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Markus Schwaiger

Publications and source records attributed to Markus Schwaiger.

At least 91 records · Page 5Linked to original sources
PubMed2004

Presence of sympathetically denervated but viable myocardium and its electrophysiologic correlates after early revascularised, acute myocardial infarction.

AIMS: After acute myocardial infarction (AMI), regional denervation exceeding the scar area has been described. We sought to define the electrophysiologic correlates of denervated, but viable, myocardium by combining scintigraphic imaging with extensive electrocardiographic evaluation in AMI patients treated with early reperfusion therapy. METHODS AND RESULTS: Within 14 days after AMI, 67 consecutive patients underwent radionuclide imaging of myocardial resting perfusion using (201)thallium and of presynaptic sympathetic innervation using (123)I-metaiodobenzylguanidine (MIBG). The mean left ventricular ejection fraction was 58+/-15%. Electrophysiologic studies included evaluation of ventricular repolarisation (resting ECG), depolarisation (signal-averaged ECG), and 24-h Holter monitoring. The perfusion defect, innervation defect, and perfusion/innervation mismatch size of the left ventricle were 14+/-15%, 39+/-22%, and 26+/-16%, respectively. Mismatch was present in 60/67 patients (90%) and correlated with prolonged repolarisation defined by QTc interval (r = 0.40; P < 0.001), and with indexes of delayed depolarisation from signal-averaged ECG (r = -0.32; P = 0.014). Other electrophysiologic parameters did not correlate. During follow-up (4.3+/-1 years) event rates were low, with two cardiac deaths and no severe ventricular arrhythmia causing hospitalisation. CONCLUSIONS: After early reperfusion for myocardial infarction, viable but denervated myocardium is frequent and correlates with slow depolarisation and repolarisation. However, in patients with small infarct size and preserved left ventricular function, these findings seem to have little influence on outcome.

3-Iodobenzylguanidine↗
PubMed2004

Sympathetic reinnervation, exercise performance and effects of beta-adrenergic blockade in cardiac transplant recipients.

AIMS: To evaluate effects of beta-adrenergic receptor blockade on allograft performance, and to correlate these effects with sympathetic reinnervation. METHODS AND RESULTS: Myocardial catecholamine storage capacity was determined in 12 non-rejecting transplant recipients using PET and C-11 adrenaline (epinephrine). Haemodynamics and left ventricular function were measured using radionuclide angiography at rest and during symptom-limited exercise before and after non-selective beta-blockade (propranolol iv). Exercise time and stress-induced increases of heart rate and LVEF before beta-blockade were significantly higher in reinnervated compared to denervated recipients. While resting LVEF remained unchanged, heart rate and blood pressure were generally reduced by beta-blockade, which was well tolerated by all patients. Exercise time and increases of heart rate and LVEF were more attenuated in reinnervated recipients. Differences of chronotropic and inotropic response to exercise between groups were no longer present following beta-blockade. Correlations between myocardial adrenaline retention, peak heart rate and increase of global, as well as regional ejection fraction during exercise were observed before, but not during beta-blockade. CONCLUSION: Acute, non-selective beta-blockade is well tolerated by transplant recipients, but significantly attenuates beneficial functional effects of sympathetic reinnervation on exercise performance. The data suggest that reappearance of sympathetic nerve terminals is associated with reestablishment of intact pre-/postsynaptic interaction.

Adrenergic beta-Antagonists↗
PubMed2004

Short-term modulation of regional excitability and blood flow in human motor cortex following rapid-rate transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) of the human primary motor cortex (M1) provides a means of inducing lasting changes in cortical excitability and synaptic activity. Here we combined rTMS with positron emission tomography of regional cerebral blood flow (rCBF) to examine how an rTMS-induced change in intracortical excitability of inhibitory circuits affects regional synaptic activity. In a first set of experiments, we gave 150 biphasic pulses of 5 Hz rTMS at 90% of active motor threshold to left M1 and used single- and paired-pulse TMS to assess the conditioning effects of rTMS on motor cortical excitability at rest. rTMS conditioning led to a selective decrease in short-latency intracortical inhibition (SICI) without affecting short-latency intracortical facilitation or corticospinal excitability. The decrease in SICI lasted for approximately 8 min. In a second experiment, we used the same rTMS protocol and measured changes in regional synaptic activity (as indexed by rCBF) during and for up to 14 min after the end of rTMS. Subthreshold 5 Hz rTMS induced a region-specific increase in resting rCBF in the stimulated M1 lasting approximately 8 min. These results suggest that in the stimulated M1, temporary attenuation of SICI is paralleled by an increase in synaptic activity, consistent with reduced efficacy of intracortical GABA(A)-ergic synapses. The present findings demonstrate that short trains of low-intensity 5 Hz rTMS can be used to induce a transient change in function within a distinct cortical area. This opens up new possibilities for studying acute reorganization at the systems level in the intact human brain.

