Non-invasive assessment of distribution volume ratios and binding potential: tissue heterogeneity and interindividually averaged time-activity curves

Due to the stochastic nature of radioactive decay, any measurement of radioactivity concentration requires spatial averaging. In pharmacokinetic analysis of time-activity curves (TAC), such averaging over heterogeneous tissues may introduce a systematic error (heterogeneity error) but may also improve the accuracy and precision of parameter estimation. In addition to spatial averaging (inevitable due to limited scanner resolution and intended in ROI analysis), interindividual averaging may theoretically be beneficial, too. The aim of this study was to investigate the effect of such averaging on the binding potential (BP) calculated with Logans non-invasive graphical analysis and the simplified reference tissue method (SRTM) proposed by Lammertsma and Hume, on the basis of simulated and measured positron emission tomography data {[¹¹C]d-threo-methylphenidate (dMP) and [¹¹C]raclopride (RAC) PET}. dMP was not quantified with SRTM since the low k ₂ (washout rate constant from the first tissue compartment) introduced a high noise sensitivity. Even for considerably different shapes of TAC (dMP PET in parkinsonian patients and healthy controls, [¹¹C]raclopride in patients with and without haloperidol medication) and a high variance in the rate constants (e.g. simulated standard deviation of K ₁=25%), the BP obtained from average TAC was close to the mean BP (error <5%). However, unfavourably distributed parameters, especially a correlated large variance in two or more parameters, may lead to larger errors. In Monte Carlo simulations, interindividual averaging before quantification reduced the variance from the SRTM (beyond a critical signal to noise ratio) and the bias in Logans method. Interindividual averaging may further increase accuracy when there is an error term in the reference tissue assumption E=DV ₂–DV (DV ₂ = distribution volume of the first tissue compartment, DV = distribution volume of the reference tissue). This can be explained by the fact that the distribution volume ratio (DVR=DV/DV) obtained from averaged TAC is an approximation for DV/DV rather than for DVR/n. We conclude that Logans non-invasive method and SRTM are suitable for heterogeneous tissues and that discussion of group differences in PET studies generally should include qualitative and quantitative assessment of interindividually averaged TAC.     

The “dural tail” adjacent to meningiomas studied by dynamic contrast-enhanced MRI: a comparison with histopathology

We examined 32 patients with intracranial tumors (17 meningiomas, 8 neuromas, 7 pituitary adenomas) by conventional and dynamic contrast-enhanced MRI. Our aim was to clarify whether the pathological dural contrast enhancement adjacent to meningiomas (the dural tail) is specific to meningiomas and, more important, whether it represents neoplastic dural infiltration or hypervascularization as a tumor accompanying reaction. A dural tail was found in 9 of 17 meningiomas. None of the other extra-axial tumours (neuromas, pituitary adenomas) showed comparable dural enhancement. Dynamic examinations with an ultrafast single slice imaging technique (snapshot-FLASH) after a bolus injection of contrast medium showed a dural tail in seven out of these nine meningiomas, while in two cases the dural tail turned out to be a cortical vein with a characteristic dynamic contrast enhancement pattern. In the dynamic study all seven dural tails were found to have earlier, steeper contrast enhancement than the corresponding tumours. All the tumours and part of the adjacent dura mater in four of the seven meningiomas with dural enhancement were examined histopathologically. In none of these four cases was neoplastic tissue found more than 2 mm away from the main tumour. The results strongly support the suggestion that the dural tail adjacent to meningiomas represents a hypervascular, non-neoplastic dural reaction.     

In vitro and in vivo characterisation of nor-β-CIT: a potential radioligand for visualisation of the serotonin transporter in the brain

Radiolabelled 2-Cabomethoxy-3-(4-iodophenyl)tropane (-CIT) has been used in clinical studies for the imaging of dopamine and serotonin transporters with single-photon emission tomography (SPET). 2-Carbomethoxy-3-(4-iodophenyl)nortropane (nor--CIT) is a des-methyl analogue of -CIT, which in vitro has tenfold higher affinity (IC₅₀=0.36 nM) to the serotonin transporter than -CIT (IC₅₀=4.2 nM). Nor--CIT may thus be a useful radioligand for imaging of the serotonin transporter. In the present study iodine-125 and carbon-11 labelled nor--CIT were prepared for in vitro autoradiographic studies on post-mortem human brain cryosections and for in vivo positron emission tomography (PET) studies in Cynomolgus monkeys. Whole hemisphere autoradiography with [¹²⁵I]nor--CIT demonstrated high binding in the striatum, the thalamus and cortical regions of the human brain. Addition of a high concentration (1 M) of citalopram inhibited binding in the thalamus and the neocortex, but not in the striatum. In PET studies with [¹¹C]nor--CIT there was rapid uptake of radioactivity in the monkey brain (6% of injected dose at 15 min) and high accumulation of radioactivity in the striatum, thalamus and neocortex. Thalamus to cerebellum and cortex to cerebellum ratios were 2.5 and 1.8 at 60 min, respectively. The ratios obtained with [¹¹C]nor--CIT were 20%–40% higher than those previously obtained with [¹¹C]-CIT. Radioactivity in the thalamus and the neocortex but not in the striatum was displaceable with citalopram (5 mg/kg). In conclusion, nor--CIT binds to the serotonin transporter in the primate brain in vitro and in vivo and has potential for PET and SPET imaging of the serotonin transporter in human brain.     

