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Radiomics describes the extraction of multiple features from medical images, including molecular imaging modalities, that with bioinformatic approaches, provide additional clinically relevant information that may be invisible to the human eye. This information may complement standard radiological interpretation with data that may better characterize a disease or that may provide predictive or prognostic information. Progressing from predefined image features, often describing heterogeneity of voxel intensities within a volume of interest, there is increasing use of machine learning to classify disease characteristics and deep learning methods based on artificial neural networks that can learn features without a priori definition and without the need for preprocessing of images. There have been advances in standardization and harmonization of methods to a level that should support multicenter studies. However, in this relatively early phase of research in the field, there are limited aspects that have been adopted into routine practice. Most of the reports in the molecular imaging field describe radiomic approaches in cancer using 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET). In this review, we will describe radiomics in molecular imaging and summarize the pertinent literature in lung cancer where reports are most prevalent and mature., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to determine if 18 F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging ( 18 F-FDG PET/MRI) features are associated with contemporaneous metastases in patients with oesophageal/gastroesophageal cancer., Methods: Following IRB approval and informed consent, patients underwent a staging PET/MRI following 18 F-FDG injection (326 ± 28 MBq) and 156 ± 23 min uptake time. First-order histogram and second-order grey level co-occurrence matrix features were computed for PET standardized uptake value (SUV) and MRI T1-W, T2-W, diffusion weighted (DWI) and apparent diffusion coefficient (ADC) images for the whole tumour volume. K-means clustering assessed the correlation of feature-pairs with metastases. Multivariate analysis of variance (MANOVA) was performed to assess the statistical separability of the groups identified by feature-pairs. Sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and accuracy (ACC) were calculated for these features and compared with SUV max , ADC mean and maximum diameter alone for predicting contemporaneous metastases., Results: Twenty patients (18 males, 2 female; median 67 years, range 52-86) comprised the final study cohort; ten patients had metastases. Lower second-order SUV entropy combined with higher second-order ADC entropy were the best feature-pair for discriminating metastatic patients, MANOVA p value <0.001 (SN = 80%, SP = 80%, PPV = 80%, NPV = 80%, ACC = 80%). SUV max (SN = 30%, SP = 80%, PPV = 60%, NPV = 53%, ACC = 55%), ADC mean (SN = 20%, SP = 70%, PPV = 40%, NPV = 47%, ACC = 45%) and tumour maximum diameter (SN = 10%, SP = 90%, PPV = 50%, NPV = 50%, ACC = 50%) had poorer sensitivity and accuracy., Conclusion: High ADC entropy combined with low SUV entropy is associated with a higher prevalence of metastases and a promising initial signature for future study.

Purpose: Despite the growing use of fluorine-18-fluorodeoxyglucose (F-FDG) PET texture analysis to measure intratumoural heterogeneity in cancer research, the biologic basis of F-FDG PET-derived texture variables is poorly understood. We aimed to assess correlations between F-FDG PET-derived texture variables and whole-slide image (WSI)-derived metrics of tumour cellularity and spatial heterogeneity., Patients and Methods: Twenty-two patients with non-small-cell lung cancer prospectively underwent F-FDG PET imaging before tumour resection. We tested nine F-FDG PET parameters: metabolically active tumour volume, total lesion glycolysis, mean standardized uptake value (SUVmean), first-order entropy, energy, skewness, kurtosis, grey-level co-occurrence matrix entropy and lacunarity (SUV-lacunarity). From the haematoxylin and eosin-stained WSIs, we derived mean tumour-cell density (MCD) and lacunarity (path-lacunarity). Spearman's correlation analysis and agglomerative hierarchical clustering were performed to assess variable associations., Results: Tumour volumes ranged from 2.2 to 74 cm (median: 17.9 cm). MCD correlated positively with total lesion glycolysis (rs: 0.46, P: 0.007) and SUVmean (rs : 0.55; P: 0.008) and negatively with skewness and kurtosis (rs: -0.47 for both; P: 0.028 and 0.026, respectively). SUV-lacunarity and path-lacunarity were positively correlated (rs: 0.5; P: 0.018). On cluster analysis, larger tumours trended towards higher SUVmean and entropy with a predominance of tightly concentrated high SUV-voxels (negative skewness and low kurtosis on the histogram); on WSI analysis such larger tumours also displayed generally higher MCD and low SUV-lacunarity and path-lacunarity., Conclusion: Our data suggest that histopathological MCD and lacunarity are associated with several commonly used F-FDG PET-derived indices including SUV-lacunarity, metabolically active tumour volume, SUVmean, entropy, skewness, and kurtosis, and thus may explain the biological basis of F-FDG PET-uptake heterogeneity in non-small-cell lung cancer.

Purpose: Radiomics describes the extraction of multiple, otherwise invisible, features from medical images that, with bioinformatic approaches, can be used to provide additional information that can predict underlying tumor biology and behavior., Methods and Materials: Radiomic signatures can be used alone or with other patient-specific data to improve tumor phenotyping, treatment response prediction, and prognosis, noninvasively. The data describing 18 F-fluorodeoxyglucose positron emission tomography radiomics, often using texture or heterogeneity parameters, are increasing rapidly., Results: In relation to radiation therapy practice, early data have reported the use of radiomic approaches to better define tumor volumes and predict radiation toxicity and treatment response., Conclusions: Although at an early stage of development, with many technical challenges remaining and a need for standardization, promise nevertheless exists that PET radiomics will contribute to personalized medicine, especially with the availability of increased computing power and the development of machine-learning approaches for imaging., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The purposes of this article are to review the common biologic features of cancer and coronary artery disease assessed with PET tracers, focusing on those already used in the clinic and those with translational potential, and to discuss the current value and expected contribution of PET in diagnosis, risk stratification, and treatment monitoring., Conclusion: PET using a wide variety of radiotracers enhances understanding of pathophysiologic changes shared by cancer and coronary artery disease, helps establish an accurate diagnosis, and aids in prognostic assessment and management decisions. It is likely that with the evolution of therapeutic strategies for blocking the development and progression of both diseases and with the introduction of novel, specific ligands in clinical practice, PET will play an ever stronger role in diagnosis, risk stratification, and monitoring of therapy.

