L.F. de Geus-Oei

The role of [(18)F]-2-fluoro-2deoxy-d-dglucose-positron emission tomography in thyroid nodules iwht indeterminate fine-needle aspiration biopsy: sysematic review and meta-analysis of the literature

Indeterminate results at fine‐needle aspiration biopsy (FNAB) of thyroid nodules pose a clinical dilemma, because only 20% to 30% of patients suffer from malignancy. Previous studies suggested that the false‐negative ratio of [18F]‐2‐fluoro‐2‐deoxy‐D‐glucose–positron emission tomography (FDG‐PET) is very low; therefore, it may help identify patients who would benefit from (hemi)thyroidectomy. A systematic literature search was performed in 5 databases. After assessment, the identified studies were analyzed for heterogeneity, and the extracted data of test characteristics were pooled using a random‐effects model. Threshold effects were examined, and publication bias was assessed. The query resulted in 239 records, of which 6 studies met predefined inclusion criteria. Data from 225 of the 241 described patients could be extracted. There was mild to moderate heterogeneity in study results (inconsistency index [I2] = 0.390‐0.867). The pooled prevalence of malignancy was 26%. Pooled sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 95% (95% confidence interval [95% CI], 86%‐99%), 48% (95% CI, 40%‐56%), 39% (95% CI, 31%‐47%), 96% (95% CI, 90%‐99%), and 60% (95% CI, 53%‐67%), respectively. Sensitivity increased to 100% for the 164 lesions that measured >15 mm in greatest dimension. There was no evidence of threshold effects or publication bias. A negative FDG‐PET scan in patients who had thyroid nodules >15 mm with indeterminate FNAB results excluded thyroid cancer in a pooled population of 225 patients. Conversely, a positive FDG‐PET result did not identify cancer, because approximately 50% of these patients had benign nodules. The authors concluded that the incorporation of FDG‐PET into the initial workup of such patients before surgery deserves further investigation. Cancer 2011.

A Curve-Fitting Approach to Estimate the Arterial Plasma Input Function for the Assessment of Glucose Metabolic Rate and Response to Treatment

For the quantification of dynamic 18F-FDG PET studies, the arterial plasma time–activity concentration curve (APTAC) needs to be available. This can be obtained using serial sampling of arterial blood or an image-derived input function (IDIF). Arterial sampling is invasive and often not feasible in practice; IDIFs are biased because of partial-volume effects and cannot be used when no large arterial blood pool is in the field of view. We propose a mathematic function, consisting of an initial linear rising activity concentration followed by a triexponential decay, to describe the APTAC. This function was fitted to 80 oncologic patients and verified for 40 different oncologic patients by area-under-the-curve (AUC) comparison, Patlak glucose metabolic rate (MRglc) estimation, and therapy response monitoring (ΔMRglc). The proposed function was compared with the gold standard (serial arterial sampling) and the IDIF. Methods: To determine the free parameters of the function, plasma time–activity curves based on arterial samples in 80 patients were fitted after normalization for administered activity (AA) and initial distribution volume (iDV) of 18F-FDG. The medians of these free parameters were used for the model. In 40 other patients (20 baseline and 20 follow-up dynamic 18F-FDG PET scans), this model was validated. The population-based curve, individually calibrated by AA and iDV (APTACAA/iDV), by 1 late arterial sample (APTAC1sample), and by the individual IDIF (APTACIDIF), was compared with the gold standard of serial arterial sampling (APTACsampled) using the AUC. Additionally, these 3 methods of APTAC determination were evaluated with Patlak MRglc estimation and with ΔMRglc for therapy effects using serial sampling as the gold standard. Results: Excellent individual fits to the function were derived with significantly different decay constants (P < 0.001). Correlations between AUC from APTACAA/iDV, APTAC1sample, and APTACIDIF with the gold standard (APTACsampled) were 0.880, 0.994, and 0.856, respectively. For MRglc, these correlations were 0.963, 0.994, and 0.966, respectively. In response monitoring, these correlations were 0.947, 0.982, and 0.949, respectively. Additional scaling by 1 late arterial sample showed a significant improvement (P < 0.001). Conclusion: The fitted input function calibrated for AA and iDV performed similarly to IDIF. Performance improved significantly using 1 late arterial sample. The proposed model can be used when an IDIF is not available or when serial arterial sampling is not feasible.

