Natascha Döbert

Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI)

Background—Experimental studies suggest that transplantation of blood-derived or bone marrow–derived progenitor cells beneficially affects postinfarction remodeling. The safety and feasibility of autologous progenitor cell transplantation in patients with ischemic heart disease is unknown. Methods and Results—We randomly allocated 20 patients with reperfused acute myocardial infarction (AMI) to receive intracoronary infusion of either bone marrow–derived (n=9) or circulating blood–derived progenitor cells (n=11) into the infarct artery 4.3±1.5 days after AMI. Transplantation of progenitor cells was associated with a significant increase in global left ventricular ejection fraction from 51.6±9.6% to 60.1±8.6% (P =0.003), improved regional wall motion in the infarct zone (−1.5±0.2 to −0.5±0.7 SD/chord;P <0.001), and profoundly reduced end-systolic left ventricular volumes (56.1±20 mL to 42.2±15.1 mL;P =0.01) at 4-month follow-up. In contrast, in a nonrandomized matched reference group, left ventricular ejection fraction only slightly increased from 51±10% to 53.5±7.9%, and end-systolic volumes remained unchanged. Echocardiography revealed a profound enhancement of regional contractile function (wall motion score index 1.4±0.2 at baseline versus 1.19±0.2 at follow-up;P <0.001). At 4 months, coronary blood flow reserve was significantly (P <0.001) increased in the infarct artery. Quantitative F-18-fluorodeoxyglucose–positron emission tomography analysis revealed a significant (P <0.01) increase in myocardial viability in the infarct zone. There were no differences for any measured parameter between blood-derived or bone marrow–derived progenitor cells. No signs of an inflammatory response or malignant arrhythmias were observed. Conclusions—In patients with AMI, intracoronary infusion of autologous progenitor cells appears to be feasible and safe and may beneficially affect postinfarction remodeling processes.

Pilot Trial on Determinants of Progenitor Cell Recruitment to the Infarcted Human Myocardium

Background— Clinical trials indicate a beneficial effect of intracoronary infusion of progenitor cells on myocardial function in patients with ischemic heart disease. The extent and potential determinants of proangiogenic progenitor cell homing into the damaged myocardium after intracoronary infusion and the underlying mechanisms are still unknown. Method and Results— Circulating proangiogenic progenitor cells isolated from peripheral blood and cultivated for 3 days were labeled with radioactive indium oxine (111In-oxine). Radiolabeled proangiogenic progenitor cells (7.6±3.0 MBq, mean±SD) were administered to patients with previous myocardial infarction and a revascularized infarct vessel at various stages after infarction (5 days to 17 years). Viability of the infarcted myocardium was determined by 18F-fluorodeoxyglucose–positron emission tomography and microcirculatory function by intracoronary Doppler measurements. One hour after application of progenitor cells, a mean of 6.9±4.7% (range, 1% to 19%; n=17) of total radioactivity was detected in the heart, which declined to 2±1% after 3 to 4 days. Average activity within the first 24 hours was highest among patients with acute myocardial infarction (≤14 days; 6.3±2.9%; n=8) and progressively decreased in patients treated in an intermediate phase (>14 days to 1 year; 4.5±3.2%; n=4) or a chronic stage (infarct age >1 year; 2.5±1.6%; n=5). Low viability of the infarcted myocardium and reduced coronary flow reserve were significant (P<0.05) predictors of proangiogenic progenitor cell homing. Conclusions— In patients after myocardial infarction undergoing intracoronary infusion of 111In-oxine–labeled proangiogenic progenitor cells, a substantial amount of radioactivity is detected for several days in the heart, indicating homing of progenitor cells to the myocardium. The amount of proangiogenic progenitor cells retained in the heart decreased progressively with time after the acute myocardial infarction. Proangiogenic progenitor cells preferentially home to extensive acute myocardial infarcts characterized by low viability and reduced coronary flow reserve.

Transplantation of progenitor cells after reperfused acute myocardial infarction: evaluation of perfusion and myocardial viability with FDG-PET and thallium SPECT

