Otmar Schober

Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial

BACKGROUND The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkins lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy. METHODS In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkins lymphoma aged 18-60 years were randomly assigned to receive either eight cycles of BEACOPP(escalated) (8×B(esc) group), six cycles of BEACOPP(escalated) (6×B(esc) group), or eight cycles of BEACOPP(14) (8×B(14) group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041. FINDINGS Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×B(esc) group, 711 in the 6×B(esc) group, and 710 in the 8×B(14) group. Freedom from treatment failure was sequentially non-inferior for the 6×B(esc) and 8×B(14) groups as compared with 8×B(esc). 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0-87·7) for the 8×B(esc) group, 89·3% (86·5-92·1) for 6×B(esc) group, and 85·4% (82·1-88·7) for the 8×B(14) group (97·5% CI for difference between 6×B(esc) and 8×B(esc) was 0·5-9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×B(esc) than with 8×B(esc) (97·5% CI 0·2-6·5). The 8×B(esc) group showed a higher mortality (7·5%) than the 6×B(esc) (4·6%) and 8×B(14) (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1-96·1); and 225 (11%) of 2126 patients received additional radiotherapy. INTERPRETATION Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPP(escalated) should be the treatment of choice for advanced stage Hodgkins lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting. FUNDING Deutsche Krebshilfe and the Swiss Federal Government.

Fluorine-18 fluorodeoxyglucose positron emission tomography in thyroid cancer: results of a multicentre study

n=222) and the group with negative radioiodine scan (n=166), respectively. Specificity was 90% in the whole patient group. Sensitivity and specificity of WBS were 50% and 99%, respectively. When the results of FDG-PET and WBS were considered in combination, tumour tissue was missed in only 7%. Sensitivity and specificity of MIBI/Tl were 53% and 92%, respectively (n=117). We conclude that FDG-PET is a sensitive method in the follow-up of thyroid cancer which should be considered in all patients suffering from differentiated thyroid cancer with suspected recurrence and/or metastases, and particularly in those with elevated thyroglobulin values and negative WBS.

High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P3 Lysophospholipid Receptor

Background— All treatments of acute myocardial infarction are aimed at rapid revascularization of the occluded vessel; however, no clinical strategies are currently available to protect the heart from ischemia/reperfusion injury after restitution of blood flow. We hypothesized that some of the cholesterol transport–independent biological properties of high-density lipoprotein (HDL) implied in atheroprotection may also be beneficial in settings of acute myocardial reperfusion injury. Methods and Results— In an in vivo mouse model of myocardial ischemia/reperfusion, we observed that HDL and its sphingolipid component, sphingosine-1-phosphate (S1P), dramatically attenuated infarction size by ≈20% and 40%, respectively. The underlying mechanism was an inhibition of inflammatory neutrophil recruitment and cardiomyocyte apoptosis in the infarcted area. In vitro, HDL and S1P potently suppressed leukocyte adhesion to activated endothelium under flow and protected rat neonatal cardiomyocytes against apoptosis. In vivo, HDL- and S1P-mediated cardioprotection was dependent on nitric oxide (NO) and the S1P3 lysophospholipid receptor, because it was abolished by pharmacological NO synthase inhibition and was completely absent in S1P3-deficient mice. Conclusions— Our data demonstrate that HDL and its constituent, S1P, acutely protect the heart against ischemia/reperfusion injury in vivo via an S1P3-mediated and NO-dependent pathway. A rapid therapeutic elevation of S1P-containing HDL plasma levels may be beneficial in patients at high risk of acute myocardial ischemia.

FDG-PET for detection of osseous metastases from malignant primary bone tumours: comparison with bone scintigraphy

