Christiaan Schiepers

Histological alterations in chronically hypoperfused myocardium. Correlation with PET findings.

BackgroundIn patients with chronic coronary artery disease (CAD) and left ventricular dysfunction, flow/metabolic studies of the myocardium with positron emission tomography (PET) are able to distinguish viable but dysfunctional myocardium from irreversible ischemic injury and scar tissue. In this study, PET findings of blood flow and metabolism in chronically hypoperfused myocardium were correlated with histology. Methods and ResultsWe studied 33 patients suffering from CAD. In each patient, myocardial blood flow and metabolism were measured with PET 1 or 2 days before revascularization. During surgery, transmural biopsies were taken from the left ventricular anterior wall and planimetrically scored for the degree of myolysis (sarcomere loss). The amount of connective tissue was calculated using morphometric techniques. Contrast ventriculography demonstrated abnormal wall motion in 23 patients. Fourteen patients with a mismatch pattern (decreased flow with preserved metabolism) in the biopsy region after quantitative analysis of the PET data showed 11±6 vol% fibrosis and 25±13% cells with sarcomere loss. The space formerly occupied by sarcomeres was mainly replaced by glycogen and mitochondria. A significant wall motion improvement was noted 3 months after surgery. Nine patients showed a match pattern (concordant flow/metabolism defects). The biopsies revealed 35±25% fibrosis and 24±15% glycogen-storing cells. The biopsies of the 10 patients with normal anterior wall motion showed 8±4% fibrosis and 12±8% glycogen-accumulating cells. ConclusionsIt can be concluded that areas with impaired wall motion and a PET match pattern show extensive fibrosis. Regions with reduced flow and preserved FDG metabolism, however, contain predominantly viable cells. In these regions, significant recovery of wall motion is found after revascularization. Regions with normal wall motion contain predominantly viable cells. Cells with reduced contractile material and increased glycogen content are mainly found in areas with wall motion impairment but are also present in areas with normal wall motion and a severe stenosis of the coronary vessel.

Cancer detection with whole-body PET using 2-[18F]fluoro-2-deoxy-D-glucose.

Objective This study was done to determine the feasibility and potential utility of whole-body PET using the glucose analogue 2-[18F]fluoro-2-deoxy-D-glucose (FDG) for the detection of primary malignancies and metastatic lesions. Materials and Methods This was a prospective, nonrandomized study of whole-body FDG-PET imaging carried out at a large university teaching hospital in Los Angeles, CA, U.S.A. The study group consisted of all patients referred for PET imaging (87) with a suspected diagnosis of primary or recurrent malignancy and who had eventual histological confirmation of their lesions. Results In the 87 patients, whole-body PET studies were positive (presence of focal FDG uptake relative to surrounding tissues uptake) in 61 of 70 patients (87%) with subsequent biopsy-confirmed primary or recurrent malignant lesions, including carcinomas of breast, lung, ovary, prostate, colon, urinary bladder, and gallbladder origin, as well as malignant melanoma, carcinoid, osteosarcoma, lymphoma, and spinal cord astrocytoma. The PET images revealed no focal hypermetabolism at the known site of tumor in patients with primary prostate carcinoma (two), microscopic ovarian carcinoma (two), breast carcinoma (one), low-grade carcinoid tumors (two), and one patient with recurrent microscopic osteogenic sarcoma. The PET studies detected the primary lesion in 15 of 17 patients with breast carcinoma and in 6 of 6 patients with primary lung carcinoma. Of the 17 patients with benign biopsies, 13 patients had FDG-PET studies without focal areas of uptake. Conclusion Because of the high glycolytic rate of malignant tissue, the whole-body FDG-PET technique has promise in the detection of a wide variety of both primary and metastatic malignancies. The presence of FDG uptake in benign inflammatory conditions may limit the specificity of the technique. The sensitivity for the detection of malignant lesions was 87% and the positive predictive value was 94%. The whole-body FDG-PET method is promising both in determining the nature of a localized lesion and in defining the systemic extent of malignant disease.

