Integrated Biomarkers for the Management of Indeterminate Pulmonary Nodules.

Rationale: Patients with indeterminate pulmonary nodules (IPNs) at risk of cancer undergo high rates of invasive, costly, and morbid procedures. Objectives: To train and externally validate a risk prediction model that combined clinical, blood, and imaging biomarkers to improve the noninvasive management of IPNs. Methods: In this prospectively collected, retrospective blinded evaluation study, probability of cancer was calculated for 456 patient nodules using the Mayo Clinic model, and patients were categorized into low-, intermediate-, and high-risk groups. A combined biomarker model (CBM) including clinical variables, serum high sensitivity CYFRA 21-1 level, and a radiomic signature was trained in cohort 1 (n = 170) and validated in cohorts 2-4 (total n = 286). All patients were pooled to recalibrate the model for clinical implementation. The clinical utility of the CBM compared with current clinical care was evaluated in 2 cohorts. Measurements and Main Results: The CBM provided improved diagnostic accuracy over the Mayo Clinic model with an improvement in area under the curve of 0.124 (95% bootstrap confidence interval, 0.091-0.156; P < 2 × 10-16). Applying 10% and 70% risk thresholds resulted in a bias-corrected clinical reclassification index for cases and control subjects of 0.15 and 0.12, respectively. A clinical utility analysis of patient medical records estimated that a CBM-guided strategy would have reduced invasive procedures from 62.9% to 50.6% in the intermediate-risk benign population and shortened the median time to diagnosis of cancer from 60 to 21 days in intermediate-risk cancers. Conclusions: Integration of clinical, blood, and image biomarkers improves noninvasive diagnosis of patients with IPNs, potentially reducing the rate of unnecessary invasive procedures while shortening the time to diagnosis.

Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging.

Activated brown adipose tissue (BAT) plays an important role in thermogenesis and whole body metabolism in mammals. Positron emission tomography (PET)-computed tomography (CT) imaging has identified depots of BAT in adult humans, igniting scientific interest. The purpose of this study is to characterize both active and inactive supraclavicular BAT in adults and compare the values to those of subcutaneous white adipose tissue (WAT). We obtained [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET-CT and magnetic resonance imaging (MRI) scans of 25 healthy adults. Unlike [(18)F]FDG PET, which can detect only active BAT, MRI is capable of detecting both active and inactive BAT. The MRI-derived fat signal fraction (FSF) of active BAT was significantly lower than that of inactive BAT (means ± SD; 60.2 ± 7.6 vs. 62.4 ± 6.8%, respectively). This change in tissue morphology was also reflected as a significant increase in Hounsfield units (HU; -69.4 ± 11.5 vs. -74.5 ± 9.7 HU, respectively). Additionally, the CT HU, MRI FSF, and MRI R2* values are significantly different between BAT and WAT, regardless of the activation status of BAT. To the best of our knowledge, this is the first study to quantify PET-CT and MRI FSF measurements and utilize a semiautomated algorithm to identify inactive and active BAT in the same adult subjects. Our findings support the use of these metrics to characterize and distinguish between BAT and WAT and lay the foundation for future MRI analysis with the hope that some day MRI-based delineation of BAT can stand on its own.

Accuracy of FDG-PET to diagnose lung cancer in areas with infectious lung disease: a meta-analysis.

