PET/CT imaging in recurrent head and neck cancer

PET/CT offers advantages over PET alone, which is limited by poor anatomic localization and CT alone, which provides morphologic data only. Retrospective fusion of separately acquired PET and CT images allows for potential fusion misregistration in the mobile head and neck between imaging sessions. Indications for PET/CT include recurrent neoplasm, tumor surveillance, and staging. This article will focus on recurrent head and neck neoplasm including, head and neck cancer, thyroid cancer, recurrent skull base tumor. PET/CT may change management in facilitating earlier detection of recurrence than is possible with conventional CT or MR imaging, in guiding biopsy, and in detecting second primary sites and distant metastases. Limitations of PET/CT include physiologic uptake, metabolically active tissue, and muscle contraction during uptake phase. PET/CT, however, is better equipped than is PET alone to mitigate these limitations by precisely localizing FDG uptake to anatomic structures. In addition, small lesions (< 1 cm) may be below scanner resolution and, therefore, a lower SUV (that is < or = 3), may suggest neoplasm. Recent treatment may result in false negative findings, especially when PET is performed within 4 months of radiation therapy. Finally, tumors of low metabolic activity (e.g., salivary gland tumors) may be prone to false negative results. In the future, PET/CT imaging will become more useful in staging head and neck cancer with improved scanner resolution. Development of specific tumor markers may allow for tumor-specific ligands that will increase sensitivity to head and neck neoplasia. Treatment targeting for radiation therapy is an application that is likely to become widely used.     

Combined motion blur and partial volume correction for computer aided diagnosis of pulmonary nodules in PET/CT

Objective

We present an automated scheme to correct PET max-uptake-values of small to medium-sized pulmonary nodules for motion blur and partial volume averaging. Both effects cause significant underestimation of PET max-uptake-values, particularly in nodules below 25 mm diameter, but nodules up to 75 mm might be affected. This compromises the power of PET for the differential diagnosis of such nodules, in particular benign versus malignant. Thus, correcting PET max-uptake-values has the potential to improve the classification of PET-positive pulmonary nodules.

Methods

The proposed correction algorithm relies on (i) determination of the actual size and shape of the nodule by segmentation of the nodule in the CT image and (ii) estimation of the effective local point-spread-function in the PET image, taking into account not only the inherently limited spatial resolution of the PET scanner, but also respiratory motion effects. Then the expected under-estimation of the PET max-uptake value in the nodule can be computed by simulation, and the correct PET max-uptake is obtained by multiplication with the correction factor (inverse of the under-estimation/recovery factor).

Results

Depending on the estimated nodule shape and blur width, the resulting SUV correction factors ranged from 1.0 to 11, with an average correction factor of 3.0, with higher values for smaller nodules. In comparison to SUV correction using a simplified spherical nodule model, the true-shape SUV correction factors were on average 30% higher. The feasibility of the method presented here is indicated by the high correlation between fitted and observed PET image profiles for clinical cases (average 0.995).

Conclusion

Blur and motion correction factors for standardized PET uptake values may significantly change the differential diagnosis of small pulmonary nodules. Feasibility and stability of the proposed automated combined SUV correction method as well as ease of use of the software tool have been demonstrated by retrospective analysis of real PET/CT patient datasets from clinical routine.     

Electrical conductivity images of biological tissue phantoms in MREIT

We present cross-sectional conductivity images of two biological tissue phantoms. Each of the cylindrical phantoms with both diameter and height of 140 mm contained chunks of biological tissues such as bovine tongue and liver, porcine muscle and chicken breast within a conductive agar gelatin as the background medium. We attached four recessed electrodes on the sides of the phantom with equal spacing among them. Injecting current pulses of 480 or 120 mA ms into the phantom along two different directions, we measured the z-component Bz of the induced magnetic flux density B=(Bx, By, Bz) with a magnetic resonance electrical impedance tomography (MREIT) system based on a 3.0 T MRI scanner. Using the harmonic Bz algorithm, we reconstructed cross-sectional conductivity images from the measured Bz data. Reconstructed images clearly distinguish different tissues in terms of both their shapes and conductivity values. In this paper, we experimentally demonstrate the feasibility of the MREIT technique in producing conductivity images of different biological soft tissues with a high spatial resolution and accuracy when we use a sufficient amount of the injection current.     