In oncology, the skeleton is one of the most frequently encountered sites for metastatic disease and thus early detection not only has an impact on an individual patient's management but also on the overall outcome. Multiparametric and multimodal hybrid PET/computed tomography and PET/MR imaging have revolutionized imaging for bone metastases, but irrespective of tumor biology or morphology of the bone lesion it remains unclear which imaging modality is the most clinically relevant to guide individualized cancer care. In this review, we highlight the current clinical challenges of PET imaging in evaluation and quantification of skeletal tumor burden and its impact on personalized cancer management., (Copyright © 2016 Elsevier Inc. All rights reserved.)

18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) is established for characterising indeterminate pulmonary nodules and staging lung cancer where there is curative intent. Whilst a sensitive technique, specificity for characterising lung cancer is limited. There is recognition that evaluation of other aspects of abnormal cancer biology in addition to glucose metabolism may be more helpful in characterising tumours and predicting response to novel targeted cancer therapeutics. Therefore, efforts have been made to develop and evaluate new radiopharmaceuticals in order to improve the sensitivity and specificity of PET imaging in lung cancer with regards to characterisation, treatment stratification and therapeutic monitoring. 18F-fluorothymidine (18F-FLT) is a marker of cellular proliferation. It shows a lower accumulation in tumours than 18F-FDG as it only accumulates in the cells that are in the S phase of growth and demonstrates a low sensitivity for nodal staging. Its main role is in evaluating treatment response. Methionine is an essential amino acid. 11C-methionine is more specific and sensitive than 18F-FDG in differentiating benign and malignant thoracic nodules. 18Ffluoromisonidazole (18F-FMISO) is used for imaging tumour hypoxia. Tumour response to treatment is significantly related to the level of tumour oxygenation. Angiogenesis is the process by which new blood vessels are formed in tumours and is involved in tumour growth and metastatic tumour spread and is a therapeutic target. Most clinical studies have focused on targeted integrin PET imaging of which αvβ3 integrin is the most extensively investigated. It is upregulated on activated endothelial cells in association with tumour angiogenesis. Neuroendocrine tumour tracers, particularly 68Ga-DOTA-peptides, have an established role in imaging of carcinoid tumours. Whilst most of these tracers have predominantly been used in the research environment, they offer exciting opportunities for improving staging, characterisation, stratification and response assessment in an era of increased personalised therapy in lung cancer., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Bone metastases are common in patients with advanced breast cancer. Given the significant associated morbidity, the introduction of new, effective systemic therapies, and the improvement in survival time, early detection and response assessment of skeletal metastases have become even more important. Although planar bone scanning has recognized limitations, in particular, poor specificity in staging and response assessment, it continues to be the main method in current clinical practice for staging of the skeleton in patients at risk of bone metastases. However, the accuracy of bone scanning can be improved with the addition of SPECT/CT. There have been reported improvements in sensitivity and specificity for staging of the skeleton with either bone-specific PET/CT tracers, such as (18)F-NaF, or tumor-specific tracers, such as (18)F-FDG, although these methods are less widely available and more costly. There is a paucity of data on the use of (18)F-NaF PET/CT for response assessment in breast cancer, but there is increasing evidence that (18)F-FDG PET/CT may improve on current methods in this regard. At the same time, interest and experience in using whole-body morphologic MRI augmented with diffusion-weighted imaging for both staging and response assessment in the skeleton have been increasing. However, data on comparisons of these methods with PET methods to determine the best technique for current clinical practice or for clinical trials are insufficient. There are early data supporting the use (18)F-FDG PET/MRI to assess malignant disease in the skeleton, with the possibility of taking advantage of the synergies offered by combining morphologic, physiologic, and metabolic imaging., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Purpose: To determine if first-order and high-order textural features on fluorine 18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET) images of non-small cell lung cancer (NSCLC) (a) at baseline, (b) at 6 weeks, or (c) the percentage change between baseline and 6 weeks can predict response or survival in patients treated with erlotinib., Materials and Methods: Institutional review board approval was obtained for post hoc analysis of data from a prospective single-center study for which informed consent was obtained. The study included 47 patients with NSCLC who underwent (18)F-FDG PET/computed tomography (CT) at baseline (n = 47) and 6 weeks (n = 40) after commencing treatment with erlotinib. First-order and high-order primary tumor texture features reflecting image heterogeneity, standardized uptake values, metabolic tumor volume, and total lesion glycolysis were measured for all (18)F-FDG PET studies. Response to erlotinib was assessed by using the Response Evaluation Criteria in Solid Tumors (RECIST) on CT images obtained at 12 weeks (n = 32). Associations between PET parameters, overall survival (OS), and RECIST-based treatment response were tested by Cox and logistic regression analyses, respectively., Results: Median OS was 14.1 months. According to CT RECIST at 12 weeks, there were 21 nonresponders and 11 responders. Response to erlotinib was associated with reduced heterogeneity (first-order standard deviation, P = .01; entropy, P = .001; uniformity, P = .001). At multivariable analysis, high-order contrast at 6 weeks (P = .002) and percentage change in first-order entropy (P = .03) were independently associated with survival. Percentage change in first-order entropy was also independently associated with treatment response (P = .01)., Conclusion: Response to erlotinib is associated with reduced heterogeneity at (18)F-FDG PET. Changes in first-order entropy are independently associated with OS and treatment response.

