Correction: Quantitative Computed Tomographic Descriptors Associate Tumor Shape Complexity and Intratumor Heterogeneity with Prognosis in Lung Adenocarcinoma.

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

ACRIN 6684: Assessment of Tumor Hypoxia in Newly Diagnosed Glioblastoma Using 18F-FMISO PET and MRI.

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.

Metabolic Activity by 18F-FDG-PET/CT Is Prognostic for Stage I and II Pancreatic Cancer.

PURPOSE: Metabolic activity, as defined by F-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. METHODS: We 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 χ tests. RESULTS: One 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). CONCLUSIONS: Low 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.

Semiquantitative Computed Tomography Characteristics for Lung Adenocarcinoma and Their Association With Lung Cancer Survival.

UNLABELLED: 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.

Quantitative computed tomographic descriptors associate tumor shape complexity and intratumor heterogeneity with prognosis in lung adenocarcinoma.

Two CT features were developed to quantitatively describe lung adenocarcinomas by scoring tumor shape complexity (feature 1: convexity) and intratumor density variation (feature 2: entropy ratio) in routinely obtained diagnostic CT scans. The developed quantitative features were analyzed in two independent cohorts (cohort 1: n = 61; cohort 2: n = 47) of patients diagnosed with primary lung adenocarcinoma, retrospectively curated to include imaging and clinical data. Preoperative chest CTs were segmented semi-automatically. Segmented tumor regions were further subdivided into core and boundary sub-regions, to quantify intensity variations across the tumor. Reproducibility of the features was evaluated in an independent test-retest dataset of 32 patients. The proposed metrics showed high degree of reproducibility in a repeated experiment (concordance, CCC≥0.897; dynamic range, DR≥0.92). Association with overall survival was evaluated by Cox proportional hazard regression, Kaplan-Meier survival curves, and the log-rank test. Both features were associated with overall survival (convexity: p = 0.008; entropy ratio: p = 0.04) in Cohort 1 but not in Cohort 2 (convexity: p = 0.7; entropy ratio: p = 0.8). In both cohorts, these features were found to be descriptive and demonstrated the link between imaging characteristics and patient survival in lung adenocarcinoma.

Technology integration performance assessment using lean principles in health care.

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.

Variance of SUVs for FDG-PET/CT is greater in clinical practice than under ideal study settings.

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 (18)F-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 (SUV(max)) and for a mean of sampled tumor voxels (SUV(mean)). RESULTS: The range of SUV(max) and SUV(mean) was 1.07 to 21.47 and 0.91 to 14.69, respectively. Intraclass correlation coefficient between log of SUV(max) and log of SUV(mean) 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 SUV(max) or SUV(mean), 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.

Promise and pitfalls of quantitative imaging in oncology clinical trials.

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.

A multicenter prospective evaluation of the clinical utility of F-18 FDG-PET/CT in patients with AJCC stage IIIB or IIIC extremity melanoma.

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.

Negative predictive value of positron emission tomography/computed tomography in patients with a clinical suspicion of pancreatic cancer.

OBJECTIVES: The aim of this study was to determine the negative predictive value of positron emission tomography (PET)/computed tomography (CT) in patients with lesions suggestive of pancreatic cancer. METHODS: A retrospective review from January 2005 to August 2008 of all patients who underwent a PET/CT to evaluate a lesion suggestive of pancreatic cancer based on prior imaging. One hundred eighty-four patients underwent PET/CT, of which 60 patients had a negative PET scan. Of these 60 patients, 56 patients (30 women, 26 men) had endoscopic ultrasound-guided fine-needle aspiration or surgical pathology for clinical correlation. The Fisher exact test was used for statistical analysis. RESULTS: The negative predictive value of PET/CT was 75%. Eighteen patients had a benign lesion, 24 patients had a premalignant lesion, and 14 patients had a malignant lesion. In the cystic group, 72.4% of the PET/CT-negative lesions were premalignant compared with the solid group that was only 5.9%. This was in contrast to the solid group, where 64.7% was malignant versus 6.9% in the cystic group. Two of 14 patients with malignancy had metastatic disease. CONCLUSIONS: The negative predictive value of PET/CT in pancreatic lesions suggestive of pancreatic cancer was 75%. A negative PET/CT does not exclude pancreatic cancer, and further workup of these PET-negative lesions is warranted.

