Visualizing inflammation activity in rheumatoid arthritis with Tc-99 m anti-CD4-mAb fragment scintigraphy.

PURPOSE: T-cell-located CD4 antigen represents one of the therapeutic targets in rheumatoid arthritis (RA). However, up to now there is no established imaging tool to visualize this target in vivo. The aim of our study was to assess the safety and tolerability of a technetium-99m labelled murine anti-human CD4 IgG1-Fab fragment ([(99m)Tc]-anti-CD4-Fab, [(99m)Tc]-EP1645) in patients with active synovitis due to RA, and to evaluate its potential as a marker of disease activity. METHODS: In the present phase I proof of principle study five patients with RA were examined. Planar scans of the whole body, hands, and feet were taken 30 min up to 24h after application of 550 ± 150 MBq [(99m)Tc]-anti-CD4-Fab, followed by visual analyses, comparison with clinical data in 68 joints per patient and semiquantitative analysis of hand and wrist joints. RESULTS: Neither infusion related adverse events nor adverse events during follow up were observed. No increase in human anti-murine antibody titres was seen. All patients had positive scans in almost 70% of clinically affected joints. Positive scans were also found in 8% of joints without evidence of swelling or tenderness. CONCLUSION: Scintigraphy with [(99m)Tc]-anti-CD4-Fab is a promising technique for evaluation of inflammatory activity in patients with RA, pre-therapeutical evaluation of CD4 status and therapy control. Tracer uptake in clinically inconspicuous joints strongly indicates diagnostic potential of [(99m)Tc]-anti-CD4-Fab. Whether this technique is eligible as a prognostic factor in RA needs to be analysed in further studies as well as the pathophysiological background of clinically affected joints lacking tracer uptake.

Paediatric Crohn disease patients with stricturing behaviour exhibit ileal granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody production and reduced neutrophil bacterial killing and GM-CSF bioactivity.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies are associated with stricturing behaviour in Crohn disease (CD). We hypothesized that CD ileal lamina propria mononuclear cells (LPMC) would produce GM-CSF autoantibodies and peripheral blood (PB) samples would contain GM-CSF neutralizing capacity (NC). Paediatric CD and control PBMC and ileal biopsies or LPMC were isolated and cultured and GM-CSF, immunoglobulin (Ig)G and GM-CSF autoantibodies production were measured by enzyme-linked immunosorbent assay (ELISA). Basal and GM-CSF-primed neutrophil bacterial killing and signal transducer and activator of transcription 5 (STAT5) tyrosine phosphorylation (pSTAT5) were measured by flow cytometry. GM-CSF autoantibodies were enriched within total IgG for LPMC isolated from CD ileal strictures and proximal margins compared to control ileum. Neutrophil bacterial killing was reduced in CD patients compared to controls. Within CD, neutrophil GM-CSF-dependent STAT5 activation and bacterial killing were reduced as GM-CSF autoantibodies increased. GM-CSF stimulation of pSTAT5 did not vary between controls and CD patients in washed PB granulocytes in which serum was removed. However, GM-CSF stimulation of pSTAT5 was reduced in whole PB samples from CD patients. These data were used to calculate the GM-CSF NC. CD patients with GM-CSF NC greater than 25% exhibited a fourfold higher rate of stricturing behaviour and surgery. The likelihood ratio (95% confidence interval) for stricturing behaviour for patients with elevation in both GM-CSF autoantibodies and GM-CSF NC was equal to 5 (2, 11). GM-CSF autoantibodies are produced by LPMC isolated from CD ileal resection specimens and are associated with reduced neutrophil bacterial killing. CD peripheral blood contains GM-CSF NC, which is associated with increased rates of stricturing behaviour.

Positron emission tomography with [(18)F]fluoro-2-deoxy-D-glucose for diagnosis and staging of bile duct cancer.

