Ingo Brink

18F-DOPA positron emission tomography for tumour detection in patients with medullary thyroid carcinoma and elevated calcitonin levels

Abstract. In spite of the availability of numerous procedures, diagnostic imaging of tumour manifestations in patients with medullary thyroid carcinoma and elevated calcitonin levels is often difficult. In the present study, the new procedure of fluorine-18 dihydroxyphenylalanine positron emission tomography (18F-DOPA PET) was compared with the established functional and morphological imaging methods. After evaluation of the normal distribution of 18F-DOPA, 11 patients with medullary thyroid carcinoma were examined using 18F-DOPA PET. Results of 18F-fluorodeoxyglucose (18F-FDG) PET, somatostatin receptor scintigraphy (SRS) and morphological tomographic imaging (CT/MRI) were available for all patients. All individual procedures were evaluated without reference to prior information. Data assessment for each patient was based on cooperation between experienced radiologists and specialists in nuclear medicine, who considered all the available findings (histological results, imaging, follow-up studies). This cooperation served as the gold standard against which the results of the individual procedures were evaluated. A total of 27 tumours were studied [three primary tumours (PT)/local recurrence (LR), 16 lymph node metastases (LNM) and eight organ metastases (OM)]. 18F-DOPA PET produced 17 true-positive findings (2 PT/LR, 14 LNM, 1 OM), 18F-FDG PET 12 (2 PT/LR, 7 LNM, 3 OM), SRS 14 (2 PT/LR, 8 LNM, 4 OM) and morphological imaging 22 (3 PT/LR, 11 LNM, 8 OM). The following sensitivities were calculated with respect to total tumour manifestations: 18F-DOPA PET 63%, 18F-FDG PET 44%, SRS 52%, morphological imaging 81%. Thus, the morphological imaging procedures produce the best overall sensitivity, but the specificity for PT/LR (55%) and LNM (57%) was low. With respect to lymph node staging, the best results were obtained with 18F-DOPA PET. 18F-DOPA PET is a new functional imaging procedure for medullary thyroid carcinoma that seems to provide better results than SRS and 18F-FDG PET. Moreover, the data indicate that no single procedure provides adequate diagnostic certainty. Therefore, 18F-DOPA PET is a useful supplement to morphological diagnostic imaging, improving lymph node staging and enabling a more specific diagnosis of primary tumour and local recurrence.

Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer

PurposeThe purpose of this study was to evaluate the impact of [18F]fluorodeoxy-d-glucose positron emission tomography (FDG-PET) on the primary staging of patients with small-cell lung cancer (SCLC).MethodsFDG-PET was performed in 120 consecutive patients with SCLC during primary staging. In addition, brain examinations with both FDG-PET and cranial magnetic resonance imaging (MRI) or computed tomography (CT) were performed in 91 patients. Results of FDG-PET were compared with those of conventional staging procedures. FDG-PET detected markedly increased FDG uptake in the primary tumours of all 120 patients (sensitivity 100%).ResultsComplete agreement between FDG-PET results and other staging procedures was observed in 75 patients. Differences occurred in 45 patients at 65 sites. In 47 sites the FDG-PET results were proven to be correct, and in ten, incorrect. In the remaining eight sites, the discrepancies could not be clarified. In 14/120 patients, FDG-PET caused a stage migration, correctly upstaging ten patients to extensive disease and downstaging three patients by not confirming metastases of the adrenal glands suspected on the basis of CT. Only 1/120 patients was incorrectly staged by FDG-PET, owing to failure to detect brain metastases. In all cases the stage migration led to a significant change in the treatment protocol. Sensitivity of FDG-PET was significantly superior to that of CT in the detection of extrathoracic lymph node involvement (100% vs 70%, specificity 98% vs 94%) and distant metastases except to the brain (98% vs 83%, specificity 92% vs 79%). However, FDG-PET was significantly less sensitive than cranial MRI/CT in the detection of brain metastases (46% vs 100%, specificity 97% vs 100%).ConclusionThe introduction of FDG-PET in the diagnostic evaluation of SCLC will improve the staging results and affect patient management, and may reduce the number of tests and invasive procedures.