Clinical outcome after myocardial infarction depends on the extent of irreversibly damaged myocardium. Implantation of bone marrow-/circulating blood-derived progenitor cells has been shown to improve contractile cardiac function after myocardial infarction in both experimental and initial clinical studies. In the present study, first observations of the effect of local intracoronary progenitor cell infusion on the regeneration of infarcted cardiac tissue after acute myocardial infarction was evaluated by means of 18F-fluorodeoxyglucose positron emission tomography (PET) and 201Tl single-photon emission computed tomography (SPECT). Twenty-six patients underwent intracoronary infusion of bone marrow-derived (BMCs) (15 patients) or circulating blood-derived endothelial progenitor cells (EPCs) (11 patients) 4±2 days after acute myocardial infarction. Based on a left ventricular segmentation model (17 segments), mean signal intensities as a parameter of viability and perfusion in the infarct zone and non-infarct areas were calculated quantitatively by PET and SPECT at baseline and at 4 months of follow-up. Transplantation of progenitor cells was associated with a significant increase in the mean signal intensity (MSI) in the infarct zone from 54.5% (25th and 75th percentiles: 47.7%, 60.0%) to 58.0% (52.7%, 66.7%) on PET (P=0.013) and from 58.0% (49.5%, 63.0%) to 61.5% (52.5%, 70.2%) on SPECT (P=0.005). Global left ventricular ejection fraction (LVEF) increased from 53.5% (42.6%, 60.0%) to 58.0% (53.0%, 65.8%) (P<0.001). In the five patients without an increase in MSI on PET, LVEF changed from 60.0% (50.0%, 64.0%) to 72.0% (64.0%, 75.5%) at follow-up. PET and SPECT did not show any significant changes in MSI in the non-infarct areas [from 73% (68.5%, 76.2%) to 73% (69.7%, 78.0%) for PET and from 72.0% (66.5%, 77.6%) to 73.0% (67.5%, 78.2%) for SPECT]. There were no significant differences in myocardial viability and perfusion between BMC and EPC infusion. These preliminary results show that coronary stenting and transplantation of progenitor cells result in a significant increase in myocardial viability and perfusion. Therapeutic effects can be reliably measured by PET and SPECT.

Positron Emission Tomography in Combination With Sentinel Node Biopsy Reduces the Rate of Elective Neck Dissections in the Treatment of Oral and Oropharyngeal Cancer

PURPOSE To assess the impact of a diagnostic ladder including [(18)F]fluorodeoxyglucose positron emission tomography (PET) and lymphoscintigraphy guided sentinel node biopsy (LS/SNB) on neck treatment in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC). PATIENTS AND METHODS Prospectively, 62 patients with resectable T1-3 OOSCC underwent computed tomography (CT) and PET. Patients without neck uptake in PET were defined as cN0 and were accrued for LS/SNB. Results were correlated with histopathology. The traditional guidelines according to CT findings were compared to the actual regimen and the outcome. RESULTS Sensitivity, specificity, validity, and positive and negative predictive value of PET versus CT were 72% v 89%, 82% v 77%, 79% v 80.5%, 62% v 61.5%, and 88% v 94.5% (not significant). Thirty-eight PET negative patients underwent LS/SNB. Sentinel lymph nodes were found in all 38 patients. Five patients had positive nodes (PET false-negatives) and underwent neck dissection (ND). Fifty-one neck sides in 36 patients who were CT-negative would have been treated with selective ND according to the guidelines, and at least 45 neck sides would have had to undergo extensive ND because of positive CT findings (96 of 124 neck sides). In contrast, PET in combination with LS/SNB spared 59 neck sides, and 41 of 124 neck sides actually underwent ND as a result of PET staging, LS/SNB, and intraoperative decision. After a median follow-up of 35 months, two patients (both cN+ve and pN+ve) suffered from neck relapses. CONCLUSION Diagnostics using PET in combination with LS/SNB considerably reduced the number of extensive ND in OOSCC as compared to CT without locoregional hazard.

Positron emission tomography for the staging of Hodgkin's lymphoma: Increasing the body of evidence in favor of the method

The staging of Hodgkins lymphoma (HL) is crucial for an optimal therapy, and fluorine-18-deoxyglucose-positron emission tomography (FDG-PET) is increasingly used in this regard. However, there is still a scarcity of available data on the staging of HL. Twenty-eight consecutive patients with newly diagnosed HL were included in this study. PET results were compared with conventional staging, including clinical workup, computerized tomography (CT) and sonography. Evaluation was focused on the description of involved lymph node (LN) regions or organs rather than on a lesion-by-lesion analysis. In supradiaphragmal LN, the results of PET and CT scans were positive in 26% and negative in 68% of cases. Furthermore, PET was positive in 5% (CT negative), and CT showed enlarged LN in 1% of cases (PET negative). In infradiaphragmal LN, PET/CT results were positive in 10% and negative in 88% of cases. In 2% of cases, PET showed additional foci, while in 1% the CT was positive. PET changed the staging in 21% of cases (4 up-stagings, 2 down-stagings) and this was confirmed during follow-up. PET should therefore be routinely used for staging HL until larger clinical studies can demonstrate patients who may not require this additional investigation or those patients who are reliably staged on the basis of PET alone.

