Supplemental Table 1: Participating centers that enrolled patients; Supplemental Table 2: Serial FMISO PET Imaging.

[This corrects the article DOI: 10.1371/journal.pone.0118261.].

Abstract Purpose: Structural and functional alterations in tumor vasculature are thought to contribute to tumor hypoxia which is a primary driver of malignancy through its negative impact on the efficacy of radiation, immune surveillance, apoptosis, genomic stability, and accelerated angiogenesis. We performed a prospective, multicenter study to test the hypothesis that abnormal tumor vasculature and hypoxia, as measured with MRI and PET, will negatively impact survival in patients with newly diagnosed glioblastoma. Experimental Design: Prior to the start of chemoradiation, patients with glioblastoma underwent MRI scans that included dynamic contrast enhanced and dynamic susceptibility contrast perfusion sequences to quantitate tumor cerebral blood volume/flow (CBV/CBF) and vascular permeability (ktrans) as well as 18F-Fluoromisonidazole (18F-FMISO) PET to quantitate tumor hypoxia. ROC analysis and Cox regression models were used to determine the association of imaging variables with progression-free and overall survival. Results: Fifty patients were enrolled of which 42 had evaluable imaging data. Higher pretreatment 18F-FMISO SUVpeak (P = 0.048), mean ktrans (P = 0.024), and median ktrans (P = 0.045) were significantly associated with shorter overall survival. Higher pretreatment median ktrans (P = 0.021), normalized RCBV (P = 0.0096), and nCBF (P = 0.038) were significantly associated with shorter progression-free survival. SUVpeak [AUC = 0.75; 95% confidence interval (CI), 0.59–0.91], nRCBV (AUC = 0.72; 95% CI, 0.56–0.89), and nCBF (AUC = 0.72; 95% CI, 0.56–0.89) were predictive of survival at 1 year. Conclusions: Increased tumor perfusion, vascular volume, vascular permeability, and hypoxia are negative prognostic markers in newly diagnosed patients with gioblastoma, and these important physiologic markers can be measured safely and reliably using MRI and 18F-FMISO PET. Clin Cancer Res; 22(20); 5079–86. ©2016 AACR.

2024 Background: Tumor hypoxia is a potent mediator of treatment resistance because of the negative impact on the efficacy of radiation and associated poor tumor delivery of cytotoxic chemotherapy....

PurposeMetabolic activity, as defined by F-18-FDG uptake on PET, is a prognostic marker for multiple malignancies; however, no study has examined the prognostic value of imaging with FDG PET in stage I and II pancreatic cancer. We examined the value of PET FDG uptake in early-stage pancreatic cancer patients.MethodsWe identified patients with early-stage pancreatic cancer (I-II) who had FDG PET scan performed as part of their preoperative evaluation. The patients were divided into either high or low FDG uptake according to the median primary tumor standard uptake value (SUVmax). Our primary end points were overall survival (OS) and recurrence-free survival (RFS). Kaplan-Meier estimate was used for survival analysis. Pathologic data were compared using the Fisher exact and chi(2) tests.ResultsOne hundred five patients were identified: 51 patients with low FDG uptake and 54 patients with high FDG uptake. Eighty-five patients (81%) had PET avid tumors, whereas 20 (19%) patients did not. High FDG uptake correlated with pathologic stage (P = 0.012). Patients with low FDG uptake had significantly better median OS than patients with high FDG uptake (28 vs. 16 months; P = 0.036). Patients with low-FDG uptake had significantly longer median RFS than patients with high FDG uptake (14 vs. 12 months; P = 0.049).ConclusionsLow FDG uptake in PET scans in patients with stage I and II pancreatic cancer correlates with improved OS and RFS. This supports the concept that glucose metabolic pathways are important in pancreatic cancer biology and that PET scan activity can be used as a prognostic biomarker after pancreatectomy.