Contribution of PET in the diagnosis of recurrent colorectal cancer: comparison with conventional imaging

The clinical value of total body PET with FDG was evaluated in 76 patients presenting with or suspected of recurrent local or distant colorectal cancer. PET results were compared to those of routine imaging (CT pelvis, CT/US liver and CXR). The accuracy of PET for local disease was 95% which was superior to CT-pelvis (accuracy 65%). PET accuracy for liver metastases (98%) compared favourably to CT/US-liver accuracy (93%). Unexpected extra-hepatic mestastases were detected by PET in 14 locations in 10 patients. Also, a primary breast cancer was found in one patient. The main value of PET appeared an improved staging of apparently resectable, local or distant recurrent disease. Thereby, a more adequate indication of major secondary surgery could be attained.

PET in oncology: will it replace the other modalities?

Medical imaging technology is rapidly expanding and the role of each modality is being redefined constantly. PET has been around since the early sixties and gained clinical acceptance in oncology only after an extreme number of scientific publications. Although PET has the unique ability to image biochemical processes in vivo, this ability is not fully used as a clinical imaging tool. In this overview, the role of PET in relation to other tumor imaging modalities will be discussed and the reported results in the literature will be reviewed. In predicting the future of PET, technical improvements of other imaging modalities need to be dealt with. The fundamental physical principles for image formation with computed tomography (CT), ultrasound (US), magnetic resonance imaging (MRI), photon-emission tomography (PET), and single photon emission CT (SPECT) will not change. The potential variety of radiopharmaceuticals which may be developed is unlimited, however, and this provides nuclear imaging techniques with a significant advantage and adaptive features for future biologic imaging. The current applications of PET in oncology have been in characterizing tumor lesions, differentiating recurrent disease from treatment effects, staging tumors, evaluating the extent of disease, and monitoring therapy. The future developments in medicine may use the unique capabilities of PET not only in diagnostic imaging but also in molecular medicine and genetics. The articles discussed in this review were selected from a literature search covering the last 3 years, and in which comparisons of PET with conventional imaging were addressed specifically. PET studies with the glucose analogue fluorine-18-labeled deoxyglucose (FDG) have shown the ability of detecting tumor foci in a variety of histological neoplasms such as thyroid cancer, breast cancer, lymphoma, lung cancer, head and neck carcinoma, colorectal cancer, ovarian carcinoma, and musculoskeletal tumors. Also, the contribution of the whole body PET (WBPET) imaging technique in diagnosis will be discussed. In the current health care environment, a successful imaging technology must not only change medical management but also demonstrate that those changes improve patient outcome.

Molecular Mechanisms of Bone 18F-NaF Deposition

There is renewed interest in 18F-NaF bone imaging with PET or PET/CT. The current brief discussion focuses on the molecular mechanisms of 18F-NaF deposition in bone and presents model-based approaches to quantifying bone perfusion and metabolism in the context of preclinical and clinical applications of bone imaging with PET.

FDG-PET imaging in lung cancer: how sensitive is it for bronchioloalveolar carcinoma?