IMPORTANCE: Positron emission tomography (PET) combined with fludeoxyglucose F 18 (FDG) is recommended for the noninvasive diagnosis of pulmonary nodules suspicious for lung cancer. In populations with endemic infectious lung disease, FDG-PET may not accurately identify malignant lesions. OBJECTIVES: To estimate the diagnostic accuracy of FDG-PET for pulmonary nodules suspicious for lung cancer in regions where infectious lung disease is endemic and compare the test accuracy in regions where infectious lung disease is rare. DATA SOURCES AND STUDY SELECTION: Databases of MEDLINE, EMBASE, and the Web of Science were searched from October 1, 2000, through April 28, 2014. Articles reporting information sufficient to calculate sensitivity and specificity of FDG-PET to diagnose lung cancer were included. Only studies that enrolled more than 10 participants with benign and malignant lesions were included. Database searches yielded 1923 articles, of which 257 were assessed for eligibility. Seventy studies were included in the analysis. Studies reported on a total of 8511 nodules; 5105 (60%) were malignant. DATA EXTRACTION AND SYNTHESIS: Abstracts meeting eligibility criteria were collected by a research librarian and reviewed by 2 independent reviewers. Hierarchical summary receiver operating characteristic curves were constructed. A random-effects logistic regression model was used to summarize and assess the effect of endemic infectious lung disease on test performance. MAIN OUTCOME AND MEASURES: The sensitivity and specificity for FDG-PET test performance. RESULTS: Heterogeneity for sensitivity (I2 = 87%) and specificity (I2 = 82%) was observed across studies. The pooled (unadjusted) sensitivity was 89% (95% CI, 86%-91%) and specificity was 75% (95% CI, 71%-79%). There was a 16% lower average adjusted specificity in regions with endemic infectious lung disease (61% [95% CI, 49%-72%]) compared with nonendemic regions (77% [95% CI, 73%-80%]). Lower specificity was observed when the analysis was limited to rigorously conducted and well-controlled studies. In general, sensitivity did not change appreciably by endemic infection status, even after adjusting for relevant factors. CONCLUSIONS AND RELEVANCE: The accuracy of FDG-PET for diagnosing lung nodules was extremely heterogeneous. Use of FDG-PET combined with computed tomography was less specific in diagnosing malignancy in populations with endemic infectious lung disease compared with nonendemic regions. These data do not support the use of FDG-PET to diagnose lung cancer in endemic regions unless an institution achieves test performance accuracy similar to that found in nonendemic regions.

18F-FSPG PET imaging for the evaluation of indeterminate pulmonary nodules.

BACKGROUND: 18F-fluorodeoxyglucose (FDG) PET/CT is recommended for evaluation of intermediate-risk indeterminate pulmonary nodules (IPNs). While highly sensitive, the specificity of FDG remains suboptimal for differentiating malignant from benign nodules, particularly in areas where fungal lung diseases are prevalent. Thus, a cancer-specific imaging probe is greatly needed. In this study, we tested the hypothesis that a PET radiotracer (S)-4-(3-[18F]-fluoropropyl)-L-glutamic acid (FSPG) improves the diagnostic accuracy of IPNs compared to 18F-FDG PET/CT. METHODS: This study was conducted at a major academic medical center and an affiliated VA medical center. Twenty-six patients with newly discovered IPNs 7-30mm diameter or newly diagnosed lung cancer completed serial PET/CT scans utilizing 18F-FDG and 18F-FSPG, without intervening treatment of the lesion. The scans were independently reviewed by two dual-trained diagnostic radiology and nuclear medicine physicians. Characteristics evaluated included quantitative SUVmax values of the pulmonary nodules and metastases. RESULTS: A total of 17 out of 26 patients had cancer and 9 had benign lesions. 18F-FSPG was negative in 6 of 9 benign lesions compared to 7 of 9 with 18F-FDG. 18F-FSPG and 18F-FDG were positive in 14 of 17 and 12 of 17 malignant lesions, respectively. 18F-FSPG detected brain and intracardiac metastases missed by 18F-FDG PET in one case, while 18F-FDG detected a metastasis to the kidney missed by 18F-FSPG. CONCLUSION: In this pilot study, there was no significant difference in overall diagnostic accuracy between 18F-FSPG and 18F-FDG for the evaluation of IPNs and staging of lung cancer. Additional studies will be needed to determine the clinical utility of this tracer in the management of IPNs and lung cancer.

Establishing a Cohort and a Biorepository to Identify Biomarkers for Early Detection of Lung Cancer: The Nashville Lung Cancer Screening Trial Cohort.

