Heteronuclear NMR spectroscopic investigations of hydrogen bonding in 2-(benzo[d]thiazole-2'-yl)-N-alkylanilines.

The 2-(benzo[d]thiazole-2'-yl)-N-alkylanilines have previously revealed the presence of a strong intramolecular hydrogen bond. This in turn gives rise to a more complicated multiplet for the protons attached to the carbon adjacent to the amino group. This intramolecular hydrogen bond was investigated by a deuterium exchange experiment using heteronuclear NMR spectroscopy (1H, 13C, 15N and 2H). We observed changes in the multiplet structure and chemical shifts providing further evidence that the deuterium replaces the hydrogen in the intramolecular hydrogen bond. A time course study of the D2O exchange confirmed the presence of a strong hydrogen bond. The comparison of the structures obtained by X-ray crystallography showed a very small difference in planarity between the two-substituted and four-substituted amino compounds. In both the cases, the phenyl ring is not absolutely coplanar with the thiazole unit. The existence of this intramolecular hydrogen bond in 2-(benzo[d]thiazole-2'-yl)-N-alkylanilines was further confirmed by single crystal X-ray crystallography.

Artificial ionospheric layers during pump frequency stepping near the 4th gyroharmonic at HAARP.

We report on artificial descending plasma layers created in the ionosphere F region by high-power high-frequency (HF) radio waves from High-frequency Active Auroral Research Program at frequencies f(0) near the fourth electron gyroharmonic 4f(ce). The data come from concurrent measurements of the secondary escaping radiation from the HF-pumped ionosphere, also known as stimulated electromagnetic emission, reflected probing signals at f(0), and plasma line radar echoes. The artificial layers appeared only for injections along the magnetic field and f(0)>4f(ce) at the nominal HF interaction altitude in the background ionosphere. Their average downward speed ~0.5 km/s holds until the terminal altitude where the local fourth gyroharmonic matches f(0). The total descent increases with the nominal offset f(0)-4f(ce).

Active Precipitation of Radiation Belt Electrons Using Rocket Exhaust Driven Amplification (REDA) of Man-Made Whistlers.

Ground-based very low frequency (VLF) transmitters located around the world generate signals that leak through the bottom side of the ionosphere in the form of whistler mode waves. Wave and particle measurements on satellites have observed that these man-made VLF waves can be strong enough to scatter trapped energetic electrons into low pitch angle orbits, causing loss by absorption in the lower atmosphere. This precipitation loss process is greatly enhanced by intentional amplification of the whistler waves using a newly discovered process called rocket exhaust driven amplification (REDA). Satellite measurements of REDA have shown between 30 and 50 dB intensification of VLF waves in space using a 60 s burn of the 150 g/s thruster on the Cygnus satellite that services the International Space Station. This controlled amplification process is adequate to deplete the energetic particle population on the affected field lines in a few minutes rather than the multi-day period it would take naturally. Numerical simulations of the pitch angle diffusion for radiation belt particles use the UCLA quasi-linear Fokker Planck model to assess the impact of REDA on radiation belt remediation of newly injected energetic electrons. The simulated precipitation fluxes of energetic electrons are applied to models of D-region electron density and bremsstrahlung X-rays for predictions of the modified environment that can be observed with satellite and ground-based sensors.

Objective assessment of tumour response to therapy based on tumour growth kinetics.

BACKGROUND: Current standards for assessment of tumour response to therapy (a) categorise therapeutic efficacy values, inappropriate for patient-specific and deterministic studies, (b) neglect the natural growth characteristics of tumours, (c) are based on tumour shrinkage, inappropriate for cytostatic therapies, and (d) do not accommodate integration of functional/biological means of therapeutic efficacy assessed with, for example, positron emission tomography or magnetic resonance imaging, with data from anatomical changes in tumour. METHODS: A quantity for tumour response was formulated assuming that an effective treatment may decrease the cell proliferation rate (cytostatic) and/or increase the cell loss rate (cytotoxic) of the tumour. Tumour response values were analysed for 11 non-Hodgkin's lymphoma patients treated with (131)I-labelled anti-B1 antibody and 12 prostate cancer patients treated with a nutritional supplement. RESULTS: Tumour response was found to be equal to the logarithm of the ratio of post-treatment tumour volume to the volume of corresponding untreated tumour. Neglecting the natural growth characteristics of tumours results in underestimation of treatment effectiveness based on currently used methods. The model also facilitates the integration of data from tumour volume changes, with data from functional imaging. CONCLUSION: Tumour response to therapy can be assessed with a continuous dimensionless quantity for both cytotoxic and cytostatic treatments.