Unlabelled: (18)F-fluoride PET/CT offers the opportunity for accurate skeletal metastasis staging, compared with conventional imaging methods. (18)F-fluoride is a bone-specific tracer whose uptake depends on osteoblastic activity. Because of the resulting increase in bone mineralization and sclerosis, the osteoblastic process can also be detected morphologically in CT images. Although CT is characterized by high resolution, the potential of PET is limited by its lower spatial resolution and the resulting partial-volume effect. In this context, the synergy between PET and CT presents an opportunity to resolve this limitation using a novel multimodal approach called synergistic functional-structural resolution recovery (SFS-RR). Its performance is benchmarked against current resolution recovery technology using the point-spread function (PSF) of the scanner in the reconstruction procedure., Methods: The SFS-RR technique takes advantage of the multiresolution property of the wavelet transform applied to both functional and structural images to create a high-resolution PET image that exploits the structural information of CT. Although the method was originally conceived for PET/MR imaging of brain data, an ad hoc version for whole-body PET/CT is proposed here. Three phantom experiments and 2 datasets of metastatic bone (18)F-fluoride PET/CT images from primary prostate and breast cancer were used to test the algorithm performances. The SFS-RR images were compared with the manufacturer's PSF-based reconstruction using the standardized uptake value (SUV) and the metabolic volume as metrics for quantification., Results: When compared with standard PET images, the phantom experiments showed a bias reduction of 14% in activity and 1.3 cm(3) in volume estimates for PSF images and up to 20% and 2.5 cm(3) for the SFS-RR images. The SFS-RR images were characterized by a higher recovery coefficient (up to 60%) whereas noise levels remained comparable to those of standard PET. The clinical data showed an increase in the SUV estimates for SFS-RR images up to 34% for peak SUV and 50% for maximum SUV and mean SUV. Images were also characterized by sharper lesion contours and better lesion detectability., Conclusion: The proposed methodology generates PET images with improved quantitative and qualitative properties. Compared with standard methods, SFS-RR provides superior lesion segmentation and quantification, which may result in more accurate tumor characterization., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Objectives: Measuring tumour heterogeneity by textural analysis in (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) provides predictive and prognostic information but technical aspects of image processing can influence parameter measurements. We therefore tested effects of image smoothing, segmentation and quantisation on the precision of heterogeneity measurements., Methods: Sixty-four (18)F-FDG PET/CT images of oesophageal cancer were processed using different Gaussian smoothing levels (2.0, 2.5, 3.0, 3.5, 4.0 mm), maximum standardised uptake value (SUVmax) segmentation thresholds (45%, 50%, 55%, 60%) and quantisation (8, 16, 32, 64, 128 bin widths). Heterogeneity parameters included grey-level co-occurrence matrix (GLCM), grey-level run length matrix (GLRL), neighbourhood grey-tone difference matrix (NGTDM), grey-level size zone matrix (GLSZM) and fractal analysis methods. The concordance correlation coefficient (CCC) for the three processing variables was calculated for each heterogeneity parameter., Results: Most parameters showed poor agreement between different bin widths (CCC median 0.08, range 0.004-0.99). Segmentation and smoothing showed smaller effects on precision (segmentation: CCC median 0.82, range 0.33-0.97; smoothing: CCC median 0.99, range 0.58-0.99)., Conclusions: Smoothing and segmentation have only a small effect on the precision of heterogeneity measurements in (18)F-FDG PET data. However, quantisation often has larger effects, highlighting a need for further evaluation and standardisation of parameters for multicentre studies., Key Points: • Heterogeneity measurement precision in (18) F-FDG PET is influenced by image processing methods. • Quantisation shows large effects on precision of heterogeneity parameters in (18) F-FDG PET/CT. • Smoothing and segmentation show comparatively smaller effects on precision of heterogeneity parameters.

Objectives: The aim of this study was to determine the utility of fluorine-18 fluorodeoxyglucose PET/computed tomography ((18)F-FDG PET/CT) in managing testicular cancer., Patients and Methods: Sixty-two patients (29 seminoma, 28 nonseminoma and five mixed) underwent 75 (18)F-FDG PET/CT scans (16 scans for primary staging, 44 for residual masses and 15 for rising tumour markers). Follow-up histology, clinical scans and tumour marker results were included for retrospective analysis., Results: (i) Primary staging: eight of 11 patients with equivocal CT scans had true-negative (18)F-FDG PET/CT scans. Five high-risk patients with normal stage 1 CT scans had negative (18)F-FDG PET/CT scans, but two subsequently relapsed. (ii) Residual masses: of the 20 scans interpreted as showing viable disease, five were false positive. Nineteen scans were negative (18 true negative and one false negative). (iii) Rising tumour markers: of the 15 scans, two were false negative and 13 were true positive., Conclusion: (18)F-FDG PET/CT is helpful when primary staging CT scans are equivocal but insufficiently sensitive to predict relapse in high-risk patients with normal CT scans. With residual masses, a negative scan is rarely associated with relapse. (18)F-FDG PET/CT is helpful in defining recurrent disease in the majority of patients with rising tumour markers and negative CT scans.

Objective: The aim of this study was to determine the value of SUV-based metabolic parameters derived from pretreatment F-FDG PET/CT of colorectal liver metastases in predicting disease response, progression-free survival (PFS), and overall survival (OS)., Patients and Methods: We retrospectively reviewed 70 colorectal patients with liver metastases who underwent pretreatment F-FDG PET/CT. SUVmean, SUVmax, TLG (total lesion glycolysis), metabolic tumor volume, and metabolic tumor diameter were the metabolic parameters derived from volume of interest analysis of the most FDG-avid liver lesion in each subject. Clinical and laboratory parameters were recorded. Tumor response was assessed by response evaluation criteria in solid tumors 1.1 criteria at 12 weeks after treatment. Associations between tumor response, metabolic parameters, and clinical/laboratory parameters were examined by 1-way analysis of variance. The relationship of the metabolic parameters with PFS and OS was determined by Kaplan-Meier analyses and further confirmed with multivariate Cox regression analyses., Results: SUVmean less than 4.48, SUVmax less than 6.59, TLG less than 75.2, metabolic tumor volume less than 4.49 cm, and hemoglobin level greater than or equal to 11 g/dL were associated with longer PFS (P < 0.05). Prior surgery or radiofrequency ablation to the liver metastases was the only additional factor shown to be associated with longer OS., Conclusions: SUV-based metabolic parameters derived from pretreatment F-FDG PET/CT can predict PFS in colorectal liver metastases.