Malignant tumors with high glucose metabolic rates accumulate [18F]-fluorodeoxyglucose (FDG), a positron emitting tracer. The aim of this study was to evaluate FDG positron emission tomography (PET) for detection and staging of human cholangiocarcinoma (CC). Patients with adenocarcinoma of the biliary tree (n = 26), with benign lesions of the bile ducts (n = 8), and 20 control patients underwent FDG-PET (370 MBq [18F]-FDG, Siemens ECAT EXACT HR(+)). In a blinded fashion, 4 independent experts evaluated the PET scans visually and semiquantitatively using the standardized uptake value and a tumor/non-tumor ratio. All adenocarcinomas and benign lesions (sclerosing cholangitis, bile duct adenoma, Caroli's disease) were histologically proven and imaged by magnetic resonance imaging and endoscopic retrograde cholangioscopy. True-positive PET scans were obtained in 24 of 26 CC and false-negative scans in the other 2 (sensitivity 92.3%). The PET scan was true-negative in 18 of 20 controls and in all 8 benign biliary lesions (specificity 92.9%). Visual and semiquantitative evaluation using tumor/non-tumor ratios were equally accurate (accuracy 92.6%) whereas evaluation by standardized uptake value revealed lower accuracy (P <.05). Regional or hepatoduodenal lymph node metastases were detected with PET in only 2 of 15 cases whereas distant metastases (peritoneal carcinomatosis, pulmonary metastases) were diagnosed in 7 of 10 cases. In conclusion, PET is highly sensitive and specific for the detection and localization of CC. It can be helpful for diagnosis of distant metastases but is not suitable for detection of regional lymph node metastases.

[18F-FDG positron-emission-tomography in cervical carcinoma: preliminary findings]. / 18F-FDG-Positronen-Emissions-Tomographie bei Zervixkarzinom: Erste Ergebnisse.

18F-Fluorodesoxyglucose-Positron-Emission-Tomography (18F-FDG-PET) is a novel imaging modality for malignancies. This study was initiated to define the efficiency of PET in detecting and characterizing metabolically the primaries and in preoperatively assessing of lymphonodal metastases of cervical cancer. 15 patients with histologically proven cervical carcinoma were studied with 18F-FDG-PET regarding 18F-FDG-uptake of primary tumor and evidence as well as extent of lymphonodal metastases. 18F-FDG-PET and histopathological results were compared after radical hysterectomy with pelvic and supplementary in 7 cases paraaortal lymphadenectomy. All primary tumours showed 18F-FDG accumulation and had a mean maximal standardized uptake value (SUV) of 8.0 +/- 5.3. 3/6 lymph node metastases were obtained with 18F-FDG-PET. Micrometastases (size of metastasis < or = 0.2 cm) were present in 2 patients with false negative PET results. Regarding the subgroup with paraaortal lymph node dissection, PET detected one patient with metastases, the other one had micrometastasis, while metastasis was not observed by PET. The accuracy of PET is 73% for assessment of pelvic lymph nodes and 86% for assessment of paraaortal lymph nodes. In conclusion 18F-FDG accumulates reliably in primaries of cervical cancer. Regarding assessment of lymph node metastases PET seems to be of potential use, offering metabolic information independent of the size of metastatic lymph nodes. An improvement of accuracy can be expected if combined evaluation of morphologic and metabolic images is performed.

[Diminution of hand writing area and D2-dopamine receptor blockade. Results from treatment with typical and atypical neuroleptics]. / Verkleinerung der Handschriftfläche und D2-Dopaminrezeptorblockade. Ergebnisse unter Behandlung mit typischen und atypischen Neuroleptika.