Efficacy and safety of enteric-coated mycophenolate sodium in combination with two glucocorticoid regimens for the treatment of active lupus nephritis.

Mycophenolic acid, in combination with glucocorticoids, has been shown in a series of trials to be safe and effective for treatment of lupus nephritis. Regimens that permit glucocorticoid dose reduction without loss of efficacy would be advantageous. MyLupus was a 24-week, multicentre, open-label, study in patients with active proliferative lupus nephritis treated with enteric-coated mycophenolate sodium (EC-MPS), randomized to standard-dose (n = 42) or reduced-dose (n = 39) glucocorticoids. Complete response at week 24, the primary endpoint, was achieved in 19.8% (16/81) of patients (19.0% standard-dose, 20.5% reduced-dose; lower limit of 97.5% CI for the difference -15.9%, p = 0.098, i.e. non-inferiority was not shown). Partial response occurred in 42.0% of patients (34/81). From baseline to week 24, the mean global British Isles Lupus Assessment Group (BILAG) score decreased from 14.0 ± 5.4 to 5.0 ± 3.8 (p < 0.001). The incidence of adverse events was 80.2% (65/81), most frequently gastrointestinal complications (31/81, 38.3%). Infections were reported in 57.1% and 35.9% of standard- and reduced-dose glucocorticoid patients, respectively (p = 0.056), with herpes zoster in 16.7% and 0% (p = 0.012). Three patients discontinued study medication due to adverse events. This exploratory study suggests that EC-MPS may facilitate glucocorticoid reduction without loss of efficacy in patients with active lupus nephritis, but results require confirmation in a controlled, longer-term study versus the current standard of care.

[The role of cardiovascular magnetic resonance imaging in the diagnosis and prognosis of patients with heart failure]. / Die Rolle der Kardio-MRT bei Diagnose und Prognosebeurteilung der Herzinsuffizienz.

Cardiovascular magnetic resonance (CMR) imaging is a tomographic technique, which allows three-dimensional slice orientation without limitations from acoustic windows inherent to echocardiography. Further advantages of CMR are its high temporal and spatial resolution, its excellent soft tissue resolution and its high blood-to-tissue contrast. Cardiovascular magnetic resonance is currently the only imaging technique, which provides a comprehensive study of both structure and function of the heart as well as myocardial perfusion and viability. Moreover, post-processing of CMR images does not require any geometric assumptions as in echocardiography to determine ventricular dimensions. This is particularly important when evaluating ventricles of patients with chronic heart failure with severely altered morphology that may have regional variations in wall thickness and contractility at least in ischemic cardiomyopathy. The highly reproducible results of CMR imaging have turned this technique into a reference standard for the non-invasive assessment of ventricular dimensions, mass and function. In cases with indeterminate results of clinical, electrocardiographic and particularly echocardiographic findings CMR should be used early in the process of diagnosis of patients with heart failure. Not only can altered structure and degree of ventricular and valvular dysfunctions be accurately assessed but also regional perfusion deficits and/or myocardial scars are easily detected. For therapeutic and prognostic reasons a simple differentiation between ischemic and non-ischemic cardiomyopathy should be achieved as the first diagnostic step. In addition, the type and localization of the late gadolinium enhancement (LGE) phenomenon may aid in non-invasively differentiating the etiology of non-ischemic cardiomyopathy. CMR may also improve the assessment and extent of interventricular and intraventricular dyssynchrony in patients to be selected for cardiac resynchronization therapy (CRT). Lastly, the LGE phenomenon may provide independent prognostic information in patients with a CRT system implanted, as well as in patients with ischemic and non-ischemic cardiomyopathy. Thus, CMR imaging should be implemented early in the diagnostic process of patients with heart failure to significantly improve the speed and accuracy of diagnostic procedures, to control the effect of therapeutic measures, and to select patients with a limited prognosis by assessing the degree of ventricular dysfunction and the extent of myocardial scarring.

IMPROVEMENTS OF 111IN SPECT IMAGES RECONSTRUCTED WITH SPARSELY ACQUIRED PROJECTIONS BY DEEP LEARNING GENERATED SYNTHETIC PROJECTIONS.