Adult↗
PubMed2004

Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C]diprenorphine PET study.

Based on concepts that endogenous opioids participate in neural transmission of pain, the present study in central poststroke pain (CPSP) patients investigated changes in opioid receptor (OR) binding in neural structures centrally involved in the processing of pain. Five patients with central pain after lesions in the brain stem, thalamus or parietal cortex and twelve healthy volunteers underwent a [11C]diprenorphine positron emission tomography study. Binding potentials were calculated using a reference region model in all subjects. Statistical parametric mapping was applied for t-statistical analysis on voxel-basis. Binding potential values for each individual were extracted from a volume of interest at each identified significant peak. Spectral analysis was applied for quantification of global values. Significant regional reduced 11C-diprenorphine binding (corrected for multiple tests) was detected in contralateral thalamus, parietal, secondary somatosensory, insular and lateral prefrontal cortices, and along the midline in anterior cingulate, posterior cingulate and midbrain gray matter. Individual extracted binding values disclosed a reduced binding in these regions in all patients independent from the particular lesion site. The poststroke pain syndrome is associated with a characteristic pattern of reduced OR binding within the neural circuitry processing pain. It is suggested that an imbalance of excitatory-inhibitory mechanisms in certain brain structures, as evidenced in decreased [11C]diprenorphine binding, is one of the causes or the consequences of poststroke pain.

Aged↗
PubMed2004

Myocardial salvage after reduced-dose thrombolysis combined with glycoprotein IIb/IIIa blockade versus thrombolysis alone in patients with acute myocardial infarction.

BACKGROUND: The aim of study was to examine the efficacy of reduced-dose alteplase plus abciximab versus alteplase alone by quantifying the amount of myocardium salvaged using myocardial scintigraphy. METHODS: This study analyzed 150 patients with acute myocardial infarction who received alteplase (69 patients) or reduced-dose alteplase plus abciximab (81 patients) in the setting of the Stent versus Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction (STOPAMI) 1 and 2 trials. Salvage index (proportion of initial perfusion defect salvaged by reperfusion therapy), which was obtained by paired scintigraphic studies performed 7-14 days apart, was the primary endpoint of the study. One-year clinical follow-up was also done. RESULTS: Salvage index did not differ significantly among patients treated with reduced-dose alteplase plus abciximab (median, 0.41 [25th; 75th percentiles: 0.13; 0.58]) compared to patients who received alteplase (0.26 [0.09; 0.61], p = 0.30). Final infarct size was 16.0% [4.0; 31.0] of the left ventricle in the group with reduced-dose alteplase plus abciximab and 19.4% [7.9; 34.2] of left ventricle in the group with alteplase (p = 0.44). Within a time-to-admission interval of <2 hours, there was a trend for higher values of salvage index in patients who received reduced-dose alteplase plus abciximab compared with patients who received alteplase (0.55 [0.35; 0.73] versus 0.29 [0.11; 0.69], p = 0.15). For time-to-admission intervals > or = 2 hours, no such trend was observed between those who received reduced-dose alteplase plus abciximab or alteplase (0.25 [0.08; 0.48] versus 0.22 [0.08; 0.46], p = 0.79). Major bleeding occurred in 4 patients (5.0%) in the group with reduced-dose alteplase plus abciximab versus 2 patients (3.0%) in the group with alteplase alone (p = 0.58). CONCLUSION: When used as a general strategy in patients with acute myocardial infarction, adding abciximab to alteplase does not increase significantly the amount of salvaged myocardium as compared with alteplase alone. Combination therapy may offer advantages over thrombolytic agents alone if such therapy is applied within 2 hours from symptom onset; however these data need to be proven by studies of adequate power.