Impact of CT in the neurosurgical management of intracranial tumors

Summary A total of 103 brain tumor patients examined with CT, radionuclide brain scan, and angiography or pneumoencephalography, and all surgically verified, were studied to evaluate the impact of CT on the neurosurgical handling of brain tumors. CT alone was usually sufficient for optimal handling of astrocytoma patients, angiography in most meningioma cases, and pneumoencephalography in cases with sellar, suprasellar, and some other midline tumors. Information obtained only through CT sometimes altered the therapy. Sometimes it led to biopsy instead of a meaningless attempt at a radical excision; in other cases it permitted a radical excision otherwise not possible.     

Evaluation of [1-11C]-α-aminoisobutyric acid for tumor detection and amino acid transport measurement: spontaneous canine tumor studies

Alpha-aminoisobutyric acid (AIB), or -methyl alanine, is a nonmetabolized amino acid transported into cells, particularly malignant cells, predominantly by the A amino acid transport system. Since it is not metabolized, [1-¹¹C]-AIB can be used to quantify A-type amino acid transport into cells using a relatively simple compartmental model and quantitative imaging procedures (e.g. positron tomography). The tissue distribution of [1-¹¹C]-AIB was determined in six dogs bearing spontaneous tumors, including lymphosarcoma, osteogenic sarcoma, mammary carcinoma, and adenocarcinoma. Quantitative imaging with tissue radioassay confirmation at necropsy showed poor to excellent tumor localization. However, in all cases the concentrations achieved appear adequate for amino acid transport measurement at known tumor locations. The observed low normal brain (due to blood-brain barrier exclusion) and high (relative to brain) tumor concentrations of [1-¹¹C]-AIB suggest that this agent may prove effective for the early detection of human brain tumors.     

γ-Glutamyltransferase test as a new tool for identification of seminal stains

Summary A simple qualitative method for identification of seminal stains based on a high activity of -glutamyltransferase (-GTP) in human semen is described. It employs the release of -naphthylamine from N--glutamyl--naphthylamide by the -GTP action; -naphthylamine couples with Fast Garnet GBC salt to produce a strong brownish-red color. The data on its simplicity, specificity, and stability show that the present method is suitable for medicolegal examination of seminal stains as a preliminary test.     

The reduction of inter- and intra-observer variability for defining regions of interest in nuclear medicine

The use of region-of-interest (ROI) techniques to quantify data obtained in radionuclide images is common-place. However, the reproducibility of quantitation due to inter- and intra-observer variations using particular methods of deriving ROIs is often not appreciated. We examined such variations in the results obtained by four independent observers of varying experience using four methods of depicting a ROI about an organ. The set of image data consisted of renal scans with varying target-to-background ratios, and the ROI facilities included two edge-detection methods. The results indicated that, once observers were experienced with edge-detection methods, a lower inter- and intra-observer variation could be achieved, although the technique of shrinking a ROI about a subjectively chosen display level was reasonably satisfactory. In terms or reproducibility, the least satisfactory method of depicting a ROI was the commonly used manually guided bug around arbitarily chosen display levels representing the boundary of an organ.     

Scintigraphic visualisation of Walker carcinoma-256 in Sprague-Dawley rats by means of 99mTc-labelled monocytes

Labelled macrophages accumulate in Walker carcinosarcoma-256 after in vivo and in vitro stimulation with a lectin and are theretically suitable for scintigraphic tumour detection. At present, routine application of the technique in man is precluded by: (1) the use of PHA, and (2) a labelling method for macrophages with considerable limitations to its application and which results in significant uptake of activity in liver and spleen. However, the purpose of the study was primarily to demonstrate the principle of a possible alternative to the use of labelled monoclonal antibodies for the scintigraphic detection of tumours.     