The aim was to improve single-photon emission computed tomography (SPECT) quality for sparsely acquired 111In projections by adding deep learning generated synthetic intermediate projections (SIPs). Method: The recently constructed deep convolutional network for generating synthetic intermediate projections (CUSIP) was used for improving 20 sparsely acquired 111In-octreotide SPECTs. Reconstruction was performed with 120 (120P) or 30 (30P) projections, or 120 projections with 90 SIPs generated from 30 projections (30-120SIP). The SPECT reconstructions were performed with attenuation, scatter and collimator response corrections. Postfiltered 30P reconstructed SPECT was also analyzed. Image quality were quantitatively evaluated with root-mean-square error, peak signal-to-noise ratio and structural similarity index metrics. Result: The 30-120SIP reconstructed SPECT had statistically significant improved image quality parameters compared to 30P reconstructed SPECT with and without post filtering. The images visual appearance was similar to slightly filtered 120P SPECTs. Thereby, substantial acquisition time reduction with SIPs seems possible without image quality degradation.

Stimulated Brillouin scatter in a magnetized ionospheric plasma.

High power electromagnetic waves transmitted from the HAARP facility in Alaska can excite low-frequency electrostatic waves by magnetized stimulated Brillouin scatter. Either an ion-acoustic wave with a frequency less than the ion cyclotron frequency (f(CI)) or an electrostatic ion cyclotron (EIC) wave just above f(CI) can be produced. The coupled equations describing the magnetized stimulated Brillouin scatter instability show that the production of both ion-acoustic and EIC waves is strongly influenced by the wave propagation relative to the background magnetic field. Experimental observations of stimulated electromagnetic emissions using the HAARP transmitter have confirmed that only ion-acoustic waves are excited for propagation along the magnetic zenith and that EIC waves can only be detected with oblique propagation angles. The ion composition can be obtained from the measured EIC frequency.

Establishment of a clinical SPECT/CT protocol for imaging of 161Tb.

BACKGROUND: It has been proposed, and preclinically demonstrated, that 161Tb is a better alternative to 177Lu for the treatment of small prostate cancer lesions due to its high emission of low-energy electrons. 161Tb also emits photons suitable for single-photon emission computed tomography (SPECT) imaging. This study aims to establish a SPECT protocol for 161Tb imaging in the clinic. MATERIALS AND METHODS: Optimal settings using various γ-camera collimators and energy windows were explored by imaging a Jaszczak phantom, including hollow-sphere inserts, filled with 161Tb. The collimators examined were extended low-energy general purpose (ELEGP), medium-energy general purpose (MEGP), and low-energy high resolution (LEHR), respectively. In addition, three ordered subset expectation maximization (OSEM) algorithms were investigated: attenuation-corrected OSEM (A-OSEM); attenuation and dual- or triple-energy window scatter-corrected OSEM (AS-OSEM); and attenuation, scatter, and collimator-detector response-corrected OSEM (ASC-OSEM), where the latter utilized Monte Carlo-based reconstruction. Uniformity corrections, using intrinsic and extrinsic correction maps, were also investigated. Image quality was assessed by estimated recovery coefficients (RC), noise, and signal-to-noise ratio (SNR). Sensitivity was determined using a circular flat phantom. RESULTS: The best RC and SNR were obtained at an energy window between 67.1 and 82.1 keV. Ring artifacts, caused by non-uniformity, were removed with extrinsic uniformity correction for the energy window between 67.1 and 82.1 keV, but not with intrinsic correction. Analyzing the lower energy window between 48.9 and 62.9 keV, the ring artifacts remained after uniformity corrections. The recovery was similar for the different collimators when using a specific OSEM reconstruction. Recovery and SNR were highest for ASC-OSEM, followed by AS-OSEM and A-OSEM. When using the optimized parameter setting, the resolution of 161Tb was higher than for 177Lu (8.4 ± 0.7 vs. 10.4 ± 0.6 mm, respectively). The sensitivities for 161Tb and 177Lu were 7.41 and 8.46 cps/MBq, respectively. CONCLUSION: SPECT with high resolution is feasible with 161Tb; however, extrinsic uniformity correction is recommended to avoid ring artifacts. The LEHR collimator was the best choice of the three tested to obtain a high-resolution image. Due to the complex emission spectrum of low-energy photons, window-based scatter correction had a minor impact on the image quality compared to using attenuation correction only. On the other hand, performing attenuation, scatter, and collimator-detector correction clearly improved image quality. Based on these data, SPECT-based dosimetry for 161Tb-labeled radiopharmaceuticals is feasible.