FDG-PET imaging for the staging and follow-up of small cell lung cancer

Abstract. The staging procedures for small cell lung cancer do not differ appreciably from those for other forms of lung cancer. For practical purposes, the TNM stages are usually collapsed into a simple binary classification: limited disease and extensive disease. This study was performed to answer the question of whether fluorine-18 labelled 2-deoxy-2-D-glucose positron emission tomography (FDG-PET) imaging permits appropriate work-up (including both primary and follow-up staging) of patients presenting with small cell lung cancer, as compared with currently recommended staging procedures. Thirty-six FDG-PET examinations were performed in 30 patients with histologically proven small cell lung cancer. Twenty-four patients were examined for primary staging while four were imaged for therapy follow-up only. Two patients underwent both primary staging and up to four examinations for therapy follow-up. Static PET imaging was performed according to a standard protocol. Image reconstruction was based on an ordered subset expectation maximization algorithm including post-injection segmented attenuation correction. Results of FDG-PET were compared with those of the sum of other staging procedures. Identical results from FDG-PET and the sum of the other staging procedures were obtained in 23 of 36 examinations (6× limited disease, 12× extensive disease, 5× no evidence of disease). In contrast to the results of conventional staging, FDG-PET indicated extensive disease resulting in an up-staging in seven patients. In one patient in whom there was no evidence for tumour on conventional investigations following treatment, FDG-PET was suggestive of residual viability of the primary tumour. Furthermore, discordant results were observed in five patients with respect to lung, bone, liver and adrenal gland findings, although in these cases the results did not affect staging as limited or extensive disease. Moreover, FDG-PET appeared to be more sensitive for the detection of metastatic mediastinal and hilar lymph nodes and bone metastases. Finally, all findings considered suspicious for tumour involvement on the other staging procedures were also detected by FDG-PET. It is concluded that FDG-PET has potential for use as a simplified staging tool for small cell lung cancer.

Diagnosis and monitoring of central nervous system involvement in systemic lupus erythematosus: value of F-18 fluorodeoxyglucose PET

OBJECTIVE To investigate prospectively abnormalities of brain glucose utilisation in relation to major or minor neuropsychiatric symptoms in systemic lupus erythematosus (SLE). METHODS Positron emission tomography (PET) using F-18-labelled fluorodeoxyglucose was performed in 28 patients with SLE. Patients were classified as having severe neuropsychiatric manifestations (seizures, focal neurological deficits, acute confusional states, mood disorders) (n=12), or mild neuropsychiatric manifestations (headache, reactive depression, cognitive dysfunction, anxiety disorders) (n=11) and five patients without signs of central nervous system (CNS) involvement. Ten clinically and neurologically healthy volunteers served as controls. In 26 patients magnetic resonance imaging (MRI) was performed and autoantibodies against CNS tissue, ribosomal P protein and cardiolipin were measured. In 14 patients follow up PET scans were performed after a mean (SD) period of 11.6 (9.5) months. RESULTS PET scans showed hypometabolism in at least one brain region in all patients with severe or mild CNS symptoms (100%) as compared with patients without cerebral symptoms (40%) (p<0.0025). Parieto-occipital regions were most commonly affected (96%), followed by parietal regions (32%). In contrast, MRI images were abnormal in only 11 of 22 patients (50%) with neuropsychiatric symptoms and in one of four patients (25%) without symptoms. In 12 of 14 patients examined in follow up PET scans persistence, improvement or worsening of cerebral symptoms were associated with unchanged, decreased or increased brain hypometabolism, respectively. No significant correlation was found between PET or MRI findings and autoantibody profiles. CONCLUSIONS PET imaging represents a sensitive tool to detect manifest or subclinical CNS involvement in SLE and PET findings correlate well with the clinical course of disease.