In this study we developed 25 computed tomography descriptors among 117 patients with lung adenocarcinoma to semiquantitatively assess their association with overall survival. Pleural attachment was significantly associated with an increased risk of death and texture was most important for distinguishing histological subtypes. This approach has the potential to support automated analyses and develop decision-support clinical tools.Background: Computed tomography (CT) characteristics derived from noninvasive images that represent the entire tumor might have diagnostic and prognostic value. The purpose of this study was to assess the association of a standardized set of semiquantitative CT characteristics of lung adenocarcinoma with overall survival. Patients and Methods: An initial set of CT descriptors was developed to semiquantitatively assess lung adenocarcinoma in patients (n = 117) who underwent resection. Survival analyses were used to determine the association between each characteristic and overall survival. Principle component analysis (PCA) was used to determine characteristics that might differentiate histological subtypes. Results: Characteristics significantly associated with overall survival included pleural attachment (P < .001), air bronchogram (P = .03), and lymphadenopathy (P = .02). Multivariate analyses revealed pleural attachment was significantly associated with an increased risk of death overall (hazard ratio [HR], 3.21; 95% confidence interval [CI], 1.53-6.70) and among patients with lepidic predominant adenocarcinomas (HR, 5.85; 95% CI, 1.75-19.59), and lymphadenopathy was significantly associated with an increased risk of death among patients with adenocarcinomas without a predominant lepidic component (HR, 3.07; 95% CI, 1.09-8.70). A PCA model showed that texture (ground-glass opacity component) was most important for separating the 2 subtypes. Conclusion: A subset of the semiquantitative characteristics described herein has prognostic importance and provides the ability to distinguish between different histological subtypes of lung adenocarcinoma.

6047 Background: Re-irradiation (Re-RT) is a treatment option for recurrent, previously irradiated head and neck cancers. Nevertheless, most patients will still develop progressive disease after Re-RT. We sought to evaluate the predictive value of metabolic response by 18F-FDG-PET/CT (PET/CT) on the survival after Re-RT. Methods: Patients with locally recurrent squamous cell carcinoma of head and neck treated by Re-RT at our institution during 2005-2012 who had pre- and post-treatment PET/CT were identified. Their scans were re-analyzed by a nuclear medicine physician who was unaware of patient outcome. PET/CT analysis comprised qualitative analysis and measurement of maximum standardized uptake value (SUVmax) as a semi-quantitative index of relative tissue uptake. Complete metabolic response (CR) was defined as resolution of hypermetabolism without new lesion. Results: Fifty-five patients were analyzed: 41 patients (76%) had definitive Re-RT and 13 patients (24%) had adjuvant Re-RT. Median radiation dose delivered was 60 Gy (40-70 Gy). Concurrent chemotherapy was cisplatin in 28, carboplatin in 13, cetuximab in 10, and none in 3 patients. Median pre- and post-treatment SUVmax were 8.5 (range 3.3-18.9) and 4.3 (range 0-15.7), respectively. At a median of 13 weeks after Re-RT, the median metabolic response was 63% (range -80-100%), with 16 patients (30%) achieving CR. Median overall survival was 38.7 months among patients with CR vs. 12.2 months among those without CR (p<0.0001); Median PFS was 29.3 vs. 5.6 months (p<0.0001); and 5-year survival rates were 37% vs. 3%, respectively. Multivariate analysis adjusting for age, duration since previous radiation, comorbidity, organ dysfunction and sum of tumor sizes showed that achieving CR was a strong, independent predictor of survival, Hazard Ratio 5.52 (95% CI: 2.3-13.5). We found no significant difference in the survival of patients with partial metabolic response (≥50% reduction of SUVmax) and those without response. For the prediction of 5-year survival, the negative predictive value of achieving CR by PET/CT was 97%. Conclusions: Failure to achieve a complete metabolic response after Re-RT is highly predictive of disease progression or death.