Abstract.While characterization of lung lesions and staging of lung cancer with fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) is an established clinical procedure, a lower diagnostic accuracy of FDG-PET for diagnosis and staging of so-called bronchioloalveolar carcinoma (BAC) has been reported. Therefore, the accuracy of PET for diagnosing and staging of BAC was investigated. We studied 41 patients eventually found to have adenocarcinoma with a bronchioloalveolar growth pattern who were referred for characterization or staging of lung lesions with whole-body FDG-PET between January 1998 and March 2001: there were 11 males (27%) and 30 females (73%), with a mean age of 66.0±10.9 (range =44–84 years). Patients were imaged using ECAT EXACT or HR+ systems. All patients had non-attenuation-corrected scans, while transmission data for attenuation correction were also available for 12 patients (29%). PET correctly identified BAC in 41 of the 46 (89%) lesions and 39 of the 41 patients (95%). By pathology, 25 patients (61%) were found to have unifocal or nodular lesions; this pattern was correctly identified by PET in 20 patients (80%) and by CT in 18 (72%). PET correctly identified 7 (44%) of 16 patients (39%) who had multicentric or diffuse BAC, and CT identified 11 (69%). Of the 35 patients whose lymph node status was verified pathologically, PET was correct in 27 (77%) and CT in 24 (69%). PET missed 67% of the rare tumors that had a pure BAC pattern with no invasive component. It is concluded that the diagnostic performance of whole-body FDG-PET is similar in most patients with lesions with a BAC pattern and in other non-small cell lung cancer types. PET is less accurate in patients with rare BAC tumors that have no invasive component.

Correlation of 6-18F-Fluoro-l-Dopa PET Uptake with Proliferation and Tumor Grade in Newly Diagnosed and Recurrent Gliomas

6-18F-fluoro-l-dopa (18F-FDOPA) measured with PET as a biomarker of amino acid uptake has been investigated in brain tumor imaging. The aims of the current study were to determine whether the degree of 18F-FDOPA uptake in brain tumors predicted tumor grade and was associated with tumor proliferative activity in newly diagnosed and recurrent gliomas. Methods: Fifty-nine patients (40 men, 19 women; mean age ± SD, 44.4 ± 12.3 y) with newly diagnosed (n = 22) or recurrent (n = 37) gliomas underwent 18F-FDOPA PET perioperatively. Tumor tissue was obtained by resection or biopsy in all patients. The tumor grade and Ki-67 proliferation index were obtained by standard pathology assays. Tumor 18F-FDOPA uptake was quantified by determining various standardized uptake value (SUV) parameters (mean SUV, maximum SUV [SUVmax], mean values of voxels with top 20% SUVs, and tumor–to–normal-brain tissue ratios) that were then correlated with histopathologic grade and Ki-67 proliferation index. Results: Fifty-nine lesions in 59 patients were analyzed. 18F-FDOPA uptake was significantly higher in high-grade than in low-grade tumors for newly diagnosed tumors (SUVmax, 4.22 ± 1.30 vs. 2.34 ± 1.35, P = 0.005) but not for recurrent tumors that had gone through treatment previously (SUVmax, 3.36 ± 1.26 vs. 2.67 ± 1.18, P = 0.22). An SUVmax threshold of 2.72 differentiated low-grade from high-grade tumors, with a sensitivity and specificity of 85% and 89%, respectively, using receiver-operating-characteristic curve analysis (area under the curve, 0.86). 18F-FDOPA PET uptake correlated significantly with Ki-67 tumor proliferation index in newly diagnosed tumors (r = 0.66, P = 0.001) but not in recurrent tumors (r = 0.14, P = 0.41). Conclusion: 18F-FDOPA uptake is significantly higher in high-grade than in low-grade tumors in newly diagnosed but not recurrent tumors that had been treated previously. A significant correlation between 18F-FDOPA uptake and tumor proliferation in newly diagnosed tumors was observed, whereas this correlation was not identified for recurrent tumors. Thus, 18F-FDOPA PET might serve as a noninvasive marker of tumor grading and might provide a useful surrogate of tumor proliferative activity in newly diagnosed gliomas.

PET for staging of Hodgkin's disease and non-Hodgkin's lymphoma

Metabolic or molecular imaging with fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has emerged as a powerful imaging modality for diagnosis, staging, and therapy monitoring of a variety of cancers. The accuracy of FDG-PET as an imaging tool for the primary staging of lymphoma suffers from the absence of a reference criterion to which all imaging modalities can be compared. For ethical reasons, pathological diagnosis is usually not possible for all of the lesions and abnormalities found. In this article, the current state of the art for staging of primary lymphoma is reviewed and the implications for staging and the impact on patient management discussed. Whole-body PET using FDG is superior to conventional staging, i.e., physical examination, laboratory tests, plain radiography, and CT, by 10–20%. The sensitivity of FDG-PET varies for different regions of the body and appears lowest for infradiaphragmatic disease involvement. Staging with metabolic imaging leads in 10–40% of patients to a change in clinical stage. Highly variable results have been reported on whether up- or downstaging of lymphoma with PET leads to changes in the therapeutic approach for primary lymphoma.