Coronary Vasoregulation in Patients With Various Risk Factors in Response to Cold Pressor Testing Contrasting Myocardial Blood Flow Responses to Short- and Long-Term Vitamin C Administration

OBJECTIVES We sought to determine whether abnormal myocardial blood flow (MBF) responses to the cold pressor test (CPT) in patients with various risk factors may involve different mechanisms that could lead to varying responses of short- and long-term administration of antioxidants. BACKGROUND There is a growing body of evidence that increased vascular production of reactive oxygen species markedly reduces the bioavailability of endothelium-derived nitric oxide, leading to impaired vasodilator function. It is unknown whether increased oxidative stress is the prevalent mechanism underlying endothelial dysfunction in patients with different coronary risk factors. METHODS Fifty patients with normal coronary angiograms were studied. The MBF responses to CPT was determined by means of positron emission tomography before and after intravenous infusion of 3 g vitamin C or saline (placebo), as well as after 3 months and 2 years of 2 g vitamin C or placebo supplementation daily. RESULTS In hypertensive patients, the change in MBF (DeltaMBF) was not modified significantly by short-term vitamin C administration challenges (0.20 +/- 0.20 ml/g/min; p = NS) but was significantly increased after three months and two years of treatment with vitamin C versus baseline (0.58 +/- 0.27 and 0.63 +/- 0.17 vs. 0.14 +/- 0.18 ml/g/min; both p < or = 0.001). In smokers, DeltaMBF in response to CPT was significantly increased after short-term vitamin C infusion and long-term vitamin C treatment (0.52 +/- 0.10, 0.54 +/- 0.13, 0.50 +/- 0.07 vs. -0.08 +/- 0.10 ml/g/min; all p < or = 0.001). In hypercholesterolemic patients, no improvement in DeltaMBF during CPT was observed after short- and long-term vitamin C treatment (0.05 +/- 0.14, 0.08 +/- 0.18, 0.02 +/- 0.19 vs. 0.08 +/- 0.16 ml/g/min; p = NS). The CPT-induced DeltaMBF in hypertensive patients and smokers after follow-up was significant as compared with placebo and control subjects (p < or = 0.001). CONCLUSIONS The present study revealed marked heterogeneous responses in MBF changes to short- and long-term vitamin C treatment in patients with various risk factors, which highlights the quite complex nature underlying abnormal coronary vasomotion.

First Clinical Evidence That Imaging with Somatostatin Receptor Antagonists Is Feasible

Preclinical studies have indicated that somatostatin receptor (sst)–expressing tumors demonstrate higher uptake of radiolabeled sst antagonists than of sst agonists. In this study, we evaluated whether imaging with sst antagonists was feasible in patients. Methods: Biodistribution and tumor uptake of the sst antagonist 111In-DOTA-pNO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)DTyrNH2 (111In-DOTA-BASS) were studied in 5 patients with metastatic thyroid carcinoma or neuroendocrine tumors. Findings were compared with 111In-pentetreotid (111In-DTPA-octreotide) scan. Results: No adverse effects of 111In-DOTA-BASS (20 μg) were observed. 111In-DOTA-BASS detected 25 of 28 lesions, whereas 111In-DTPA-octreotide detected only 17 of 28 lesions. In the same patient, 111In-DOTA-BASS showed higher tumor and lower renal uptake than 111In-DTPA-octreotide (3.5 ± 2.8 percentage injected activity [%IA] vs. 1.0 ± 0.99%IA and 1.5 ± 0.3 %IA vs. 2.3 ± 0.7 %IA) at 4 h after injection. Conclusion: Imaging of neuroendocrine tumors with sst antagonists is clinically feasible. The favorable human biodistribution data suggest that sst antagonists could significantly affect peptide receptor–mediated imaging and therapy.