Accumulation of radioiodinated tyrosine derivatives in the adrenal medulla and in melanomas

Because tyrosine and dopa can be regarded as precursors of adrenomedullary hormones and melanin, radioiodinated derivatives of these compounds were tested for their accumulation in the adrenal medulla and in melanomas of various animal species. The highest level of accumulation in the adrenal medulla was attained in mice and rats with iodinated -hydroxy--methyltyramine, and in melanomas of mice with iodinated -methyltyrosine. The results could not be reproduced to the same extent in other species.     

Application of DNA techniques for identification using human dental pulp as a source of DNA

Summary Dental pulp tissue could be obtained in most cases from materials obtained under experimental conditions and from forensic casework (air accidents, burned and putrefied bodies). Teeth extracted during dental treatment (n = 30) were stored for 6 weeks and 4 years at room temperature. In addition teeth (n = 10) extracted from jaw fragments that had been stored for 15 years at room temperature, and teeth extracted post mortem from actual identification cases (n = 8) were investigated. Following extraction from dental pulp tissue the DNA concentration was measured by fluorometry. The amount of DNA obtained from the dental pulp tissue of a single tooth varied from 6 g to 50 g DNA. In most cases high molecular weight DNA was still present although the major portion consisted of degraded DNA. Genomic dot blot hybridization for sex determination using the biotinylated repetitive DNA probe pHY 2.1 was performed and sex was correctly classified in all cases using 50–100 ng target DNA. PCR typing of the HLA-DQ and ApoB 3 VNTR systems from dental pulp tissue DNA was in agreement with the results obtained from blood, bloodstains, or lung tissue. In addition, Southern blot analysis of selected samples using the single locus VNTR probe pYNH24 was successfully performed. In all cases the DNA recovered from dental pulp was unsuitable for multilocus probe analysis.

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Abbreviations BCIP 5-bromo-4-chloro-3-indolylphosphate - RFLP Restriction fragment length polymorphism - VNTR Variable number of tandem repeats - AMP-FLP Amplified fragment length polymorphism Presented in part as poster demonstration at the International Symposium on Mass Disasters, Lausanne 1991     

Zur Entstehung fluoreszierender Verbindungen in formalinfixierten Organen

Zusammenfassung In formalinfixierten Organen bilden sich fluoreszierende Verbindungen. Wir konnten nachweisen, daß es sich bei diesen Verbindungen um 3,4 Dihydroisochinoline bzw. 3,4 Dihydro--carboline handelt, die durch eine Reaktion des Formaldehyds mit biogenen Aminen des Typs -Phenyläthylamin bzw. -(3 Indolyl)äthylamin entstehen.

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On formation of fluorescent compounds in formaldehyde treated tissues

Summary In formaldehyde treated tissues, fluorescent compounds are formed. We could demonstrate, that these compounds result from a reaction of biogenic amines such as -phenylethylamines or -(3 indolyl) ethylamines with formaldehyde to yield the fluorescent 3,4 dihydroisoquinolines or 3,4 dihydro--carbolines.

Auszugsweise vorgetragen auf der 54. Jahrestagung der Deutschen Gesellschaft für Rechtsmedizin in Frankfurt, September 1975     

A pattern of post-traumatic demineralization of bone simulating permeative neoplastic replacement: A potential source of misinterpretation

Long bones with a prominent endosteal trabecular pattern, particularly the herringbone configuration, when immobilized, will demineralize in a striking spotty pattern which may simulate neoplastic permeative replacement of bone. The recognition of this phenomenon will obviate needless concern and investigation.     

Usefulness of brain <Superscript>99m</Superscript>Tc-TRODAT-1 SPET for the evaluation of Parkinson’s disease

Nigral dopaminergic projections to the striatum are targeted in Parkinsons disease (PD). The extent of the degeneration of the dopaminergic system in PD can be visualised by dopamine transporter imaging using single-photon emission tomography (SPET). In this study in 188 patients with PD, we analysed the image patterns and compared them with the clinical features in order to verify the usefulness of technetium-99m TRODAT-1 brain SPET in the evaluation of patients with PD. Two independent readers visually assessed SPET slices from three brain axes according to a fine visual scale; results were also grouped according to a rough visual scale. Results of both visual and semi-quantitative analyses were compared among patients with different stages of PD and healthy controls. There was good agreement between the readers in the interpretation of the image patterns [kappa statistic ()=0.85 for the presence of PD; =0.88 for the rough scale and 0.81 for the fine scale]. Good concordance was obtained when visual interpretation was used to evaluate the presence of PD (sensitivity =98%, specificity =86%, =0.85). Semi-quantitative analyses revealed significant negative correlations between both striatal and putaminal uptake and disease severity as assessed using the Hoehn and Yahr scale (=–0.89 and –0.93 respectively). An apparent decrease in striatal uptake in early PD, hardly discernible from the uptake level in advanced PD, was commonly found in visual analyses. The results suggest that both visual and semi-quantitative analyses of ^99mTc-TRODAT-1 SPET images reflect neurodegeneration in PD, and that ^99mTc-TRODAT-1 SPET represents an adequate means for evaluation of the status of patients with PD.     