Abciximab↗
PubMed2004

Radiolabeled carbohydrated somatostatin analogs: a review of the current status.

During the last decade, peptide radiopharmaceuticals have become an important class of tracers for the detection and localization of malignant neoplasms by peptide receptor imaging (PRI) and for therapeutic intervention by peptide receptor radiotherapy (PRRT). Various radiometalated peptides have entered detailed clinical studies or found broad application for peptide receptor radiotherapy. In contrast, radiohalogenated peptides could not benefit from this development. Especially with respect to the growing number of peptidic structures with high receptor affinity and the increasing demand for means of corresponding receptor status quantification for therapy planning and control, the development of methods for the improved availability of 18F-labeled peptides for positron emission tomography imaging is still a very important objective in radiopharmaceutical research. Consequently, as part of our ongoing efforts in this field, we investigated the potential of carbohydration as a valuable tool to modify pharmacokinetics of peptides and evaluated the influence of this modification on the in vitro and in vivo behavior of octreotide analogs. Furthermore, a new methodology is presented allowing for the fast and straightforward labeling of peptides in a chemoselective manner. This combined approach to the chemoselective conjugation of unprotected, carbohydrated peptides seems to have the potential for a redirection and reevaluation of the future of radiohalogenated peptides in nuclear medicine.

Carbohydrates↗
PubMed2004

PlA polymorphism of the glycoprotein IIIa and efficacy of reperfusion therapy in patients with acute myocardial infarction.

The Pl(A) polymorphism of the platelet glycoprotein IIIa gene is associated with altered platelet function and response to antiplatelet drugs. We sought to assess whether the Pl(A) polymorphism influences myocardial salvage achieved by reperfusion therapy in patients with acute myocardial infarction. We analyzed 292 patients enrolled in 2 randomized trials that compared stenting plus abciximab with thrombolysis (alteplase alone or alteplase plus abciximab) in acute myocardial infarction. Patients were genotyped for the Pl (A) polymorphism using polymerase chain reaction with fluorogenic probes. Technetium-99m sestamibi was injected before and 1-2 weeks after reperfusion treatment. The scintigrams enabled the calculation of the initial perfusion defect, final infarct size, and the proportion of initial defect salvaged by reperfusion (salvage index). Clinical follow-up was done up to 18 months after primary treatment. The genotype distribution was as follows: Pl (A2/A2) in 3.4%, Pl (A1/A2) in 24.7% and Pl (A1/A1) in 71.9% of patients. There were no significant differences between Pl( A2) allele carriers and Pl(A1/A1) patients in salvage index (0.4+/-0.50 vs. 0.4+/-0.43, respectively, P=0.48), final infarct size (16.8+/-20.8% vs. 18.4+/-19.1% of left ventricle, respectively, P=0.46) as well as 18-month mortality (8.5% vs.7.1%, respectively, P=0.69). The lack of relationship between Pl(A2) allele and myocardial salvage was observed for both reperfusion strategies, stenting and thrombolysis. Thus, these findings show that the functional Pl(A) polymorphism of platelet glycoprotein IIIa has no influence on the degree of myocardial salvage achieved by reperfusion therapies in patients with acute myocardial infarction.

Abciximab↗
PubMed2004

Evaluation of cardiac beta-adrenoreceptors in the isolated perfused rat heart using (S)-11C-CGP12388.