18F-FDOPA Kinetics in Brain Tumors

l-3,4-Dihydroxy-6-18F-fluoro-phenyl-alanine (18F-FDOPA) is an amino acid analog used to evaluate presynaptic dopaminergic neuronal function. Evaluation of tumor recurrence in neurooncology is another application. Here, the kinetics of 18F-FDOPA in brain tumors were investigated. Methods: A total of 37 patients underwent 45 studies; 10 had grade IV, 10 had grade III, and 13 had grade II brain tumors; 2 had metastases; and 2 had benign lesions. After 18F-DOPA was administered at 1.5–5 MBq/kg, dynamic PET images were acquired for 75 min. Images were reconstructed with iterative algorithms, and corrections for attenuation and scatter were applied. Images representing venous structures, the striatum, and tumors were generated with factor analysis, and from these, input and output functions were derived with simple threshold techniques. Compartmental modeling was applied to estimate rate constants. Results: A 2-compartment model was able to describe 18F-FDOPA kinetics in tumors and the cerebellum but not the striatum. A 3-compartment model with corrections for tissue blood volume, metabolites, and partial volume appeared to be superior for describing 18F-FDOPA kinetics in tumors and the striatum. A significant correlation was found between influx rate constant K and late uptake (standardized uptake value from 65 to 75 min), whereas the correlation of K with early uptake was weak. High-grade tumors had significantly higher transport rate constant k1, equilibrium distribution volumes, and influx rate constant K than did low-grade tumors (P < 0.01). Tumor uptake showed a maximum at about 15 min, whereas the striatum typically showed a plateau-shaped curve. Patlak graphical analysis did not provide accurate parameter estimates. Logan graphical analysis yielded reliable estimates of the distribution volume and could separate newly diagnosed high-grade tumors from low-grade tumors. Conclusion: A 2-compartment model was able to describe 18F-FDOPA kinetics in tumors in a first approximation. A 3-compartment model with corrections for metabolites and partial volume could adequately describe 18F-FDOPA kinetics in tumors, the striatum, and the cerebellum. This model suggests that 18F-FDOPA was transported but not trapped in tumors, unlike in the striatum. The shape of the uptake curve appeared to be related to tumor grade. After an early maximum, high-grade tumors had a steep descending branch, whereas low-grade tumors had a slowly declining curve, like that for the cerebellum but on a higher scale.

Decision analysis for the cost-effective management of recurrent colorectal cancer.

ObjectiveTo determine whether the use of [18F]2-fluoro-2-deoxyglucose positron emission tomography (FDG PET) in addition to computed axial tomography (CT) is helpful in managing recurrent colorectal cancer (CRC). Summary Background DataThere is no consensus on a management algorithm for CRC. However, when recurrence is suspected, CT is generally used for further evaluation and staging of disease. MethodsThe authors used decision trees based on theoretical models to assess the cost-effectiveness of a CT + FDG PET strategy for the diagnosis and management of recurrent CRC compared with a CT-alone strategy. These theoretical models focus on patients with hepatic recurrence who are potentially curable through surgical hepatic resection. The population entering the decision trees consisted of patients with CRC who had undergone surgical resection of their primary CRC and who were suspected of having recurrence based on elevated levels of carcinoembryonic antigen. ResultsThe CT + FDG PET strategy was found to be cost-effective for managing patients with elevated carcinoembryonic antigen levels who were candidates for hepatic resection. The CT + FDG PET strategy was higher in mean cost by