Differentiated Thyroid Carcinoma: The New UICC 6th Edition TNM Classification System in a Retrospective Analysis of 169 Patients

AIM To compare the new, 6th edition, UICC TNM staging system with the former edition, we updated TNM staging in patients with differentiated thyroid carcinoma. METHODS The new and old TNM classification systems for differentiated thyroid carcinoma were applied in a retrospective analysis of 169 patients who underwent therapy with radioiodine (131I) from 1975 through 2002 at the Department of Nuclear Medicine, Frankfurt. RESULTS According to the new staging system, 83 patients (49%) were classified as T1 compared to 54 patients (32%) based on the former edition; 32 patients (19%) as T2 compared to 61 (36%) patients formerly. In 44 patients with minimal extrathyroid extension, formerly classified T4, the new TNM staging changed to T3, and no patient was classified T4. The one year relapse-free survival fraction under the former edition staging was 100% for T1 and 92.2% for T2, compared to 96.8% for new edition T1 and 93.3% for T2. CONCLUSION The new TNM classification causes a significant change in staging. New T1 classified tumors had a slightly worse relapse-free survival fraction compared with the old T1 carcinomas. For patients treated at our department, the altered criteria for classifying extrathyroid extensions have had only a minor impact on disease management.

Diagnostic Value of FDG-PET and HMPAO-SPET in Patients with Mild Dementia and Mild Cognitive Impairment: Metabolic Index and Perfusion Index

Objective: The diagnostic potential of F-18-2-fluoro-2-deoxy-D-glucose positron emission tomography (PET) and technetium-99m hexamethylpropylene amine oxime single-photon emission tomography (SPET) in early detection and differential diagnosis of early dementia was evaluated including a comparison of metabolic and perfusion indices (PI). Methods: Twenty-four patients with initial clinical suspicion of beginning dementia were examined, 12 of them with mild cognitive impairment. All patients underwent SPET and PET within 2 weeks. Data were compared with the final clinical diagnosis at follow-up – 9 with Alzheimer’s disease (AD), 1 with frontotemporal dementia, 1 with vascular dementia (VD), 7 with mixed type of dementia (MIX) and 6 without any type of dementia. Metabolic indices (MI) and PI were compared with each other. The regional cerebral blood flow difference (rCBFdiff) calculated as local uptake difference between the right and left hemisphere was measured for patients with VD and MIX. Results: PET showed higher sensitivity and specificity in identifying the different types of early dementia (44–91 and 78–89%, respectively) than SPET (11–64 and 79–89%, respectively), especially in detecting AD (sensitivity 44%, specificity 83%) and MIX (sensitivity 71%, specificity 78%). Especially in patients with mild cognitive impairment, PET was the superior imaging modality for predicting dementia. Using PET, dementia could be excluded in all patients who did not develop dementia during the follow-up. In all patients, a weak correlation between PI and MI was observed (rho = 0.64, p < 0.002). The rCBFdiff in patients with VD and MIX ranged from 7 to 37%. Conclusion: In this study on patients with initial suspicion of beginning dementia who underwent both imaging modalities, PET and SPET, PET was the superior imaging method, especially in the detection of early AD or MIX.

The Influence of CA 125 and CEA Levels on the Results of 18F-Deoxyglucose Positron Emission Tomography in Suspected Recurrence of Epithelial Ovarian Cancer