Rationale: A prospective longitudinal cohort of individuals at high risk of developing lung cancer was established to build a biorepository of carefully annotated biological specimens and low-dose computed tomography (LDCT) chest images for derivation and validation of candidate biomarkers for early detection of lung cancer.Objectives: The goal of this study is to characterize individuals with high risk for lung cancer, accumulating valuable biospecimens and LDCT chest scans longitudinally over 5 years.Methods: Participants 55-80 years of age with a 5-year estimated risk of developing lung cancer >1.5% were recruited and enrolled from clinics at the Vanderbilt University Medical Center, Veteran Affairs Medical Center, and Meharry Medical Center. Individual demographic characteristics were assessed via questionnaire at baseline. Participants underwent an LDCT scan, spirometry, sputum cytology, and research bronchoscopy at the time of enrollment. Participants will be followed yearly for 5 years. Positive LDCT scans are followed-up according to standard of care. The clinical, imaging, and biospecimen data are collected prospectively and stored in a biorepository. Participants are offered smoking cessation counseling at each study visit.Results: A total of 480 participants were enrolled at study baseline and consented to sharing their data and biospecimens for research. Participants are followed with yearly clinic visits to collect imaging data and biospecimens. To date, a total of 19 cancers (13 adenocarcinomas, four squamous cell carcinomas, one large cell neuroendocrine, and one small-cell lung cancer) have been identified.Conclusions: We established a unique prospective cohort of individuals at high risk for lung cancer, enrolled at three institutions, for whom full clinical data, well-annotated LDCT scans, and biospecimens are being collected longitudinally. This repository will allow for the derivation and independent validation of clinical, imaging, and molecular biomarkers of risk for diagnosis of lung cancer.Clinical trial registered with ClinicalTrials.gov (NCT01475500).

Accuracy of a Novel Histoplasmosis Enzyme Immunoassay to Evaluate Suspicious Lung Nodules.

BACKGROUND: Granulomas caused by infectious lung diseases present as indeterminate pulmonary nodules (IPNs) on radiography. Newly available serum enzyme immunoassay (EIA) for histoplasmosis has not been studied for the evaluation of IPNs. We investigated serum biomarkers of histoplasmosis antibodies as an indication of benign disease in IPNs from a highly endemic region. METHODS: A total of 152 serum samples from patients presenting with pulmonary nodules ≤30 mm in maximum diameter were analyzed for histoplasmosis antibodies by immunodiffusion and EIA IgG and IgM tests. Serology and FDG-PET/CT scan diagnostic test characteristics were estimated and compared. RESULTS: Cancer prevalence was 55% (n = 83). Thirty-nine (26%) individuals were positive for IgG histoplasmosis antibodies. Twelve samples were IgM antibody positive. Immunodiffusion serology was similar to IgM antibody results with 13 positive tests. Diagnostic likelihood ratios for benign disease were 0.62, 0.33, and 0.28 for FDG-PET/CT, IgG, and IgM antibodies, respectively. When both IgG and IgM were positive (n = 8), no nodules were cancerous and six were FDG-PET/CT avid. CONCLUSIONS: A positive EIA test for both IgM and IgG strongly suggested histoplasmosis etiology and benign granuloma for 12% of benign nodules arising from a highly endemic region. Presence of either IgG or IgM histoplasma antibodies was associated with benign disease. The EIA test was more sensitive in assessing histoplasma exposure than immunodiffusion serology. IMPACT: A new CLIA-certified histoplasmosis antibody EIA test measures histoplasmosis exposure, offers a possible alternative clinical diagnosis for benign IPNs, and may improve IPN evaluation while avoiding harmful invasive biopsies.

To Use or Not to Use 131I in Thyroid Cancer.