Abstract. The purpose of this study was to compare positron emission tomography using fluorine-18 fluorodeoxyglucose (FDG-PET) and technetium-99m methylene diphosphonate (MDP) bone scintigraphy in the detection of osseous metastases from malignant primary osseous tumours. In 70 patients with histologically proven malignant primary bone tumours (32 osteosarcomas, 38 Ewings sarcomas), 118 FDG-PET examinations were evaluated. FDG-PET scans were analysed with regard to osseous metastases in comparison with bone scintigraphy. The reference methods for both imaging modalities were histopathological analysis, morphological imaging [additional conventional radiography, computed tomography (CT) or magnetic resonance imaging (MRI)] and/or clinical follow-up over 6–64 months (median 20 months). In 21 examinations (18%) reference methods revealed 54 osseous metastases (49 from Ewings sarcomas, five from osteosarcomas). FDG-PET had a sensitivity of 0.90, a specificity of 0.96 and an accuracy of 0.95 on an examination-based analysis. Comparable values for bone scintigraphy were 0.71, 0.92 and 0.88. On a lesion-based analysis the sensitivity of FDG-PET and bone scintigraphy was 0.80 and 0.72, respectively. Analysing only Ewings sarcoma patients, the sensitivity, specificity and accuracy of FDG-PET and bone scan were 1.00, 0.96 and 0.97 and 0.68, 0.87 and 0.82, respectively (examination-based analysis). None of the five osseous metastases from osteosarcoma were detected by FDG-PET, but all of them were true-positive using bone scintigraphy. In conclusion, the sensitivity, specificity and accuracy of FDG-PET in the detection of osseous metastases from Ewings sarcomas are superior to those of bone scintigraphy. However, in the detection of osseous metastases from osteosarcoma, FDG-PET seems to be less sensitive than bone scintigraphy.

Scintigraphic Imaging of Matrix Metalloproteinase Activity in the Arterial Wall In Vivo

Background—Matrix metalloproteinases (MMPs) are enzymes involved in the proteolytic degradation of extracellular matrix. They play an important role in several disease processes, such as inflammation, cancer, and atherosclerosis. Methods and Results—In this study, we have used the broad-spectrum MMP inhibitor CGS 27023A to develop the radioligand [123I]I-HO-CGS 27023A for in vivo imaging of MMP activity. Using this radioligand, we were able to specifically image MMP activity by scintigraphy in vivo in the MMP-rich vascular lesions that develop after carotid artery ligation and cholesterol-rich diet in apolipoprotein E–deficient mice. These results were confirmed by gamma counting of lesional tissue (counts per minute per milligram). Conclusions—Imaging of MMP activity in vivo is feasible using radiolabeled MMP inhibitors. Additional studies are needed to test the potential of this approach as a novel noninvasive clinical diagnostic tool for the management of human MMP-related diseases.

Regional myocardial sympathetic dysinnervation in arrhythmogenic right ventricular cardiomyopathy. An analysis using 123I-meta-iodobenzylguanidine scintigraphy.

BackgroundIn patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), the frequent provocation of ventricular tachycardia during exercise, the sensitivity toward catecholamines, and the response toward antiarrhythmic drug regimen with antiadrenergic properties suggest an involvement of the sympathetic nervous system in arrhythmogenesis. Methods and ResultsTo analyze the presence, extent, and location of impaired myocardial sympathetic innervation in ARVC, 123I–meta-iodobenzylguanidine (123I-MIBG) scintigraphy was performed in 48 patients with ARVC. For comparison, 9 patients with idiopathic ventricular tachycardia and a control group of 7 patients without heart disease were investigated. In patients with ARVC, the clinical sustained (n=25; 52%) or nonsustained (n=23; 48%) ventricular tachycardia originated in the right ventricular outflow tract in 38 patients (79%), whereas in the remaining 10 patients (21%), the site of origin was the apical (n=5) or inferior (n=5) right ventricle. In 33 patients (69%), nonsustained or sustained ventricular tachycardia was provocable by exercise (n=28 of 48; 58%) and/or by isoproterenol infusion (n= 16 of 37; 43%), whereas programmed ventricular stimulation induced sustained or nonsustained ventricular tachycardia in 16 patients each (33% each). With I MIBG scintigraphy, the right ventricle was not visible in any patient. No areas of intense 11I-MIBG uptake (“hot spots”) were observed. All patients of the control group and 7 of 9 patients (78%) with idiopathic ventricular tachycardia showed a uniform tracer uptake in the left ventricle. In contrast, only 8 of 48 ARVC patients (17%) showed a homogeneous distribution of 123I-MIBG uptake, whereas 40 patients (83%) demonstrated regional reductions or defects of tracer uptake. In 3 of 48 patients (6%), the defect area was < 15%; in 21 patients (44%), it was 15% to 30%; and in 16 patients (33%), it was >30% of the polar map area of the left ventricle (mean, 23±15%; range, 0% to 57%). In 38 of 40 patients (95%) with an abnormal 123I-MIBG scan, reduced tracer uptake was located in the basal posteroseptal left ventricle, involving the adjacent lateral wall in 10, the anterior wall in 2, and the apex in 12 patients. Only 2 patients demonstrated isolated defects of the anterior or lateral wall; one involved the apex. Perfusion abnormalities in the areas of 123I-MIBG defects were excluded by stress/redistribution 201Tl single-photon emission computed tomography scintigraphy and by normal coronary angiograms in all patients. Abnormalities in 123I-MIBG scintigraphy in patients with ARVC correlated with the site of origin of ventricular tachycardia, demonstrating a regionally reduced tracer uptake in 36 of 38 patients (95%) with right ventricular outflow tract tachycardia compared with only 4 of 10 patients (40%) with other right ventricular origins of tachycardia. There was no correlation between the results of 123I-MIBG scintigraphy and the extent of right ventricular contraction abnormalities, right ventricular ejection fraction, biopsy results, coronary anatomy, or left ventricular involvement in ARVC. ConclusionsIn patients with ARVC, regional abnormalities of sympathetic innervation are frequent and can be demonstrated by 123I-MIBG scintigraphy. Sympathetic denervation appears to be the underlying mechanism of reduced 123I-MIBG uptake and may be related to frequent provocation of ventricular arrhythmias by exercise or catecholamine exposure in ARVC. Therefore, in patients with ARVC, the noninvasive detection of localized sympathetic denervation by 123I-MIBG imaging may have implications for the early diagnosis and for the choice of antiarrhythmic drugs in the treatment of arrhythmias.