Computed tomography response, but not positron emission tomography scan response, predicts survival after neoadjuvant chemotherapy for resectable non-small-cell lung cancer.

PURPOSE: Tumor response is considered a surrogate marker of survival. We investigated whether tumor response based on computed tomography (CT) scan or whole-body [(18)F]fluorodeoxyglucose positron emission tomography (PET) scan after neoadjuvant chemotherapy for resectable non-small-cell lung cancer (NSCLC) is prognostic of survival. PATIENTS AND METHODS: Two consecutive phase II clinical trials were jointly analyzed. Patients underwent CT and PET scans before and after completion of neoadjuvant chemotherapy, followed by surgery. RESULTS: Eighty-nine patients were included. Patients with a partial or complete response based on Response Evaluation Criteria in Solid Tumors categories (n = 33) had a better overall survival than those with stable or progressive disease (n = 56; median survival time, not reached v 36 months, respectively; P = .04). Of all patients, those with response in the highest quartile had 1- and 2-year survival rates of 100% and 81%, respectively, compared with 77% and 61%, respectively, among patients in the lowest quartile. However, on the basis of visual analysis of PET scan, patients with a metabolic response (n = 28) had no significant difference in survival compared with patients without response (n = 61; median survival time, 35.6 months v not reached, respectively; P = .94). In addition, on the basis of a semiquantitative analysis of PET scan, using at least 30% reduction in tumor metabolism as a response (n = 59), we also found no significant difference in survival among those with or without response. CONCLUSION: Among patients with resectable NSCLC treated with neoadjuvant chemotherapy, we found no evidence that tumor response by PET scan after chemotherapy is prognostic of survival; however, response by CT scan was associated with better survival.

PET/CT fusion scan enhances CT staging in patients with pancreatic neoplasms.

BACKGROUND: The role of fusion positron emission tomography/computed tomography scans (PET/CT) in staging of patients with pancreatic neoplasms (PN) is poorly defined. PET/CT may serve as an adjunct to standard imaging by increasing occult metastases detection. The purpose of this study was to assess the additional value, in relation to computed tomography (CT), of PET/CT imaging for patients with PN. METHODS: Eighty-two patients with potentially resectable PN underwent staging with PET/CT and CT of the chest and abdomen. Sensitivity of diagnosing pancreatic cancer by PET/CT avidity was evaluated. The sensitivity of detecting metastases was compared between PET/CT, standard CT, and the combination of PET/CT and CT. The impact of PET/CT on patient management was estimated by calculating the percentage of patients whose treatment plan was altered due to PET/CT. RESULTS: The sensitivity and specificity of PET/CT in diagnosing pancreatic cancer were 89% and 88%, respectively. Sensitivity of detecting metastatic disease for PET/CT alone, standard CT alone, and the combination of PET/CT and CT were 61%, 57%, and 87%, respectively. Findings on PET/CT influenced the clinical management in seven patients (11%), two with a supraclavicular lymph node (LN), two occult liver lesions, two peritoneal implants, and one peri-esophageal LN. CONCLUSION: This study evaluated PET/CT in the initial work-up of patients with PN. PET/CT increased sensitivity (87%) for detection of metastatic disease when combined with standard CT. In invasive cancer, PET/CT changed the management in 11% of our patients. PET/CT should be considered in the initial work-up of patients with potentially resectable pancreatic lesions.

Computer-aided mass detection based on ipsilateral multiview mammograms.