PURPOSE: The purpose of the following commentary is to discuss recent controversies in the use of radioactive iodine for differentiated thyroid cancer (DTC). METHODS: R. M. Tuttle (Thyroid 2010; 20:257-263), at Memorial Sloan Kettering Cancer Center, has enumerated the well-accepted goals of radioactive iodine therapy (RAIT) in DTC: (1) ablate residual thyroid to facilitate future surveillance, (2) "adjuvant therapy" for residual radioactive iodine-avid disease, and (3) a post-RAIT scan may reveal unknown local and/or distant metastases. Using these goals as a guide, the authors have critically reviewed a recent movement to decrease the use of RAIT in DTC that is being advocated by some investigators. RESULTS: As a result, a recent article has highlighted this new treatment philosophy. A 2017 publication in the Journal of Clinical Oncology (Molenaar et al, 2017 0:JCO.2017.75.0232) recommends that RAIT not be used in low- or intermediate-risk DTC. In this article, the authors claim that the RAIT risks in DTC, particularly leukemia, outweigh its potential benefits. This change, if adopted, in our opinion will have profound deleterious consequences on patient outcomes. We also have identified a major problem with the article of Molenaar et al. The authors use the American Thyroid Association's criteria for staging thyroid cancer. In our opinion, this method of staging is severely flawed. We also quantitatively compare the article's alleged risk of RAIT-induced leukemia with the benefits of RAIT for DTC. CONCLUSIONS: In summary, this matter must be debated before eliminating RAIT in low- or intermediate-risk DTC. If RAIT is eliminated for these patients, many such patients will no longer benefit from the RAIT goals listed by R. M. Tuttle, including the critical advantage of potentially improved overall and event-free survival.

ACR Practice Parameter for the Performance of Gallium-68 DOTATATE PET/CT for Neuroendocrine Tumors.

Radiopharmaceuticals targeting cell surface expression of somatostatin receptors (SSTRs) are particularly useful in the evaluation of neuroendocrine tumors. Gallium-68 DOTA-Tyr-octreotatate (Ga-DOTATATE) primarily binds to SSTR type 2 receptors. Ga DOTATATE PET/CT is proven to have high impact on the management of neuroendocrine patients compared to traditional anatomical imaging as well as provides additional information over that of conventional nuclear medicine studies (indium-III DTPA-octreotide). It can result in change in management of approximately 75% of patients with neuroendocrine tumors. Ga DOTATATE and F FDG PET/CT imaging are complementary, with the degree of uptake varying depending on the degree of differentiation of the tumor. Well-differentiated tumors maintain their SSTRs and are positive on Ga DOTATATE PET/CT scan, while dedifferentiated tumors are less likely to demonstrate uptake of Ga DOTATATE but will demonstrate uptake with F FDG PET/CT. In addition, Ga DOTATATE PET/CT identifies patients with SSTR expression in their tumors, who have progressed on somatostatin analog therapy, for treatment with Lu DOTATATE.

Intracardiac Metastases Detected by 18F-FSPG PET/CT.

PET/CT imaging is frequently used for cancer diagnosis and restaging as metabolically active cells, including cancer, utilize glucose for proliferation. F-FDG is the most commonly utilized radiopharmaceutical in PET/CT imaging. Limitations of F-FDG imaging include intense physiologic uptake in benign tissues such as the brain and myocardium. We present a case of non-small cell lung cancer with myocardial and pericardial metastases obscured by physiologic F-FDG cardiac uptake but detected with the investigational PET radiotracer (4S)-4-(3-F-fluoropropyl)-L-glutamate (F-FSPG), which targets a pathway associated with glutathione biosynthesis. This case demonstrates the added value of F-FSPG PET/CT imaging.

Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases.

Heparanase is an enzyme that cleaves heparan sulfate and through this activity promotes tumor growth, angiogenesis, invasion, and metastasis in several tumor types. In human breast cancer patients, heparanase expression is associated with sentinel lymph node metastases. However, the precise role of heparanase in the malignant progression of breast cancer is unknown. To examine this, a variant of MDA-MB-231 cells was transfected with the cDNA for human heparanase (HPSE cells) or with vector alone as a control (NEO cells). Transfection produced a 6-fold increase in heparanase activity in HPSE cells relative to NEO cells. When injected into the mammary fat pads of severe combined immunodeficient mice, the tumors formed by HPSE cells initially grow significantly faster than the tumors formed by NEO cells. The rapid growth is due in part to increased angiogenesis, as microvessel densities are substantially elevated in primary HPSE tumors compared with NEO tumors. Although metastases to bones are not detected, surprisingly vigorous bone resorption is stimulated in animals bearing tumors formed by the HPSE cells. These animals have high serum levels of the C-telopeptide derived from type I collagen as well as significant elevation of the active form of tartrate-resistant acid phosphatase (TRAP)-5b. In contrast, in animals having a high tumor burden of Neo cells, the serum levels of C-telopeptide and TRAP-5b never increase above the levels found before tumor injection. Consistent with these findings, histologic analysis for TRAP-expressing cells reveals extensive osteoclastogenesis in animals harboring HPSE tumors. In vitro osteoclastogenesis assays show that the osteoclastogenic activity of HPSE cell conditioned medium is significantly enhanced beyond that of NEO conditioned medium. This confirms that a soluble factor or factors that stimulate osteoclastogenesis are specifically produced when heparanase expression is elevated. These factors exert a distal effect resulting in resorption of bone and the accompanying enrichment of the bone microenvironment with growth-promoting factors that may nurture the growth of metastatic tumor cells. This novel role for heparanase as a promoter of osteolysis before tumor metastasis suggests that therapies designed to block heparanase function may disrupt the early progression of bone-homing tumors.

