, Tannock IF. Reversal of ATP-binding cassette drug transporter activity to modulate chemoresistance: why has it failed to provide clinical benefit? Cancer Metastasis Rev. 2013;32(1–2):211-227.

    Not in our library10.1007/s10555-012-9402-8

  62. 62.
    HIF-1α Induces Multidrug Resistance in Gastric Cancer Cells by Inducing MiR-27a. · 2015
    Not checked
  63. 63.
    HIF-1α Inhibition Reverses Multidrug Resistance in Colon Cancer Cells via Downregulation of MDR1/P-Glycoprotein · 2014
    No notice
  64. 64.

    Thews O, Gassner B, Kelleher DK, Gekle M. Activity of drug efflux transporters in tumor cells under hypoxic conditions. Adv Exp Med Biol. 2008;614:157-164.

    Not in our library10.1007/978-0-387-74911-2_19

  65. 65.

    Thews O, Gassner B, Kelleher DK, Schwerdt G, Gekle M. Impact of extracellular acidity on the activity of p-glycoprotein and the cytotoxicity of chemotherapeutic drugs. Neoplasia. 2006;8(2):143-152.

    Not in our library10.1593/neo.05697

  66. 66.

    Dorr RT. Bleomycin pharmacology: mechanism of action and resistance, and clinical pharmacokinetics. Semin Oncol. 1992;19(2 Suppl 5):3-8.

    Not in our library

  67. 67.

    Chen J, Stubbe J. Bleomycins: towards better therapeutics. Nat Rev Cancer. 2005;5(2):102-112.

    Not in our library10.1038/nrc1547

  68. 68.

    Cosse JP, Michiels C. Tumour hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer progression. Anticancer Agents Med Chem. 2008;8(7):790-797.

    Not in our library10.2174/187152008785914798

  69. 69.

    Hunter FW, Wouters BG, Wilson WR. Hypoxia-activated prodrugs: paths forward in the era of personalised medicine. Br J Cancer. 2016;114(10):1071-1077.

    Not in our library10.1038/bjc.2016.79

  70. 70.

    Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer. 2006;6(8):583-592.

    Not in our library10.1038/nrc1893

  71. 71.

    Du J, Chen Y, Li Q, Han X, Cheng C, Wang Z, Danielpour D, Dunwoodie SL, Bunting KD, Yang YC. HIF-1alpha deletion partially rescues defects of hematopoietic stem cell quiescence caused by Cited2 deficiency. Blood. 2012;119(12):2789-2798.

    Not in our library10.1182/blood-2011-10-387902

  72. 72.

    Das B, Tsuchida R, Malkin D, Koren G, Baruchel S, Yeger H. Hypoxia enhances tumor stemness by increasing the invasive and tumorigenic side population fraction. Stem Cells. 2008;26(7):1818-1830.

    Not in our library10.1634/stemcells.2007-0724

  73. 73.

    Ishii A, Kimura T, Sadahiro H, Kawano H, Takubo K, Suzuki M, Ikeda E. Histological characterization of the tumorigenic “peri-necrotic niche” harboring quiescent stem-like tumor cells in glioblastoma. PLoS ONE. 2016;11(1):e0147366.

    Not in our library10.1371/journal.pone.0147366

  74. 74.

    Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. 2007;11(4):335-347.

    Not in our library10.1016/j.ccr.2007.02.006

  75. 75.

    Gordan JD, Thompson CB, Simon MC. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell. 2007;12(2):108-113.

    Not in our library10.1016/j.ccr.2007.07.006

  76. 76.

    Sullivan R, Pare GC, Frederiksen LJ, Semenza GL, Graham CH. Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Mol Cancer Ther. 2008;7(7):1961-1973.

    Not in our library10.1158/1535-7163.mct-08-0198

  77. 77.

    Barker HE, Paget JT, Khan AA, Harrington KJ. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer. 2015;15(7):409-425.

    Not in our library10.1038/nrc3958

  78. 78.

    Hockel M, Knoop C, Schlenger K, Vorndran B, Baussmann E, Mitze M, Knapstein PG, Vaupel P. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol. 1993;26(1):45-50.

    Not in our library10.1016/0167-8140(93)90025-4

  79. 79.

    Hockel M, Schlenger K, Knoop C, Vaupel P. Oxygenation of carcinomas of the uterine cervix: evaluation by computerized O2 tension measurements. Cancer Res. 1991;51(22):6098-6102.

    Not in our library

  80. 80.

    Vaupel P, Schlenger K, Knoop C, Hockel M. Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res. 1991;51(12):3316-3322.

    Not in our library

  81. 81.

    Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, Becker A, Adam M, Molls M, Dunst J, Terris DJ, Overgaard J. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol. 2005;77(1):18-24.

    Not in our library10.1016/j.radonc.2005.06.038

  82. 82.

    Rudat V, Vanselow B, Wollensack P, Bettscheider C, Osman-Ahmet S, Eble MJ, Dietz A. Repeatability and prognostic impact of the pretreatment pO(2) histography in patients with advanced head and neck cancer. Radiother Oncol. 2000;57(1):31-37.

    Not in our library10.1016/s0167-8140(00)00200-0

  83. 83.

    Rudat V, Stadler P, Becker A, Vanselow B, Dietz A, Wannenmacher M, Molls M, Dunst J, Feldmann HJ. Predictive value of the tumor oxygenation by means of pO2 histography in patients with advanced head and neck cancer. Strahlenther Onkol. 2001;177(9):462-468.

    Not in our library10.1007/pl00002427

  84. 84.

    Bussink J, Kaanders JH, Strik AM, van der Kogel AJ. Effects of nicotinamide and carbogen on oxygenation in human tumor xenografts measured with luminescense based fiber-optic probes. Radiother Oncol. 2000;57(1):21-30.

    Not in our library10.1016/s0167-8140(00)00275-9

  85. 85.

    Kaanders JH, Wijffels KI, Marres HA, Ljungkvist AS, Pop LA, van den Hoogen FJ, de Wilde PC, Bussink J, Raleigh JA, van der Kogel AJ. Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res. 2002;62(23):7066-7074.

    Not in our library

  86. 86.

    Evans SM, Du KL, Chalian AA, Mick R, Zhang PJ, Hahn SM, Quon H, Lustig R, Weinstein GS, Koch CJ. Patterns and levels of hypoxia in head and neck squamous cell carcinomas and their relationship to patient outcome. Int J Radiat Oncol Biol Phys. 2007;69(4):1024-1031.

    Not in our library10.1016/j.ijrobp.2007.04.067

  87. 87.

    Lord EM, Harwell L, Koch CJ. Detection of hypoxic cells by monoclonal antibody recognizing 2-nitroimidazole adducts. Cancer Res. 1993;53(23):5721-5726.

    Not in our library

  88. 88.

    Minchinton AI, Durand RE, Chaplin DJ. Intermittent blood flow in the KHT sarcoma–flow cytometry studies using Hoechst 33342. Br J Cancer. 1990;62(2):195-200.

    Not in our library10.1038/bjc.1990.259

  89. 89.

    Chia SK, Wykoff CC, Watson PH, Han C, Leek RD, Pastorek J, Gatter KC, Ratcliffe P, Harris AL. Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol. 2001;19(16):3660-3668.

    Not in our library10.1200/jco.2001.19.16.3660

  90. 90.

    Griffiths EA, Pritchard SA, McGrath SM, Valentine HR, Price PM, Welch IM, West CM. Increasing expression of hypoxia-inducible proteins in the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence. Br J Cancer. 2007;96(9):1377-1383.

    Not in our library10.1038/sj.bjc.6603744

  91. 91.

    Griffiths EA, Pritchard SA, Valentine HR, Whitchelo N, Bishop PW, Ebert MP, Price PM, Welch IM, West CM. Hypoxia-inducible factor-1alpha expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas. Br J Cancer. 2007;96(1):95-103.

    Not in our library10.1038/sj.bjc.6603524

  92. 92.

    Kon-no H, Ishii G, Nagai K, Yoshida J, Nishimura M, Nara M, Fujii T, Murata Y, Miyamoto H, Ochiai A. Carbonic anhydrase IX expression is associated with tumor progression and a poor prognosis of lung adenocarcinoma. Lung Cancer. 2006;54(3):409-418.

    Not in our library10.1016/j.lungcan.2006.08.017

  93. 93.

    Koukourakis MI, Bentzen SM, Giatromanolaki A, Wilson GD, Daley FM, Saunders MI, Dische S, Sivridis E, Harris AL. Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck cancer patients recruited in the CHART randomized trial. J Clin Oncol. 2006;24(5):727-735.

    Not in our library10.1200/jco.2005.02.7474

  94. 94.

    Bache M, Kappler M, Said HM, Staab A, Vordermark D. Detection and specific targeting of hypoxic regions within solid tumors: current preclinical and clinical strategies. Curr Med Chem. 2008;15(4):322-338.

    Not in our library10.2174/092986708783497391

  95. 95.