Technical parameters influencing the severity of injury of front-seat,belt-protected car passengers on the impact side in car-to-car side collisions with the main impact between the front and rear seats (B-pillars)

Summary Authentic car-to-car side collisions (n = 30) with the main impact area at the B-pillar were analyzed to find technical parameters corresponding with the injury severities of the front seat, belt-protected car passengers on the impact side. EES (Energy Equivalent Speed) and Av (delta v, change in velocity) were highly significant predictors of the severity of thoracic and abdominal injuries and total injury severity coded according to the Abbreviated Injury Scale (AIS). At an EES or v 40 km/h all front-seat car passengers on the impact side sustained a total injury severity of Maximum AIS (MAIS) 4 and died. Although a passenger could survive the crash without injury to one or more body regions up to the highest EES- and Av-values, at EES or v 40 km/h fatal injuries were sustained in at least one body region. At an EES 35 km/h or a Av 15 km/h no front-seat car passenger on the impact side remained uninjured.     

Pretargeting in tumored mice with radiolabeled morpholino oligomer showing low kidney uptake

We have recently shown that accumulation in mouse kidneys of technetium-99m labeled phosphorodiamidate morpholinos (MORFs) increases with the number of cytosines in the base sequence. To improve tumor/kidney ratios in tumored mice, pretargeting studies were performed with a cytosine-free MORF. An 18-mer MORF (5-TCTTCTACTTCACAACTA) was conjugated to the anti-CEA antibody MN14 (Immunomedics) and administered to nude mice bearing LS174T tumors. Thereafter, the ^99mTc-labeled cytosine-free cMORF (5-TAGTTGTGAAGTAGAAGA-amide-MAG₃) was administered. For comparison, the identical study was repeated but with our original pair of 18-mer MORFs (5-GGGTGTACGTCACAACTA-conjugated MN14 and ^99mTc-labeled 5-TAGTTGTGACGTACACCC-amide-MAG₃). Surface plasmon resonance was used to show that the hybridization affinities of the original and the modified pair of MORFs were essentially equal. Hybridization of the cytosine-free cMORF-^99mTc to MN14-MORF was demonstrated in vitro by size-exclusion high-performance liquid chromatography. At 3 h, kidney levels in normal mice were 2.0%ID/organ for the modified cMORF vs. 4.1%ID/organ for the original cMORF sequence, while at 24 h, these values were 0.9% vs 1.8%ID/organ. Pretargeting studies in tumored mice receiving 25 g of conjugated antibody, 0.5 g of labeled cMORF 48 h later, followed by imaging and sacrifice at 3 h showed that kidney levels were reduced using the cytosine-free cMORF. Moreover, tumor accumulation was about 3.6%ID/g and was independent of sequence. The whole-body images clearly reflected the improved tumor to kidney ratios. By choosing a cytosine-free base sequence for pretargeting studies, kidney accumulation of cMORF-^99mTc was reduced without adversely influencing tumor accumulation. The lowering of kidney radioactivity levels in this way may be important to reduce toxicity to this organ in connection with pretargeting radiotherapy studies.     

Analytische Daten des neuen Benzodiazepinderivates Midazolam (Dormicum) und seiner Metaboliten

Zusammenfassung In der Arbeit werden analytische Daten zum Nachweis von Midazolam, -Hydroxi-midazolam, 4-Hydroxi-midazolam and ,4-Dihydroxi-midazolam sowie wichtige pharmakokinetische Eigenschaften mitgeteilt. Weiterhin wird über die Extraktion aus biologischem Material berichtet.Herrn Dr. James Bäumler (Basel) zum 60. Geburtstag gewidmet     

Stress induced right ventricular dysfunction: An indication of reversible right ventricular ischaemia