Image derived input functions for dynamic High Resolution Research Tomograph PET brain studies

The High Resolution Research Tomograph (HRRT) is a dedicated human brain positron emission tomography (PET) scanner. The aim of the present study was to validate the use of image derived input functions (IDIF) as an alternative for arterial sampling for HRRT human brain studies. To this end, IDIFs were extracted from 3D ordinary Poisson ordered subsets expectation maximization (OP-OSEM) and reconstruction based partial volume corrected (PVC) OP-OSEM images.IDIFs, either derived directly from regions of interest or further calibrated using manual samples taken during scans, were evaluated for dynamic [¹¹C]flumazenil data (n = 6). Results obtained with IDIFs were compared with those obtained using blood sampler input functions (BSIF). These comparisons included areas under the curve (AUC) for peak (0–3.3 min) and tail (3.3–55.0 min). In addition, slope, intercept and Pearson's correlation coefficient of tracer kinetic analysis results based on IDIF and BSIF were calculated for each subject.Good peak AUC ratios (0.83 ± 0.21) between IDIF and BSIF were found for calibrated IDIFs extracted from OP-OSEM images. This combination of IDIFs and images also provided good slope values (1.07 ± 0.11). Improved resolution, as obtained with PVC OP-OSEM, changed AUC ratios to 1.14 ± 0.35 and, for tracer kinetic analysis, slopes changed to 0.95 ± 0.13. For all reconstructions, non-calibrated IDIFs gave poorer results (> 61 ± 34% higher slopes) compared with calibrated IDIFs.The results of this study indicate that the use of IDIFs, extracted from OP-OSEM or PVC OP-OSEM images, is feasible for dynamic HRRT data, thereby obviating the need for online arterial sampling.     

PET/CT检查过程中口服增强造影剂泛影葡胺对体内FDG代谢的影响

目的:研究口服增强造影剂对体内FDG代谢的影响。方法:63例行PET／CT检查且显像图像未见异常FDG摄取的病人随机分为3组。对照组20例,显像前未口服任何造影剂;增强组26例,显像前40 min服1％的泛影葡胺溶液1 000ml;饮水组(阴性对照组)17例,显像前40 min服清水1 000 ml。静脉注射18F-FDG 0．15 mCi／Kg后45 min进行全身PET／CT显像。在PET横断面图像的左侧小脑皮质、主动脉弓、右肺、肝右叶、第5腰椎椎体和臀部肌肉位置勾画圆形感兴趣区(ROI),计算ROI内的标准摄取值 SUV,并将3组病人各部位SUV的数值进行比较。结果:增强组病人肺、主动脉弓、肝脏及肌肉的FDG摄取均显著低于对照组和阴性对照组(饮水组)(P<0．05);而对照组和饮水组间各部位FDG摄取无显著差异(P>0．05)。结论:PET／CT检查时口服造影剂泛影葡胺有可能影响体内FDG的代谢水平,从而可能影响肿瘤组织对FDG的摄取,在进行诊断和对SUV值分析时应加注意。     

A Dedicated Breast Positron Emission Tomography Scanner: Proof of Concept

PurposeThis study developed and tested a novel scanner constructed for dedicated positron emission tomography (PET) of the breast. The breast PET (B-PET) scanner is designed with two opposing detectors using curve plate NaI(Tl) detectors to achieve a combination of high spatial resolution and energy resolution.MethodsPhantom and clinical studies (n = 20) with ¹⁸F-fluorodeoxyglucose were carried out on the whole-body Philips Allegro scanner and the B-PET scanner. Images were subjectively assessed by an expert panel.ResultsPhantom studies indicated improved contrast for B-PET over conventional PET. Of the 20 clinical studies with breast cancer demonstrated on whole-body fluorodeoxyglucose PET, 10 B-PET scans showed agreement. Of the remaining 10 studies, three had breasts that were too small to be imaged, four had lesions that were too deep to be captured in the field of view, and three were excluded due to technical errors.ConclusionsCompared with conventional PET, B-PET images provided greater detail in breast lesions suggesting that the low-cost and relatively simple design of B-PET may potentially be an important adjunct to traditional mammography in helping determine the nature of a lesion.     

Total-body PET/CT临床应用进展

Total-body(TB)PET/CT扫描仪于2019年用于人体显像并逐步在临床开展。相比传统PET/CT,TB PET/CT具有所需显像剂剂量低、采集时间短、图像质量高、可全身动态成像及以多种显像剂检查等优点,提高了诊断肿瘤、评价疗效及预测预后的准确性。本文就TB PET/CT临床应用进展进行综述。     

Glucose metabolism of the midline nuclei raphe in the brainstem observed by PET-MRI fusion imaging

The brainstem contains various important monoaminergic neuronal centers, including the raphe nuclei which contain serotonergic neurons. The raphe nuclei, however, are not easily identifiable and located by conventional neuroimaging.

