Christian Menzel

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.

Local Recurrence Rates in Breast Cancer Patients Treated with Intraoperative Electron-Boost Radiotherapy Versus Postoperative External-Beam Electron-Boost Irradiation A Sequential Intervention Study

Background and Purpose:The purpose of this sequential intervention study was to determine the rate of local recurrences and the rate of distant metastases in patients with invasive breast cancer who had been treated with breast-conserving surgery and postoperative radiation therapy to the whole breast either with postoperative electron boost in group 1 or with intraoperative electron boost (IORT) in group 2.Patients and Methods:After breast-conserving surgery, 378 women with invasive breast cancer of tumor sizes T1 and T2 received 51–56.1 Gy of postoperative radiation therapy to the whole breast in 1.7-Gy fractions. 188 of those patients additionally received a postoperative electron boost of 12 Gy in group 1 from January 1996 to October 1998. Consecutively, from October 1998 to March 2001, 190 patients received intraoperative electron-boost radiotherapy of 9 Gy to the tumor bed in group 2. The groups were comparable with regard to age, menopausal status, tumor size, grading, and nodal status. All statistical tests were twosided.Results:During a median follow-up period of 55.3 months in group 1 and 25.8 months in group 2, local recurrences were observed in eight of 188 patients (4.3%) in group 1, and no local recurrence was seen in group 2 (p = 0.082). Distant metastases occurred in 15 of the 188 patients (7.9%) in group 1 and in two of the 190 patients (1.1%) in group 2 (p = 0.09). The 4-year actuarial rates of local recurrence were 4.3% (95% confidence interval, 1.8–8.2%) and 0.0% (95% confidence interval, 0.0–1.9%) and the 4-year actuarial rates of distant metastases were 7.9% (95% confidence interval, 4.5–12.8%) and 1.1% (95% confidence interval, 0.1–3.8%).Conclusion:Immediate IORT boost yielded excellent local control figures in this prospective investigation and appears to be superior to conventional postoperative boost in a short-term follow-up.Hintergrund und Ziel:Ziel dieser sequentiellen Interventionsstudie war die Bestimmung der Lokalrezidiv- und Fernmetastasenrate von Patientinnen mit invasivem Mammakarzinom, die mit brusterhaltender Operation und anschließender Bestrahlung der gesamten Brust, aber verschiedenen Boostbestrahlungen therapiert worden waren. Gruppe 1 erhielt eine postoperative Boostbestrahlung und Gruppe 2 eine intraoperative Radiotherapie (IORT) in Boostmodalität.Patienten und Methodik:Nach brusterhaltender Operation erhielten 378 Patientinnen mit invasivem Mammakarzinom mit T1- und T2-Tumoren eine postoperative Bestrahlung der gesamten Brust von 51–56.1 Gy in 1.7-Gy-Fraktionen. Von Januar 1996 bis Oktober 1998 bekamen 188 Patientinnen in Gruppe 1 postoperativ zusätzlich eine Elektronenboostbestrahlung von 12 Gy. Von Oktober 1998 bis März 2001 erhielten 190 Patientinnen in Gruppe 2 eine intraoperative Elektronenboostbestrahlung von 9 Gy direkt auf das Tumorbett. Beide Gruppen waren bezüglich Alter, Menopausenstatus, Tumorgröße, Grading und Nodalstatus vergleichbar. Die statistische Analyse erfolgte zweiseitig.Ergebnisse:Nach einer mittleren Nachbeobachtungszeit von 55,3 Monaten in Gruppe 1 und 25,8 Monaten in Gruppe 2 traten bei acht der 188 Patientinnen in Gruppe 1 (4,3%) Lokalrezidive auf, während es in Gruppe 2 zu keinem Lokalrezidiv kam (p = 0.082). Fernmetastasen ereigneten sich bei 15 der 188 Patientinnen (7,9%) in Gruppe 1 und zwei der 190 Patientinnen (1,1%) in Gruppe 2 (p = 0.09). Die 4-Jahres-Raten für Lokalrezidive betrugen 4,3% (95%-Konfidenzintervall 1,8–8,2%) und 0% (95%- Konfidenzintervall 0–1,9%) und die 4-Jahres-Raten für Fernmetastasen 7,9% (95%-Konfidenzintervall 4.5–12,8%) und 1,1% (95%-Konfidenzintervall 0,1–3,8%).Schlussfolgerung:Die intraoperative Boostbestrahlung zeigt exzellente Ergebnisse bezüglich der Lokalrezidivrate und scheint der postoperativen Boostbestrahlung in der Kurzzeitnachbeobachtung überlegen zu sein.