Background and Purpose:The follow-up of epithelial ovarian cancer (OCA) consists of clinical investigation, sonography, and tumor markers (TMs), especially CA 125. If tumor recurrence is suspected, other imaging modalities including positron emission tomography (PET) with 18F-deoxyglucose (FDG) are often used. While there is still no consensus about the method of choice and the timing of its application, this study aims to find a TM threshold at which a PET would be appropriate.Material and Methods:A total of 90 PET studies and the associated CA 125 values (normal value < 35 U/ml) were available in 71 patients during the follow-up after primary therapy for OCA. In 48 studies a CEA value (normal value < 3 ng/ml) was also available. The results of PET imaging were related to the level of TM increase.Results:In 23/90 studies the PET scan was normal. These patients had a median CA 125 of 13.3 U/ml (range 4.2–168 U/ml). In 67/90 studies the PET indicated a potential recurrence of OCA and the median CA 125 was 166.7 U/ml (range 13.3–4,060 U/ml). The TM levels were significantly different (p < 0.001, U-test). With one exception, there were no normal PET scans above CA 125 levels of 30 U/ml; between 20 and 30 U/ml PET was positive in 4/7 studies.Conclusion:In suspected recurrence of OCA, if imaging modalities are to be used, an FDG PET may be considered. Since the costs of this investigation are high, it should be restricted to clinical situations where it is likely to be most effective. In this study a PET indication is worthwhile at CA 125 levels of approximately 30 U/ml.Hintergrund und Ziel:Patientinnen mit epithelialen Ovarialkarzinomen (OCA) werden durch regelmäßige Bestimmungen der Tumormarker CA 125 und CEA verlaufskontrolliert. Bei Rezidivverdacht hat sich hier die 18F-Desoxyglucose-Positronenemissionstomographie (FDG-PET) als eine sensitive und auch spezifische Methode etabliert. In dieser Studie soll untersucht werden, ob sich der Einsatz der PET in Abhängigkeit von der Höhe des CA-125-Spiegels an einem Schwellenwert orientieren kann.Material und Methodik:Es wurden insgesamt 90 PET-Studien von 71 Patientinnen in die Untersuchung eingeschlossen, bei denen der aktuelle CA-125-Wert (Normalwert < 35 U/ml) vorlag. Bei 48 Studien stand zusätzlich der CEA-Wert (Normalwert < 3 ng/ml) zur Verfügung.Ergebnisse:In 23/90 Untersuchungen lag in der PET ein unauffälliger Befund vor. Diese Patientinnen wiesen einen medianen CA- 125-Spiegel von 13,3 U/ml auf (Spannweite 4,2–168 U/ml). In 67/90 Studien konnte in der PET ein tumorsuspekter Befund dargestellt werden. Der mediane CA-125-Spiegel lag hier bei 166,7 U/ml (Spannweite 13,3–4 060 U/ml). Beide Gruppen unterschieden sich hinsichtlich der Tumormarkerspiegel signifikant (p < 0,001, U-Test). Mit einer Ausnahme wurden dabei oberhalb eines CA-125-Spiegels von 30 U/ml keine normalen PET-Befunde mehr erhoben. Im Bereich zwischen 20 und 30 U/ml lieferte die PET in vier von sieben Fällen den Nachweis einer rezidivsuspekten Lokalisation.Schlussfolgerung:Im Fall eines Tumormarkeranstiegs in der Verlaufskontrolle des OCA sollten die Möglichkeiten der FDG-PET frühzeitig berücksichtigt werden. Die PET liefert dabei offenbar in Abhängigkeit von der Höhe des CA-125-Spiegels auf die Tumorlokalisation hinweisende Befunde, wobei die PET überwiegend bereits bei Werten zwischen 20 und 30 U/ml positive Befunde erbringt und ab einem Schwellenwert von 30 U/l nahezu bei jeder Patientin einen Rezidivhinweis darstellen kann.

Positron Emission Tomography in Patients with Hodgkin's Disease: Correlation to Histopathologic Subtypes

The aim of this study was to evaluate the initial staging and restaging of Hodgkins disease (HD) according to histopathologic subtype (HST) using fluorine-18-deoxyglucose-positron emission tomography (PET). Special attention was paid to the accuracy of PET for detection of bone marrow infiltration (BMI). 44 patients with HD (m:f = 28:16, mean age 36 +/- 15 years) underwent PET; 16 were primary stagings and 28 restaging examinations. PET results were compared with methods of conventional staging including computed tomography (CT) and bone marrow biopsy. Viable tumor tissue was detected by PET in 25/44 cases, 16 nodular sclerosis (NS), 4 mixed cellularity (MC), 3 lymphocyte predominance (LP) and 2 cases with a nonclassified subtype (NC). FDG tumor uptake, measured as standard uptake value (SUV), ranged from 1.7 to 13. Maximum SUV in NS was 5.2 +/- 1.5 (2.5-7.3), 3.2 +/- 2.4 for MC, 2.6 +/- 0.7 for LP, and 9.1 +/- 3.8 for NC, respectively. In 7% of all patients (3/44) bone marrow infiltrations were detected by PET. PET is known for its superior detection of viable tissue in HD. In this study it was shown that HST does not influence the intensity of glucose metabolism, although 2 patients with NC showed the highest SUVs. In addition PET accurately detected focal BMI and may thus be applied before BMB to guide its optimal use.

Enchondroma: a benign osseous lesion with high F-18 FDG uptake.

A woman was referred for fluorodeoxyglucose positron emission tomography for the staging of a malignant melanoma. Although no signs of metastatic melanoma were evident on the whole-body scan, focally increased uptake within the femoral metaphysis was noted. Radiographic and magnetic resonance examinations revealed an enchondroma as the cause of the increased uptake. Histopathologic verification was obtained. The final diagnosis was actively proliferating enchondroma. A grade I chondrosarcoma could be ruled out. Enchondromas may be responsible for focally increased FDG uptake in bone lesions and must be considered when positron emission tomographic scans obtained with FDG are evaluated in cancer staging.