Methods

Fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) were performed in seven healthy subjects using a new PET-MRI, which consists of a high-resolution research tomograph (HRRT) PET and 7.0 T-MRI. Glucose metabolism of raphe nuclei was semiquantitatively measured and identified along the midline brainstem region in vivo.

Results

Midline nuclei clustered in four groups appeared to be the raphe nuclei and could be clearly visualized; specifically, we identified the groups as the dorsal raphe, raphe reticularis centralis superior, raphe pontis, and raphe magnus group.

Conclusion

FDG imaging of the midline raphe nuclei in vivo could potentially be an important tool for investigating brain diseases as well as conducting functional brain studies in the context of sleep disorders, depression, and neurodegenerative disease.     

Acoustic Radiation Force Impulse Imaging of Human Prostates Ex Vivo

It has been challenging for clinicians using current imaging modalities to visualize internal structures and detect lesions inside human prostates. Lack of contrast among prostatic tissues and high false positive or negative detection rates of prostate lesions have limited the use of current imaging modalities in the diagnosis of prostate cancer. In this study, acoustic radiation force impulse (ARFI) imaging is introduced to visualize the anatomical and abnormal structures in freshly excised human prostates. A modified Siemens Antares ultrasound scanner (Siemens Medical Solutions USA Inc., Malvern, PA) and a Siemens VF10-5 linear array were used to acquire ARFI images. The transducer was attached to a three-dimensional (3-D) translation stage, which was programmed to automate volumetric data acquisition. A depth dependent gain (DDG) method was developed and applied to 3-D ARFI datasets to compensate for the displacement gradients associated with spatially varying radiation force magnitudes as a function of depth. Nine human prostate specimens were collected and imaged immediately after surgical excision. Prostate anatomical structures such as seminal vesicles, ejaculatory ducts, peripheral zone, central zone, transition zone and verumontanum were visualized with high spatial resolution and in good agreement with McNeal's zonal anatomy. The characteristic appearance of prostate pathologies, such as prostate cancerous lesions, benign prostatic hyperplasia, calcified tissues and atrophy were identified in ARFI images based upon correlation with the corresponding histologic slides. This study demonstrates that ARFI imaging can be used to visualize internal structures and detecting suspicious lesions in the prostate and appears promising for image guidance of prostate biopsy. (E-mail:liang.zhai@duke.edu)     

Evaluation of [18F]F-DPA PET for Detecting Microglial Activation in the Spinal Cord of a Rat Model of Neuropathic Pain

Molecular Imaging and Biology - Recent studies have&nbsp;linked activated spinal glia to neuropathic pain. Here, using a positron emission tomography (PET) scanner with high spatial resolution...     

正电子发射断层成像/CT观察健康人空腹时不同器官对~（18）F脱氧葡萄糖的摄取

背景：既往国内外研究中,主要针对肿瘤患者体内葡萄糖的摄取情况,而关于正常人在空腹状态下不同器官对葡萄糖的摄取作用研究很少。目的：正电子发射断层成像/CT观察健康人在空腹状态下不同器官对18F脱氧葡萄糖的摄取情况,分析空腹时脑、肝、肾、心脏和骨骼肌组织在糖代谢中的相关性。方法：31例健康成年人空腹抽血测肝肾功能、血糖和血脂,并行正电子发射断层成像/CT检查,测脑、心脏、肝、肾脏和骨骼肌的18F脱氧葡萄糖的平均标准摄入值以及最大标准摄入值。结果与结论：空腹时脑皮质18F脱氧葡萄糖的平均标准摄入值约是心脏和肾脏的两三倍,是肝脏的4倍左右,是骨骼肌的15倍。肝脏平均标准摄入值与肾脏和骨骼肌的平均标准摄入值呈显著正相关（r=0.406,0.391,P=0.023,0.030）,但肝脏的平均标准摄入值与心和脑的平均标准摄入值无相关性。结果提示空腹状态下脑组织对葡萄糖摄取最多,骨骼肌最少,心脏、肝脏和肾脏居中;空腹状态下肝脏与肾脏和骨骼肌之间对葡萄糖的代谢存在显著相关性。     

The Impact of Positron Range on PET Resolution,Evaluated with Phantoms and PHITS Monte Carlo Simulations for Conventional and Non-conventional Radionuclides

Purpose

The increasing interest and availability of non-standard positron-emitting radionuclides has heightened the relevance of radionuclide choice in the development and optimization of new positron emission tomography (PET) imaging procedures, both in preclinical research and clinical practice. Differences in achievable resolution arising from positron range can largely influence application suitability of each radionuclide, especially in small-ring preclinical PET where system blurring factors due to annihilation photon acollinearity and detector geometry are less significant. Some resolution degradation can be mitigated with appropriate range corrections implemented during image reconstruction, the quality of which is contingent on an accurate characterization of positron range.