Local recurrence rates in breast cancer patients treated with intraoperative electron-boost radiotherapy versus postoperative external-beam electron-boost irradiation

Background and Purpose:The purpose of this sequential intervention study was to determine the rate of local recurrences and the rate of distant metastases in patients with invasive breast cancer who had been treated with breast-conserving surgery and postoperative radiation therapy to the whole breast either with postoperative electron boost in group 1 or with intraoperative electron boost (IORT) in group 2.Patients and Methods:After breast-conserving surgery, 378 women with invasive breast cancer of tumor sizes T1 and T2 received 51–56.1 Gy of postoperative radiation therapy to the whole breast in 1.7-Gy fractions. 188 of those patients additionally received a postoperative electron boost of 12 Gy in group 1 from January 1996 to October 1998. Consecutively, from October 1998 to March 2001, 190 patients received intraoperative electron-boost radiotherapy of 9 Gy to the tumor bed in group 2. The groups were comparable with regard to age, menopausal status, tumor size, grading, and nodal status. All statistical tests were twosided.Results:During a median follow-up period of 55.3 months in group 1 and 25.8 months in group 2, local recurrences were observed in eight of 188 patients (4.3%) in group 1, and no local recurrence was seen in group 2 (p = 0.082). Distant metastases occurred in 15 of the 188 patients (7.9%) in group 1 and in two of the 190 patients (1.1%) in group 2 (p = 0.09). The 4-year actuarial rates of local recurrence were 4.3% (95% confidence interval, 1.8–8.2%) and 0.0% (95% confidence interval, 0.0–1.9%) and the 4-year actuarial rates of distant metastases were 7.9% (95% confidence interval, 4.5–12.8%) and 1.1% (95% confidence interval, 0.1–3.8%).Conclusion:Immediate IORT boost yielded excellent local control figures in this prospective investigation and appears to be superior to conventional postoperative boost in a short-term follow-up.Hintergrund und Ziel:Ziel dieser sequentiellen Interventionsstudie war die Bestimmung der Lokalrezidiv- und Fernmetastasenrate von Patientinnen mit invasivem Mammakarzinom, die mit brusterhaltender Operation und anschließender Bestrahlung der gesamten Brust, aber verschiedenen Boostbestrahlungen therapiert worden waren. Gruppe 1 erhielt eine postoperative Boostbestrahlung und Gruppe 2 eine intraoperative Radiotherapie (IORT) in Boostmodalität.Patienten und Methodik:Nach brusterhaltender Operation erhielten 378 Patientinnen mit invasivem Mammakarzinom mit T1- und T2-Tumoren eine postoperative Bestrahlung der gesamten Brust von 51–56.1 Gy in 1.7-Gy-Fraktionen. Von Januar 1996 bis Oktober 1998 bekamen 188 Patientinnen in Gruppe 1 postoperativ zusätzlich eine Elektronenboostbestrahlung von 12 Gy. Von Oktober 1998 bis März 2001 erhielten 190 Patientinnen in Gruppe 2 eine intraoperative Elektronenboostbestrahlung von 9 Gy direkt auf das Tumorbett. Beide Gruppen waren bezüglich Alter, Menopausenstatus, Tumorgröße, Grading und Nodalstatus vergleichbar. Die statistische Analyse erfolgte zweiseitig.Ergebnisse:Nach einer mittleren Nachbeobachtungszeit von 55,3 Monaten in Gruppe 1 und 25,8 Monaten in Gruppe 2 traten bei acht der 188 Patientinnen in Gruppe 1 (4,3%) Lokalrezidive auf, während es in Gruppe 2 zu keinem Lokalrezidiv kam (p = 0.082). Fernmetastasen ereigneten sich bei 15 der 188 Patientinnen (7,9%) in Gruppe 1 und zwei der 190 Patientinnen (1,1%) in Gruppe 2 (p = 0.09). Die 4-Jahres-Raten für Lokalrezidive betrugen 4,3% (95%-Konfidenzintervall 1,8–8,2%) und 0% (95%- Konfidenzintervall 0–1,9%) und die 4-Jahres-Raten für Fernmetastasen 7,9% (95%-Konfidenzintervall 4.5–12,8%) und 1,1% (95%-Konfidenzintervall 0,1–3,8%).Schlussfolgerung:Die intraoperative Boostbestrahlung zeigt exzellente Ergebnisse bezüglich der Lokalrezidivrate und scheint der postoperativen Boostbestrahlung in der Kurzzeitnachbeobachtung überlegen zu sein.