Non-small-cell lung cancer (NSCLC) is the commonest cancer worldwide but survival remains poor with a high risk of relapse, particularly after nonsurgical treatment. Hypoxia is present in a variety of solid tumours, including NSCLC. It is associated with treatment resistance and a poor prognosis, although when recognised may be amenable to different treatment strategies. Thus, noninvasive assessment of intratumoral hypoxia could be used to stratify patients for modification of subsequent treatment to improve tumour control. Molecular imaging approaches targeting hypoxic cells have shown some early success in the clinical setting. This review evaluates the evidence for hypoxia imaging using PET in NSCLC and explores its potential clinical utility.

Aim: The aim of this study was to assess the utility of combined C-methionine and F-FDG PET/CT imaging in hyperparathyroidism., Patients and Methods: We reviewed all scans performed for hyperparathyroidism with both C-methionine and F-FDG PET/CT or PET in our institution since 1993. Forty-three patients (47 pairs of scans) were included (13 men and 30 women) with a mean age of 63 years. C-methionine and F-FDG PET/CT scans were classified as positive or negative for localization of abnormal parathyroid tissue, and the site of uptake was noted in the positive scans. Other concurrent imaging (Tc-MIBI scintigraphy, ultrasonography, CT, or MRI) findings were also noted when performed. Clinical follow-up information was available in 27 patients (30 episodes)., Results: Of the 47 PET scan episodes, 23 (49%) were positive. Twenty-two C-methionine scans showed abnormal focal localization of which 10 also showed concordant abnormal F-FDG uptake. One patient was positive with F-FDG and negative with C-methionine.Of the 16 patients who underwent subsequent surgery, 6 had concordant C-methionine, F-FDG, and surgical findings; 6 had concordant C-methionine and surgical findings; 1 had concordant F-FDG and surgical findings; and 3 had both PET scans negative but had adenomas excised during surgery.Of the 3 with both PET scans negative and discordant surgical findings, 1 had mediastinal parathyroid lipoadenoma excised and 2 had normally sited parathyroid adenoma excised., Conclusions: F-FDG PET/CT rarely provides additional information and could be saved for patients in whom C-methionine PET/CT is negative.

Purpose: Malignant pleural mesothelioma (MPM) is a disease with poor prognosis despite multimodal therapy but there is variation in survival between patients. Prognostic information is therefore potentially valuable in managing patients, particularly in the context of clinical trials where patients could be stratified according to risk. Therefore we have evaluated the prognostic ability of parameters derived from baseline 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT)., Methods: In order to determine the relationships between metabolic activity and prognosis we reviewed all (18)F-FDG PET/CT scans used for pretreatment staging of MPM patients in our institution between January 2005 and December 2011 (n = 60) and measured standardised uptake values (SUV) including mean, maximum and peak values, metabolic tumour volume (MTV) and total lesion glycolysis (TLG). Overall survival (OS) or time to last censor was recorded, as well as histological subtypes., Results: Median follow-up was 12.7 months (1.9-60.9) and median OS was 14.1 months (1.9-54.9). By univariable analysis histological subtype (p = 0.013), TLG (p = 0.024) and MTV (p = 0.038) were significantly associated with OS and SUVmax was borderline (p = 0.051). On multivariable analysis histological subtype and TLG were associated with OS but at borderline statistical significance (p = 0.060 and 0.058, respectively). No statistically significant differences in any PET parameters were found between the epithelioid and non-epithelioid histological subtypes., Conclusion: (18)F-FDG PET/CT parameters that take into account functional volume (MTV, TLG) show significant associations with survival in patients with MPM before adjusting for histological subtype and are worthy of further evaluation to determine their ability to stratify patients in clinical trials.

Purpose: To evaluate the utility of ¹⁸F-FDG PET/CT in suspected cerebral pathology in HIV-infected individuals., Methods: ¹⁸F-FDG PET/CT scans from 29 HIV-infected individuals (29 brain scans, 22 whole-body scans) who presented with neurological symptoms and signs were retrospectively reviewed and compared with subsequent clinical investigations., Results: The majority of patients (n=25) were referred to differentiate infection from malignant causes of cerebral pathology. Ten of the 11 patients with an eventual diagnosis of toxoplasmosis infection were correctly diagnosed by ¹⁸F-FDG PET/CT showing lesional uptake less than that of normal brain cortex (mean SUVmax 3.5, range 1.9 - 5.8). All five patients with a final diagnosis of primary central nervous system lymphoma (PCNSL) were correctly diagnosed by ¹⁸F-FDG PET/CT showing lesional uptake greater than that of normal brain cortex (mean SUVmax 18.8, range 12.4 - 29.9). Four of the five patients with ¹⁸F-FDG PET/CT features suggesting a vasculitic process had vasculitis confirmed as the final diagnosis. Three patients showed variable uptake in multiple cerebral lesions (including final diagnoses of tuberculosis and metastases from lung cancer in two patients) and there were four other miscellaneous diagnoses. In 12 patients biopsies were performed at sites guided by PET abnormality (7 brain, 5 lymph nodes) confirming or excluding significant disease in 11., Conclusion: ¹⁸F-FDG PET/CT is particularly useful for differentiating between infection and PCNSL in HIV-infected patients with a cerebral lesion on MRI or CT. ¹⁸F-FDG PET/CT was also a helpful tool in the diagnostic work-up of patients with other HIV-related cerebral pathology. Additional advantages of ¹⁸F-FDG PET/CT are the abilities to assess abnormally increased glucose metabolism in the body and to identify potential sites for biopsy.