Beside the typical extrapyramidal motor symptoms such as rigidity, tremor, and dyskinesia, a reduction in handwriting area may occur under neuroleptic therapy. To date, the nature of the relationship between a reduction in handwriting area and striatal D2 dopamine receptor occupancy has remained unclear, and it is not known whether such a reduction also occurs under treatment with atypical neuroleptic drugs. In 23 schizophrenic patients treated with haloperidol, haloperidol decanoate, risperidone, and clozapine, the handwriting are was examined using a planimetric computer program. 123I-iodobenzamide (IBZM) single photon emission tomography (SPET) was used to measure the D2 dopamine receptor occupancy. A statistically significant correlation was found between a reduction in handwriting area and D2 dopamine receptor occupancy (r = 0.86; P < 0.0001). The curve derived from the plotted data resulted in a hyperbolic function. The regression was present regardless of whether the patients were treated with typical or atypical neuroleptic drugs.

Improvement of brain SPECT by stabilization of Tc-99m-HMPAO with methylene blue or cobalt chloride. Comparison with Tc-99m-ECD.

AIM: This present study was carried out to investigate whether stabilization of Tc-99m-HMPAO with methylene blue (MB) or cobalt chloride (CC) causes a sensible improvement in image quality and how cerebral to noncerebral activity ratios compare with those of Tc-99m-ECD. METHODS: 30 minutes after preparation 400-600 MBq unstabilized Tc-99m-HMPAO (N = 35 patients), Tc-99m-HMPAO added with MB (N = 24 patients), added with CC (N = 30 patients) or Tc-99m-ECD (N = 28 patients) were injected. Radiochemical stability was measured in vitro with three chromatographical methods. Image quality was assessed quantitatively using two ratios, one of them determined by count densities of brain/scalp (Os), the other one by count densities of brain/nose (QN). In addition, image quality (0 = bad, 3 = excellent) and background activity (0 = high, 3 = no) were visually assessed by three independent observers. RESULTS: In contrast to unstabilized Tc-99m-HMPAO the integrity of the complexes of MB-Tc-99m-HMPAO, CC-Tc-99m-HMPAO and Tc-99m-ECD decreased only by a few percent during a period of 2 hours after reconstitution (66.8 +/- 9.9 vs. 93.0 +/- 2.5, 91.8 +/- 1.9 and 96.9 +/- 1.4%, p < 0.001). Qs and Qn (m.v. +/- SD) differed significantly between studies using unstabilized Tc-99m-HMPAO (3.0 +/- 0.4 and 2.1 +/- 0.3), MB-Tc-99m-HMPAO (3.4 +/- 0.4 and 2.3 +/- 0.3), CC-Tc-99m-HMPAO (3.6 +/- 0.6 and 2.6 +/- 0.4) and those using Tc-99m-ECD (4.3 +/- 0.7 and 4.8 +/- 1.4, p < 0.05 and < 0.001). Stabilization with CC or MB resulted in significant higher scoring of image quality and lower scoring of background activity in comparison to that of unstabilized Tc-99m-HMPAO, without reaching the scores obtained with Tc-99m-ECD. CONCLUSIONS: It is concluded that stabilization of Tc-99m-HMPAO with MB or CC definitely improves image quality in rCBF-SPECT, without reaching that of Tc-99m-ECD. Improvement of image quality results from the reduction of the amount of decomposition products that contribute to considerable extracerebral activity.

Attenuation correction by simultaneous emission-transmission myocardial single-photon emission tomography using a technetium-99m-labelled radiotracer: impact on diagnostic accuracy.

