Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study.

Differentiated thyroid cancer is a malignant tumour that has a fairly good prognosis, with patients surviving for many years. Multimodal therapy with surgery, radioiodine therapy and TSH suppressive medication is of proven efficacy. However, loss of differentiation is observed in up to one-third of patients with differentiated thyroid cancer, paralleled by an increase in tumour grading and loss of thyroid-specific functions (thyrotropin receptor, iodine accumulation). Such tumours may no longer be amenable to standard treatment protocols, including TSH suppression and radioiodide therapy. Retinoic acids have been shown to exert re-differentiating effects on thyrocytes in various experimental studies and case reports, and it was on this basis that this pilot study was initiated. Patients with advanced thyroid cancer and without the therapeutic options of operation or radioiodide therapy were treated with 13- cis-retinoic acid at a dosage of 1.5 mg/kg body weight daily over 5 weeks. Parameters for assessment of the therapeutic effect were serum thyroglobulin (TG) levels, radioiodine uptake, and tumour size prior to and after retinoid treatment. Fifty patients were evaluated for response, classified as reduction in tumour size and TG levels, stable disease or disease progression. Thirteen patients showed a clear increase in radioiodine uptake, and eight a mild increase. TG levels were unchanged or decreased in 20 patients. Tumour size was assessable in 37 patients; tumour regression was observed in six, and there was no change in 22. In total, a response was seen in 19 patients (38%). Response to retinoid therapy did not always correlate with increased radioiodine uptake, so other direct antiproliferative effects have to be assumed. The encouraging results of the study and the low rate of side-effects with good tolerability of retinoids warrant further studies with altered inclusion criteria and employment of other redifferentiating drugs or combinations of agents.

Functional anatomy of intrinsic alertness: evidence for a fronto-parietal-thalamic-brainstem network in the right hemisphere.

Alertness, the most basic intensity aspect of attention, probably is a prerequisite for the more complex and capacity demanding domains of attention selectivity. Behaviorally, intrinsic alertness represents the internal (cognitive) control of wakefulness and arousal; typical tasks to assess optimal levels of intrinsic alertness are simple reaction time measurements without preceding warning stimuli. Up until now only parts of the cerebral network subserving alertness have been revealed in animal, lesion, and functional imaging studies. Here, in a 15O-butanol PET activation study in 15 right-handed young healthy male volunteers for this basic attention function we found an extended right hemisphere network including frontal (anterior cingulate-dorsolateral cortical)-inferior parietal-thalamic (pulvinar and possibly the reticular nucleus) and brainstem (ponto-mesencephalic tegmentum, possibly involving the locus coeruleus) structures, when subjects waited for and rapidly responded to a centrally presented white dot by pressing a response key with the right-hand thumb.

Mathematical analysis of lead field expansions.

The solution to the bioelectromagnetic inverse problem is discussed in terms of a generalized lead field expansion, extended to weights depending polynomially on the current strength. The expansion coefficients are obtained from the resulting system of equations which relate the lead field expansion to the data. The framework supports a family of algorithms which include the class of minimum norm solutions and those of weighted minimum norm, including FOCUSS (suitably modified to conform to requirements of rotational invariance). The weighted-minimum-norm family is discussed in some detail, making explicit the dependence (or independence) of the weighting scheme on the modulus of the unknown current density vector. For all but the linear case, and with a single power in the weight, a highly nonlinear system of equations results. These are analyzed and their solution reduced to tractable problems for a finite number of degrees of freedom. In the simplest magnetic field tomography (MFT) case, this is shown to possess expected properties for localized distributed sources. A sensitivity analysis supports this conclusion.

Episodic retrieval activates the precuneus irrespective of the imagery content of word pair associates. A PET study.

The aim of this study was to evaluate further the role of the precuneus in episodic memory retrieval. The specific hypothesis addressed was that the precuneus is involved in episodic memory retrieval irrespective of the imagery content. Two groups of six right-handed normal male volunteers took part in the study. Each subject underwent six [15O]butanol-PET scans. In each of the six trials, the memory task began with the injection of a bolus of 1500 MBq of [15O]butanol. For Group 1, 12 word pair associates were presented visually, for Group 2 auditorily. The subjects of each group had to learn and retrieve two sets of 12 word pairs each. One set consisted of highly imaginable words and another one of abstract words. Words of both sets were not related semantically, representing 'hard' associations. The presentations of nonsense words served as reference conditions. We demonstrate that the precuneus shows consistent activation during episodic memory retrieval. Precuneus activation occurred in visual and auditory presentation modalities and for both highly imaginable and abstract words. The present study therefore provides further evidence that the precuneus has a specific function in episodic memory retrieval as a multimodal association area.

Influence of acoustic masking noise in fMRI of the auditory cortex during phonetic discrimination.