This study assesses the impact of an automated infusion system (AIS) integration at a positron emission tomography (PET) center based on “lean thinking” principles. The authors propose a systematic measurement system that evaluates improvement in terms of the “8 wastes.” This adaptation to the health care context consisted of performance measurement before and after integration of AIS in terms of time, utilization of resources, amount of materials wasted/saved, system variability, distances traveled, and worker strain. The authors’ observations indicate that AIS stands to be very effective in a busy PET department, such as the one in Moffitt Cancer Center, owing to its accuracy, pace, and reliability, especially after the necessary adjustments are made to reduce or eliminate the source of errors. This integration must be accompanied by a process reengineering exercise to realize the full potential of AIS in reducing waste and improving patient care and worker satisfaction.

Purpose Measurement variance affects the clinical effectiveness of PET-based measurement as a semiquantitative imaging biomarker for cancer response in individual patients and for planning clinical trials. In this study, we measured test-retest reproducibility of SUV measurements under clinical practice conditions and recorded recognized deviations from protocol compliance. Methods Instrument performance calibration, display, and analyses conformed to manufacture recommendations. Baseline clinical 18F-FDG PET/CT examinations were performed and then repeated at 1 to 7 days. Intended scan initiation uptake period was to repeat the examinations at the same time for each study after injection of 12 mCi FDG tracer. Avidity of uptake was measured in 62 tumors in 21 patients as SUV for maximum voxel (SUVmax) and for a mean of sampled tumor voxels (SUVmean). Results The range of SUVmax and SUVmean was 1.07 to 21.47 and 0.91 to 14.69, respectively. Intraclass correlation coefficient between log of SUVmax and log of SUVmean was 0.93 (95% confidence interval [CI], 0.88–0.95) and 0.92 (95% CI, 0.87–0.95), respectively. Correlation analysis failed to show an effect on uptake period variation on SUV measurements between the 2 examinations, suggesting additional sources of noise. The threshold criteria for relative difference from baseline for the 95% CI were ±49% or ±44% for SUVmax or SUVmean, respectively. Conclusions Variance of SUV for FDG-PET/CT in current clinical practice in a single institution was greater than expected when compared with benchmarks reported under stringent efficacy study settings. Under comparable clinical practice conditions, interpretation of changes in tumor avidity in individuals and assumptions in planning clinical trials may be affected.

310 Background: A higher initial metabolic tumor burden is associated with lower median survival in locally advanced pancreatic cancer (LAPC), yet the prognostic utility of PET/CT is not defined in the setting of borderline resectable pancreatic cancer (BRPC). Methods: We performed a retrospectivereview of our institutional experience treating BRPC. Initial staging included endoscopic ultrasound as well as pancreatic protocol CT and PET/CT scans. All patients underwent neoadjuvant gemcitabine-based chemotherapy and radiation therapy (RT). RT was delivered using standard fractionation intensity modulated radiation therapy (IMRT) or stereotactic body radiation therapy (SBRT). Restaging CT and PET/CT scans were obtained approximately 4 weeks following RT completion. We measured the significance of the pre-treatment and post-treatment SUV maximum and metabolic tumor volume (MTV) 2.5 to 5.0, which was defined as the MTV above a threshold SUV of 2.5, 3.0, 4.0 and 5.0. Cox regression models were used to evaluate the significance between these parameters and disease free survival (DFS) and overall survival (OS). Results: We evaluated a total of 72 BRPC patients. Median follow up was 12.7 months. 56 patients (77%) received induction chemotherapy with gemcitabine, docetaxel and capecitabine (GTX). 43 (59.7 %) underwent surgical resection. Significant predictors for OS in the whole cohort included pre-treatment SUV maximum (p=0.0042), post-treatment SUV maximum (p=0.0183), pre-treatment MTV 2.5 (p=0.0016) and pre-treatment MTV 4.0 (p=0.0111). In addition, the difference between the MTV 4.0 pre-treatment and post-treatment was significant (p=0.0285). In patients who underwent surgical resection, there was a significant correlation between OS with pre-treatment SUV max (p=0.0229) and post-treatment SUV maximum (p=0.0325) but not pre-treatment MTV 2.5 (p=0.0654) nor MTV 4.0 (p=0.0928) nor the differences between each variable pre (0.1482) or post-treatment (0.0959). Conclusions: This is the first study to suggest that pre and post treatment PET activity is prognostic for BRPC.