Introduction: Where chemoradiotherapy or radiotherapy alone with curative intent is used as the primary treatment of locally advanced head and neck cancers, salvage surgery may offer a second chance of cure in the face of recurrent or residual disease. Early detection of recurrent or residual disease is therefore the key to facilitating timely and efficacious salvage surgery. CT and MRI can be difficult to interpret in the posttreatment neck. Functional imaging, such as F-FDG PET/CT, has the potential to improve restaging accuracy. The aim of our study was to assess the efficacy of F-FDG PET/CT performed 3 months following primary treatment of head and neck cancer., Methods: We retrospectively reviewed 35 patients with head and neck squamous cell cancer (mean age, 61 years; 28 male patients) who underwent F-FDG PET/CT imaging at 3 months following primary treatment, which included chemoradiotherapy (n = 31) or radiotherapy alone (n = 4). Patient follow-up was available for at least 12 months (range, 12-48 months; median, 36 months). Scans were categorized as true positive, true negative, false positive, and false negative based on clinicoradiological follow-up and histology., Results: Twenty patients had negative scans with no recurrence during the follow-up period, and 3 had false-negative scans with recurrent disease at 5, 8, and 12 months. Eleven patients had true-positive scans, confirmed histologically in all, and there was 1 false-positive scan giving a sensitivity of 79%, specificity of 96%, positive predictive value of 92%, negative predictive value of 87%, and overall accuracy of 89%., Conclusions: F-FDG PET/CT is an accurate method for assessing response after primary locally advanced head and neck cancer treatment. Although false-positive scans are rare, a few patients will have a relapse after a negative scan, and so continued close follow-up is required.

Unlabelled: There is evidence in some solid tumors that textural features of tumoral uptake in (18)F-FDG PET images are associated with response to chemoradiotherapy and survival. We have investigated whether a similar relationship exists in non-small cell lung cancer (NSCLC)., Methods: Fifty-three patients (mean age, 65.8 y; 31 men, 22 women) with NSCLC treated with chemoradiotherapy underwent pretreatment (18)F-FDG PET/CT scans. Response was assessed by CT Response Evaluation Criteria in Solid Tumors (RECIST) at 12 wk. Overall survival (OS), progression-free survival (PFS), and local PFS (LPFS) were recorded. Primary tumor texture was measured by the parameters coarseness, contrast, busyness, and complexity. The following parameters were also derived from the PET data: primary tumor standardized uptake values (SUVs) (mean SUV, maximum SUV, and peak SUV), metabolic tumor volume, and total lesion glycolysis., Results: Compared with nonresponders, RECIST responders showed lower coarseness (mean, 0.012 vs. 0.027; P = 0.004) and higher contrast (mean, 0.11 vs. 0.044; P = 0.002) and busyness (mean, 0.76 vs. 0.37; P = 0.027). Neither complexity nor any of the SUV parameters predicted RECIST response. By Kaplan-Meier analysis, OS, PFS, and LPFS were lower in patients with high primary tumor coarseness (median, 21.1 mo vs. not reached, P = 0.003; 12.6 vs. 25.8 mo, P = 0.002; and 12.9 vs. 20.5 mo, P = 0.016, respectively). Tumor coarseness was an independent predictor of OS on multivariable analysis. Contrast and busyness did not show significant associations with OS (P = 0.075 and 0.059, respectively), but PFS and LPFS were longer in patients with high levels of each (for contrast: median of 20.5 vs. 12.6 mo, P = 0.015, and median not reached vs. 24 mo, P = 0.02; and for busyness: median of 20.5 vs. 12.6 mo, P = 0.01, and median not reached vs. 24 mo, P = 0.006). Neither complexity nor any of the SUV parameters showed significant associations with the survival parameters., Conclusion: In NSCLC, baseline (18)F-FDG PET scan uptake showing abnormal texture as measured by coarseness, contrast, and busyness is associated with nonresponse to chemoradiotherapy by RECIST and with poorer prognosis. Measurement of tumor metabolic heterogeneity with these parameters may provide indices that can be used to stratify patients in clinical trials for lung cancer chemoradiotherapy.

(18)F-Fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) is now routinely used in oncological imaging for diagnosis and staging and increasingly to determine early response to treatment, often employing semiquantitative measures of lesion activity such as the standardized uptake value (SUV). However, the ability to predict the behaviour of a tumour in terms of future therapy response or prognosis using SUVs from a baseline scan prior to treatment is limited. It is recognized that medical images contain more useful information than may be perceived with the naked eye, leading to the field of "radiomics" whereby additional features can be extracted by computational postprocessing techniques. In recent years, evidence has slowly accumulated showing that parameters obtained by texture analysis of radiological images, reflecting the underlying spatial variation and heterogeneity of voxel intensities within a tumour, may yield additional predictive and prognostic information. It is hoped that measurement of these textural features may allow better tissue characterization as well as better stratification of treatment in clinical trials, or individualization of future cancer treatment in the clinic, than is possible with current imaging biomarkers. In this review we focus on the literature describing the emerging methods of texture analysis in (18)FDG PET/CT, as well as other imaging modalities, and how the measurement of spatial variation of voxel grey-scale intensity within an image may provide additional predictive and prognostic information, and postulate the underlying biological mechanisms.

The evaluation of drug pharmacodynamics and early tumour response are integral to current clinical trials of novel cancer therapeutics to explain or predict long term clinical benefit or to confirm dose selection. Tumour vascularity assessment by positron emission tomography could be viewed as a generic pharmacodynamic endpoint or tool for monitoring response to treatment. This review discusses methods for semi-quantitative and quantitative assessment of tumour vascularity. The radioligands and radiotracers range from direct physiological functional tracers like [(15)O]-water to macromolecular probes targeting integrin receptors expressed on neovasculature. Finally we make recommendations on ways to incorporate such measurements of tumour vascularity into early clinical trials of novel therapeutics. Key Points • [ ( 15 ) O]-water is the gold standard for blood flow/tissue perfusion with PET • In some instances dynamic [ ( 18 ) F]-FDG uptake may be used to estimate perfusion • Radiopharmaceuticals that target integrins are now being evaluated for measuring tumour vascularity.