RATIONALE AND OBJECTIVES: Recent reports on advances in computer-aided detection (CAD) indicate that current schemes miss early-stage breast cancers and result in a relatively large false-positive detection rate in order to achieve a high sensitivity rate for mass detection. This paper is inspired by the interpretation procedure from mammographers. The abnormal diagnosis can be derived from multiple views but is not available through single-view image analysis. MATERIALS AND METHODS: A new multiview CAD system for early-stage breast cancer detection, which is based on modifying the optimized CAD algorithms from our prior single-view CAD system for constructing an adaptive ipsilateral multiview concurrent CAD system, is presented in this paper. The selection and design for the training and testing ipsilateral multiview mammogram databases are described here. RESULTS: The performance evaluation of the developed ipsilateral multiview CAD system using free-response receiver operating characteristic analysis and computerized receiver operating characteristic experiments are presented. The results indicated that the proposed multiview CAD system is significantly superior to the single-view CAD systems based on statistically standard P-values. CONCLUSION: This paper addresses a very important and timely project. It is related to two main problems regarding the development of breast cancer detection and diagnosis: early-stage detection and diagnosis of breast cancer with digital mammogram, and overall improvement of CAD system performance for clinical implementation. In order to improve the efficacy, accuracy, and efficiency of the current CAD scheme, an entirely new class of CAD method is required. This paper is unique in that a comprehensive and state-of-the-art approach is proposed for the CAD scheme of digital mammography. From the design aspect of the CAD scheme, the proposed ipsilateral multiview CAD method is innovative and quite different from current single-view CAD methods.

Analysis of a mammography teaching program based on an affordance design model.

RATIONALE AND OBJECTIVES: The wide use of computer technology in education, particularly in mammogram reading, asks for e-learning evaluation. The existing media comparative studies, learner attitude evaluations, and performance tests are problematic. Based on an affordance design model, this study examined an existing e-learning program on mammogram reading. MATERIALS AND METHODS: The selection criteria include content relatedness, representativeness, e-learning orientation, image quality, program completeness, and accessibility. A case study was conducted to examine the affordance features, functions, and presentations of the selected software. Data collection and analysis methods include interviews, protocol-based document analysis, and usability tests and inspection. Also some statistics were calculated. RESULTS: The examination of PBE identified that this educational software designed and programmed some tools. The learner can use these tools in the process of optimizing displays, scanning images, comparing different projections, marking the region of interests, constructing a descriptive report, assessing one's learning outcomes, and comparing one's decisions with the experts' decisions. Further, PBE provides some resources for the learner to construct one's knowledge and skills, including a categorized image library, a term-searching function, and some teaching links. Besides, users found it easy to navigate and carry out tasks. The users also reacted positively toward PBE's navigation system, instructional aids, layout, pace and flow of information, graphics, and other presentation design. CONCLUSION: The software provides learners with some cognitive tools, supporting their perceptual problem-solving processes and extending their capabilities. Learners can internalize the mental models in mammogram reading through multiple perceptual triangulations, sensitization of related features, semantic description of mammogram findings, and expert-guided semantic report construction. The design of these cognitive tools and the software interface matches the findings and principles in human learning and instructional design. Working with PBE's case-based simulations and categorized gallery, learners can enrich and transfer their experience to their jobs.

Acute and chronic aortic dissection.

Each year acute aortic dissection is diagnosed in 2,000 individuals in the United States. Acute aortic dissection is no longer a catastrophic event because this problem can be rapidly diagnosed with current medical technology, and therefore promptly treated with medication and surgery. Consequently, patients with aortic dissection can survive for 10 to 20 or more years after the initial event. However, there is considerable current debate regarding the most optimal technique(s) for the diagnosis of aortic dissection. Moreover, little information is available on the best methods for the long-term assessment and treatment of patients who have been successfully treated for acute aortic dissection. This report reviews the current techniques that are available for the diagnosis of aortic dissection and discusses the important issues regarding the acute and long-term treatment of patients with this problem.