Validation of FDG positron emission tomography for differentiation of unknown pulmonary lesions

OBJECTIVE The impact of the (2-(fluorine-18)-fluoro-2-2deoxy-D-glucose)-positron emission tomography ((18)F-FDG-PET) for discrimination of pulmonary lesions was evaluated in a single centre prospective study. METHODS In the study, 109 patients with pulmonary lesions of unknown origin verified by computed tomography were enrolled consecutively (April 1999--May 2000). They were subject to (18)F-FDG-PET diagnostics. (18)F-FDG-PET images were interpreted by two independent nuclear medicine physicians who were blinded to the results of other imaging procedures. In 87 patients, surgery was applied followed by histological investigation, which served as the gold standard. In 22 other patients, extensive tumour load or assumed benign dignity of the lesions prevented surgery. RESULTS Overall sensitivity of (18)F-FDG-PET in 87 resected patients was 0.86. Differentiation in malignant (n = 69) and benign lesions (n = 18) revealed sensitivities of 0.9 and 0.72, respectively. Sensitivity of (18)F-FDG-PET in inflammatory lesions was markedly lower (0.43) than in benign tumours (0.91). Standard uptake values were significantly increased in malignant tumours compared with benign lesions (9.9 and 1.6, respectively; P = 0.035). There was a clear correlation of sensitivity with tumour size with a failure rate of 27% in lesions < or = 1cm (n = 15), 10% (n = 20) in lesions between 1 and 2 cm and 12% (n = 45) above 2 cm. In primary bronchial carcinoma, a clear correlation of sensitivity was observed with regard to tumour grading (G1, three out of five; G2, 24 out of 27; G3, 26 out of 26; and G4, one out of one). Lymph node involvement was correctly suggested in 10 out of 19 (52.6%) patients. However, false positive lymph node enhancement was indicated in one out of 18 (5.5%) operated patients with benign lesions and eight out of 39 (20.5%) with bronchial carcinoma. CONCLUSION (18)F-FDG-PET at present does not serve as the gold standard for early detection of small and well-differentiated tumours. However, it contributes efficiently to the detection of malignancy in tumours >1cm, which are moderately or poorly differentiated. Positive lymph node imaging must not preclude surgery but requires histological proof. Discrimination of benign and malignant pulmonary tumours by (18)F-FDG-PET appears to be hampered in inflammatory lesions.

Positron Emission Tomography/Computed Tomography and Whole-Body Magnetic Resonance Imaging in Staging of Advanced Nonsmall Cell Lung Cancer-Initial Results

Objective:To evaluate and compare positron emission tomography/computed tomography (PET/CT) with whole-body magnetic resonance imaging (wbMRI) in the correct staging of patients with advanced nonsmall cell lung cancer (NSCLC). Materials and Methods:Fifty-two patients with an NSCLC stage IIIa or IIIb (36 males and 16 females) were included in this study. Patients were referred to our department for restaging. Within 1 week PET/CT and wbMRI were performed in all patients. Images were examined independently by 2 experienced physicians from the Department of Nuclear Medicine and Radiology. Afterward, consensus reading was performed. In 22 patients, surgery served as gold standard, whereas in 30 patients, follow-up controls (after 2 months) were performed. Results:The use of wbMRI correctly T-staged all patients. Especially volume interpolated breathhold examination sequence correctly T-staged all tumors. PET/CT did not correctly stage chest wall infiltration in 4 cases [sensitivity 92.3% (P < 0.05 to wbMRI)/specificity 100%], verified by surgery. PET/CT correctly N-staged 51 patients (sensitivity 96.1%/specificity 100%). WbMRI showed a significant tendency to understage N-status [sensitivity 88.5% (P < 0.05)/specificity 96.1%]. Different N-status by PET/CT changed operability in 4 patients. In 2 patients, distant metastases were detected by both techniques. Conclusion:In the correct staging of advanced NSCLC, PET/CT has advantages in N-staging. This is of high relevance for therapy planning. WbMRI especially using volume interpolated breathhold examination sequences, has certain advantages in T-staging.