Procedures

To address this need, we have characterized the positron range of several standard and non-standard PET radionuclides (As-72, F-18, Ga-68, Mn-52, Y-86, and Zr-89) through imaging of small-animal quality control phantoms on a benchmark preclinical PET scanner. Further, the Particle and Heavy Ion Transport code System (PHITS v3.02) code was utilized for Monte Carlo modeling of positron range-dependent blurring effects.

Results

Positron range kernels for each radionuclide were derived from simulation of point sources in ICRP reference tissues. PET resolution and quantitative accuracy afforded by various radionuclides in practicable imaging scenarios were characterized using a convolution-based method based on positron annihilation distributions obtained from PHITS. Our imaging and simulation results demonstrate the degradation of small animal PET resolution, and quantitative accuracy correlates with increasing positron energy; however, for a specific “benchmark” preclinical PET scanner and reconstruction workflow, these differences were observed to be minimal given radionuclides with average positron energies below ~?400 keV.

Conclusion

Our measurements and simulations of the influence of positron range on PET resolution compare well with previous efforts documented in the literature and provide new data for several radionuclides in increasing clinical and preclinical use. The results will support current and future improvements in methods for positron range corrections in PET imaging.

     

Autoradiography with positron emitting isotopes in positron emission tomography tracer discovery.

Rapid development of labeling chemistry and generation of new chemical entities for biologic interactions via combinatorial chemistry and high throughput screening gives great potential for the development of new positron emission tomography (PET) tracer candidates. It must, however, be realized that a large fraction of these candidates will fail to characterize the desired biochemistry in vivo due to undesirable properties that are not relevant to providing a specific signal in vitro. A full characterization of a PET tracer is a lengthy and expensive procedure, and it is necessary to establish confidence via a number of assays that a tracer will provide useful data in the target species (generally human). These assays should also serve as a background to choose or to reject a tracer at an early time point, conserving valuable resources and time. Autoradiography performed as an ex vivo binding technique or as ex vivo recording of in vivo tracer distribution are, in this respect, very important tools. Autoradiography binding methods allow a range of frozen tissues to be sectioned and incubated with the PET tracer, and with due caution and controls with selective blockade of binding, quantitative values can be obtained with respect to tracer binding and its regional distribution. The method is easy to learn and set up, and should be included in all PET research and development labs. Ex vivo autoradiography of selected organs or whole animals gives qualitative images of a tracer's distribution with high resolution and is especially valid for 18F-labeled tracers. When tracer administration is not limited by mass due to specific radioactivity, 11C-tracers can also be readily used. This method is attractive to use as a complement to small animal imaging due to its high resolution and anatomical correlate. Living slice autoradiography is a more cumbersome method, but has an advantage of utilizing live tissue that retains certain metabolic functions. The use of these different methods in the validation of tracers and for supplying complementary information is illustrated.     

Correction for Partial Volume Effect Is a Must,Not a Luxury,to Fully Exploit the Potential of Quantitative PET Imaging in Clinical Oncology

The partial volume effect (PVE) is considered as one of the major degrading factors impacting image quality and hampering the accuracy of quantitative PET imaging in clinical oncology. This effect is the consequence of the limited spatial resolution of whole-body PET scanners, which results in blurring of the generated images by the scanner’s response function. A number of strategies have been devised to deal with partial volume effect. However, the lack of consensus on the clinical relevance of partial volume correction and the most appropriate technique to be used in the context of clinical oncology limited their application in clinical setting. This issue is debated in this commentary.     