    Baer S, Casaubon L, Schwartz MR, Marcogliese A, Younes M. Glut3 expression in biopsy specimens of laryngeal carcinoma is associated with poor survival. Laryngoscope. 2002;112(2):393-396.

    Not in our library10.1097/00005537-200202000-00034

  96. 96.

    Mineta H, Miura K, Takebayashi S, Misawa K, Araki K, Misawa Y, Ueda Y. Prognostic value of glucose transporter 1 expression in patients with hypopharyngeal carcinoma. Anticancer Res. 2002;22(6B):3489-3494.

    Not in our library

  97. 97.

    Mineta H, Miura K, Ogino T, Takebayashi S, Misawa K, Ueda Y. Vascular endothelial growth factor (VEGF) expression correlates with p53 and ki-67 expressions in tongue squamous cell carcinoma. Anticancer Res. 2002;22(2B):1039-1044.

    Not in our library

  98. 98.

    O’Connor JP, Boult JK, Jamin Y, Babur M, Finegan KG, Williams KJ, Little RA, Jackson A, Parker GJ, Reynolds AR, Waterton JC, Robinson SP. Oxygen-enhanced MRI accurately identifies, quantifies, and maps tumor hypoxia in preclinical cancer models. Cancer Res. 2016;76(4):787-795.

    Not in our library10.1158/0008-5472.can-15-2062

  99. 99.

    Mason RP, Shukla H, Antich PP. In vivo oxygen tension and temperature: simultaneous determination using 19F NMR spectroscopy of perfluorocarbon. Magn Reson Med. 1993;29(3):296-302.

    Not in our library10.1002/mrm.1910290304

  100. 100.

    Baldwin NJ, Ng TC. Oxygenation and metabolic status of KHT tumors as measured simultaneously by 19F magnetic resonance imaging and 31P magnetic resonance spectroscopy. Magn Reson Imaging. 1996;14(5):541-551.

    Not in our library10.1016/0730-725x(96)00049-5

  101. 101.

    Baldwin NJ, Wang Y, Ng TC. In situ 19F MRS measurement of RIF-1 tumor blood volume: corroboration by radioisotope-labeled [125I]-albumin and correlation to tumor size. Magn Reson Imaging. 1996;14(3):275-280.

    Not in our library10.1016/0730-725x(95)02080-d

  102. 102.

    Baudelet C, Gallez B. How does blood oxygen level-dependent (BOLD) contrast correlate with oxygen partial pressure (pO2) inside tumors? Magn Reson Med. 2002;48(6):980-986.

    Not in our library10.1002/mrm.10318

  103. 103.

    Fleming IN, Manavaki R, Blower PJ, West C, Williams KJ, Harris AL, Domarkas J, Lord S, Baldry C, Gilbert FJ. Imaging tumour hypoxia with positron emission tomography. Br J Cancer. 2015;112(2):238-250.

    Not in our library10.1038/bjc.2014.610

  104. 104.

    Kim YR, Huang IJ, Lee SR, Tejima E, Mandeville JB, van Meer MP, Dai G, Choi YW, Dijkhuizen RM, Lo EH, Rosen BR. Measurements of BOLD/CBV ratio show altered fMRI hemodynamics during stroke recovery in rats. J Cereb Blood Flow Metab. 2005;25(7):820-829.

    Not in our library10.1038/sj.jcbfm.9600084

  105. 105.

    Leontiev O, Buxton RB. Reproducibility of BOLD, perfusion, and CMRO2 measurements with calibrated-BOLD fMRI. Neuroimage. 2007;35(1):175-184.

    Not in our library10.1016/j.neuroimage.2006.10.044

  106. 106.

    Padhani AR, Krohn KA, Lewis JS, Alber M. Imaging oxygenation of human tumours. Eur Radiol. 2007;17(4):861-872.

    Not in our library10.1007/s00330-006-0431-y

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    Rijpkema M, Kaanders JH, Joosten FB, van der Kogel AJ, Heerschap A. Effects of breathing a hyperoxic hypercapnic gas mixture on blood oxygenation and vascularity of head-and-neck tumors as measured by magnetic resonance imaging. Int J Radiat Oncol Biol Phys. 2002;53(5):1185-1191.

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    Jiang L, Weatherall PT, McColl RW, Tripathy D, Mason RP. Blood oxygenation level-dependent (BOLD) contrast magnetic resonance imaging (MRI) for prediction of breast cancer chemotherapy response: a pilot study. J Magn Reson Imaging. 2013;37(5):1083-1092.

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    Tarnawski R, Fowler J, Skladowski K, Swierniak A, Suwinski R, Maciejewski B, Wygoda A. How fast is repopulation of tumor cells during the treatment gap? Int J Radiat Oncol Biol Phys. 2002;54(1):229-236.

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    Tarnawski R, Sokol M, Pieniazek P, Maciejewski B, Walecki J, Miszczyk L, Krupska T. 1H-MRS in vivo predicts the early treatment outcome of postoperative radiotherapy for malignant gliomas. Int J Radiat Oncol Biol Phys. 2002;52(5):1271-1276.

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    Colliez F, Gallez B, Jordan BF. Assessing tumor oxygenation for predicting outcome in radiation oncology: a review of studies correlating tumor hypoxic status and outcome in the preclinical and clinical settings. Front Oncol. 2017;7:10.

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    Chia K, Fleming IN, Blower PJ. Hypoxia imaging with PET: which tracers and why? Nucl Med Commun. 2012;33(3):217-222.

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    Bussink J, van Herpen CM, Kaanders JH, Oyen WJ. PET-CT for response assessment and treatment adaptation in head and neck cancer. Lancet Oncol. 2010;11(7):661-669.

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    Chapman JD. Hypoxic sensitizers–implications for radiation therapy. N Engl J Med. 1979;301(26):1429-1432.

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    Gronroos T, Minn H. Imaging of tumour hypoxia using PET and 18F-labelled tracers: biology meets technology. Eur J Nucl Med Mol Imaging. 2007;34(10):1563-1565.

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    Yip C, Blower PJ, Goh V, Landau DB, Cook GJ. Molecular imaging of hypoxia in non-small-cell lung cancer. Eur J Nucl Med Mol Imaging. 2015;42(6):956-976.

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    Postema EJ, McEwan AJ, Riauka TA, Kumar P, Richmond DA, Abrams DN, Wiebe LI. Initial results of hypoxia imaging using 1-alpha-d: -(5-deoxy-5-[18F]-fluoroarabinofuranosyl)-2-nitroimidazole (18F-FAZA). Eur J Nucl Med Mol Imaging. 2009;36(10):1565-1573.

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    Koch CJ, Scheuermann JS, Divgi C, Judy KD, Kachur AV, Freifelder R, Reddin JS, Karp J, Stubbs JB, Hahn SM, Driesbaugh J, Smith D, Prendergast S, Evans SM. Biodistribution and dosimetry of (18)F-EF5 in cancer patients with preliminary comparison of (18)F-EF5 uptake versus EF5 binding in human glioblastoma. Eur J Nucl Med Mol Imaging. 2010;37(11):2048-2059.

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    van Loon J, Janssen MH, Ollers M, Aerts HJ, Dubois L, Hochstenbag M, Dingemans AM, Lalisang R, Brans B, Windhorst B, van Dongen GA, Kolb H, Zhang J, De Ruysscher D, Lambin P. PET imaging of hypoxia using [18F]HX4: a phase I trial. Eur J Nucl Med Mol Imaging. 2010;37(9):1663-1668.

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    Lehtio K, Oikonen V, Gronroos T, Eskola O, Kalliokoski K, Bergman J, Solin O, Grenman R, Nuutila P, Minn H. Imaging of blood flow and hypoxia in head and neck cancer: initial evaluation with [(15)O]H(2)O and [(18)F]fluoroerythronitroimidazole PET. J Nucl Med. 2001;42(11):1643-1652.

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    Gronroos T, Eskola O, Lehtio K, Minn H, Marjamaki P, Bergman J, Haaparanta M, Forsback S, Solin O. Pharmacokinetics of [18F]FETNIM: a potential marker for PET. J Nucl Med. 2001;42(9):1397-1404.

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    Beppu T, Terasaki K, Sasaki T, Fujiwara S, Matsuura H, Ogasawara K, Sera K, Yamada N, Uesugi N, Sugai T, Kudo K, Sasaki M, Ehara S, Iwata R, Takai Y. Standardized uptake value in high uptake area on positron emission tomography with 18F-FRP170 as a hypoxic cell tracer correlates with intratumoral oxygen pressure in glioblastoma. Mol Imaging Biol. 2014;16(1):127-135.

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    Fujibayashi Y, Taniuchi H, Yonekura Y, Ohtani H, Konishi J, Yokoyama A. Copper-62-ATSM: a new hypoxia imaging agent with high membrane permeability and low redox potential. J Nucl Med. 1997;38(7):1155-1160.

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    Dehdashti F, Grigsby PW, Mintun MA, Lewis JS, Siegel BA, Welch MJ. Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response-a preliminary report. Int J Radiat Oncol Biol Phys. 2003;55(5):1233-1238.