The application of functional magnetic resonance imaging (fMRI) to study activation of auditory cortex suffers from one significant confounding factor, namely, that of the acoustic noise generated by the gradient system, which is an integral part of the imaging process. Earlier work has shown that it is indeed possible to distinguish cortical activation resulting from presentation of auditory stimuli despite the presence of background noise from the gradient system. The influence of acoustic noise from the gradient system of the MRI scanner on the blood oxygen level-dependent (BOLD) response during functional activation of the auditory cortex has been investigated in six healthy subjects with no hearing difficulties. Experiments were performed using gradient-echo echoplanar imaging (EPI) and a verbal, auditory discrimination paradigm, presented in a block-wise manner, in which carefully aligned consonant-vowel syllables were presented at a rate of 1 Hz. For each volunteer the experiment was repeated three times with all parameters fixed, except slice number, which was 4, 16, or 64. The positioning of the central four slices in each experiment was common. Thus, the fraction of TR during which the stimulus is on but no imaging is being performed, varies from almost zero, in the case of 64 slices, to over 8 seconds, in the case of four slices. Only the central four slices were of interest; additional slices simply generated acoustic noise and were discarded. During the four-slice experiment, all subjects showed a robust BOLD response in the superior temporal gyrus covering the primary and secondary auditory cortex. The spatial extent and the z-scores of the activated regions decreased with longer duration of gradient noise from the scanner. For a phonetic discrimination task, the results indicate that presentation of the stimulus during periods free from scanner noise leads to a more pronounced BOLD response.

Bi-hemispheric study of single trial MEG signals of the human auditory cortex.

Auditory evoked magnetic fields were recorded from 5 human subjects, simultaneously over each hemisphere, using the BTi twin MAGNES system (2 x 37 channel). Accurate placing of each probe and the use of optimally designed linear sums of signals allow the estimation of the millisecond by millisecond history of activation of the complex of generators responsible for the M100 response in each single trial. Thus it can be shown in much greater detail than any study so far, how the average signal around the M100 period is built up by events in single trials. We found consistent features across subjects, defining a dynamic baseline from which the stimulus related activity can be differentiated. Our analysis indicates that prior to the stimulus onset the activity in each auditory cortex proceeds more or less independently. The onset of the stimulus establishes a binding of activity in the two hemispheres, probably through a common input. The coordinated activity is well described by an exponentially saturating function with a characteristic time constant in the 'magic' 15-30 ms range.

A three stage model of awareness: formulation and initial experimental support.

The various components which together make up the complex state of consciousness require neural support involving a connected network of many brain areas at differing levels. At the lowest level is non-aware processing, of which there is not direct awareness. There are also modules involved in processing with awareness but without focussed attention. Finally there must be a set of modules involved in directing attention in a controlled manner. We expect to be able to dissociate the various components of the three-stage network by using different levels of attention. The results of an auditory experiment performed under three different levels of awareness and attention are analysed to show support for the three-stage model of awareness. The relevant auditory areas are delineated.

[Radioiodine therapy and radioiodine after-care in differentiated thyroid gland carcinomas]. / Radiojodtherapie und Radiojodnachsorge bei differenzierten Schilddrüsenkarzinomen.

Differentiated thyroid carcinoma (DTC) is a rare tumor with a generally good prognosis. Still some of these cancers cause the patient's death after many years of illness. Thus, treatment and aftercare have to be risk-adapted according to tumor type and staging. Surgery is the primary treatment for this tumor and its metastases, followed by therapy with radioiodine. According to the guidelines edited by the German Association for Nuclear Medicine (DGN)--work group for therapy--radioiodine therapy is an effective regimen with minimal side-effects. Radioiodine scintigraphy is the most important part of the aftercare program, together with the monitoring of the highly specific tumormarker thyreoglobulin. Other diagnostic modalities may be added when considering therapeutic options or confirming clinical suspicions. This paper aims at giving an update and overview on the applications of radioiodine, other radioisotopes and additional diagnostic and therapeutic options in differentiated thyroid cancer and related aspects of radiation exposure and radiation protection. As new therapeutic procedures and optimised diagnostic modalities become available, there is new hope for patients with locally advanced or metastatic DTC.

Task-relevant late positive component in rats: is it related to hippocampal theta rhythm?

Long-latency components of event-related potentials (like the P300 or P3) correlate with the ability of subjects to detect and process unexpected, novel or task-relevant events. Task-relevant late positive components were recorded in the neocortex and hippocampus of rats performing an auditory discrimination task, similar to the "odd-ball" paradigm used in human experiments. Surface and depth electrodes were implanted in anaesthetized rats at frontal, temporal and anterior occipital neocortical regions and the hippocampus. After recovery from surgery rats were trained to discriminate two auditory signals, a frequent irrelevant tone and a rare tone related to water reward. In response to the task-relevant tone but not the irrelevant tone, P300-like late positive components (mean latency of 274 ms) were recorded throughout the surface of the neocortex. The largest amplitudes were found at the anterior occipital cortex situated above the hippocampal CA1 region. The amplitude of the task-relevant positive component increased further with cortical depth without reversing its polarity. An amplitude maximum was found in the CA1 region with a polarity reversal at the pyramidal cell layer and the largest negative amplitude in stratum radiatum. Power spectra of differences between responses evoked by task-relevant tones and those evoked by irrelevant tones revealed peaks in the theta range (4-12 Hz). It is suggested that the P300-like component in rats corresponds to a theta wave out of a burst of hippocampal theta cycles.