FDG-PET for detection of pulmonary metastases from malignant primary bone tumors: Comparison with spiral CT

BACKGROUND The purpose was the comparison of positron emission tomography using F-18-fluorodeoxy-glucose (FDG-PET) and spiral thoracic CT to detect pulmonary metastases from malignant primary osseous tumors. PATIENTS AND METHODS In 71 patients with histologically confirmed malignant primary bone tumors (32 osteosarcomas, 39 Ewings sarcomas) 111 FDG-PET examinations were evaluated with regard to pulmonary/pleural metastases in comparison with spiral thoracic CT. Reference methods were the clinical follow-ups for 6-64 months (median 20 months) or a histopathologic analysis. RESULTS In 16 patients (23%) reference methods revealed a pulmonary/pleural metastatic disease. FDG-PET had a sensitivity of 0.50, a specificity of 0.98, and an accuracy of 0.87 on a patient based analysis. Comparable values for spiral CT were 0.75, 1.00, and 0.94. It was shown that no patient who had a true positive FDG-PET had a false negative CT scan, nor was a pulmonary metastases detected earlier by FDG-PET than by spiral CT. CONCLUSIONS There seems to be a superiority of spiral CT in the detection of pulmonary metastases from malignant primary bone tumors as compared with FDG-PET. Therefore, at present a negative FDG-PET cannot be recommended to exclude lung metastases. However, as specificity of FDG-PET is high, a positive FDG-PET result can be used to confirm abnormalities seen on thoracic CT scans as metastatic.

Respiratory gating in positron emission tomography: A quantitative comparison of different gating schemes

Respiratory gating is used for reducing the effects of breathing motion in a wide range of applications from radiotherapy treatment to diagnostical imaging. Different methods are feasible for respiratory gating. In this study seven gating methods were developed and tested on positron emission tomography (PET) listmode data. The results of seven patient studies were compared quantitatively with respect to motion and noise. (1) Equal and (2) variable time-based gating methods use only the time information of the breathing cycle to define respiratory gates. (3) Equal and (4) variable amplitude-based gating approaches utilize the amplitude of the respiratory signal. (5) Cycle-based amplitude gating is a combination of time and amplitude-based techniques. A baseline correction was applied to methods (3) and (4) resulting in two new approaches: Baseline corrected (6) equal and (7) variable amplitude-based gating. Listmode PET data from seven patients were acquired together with a respiratory signal. Images were reconstructed applying the seven gating methods. Two parameters were used to quantify the results: Motion was measured as the displacement of the heart due to respiration and noise was defined as the standard deviation of pixel intensities in a background region. The amplitude-based approaches (3) and (4) were superior to the time-based methods (1) and (2). The improvement in capturing the motion was more than 30% (up to 130%) in all subjects. The variable time (2) and amplitude (4) methods had a more uniform noise distribution among all respiratory gates compared to equal time (1) and amplitude (3) methods. Baseline correction did not improve the results. Out of seven different respiratory gating approaches, the variable amplitude method (4) captures the respiratory motion best while keeping a constant noise level among all respiratory phases.