Stress induced changes in left ventricular ejection fraction are widely used in the detection and assessment of coronary artery disease. This study demonstrates that right ventricular dysfunction may also occur, and assesses its significance in terms of coronary artery anatomy. This study involved 14 normal subjects and 26 with coronary artery disease investigated by equilibrium radionuclide ventriculography, at rest and during maximal dynamic exercise. Mean normal resting right ventricular ejection fraction (RVEF) was 0.40 (SD 0.118), and all normal subjects increased RVEF with stress (mean RVEF+0.13 SD 0.099). Mean RVEF in the subjects with coronary artery disease was significantly lower at 0.00 (SD 0.080), but there was overlap between the two groups. The largest falls in RVEF were seen if the right coronary artery was occluded without retrograde filling. In this subgroup with the most severely compromised right ventricular perfusion (nine subjects), RVEF always fell with stress, and mean RVEF was-0.08 (SD 0.050). There was no significant correlation between LVEF and RVEF, implying that the right ventricular dysfunction was due to right ventricular ischaemia, rather than secondary to left ventricular dysfunction. Stress induced right ventricular ischaemia can therefore be detected readily by radionuclide ventriculography.     

ROC analysis in radioimmunoassay: An application to the interpretation of thyroglobulin measurement in the follow-up of thyroid carcinoma

This study is an application of the ROC technique to the determination of threshold values (TV) for the interpretation of serum thyroglobulin (Tg) measurements in the follow-up of differentiated thyroid cancer. Serum Tg was assayed using the Henning kit in 1466 samples from 245 individuals. A local or distant recurrence was assessed by clinical examination, radiological and scintigraphic investigations, and was present in 23 patients. The measurements were divided into four groups: 1) measurements performed less than 6 months after thyroidectomy; 2) measurements performed more than 6 months after thyroidectomy; 3) measurements performed during the suppression of pituitary secretion; 4) measurements performed during withdrawal of the substitutive therapy. An ROC curve was calculated for each group and for each curve three TVs were determined: TV1, TV2, and TV3 corresponding to a high sensitivity, a high specificity and a high sum of sensitivity and specificity respectively. TV1 is 3.12 g/l in the four groups. TV2 is 44 g/l, 19 g/l and 30 g/l, in the first, second, third and fourth groups respectively. TV3 is 35 g/l in the first group, 3.12 g/l in both the second and third groups and 30 g/l in the fourth group. When the classical method allows the determination of only one threshold value, the ROC technique allows us to determine threshold values adapted to both the patient clinical status and the chosen sensitivity or specificity.     

“Fingerprints” of vertebral trauma—a unifying concept based on mechanisms

Vertebral fractures, like fractures in the peripheral skeleton, occur, in predictable and reproducible patterns that are related to the kind of force applied to the affected bone. The same force applied to the cervical, thoracic, or lumbar column will result in injuries which appear quite similar. A review of 621 injuries to the vertebral column revealed that there are basically four mechanisms of injury: flexion, extension, shearing, and torque (rotation). These injuries may occur by themselves or in combination with one another. The severity and extent of damage produced by any mechanisms is dependent upon the incident force, the position of the patient at the time of injury, and the velocity of the patient. Thus, there is a pattern of recognizable signs which span the spectrum from mild soft tissue damage to severe skeletal and ligamentous disruption. These patterns are termed the fingerprints of the injury, and this presentation illustrates the four basic types of vertebral injury producing those fingerprints.     

Anatomic Relationship of the InternalJugular Vein and the Common Carotid Artery Applied to Percutaneous Transjugular Procedures

Purpose To demonstrate the anatomic relationship of the internal jugular vein (IJV) with the common carotid artery (CCA) in order to avoid inadvertent puncture of the CCA during percutaneous central venous access or transjugular interventional procedures.Methods One hundred and eighty-eight consecutive patients requiring either central venous access or interventional procedures via the IJV were included in the analysis. The position of the IJV in relation to the CCA was demonstrated by portable ultrasonography. The IJV location was recorded in a clock-dial system using the carotid as the center of the dial and the angles were measured. Outcomes of the procedure were also recorded.Results The IJV was lateral to the CCA in 187 of 188 patients and medial to the CCA in one patient. The left IJV was at the 12 oclock position in 12 patients (6%), the 11 oclock position in 17 patients (9%), the 10 oclock position in 142 patients (75%) and at the 9 oclock position in 17 patients (9%). The right IJV was at the 12 oclock position in 8 patients (4%), the 1 oclock position in 31 patients (16%), the 2 oclock position in 134 patients (71%) and the 3 oclock position in 17 patients (9%). In one patient the left IJV was located approximately 60° medial to the left CCA; this was recorded as 2 oclock on the left since it is opposite to the 10 oclock position.Conclusion Knowledge of the IJV anatomy and relationship to the CCA is important information for the operator performing an IJV puncture, to potentially reduce the chance of laceration of the CCA and avoid placement of a large catheter within a critical artery, even when ultrasound guidance is used.