Aim: The aim of this study was to evaluate the relationship between different quantification methods used for the measurement of bone plasma clearance (K(i)) using F-PET at the hip and lumbar spine., Methods: Twelve healthy postmenopausal women aged 52-71 years were recruited. Each participant underwent 60-min dynamic F-PET scans at the lumbar spine and hip on two separate occasions with an injected activity of 90 and 180 MBq, respectively. Image-derived input functions were obtained at the aorta from the lumbar spine scans. K(i) was evaluated using a three-compartment four-parameter model (K(i-4k)), three-compartment three-parameter model (K(i-3k)), Patlak analysis (K(i-Pat)), spectral analysis (K(i-Spec)) and deconvolution (K(i-Decon)). Standardized uptake values (SUVs) were also measured., Results: The Pearson correlation between K(i-4k) and K(i-3k), K(i-Pat), K(i-Spec), K(i-Decon) and SUV were 0.91, 0.97, 0.94, 0.95 and 0.93, respectively, with a significance of P less than 0.0001. The differences between the correlations measured using Fisher's Z-test were not significant (P>0.05). Bland-Altman analysis showed that the limits of agreement for K(i) measured as the SD of the differences were 0.0082 (25.9%), 0.0062 (11.7%), 0.0098 (20.1%) and 0.0056 (25.5%) ml/min/ml, respectively, and the biases were -0.0081 (-23.8%), -0.0075 (-23.7%), -0.0107 (-29.5%) and -0.0015 (0.8%) ml/min/ml, respectively., Conclusion: All five methods of quantification (K(i-3k), K(i-Pat), K(i-Spec), K(i-Decon) and SUV) strongly correlated with K(i-4k). Although systematic differences of up to 29% were found between K(i-4k) and the other methods (K(i-3k), K(i-Pat), K(i-Spec) and K(i-Decon)), these should not affect the conclusions of clinical studies, provided the methods are applied consistently. However, care should be taken when comparing reports that use different methods of quantification.

The role of positron emission tomography computed tomography in oncological imaging has rapidly evolved. It has proven itself to be cost effective and alters patient management in a significant proportion of cases. This article discusses its current and future applications.

Introduction: The use of image-derived arterial input functions (IDAIF) for the dynamic quantification of bone metabolism using 18F-fluoride positron emission tomography 18F-PET is an attractive alternative to direct arterial blood sampling., Purposes: (a) To validate a method for obtaining the IDAIF by imaging the femoral artery against a method for deriving the IDAIF at the aorta that was previously validated against direct arterial sampling. (b) To compare the accuracy of bone plasma clearance measurements (Ki) at the total hip site obtained using the femoral artery IDAIF against Ki values at the same site obtained using the aorta IDAIF., Methods: Twelve healthy postmenopausal women with a mean age of 62.6 years (range, 52.3-70.6 years) had 60-min dynamic 18F-PET scans of the lumbar spine and proximal femur 2 weeks apart. The femoral artery IDAIF was obtained from the proximal femur scan using four different algorithms: (a) fixed partial volume correction (PVC) method; (b) variable PVC method; (c) Chen method; and (d) Cook-Lodge method. The aorta IDAIF was obtained from the lumbar spine scan using a previously validated method and the respective Ki values in the hip were used to assess the performance of each of the femoral artery algorithms., Results: When the femoral artery IDAIF methods were compared with the aorta IDAIF in terms of the area under the curve AUC values calculated in 4-min time intervals over 0-60 min, the absolute root mean square errors were: (a) fixed PVC, 0.52; (b) variable PVC, 0.54; (c) Chen, 0.72; and (d) Cook-Lodge, 0.49 in MBq s/ml. There were small, but statistically significant differences, in the Ki values found by all four femoral artery IDAIF methods when compared with the figures obtained using the aorta IDAIF. Bland-Altman plots of Ki values showed the best agreement for the fixed PVC method with a standard deviation of 0.0020 ml/min/ml, followed by variable PVC, Cook-Lodge and Chen method with standard deviations of 0.0022, 0.0024 and 0.0042 ml/min/ml, respectively., Conclusion: We have demonstrated that it is possible to measure regional bone turnover at the hip without the need to perform direct arterial sampling to acquire the arterial input function (AIF). The differences in the Ki values obtained at the hip by using aorta IDAIF and any of the four image-based AIF methods at the femoral artery were small and clinically insignificant. The performance of fixed PVC, variable PVC and Cook-Lodge method was similar although the latter was less robust than the other two methods.

Objectives: (i) To validate two new image-based methods for finding the plasma arterial input function (AIF) and evaluate the performance of these and two similar techniques against arterial sampling. (ii) To evaluate the performance of all four image-derived AIF (IDAIF) methods against arterial sampling for measuring the F plasma clearance (Ki) to the lumbar spine., Methods: Eight healthy postmenopausal women had a F-fluoride positron emission tomography scan of the lumbar spine. Venous blood samples were used to estimate the IDAIFs from: (i) a fixed population-based partial volume correction (PVC) factor method, (ii) a variable PVC factor method, (iii) the Chen method, and (iv) the Cook-Lodge method. Continuous arterial sampling and the respective Ki values were used as the gold standard against which the performance of the IDAIF methods was compared., Results: The IDAIFs were compared with direct arterial sampling in terms of the area under the curve values. The percentage root mean square error in area under the curves compared with arterial sampling were: (i) fixed PVC: 12.7%, (ii) variable PVC: 12.0%, (iii) Chen: 39.0%, and (iv) Cook-Lodge: 17.3%. There were small but significant differences in the Ki values found by all four methods compared with arterial sampling. Bland-Altman plots of Ki values showed the best agreement for the variable and fixed PVC methods with a standard deviation of 0.0026 and 0.0030 ml/min/ml, respectively., Conclusion: The differences in the Ki values obtained at the lumbar spine using direct arterial sampling and any of the IDAIF methods at the aorta were clinically nonsignificant. The variable PVC and fixed PVC methods performed better than the Cook-Lodge and Chen methods.

Bone scintigraphy augmented with radiographs or cross-sectional imaging, such as computed tomography (CT) or magnetic resonance imaging (MRI), has remained the commonest method to diagnose and follow up skeletal metastases. However, bone scintigraphy is associated with relatively poor spatial resolution, limited diagnostic specificity and reduced sensitivity for bone marrow disease. It also shows limited diagnostic accuracy in assessing response to therapy in a clinically useful time period. With the advent of hybrid positron emission tomography (PET)/CT scanners there has been an increasing interest in using various PET tracers to evaluate skeletal disease including [(18)F]fluoride (NaF) as a bone-specific tracer and [(18)F]fluorodeoxyglucose and [(18)F]choline as tumour-specific tracers. There is also early work exploring the receptor status of skeletal metastases with somatostatin receptor analogues. This review describes the potential utility of these tracers in the assessment of skeletal metastases.