Synthesis, characterization, and monkey positron emission tomography (PET) studies of [18F]Y1-973, a PET tracer for the neuropeptide Y Y1 receptor

Neuropeptide Y receptor subtype 1 (NPY Y1) has been implicated in appetite regulation, and antagonists of NPY Y1 are being explored as potential therapeutics for obesity. An NPY Y1 PET tracer is useful for determining the level of target engagement by NPY Y1 antagonists in preclinical and clinical studies. Here we report the synthesis and evaluation of [(18)F]Y1-973, a novel PET tracer for NPY Y1. [(18)F]Y1-973 was radiolabeled by reaction of a primary chloride with [(18)F]KF/K2.2.2 followed by deprotection with HCl. [(18)F]Y1-973 was produced with high radiochemical purity (>98%) and high specific activity (>1000 Ci/mmol). PET studies in rhesus monkey brain showed that the distribution of [(18)F]Y1-973 was consistent with the known NPY Y1 distribution; uptake was highest in the striatum and cortical regions and lowest in the pons, cerebellum nuclei, and brain stem. Blockade of [(18)F]Y1-973 uptake with NPY Y1 antagonist Y1-718 revealed a specific signal that was dose-dependently reduced in all regions of grey matter to a similarly low level of tracer uptake, indicative of an NPY Y1 specific signal. In vitro autoradiographic studies with [(18)F]Y1-973 in rhesus monkey and human brain tissue slices revealed an uptake distribution consistent with the in vivo PET studies. Highest binding density was observed in the dentate gyrus, caudate-putamen, and cortical regions; moderate binding density in the hypothalamus and thalamus; and lowest binding density in the globus pallidus and cerebellum. In vitro saturation binding studies in rhesus monkey and human caudate-putamen homogenates confirmed a similarly high B(max)/K(d) ratio for [(18)F]Y1-973, suggesting the tracer may provide a specific signal in human brain of similar magnitude to that observed in rhesus monkey. [(18)F]Y1-973 is a suitable PET tracer for imaging NPY Y1 in rhesus monkey with potential for translation to human PET studies.     

Positron emission tomography/computed tomography--imaging protocols, artifacts, and pitfalls.

There has been a longstanding interest in fused images of anatomical information, such as that provided by computed tomography (CT) or magnetic resonance imaging (MRI) systems, with biological information obtainable by positron emission tomography (PET). The near-simultaneous data acquisition in a fixed combination of a PET and a CT scanner in a combined PET/CT imaging system minimizes spatial and temporal mismatches between the modalities by eliminating the need to move the patient in between exams. In addition, using the fast CT scan for PET attenuation correction, the duration of the examination is significantly reduced compared to standalone PET imaging with standard rod-transmission sources. The main source of artifacts arises from the use of the CT-data for scatter and attenuation correction of the PET images. Today, CT reconstruction algorithms cannot account for the presence of metal implants, such as dental fillings or prostheses, properly, thus resulting in streak artifacts, which are propagated into the PET image by the attenuation correction. The transformation of attenuation coefficients at X-ray energies to those at 511 keV works well for soft tissues, bone, and air, but again is insufficient for dense CT contrast agents, such as iodine or barium. Finally, mismatches, for example, due to uncoordinated respiration result in incorrect attenuation-corrected PET images. These artifacts, however, can be minimized or avoided prospectively by careful acquisition protocol considerations. In doubt, the uncorrected images almost always allow discrimination between true and artificial finding. PET/CT has to be integrated into the diagnostic workflow for harvesting the full potential of the new modality. In particular, the diagnostic power of both, the CT and the PET within the combination must not be underestimated. By combining multiple diagnostic studies within a single examination, significant logistic advantages can be expected if the combined PET/CT examination is to replace separate state-of-the-art PET and CT exams, thus resulting in significantly accelerated diagnostics.     

Muscle-specific overexpression of lipoprotein lipase causes a severe myopathy characterized by proliferation of mitochondria and peroxisomes in transgenic mice.

In extrahepatic tissues lipoprotein lipase (LPL) hydrolyzes triglycerides thereby generating FFA for tissue uptake and metabolism. To study the effects of increased FFA uptake in muscle tissue, transgenic mouse lines were generated with a human LPL minigene driven by the promoter of the muscle creatine kinase gene. In these mice human LPL was expressed in skeletal muscle and cardiac muscle, but not in other tissues. In proportion to the level of LPL overexpression, decreased plasma triglyceride levels, elevated FFA uptake by muscle tissue, weight loss, and premature death were observed in three independent transgenic mouse lines. The animals developed a severe myopathy characterized by muscle fiber degeneration, fiber atrophy, glycogen storage, and extensive proliferation of mitochondria and peroxisomes. This degree of proliferation suggests that FFA play an important role in the biogenesis of these organelles. Our experiments indicate that LPL is rate limiting for the supply of muscle tissue with triglyceride-derived FFA. Improper regulation of muscle LPL can lead to major pathological changes and may be important in the pathogenesis of some human myopathies. Muscle-specific LPL transgenic mouse lines will serve as a useful animal model for the investigation of myopathies and the biogenesis of mitochondria and peroxisomes.     