Radiological Image Traits Predictive of Cancer Status in Pulmonary Nodules.

Purpose: We propose a systematic methodology to quantify incidentally identified pulmonary nodules based on observed radiological traits (semantics) quantified on a point scale and a machine-learning method using these data to predict cancer status.Experimental Design: We investigated 172 patients who had low-dose CT images, with 102 and 70 patients grouped into training and validation cohorts, respectively. On the images, 24 radiological traits were systematically scored and a linear classifier was built to relate the traits to malignant status. The model was formed both with and without size descriptors to remove bias due to nodule size. The multivariate pairs formed on the training set were tested on an independent validation data set to evaluate their performance.Results: The best 4-feature set that included a size measurement (set 1), was short axis, contour, concavity, and texture, which had an area under the receiver operator characteristic curve (AUROC) of 0.88 (accuracy = 81%, sensitivity = 76.2%, specificity = 91.7%). If size measures were excluded, the four best features (set 2) were location, fissure attachment, lobulation, and spiculation, which had an AUROC of 0.83 (accuracy = 73.2%, sensitivity = 73.8%, specificity = 81.7%) in predicting malignancy in primary nodules. The validation test AUROC was 0.8 (accuracy = 74.3%, sensitivity = 66.7%, specificity = 75.6%) and 0.74 (accuracy = 71.4%, sensitivity = 61.9%, specificity = 75.5%) for sets 1 and 2, respectively.Conclusions: Radiological image traits are useful in predicting malignancy in lung nodules. These semantic traits can be used in combination with size-based measures to enhance prediction accuracy and reduce false-positives. Clin Cancer Res; 23(6); 1442-9. ©2016 AACR.

Avascular necrosis of femoral and/or humeral heads in multiple myeloma: results of a prospective study of patients treated with dexamethasone-based regimens and high-dose chemotherapy.

PURPOSE: To assess the prevalence, time of onset, risk factors, and outcome of avascular necrosis (AVN) of bone in patients with multiple myeloma undergoing antineoplastic therapy. PATIENTS AND METHODS: A total of 553 consecutive assessable patients were enrolled onto a treatment protocol consisting of dexamethasone-containing induction chemotherapy, autologous stem-cell transplantation, consolidation chemotherapy, and maintenance with interferon alfa. Patients were randomly assigned to receive thalidomide (269 patients) or no thalidomide (284 patients) throughout the study period. RESULTS: With a median follow-up of 33 months (range, 5 to 114 months), AVN of the femoral head(s) developed in 49 patients (9%). Median time to onset of AVN was 12 months (range, 2 to 41 months). Three risk factors for AVN were identified by multivariate analysis: cumulative dexamethasone dose (odds ratio [OR], 1.028; 95% CI, 1.012 to 1.044; P = .0006 [per 40 mg dexamethasone]), male sex (OR, 0.390; 95% CI, 0.192 to 0.790; P = .009), and younger age (OR, 0.961; 95% CI, 0.934 to 0.991 per year; P = .0122). Thalidomide-treated patients had a prevalence of AVN similar to that of the control group (8% v 10%, respectively; P = .58). AVN-related pain and limited range of motion of the affected joint were present in only nine and four patients, respectively, and four patients underwent hip replacement because of AVN. Fluorine-18 fluorodeoxyglucose positron emission tomography failed to detect abnormal uptake in the AVN-affected bones. CONCLUSION: AVN is a rare and usually asymptomatic complication during myeloma therapy. Cumulative dexamethasone dose, male sex, and younger age, but not thalidomide, increase the risk of AVN.