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    Aboagye EO, Kelson AB, Tracy M, Workman P. Preclinical development and current status of the fluorinated 2-nitroimidazole hypoxia probe N-(2-hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-1-imidazolyl) acetamide (SR 4554, CRC 94/17): a non-invasive diagnostic probe for the measurement of tumor hypoxia by magnetic resonance spectroscopy and imaging, and by positron emission tomography. Anticancer Drug Des. 1998;13(6):703-730.

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    Lee CP, Payne GS, Oregioni A, Ruddle R, Tan S, Raynaud FI, Eaton D, Campbell MJ, Cross K, Halbert G, Tracy M, McNamara J, Seddon B, Leach MO, Workman P, Judson I. A phase I study of the nitroimidazole hypoxia marker SR4554 using 19F magnetic resonance spectroscopy. Br J Cancer. 2009;101(11):1860-1868.

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    Grierson JR, Link JM, Mathis CA, Rasey JS, Krohn KA. A radiosynthesis of fluorine-18 fluoromisonidazole. J Nucl Med. 1989;30(3):343-350.

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    Krohn KA, Link JM, Mason RP. Molecular imaging of hypoxia. J Nucl Med. 2008;49(Suppl 2):129S-148S.

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    Lee ST, Scott AM. Hypoxia positron emission tomography imaging with 18f-fluoromisonidazole. Semin Nucl Med. 2007;37(6):451-461.

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    Aboagye EO, Lewis AD, Tracy M, Workman P. Bioreductive metabolism of the novel fluorinated 2-nitroimidazole hypoxia probe N-(2-hydroxy-3,3,3-trifluoropropyl)-2-(2-nitroimidazolyl) acetamide (SR-4554). Biochem Pharmacol. 1997;54(11):1217-1224.

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    Hunter FW, Young RJ, Shalev Z, Vellanki RN, Wang J, Gu Y, Joshi N, Sreebhavan S, Weinreb I, Goldstein DP, Moffat J, Ketela T, Brown KR, Koritzinsky M, Solomon B, Rischin D, Wilson WR, Wouters BG. Identification of P450 oxidoreductase as a major determinant of sensitivity to hypoxia-activated prodrugs. Cancer Res. 2015;75(19):4211-4223.

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    Prekeges JL, Rasey JS, Grunbaum Z, Krohn KH. Reduction of fluoromisonidazole, a new imaging agent for hypoxia. Biochem Pharmacol. 1991;42(12):2387-2395.

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    Jerabek PA, Patrick TB, Kilbourn MR, Dischino DD, Welch MJ. Synthesis and biodistribution of 18F-labeled fluoronitroimidazoles: potential in vivo markers of hypoxic tissue. Int J Rad Appl Instrum A. 1986;37(7):599-605.

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    McClelland RA. Molecualr interactions and biological effects of the products of reduction of nitroimidazoles. NATO advanced research workshop on selective activation of drugs by redox processes. 1990.

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    Cheng X, Bayer C, Maftei CA, Astner ST, Vaupel P, Ziegler SI, Shi K. Preclinical evaluation of parametric image reconstruction of [18F]FMISO PET: correlation with ex vivo immunohistochemistry. Phys Med Biol. 2014;59(2):347-362.

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    Rasey JS, Koh WJ, Evans ML, Peterson LM, Lewellen TK, Graham MM, Krohn KA. Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients. Int J Radiat Oncol Biol Phys. 1996;36(2):417-428.

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    Troost EG, Laverman P, Philippens ME, Lok J, van der Kogel AJ, Oyen WJ, Boerman OC, Kaanders JH, Bussink J. Correlation of [18F]FMISO autoradiography and pimonidazole [corrected] immunohistochemistry in human head and neck carcinoma xenografts. Eur J Nucl Med Mol Imaging. 2008;35(10):1803-1811.

    Not in our library10.1007/s00259-008-0772-7

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    Gagel B, Reinartz P, Dimartino E, Zimny M, Pinkawa M, Maneschi P, Stanzel S, Hamacher K, Coenen HH, Westhofen M, Bull U, Eble MJ. pO(2) Polarography versus positron emission tomography ([(18)F] fluoromisonidazole, [(18)F]-2-fluoro-2′-deoxyglucose). An appraisal of radiotherapeutically relevant hypoxia. Strahlenther Onkol. 2004;180(10):616-622.

    Not in our library10.1007/s00066-004-1229-y

  140. 140.

    Gagel B, Piroth M, Pinkawa M, Reinartz P, Zimny M, Kaiser HJ, Stanzel S, Asadpour B, Demirel C, Hamacher K, Coenen HH, Scholbach T, Maneschi P, DiMartino E, Eble MJ. pO polarography, contrast enhanced color duplex sonography (CDS), [18F] fluoromisonidazole and [18F] fluorodeoxyglucose positron emission tomography: validated methods for the evaluation of therapy-relevant tumor oxygenation or only bricks in the puzzle of tumor hypoxia? BMC Cancer. 2007;7:113.

    Not in our library10.1186/1471-2407-7-113

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    Hicks RJ, Rischin D, Fisher R, Binns D, Scott AM, Peters LJ. Utility of FMISO PET in advanced head and neck cancer treated with chemoradiation incorporating a hypoxia-targeting chemotherapy agent. Eur J Nucl Med Mol Imaging. 2005;32(12):1384-1391.

    Not in our library10.1007/s00259-005-1880-2

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    Thorwarth D, Eschmann SM, Holzner F, Paulsen F, Alber M. Combined uptake of [18F]FDG and [18F]FMISO correlates with radiation therapy outcome in head-and-neck cancer patients. Radiother Oncol. 2006;80(2):151-156.

    Not in our library10.1016/j.radonc.2006.07.033

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    Zimny M, Gagel B, DiMartino E, Hamacher K, Coenen HH, Westhofen M, Eble M, Buell U, Reinartz P. FDG–a marker of tumour hypoxia? A comparison with [18F]fluoromisonidazole and pO2-polarography in metastatic head and neck cancer. Eur J Nucl Med Mol Imaging. 2006;33(12):1426-1431.

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    Mortensen LS, Buus S, Nordsmark M, Bentzen L, Munk OL, Keiding S, Overgaard J. Identifying hypoxia in human tumors: a correlation study between 18F-FMISO PET and the Eppendorf oxygen-sensitive electrode. Acta Oncol. 2010;49(7):934-940.

    Not in our library10.3109/0284186x.2010.516274

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    Abolmaali N, Haase R, Koch A, Zips D, Steinbach J, Baumann M, Kotzerke J, Zophel K. Two or four hour [(1)(8)F]FMISO-PET in HNSCC. When is the contrast best? Nuklearmedizin. 2011;50(1):22-27.

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    Sato J, Kitagawa Y, Yamazaki Y, Hata H, Okamoto S, Shiga T, Shindoh M, Kuge Y, Tamaki N. 18F-fluoromisonidazole PET uptake is correlated with hypoxia-inducible factor-1alpha expression in oral squamous cell carcinoma. J Nucl Med. 2013;54(7):1060-1065.

    Not in our library10.2967/jnumed.112.114355

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    Hatano T, Zhao S, Zhao Y, Nishijima K, Kuno N, Hanzawa H, Sakamoto T, Tamaki N, Kuge Y. Biological characteristics of intratumoral [F-18]fluoromisonidazole distribution in a rodent model of glioma. Int J Oncol. 2013;42(3):823-830.

    Not in our library10.3892/ijo.2013.1781

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    Valk PE, Mathis CA, Prados MD, Gilbert JC, Budinger TF. Hypoxia in human gliomas: demonstration by PET with fluorine-18-fluoromisonidazole. J Nucl Med. 1992;33(12):2133-2137.

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    Bruehlmeier M, Roelcke U, Schubiger PA, Ametamey SM. Assessment of hypoxia and perfusion in human brain tumors using PET with 18F-fluoromisonidazole and 15O-H2O. J Nucl Med. 2004;45(11):1851-1859.

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    Rajendran JG, Mankoff DA, O’Sullivan F, Peterson LM, Schwartz DL, Conrad EU, Spence AM, Muzi M, Farwell DG, Krohn KA. Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging. Clin Cancer Res. 2004;10(7):2245-2252.

    Not in our library10.1158/1078-0432.ccr-0688-3

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    Cher LM, Murone C, Lawrentschuk N, Ramdave S, Papenfuss A, Hannah A, O’Keefe GJ, Sachinidis JI, Berlangieri SU, Fabinyi G, Scott AM. Correlation of hypoxic cell fraction and angiogenesis with glucose metabolic rate in gliomas using 18F-fluoromisonidazole, 18F-FDG PET, and immunohistochemical studies. J Nucl Med. 2006;47(3):410-418.

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    Swanson KR, Chakraborty G, Wang CH, Rockne R, Harpold HL, Muzi M, Adamsen TC, Krohn KA, Spence AM. Complementary but distinct roles for MRI and 18F-fluoromisonidazole PET in the assessment of human glioblastomas. J Nucl Med. 2009;50(1):36-44.