Functional and structural synergy for resolution recovery and partial volume correction in brain PET

Purpose: Positron Emission Tomography (PET) has the unique capability of measuring brain function but its clinical potential is affected by low resolution and lack of morphological detail. Here we propose and evaluate a wavelet synergistic approach that combines functional and structural information from a number of sources (CT, MRI and anatomical probabilistic atlases) for the accurate quantitative recovery of radioactivity concentration in PET images. When the method is combined with anatomical probabilistic atlases, the outcome is a functional volume corrected for partial volume effects.Methods: The proposed method is based on the multiresolution property of the wavelet transform. First, the target PET image and the corresponding anatomical image (CT/MRI/atlas-based segmented MRI) are decomposed into several resolution elements. Secondly, high-resolution components of the PET image are replaced, in part, with those of the anatomical image after appropriate scaling. The amount of structural input is weighted by the relative high frequency signal content of the two modalities. The method was validated on a digital Zubal phantom and clinical data to evaluate its quantitative potential.Results: Simulation studies showed the expected relationship between functional recovery and the amount of correct structural detail provided, with perfect recovery achieved when true images were used as anatomical reference. The use of T1-MRI images brought significant improvements in PET image resolution. However improvements were maximized when atlas-based segmented images as anatomical references were used; these results were replicated in clinical data sets.Conclusion: The synergistic use of functional and structural data, and the incorporation of anatomical probabilistic information in particular, generates morphologically corrected PET images of exquisite quality.     

多层螺旋CT血管成像诊断下肢闭塞性动脉硬化症31例

目的探讨多层螺旋CT血管成像（MSCTA）技术对下肢闭塞性动脉硬化症（ASD）的应用价值。方法对2007年1月2009年12月收治的31例ASD患者进行检查,将数据在ADW4.1工作站行容积再现（VR）、最大密度投影（MIP）、多平面重组（MPR）、曲面重组（CPR）等后处理技术并结合原始图像进行综合分析。结果血管重建图像31例显示良好,存在不同程度的阻塞,闭塞动脉周围有代偿侧支血管。结论 MSCTA可清楚地观察下肢动脉的血管形态及管壁的钙化斑块,狭窄程度及闭塞情况。     

Modulation of intratumoral hypoxia by the epidermal growth factor receptor inhibitor gefitinib detected using small animal PET imaging

Blockade of signaling through the epidermal growth factor receptor (EGFR) tyrosine kinase by inhibitors such as gefitinib (Iressa) can inhibit tumor angiogenesis and enhance responses to ionizing radiation. In this study, the ability of gefitinib to modulate intratumoral oxygenation was evaluated in human EGFR-expressing A431 squamous cell carcinoma xenografts using in vivo small animal positron emission tomography (PET) imaging with the hypoxia marker [(18)F]fluoroazomycin arabinoside (FAZA) and by the immunohistochemical detection of hypoxia-induced adducts of the 2-nitroimidazole, pimonidazole. Serial noninvasive PET imaging of A431 xenografts showed a significant reduction in FAZA uptake following treatment with 75 mg/kg/d of gefitinib [tumor to background ratio, 6.1 +/- 1.0 (pretreatment) versus 2.3 +/- 0.6 (posttreatment); P = 0.0004]. Similarly, ex vivo quantitation of FAZA uptake showed significantly reduced FAZA uptake in established A431 xenografts treated with gefitinib compared with vehicle control (tumor to blood ratio for controls versus gefitinib, 8.0 +/- 3.0 versus 2.7 +/- 0.8; P = 0.007; or tumor to muscle ratio controls versus gefitinib, 8.6 +/- 2.8 versus 2.6 +/- 1.0; P = 0.002). The effect of gefitinib treatment seemed to be independent of tumor size. In addition, gefitinib treatment reduced pimonidazole-binding in A431 xenografts measured after 5 and 8 days of gefitinib treatment compared with baseline and with tumors treated with vehicle alone. A strong correlation was observed between pimonidazole binding and FAZA uptake. Together, these findings show that gefitinib reduces intratumoral hypoxia.