68Ga-DOTATATE Compared with 111In-DTPA-Octreotide and Conventional Imaging for Pulmonary and Gastroenteropancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis.

UNLABELLED: Neuroendocrine tumors (NETs) are uncommon tumors with increasing incidence and prevalence. Current reports suggest that (68)Ga-DOTATATE PET/CT imaging improves diagnosis and staging of NETs compared with (111)In-DTPA-octreotide and conventional imaging. We performed a systematic review of (68)Ga-DOTATATE for safety and efficacy compared with octreotide and conventional imaging to determine whether available evidence supports U.S. Food and Drug Administration approval. METHODS: Medline, EMBASE, Web of Science, and Cochrane Reviews electronic databases were searched from January 1999 to September 2015. Results were restricted to human studies comparing diagnostic accuracy of (68)Ga-DOTATATE with octreotide or conventional imaging for pulmonary or gastroenteropancreatic NET and for human studies reporting safety/toxicity for (68)Ga-DOTATATE with 10 subjects or more thought to have NETs. Direct communication with corresponding authors was attempted to obtain missing information. Abstracts meeting eligibility criteria were collected by a research librarian and assembled for reviewers; 2 reviewers independently determined whether or not to include each abstract. If either reviewer chose inclusion, the abstract was accepted for review. RESULTS: Database and bibliography searches yielded 2,479 articles, of which 42 were eligible. Three studies compared the 2 radiopharmaceuticals in the same patient, finding (68)Ga-DOTATATE to be more sensitive than octreotide. Nine studies compared (68)Ga-DOTATATE with conventional imaging. (68)Ga-DOTATATE estimated sensitivity, 90.9% (95% confidence interval, 81.4%-96.4%), and specificity, 90.6% (95% confidence interval, 77.8%-96.1%), were high. Five studies were retained for safety reporting only. Report of harm possibly related to (68)Ga-DOTATATE was rare (6 of 974), and no study reported major toxicity or safety issues. CONCLUSION: No direct comparison of octreotide and (68)Ga-DOTATATE imaging for diagnosis and staging in an unbiased population of NETs has been published. Available information in the peer-reviewed literature regarding diagnostic efficacy and safety supports the use of (68)Ga-DOTATATE for imaging of NETs where it is available.

Safety and Efficacy of 68Ga-DOTATATE PET/CT for Diagnosis, Staging, and Treatment Management of Neuroendocrine Tumors.

UNLABELLED: Our purpose was to evaluate the safety and efficacy of (68)Ga-DOTATATE PET/CT compared with (111)In-pentetreotide imaging for diagnosis, staging, and restaging of pulmonary and gastroenteropancreatic neuroendocrine tumors. METHODS: (68)Ga-DOTATATE PET/CT and (111)In-pentetreotide scans were obtained for 78 of 97 consecutively enrolled patients with known or suspected pulmonary or gastroenteropancreatic neuroendocrine tumors. Safety and toxicity were measured by comparing vital signs, serum chemistry values, or acquisition-related medical complications before and after (68)Ga-DOTATATE injection. Added value was determined by changes in treatment plan when (68)Ga-DOTATATE PET/CT results were added to all prior imaging, including (111)In-pentetreotide. Interobserver reproducibility of (68)Ga-DOTATATE PET/CT scan interpretation was measured between blinded and nonblinded interpreters. RESULTS: (68)Ga-DOTATATE PET/CT and (111)In-pentetreotide scans were significantly different in impact on treatment (P < 0.001). (68)Ga-DOTATATE PET/CT combined with CT or liver MRI changed care in 28 of 78 (36%) patients. Interobserver agreement between blinded and nonblinded interpreters was high. No participant had a trial-related event requiring treatment. Mild, transient events were tachycardia in 1, alanine transaminase elevation in 1, and hyperglycemia in 2 participants. No clinically significant arrhythmias occurred. (68)Ga-DOTATATE PET/CT correctly identified 3 patients for peptide-receptor radiotherapy incorrectly classified by (111)In-pentetreotide. CONCLUSION: (68)Ga-DOTATATE PET/CT was equivalent or superior to (111)In-pentetreotide imaging in all 78 patients. No adverse events requiring treatment were observed. (68)Ga-DOTATATE PET/CT changed treatment in 36% of participants. Given the lack of significant toxicity, lower radiation exposure, and improved accuracy compared with (111)In-pentetreotide, (68)Ga-DOTATATE imaging should be used instead of (111)In-pentetreotide imaging where available.