Correlation of hippocampal glucose oxidation capacity and interictal FDG-PET in temporal lobe epilepsy

Summary:  Purpose: Interictal [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) demonstrates temporal hypometabolism in the epileptogenic zone of 60–90% of patients with temporal lobe epilepsy. The pathophysiology of this finding is still unknown. Several studies failed to show a correlation between hippocampal FDG‐PET hypometabolism and neuronal cell loss. Because FDG is metabolized by hexokinase bound to the outer mitochondrial membrane, we correlated the glucose‐oxidation capacity of hippocampal subfields obtained after surgical resection with the corresponding hippocampal presurgical FDG‐PET activity.

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.

Time-efficient T2 relaxometry of the entire hippocampus is feasible in temporal lobe epilepsy

Objective: To test the clinical usefulness and reliability of a new dual-echo turbo-spin-echo (TSE) sequence for rapid and regional hippocampal T2 relaxometry. Methods: Hippocampal T2 relaxation time (HRT) was determined by a TSE sequence on three to four consecutive coronal images in 16 control subjects and 12 patients with mesial temporal lobe epilepsy. HRT was related to neuropathology findings in hippocampal specimens including neuronal cell density (ND), results of visual analysis of MR images, clinical outcome after epilepsy surgery, and hippocampal volumetry. Results: Rapid HRT differentiated patients from control subjects; all cases of hippocampal sclerosis (HS; n = 10) were correctly diagnosed. HRT showed a strong correlation with ND in CA1 (p < 0.02) and CA3 (p < 0.05). Diagnoses based on rapid relaxometry concurred fully with results of visual inspection. Mean HRT was prolonged ipsilaterally in all patients with excellent postoperative seizure outcome and bilaterally prolonged or normal in patients with poorer outcome. Rapid HRT was concordant with hippocampal volumetry in 10 of 12 patients. Regional HRT of control subjects revealed significantly higher values in the anterior than posterior hippocampus. In patients with unilateral HS, this gradient was absent. The gradient was also absent contralaterally to HS, although surgical outcome was excellent. Conclusions: Hippocampal dual-echo TSE-relaxometry can be regarded a reliable technique to detect and quantify HS. With a scan time of 3.31 minutes and immediate off-line analysis lasting a few minutes only, TSE-T2 relaxometry is easy to integrate in the routine diagnostic assessment of hippocampal morphology in large numbers of patients.

Sentinel Node Biopsy as Staging Tool in a Multimodality Treatment Approach to Cancer of the Oral Cavity and the Oropharynx

OBJECTIVES: Feasibility of sentinel lymph node (SLN) biopsy in head and neck cancer as a staging tool embedded in a multimodality regimen including neoadjuvant intraarterial chemotherapy. STUDY DESIGN AND SETTING: 39 patients with oral and anterior oropharyngeal cancer classified N0 by [18F]FDG-PET underwent SLN scintigraphy. Selective SLN biopsy without elective neck dissection (ND) was performed, immediately followed by radical resection of the primary tumor. Histopathology included step-serial sections and immunocyto-chemistry. RESULTS: Lymphoscintigraphy detected 104 spots. In 15 patients there was bilateral drainage. 114 SLN were excised due to additional intraoperative discrimination. 95% of visualised SLN could be removed. Histology was positive in 3 patients (8%), all underwent ND which yielded another positive node in 2 cases. Median observation time was 30 months. Two patients (5%) had a neck relapse in combination with a second primary. CONCLUSIONS: SLN biopsy as only surgical staging tool seems to be feasible. SIGNIFICANCE: Method promises reduction of elective ND and morbidity in N0 patients.

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.

Malignant Melanoma and Soft Tissue Sarcomas

Malignant melanoma (MM) of the skin has increased dramatically throughout the world during recent years. The overall increase in incidence has been dominated by new cases in the developed countries, with most patients being diagnosed in North America and Western Europe and, relative to population size, a large number of cases in Australia and New Zealand. While it is obvious that a combination of light-colored populations and increasing exposure to ultraviolet radiation has led to an increased risk of the development of malignant melanomas, it remains largely unknown in detail which factors are responsible for the transformation of a rarely proliferating melanocyte into a highly aggressive, often fatal tumor. Recently it has been shown that surface anomalies on the melanoma cells are responsible for a loosely bound architecture of tumor clones, leading to the easy development of metastatic disease. For these reasons there is an increasing need for advanced diagnostic strategies and new therapy modalities.