UNLABELLED: (S)-(11)C-CGP12388 ((11)C-CGP12388) was recently developed as an in vivo PET tracer for the evaluation of cardiac beta-adrenergic receptors. The purpose of this study was to evaluate the myocardial kinetics of (11)C-CGP12388 using the perfused rat heart model. METHODS: Normal rat hearts were cannulated for retrograde perfusion according to the Langendorff method. Studies were performed using constant coronary flow rates of 12 mL/min (high flow: n = 6) and 6 mL/min (low flow: n = 6). Beta-adrenergic-blocking studies were also done using propranolol (blocking: n = 6). Two bolus injections of (11)C-CGP12388 were administered at a 25-min interval, and time-activity curves were measured using bismuth germanate detectors. The beta-adrenergic receptor density (B(max)) and total distribution volume (DV(tot)) were estimated using compartmental modeling. After the experiment, B(max) in vitro was measured for all hearts using (3)H-CGP12177, and the values were compared with the B(max) estimated in isolated hearts. RESULTS: DV(tot) was significantly lower in the blocking group than in the high-flow group (P < 0.01), and there was no significant difference in DV(tot) between the high- and the low-flow groups. B(max) values estimated from (11)C-CGP12388 kinetics were 5.05 +/- 0.90 pmol/g under the high-flow model and 5.20 +/- 0.63 pmol/g under the low-flow model. The B(max) results in isolated hearts correlated significantly with the measured in vitro B(max) values (r(2) = 0.69; P < 0.001). CONCLUSION: Beta-adrenoreceptor density in the isolated rat heart can be quantified using (11)C-CGP12388 and a 2-injection protocol. The binding of the tracer was flow independent, with low nonspecific binding. These results suggest that (11)C-CGP12388 is a promising PET tracer that may be applicable to human studies.

Animals↗
PubMed2004

Prognostic value of myocardial salvage achieved by reperfusion therapy in patients with acute myocardial infarction.

UNLABELLED: Myocardial salvage assessed by (99m)Tc-sestamibi scintigraphy is a marker of myocardial tissue reperfusion in patients with acute myocardial infarction. The prognostic value of myocardial salvage index in patients with acute myocardial infarction after reperfusion therapy has not, however, been investigated. METHODS: We analyzed 765 patients with acute myocardial infarction randomized to treatment by coronary stenting (383 patients), primary coronary angioplasty (251 patients), or thrombolysis (131 patients) in the setting of 3 randomized trials. Initial (before reperfusion therapy) and follow-up (7-14 d after reperfusion therapy) scintigraphic examinations were performed to assess the initial perfusion defect, final infarct size, and salvage index. Patients were categorized into 2 groups defined by the median salvage index (0.5): the group with salvage index < 0.5 (374 patients) and the group with salvage index >or= 0.5 (391 patients). The primary endpoint of the study was mortality at 6 mo after the index event. RESULTS: Six-month mortality was 5.1% (19 deaths) in the group with salvage index < 0.5, compared with 1.0% (4 deaths) in the group with salvage index >or= 0.5 (odds ratio, 5.1; 95% confidence interval, 1.9-13.3; P = 0.001). Salvage index (median [25th, 75th percentiles] was significantly smaller in nonsurvivors than in survivors (0.19 [0.05, 0.37] vs. 0.50 [0.26, 0.80], P = 0.0004). The Cox proportional hazards model showed that myocardial salvage index (P = 0.0007), initial perfusion defect (P = 0.0007), and age (P = 0.04) were independently associated with 6-mo mortality. CONCLUSION: Myocardial salvage achieved by reperfusion therapy predicts mortality in patients with acute myocardial infarction. Our findings support the use of salvage index as a surrogate of mortality in clinical trials designed to test the efficacy of reperfusion therapies among patients with acute myocardial infarction.

Angioplasty, Balloon, Coronary↗
PubMed2004

Two-step methodology for high-yield routine radiohalogenation of peptides: (18)F-labeled RGD and octreotide analogs.