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    Oehler C, O’Donoghue JA, Russell J, Zanzonico P, Lorenzen S, Ling CC, Carlin S. 18F-fluromisonidazole PET imaging as a biomarker for the response to 5,6-dimethylxanthenone-4-acetic acid in colorectal xenograft tumors. J Nucl Med. 2011;52(3):437-444.

    Not in our library10.2967/jnumed.110.081372

  154. 154.

    Cheng J, Lei L, Xu J, Sun Y, Zhang Y, Wang X, Pan L, Shao Z, Liu G. 18F-fluoromisonidazole PET/CT: a potential tool for predicting primary endocrine therapy resistance in breast cancer. J Nucl Med. 2013;54(3):333-340.

    Not in our library10.2967/jnumed.112.111963

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    Cherk MH, Foo SS, Poon AM, Knight SR, Murone C, Papenfuss AT, Sachinidis JI, Saunder TH, O’Keefe GJ, Scott AM. Lack of correlation of hypoxic cell fraction and angiogenesis with glucose metabolic rate in non-small cell lung cancer assessed by 18F-Fluoromisonidazole and 18F-FDG PET. J Nucl Med. 2006;47(12):1921-1926.

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    Vera P, Bohn P, Edet-Sanson A, Salles A, Hapdey S, Gardin I, Menard JF, Modzelewski R, Thiberville L, Dubray B. Simultaneous positron emission tomography (PET) assessment of metabolism with (1)(8)F-fluoro-2-deoxy-d-glucose (FDG), proliferation with (1)(8)F-fluoro-thymidine (FLT), and hypoxia with (1)(8)fluoro-misonidazole (F-miso) before and during radiotherapy in patients with non-small-cell lung cancer (NSCLC): a pilot study. Radiother Oncol. 2011;98(1):109-116.

    Not in our library10.1016/j.radonc.2010.10.011

  157. 157.

    Murakami M, Zhao S, Zhao Y, Chowdhury NF, Yu W, Nishijima K, Takiguchi M, Tamaki N, Kuge Y. Evaluation of changes in the tumor microenvironment after sorafenib therapy by sequential histology and 18F-fluoromisonidazole hypoxia imaging in renal cell carcinoma. Int J Oncol. 2012;41(5):1593-1600.

    Not in our library10.3892/ijo.2012.1624

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    Hugonnet F, Fournier L, Medioni J, Smadja C, Hindie E, Huchet V, Itti E, Cuenod CA, Chatellier G, Oudard S, Faraggi M. Metastatic renal cell carcinoma: relationship between initial metastasis hypoxia, change after 1 month’s sunitinib, and therapeutic response: an 18F-fluoromisonidazole PET/CT study. J Nucl Med. 2011;52(7):1048-1055.

    Not in our library10.2967/jnumed.110.084517

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    Piert M. Hypoxia imaging. Principles and practice of PET and PET/CT. 2009.

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  160. 160.

    Ballinger JR. Imaging hypoxia in tumors. Semin Nucl Med. 2001;31(4):321-329.

    Not in our library10.1053/snuc.2001.26191

  161. 161.

    Lopci E, Grassi I, Chiti A, Nanni C, Cicoria G, Toschi L, Fonti C, Lodi F, Mattioli S, Fanti S. PET radiopharmaceuticals for imaging of tumor hypoxia: a review of the evidence. Am J Nucl Med Mol Imaging. 2014;4(4):365-384.

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    Horsman MR, Mortensen LS, Petersen JB, Busk M, Overgaard J. Imaging hypoxia to improve radiotherapy outcome. Nat Rev Clin Oncol. 2012;9(12):674-687.

    Not in our library10.1038/nrclinonc.2012.171

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    Barthel H, Wilson H, Collingridge DR, Brown G, Osman S, Luthra SK, Brady F, Workman P, Price PM, Aboagye EO. In vivo evaluation of [18F]fluoroetanidazole as a new marker for imaging tumour hypoxia with positron emission tomography. Br J Cancer. 2004;90(11):2232-2242.

    Not in our library10.1038/sj.bjc.6601862

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    Bollineni VR, Kerner GS, Pruim J, Steenbakkers RJ, Wiegman EM, Koole MJ, de Groot EH, Willemsen AT, Luurtsema G, Widder J, Groen HJ, Langendijk JA. PET imaging of tumor hypoxia using 18F-fluoroazomycin arabinoside in stage III-IV non-small cell lung cancer patients. J Nucl Med. 2013;54(8):1175-1180.

    Not in our library10.2967/jnumed.112.115014

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    Trinkaus ME, Blum R, Rischin D, Callahan J, Bressel M, Segard T, Roselt P, Eu P, Binns D, MacManus MP, Ball D, Hicks RJ. Imaging of hypoxia with 18F-FAZA PET in patients with locally advanced non-small cell lung cancer treated with definitive chemoradiotherapy. J Med Imaging Radiat Oncol. 2013;57(4):475-481.

    Not in our library10.1111/1754-9485.12086

  166. 166.

    Grosu AL, Souvatzoglou M, Roper B, Dobritz M, Wiedenmann N, Jacob V, Wester HJ, Reischl G, Machulla HJ, Schwaiger M, Molls M, Piert M. Hypoxia imaging with FAZA-PET and theoretical considerations with regard to dose painting for individualization of radiotherapy in patients with head and neck cancer. Int J Radiat Oncol Biol Phys. 2007;69(2):541-551.

    Not in our library10.1016/j.ijrobp.2007.05.079

  167. 167.

    Mortensen LS, Johansen J, Kallehauge J, Primdahl H, Busk M, Lassen P, Alsner J, Sorensen BS, Toustrup K, Jakobsen S, Petersen J, Petersen H, Theil J, Nordsmark M, Overgaard J. FAZA PET/CT hypoxia imaging in patients with squamous cell carcinoma of the head and neck treated with radiotherapy: results from the DAHANCA 24 trial. Radiother Oncol. 2012;105(1):14-20.

    Not in our library10.1016/j.radonc.2012.09.015

  168. 168.

    Souvatzoglou M, Grosu AL, Roper B, Krause BJ, Beck R, Reischl G, Picchio M, Machulla HJ, Wester HJ, Piert M. Tumour hypoxia imaging with [18F]FAZA PET in head and neck cancer patients: a pilot study. Eur J Nucl Med Mol Imaging. 2007;34(10):1566-1575.

    Not in our library10.1007/s00259-007-0424-3

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    Schuetz M, Schmid MP, Potter R, Kommata S, Georg D, Lukic D, Dudczak R, Kletter K, Dimopoulos J, Karanikas G, Bachtiary B. Evaluating repetitive 18F-fluoroazomycin-arabinoside (18FAZA) PET in the setting of MRI guided adaptive radiotherapy in cervical cancer. Acta Oncol. 2010;49(7):941-947.

    Not in our library10.3109/0284186x.2010.510145

  170. 170.

    Havelund BM, Holdgaard PC, Rafaelsen SR, Mortensen LS, Theil J, Bender D, Ploen J, Spindler KL, Jakobsen A. Tumour hypoxia imaging with 18F-fluoroazomycinarabinofuranoside PET/CT in patients with locally advanced rectal cancer. Nucl Med Commun. 2013;34(2):155-161.

    Not in our library10.1097/mnm.0b013e32835bd5bc

  171. 171.

    Dolbier WR, Li AR, Koch CJ, Shiue CY, Kachur AV. [18F]-EF5, a marker for PET detection of hypoxia: synthesis of precursor and a new fluorination procedure. Appl Radiat Isot. 2001;54(1):73-80.

    Not in our library10.1016/s0969-8043(00)00102-0

  172. 172.

    Dubois L, Landuyt W, Haustermans K, Dupont P, Bormans G, Vermaelen P, Flamen P, Verbeken E, Mortelmans L. Evaluation of hypoxia in an experimental rat tumour model by [(18)F]fluoromisonidazole PET and immunohistochemistry. Br J Cancer. 2004;91(11):1947-1954.

    Not in our library10.1038/sj.bjc.6602219

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    Chen L, Zhang Z, Kolb HC, Walsh JC, Zhang J, Guan Y. (1)(8)F-HX4 hypoxia imaging with PET/CT in head and neck cancer: a comparison with (1)(8)F-FMISO. Nucl Med Commun. 2012;33(10):1096-1102.

    Not in our library10.1097/mnm.0b013e3283571016

  174. 174.

    Zegers CM, van Elmpt W, Wierts R, Reymen B, Sharifi H, Ollers MC, Hoebers F, Troost EG, Wanders R, van Baardwijk A, Brans B, Eriksson J, Windhorst B, Mottaghy FM, De Ruysscher D, Lambin P. Hypoxia imaging with [(1)(8)F]HX4 PET in NSCLC patients: defining optimal imaging parameters. Radiother Oncol. 2013;109(1):58-64.

    Not in our library10.1016/j.radonc.2013.08.031

  175. 175.