Artificial airglow excited by high-power radio waves.

High-power electromagnetic waves beamed into the ionosphere from ground-based transmitters illuminate the night sky with enhanced airglow. The recent development of a new intensified, charge coupled-device imager made it possible to record optical emissions during ionospheric heating. Clouds of enhanced airglow are associated with large-scale plasma density cavities that are generated by the heater beam. Trapping and focusing of electromagnetic waves in these cavities produces accelerated electrons that collisionally excite oxygen atoms, which emit light at visible wavelengths. Convection of plasma across magnetic field lines is the primary source for horizontal motion of the cavities and the airglow enhancements. During ionospheric heating experiments, quasi-cyclic formation, convection, dissipation and reappearance of the cavites comprise a major source of long-term variability in plasma densities during ionospheric heating experiments.

The pollination of zygogynum (winteraceae) by a moth, sabatinca (micropterigidae): an ancient association?

The primitive and vesselless angiosperm Zygogynum (Winteraceae), which is restricted to New Caledonia, is pollinated by a moth, Sabatinca (Micropterigidae). Fossil records of both the moth and the plant families extend to the Early Cretaceous. Adult Sabatinca have grinding mandibles and usually feed on the spores of ferns and on pollen. The insects use the flowers as mating sites and eat the pollen which is immersed in a dense pollenkitt. This mode of pollination in which flowers serve as mating and feeding stations with floral odors acting as cues may have been common in the early evolution of flowering plants.

Pollination by deceit in Paphiopedilum barbigerum (Orchidaceae): a staminode exploits the innate colour preferences of hoverflies (Syrphidae).

Paphiopedilum barbigerum T. Tang et F. T. Wang, a slipper orchid native to southwest China and northern Vietnam, produces deceptive flowers that are self-compatible but incapable of mechanical self-pollination (autogamy). The flowers are visited by females of Allograpta javana and Episyrphus balteatus (Syrphidae) that disperse the orchid's massulate pollen onto the receptive stigmas. Measurements of insect bodies and floral architecture show that the physical dimensions of these two fly species correlate with the relative positions of the receptive stigma and dehiscent anthers of P. barbigerum. These hoverflies land on the slippery centralised wart located on the shiny yellow staminode and then fall backwards through the labellum entrance. They are temporarily trapped in the inflated chamber composed of the interconnected labellum and column. The attractive staminode of P. barbigerum strongly reflects the colour yellow (500-560 nm), a colour preferred innately by most pollen-eating members of the Syrphidae. No scent molecules were detected using GC mass spectrometry analysis, showing that the primary attractant in this system is visual, not olfactory. Pollination-by-deceit in P. barbigerum is contrasted with its congener, P. dianthum, a brood site mimic that is pollinated by ovipositing females of E. balteatus. As the natural rate of fruit set in P. barbigerum (mean 26.3% pooled over three seasons) is lower than that of P. dianthum (mean 58.5% over two seasons), the evolution of false brood sites in some Paphiopedilum spp. should be selectively advantageous as they may provide an increase in the attention and return rates of dependable pollinators to flowers that always lack a reward.

Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study.

OBJECTIVES: Everolimus, a proliferation signal inhibitor with disease-modifying properties, may be useful in treating rheumatoid arthritis (RA). This proof-of-concept study assessed efficacy and safety of everolimus in combination with methotrexate (MTX) in patients with refractory RA. METHODS: A multi-centre, randomised, double-blind, placebo-controlled trial was performed in 121 patients with active RA receiving MTX. Patients were randomised to receive everolimus (6 mg/day) or placebo. The primary endpoint was the American College of Rheumatology criteria for a 20% improvement in measures of disease activity (ACR20) at 12 weeks. RESULTS: There was a rapid onset of action and at 12 weeks the ACR20 response rate was significantly higher in the everolimus group (36.1%) than in the placebo group (16.7%; p = 0.022). Improvements from baseline in tender and swollen joint counts, patient's assessment of pain, and patient's and physician's global assessment of disease activity were significantly greater after treatment with everolimus. The most common adverse events (AEs) in the everolimus group were gastrointestinal (52.5% vs 31.7% in the placebo group), skin (29.5% vs 8.3%), and nervous system disorders (21.3% vs 10.0%); AEs leading to treatment discontinuation were reported for 16.4% and 10.0% of patients, respectively. Changes in haematological parameters, liver function tests, and lipid levels occurred more frequently with everolimus compared to placebo, but were mild and reversible. CONCLUSIONS: The study indicates that everolimus plus MTX provides clinical benefit with an acceptable safety and tolerability profile. It may offer a new treatment option in RA patients with inadequate response to MTX.