Comparison of Tumor Volumes Derived from Glucose Metabolic Rate Maps and SUV Maps in Dynamic 18F-FDG PET

Tumor delineation using noninvasive medical imaging modalities is important to determine the target volume in radiation treatment planning and to evaluate treatment response. It is expected that combined use of CT and functional information from 18F-FDG PET will improve tumor delineation. However, until now, tumor delineation using PET has been based on static images of 18F-FDG standardized uptake values (SUVs). 18F-FDG uptake depends not only on tumor physiology but also on blood supply, distribution volume, and competitive uptake processes in other tissues. Moreover, 18F-FDG uptake in tumor tissue and in surrounding healthy tissue depends on the time after injection. Therefore, it is expected that the glucose metabolic rate (MRglu) derived from dynamic PET scans gives a better representation of the tumor activity than does SUV. The aim of this study was to determine tumor volumes in MRglu maps and to compare them with the values from SUV maps. Methods: Twenty-nine lesions in 16 dynamic 18F-FDG PET scans in 13 patients with non–small cell lung carcinoma were analyzed. MRglu values were calculated on a voxel-by-voxel basis using the standard 2-compartment 18F-FDG model with trapping in the linear approximation (Patlak analysis). The blood input function was obtained by arterial sampling. Tumor volumes were determined in SUV maps of the last time frame and in MRglu maps using 3-dimensional isocontours at 50% of the maximum SUV and the maximum MRglu, respectively. Results: Tumor volumes based on SUV contouring ranged from 1.31 to 52.16 cm3, with a median of 8.57 cm3. Volumes based on MRglu ranged from 0.95 to 37.29 cm3, with a median of 3.14 cm3. For all lesions, the MRglu volumes were significantly smaller than the SUV volumes. The percentage differences (defined as 100% × (VMRglu − VSUV)/VSUV, where V is volume) ranged from −12.8% to −84.8%, with a median of −32.8%. Conclusion: Tumor volumes from MRglu maps were significantly smaller than SUV-based volumes. These findings can be of importance for PET-based radiotherapy planning and therapy response monitoring.

FDG-PET in colorectal cancer

[18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) is a useful imaging tool in the evolving management of patients with colorectal carcinoma. This technique is able to measure and visualize metabolic changes in cancer cells. This feature results in the ability to distinguish viable tumor from scar tissue, in the detection of tumor foci at an earlier stage than possible by conventional anatomic imaging and in the measurement of alterations in tumor metabolism, indicative of tumor response to therapy. Nowadays, FDG-PET plays a pivotal role in staging patients before surgical resection of recurrence and metastases, in the localization of recurrence in patients with an unexplained rise in serum carcinoembryonic antigen and in assessment of residual masses after treatment. In the presurgical evaluation, FDG-PET may be best used in conjunction with anatomic imaging in order to combine the benefits of both anatomical (CT) and functional (PET) information, which leads to significant improvements in preoperative liver staging and preoperative judgment on the feasibility of resection. Integration of FDG-PET into the management algorithm of these categories of patients alters and improves therapeutic management, reduces morbidity due to futile surgery, leads to substantial cost savings and probably also to a better patient outcome. FDG-PET also appears to have great potential in monitoring the success of local ablative therapies soon after intervention and in the prediction and evaluation of response to radiotherapy, systemic therapy, and combinations thereof. This review aims to outline the current and future role of FDG-PET in the field of colorectal cancer.