To integrate clinical 3D and 4D PET/CT and radiation treatment planning. In 2009 two 4D PET/CT protocols were standardized for use by Radiation Therapy based on a trial population of 116 4D PET/CT studies. Protocol A acquires the 3D and the 4D PET/CT in the same scan, extending the imaging time of the bed positions over the region of interest. This ROI is post processed separately after the scan is ended. Protocol B uses separate acquisitions for the 3D and the 4D PET/CT. Both scans result in two reconstructions, one for gated data, and one for standard data. Variables such as dose amount (10-15mCi FDG), acquisition times (3–15 minutes per bed), and reconstruction parameters (matrices, filters, bins to phase attenuation, subsets and iterations) have been tested. A committee composed of radiation oncologists, radiologists, physicists and PET technologists meets regularly to review data and technical issues. Over 140 RT patients have been scanned using these 4D PET/CT protocols as of August 1, 2012. Protocol A is best suited for patients who are able to keep their arms overhead for approximately 45 minutes. Many patients have difficulty holding still during this lengthy acquisition. Protocol B results in better patient compliance but requires an extra 25 minutes of scan time for the additional exam. Quantification by imaging physicists may identify reconstruction parameters which can optimize results, and should be carefully considered when structuring the final protocol. Using our standard 3D PET/CT matrices, iterations and subsets for initial reconstruction of the gated 4D PET/CT yielded good visual quality, lowering the FWHM (Gaussian) filter slightly to give a better edge of definition to the ROI by decreasing the smoothing effect on the images prior to binning. Our 3D PET/CT FDG dose is 10mCi, with uptake time of 90 minutes and 2–3 minutes scan time per bed; our 4D PET/CT FDG dose is 13-15mCi for best visualization of 8–10 bins, with uptake time of 60 minutes and 10 minutes per bed. We are currently studying tumor motion as relates to the optimal number of PET and CT bins for XRT use. Our protocols have been successful but challenges remain. Physical characteristics of the patient, varying levels of technologist skill and knowledge of the mechanics of the hardware/software may affect the outcome of the 4D scan. New techniques are in progress that may decrease acquisition and reconstruction times, these will need to be implemented clinically in a manner similar to what has been described. A multidisciplinary team approach is necessary for a thorough understanding and execution of the process, from patient prep through scan acquisition and therapy planning to radiation treatment.

The standard uptake value (SUV), gross tumor volume, and thus the stage of cancer in the thoracic region, are affected by respiratory or cardiac motion. The state of current technology allows tracking of spatial changes using different kinds of respiratory motion management systems in combination with list-mode acquisition. Intuitively, it may seem that the more bins over the respiration period, the more accurate the data. On the contrary, increasing the number of bins (gates) lowers the counting statistics in each bin consequently requiring longer scan times. Moreover, the more bins the longer the processing time; for example, a 10-bin reconstruction can be twice as long as a 6-bin reconstruction. Therefore, the choice of number of bins is important for both accuracy and efficiency. In this study we present a technique to determine the optimal number of bins. Three sinusoidal motion patterns in 3D space were accomplished with peak-to-peak amplitudes of 1.0, 2.0 and 2.4 cm using a custom motion platform. The respiratory period was set to 4.8 s. In order to investigate target size dependency a Jaszczak Phantom™ containing six hollow spheres (0.95 - 3.18 cm inner diameters) was used. The background and the six spheres were filled with 18F-FDG solution to achieve two source-to-background ratios (SBR): 3:1 and 17:1. After the acquisition of 4D PET scans, the data were re-binned into 2, 4, 6, 8, 10, 11, 12 and 13 phased series based on the motion file from the Real-Time Position Management System (RPM, Varian Medical Systems, Inc.). Images were retrospectively reconstructed using the iterative algorithm. The corresponding 4D CT phase was used for attenuation correction for each PET phase. The targets were segmented based on a threshold of 45% of the maximum SUV. The displacement of the center of mass (DCM) between exhalation and inhalation (DEI) was plotted as a function of the number of bins in the reconstruction. The DEI was calculated for each simulated motion and SBR. The DEI increased with the number of gates until it reached a plateau corresponding to the actual value of DCM. For a 1.0 cm motion the DEI reached a plateau at 4 bins, for the 2.0 cm amplitude at 6 bins, and for 2.4 cm amplitude at 8 bins. The behavior of DEI remained the same for different SBR values and different target sizes. The optimal number of bins is a function of the motion amplitude and the scanner resolution. This phantom study shows that the DEI consistently reaches plateau as the number of bins increases. Since increasing the number of bins in the plateau region does not add information about motion, our technique can be used to determine the optimal number of bins. We will apply this technique to human data.