    Lehtio K, Eskola O, Viljanen T, Oikonen V, Gronroos T, Sillanmaki L, Grenman R, Minn H. Imaging perfusion and hypoxia with PET to predict radiotherapy response in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2004;59(4):971-982.

    Not in our library10.1016/j.ijrobp.2003.12.014

  176. 176.

    Lehtio K, Oikonen V, Nyman S, Gronroos T, Roivainen A, Eskola O, Minn H. Quantifying tumour hypoxia with fluorine-18 fluoroerythronitroimidazole ([18F]FETNIM) and PET using the tumour to plasma ratio. Eur J Nucl Med Mol Imaging. 2003;30(1):101-108.

    Not in our library10.1007/s00259-002-1016-x

  177. 177.

    Li L, Hu M, Zhu H, Zhao W, Yang G, Yu J. Comparison of 18F-Fluoroerythronitroimidazole and 18F-fluorodeoxyglucose positron emission tomography and prognostic value in locally advanced non-small-cell lung cancer. Clin Lung Cancer. 2010;11(5):335-340.

    Not in our library10.3816/clc.2010.n.042

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    Hu M, Xing L, Mu D, Yang W, Yang G, Kong L, Yu J. Hypoxia imaging with 18F-fluoroerythronitroimidazole integrated PET/CT and immunohistochemical studies in non-small cell lung cancer. Clin Nucl Med. 2013;38(8):591-596.

    Not in our library10.1097/rlu.0b013e318279fd3d

  179. 179.

    Vercellino L, Groheux D, Thoury A, Delord M, Schlageter MH, Delpech Y, Barre E, Baruch-Hennequin V, Tylski P, Homyrda L, Walker F, Barranger E, Hindie E. Hypoxia imaging of uterine cervix carcinoma with (18)F-FETNIM PET/CT. Clin Nucl Med. 2012;37(11):1065-1068.

    Not in our library10.1097/rlu.0b013e3182638e7e

  180. 180.

    Yue J, Yang Y, Cabrera AR, Sun X, Zhao S, Xie P, Zheng J, Ma L, Fu Z, Yu J. Measuring tumor hypoxia with (1)(8)F-FETNIM PET in esophageal squamous cell carcinoma: a pilot clinical study. Dis Esophagus. 2012;25(1):54-61.

    Not in our library10.1111/j.1442-2050.2011.01209.x

  181. 181.

    Shibahara I, Kumabe T, Kanamori M, Saito R, Sonoda Y, Watanabe M, Iwata R, Higano S, Takanami K, Takai Y, Tominaga T. Imaging of hypoxic lesions in patients with gliomas by using positron emission tomography with 1-(2-[18F] fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole, a new 18F-labeled 2-nitroimidazole analog. J Neurosurg. 2010;113(2):358-368.

    Not in our library10.3171/2009.10.jns09510

  182. 182.

    Kaneta T, Takai Y, Iwata R, Hakamatsuka T, Yasuda H, Nakayama K, Ishikawa Y, Watanuki S, Furumoto S, Funaki Y, Nakata E, Jingu K, Tsujitani M, Ito M, Fukuda H, Takahashi S, Yamada S. Initial evaluation of dynamic human imaging using 18F-FRP170 as a new PET tracer for imaging hypoxia. Ann Nucl Med. 2007;21(2):101-107.

    Not in our library10.1007/bf03033987

  183. 183.

    Obata A, Yoshimi E, Waki A, Lewis JS, Oyama N, Welch MJ, Saji H, Yonekura Y, Fujibayashi Y. Retention mechanism of hypoxia selective nuclear imaging/radiotherapeutic agent cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) in tumor cells. Ann Nucl Med. 2001;15(6):499-504.

    Not in our library10.1007/bf02988502

  184. 184.

    Dearling JL, Packard AB. Some thoughts on the mechanism of cellular trapping of Cu(II)-ATSM. Nucl Med Biol. 2010;37(3):237-243.

    Not in our library10.1016/j.nucmedbio.2009.11.004

  185. 185.

    O’Donoghue JA, Zanzonico P, Pugachev A, Wen B, Smith-Jones P, Cai S, Burnazi E, Finn RD, Burgman P, Ruan S, Lewis JS, Welch MJ, Ling CC, Humm JL. Assessment of regional tumor hypoxia using 18F-fluoromisonidazole and 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) positron emission tomography: comparative study featuring microPET imaging, Po2 probe measurement, autoradiography, and fluorescent microscopy in the R3327-AT and FaDu rat tumor models. Int J Radiat Oncol Biol Phys. 2005;61(5):1493-1502.

    Not in our library10.1016/j.ijrobp.2004.12.057

  186. 186.

    Holland JP, Lewis JS, Dehdashti F. Assessing tumor hypoxia by positron emission tomography with Cu-ATSM. Q J Nucl Med Mol Imaging. 2009;53(2):193-200.

    Not in our library

  187. 187.

    Carlin S, Zhang H, Reese M, Ramos NN, Chen Q, Ricketts SA. A comparison of the imaging characteristics and microregional distribution of 4 hypoxia PET tracers. J Nucl Med. 2014;55(3):515-521.

    Not in our library10.2967/jnumed.113.126615

  188. 188.

    Hueting R, Kersemans V, Cornelissen B, Tredwell M, Hussien K, Christlieb M, Gee AD, Passchier J, Smart SC, Dilworth JR, Gouverneur V, Muschel RJ. A comparison of the behavior of (64)Cu-acetate and (64)Cu-ATSM in vitro and in vivo. J Nucl Med. 2014;55(1):128-134.

    Not in our library10.2967/jnumed.113.119917

  189. 189.

    Tateishi K, Tateishi U, Sato M, Yamanaka S, Kanno H, Murata H, Inoue T, Kawahara N. Application of 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) PET imaging to predict highly malignant tumor grades and hypoxia-inducible factor-1alpha expression in patients with glioma. AJNR Am J Neuroradiol. 2013;34(1):92-99.

    Not in our library10.3174/ajnr.a3159

  190. 190.

    Tran LB, Bol A, Labar D, Jordan B, Magat J, Mignion L, Gregoire V, Gallez B. Hypoxia imaging with the nitroimidazole 18F-FAZA PET tracer: a comparison with OxyLite, EPR oximetry and 19F-MRI relaxometry. Radiother Oncol. 2012;105(1):29-35.

    Not in our library10.1016/j.radonc.2012.04.011

  191. 191.

    Valable S, Corroyer-Dulmont A, Chakhoyan A, Durand L, Toutain J, Divoux D, Barre L, MacKenzie ET, Petit E, Bernaudin M, Touzani O, Barbier EL (2016) Imaging of brain oxygenation with magnetic resonance imaging: A validation with positron emission tomography in the healthy and tumoural brain. J Cereb Blood Flow Metab. 271678X16671965. doi:10.1177/0271678X16671965

    Not in our library10.1177/0271678x16671965

  192. 192.

    Simoncic U, Leibfarth S, Welz S, Schwenzer N, Schmidt H, Reischl G, Pfannenberg C, la Fougere C, Nikolaou K, Zips D, Thorwarth D. Comparison of DCE-MRI kinetic parameters and FMISO-PET uptake parameters in head and neck cancer patients. Med Phys. 2017.

    Not in our library10.1002/mp.12228

  193. 193.

    Ali R, Apte S, Vilalta M, Subbarayan M, Miao Z, Chin FT, Graves EE. 18F-EF5 PET is predictive of response to fractionated radiotherapy in preclinical tumor models. PLoS One. 2015;10(10):e0139425.

    Not in our library10.1371/journal.pone.0139425

  194. 194.

    Burgman P, O’Donoghue JA, Lewis JS, Welch MJ, Humm JL, Ling CC. Cell line-dependent differences in uptake and retention of the hypoxia-selective nuclear imaging agent Cu-ATSM. Nucl Med Biol. 2005;32(6):623-630.

    Not in our library10.1016/j.nucmedbio.2005.05.003

  195. 195.

    Chang E, Liu H, Unterschemmann K, Ellinghaus P, Liu S, Gekeler V, Cheng Z, Berndorff D, Gambhir SS. 18F-FAZA PET imaging response tracks the reoxygenation of tumors in mice upon treatment with the mitochondrial complex I inhibitor BAY 87-2243. Clin Cancer Res. 2015;21(2):335-346.

    Not in our library10.1158/1078-0432.ccr-14-0217

  196. 196.

    Chapman DW, Jans HS, Ma I, Mercer JR, Wiebe LI, Wuest M, Moore RB. Detecting functional changes with [(18)F]FAZA in a renal cell carcinoma mouse model following sunitinib therapy. EJNMMI Res. 2014;4(1):27.

    Not in our library10.1186/s13550-014-0027-5

  197. 197.

    Chitneni SK, Bida GT, Yuan H, Palmer GM, Hay MP, Melcher T, Wilson WR, Zalutsky MR, Dewhirst MW. 18F-EF5 PET imaging as an early response biomarker for the hypoxia-activated prodrug SN30000 combined with radiation treatment in a non-small cell lung cancer xenograft model. J Nucl Med. 2013;54(8):1339-1346.