Correlations between quantitative fat-water magnetic resonance imaging and computed tomography in human subcutaneous white adipose tissue.

Beyond estimation of depot volumes, quantitative analysis of adipose tissue properties could improve understanding of how adipose tissue correlates with metabolic risk factors. We investigated whether the fat signal fraction (FSF) derived from quantitative fat-water magnetic resonance imaging (MRI) scans at 3.0 T correlates to CT Hounsfield units (HU) of the same tissue. These measures were acquired in the subcutaneous white adipose tissue (WAT) at the umbilical level of 21 healthy adult subjects. A moderate correlation exists between MRI- and CT-derived WAT values for all subjects, [Formula: see text], [Formula: see text], with a slope of [Formula: see text], (95% CI [Formula: see text]), indicating that a decrease of 1 HU equals a mean increase of 0.38% FSF. We demonstrate that FSF estimates obtained using quantitative fat-water MRI techniques correlate with CT HU values in subcutaneous WAT, and therefore, MRI-based FSF could be used as an alternative to CT HU for assessing metabolic risk factors.

Human brown adipose tissue depots automatically segmented by positron emission tomography/computed tomography and registered magnetic resonance images.

Reliably differentiating brown adipose tissue (BAT) from other tissues using a non-invasive imaging method is an important step toward studying BAT in humans. Detecting BAT is typically confirmed by the uptake of the injected radioactive tracer 18F-Fluorodeoxyglucose (18F-FDG) into adipose tissue depots, as measured by positron emission tomography/computed tomography (PET-CT) scans after exposing the subject to cold stimulus. Fat-water separated magnetic resonance imaging (MRI) has the ability to distinguish BAT without the use of a radioactive tracer. To date, MRI of BAT in adult humans has not been co-registered with cold-activated PET-CT. Therefore, this protocol uses 18F-FDG PET-CT scans to automatically generate a BAT mask, which is then applied to co-registered MRI scans of the same subject. This approach enables measurement of quantitative MRI properties of BAT without manual segmentation. BAT masks are created from two PET-CT scans: after exposure for 2 hr to either thermoneutral (TN) (24 °C) or cold-activated (CA) (17 °C) conditions. The TN and CA PET-CT scans are registered, and the PET standardized uptake and CT Hounsfield values are used to create a mask containing only BAT. CA and TN MRI scans are also acquired on the same subject and registered to the PET-CT scans in order to establish quantitative MRI properties within the automatically defined BAT mask. An advantage of this approach is that the segmentation is completely automated and is based on widely accepted methods for identification of activated BAT (PET-CT). The quantitative MRI properties of BAT established using this protocol can serve as the basis for an MRI-only BAT examination that avoids the radiation associated with PET-CT.

Reproducibility of Volumetric Computed Tomography of Stable Small Pulmonary Nodules with Implications on Estimated Growth Rate and Optimal Scan Interval.