Background: Neoadjuvant therapy response assessment is crucial in patients with non-small cell lung cancer (NSCLC). FDG-PET has emerged as a valuable tool for defining therapy response assessment in other tumours., Aim: To systematically review publications appearing in the literature describing induction therapy response assessment with FDG-PET in NSCLC., Methods: We performed a bibliographic search and selected only prospective studies in order to include the highest levels of evidence., Results: Nine of 497 potentially relevant publications were selected. The ranges of sensitivity, specificity, positive predictive value and negative predictive value for primary tumour response assessment were 80-100%, 0-100%, 42.9-100%, and 66.7-100%, respectively. Pooling data for N2 restaging after neoadjuvant response the overall sensitivity was 63.8% (95% CI, 53.3-73.7%) and overall specificity was 85.3% (95% CI, 80.4-89.4%)., Conclusion: The results of the analysis do not support the use of FDG-PET as the only re-assessment tool for mediastinal lymph node evaluation for routine clinical use. FDG-PET seems to predict primary tumour response to induction therapy but it could not be shown by pooling analysis., ((c) 2010 Wiley-Liss, Inc.)

The functional imaging technique of (18)F-fluoride positron emission tomography ((18)F-PET) allows the non-invasive assessment of regional bone blood perfusion and turnover. Bone perfusion and turnover measured using (18)F-PET correlate closely with those obtained experimentally and so they can be readily applied in clinical research studies. The aim of this study was to compare bone perfusion and turnover between the lumbar spine and humerus in both treatment naïve postmenopausal women (n=11) and those on stable antiresorptive therapy (n=12). All women had a BMD T-score of less than -2 at the spine and/or hip. Each woman had a dynamic PET scan of the lumbar spine and distal humerus after injection of 90 MBq (18)F-fluoride. Using a three-compartmental model bone perfusion (K(1)), the net plasma clearance of tracer to bone mineral (K(i)) reflecting regional bone turnover and the rate constants k(2)-k(4) describing the transport of fluoride between plasma, an extravascular bone compartment and bone mineral compartment were calculated. Mean bone perfusion (K(1)) and bone turnover (K(i)) were significantly higher at the lumbar spine compared to the humerus for both treatment-naïve and antiresorptive groups. K(1) values were on average 3 times greater while K(i) was approximately 50% greater at the lumbar spine. The rate constant k(2), the reverse transport of fluoride from the extravascular compartment to plasma, was significantly lower at the humerus compared to the lumbar spine in both groups. The ratio K(i)/K(1) describing the unidirectional extraction efficiency to bone mineral was significantly greater at the humerus compared to the lumbar spine for both study groups. No significant differences between skeletal sites were observed for k(3) or k(4). In conclusion a significant skeletal heterogeneity was observed in terms of bone perfusion and turnover between the lumbar spine and humerus. (18)F-PET may aid in our understanding of the importance of bone perfusion in osteoporosis and differences in regional bone turnover with disease and in response to therapy.

In this review, we assess the current role of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) in the imaging of skeletal metastatic disease from a miscellaneous group of malignancies, including lung, thyroid, and renal carcinomas; multiple myeloma; and neuroendocrine tumors, and consider how recent advances may enhance their effectiveness in this area. Bone scintigraphy using technetium-labeled diphosphonates has long been the mainstay of functional imaging of bony metastases, but is of limited value in myeloma and aggressive osteolytic metastases, and has the limitation of relatively poor specificity. SPECT, as a tomographic imaging technique, produces three-dimensional images of tracer distribution from multiplanar images. Its application to bone scintigrams greatly aids accurate anatomic localization and sensitivity in detection of foci of tracer uptake. SPECT can equally be applied to scintigrams using radiotracers, which are specific for particular groups of tumors, such as somatostatin analogs for neuroendocrine tumors. The advent of combined SPECT/computed tomography (CT) systems has further enhanced the accuracy of SPECT in all these malignancies. PET uses positron-emitting radiotracers and achieves a higher spatial resolution than single-photon imaging. Its high resolution and coverage of the entire body have made it a highly effective technique for the evaluation of skeletal metastatic disease, particularly when combined with CT. (18)F-fluorodeoxyglucose ((18)F-FDG)-PET/CT now forms part of routine staging for many carcinomas, such as non-small-cell lung carcinomas, and may obviate the need for routine staging scintigraphy in these patients. As uptake of the most common PET radiotracer, (18)F-FDG, is dependent on the increased cellular metabolism of most tumors, it may enable earlier detection of metastatic foci than bone scintigraphy, which relies on detecting an osteoblastic response. Another significant advantage of (18)F-FDG-PET is that it can detect soft-tissue components of metastases, which is particularly important in aggressive osteolytic metastases. The effectiveness of (18)F-FDG-PET is limited in slow-growing tumor types, but (18)F-sodium fluoride, a bone radiotracer that can detect early osteoblastic changes, shows promise in this area. Bony metastases from many neuroendocrine tumors can be detected with a high degree of specificity by PET using somatostatin analogs. Other novel and often highly specific radiotracers are under evaluation, which will further enhance the diagnostic capability of PET. The true potential of PET in this group of malignancies is gradually unfolding, although studied series of patients remain generally small and much further evaluation of its role is required.