    Not in our library10.2967/jnumed.112.116293

  198. 198.

    Chitneni SK, Bida GT, Zalutsky MR, Dewhirst MW. Comparison of the hypoxia PET tracer (18)F-EF5 to immunohistochemical marker EF5 in 3 different human tumor xenograft models. J Nucl Med. 2014;55(7):1192-1197.

    Not in our library10.2967/jnumed.114.137448

  199. 199.

    Dence CS, Ponde DE, Welch MJ, Lewis JS. Autoradiographic and small-animal PET comparisons between (18)F-FMISO, (18)F-FDG, (18)F-FLT and the hypoxic selective (64)Cu-ATSM in a rodent model of cancer. Nucl Med Biol. 2008;35(6):713-720.

    Not in our library10.1016/j.nucmedbio.2008.06.001

  200. 200.

    Dubois LJ, Lieuwes NG, Janssen MH, Peeters WJ, Windhorst AD, Walsh JC, Kolb HC, Ollers MC, Bussink J, van Dongen GA, van der Kogel A, Lambin P. Preclinical evaluation and validation of [18F]HX4, a promising hypoxia marker for PET imaging. Proc Natl Acad Sci USA. 2011;108(35):14620-14625.

    Not in our library10.1073/pnas.1102526108

  201. 201.

    Gronroos T, Bentzen L, Marjamaki P, Murata R, Horsman MR, Keiding S, Eskola O, Haaparanta M, Minn H, Solin O. Comparison of the biodistribution of two hypoxia markers [18F]FETNIM and [18F]FMISO in an experimental mammary carcinoma. Eur J Nucl Med Mol Imaging. 2004;31(4):513-520.

    Not in our library10.1007/s00259-003-1404-x

  202. 202.

    Ko YH, Pedersen PL, Geschwind JF. Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase. Cancer Lett. 2001;173(1):83-91.

    Not in our library10.1016/s0304-3835(01)00667-x

  203. 203.

    Lewis JS, McCarthy DW, McCarthy TJ, Fujibayashi Y, Welch MJ. Evaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic tumor model. J Nucl Med. 1999;40(1):177-183.

    Not in our library

  204. 204.

    Martin GV, Caldwell JH, Graham MM, Grierson JR, Kroll K, Cowan MJ, Lewellen TK, Rasey JS, Casciari JJ, Krohn KA. Noninvasive detection of hypoxic myocardium using fluorine-18-fluoromisonidazole and positron emission tomography. J Nucl Med. 1992;33(12):2202-2208.

    Not in our library

  205. 205.

    Martin GV, Cerqueira MD, Caldwell JH, Rasey JS, Embree L, Krohn KA. Fluoromisonidazole. A metabolic marker of myocyte hypoxia. Circ Res. 1990;67(1):240-244.

    Not in our library10.1161/01.res.67.1.240

  206. 206.

    Matsumoto K, Szajek L, Krishna MC, Cook JA, Seidel J, Grimes K, Carson J, Sowers AL, English S, Green MV, Bacharach SL, Eckelman WC, Mitchell JB. The influence of tumor oxygenation on hypoxia imaging in murine squamous cell carcinoma using [64Cu]Cu-ATSM or [18F]Fluoromisonidazole positron emission tomography. Int J Oncol. 2007;30(4):873-881.

    Not in our library

  207. 207.

    McCall KC, Humm JL, Bartlett R, Reese M, Carlin S. Copper-64-diacetyl-bis(N(4)-methylthiosemicarbazone) pharmacokinetics in FaDu xenograft tumors and correlation with microscopic markers of hypoxia. Int J Radiat Oncol Biol Phys. 2012;84(3):e393-e399.

    Not in our library10.1016/j.ijrobp.2012.05.005

  208. 208.

    McQuade P, Martin KE, Castle TC, Went MJ, Blower PJ, Welch MJ, Lewis JS. Investigation into 64Cu-labeled Bis(selenosemicarbazone) and Bis(thiosemicarbazone) complexes as hypoxia imaging agents. Nucl Med Biol. 2005;32(2):147-156.

    Not in our library10.1016/j.nucmedbio.2004.10.004

  209. 209.

    Obata A, Yoshimoto M, Kasamatsu S, Naiki H, Takamatsu S, Kashikura K, Furukawa T, Lewis JS, Welch MJ, Saji H, Yonekura Y, Fujibayashi Y. Intra-tumoral distribution of (64)Cu-ATSM: a comparison study with FDG. Nucl Med Biol. 2003;30(5):529-534.

    Not in our library10.1016/s0969-8051(03)00047-7

  210. 210.

    Peeters SG, Zegers CM, Biemans R, Lieuwes NG, van Stiphout RG, Yaromina A, Sun JD, Hart CP, Windhorst AD, van Elmpt W, Dubois LJ, Lambin P. TH-302 in combination with radiotherapy enhances the therapeutic outcome and is associated with pretreatment [18F]HX4 hypoxia PET imaging. Clin Cancer Res. 2015;21(13):2984-2992.

    Not in our library10.1158/1078-0432.ccr-15-0018

  211. 211.

    Peeters SG, Zegers CM, Lieuwes NG, van Elmpt W, Eriksson J, van Dongen GA, Dubois L, Lambin P. A comparative study of the hypoxia PET tracers [(1)(8)F]HX4, [(1)(8)F]FAZA, and [(1)(8)F]FMISO in a preclinical tumor model. Int J Radiat Oncol Biol Phys. 2015;91(2):351-359.

    Not in our library10.1016/j.ijrobp.2014.09.045

  212. 212.

    Piert M, Machulla HJ, Picchio M, Reischl G, Ziegler S, Kumar P, Wester HJ, Beck R, McEwan AJ, Wiebe LI, Schwaiger M. Hypoxia-specific tumor imaging with 18F-fluoroazomycin arabinoside. J Nucl Med. 2005;46(1):106-113.

    Not in our library

  213. 213.

    Rasey JS, Grunbaum Z, Krohn K, Nelson N, Chin L. Comparison of binding of [3H]misonidazole and [14C]misonidazole in multicell spheroids. Radiat Res. 1985;101(3):473-479.

    Not in our library10.2307/3576506

  214. 214.

    Silvoniemi A, Silen J, Forsback S, Loyttyniemi E, Schrey AR, Solin O, Grenman R, Minn H, Gronroos TJ. Evaluation of repeated [(18)F]EF5 PET/CT scans and tumor growth rate in experimental head and neck carcinomas. EJNMMI Res. 2014;4:65.

    Not in our library10.1186/s13550-014-0065-z

  215. 215.

    Sorger D, Patt M, Kumar P, Wiebe LI, Barthel H, Seese A, Dannenberg C, Tannapfel A, Kluge R, Sabri O. [18F]Fluoroazomycinarabinofuranoside (18FAZA) and [18F]Fluoromisonidazole (18FMISO): a comparative study of their selective uptake in hypoxic cells and PET imaging in experimental rat tumors. Nucl Med Biol. 2003;30(3):317-326.

    Not in our library10.1016/s0969-8051(02)00442-0

  216. 216.

    Troost EG, Laverman P, Kaanders JH, Philippens M, Lok J, Oyen WJ, van der Kogel AJ, Boerman OC, Bussink J. Imaging hypoxia after oxygenation-modification: comparing [18F]FMISO autoradiography with pimonidazole immunohistochemistry in human xenograft tumors. Radiother Oncol. 2006;80(2):157-164.

    Not in our library10.1016/j.radonc.2006.07.023

  217. 217.

    Valtorta S, Belloli S, Sanvito F, Masiello V, Di Grigoli G, Monterisi C, Fazio F, Picchio M, Moresco RM. Comparison of 18F-fluoroazomycin-arabinofuranoside and 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) in preclinical models of cancer. J Nucl Med. 2013;54(7):1106-1112.

    Not in our library10.2967/jnumed.112.111120

  218. 218.

    Yuan H, Schroeder T, Bowsher JE, Hedlund LW, Wong T, Dewhirst MW. Intertumoral differences in hypoxia selectivity of the PET imaging agent 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone). J Nucl Med. 2006;47(6):989-998.

    Not in our library

  219. 219.

    Schutze C, Bergmann R, Bruchner K, Mosch B, Yaromina A, Zips D, Hessel F, Krause M, Thames H, Kotzerke J, Steinbach J, Baumann M, Beuthien-Baumann B. Effect of [(18)F]FMISO stratified dose-escalation on local control in FaDu hSCC in nude mice. Radiother Oncol. 2014;111(1):81-87.

    Not in our library10.1016/j.radonc.2014.02.005

  220. 220.

    Bentzen L, Keiding S, Nordsmark M, Falborg L, Hansen SB, Keller J, Nielsen OS, Overgaard J. Tumour oxygenation assessed by 18F-fluoromisonidazole PET and polarographic needle electrodes in human soft tissue tumours. Radiother Oncol. 2003;67(3):339-344.

    Not in our library10.1016/s0167-8140(03)00081-1

  221. 221.