Myocardial presynaptic and postsynaptic autonomic dysfunction in hypertrophic cardiomyopathy

Although hypertrophic cardiomyopathy (HCM) is genetically determined, several other factors, including autonomic dysfunction, may play a role in the phenotypic expression. A recent study using positron emission tomography with [11C]CGP 12177 ([11C]CGP) demonstrated that beta-adrenoceptor (betaAR) density is reduced in HCM and is correlated with disease progression. This present study tested the hypothesis that this downregulation is associated with reduced catecholamine reuptake (uptake 1) by myocardial sympathetic nerve terminals leading to increased local norepinephrine concentration. Myocardial presynaptic catecholamine reuptake was assessed by measuring the volume of distribution (Vd) of the catecholamine analogue [11C]hydroxyephedrine ([11C]HED) in 9 unrelated HCM patients aged 45+/-15 years. The maximum number of binding sites (Bmax) for myocardial betaAR density was measured in 13 unrelated HCM patients aged 40+/-12 years using the nonselective beta blocker [11C]CGP. Six patients were studied with both [11C]HED and [11C]CGP. Comparison was made with two groups of healthy control subjects for each ligand ([11C]HED, n=10, aged 35+/-8 years; [11C]CGP, n=19, aged 44+/-16 years). Myocardial Vd of [11C]HED (33.4+/-4.3 mL/g tissue) and betaAR density (7.3+/-2.6 pmol/g tissue) were significantly reduced in HCM patients compared with control subjects (71.0+/-18.8 mL/g tissue, P<.001, and 10.2+/-2.9 pmol/g tissue, P=.008, respectively). These results are consistent with our hypothesis that myocardial betaAR downregulation in HCM is associated with an impaired uptake-1 mechanism and hence increased local catecholamine levels.

List Mode–Driven Cardiac and Respiratory Gating in PET

Gating methods acquiring biosignals (such as electrocardiography [ECG] and respiration) during PET enable one to reduce motion effects that potentially lead to image blurring and artifacts. This study evaluated different cardiac and respiratory gating methods: one based on ECG signals for cardiac gating and video signals for respiratory gating; 2 others based on measured inherent list mode events. Methods: Twenty-nine patients with coronary artery disease underwent a 20-min ECG-gated single-bed list mode PET scan of the heart. Of these, 17 were monitored by a video camera registering a marker on the patients abdomen, thus capturing the respiratory motion for PET gating (video method). Additionally, respiratory and cardiac gating information was deduced without auxiliary measurements by dividing the list mode stream in 50-ms frames and then either determining the number of coincidences (sensitivity method) or computing the axial center of mass and SD of the measured counting rates in the same frames (center-of-mass method). The gated datasets (respiratory and cardiac gating) were reconstructed without attenuation correction. Measured wall thicknesses, maximum displacement of the left ventricular wall, and ejection fraction served as measures of the exactness of gating. Results: All methods successfully captured respiratory motion and significantly decreased motion-induced blurring in the gated images. The center-of-mass method resulted in significantly larger left ventricular wall displacements than did the sensitivity method (P < 0.02); other differences were nonsignificant. List mode–based cardiac gating was found to work well for patients with high 18F-FDG uptake when the center-of-mass method was used, leading to an ejection fraction correlation coefficient of r = 0.95 as compared with ECG-based gating. However, the sensitivity method did not always result in valid cardiac gating information, even in patients with high 18F-FDG uptake. Conclusion: Our study demonstrated that valid gating signals during PET scans cannot be obtained only by tracking the external motion or applying an ECG but also by simply analyzing the PET list mode stream on a frame-by-frame basis.