PURPOSE: To use clinically measured reproducibility of volumetric CT (vCT) of lung nodules to estimate error in nodule growth rate in order to determine optimal scan interval for patient follow-up. METHODS: We performed quantitative vCT on 89 stable non-calcified nodules and 49 calcified nodules measuring 3-13 mm diameter in 71 patients who underwent 3-9 repeat vCT studies for clinical evaluation of pulmonary nodules. Calculated volume standard deviation as a function of mean nodule volume was used to compute error in estimated growth rate. This error was then used to determine the optimal patient follow-up scan interval while fixing the false positive rate at 5%. RESULTS: Linear regression of nodule volume standard deviation versus the mean nodule volume for stable non-calcified nodules yielded a slope of 0.057 ± 0.002 (r2 = 0.79, p<0.001). For calcified stable nodules, the regression slope was 0.052 ± 0.005 (r2 = 0.65, p = 0.03). Using this with the error propagation formula, the optimal patient follow-up scan interval was calculated to be 81 days, independent of initial nodule volume. CONCLUSIONS: Reproducibility of vCT is excellent, and the standard error is proportional to the mean calculated nodule volume for the range of nodules examined. This relationship constrains statistical certainty of vCT calculated doubling times and results in an optimal scan interval that is independent of the initial nodule volume.

[(18)F]-FLT PET to predict early response to neoadjuvant therapy in KRAS wild-type rectal cancer: a pilot study.

OBJECT: This pilot study evaluated the utility of 3'-deoxy-3'[18F]-fluorothymidine ([(18)F]-FLT) positron emission tomography (PET) to predict response to neoadjuvant therapy that included cetuximab in patients with wild-type KRAS rectal cancers. METHODS: Baseline [(18)F]-FLT PET was collected prior to treatment initiation. Follow-up [(18)F]-FLT was collected after three weekly infusions of cetuximab, and following a combined regimen of cetuximab, 5-FU, and radiation. Imaging-matched biopsies were collected with each PET study. RESULTS: Diminished [(18)F]-FLT PET was observed in 3/4 of patients following cetuximab treatment alone and in all patients following combination therapy. Reduced [(18)F]-FLT PET following combination therapy predicted disease-free status at surgery. Overall, [(18)F]-FLT PET agreed with Ki67 immunoreactivity from biopsy samples and surgically resected tissue, and was predictive of treatment-induced rise in p27 levels. CONCLUSION: These results suggest that [(18)F]-FLT PET is a promising imaging biomarker to predict response to neoadjuvant therapy that included EGFR blockade with cetuximab in patients with rectal cancer.

Introduction to PET imaging with emphasis on biomedical research.

Medical imaging is migrating from anatomic imaging to functional imaging and fused anatomic/functional imaging. The technology is being adapted for biomedical research using both clinical and small animal scanners. The ability to externally image real-time physiologic processes in both normal and deranged conditions, including various models to image gene expression, apoptosis, or drug biodistribution, has powerful impact on the exploration of biomedical and fundamental biological research. Positron emission tomography (PET) has a unique ability to not only provide such images but also to do so with high resolution (typically 1-2mm resolution for small animal scanners) and to provide both relative and absolute quantitation. This technology is revolutionizing biomedical and biological research. This article reviews the underlying principles involved in this technology, gives a brief history of its development, and then introduces the interested researcher to some of the important techniques that could be of use.

Diagnosis of infection of implantable central venous catheters by [18F]fluorodeoxyglucose positron emission tomography.

OBJECTIVE: The aim of this study was to evaluate the role of [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging in the diagnosis of infection of implantable vascular catheters. METHODS: We evaluated six patients with haematological cancer and infection of their implantable vascular catheter and who underwent FDG PET imaging around the time of their infection. RESULTS: Six patients with multiple myeloma who developed infection of their implantable device (five port pocket infections and one tunnel infection) were identified. FDG PET revealed increased uptake at the site of the implantable catheter (SUV 2.7-4.5) in all six patients, even in the absence of signs or symptoms of infection at the site of the device (three), and the presence of severe neutropenia (four). The three patients who did not have local inflammation at the site of the device were profoundly neutropenic. The FDG PET diagnosis led to removal of the device in two patients. CONCLUSION: FDG PET is a safe, rapid and accurate tool for diagnosing infection of an implantable catheter, including among those patients not exhibiting local signs and symptoms of infection, and in whom the diagnosis of infected device may be difficult. FDG PET may help prevent the unnecessary removal of implantable intravascular catheters and the unwarranted use of antibiotics.