    Dehdashti F, Grigsby PW, Lewis JS, Laforest R, Siegel BA, Welch MJ. Assessing tumor hypoxia in cervical cancer by PET with 60Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone). J Nucl Med. 2008;49(2):201-205.

    Not in our library10.2967/jnumed.107.048520

  222. 222.

    Francis RJ, Segard T, Morandeau L, Lee YC, Millward MJ, Segal A, Nowak AK. Characterization of hypoxia in malignant pleural mesothelioma with FMISO PET-CT. Lung Cancer. 2015;90(1):55-60.

    Not in our library10.1016/j.lungcan.2015.07.015

  223. 223.

    Garcia-Parra R, Wood D, Shah RB, Siddiqui J, Hussain H, Park H, Desmond T, Meyer C, Piert M. Investigation on tumor hypoxia in resectable primary prostate cancer as demonstrated by 18F-FAZA PET/CT utilizing multimodality fusion techniques. Eur J Nucl Med Mol Imaging. 2011;38(10):1816-1823.

    Not in our library10.1007/s00259-011-1876-z

  224. 224.

    Gronroos TJ, Lehtio K, Soderstrom KO, Kronqvist P, Laine J, Eskola O, Viljanen T, Grenman R, Solin O, Minn H. Hypoxia, blood flow and metabolism in squamous-cell carcinoma of the head and neck: correlations between multiple immunohistochemical parameters and PET. BMC Cancer. 2014;14:876.

    Not in our library10.1186/1471-2407-14-876

  225. 225.

    Hino-Shishikura A, Tateishi U, Shibata H, Yoneyama T, Nishii T, Torii I, Tateishi K, Ohtake M, Kawahara N, Inoue T. Tumor hypoxia and microscopic diffusion capacity in brain tumors: a comparison of (62)Cu-Diacetyl-Bis (N4-Methylthiosemicarbazone) PET/CT and diffusion-weighted MR imaging. Eur J Nucl Med Mol Imaging. 2014;41(7):1419-1427.

    Not in our library10.1007/s00259-014-2714-x

  226. 226.

    Jansen JF, Schoder H, Lee NY, Wang Y, Pfister DG, Fury MG, Stambuk HE, Humm JL, Koutcher JA, Shukla-Dave A. Noninvasive assessment of tumor microenvironment using dynamic contrast-enhanced magnetic resonance imaging and 18F-fluoromisonidazole positron emission tomography imaging in neck nodal metastases. Int J Radiat Oncol Biol Phys. 2010;77(5):1403-1410.

    Not in our library10.1016/j.ijrobp.2009.07.009

  227. 227.

    Komar G, Lehtio K, Seppanen M, Eskola O, Levola H, Lindholm P, Sipila H, Seppala J, Grenman R, Solin O, Minn H. Prognostic value of tumour blood flow, [(1)(8)F]EF5 and [(1)(8)F]FDG PET/CT imaging in patients with head and neck cancer treated with radiochemotherapy. Eur J Nucl Med Mol Imaging. 2014;41(11):2042-2050.

    Not in our library10.1007/s00259-014-2818-3

  228. 228.

    Lawrentschuk N. Imaging in prostate cancer with multiparametric magnetic resonance imaging and gallium positron emission tomography-computed tomography: the real deal? BJU Int. 2015;115(Suppl 5):1-2.

    Not in our library10.1111/bju.13094

  229. 229.

    Lewin J, Khamly KK, Young RJ, Mitchell C, Hicks RJ, Toner GC, Ngan SY, Chander S, Powell GJ, Herschtal A, Te Marvelde L, Desai J, Choong PF, Stacker SA, Achen MG, Ferris N, Fox S, Slavin J, Thomas DM. A phase Ib/II translational study of sunitinib with neoadjuvant radiotherapy in soft-tissue sarcoma. Br J Cancer. 2014;111(12):2254-2261.

    Not in our library10.1038/bjc.2014.537

  230. 230.

    Lewis JS, Laforest R, Dehdashti F, Grigsby PW, Welch MJ, Siegel BA. An imaging comparison of 64Cu-ATSM and 60Cu-ATSM in cancer of the uterine cervix. J Nucl Med. 2008;49(7):1177-1182.

    Not in our library10.2967/jnumed.108.051326

  231. 231.

    Lin LL, Pryma D, Koch C, Evans S. A pilot study of F18 EF5 PET/CT imaging in patients with carcinoma of the cervix. Pract Radiat Oncol. 2013;3(2 Suppl 1):S26-S27.

    Not in our library10.1016/j.prro.2013.01.092

  232. 232.

    Lohith TG, Kudo T, Demura Y, Umeda Y, Kiyono Y, Fujibayashi Y, Okazawa H. Pathophysiologic correlation between 62Cu-ATSM and 18F-FDG in lung cancer. J Nucl Med. 2009;50(12):1948-1953.

    Not in our library10.2967/jnumed.109.069021

  233. 233.

    Maity A, Lin A. Using [18F]EF5 PET to measure hypoxia modulation by Nelfinavir in larynx cancer. 2014.

    Not in our library

  234. 234.

    Nascente CM, Dhani NC, Vines D (2013) Clinical characterization of hypoxia in pancreatic ductal adenocarcinoma (PDAC) by 18F-FAZA PET and pimonidazole. J Clin Oncol 31 (suppl; abstr 4049)

    Not in our library

  235. 235.

    Nehmeh SA, Lee NY, Schroder H, Squire O, Zanzonico PB, Erdi YE, Greco C, Mageras G, Pham HS, Larson SM, Ling CC, Humm JL. Reproducibility of intratumor distribution of (18)F-fluoromisonidazole in head and neck cancer. Int J Radiat Oncol Biol Phys. 2008;70(1):235-242.

    Not in our library10.1016/j.ijrobp.2007.08.036

  236. 236.

    Okamoto S, Shiga T, Yasuda K, Ito YM, Magota K, Kasai K, Kuge Y, Shirato H, Tamaki N. High reproducibility of tumor hypoxia evaluated by 18F-fluoromisonidazole PET for head and neck cancer. J Nucl Med. 2013;54(2):201-207.

    Not in our library10.2967/jnumed.112.109330

  237. 237.

    Rajendran JG, Hendrickson KR, Spence AM, Muzi M, Krohn KA, Mankoff DA. Hypoxia imaging-directed radiation treatment planning. Eur J Nucl Med Mol Imaging. 2006;33(Suppl 1):44-53.

    Not in our library10.1007/s00259-006-0135-1

  238. 238.

    Rajendran JG, Wilson DC, Conrad EU, Peterson LM, Bruckner JD, Rasey JS, Chin LK, Hofstrand PD, Grierson JR, Eary JF, Krohn KA. [(18)F]FMISO and [(18)F]FDG PET imaging in soft tissue sarcomas: correlation of hypoxia, metabolism and VEGF expression. Eur J Nucl Med Mol Imaging. 2003;30(5):695-704.

    Not in our library10.1007/s00259-002-1096-7

  239. 239.

    Roels S, Slagmolen P, Nuyts J, Lee JA, Loeckx D, Maes F, Stroobants S, Penninckx F, Haustermans K. Biological image-guided radiotherapy in rectal cancer: is there a role for FMISO or FLT, next to FDG? Acta Oncol. 2008;47(7):1237-1248.

    Not in our library10.1080/02841860802256434

  240. 240.

    Sato J, Kitagawa Y, Yamazaki Y, Hata H, Asaka T, Miyakoshi M, Okamoto S, Shiga T, Shindoh M, Kuge Y, Tamaki N. Advantage of FMISO-PET over FDG-PET for predicting histological response to preoperative chemotherapy in patients with oral squamous cell carcinoma. Eur J Nucl Med Mol Imaging. 2014;41(11):2031-2041.

    Not in our library10.1007/s00259-014-2810-y

  241. 241.

    Segard T, Robins PD, Yusoff IF, Ee H, Morandeau L, Campbell EM, Francis RJ. Detection of hypoxia with 18F-fluoromisonidazole (18F-FMISO) PET/CT in suspected or proven pancreatic cancer. Clin Nucl Med. 2013;38(1):1-6.

    Not in our library10.1097/rlu.0b013e3182708777

  242. 242.

    Servagi-Vernat S, Differding S, Hanin FX, Labar D, Bol A, Lee JA, Gregoire V. A prospective clinical study of (1)(8)F-FAZA PET-CT hypoxia imaging in head and neck squamous cell carcinoma before and during radiation therapy. Eur J Nucl Med Mol Imaging. 2014;41(8):1544-1552.

    Not in our library10.1007/s00259-014-2730-x

  243. 243.

    Tachibana I, Nishimura Y, Shibata T, Kanamori S, Nakamatsu K, Koike R, Nishikawa T, Ishikawa K, Tamura M, Hosono M. A prospective clinical trial of tumor hypoxia imaging with 18F-fluoromisonidazole positron emission tomography and computed tomography (F-MISO PET/CT) before and during radiation therapy. J Radiat Res. 2013;54(6):1078-1084.