Irregular photon attenuation may limit the diagnostic accuracy of myocardial single-photon emission tomography (SPET). The aim of this study was to quantify the potential benefit of attenuation correction by simultaneous emission and transmission imaging for the detection of coronary artery disease (CAD) of vessels supplying the inferoposterior wall segments. In 25 male patients with >/=50% stenoses of the right coronary artery and/or circumflex artery but without significant narrowing of the left anterior descending artery, stress studies using technetium-99m tetrofosmin (400 MBq) were carried out with and without attenuation correction. A dual-head camera with L-shaped detector positioning was equipped with two scanning gadolinium-153 line sources. Tomograms were reconstructed and quantified using circumferential count rate profiles of myocardial activity (two in each patient). The profiles were compared with the respective normal ranges obtained from a database of 25 male patients with a <10% likelihood of CAD. In patients without CAD, the maximal differences in count density of different wall segments were reduced from 29.0% in non-corrected (NC) studies to 9.5% in attenuation-corrected (AC) studies. In particular, the inferoposterior and septal wall segments were represented by significantly increased relative count densities after attenuation correction. The effects of attenuation correction proved independent of body mass. In patients with CAD, segmental count densities were abnormal in 84% of the NC studies and 100% of the AC studies. In single-vessel disease the stenotic vessel was identified in 66% of cases by NC studies and in 100% by AC studies. In AC studies, the extent and depth of defects exceeded those in NC studies. For the detection of CAD of the right coronary artery, the receiver operating characteristic (ROC) curves relating to the AC studies demonstrated improved discrimination capacity (P<0.05). ROC analysis of CAD detection yielded normalcy rates of 82% (NC) and 94% (AC) for the circumflex artery and 65% (NC) and 97% (AC) for the right coronary artery area at a sensitivity level of 95%. It is concluded that attenuation correction using the above system may enhance the diagnostic accuracy of myocardial SPET when inferoposterior wall segments are to be evaluated.

[Striatal uptake of I-123-beta-CIT and I-123-IBZM in patients with extrapyramidal symptoms]. / Striatale Aufnahme von I-123-beta-CIT und I-123-IBZM bei Patienten mit extrapyramidaler Symptomatik.

AIM: This pilot study deals with the question whether characteristic changes in local cerebral dopamine transporter function and D2-receptor binding capacity can be shown with SPET in idiopathic Parkinson syndrome (IPS) and secondary Parkinson syndrome (SPS). METHODS: In 16 patients (6 with IPS, 6 with SPS except Wilson's disease, and 4 with Wilson's disease) SPET studies were performed using I-123-beta-CIT and I-123-IBZM and a dual-head gamma camera. Images were obtained 20-24 h and 2 h post injection, respectively. For semiquantitative analysis count density ratios of basal ganglia (BG) and cerebellum (CER) were determined for I-123-beta-CIT and ratios between BG and medial frontal cortex (MFC) for I-123-IBZM. RESULTS: The BG/CER ratio in the I-123-beta-CIT studies averaged 3.04 +/- 0.83 in IPS and 7.73 +/- 3.28 in SPS (p < 0.01) (except Wilson's disease). In patients with IPS, the BG/MFC I-123-IBZM ratios of basal ganglia contralateral to the symptomatic side exceeded that of the individual ipsilateral BGs (1.75 +/- 0.12 vs. 1.61 +/- 0.16); these ratios were significantly reduced when compared with those of SPS patients, although the differences were less pronounced than those of I-123-beta-CIT uptake values. In some of the patients with Wilson's disease the BG/MFC ratio for I-123-IBZM was dramatically reduced (as low as 1.29), whereas I-123-beta-CIT uptake was only slightly reduced when compared with that of SPS patients (8.00 +/- 2.90, p < 0.01). CONCLUSION: It is concluded that the neurochemical changes that can be anticipated in the above diseases can be monitored with SPET. I-123-beta-CIT, however, appears to be more adequate to differentiate IPS from SPS than I-123-IBZM.

Non-uniform attenuation correction for myocardial SPET using two Gd-153 line sources.

AIM: This study deals with the effect of the non-uniform attenuation correction method on myocardial tomograms of normal subjects. METHOD: A total of 35 patients (20 female, 15 male) without evidence of cardiac disease underwent SPET with and without attenuation correction using a dual head camera and transmission data obtained by two scanning Gd-153 line sources after administration of 400 MBq Tc-99m-tetrofosmin RESULTS: In non-corrected (NC) stress studies the lowest count rates were found in the inferior segments with mean differences in count rates between maxima and minima of 35.8 +/- 10.8%. In attenuation corrected (AC) images the respective segmental differences averaged only 20.9 +/- 3.3% and the images did not show significant count deficiency in the inferior segments. The effects of correction revealed to be sex dependent, but independent of body mass on average. CONCLUSION: AC using the above technique significantly reduces the variability of count rate distribution in normal subjects and improves the preconditions for accurate diagnostic evaluation of coronary artery disease using SPET.