UNLABELLED: Routine application of (18)F-labeled peptides for quantitative in vivo receptor imaging of receptor-expressing tissues and quantification of receptor status using PET is limited by the lack of appropriate radiofluorination methods for routine large-scale synthesis of (18)F-labeled peptides. To satisfy this demand, a new (18)F-labeling methodology based on the chemoselective oxime formation between an unprotected aminooxy-functionalized peptide and an (18)F-labeled aldehyde or ketone was investigated and optimized with respect to peptide conjugation. METHODS: 4-[(18)F]Fluorobenzaldehyde ([(18)F]FB-CHO) was prepared from the 4-formyl-N,N,N-trimethylanilinium precursor via direct no-carrier-added (18)F-fluorination (dimethyl sulfoxide, 60 degrees C, 15 min) and purified using a cation-exchange/reversed-phase cartridge system. Radiochemical yields (RCYs) of N-(4-[(18)F]fluorobenzylidene)oxime ([(18)F]FBOA) formation with various aminooxy-modified peptides such as minigastrin, RGD, and octreotate analogs were investigated as a function of reaction time and temperature, peptide concentration, and pH. Biodistribution studies were performed with an [(18)F]FBOA-RGD dimer ((c(RGDfE)HEG)(2)-K-Dpr-[(18)F]FBOA, 60 and 120 min after injection) and a gylcosylated [(18)F]FB-Tyr(3)-octreotate (Gluc-S-Dpr([(18)F]FBOA)TOCA), 10 and 60 min after injection) using M21 and M21L human melanoma and AR42J rat pancreatic tumor-bearing nude mice, respectively. RESULTS: [(18)F]FB-CHO was obtained in a nonoptimized RCY of 50% within 30 min. At low peptide concentrations (0.5 mmol/L), optimal [(18)F]FBOA-labeling efficiencies (60%-80%) were obtained within 15 min at 60 degrees C and pH 2-3, independently of the peptide used, affording the [(18)F]FBOA-peptides in overall RCYs of up to 40% (from end of bombardment) after purification. Both (c(RGDfE)HEG)(2)-K-Dpr-[(18)F]FBOA and Gluc-S-Dpr([(18)F]FBOA)TOCA showed pharmacokinetics suitable for early (<or=60 min) high-contrast PET imaging, high tumor uptake (2.48 +/- 0.15 %ID/g [RGD] and 21.8 +/- 1.4 %ID/g [TOCA] at 60 min after injection, where %ID/g = percentage injected dose per gram), and tumor-to-organ ratios that compared well with the corresponding [(18)F]fluoropropionyl analogs [(18)F] Galacto-RGD and Gluc-Lys([(18)F]FP)TOCA, which are prepared via multistep procedures. CONCLUSION: Oxime formation between aminooxy-functionalized peptides and an (18)F-labeled aldehyde or ketone-in this case, [(18)F]FB-CHO-combines fast 1-step, high-yield synthesis of an (18)F-labeled prosthetic group stable against in vivo defluorination with rapid, 1-step chemoselective conjugation to unprotected peptides under mild conditions. Thus, it allows fast and straightforward large-scale production of (18)F-labeled peptides for clinical routine PET application. Furthermore, it opens new perspectives to peptide radiohalogenation in general, permitting labeling of the same precursor both with diagnostic ((18)F, (124)I, (120 g)I, (123)I) and therapeutic ((211)At, (131)I) radiohalogens.

Animals↗
PubMed2004

Coexpression of herpesviral thymidine kinase reporter gene and VEGF gene for noninvasive monitoring of therapeutic gene transfer: an in vitro evaluation.

UNLABELLED: Coexpression of a reporter gene and a therapeutic gene may allow for noninvasive monitoring of cardiac gene therapy. We sought to evaluate the usefulness of an adenoviral vector expressing mutant herpesviral thymidine kinase reporter gene (HSV1-sr39tk) and vascular endothelial growth factor (VEGF) 121 in independent expression cassettes (Ad4tk). METHODS: Accumulation of 14C-2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (FIAU) and 9-(4-18F-fluoro-3-hydroxymethylbutyl)guanine (FHBG) as reporter probes, and secretion of VEGF into medium, were determined for Ad4tk-infected H9c2 rat cardiac cells in vitro. RESULTS: In vitro tracer uptake increased with increasing vector concentration and over time. It was comparable to cells infected with adenovirus expressing only wild-type HSV1-tk (reporter probe: 14C-FIAU) or mutant HSV1-sr39tk (reporter probe: 18F-FHBG). No significant uptake was observed in cells infected with adenovirus expressing VEGF alone. With increasing vector concentration, Ad4tk-infected cells increasingly released VEGF into medium. VEGF production correlated significantly with cellular reporter probe uptake (r = 0.93; P = 0.0003). CONCLUSION: The usefulness of a vector coexpressing HSV1-tk and VEGF for noninvasive imaging of expression of a therapeutic transgene has been demonstrated in vitro. This approach may allow for future in vivo monitoring of cardiac angiogenesis gene therapy.