    Not in our library10.1093/jrr/rrt033

  244. 244.
    Kinetic analysis of dynamic 18F-fluoromisonidazole PET correlates with radiation treatment outcome in head-and-neck cancer · 2005
    No notice
  245. 245.

    Thureau S, Chaumet-Riffaud P, Modzelewski R, Fernandez P, Tessonnier L, Vervueren L, Cachin F, Berriolo-Riedinger A, Olivier P, Kolesnikov-Gauthier H, Blagosklonov O, Bridji B, Devillers A, Collombier L, Courbon F, Gremillet E, Houzard C, Caignon JM, Roux J, Aide N, Brenot-Rossi I, Doyeux K, Dubray B, Vera P. Interobserver agreement of qualitative analysis and tumor delineation of 18F-fluoromisonidazole and 3′-deoxy-3′-18F-fluorothymidine PET images in lung cancer. J Nucl Med. 2013;54(9):1543-1550.

    Not in our library10.2967/jnumed.112.118083

  246. 246.

    Zegers CM, van Elmpt W, Reymen B, Even AJ, Troost EG, Ollers MC, Hoebers FJ, Houben RM, Eriksson J, Windhorst AD, Mottaghy FM, De Ruysscher D, Lambin P. In vivo quantification of hypoxic and metabolic status of NSCLC tumors using [18F]HX4 and [18F]FDG-PET/CT imaging. Clin Cancer Res. 2014;20(24):6389-6397.

    Not in our library10.1158/1078-0432.ccr-14-1524

  247. 247.

    Zips D, Zophel K, Abolmaali N, Perrin R, Abramyuk A, Haase R, Appold S, Steinbach J, Kotzerke J, Baumann M. Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer. Radiother Oncol. 2012;105(1):21-28.

    Not in our library10.1016/j.radonc.2012.08.019

  248. 248.

    Rajendran JG, Schwartz DL, O’Sullivan J, Peterson LM, Ng P, Scharnhorst J, Grierson JR, Krohn KA. Tumor hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck cancer. Clin Cancer Res. 2006;12(18):5435-5441.

    Not in our library10.1158/1078-0432.ccr-05-1773

  249. 249.

    Rischin D, Hicks RJ, Fisher R, Binns D, Corry J, Porceddu S, Peters LJ. Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group Study 98.02. J Clin Oncol. 2006;24(13):2098-2104.

    Not in our library10.1200/jco.2005.05.2878

  250. 250.

    Eschmann SM, Paulsen F, Bedeshem C, Machulla HJ, Hehr T, Bamberg M, Bares R. Hypoxia-imaging with (18)F-Misonidazole and PET: changes of kinetics during radiotherapy of head-and-neck cancer. Radiother Oncol. 2007;83(3):406-410.

    Not in our library10.1016/j.radonc.2007.05.014

  251. 251.

    Lee NY, Mechalakos JG, Nehmeh S, Lin Z, Squire OD, Cai S, Chan K, Zanzonico PB, Greco C, Ling CC, Humm JL, Schoder H. Fluorine-18-labeled fluoromisonidazole positron emission and computed tomography-guided intensity-modulated radiotherapy for head and neck cancer: a feasibility study. Int J Radiat Oncol Biol Phys. 2008;70(1):2-13.

    Not in our library10.1016/j.ijrobp.2007.06.039

  252. 252.

    Dirix P, Vandecaveye V, De Keyzer F, Stroobants S, Hermans R, Nuyts S. Dose painting in radiotherapy for head and neck squamous cell carcinoma: value of repeated functional imaging with (18)F-FDG PET, (18)F-fluoromisonidazole PET, diffusion-weighted MRI, and dynamic contrast-enhanced MRI. J Nucl Med. 2009;50(7):1020-1027.

    Not in our library10.2967/jnumed.109.062638

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    Lee N, Nehmeh S, Schoder H, Fury M, Chan K, Ling CC, Humm J. Prospective trial incorporating pre-/mid-treatment [18F]-misonidazole positron emission tomography for head-and-neck cancer patients undergoing concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2009;75(1):101-108.

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    Kikuchi M, Yamane T, Shinohara S, Fujiwara K, Hori SY, Tona Y, Yamazaki H, Naito Y, Senda M. 18F-fluoromisonidazole positron emission tomography before treatment is a predictor of radiotherapy outcome and survival prognosis in patients with head and neck squamous cell carcinoma. Ann Nucl Med. 2011;25(9):625-633.

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    Yamane T, Kikuchi M, Shinohara S, Senda M. Reduction of [(18)F]fluoromisonidazole uptake after neoadjuvant chemotherapy for head and neck squamous cell carcinoma. Mol Imaging Biol. 2011;13(2):227-231.

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    Chao KS, Bosch WR, Mutic S, Lewis JS, Dehdashti F, Mintun MA, Dempsey JF, Perez CA, Purdy JA, Welch MJ. A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2001;49(4):1171-1182.

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    Minagawa Y, Shizukuishi K, Koike I, Horiuchi C, Watanuki K, Hata M, Omura M, Odagiri K, Tohnai I, Inoue T, Tateishi U. Assessment of tumor hypoxia by 62Cu-ATSM PET/CT as a predictor of response in head and neck cancer: a pilot study. Ann Nucl Med. 2011;25(5):339-345.

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    Koh WJ, Bergman KS, Rasey JS, Peterson LM, Evans ML, Graham MM, Grierson JR, Lindsley KL, Lewellen TK, Krohn KA, et al. Evaluation of oxygenation status during fractionated radiotherapy in human nonsmall cell lung cancers using [F-18]fluoromisonidazole positron emission tomography. Int J Radiat Oncol Biol Phys. 1995;33(2):391-398.

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    Eschmann SM, Paulsen F, Reimold M, Dittmann H, Welz S, Reischl G, Machulla HJ, Bares R. Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non-small cell lung cancer and head and neck cancer before radiotherapy. J Nucl Med. 2005;46(2):253-260.

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    Gagel B, Reinartz P, Demirel C, Kaiser HJ, Zimny M, Piroth M, Pinkawa M, Stanzel S, Asadpour B, Hamacher K, Coenen HH, Buell U, Eble MJ. [18F] fluoromisonidazole and [18F] fluorodeoxyglucose positron emission tomography in response evaluation after chemo-/radiotherapy of non-small-cell lung cancer: a feasibility study. BMC Cancer. 2006;6:51.

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    Dehdashti F, Mintun MA, Lewis JS, Bradley J, Govindan R, Laforest R, Welch MJ, Siegel BA. In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM. Eur J Nucl Med Mol Imaging. 2003;30(6):844-850.

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    Dietz DW, Dehdashti F, Grigsby PW, Malyapa RS, Myerson RJ, Picus J, Ritter J, Lewis JS, Welch MJ, Siegel BA. Tumor hypoxia detected by positron emission tomography with 60Cu-ATSM as a predictor of response and survival in patients undergoing Neoadjuvant chemoradiotherapy for rectal carcinoma: a pilot study. Dis Colon Rectum. 2008;51(11):1641-1648.

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    Grigsby PW, Malyapa RS, Higashikubo R, Schwarz JK, Welch MJ, Huettner PC, Dehdashti F. Comparison of molecular markers of hypoxia and imaging with (60)Cu-ATSM in cancer of the uterine cervix. Mol Imaging Biol. 2007;9(5):278-283.

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    Pettersen EO, Ebbesen P, Gieling RG, Williams KJ, Dubois L, Lambin P, Ward C, Meehan J, Kunkler IH, Langdon SP, Ree AH, Flatmark K, Lyng H, Calzada MJ, Peso LD, Landazuri MO, Gorlach A, Flamm H, Kieninger J, Urban G, Weltin A, Singleton DC, Haider S, Buffa FM, Harris AL, Scozzafava A, Supuran CT, Moser I, Jobst G, Busk M, Toustrup K, Overgaard J, Alsner J, Pouyssegur J, Chiche J, Mazure N, Marchiq I, Parks S, Ahmed A, Ashcroft M, Pastorekova S, Cao Y, Rouschop KM, Wouters BG, Koritzinsky M, Mujcic H, Cojocari D. Targeting tumour hypoxia to prevent cancer metastasis. From biology, biosensing and technology to drug development: the METOXIA consortium. J Enzyme Inhib Med Chem. 2015;30(5):689-721.

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    Eustace A, Mani N, Span PN, Irlam JJ, Taylor J, Betts GN, Denley H, Miller CJ, Homer JJ, Rojas AM, Hoskin PJ, Buffa FM, Harris AL, Kaanders JH, West CM. A 26-gene hypoxia signature predicts benefit from hypoxia-modifying therapy in laryngeal cancer but not bladder cancer. Clin Cancer Res. 2013;19(17):4879-4888.

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    Milosevic M, Warde P, Menard C, Chung P, Toi A, Ishkanian A, McLean M, Pintilie M, Sykes J, Gospodarowicz M, Catton C, Hill RP, Bristow R. Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer. Clin Cancer Res. 2012;18(7):2108-2114.

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