Pollination of Cypripedium plectrochilum (Orchidaceae) by Lasioglossum spp. (Halictidae): the roles of generalist attractants versus restrictive floral architecture.

The pollination of Cypripedium plectrochilum Franch. was studied in the Huanglong Nature Reserve, Sichuan, China. Although large bees (Bombus, Apis), small bees (Ceratina, Lasioglossum), ants (Formica sp.), true flies (Diptera) and a butterfly were all found to visit the flowers, only small bees, including three Lasioglossum spp. (L. viridiclaucum, L. sichuanense and L. sp.; Halictidae) and one Ceratina sp., carried the flower's pollen and contacted the receptive stigma. Measurements of floral architecture showed that interior floral dimensions best fit the exterior dimensions of Lasioglossum spp., leading to the consistent deposition and stigmatic reception of dorsally-placed, pollen smears. The floral fragrance was dominated by one ketone, 3-methyl-Decen-2-one. The conversion rate of flowers into capsules in open (insect) pollinated flowers at the site was more than 38%. We conclude that, while pigmentation patterns and floral fragrance attracted a wide variety of insect foragers, canalization of interior floral dimensions ultimately determined the spectrum of potential pollinators in this generalist, food-mimic flower. A review of the literature showed that the specialised mode of pollination-by-deceit in C. plectrochilum, limiting pollinators to a narrow and closely related guild of 'dupes' is typical for other members of this genus.

Fast GPU-based Monte Carlo code for SPECT/CT reconstructions generates improved 177Lu images.

BACKGROUND: Full Monte Carlo (MC)-based SPECT reconstructions have a strong potential for correcting for image degrading factors, but the reconstruction times are long. The objective of this study was to develop a highly parallel Monte Carlo code for fast, ordered subset expectation maximum (OSEM) reconstructions of SPECT/CT images. The MC code was written in the Compute Unified Device Architecture language for a computer with four graphics processing units (GPUs) (GeForce GTX Titan X, Nvidia, USA). This enabled simulations of parallel photon emissions from the voxels matrix (1283 or 2563). Each computed tomography (CT) number was converted to attenuation coefficients for photo absorption, coherent scattering, and incoherent scattering. For photon scattering, the deflection angle was determined by the differential scattering cross sections. An angular response function was developed and used to model the accepted angles for photon interaction with the crystal, and a detector scattering kernel was used for modeling the photon scattering in the detector. Predefined energy and spatial resolution kernels for the crystal were used. The MC code was implemented in the OSEM reconstruction of clinical and phantom 177Lu SPECT/CT images. The Jaszczak image quality phantom was used to evaluate the performance of the MC reconstruction in comparison with attenuated corrected (AC) OSEM reconstructions and attenuated corrected OSEM reconstructions with resolution recovery corrections (RRC). RESULT: The performance of the MC code was 3200 million photons/s. The required number of photons emitted per voxel to obtain a sufficiently low noise level in the simulated image was 200 for a 1283 voxel matrix. With this number of emitted photons/voxel, the MC-based OSEM reconstruction with ten subsets was performed within 20 s/iteration. The images converged after around six iterations. Therefore, the reconstruction time was around 3 min. The activity recovery for the spheres in the Jaszczak phantom was clearly improved with MC-based OSEM reconstruction, e.g., the activity recovery was 88% for the largest sphere, while it was 66% for AC-OSEM and 79% for RRC-OSEM. CONCLUSION: The GPU-based MC code generated an MC-based SPECT/CT reconstruction within a few minutes, and reconstructed patient images of 177Lu-DOTATATE treatments revealed clearly improved resolution and contrast.

Impact of pre- and post-pollination barriers on pollen transfer and reproductive isolation among three sympatric Pedicularis (Orobanchaceae) species.