Regional myocardial perfusion defects during exercise, as assessed by three dimensional integration of morphology and function, in relation to abnormal endothelium dependent vasoreactivity of the coronary microcirculation

Objective: To test the hypothesis that scintigraphic regional myocardial perfusion defects during exercise in patients with normal coronary angiography may be related to abnormal endothelium dependent vasoreactivity of the corresponding myocardial territory in response to cold pressor testing. Methods: 38 patients were classified into two groups according to the presence or absence of exercise induced scintigraphic myocardial perfusion defects. A cold pressor test was done in all patients during routine coronary angiography, followed by dynamic positron emission tomography to establish coronary blood flow mediated vasoreactivity of the epicardial coronary artery and the myocardial territories supplied by the left anterior descending, left circumflex, and right coronary arteries. Results: 28 patients had regional myocardial perfusion defects while 10 had normal scintigraphic imaging. The three dimensional scintigraphic fusion image revealed 49 regional myocardial perfusion defects with a mean (SD) reversibility of the original stress defect of 20 (3)%. In patients with exercise induced regional myocardial perfusion defects, the responses of epicardial luminal area and regional myocardial blood flow (RMBF) to cold pressor testing were reduced compared with patients with normal perfusion imaging (epicardial luminal area: 5.2 (1.2) to 4.2 (0.86) mm2v 4.7 (0.5) to 5.8 (0.5) mm2; RMBF: 0.75 (0.16) to 0.78 (0.20) ml/g/min v 0.75 (0.15) to 1.38 (0.26) ml/g/min; p ≤ 0.03, respectively). In patients with regional abnormal scintigraphic perfusion, the corresponding RMBF response to cold pressor testing was more severely impaired than the mean myocardial blood flow in the remaining two vascular territories, but the difference was not significant (0.75 (0.16) to 0.78 (0.20) ml/g/min v 0.75 (0.10) to 0.87 (0.12) ml/g/min; NS). The endothelium independent increase in RMBF induced by glyceryl trinitrate did not differ between patients with exercise induced myocardial perfusion defects and those with normal perfusion images (0.75 (0.16) to 0.94 (0.09) ml/g/min v 0.75 (0.15) to 0.94 (0.09) ml/g/min; NS). There was a highly significant correlation between the endothelium dependent responses of RMBF to cold pressor testing and the severity of exercise induced scintigraphic regional myocardial perfusion defects (r = 0.95, p = 0.001). Conclusions: Exercise induced scintigraphic regional myocardial perfusion defects in patients with angina but normal coronary angiography may be related to abnormal endothelium dependent vasoreactivity of the corresponding myocardial territory.

Impact of FDG-PET for staging of oesophageal cancer

Background and aimsTreatment of oesophageal cancer depends on staging and the general health of the patient. In stages I–II b, as well as in some stage III diseases, surgical resection remains the therapy of choice for cure, but a curative approach is not possible in stage IV. In our hospital we give preoperative radio-chemotherapy to all patients with an oesophageal cancer T>1, Nx, M0. Therefore, the main purpose of the clinical staging of oesophageal cancer is the exclusion of M1 and T4 disease with infiltration into the tracheobronchial system or the aorta. The aim of the investigation was the assessment of positron emission tomography for detection of M1 disease.Patients/methodsBetween 1998 and 2002, 84 patients with oesophageal cancer (64% squamous cell carcinoma and 36% adenocarcinoma) were enrolled into the study. Of these, 48.8% were operated on; 35.7% of the patients were not operated on, for oncological reasons, 7.1% for medical reasons, 3.6% chose not to be operated on, and, for unknown reasons, 4.8% were not operated on.ResultsTwenty-five patients had stage IV disease or additional, synchronous cancer of the head and neck (n=2). As the only investigational procedure, positron emission tomography revealed M1 stage in 11 of 25 patients (44%). In 13/25 (52%) both computed tomography and positron emission tomography revealed stage IV disease. False positive results by positron emission tomography were observed in three patients. The sensitivity and specificity of positron emission tomography (PET) was 0.96 and 0.95, respectively. Most of the metastases detected by PET only, were localised within the neck, liver and bone. With regard to the 66 of 84 patients deemed medically fit for operation and without local infiltration into the tracheobronchial system (T4) PET as the only imaging procedure changed the therapeutic strategy in 11 of 66 (16.6%) patients with to M1 disease.ConclusionOur results demonstrated clearly the impact of the PET scan for decision-making in patients with oesophageal carcinoma. PET should be performed prior to therapy with curative intention. However, addition of a computed tomography scan of the neck might reduce the rate of unexpected metastases detected by PET.