Animals↗
PubMed2004

PET of cardiac transgene expression: comparison of 2 approaches based on herpesviral thymidine kinase reporter gene.

UNLABELLED: PET of reporter gene expression holds promise for noninvasive monitoring of gene therapy. Previously, 2 approaches based on the herpes simplex virus type 1 thymidine kinase gene (HSV1-tk) have been successfully applied to the heart. Wild-type HSV1-tk was imaged with (124)I-labeled 2'-fluoro-2'-deoxy-5-iodo-1-beta-D-arabinofuranosyl-5-iodouracil (FIAU), and a mutant HSV1-tk (HSV1-sr39tk) was imaged with (18)F-labeled 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine (FHBG). The aim of this study was to compare these 2 combinations with regard to specificity, imaging contrast, and reporter probe kinetics using dynamic PET in small and large animals. METHODS: Similar titers of adenovirus-expressing wild-type HSV1-tk (Ad(tk)), mutant HSV1-sr39tk (Ad(sr39tk)), or control genes were directly injected into the myocardium of 24 rats and 8 pigs. Two days later, dynamic PET was performed with a clinical scanner during the 120 min after injection of (124)I-FIAU (Ad(tk) animals and controls) or (18)F-FHBG (Ad(sr39tk) animals and controls). Imaging with (13)N-ammonia was performed to identify cardiac regions of interest. RESULTS: In rats, significant cardiac (124)I-FIAU accumulation occurred in images obtained early (10-30 min) after Ad(tk) injection. Because of tracer washout, however, no difference between Ad(tk)-injected animals and controls was seen in the images obtained later. For (18)F-FHBG, specific myocardial accumulation greater than background levels was detected in Ad(sr39tk)-injected animals at early imaging and, in contrast to (124)I-FIAU accumulation, increased over time until the latest imaging (105-120 min). At maximum, cardiac (18)F-FHBG concentration showed a 4.15 +/- 1.65-fold increase compared with controls (105-120 min), and cardiac (124)I-FIAU concentration reached a maximal increase of 1.34 +/- 0.38-fold compared with controls (10-30 min, P = 0.0014). Global cardiac reporter probe kinetics in rats were confirmed by regional myocardial analysis in pig hearts. Transgene expression was specifically visualized by both approaches. The highest target-to-background ratio of (124)I-FIAU in Ad(tk)-infected pig myocardium was 1.50 +/- 0.20, versus 2.64 +/- 0.49 for (18)F-FHBG in Ad(sr39tk)-infected areas (P = 0.01). In vivo results were confirmed by ex vivo counting and autoradiography. CONCLUSION: Both reporter gene/probe combinations were feasible for noninvasive imaging of cardiac transgene expression in different species. Specific probe kinetics suggest different myocardial handling of pyrimidine (FIAU) and acycloguanosine (FHBG) derivatives. The results favor (18)F-FHBG with mutant HSV1-sr39tk because of continuous accumulation over time and higher imaging contrast.

Animals↗
PubMed2003

Prediction of response to preoperative chemotherapy in gastric carcinoma by metabolic imaging: results of a prospective trial.

PURPOSE: We prospectively evaluated the predictive value of therapy-induced reduction of tumor glucose use for subsequent response and patient survival in patients with gastric cancer treated by preoperative chemotherapy. PATIENTS AND METHODS: Forty-four consecutive patients with locally advanced gastric carcinomas were studied by positron emission tomography with the glucose analog fluorine-18 fluorodeoxyglucose (FDG-PET) at baseline and 14 days after initiation of cisplatin-based polychemotherapy. On the basis of a previous study, a reduction of tumor FDG uptake by more than 35% was used as a criterion for a metabolic response. The metabolic response in FDG-PET was correlated with histopathologic response after completion of therapy (< 10% viable tumor cells in the resected specimen) and patient survival. RESULTS: Thirty-five (80%) of the 44 tumors were visualized with sufficient contrast for quantitative analysis (two of 19 intestinal and seven of 25 nonintestinal tumors showed only low FDG uptake). In the 35 assessable patients, PET imaging after 14 days of therapy correctly predicted histopathologic response after 3 months of therapy in 10 (77%) of 13 responders and 19 (86%) of 22 nonresponders. Median overall survival for patients with a metabolic response has not been reached (2-year survival rate, 90%); for patients without a metabolic response, median survival was only 18.9 months (2-year survival rate, 25%; P =.002) CONCLUSION: This study prospectively demonstrates that in patients with gastric cancer, response to preoperative chemotherapy can be predicted by FDG-PET early during the course of therapy. By avoiding the morbidity and costs of ineffective therapy, FDG-PET imaging may markedly facilitate the use of preoperative chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Noninvasive imaging of transgene expression by use of positron emission tomography in a pig model of myocardial gene transfer.