Pedicularis is the largest genus in the Orobanchaceae (>300) with many species co-occurring and co-blooming in subalpine to alpine meadows in the Himalayas. Although it is well known that different Pedicularis species place pollen on different parts of the same bumblebee's body, thus reducing interspecific pollen transfer, it is not known whether post-pollination components also contribute to reproductive isolation (RI). In this study, we quantified the individual strengths and absolute contributions of six pre- and post-pollination components of RI between three sympatric species in two pairs; Pedicularis gruina × Pedicularis tenuisecta (gru × ten) and Pedicularis comptoniifolia × Pedicularis tenuisecta (com × ten). All three Pedicularis species shared the same Bombus species. Individual foragers showed a high, but incomplete, floral constancy for each species. Therefore, pre-pollination barriers were potentially 'leaky' as Bombus species showed a low but consistent frequency of interspecific visitation. The RI strength of pre-pollination was lower in com × ten than in gru × ten. In contrast, post-pollination barriers completely blocked gene flow between both sets of species pairs. Two post-pollination recognition sites were identified. Late acting rejection of interspecific pollen tube growth occurred in com♀ × ten♂, while seeds produced in bi-directional crosses of gru × ten failed to germinate. We propose that, although floral isolation based on pollen placement on pollinators in the genus Pedicularis is crucial to avoid interspecific pollen transfer, the importance of this mode of interspecific isolation may be exaggerated. Post-pollination barriers may play even larger roles for currently established populations of co-blooming and sympatric species in this huge genus in the Himalayas.

Comparative intra- and interspecific sexual organ reciprocity in four distylous Primula species in the Himalaya-Hengduan Mountains.

Distyly is a mechanism promoting cross-pollination within a balanced polymorphism. Numerous studies show that the degree of inter-morph sexual organ reciprocity (SOR) within species relates to its pollen-mediated gene flow. Similarly, a lower interspecific SOR should promote interspecific isolation when congeners are sympatric, co-blooming and share pollinators. In this comparative study, we address the significance of SOR at both intra- and interspecific levels. Seventeen allopatric and eight sympatric populations representing four Primula species (P. anisodora, P. beesiana, P. bulleyana and P. poissonii) native to the Himalaya-Hengduan Mountains were measured for eight floral traits in both long- and short-styled morphs. GLMM and spatial overlap methods were used to compare intra- and interspecific SOR. While floral morphology differed among four Primula species, SOR within species was generally higher than between species, but in species pairs P. poissonii/P. anisodora and P. beesiana/P. bulleyana, the SOR was high at both intra- and interspecific levels. We did not detect a significant variation in intraspecific SOR or interspecific SOR when comparing allopatric versus sympatric populations for all species studied. As intraspecific SOR increased, disassortative mating may be promoted. As interspecific SOR decreased, interspecific isolation between co-flowering species pairs also may increase. Hybridisation between congeners occurred when interspecific SOR increased in sympatric populations, as confirmed in two species pairs, P. poissonii/P. anisodora and P. beesiana/P. bulleyana.

Dosimetric comparison of radionuclides for therapy of somatostatin receptor-expressing tumors.

PURPOSE: Therapy of tumors expressing somatostatin receptors, sstr, has recently been clinically tested using somatostatin analogues labeled with (111)In and (90)Y. Several other radionuclides, i.e., (131)I, (161)Tb, (64)Cu, (188)Re, (177)Lu, and (67)Ga, have also been proposed for this type of therapy. The aim of this work was to investigate the usefulness of the above-mentioned radionuclides bound to somatostatin analogues for tumor therapy. METHODS: Biokinetic data of (111)In-labeled octreotide in mice and man were used, primarily from our studies but sometimes from the literature. Dosimetric calculations were performed with the assumption that biokinetics were similar for all radionuclides bound to somatostatin analogues. The cumulated tumor:normal-tissue activity concentration, TNC was calculated for the various physical half-lives of the radionuclides. Using mathematical models, the tumor:normal-tissue mean absorbed dose rate ratio, TN D and tumor:normal-tissue mean absorbed dose ratio, TND, were calculated for various tumor sizes in mice and humans. RESULTS: TNC of radionuclide-labeled octreotide increased with physical half-life for most organs, both in mice and in humans. TN D showed that radionuclides emitting electrons with too high energy are not suitable for therapy of small tumors. Furthermore, radionuclides with a higher frequency of photon emissions relative to electron emissions will yield lower TN D and are thus less suitable for therapy than radionuclides with a lower frequency of photon emissions. The TND was highest for (161)Tb in both mice and humans. CONCLUSIONS: The results demonstrate that long-lived radionuclides, which emit electrons with rather low energy and which have low frequency of photon emissions, should be the preferred therapy for disseminated small sstr-expressing tumors.