Unlabelled: Neoadjuvant treatment is a relatively new therapeutic approach for locally advanced esophageal cancer. Response assessment is crucial for the treatment of these patients. Cross sectional imaging has traditionally being used as the elective method of response assessment. Recently, 18F fluorodeoxyglucose- positron emission tomography (FDG-PET) has emerged as a new valuable tool defining therapy response assessment in other tumors., Aim: We systematically reviewed the increasing number of publications appearing in the literature analyzing the utility of FDG-PET in the evaluation of neoadjuvant therapy response assessment., Methods: We performed a bibliographic search according to the COSI protocol and selected only prospective studies to achieve the highest levels of evidence. Quality assessment was defined with the QUADAS questionnaire., Results: Eight of 237 potentially relevant publications were selected for the analysis. Ranged sensitivity, specificity, positive predictive value, and negative predictive value for primary tumor response assessment were 27.3% to 93.3%, 41.7% to 95.2%, 70.8% to 93.3% and 71.4% to 93.5%, respectively, and for N restaging, 16.0% to 67.5%, 85.7% to 100%, 33% to 100% and 91.7% to 93.3%, respectively. The heterogeneity of the publications ruled out the possibility of meta-analysis. FDG-PET is more precise compared with computed tomography in the evaluation of induction therapy response assessment., Conclusion: FDG-PET seems to be the best available imaging modality for neoadjuvant therapy response assessment in esophageal cancer. But more prospective studies with larger populations are needed to confirm the power of this imaging tool in this aim and to determine the best analytical interpretation method and threshold to differentiate responders from nonresponding patients.

Unlabelled: (18)F-Fluoride PET allows noninvasive evaluation of regional bone metabolism and has the potential to become a useful tool for assessing patients with metabolic bone disease and evaluating novel drugs being developed for these diseases. The main PET parameter of interest, termed K(i), reflects regional bone metabolism. The aim of this study was to compare the long-term precision of (18)F-fluoride PET with that of biochemical markers of bone turnover assessed over 6 mo., Methods: Sixteen postmenopausal women with osteoporosis or significant osteopenia and a mean age of 64 y underwent (18)F-fluoride PET of the lumbar spine and measurements of biochemical markers of bone formation (bone-specific alkaline phosphatase and osteocalcin) and bone resorption (urinary deoxypyridinoline) at baseline and 6 mo later. Four different methods for analyzing the (18)F-fluoride PET data were compared: a 4k 3-compartmental model using nonlinear regression analysis (K(i-4k)), a 3k 3-compartmental model using nonlinear regression analysis (K(i-3k)), Patlak analysis (K(i-PAT)), and standardized uptake values., Results: With the exception of a small but significant decrease in K(i-3k) at 6 mo, there were no significant differences between the baseline and 6-mo values for the PET parameters or biochemical markers. The long-term precision, expressed as the coefficient of variation (with 95% confidence interval in parentheses), was 12.2% (9%-19%), 13.8% (10%-22%), 14.4% (11%-22%), and 26.6% (19%-40%) for K(i-3k), K(i-PAT), mean standardized uptake value, and K(i-4k), respectively. For comparison, the precision of the biochemical markers was 10% (7%-15%), 18% (13%-27%), and 14% (10%-21%) for bone-specific alkaline phosphatase, osteocalcin, and urinary deoxypyridinoline, respectively. Intraclass correlation between the baseline and 6-mo values ranged from 0.44 for K(i-4k) to 0.85 for K(i-3k). No significant correlation was found between the repeated mean standardized uptake value measurements., Conclusion: The precision and intraclass correlation observed for K(i-3k) and K(i-PAT) was equivalent to that observed for biochemical markers. This study provided initial data on the long-term precision of (18)F-fluoride PET measured at the lumbar spine, which will aid in the accurate interpretation of changes in regional bone metabolism in response to treatment.

Bone turnover is an important determinant of fracture risk. (18)F-fluoride positron emission tomography ((18)F-PET) allows the direct assessment of bone turnover at the clinically important skeletal sites such as the lumbar spine. The aim of this study was to determine if the relationship between regional bone turnover measured using (18)F-PET and changes in bone mineral density (BMD) is equivalent to that seen for global skeletal measurements of biochemical markers of bone turnover. Forty-three women who had previously had an (18)F-PET scan at the lumbar spine, assessment of biochemical markers of bone turnover, and a dual-energy X-ray absorptiometry scan of BMD at the lumbar spine and hip (baseline assessments) were split into 1 of 2 groups: (1) 22 women who commenced treatment for osteoporosis within 2mo of having the baseline assessments (Treatment group); (2) 21 women who had not taken any treatments for osteoporosis since having the baseline assessments (Untreated group). Sixteen of the women in the Treatment group started risedronate therapy as part of a prospective study they were participating in, whereas the decision to treat the remaining 6 women was made by the subject's treating physician. Subjects had between 2 and 5 BMD scans over a median follow-up time of 4.1yr to estimate the annual percentage change in BMD since baseline. The relationship between the tertiles of (18)F-PET skeletal kinetic parameter K(i), reflecting regional bone turnover, and annual changes in lumbar spine and hip BMD were compared to that seen for bone formation (bone-specific alkaline phosphatase, BSALP) and bone resorption (urinary deoxypyridinoline) markers. Treated women in the highest tertile of both regional ((18)F-PET) and global (biochemical markers) bone turnover showed the greatest annual percentage increases in lumbar spine BMD. The annual increase in lumbar spine BMD was 1.8%, 2.2%, and 3.2% for women in the lowest, middle, and highest tertile of BSALP, respectively, which was similar to that obtained for the regional measurement of K(i) of 1.7%, 2.2%, and 2.7% respectively. Untreated women in the highest tertile of regional and global bone turnover had larger decreases in lumbar spine BMD compared to those women in the lowest tertile, with a 1.4- to 4.8-fold difference in the annual decrease in BMD between the two. Less consistent patterns were observed when assessing the relationship between regional and global bone turnover with changes in hip BMD. This study has demonstrated that the relationship between regional bone turnover measured directly at the lumbar spine with changes in BMD is similar to that seen for global skeletal bone turnover using biochemical markers.

Increasing access to positron emission tomography-computed tomography (PET-CT) has resulted in a shift towards functional imaging, being the primary tool in the assessment of viable tumour in oncology patients. In this review, we discuss the basic principles of this evolving technology and the radio-isotopes it employs. The main clinical applications of PET-CT are reviewed and some of the limitations of the technique are highlighted. Finally, we offer insight into possible future developments and how these modify current practice.