New biomarkers for early detection of cardiotoxicity after treatment with docetaxel, doxorubicin and cyclophosphamide

Abstract Objective: Assessing a diverse biomarker panel (NT-proBNP, TNF-α, galectin-3, IL-6, Troponin I, ST2 and sFlt-1) to detect subclinical cardiotoxicity after treatment with anthracyclines. Methods: Of 55 breast cancer patients biomarkers were assessed and echocardiography was performed one year after treatment with anthracyclines. Results: 29.1% of patients showed abnormal biomarker levels: NT-proBNP in 18.2%, TNF-α and Galectin-3 in 7.3%. IL-6, troponin I, ST2 and sFlt-1 were normal in all patients. A correlation between left ventricular ejection fraction (LVEF) and NT-proBNP was observed (r = −0.564, p ≤ 0.01). Conclusion: The evaluated biomarkers do not contribute to early detection. Future research should focus on NT-proBNP. Trial registration: ClinicalTrials.gov identifier: NCT01246856.

Cost-Effectiveness of FDG-PET/CT for Cytologically Indeterminate Thyroid Nodules: A Decision Analytic Approach

CONTEXT Patients with thyroid nodules of indeterminate cytology undergo diagnostic surgery according to current guidelines. In 75% of patients, the nodule is benign. In these patients, surgery was unnecessary and unbeneficial because complications may occur. Preoperative fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) was found to have a very high negative predictive value (96%) and might therefore avoid futile surgery, complications, and costs. In the United States, two molecular tests of cytology material are routinely used for this purpose. OBJECTIVE Five-year cost-effectiveness for routine implementation of FDG-PET/CT was evaluated in adult patients with indeterminate fine-needle aspiration cytology and compared with surgery in all patients and both molecular tests. DESIGN A Markov decision model was developed to synthesize the evidence on cost-effectiveness about the four alternative strategies. The model was probabilistically analyzed. One-way sensitivity analyses of deterministic input variables likely to influence outcome were performed. SETTING AND SUBJECTS The model was representative for adult patients with cytologically indeterminate thyroid nodules. MAIN OUTCOME MEASURES The discounted incremental net monetary benefit (iNMB), the efficiency decision rule containing outcomes as quality-adjusted life-years and (direct) medical cost, of implementation of FDG-PET/CT is displayed. RESULTS Full implementation of FDG-PET/CT resulted in 40% surgery for benign nodules, compared with 75% in the conventional approach, without a difference in recurrence free and overall survival. The FDG-PET/CT modality is the more efficient technology, with a mean iNMB of €3684 compared with surgery in all. Also, compared with a gene expression classifier test and a molecular marker panel, the mean iNMB of FDG-PET/CT was €1030 and €3851, respectively, and consequently the more efficient alternative. CONCLUSION Full implementation of preoperative FDG-PET/CT in patients with indeterminate thyroid nodules could prevent up to 47% of current unnecessary surgery leading to lower costs and a modest increase of health-related quality of life. Compared with an approach with diagnostic surgery in all patients and both molecular tests, it is the least expensive alternative with similar effectiveness as the gene-expression classifier.

Clinical applications of positron emission tomography in sarcoma management.

Positron emission tomography (PET) with the fluorine-18-labeled glucose analog FDG is a technique that noninvasively visualizes glucose metabolism in the human body. In oncology, the addition of FDG-PET to the conventional anatomical imaging techniques provides very useful clinical information in diagnosis, staging, treatment response monitoring and follow-up. In the heterogeneous group of patients with sarcoma, FDG-PET has been shown to be of great value in improving patient care. In this article we will discuss the current role of FDG-PET in the management of patients with sarcoma and its value in assessing tumor grade, guiding biopsy, staging, monitoring treatment response, restaging and prognostication. Our future expectation is that the value of PET will only augment owing to the implementation of FDG-PET in clinical guidelines, the increasing availability worldwide, and the development of new tracers and new hybrid imaging techniques.

FDG-PET/CT based response-adapted treatment

Abstract It has been shown that [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) provides robust and reproducible data for early metabolic response assessment in various malignancies. This led to the initiation of several prospective multicenter trials in malignant lymphoma and adenocarcinoma of the esophagogastric junction, in order to investigate whether the use of PET-guided treatment individualization results in a survival benefit. In Hodgkin lymphoma and aggressive non-Hodgkin lymphoma, several trials are ongoing. Some studies aim to investigate the use of PET in early identification of metabolic non-responders in order to intensify treatment to improve survival. Other studies aim at reducing toxicity without adversely affecting cure rates by safely de-escalating therapy in metabolic responders. In solid tumors the first PET response-adjusted treatment trials have been realized in adenocarcinoma of the esophagogastric junction. These trials showed that patients with an early metabolic response to neoadjuvant chemotherapy benefit from this treatment, whereas metabolic non-responders should switch early to surgery, thus reducing the risk of tumor progression during chemotherapy and the risk of toxic death. The trials provide a model for designing response-guided treatment algorithms in other malignancies. PET-guided treatment algorithms are the promise of the near future; the choice of therapy, its intensity, and its duration will become better adjusted to the biology of the individual patient. Today’s major challenge is to investigate the impact on patient outcome of personalized response-adapted treatment concepts.