Evaluation of three gamma detectors for intraoperative detection of tumors using 111In-labeled radiopharmaceuticals.

UNLABELLED: Attempts to detect tumors with intraoperative scintillation using tumor-binding radiopharmaceuticals have intensified recently. In some cases previously unknown lesions were found, but in most cases no additional lesions were detected. In this study the physical characteristics of three detector systems and their ability to detect tumors through accumulation of an 111In-labeled radiopharmaceutical were investigated. The first was a sodium iodide (NaI[TI]) detector; the second, a cesium iodide (CsI[TI]) detector; and the third, a cadmium telluride (CdTe) detector. METHODS: A body phantom and tumor phantoms (diameter 5-20 mm) made of water, agarose gel or epoxy with a density and attenuation coefficient similar to those of soft tissue were used to simulate a clinical situation. The activity concentration in the body phantom was based on reported values of 111In-octreotide in normal tissue in humans. The 111In activity concentration in the tumor phantoms varied from 3 to 80 times the 111In activity concentration in the body phantom. Data were processed to determine tumor detection levels. RESULTS: The NaI(TI) detector showed the lowest values for full width at half maximum because this detector had the best collimation, leading to a high ratio between counts from tumor and counts from background, i.e., small tumors could be detected. Because of high efficiency, the CsI(TI) detector sometimes required a somewhat shorter acquisition time to produce a statistically significant difference between tumor phantom and background. For deep-lying tumors the NaI(TI) detector was superior, whereas the CdTe detector was best suited for superficial tumors with a high activity concentration in the underlying tissue. CONCLUSION: At a maximum acquisition time of 30 s, almost all superficial tumors with a diameter of 10 mm or larger were detected if the ratio between the 111In concentration in the tumor and the 111In concentration in the background exceeded 3. However, in clinical situations, biologic variations in the uptake of 111In-octreotide in tumors and in normal tissue makes difficult the determination of a distinct detection level. For such clinical conditions, the NaI(TI) detector is the best choice because it has good resolution despite a lower efficiency. Documentation of detector characteristics is important so that clinicians can make an adequate device in relation to tumor location and receptor expression.

111In-DTPA-D-Phe1-octreotide binding and somatostatin receptor subtypes in thyroid tumors.

UNLABELLED: The purpose of this study was to evaluate the potential for therapy of thyroid tumors using the radiolabeled somatostatin (SS) analog octreotide. METHODS: Concentrations of 111In activity in human thyroid tumors and normal thyroid tissue and blood samples were determined 1-15 d after intravenous injection of 111In-diethylenetriaminepentaacetic acid-Phe1-octreotide. The results were compared with SS receptor (sstr subtype profile (by Northern blot analysis) and the relative expression of the second subtype, sstr2 (by ribonuclease protection assay, RPA). The true tumor volumes in lymph node metastases from 1 patient were estimated. In total, tissues from 68 patients were included in the study. RESULTS: The highest tumor-to-blood ratio (T/B) for medullary thyroid carcinoma (MTC) was 360; for follicular adenoma (FA), 190; for Hurthle cell adenoma (HCA), 140; and for Hurthle cell carcinoma (HCC) and papillary carcinoma (PC), 70. The corresponding value was 7-18 for normal thyroid tissue, with higher values for colloid goiter (8-48) and thyroiditis (7-120). A high T/B was related to a large fraction of tumor cells in lymph node metastases. T/Bs were higher for the tumor samples with expression of sstr2 at Northern blot analysis than for those without. All thyroid tumor types regularly expressed sstr1, sstr3, sstr4, and sstr5. sstr2 was expressed in most MTC tumors but was not detected in FA or PC and was irregularly expressed in HCA and HCC. However, RPA analysis detected sstr2 in all tumors studied. CONCLUSION: Despite the lack of sstr2 at Northern blot analysis in most of the thyroid tumors studied, high T/Bs were in general found when compared with corresponding values for normal thyroid tissue. The sometimes extremely high ratios are promising and indicate a possibility of using radiolabeled octreotide for radiation therapy of sstr-positive tumors in the future.