The potential role of integrating 4D PET/CT based volumes into the treatment planning of esophageal cancer patients is not well defined. In our study, we evaluated whether there would be a potential dosimetric photon advantage of treating patients with maximum inhale vs. exhale technique.

Purpose: Texture/feature analysis of PET/CT images has great potential for predicting/monitoring tumor/normal tissue response to therapy, quantifying tumor spatiotemporal heterogeneity and radiosensitivity, and as indicators for adaptive therapy schemes. The objective of this study was to define a baseline and determine candidate texture/feature parameters. To this end, we performed image analysis on three dimensional (3D) and four dimensional (4D) PET/CT images of non‐small cell lung cancer patients. The ultimate goal is the development of radiomics tools for application in radiotherapy. Methods: All 4D‐PET data were reconstructed in 10 bins using the corresponding phases in 4D‐CT for attenuation correction. Co‐occurrence matrices of the tumor volumes were generated based on 3D and 4D PET images for 8 lung cancer patients. The texture parameters that were extracted from the original images or the co‐occurrence matrices included: entropy, local homogeneity, contrast, energy, V10‐V90, V80, V70, V40, I10‐I90, I30, Coefficient Variation, SD, Mean Intensity, Maximum Intensity, Minimum Intensity, and number of voxels. Texture comparisons between 3D and 4D PET and CT images and between various phases of 4D scans were performed. Results: A weak dependency of all the tested texture parameters on respiration phase was found for the 4D‐PET data for all patients, while large differences in some textures were found between the 3D‐PET or CT and one of the phases of the corresponding 4D data set, with larger percentage differences for the CT images. The differences for PET varied from 25% to 900%. Conclusion: Motion due to breathing altered statistical information obtained from intensity distributions from PET images, consequently 4D‐PET features were significantly different than 3D‐PET features. Texture parameters show minimal dependency on phase. PET images from one of the phases of a 4D‐PET with its corresponding 4D‐CT for attenuation correction are useful for texture analysis.

To determine if the spatial and statistical properties of Positron Emission Tomography (PET) image texture would differ between lung tumors with a necrotic core and non-necrotic tumors.

2629 Objectives To deliver a reliable 4D-PET/CT imaging protocol and integrate with clinical PET/CT radiation treatment planning. Methods A trial population of 107 patients resulted in 116 individual studies during an 18 month period spanning 2008-2009. For each scan, there were approximately 3 hours of technologist time which led to additional robotic test time and protocol refining. There were more than 21 trial versions tested. In 2009 the first patients were treated using integrated 4D-PET/CT data. In 2010 several 4D-PET/CT protocols were standardized for use by Radiation Therapy. Over 100 patients (excluding trial population) have been scanned using 4D-PET/CT protocols as of Dec. 2011. Results 4D-PET/CT images greatly improve the delineation of tumor vs normal tissue for radiation treatment planning thus allowing radiation oncologists to better target tumor while limiting dose to normal tissue. Conclusions Standard imaging (2D or 3D) does not adequately represent moving tumors in lung, esophagus, liver, pancreas or other disease sites that may be strongly affected by respiration. Respiratory motion may cause a tumor to appear larger, to have greater depth, appear to encompass a vital blood supply or encroach upon a critical organ; small tumors/nodes may be lost in background signal. Consequently, motion may significantly alter SUV values. Assessment of tumor/organ motion may impact tumor staging and radiation treatment plan design. Technical aspects such as patient positioning, body habitus, and variable breathing patterns are challenges. Patient discomfort, non-respiratory patient movements and technical errors are obstacles. Practice is crucial. Mechanical errors may occur and troubleshooting knowledge of the various hardware components is essential