BACKGROUND: Radionuclide imaging of reporter gene expression may be useful for noninvasive monitoring of clinical cardiac gene therapy. Experience until now, however, has been limited to small animals. METHODS AND RESULTS: To evaluate feasibility in a clinically applicable setting, pigs were studied by conventional positron emission tomography (PET) 2 days after regional intramyocardial injection of control adenovirus or adenovirus carrying herpesviral thymidine kinase reporter gene (HSV1-tk). Myocardial blood flow was quantified by use of [13N]ammonia. Subsequently, kinetics of the reporter substrate [124I]-2'-fluoro-2'-deoxy-5-iodo-1-beta-d-arabino-furanosyluracil (FIAU) were assessed over a period of 2 hours. Areas infected with adenovirus expressing HSV1-tk showed significantly elevated FIAU retention during the first 30 minutes after injection. At later times, washout was observed, and retention was not different from that in areas infected with control virus or remote myocardium. Early in vivo FIAU uptake correlated with ex vivo images, autoradiography, and immunohistochemistry for reporter gene product after euthanasia. After intramyocardial injection of both adenoviruses, myocardial blood flow was mildly elevated compared with that in remote areas, consistent with histological signs of regional inflammation. CONCLUSIONS: In vivo quantification of regional myocardial transgene expression is feasible with clinical PET methodology, the radioiodinated reporter probe FIAU, and the HSV1-tk reporter gene. Radioactivity efflux after specific initial uptake was not observed previously in tumor studies, suggesting that tissue-specific differences in nucleoside metabolism influence reporter probe kinetics. By coregistering reporter gene expression with additional biological parameters such as myocardial blood flow, PET allows for noninvasive characterization of the success of cardiac gene transfer along with its functional correlates.

Animals↗
PubMed2003

Selective pressure-regulated retroinfusion of fibroblast growth factor-2 into the coronary vein enhances regional myocardial blood flow and function in pigs with chronic myocardial ischemia.

OBJECTIVES: We sought to improve regional myocardial delivery and subsequent collateral perfusion induced by basic fibroblast growth factor-2 (FGF-2) using selective pressure-regulated retroinfusion of coronary veins for delivery. This hypothesis was tested in a newly developed pig model with percutaneous induction of chronic ischemia. BACKGROUND: Selective pressure-regulated retroinfusion of coronary veins is a catheter-based procedure that has been shown to provide effective regional delivery of drugs and gene vectors into ischemic myocardium. METHODS: A high-grade stenosis with subsequent progression to total occlusion within 28 days was induced by implanting a reduction stent graft into the left anterior descending artery (LAD). After seven days, a 30-min retroinfusion (anterior cardiac vein) was performed with (n = 7) or without (n = 7) 150 microg FGF-2 and compared with a 30-min antegrade infusion of 150 microg FGF-2 into the LAD (n = 7). Sonomicrometry to assess regional myocardial function at rest and during pacing, and microspheres to assess regional myocardial blood flow, were performed 28 days after implantation of the reduction stent. RESULTS: Retroinfusion of FGF-2 compared favorably with controls and with antegrade infusion of FGF-2 with regard to regional myocardial function at rest (18.5 +/- 4.1% vs. 5.7 +/- 2.9% vs. 7.9 +/- 1.8%, respectively, p < 0.05) and during pacing. Regional myocardial blood flow was also higher in the LAD territory after retroinfusion of FGF-2 (1.07 +/- 0.14 vs. 0.66 +/- 0.07 vs. 0.72 +/- 0.17 ml x min(-1) x g(-1), p < 0.05). CONCLUSIONS: Selective pressure-regulated retroinfusion increased tissue binding of FGF-2 and enhanced functionally relevant collateral perfusion compared with antegrade intracoronary delivery in pigs with chronic myocardial ischemia.