Monitoring hypoxia and vasculature during bevacizumab treatment in a murine colorectal cancer model

The purpose of this study was to assess the effect of bevacizumab on vasculature and hypoxia in a colorectal tumor model. Nude mice with subcutaneous LS174T tumors were treated with bevacizumab or saline. To assess tumor properties, separate groups of mice were imaged using (18) F-Fluoromisonidazole (FMISO) and (18) F-Fluorodeoxyglucose (FDG) positron emission tomography or magnetic resonance imaging before and 2, 6 and 10 days after the start of treatment. Tumors were harvested after imaging to determine hypoxia and vascular density immunohistochemically. The T2 * time increased significantly less in the bevacizumab group. FMISO uptake increased more over time in the control group. Vessel density significantly decreased in the bevacizumab-treated group. The Carbonic anhydrase 9 (CAIX) and glucose uptake transporter 1 (GLUT1) fractions were higher in bevacizumab-treated tumors. However, the hypoxic fraction showed no significant difference. Bevacizumab led to shorter T2 * times and higher GLUT1 and CAIX expression, suggesting an increase in hypoxia and a higher glycolytic rate. This could be a mechanism of resistance to bevacizumab. The increase in hypoxia, however, could not be demonstrated by pimonidazole/FMISO, possibly because distribution of these tracers is hampered by bevacizumab-induced effects on vascular permeability and perfusion.

The Impact of Optimal Respiratory Gating and Image Noise on Evaluation of Intratumor Heterogeneity on 18F-FDG PET Imaging of Lung Cancer

Accurate measurement of intratumor heterogeneity using parameters of texture on PET images is essential for precise characterization of cancer lesions. In this study, we investigated the influence of respiratory motion and varying noise levels on quantification of textural parameters in patients with lung cancer. Methods: We used an optimal-respiratory-gating algorithm on the list-mode data of 60 lung cancer patients who underwent 18F-FDG PET. The images were reconstructed using a duty cycle of 35% (percentage of the total acquired PET data). In addition, nongated images of varying statistical quality (using 35% and 100% of the PET data) were reconstructed to investigate the effects of image noise. Several global image-derived indices and textural parameters (entropy, high-intensity emphasis, zone percentage, and dissimilarity) that have been associated with patient outcome were calculated. The clinical impact of optimal respiratory gating and image noise on assessment of intratumor heterogeneity was evaluated using Cox regression models, with overall survival as the outcome measure. The threshold for statistical significance was adjusted for multiple comparisons using Bonferroni correction. Results: In the lower lung lobes, respiratory motion significantly affected quantification of intratumor heterogeneity for all textural parameters (P < 0.007) except entropy (P > 0.007). The mean increase in entropy, dissimilarity, zone percentage, and high-intensity emphasis was 1.3% ± 1.5% (P = 0.02), 11.6% ± 11.8% (P = 0.006), 2.3% ± 2.2% (P = 0.002), and 16.8% ± 17.2% (P = 0.006), respectively. No significant differences were observed for lesions in the upper lung lobes (P > 0.007). Differences in the statistical quality of the PET images affected the textural parameters less than respiratory motion, with no significant difference observed. The median follow-up time was 35 mo (range, 7–39 mo). In multivariate analysis for overall survival, total lesion glycolysis and high-intensity emphasis were the two most relevant image-derived indices and were considered to be independent significant covariates for the model regardless of the image type considered. Conclusion: The tested textural parameters are robust in the presence of respiratory motion artifacts and varying levels of image noise.