Changes in local cerebral blood flow by neuroactivation and vasoactivation in patients with impaired cognitive function.

Imaging of local cerebral blood flow (lCBF) may serve as an important supplementary tool in the aetiological assessment of dementias. In early or preclinical disease, however, there are less characteristic changes in lCBF. In the present study it was investigated whether vasoactivation or neuroactivation may produce more pronounced local lCBF deficits. Local CBF was investigated by using technetium-99m hexamethylpropylene amine oxime and single-photon emission tomography (SPET) in 80 patients (50 with mild cognitive impairment and 30 with dementia of Alzheimer type (DAT), all without evidence of cerebrovascular disease) at rest (baseline) and during activation. In 31 studies patients underwent vasomotor activation with acetazolamide, while 62 studies were performed under cognitive challenge (neuroactivation by labyrinth task). Cortical activity relative to that of cerebellum increased significantly in a right temporal region and tended to increase in other cortical regions upon vasoactivation. In contrast, neuroactivation reduced cortical activity relative to that of cerebellum in several left and right temporal and in left parietal regions. Visual classification of SPET images of patients with probable DAT by three observers resulted in a reduction of the number of definitely abnormal patterns from 9/12 to 4/12 by vasoactivation and an increase from 10/18 to 15/18 by neuroactivation. Correspondingly, abnormal ratings in patients with mild cognitive dysfunction were reduced from 7/19 to 5/19 by vasoactivation and were increased from 12/21 to 18/21 by neuroactivation. In conclusion, vasoactivation does not enhance local relative perfusion deficits in patients with cognitive impairment of non-vascular aetiology, whereas neuroactivation by labyrinth task produces more pronounced local flow differences and enhances abnormal patterns in lCBF imaging.

[Simple bimolecular reaction model with physical feedback mechanism in the handling of rhythmic processes and their modification of receptor populations]. / Einfaches bimolekulares Reaktionsmodell mit physikalischem Feedback-Mechanismus zur Behandlung rhythmischer Prozesse und deren Beeinflussung an Receptor-Populationen.

A bimolecular reaction model considering a physical feedback by the concentration dependence of a kinetic coefficient is proposed for the description of the receptor action. The regulatory properties will be treated in the framework of nonequilibrium thermodynamics as dynamic critical phenomena. The receptor and the bioactive agent are regarded as a system working in the vicinity of an instability point. The kinetics contains the possibility for a bifurcation to a limit cycle behavior, a stable time-periodic solution. For the transition regime, the relevant order parameter and its evolution equation can be determined with the help of a reductive pertubation approach. On this way, the magnitude of the receptor output signal may be obtained via its dependence on some essential parameters. The influence of environmentally produced fluctuations is incorporated by a Gaussian white-noise. For the stochastic model, the static probability distributions are calculated yielding some potential laws for the behavior of interesting state variables. The model results will be useful for the understanding of certain receptor related phenomena as for instance sigmoidal relationships between the response and the dose, tachyphylaxis and specific desensitization, temporal oscillations of some concentrations, and modulation effects caused by co-factors. Within the model, pertubations can be included such as a stochastic parameter variation or a competitive mechanism.

[Multivariate Free-Wilson analysis (author's transl)]. / Multivariate Free-Wilson-Analyse.

The interpretation of drug effects is improved if various biological variables are regressed against a Free-Wilson matrix (multivariate QSAR [5]. For instance, the time-dependent QSAR demonstrates that substituent effects are nonstationary.