Animals↗
PubMed2003

Hearts late after fontan operation have normal mass, normal volume, and reduced systolic function: a magnetic resonance imaging study.

OBJECTIVES: The purpose of this study was to assess ventricular mass, volume, and systolic function in patients late after Fontan operation by cardiac magnetic resonance imaging. BACKGROUND: An assessment of determinants for ventricular function in post-Fontan patients was intended. METHODS: Twenty-three unselected patients (9 female, 14 male) at a median age of 19.4 years (range, 7.8 to 31.3 years), at a median time of 10.5 years (range, 4.1 to 18 years) after Fontan operation were studied. A standard 1.5-T scanner was used, and analysis was performed using dedicated software. Ten healthy volunteers (median age 26.4, range 18 to 39.3 years) served as the control group. RESULTS: Median end-systolic mass index was 72.2 g/m(2) (range, 43 to 138 g/m(2)) and 86.6 g/m(2) (range, 52 to 123 g/m(2)) in the control group (p = NS). Median end-diastolic ventricular volume was 64 ml/m(2) (range, 32 to 117 ml/m(2)) compared with 67.7 ml/m(2) (range, 59 to 75 ml/m(2)) in the control group (p = NS). Median ejection fraction was 49.3% (range, 20% to 63%) compared with 64.8% (range, 57% to 79%) in normals (p = 0.00001). CONCLUSIONS: We conclude that long-term survivors of a Fontan operation have normal ventricular mass, normal volume, but reduced systolic ventricular function.

Adolescent↗
PubMed2003

Locoregional alpha-radioimmunotherapy of intraperitoneal tumor cell dissemination using a tumor-specific monoclonal antibody.

PURPOSE: The locoregional application of tumor-specific antibodies conjugated with highly cytotoxic alpha-emitters is a promising new strategy for therapy of i.p. tumor cell dissemination. Using this approach, an antibody specifically targeting diffuse-type gastric cancer cells was coupled to the high linear energy transfer alpha-emitter (213)Bi for treatment of i.p. tumor cell spread in a nude mouse model. EXPERIMENTAL DESIGN: Nude mice were inoculated with HSC45-M2 human gastric cancer cells expressing mutant d9-E-cadherin. Twenty-four h after cell inoculation, mice received i.p. injections of either (213)Bi-d9MAb specifically binding to mutant d9-E-cadherin of HSC45-M2 cells or unspecific (213)Bi-d8MAb (7.4 or 22.2 MBq). Survival of treated animals was monitored compared with controls that had been injected with nonlabeled monoclonal antibody (MAb) or saline. Toxicity was evaluated by WBC counts after injection of 1.85, 7.4, or 22.2 MBq and analysis of chromosomal aberrations of bone marrow cells after injection of 7.4, 14.8, or 22.2 MBq. RESULTS: Survival rates of control mice and of mice treated with (213)Bi-MAbs differed significantly: the mean survival of untreated controls and mice that were given the nonlabeled antibody was 23 and 26 days. After injection of 22.2 MBq of the specific (213)Bi-d9MAb or the unspecific (213)Bi-d8MAb, mean survival was at least 143 or 130 days, respectively. Treatment with 7.4 MBq of (213)Bi-d9MAb increased mean survival to at least 232 days and with (213)Bi-d8MAb to at least 172 days. WBC counts decreased within 2 days after (213)Bi-therapy but reached pretreatment values between day 14 and 21 after activity injection. Chromosomal aberrations in bone marrow cells could only be detected at day 1 after (213)Bi-therapy. The frequency of chromosomal damages increased depending on the applied (213)Bi-activity. CONCLUSIONS: The therapeutic efficacy of the (213)Bi-d9MAb together with a low bone marrow toxicity support the locoregional therapy for that subgroup of diffuse-type gastric carcinoma patients expressing d9-E-cadherin.

Alpha Particles↗