Objective/Background: There is a high risk of relapse in stage IIIB/IIIC melanoma. The utility of 2-[fluorine-18]-fluoro-2-deoxy-D-glucose positron emission tomography integrated with computed tomography (FDG-PET/CT) in these patients to evaluate response to treatment or for surveillance after treatment is currently not well defined.Methods: Prospective data from 2 centers identified 97 patients with stage IIIB/IIIC extremity melanoma undergoing isolated limb infusion (ILI) who had whole body FDG-PET/CT scans before and every 3 months after treatment. Clinical response was determined at 3 months by Response Evaluation Criteria In Solid Tumors.Results: Complete response (CR) after ILI occurred in 33% (32/97) of patients. FDG-PET/CT accurately identified 59% of patients who were CRs (19/32), whereas 41% (13/32) had residual metabolic activity in the extremity that was histologically negative for melanoma. The 3-year disease-free rate was 62.2% (95% CI: 40.1%-96.4%) for those patients who were CRs by both clinical/pathologic examination and FDG-PET/CT (n = 19) compared to only 29.4% (95% CI: 9.9%-87.2%) of those CRs who still had residual FDG-PET/CT activity (n = 13). FDG-PET/CT was utilized for surveillance of disease recurrence outside the regional field of treatment. Fifty-two percent (51/97) of patients developed disease outside the extremity at a median time of 212 days from pre-ILI FDG-PET/CT. In 47% (29/62) of these cases, the recurrence was resected.Conclusions: Although FDG-PET/CT does not appear to accurately identify patients who appear to be CRs to ILI, it does appear to identify a subgroup of patients whose regional progression-free survival is markedly worse. However, FDG-PET/CT appears to be an excellent method for surveillance in stage IIIB/IIIC patients after ILI with ability to identify surgically resectable recurrent disease in these high-risk patients.

Quantitative imaging using computed tomography, magnetic resonance imaging and positron emission tomography modalities will play an increasingly important role in the design of oncology trials addressing molecularly targeted, personalized therapies. The advent of molecularly targeted therapies, exemplified by antiangiogenic drugs, creates new complexities in the assessment of response. The Quantitative Imaging Network addresses the need for imaging modalities which can accurately and reproducibly measure not just change in tumor size but changes in relevant metabolic parameters, modulation of relevant signaling pathways, drug delivery to tumor and differentiation of apoptotic cell death from other changes in tumor volume. This article provides an overview of the applications of quantitative imaging to phase 0 through phase 3 oncology trials. We describe the use of a range of quantitative imaging modalities in specific tumor types including malignant gliomas, lung cancer, head and neck cancer, lymphoma, breast cancer, prostate cancer and sarcoma. In the concluding section, we discuss potential constraints on clinical trials using quantitative imaging, including complexity of trial conduct, impact on subject recruitment, incremental costs and institutional barriers. Strategies for overcoming these constraints are presented.

Objectives Partial volume effects in PET can lead to over-or under-estimation of tumor volumes depending on the local activity. This work investigates the extent of over-or under-estimation.Methods A Jaszczak phantom with hollow spheres of various sizes (0.9 mm-31mm diameter) was filled with F-18 water using 3 different sphere-to background ratios (SBR), ranging from 3.5: 1 to 10: 1. Background was 0.07 mCi/Kg approximating the average activity in a radiation oncology patient at the time of imaging. For each SBR, a single acquisition PET/CT was performed and the RAW data were reconstructed by using OSEM with 32 subsets with 2 iterations, then varying the FWHM of the Gaussian Blurring filter from 5-8 mm, and using image matrix sizes of 128 X 128, 192 X 192 and 256 X 256. Regions were automatically segmented based on a clinically used SBR threshold of 2.5, and then the threshold was varied to be …