Therapie der rezidivierten und fernmetastasierten Kopf-Hals-Tumoren

This year particularly phase II studies were presented at the 2016 ASCO Annual Meeting, in which new drugs (monoclonal antibodies, small molecules) were investigated in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC). Notably, there was a great number of studies investigating carcinoma of the nasopharynx. The studies presented in this article summarize the different therapeutic concepts in the treatment of R/M-HNSCC and represent the variety of therapeutic approaches in the recurrent and metastatic setting.     

Strahlen-, Chemo- und Targettherapie von Kopf-Hals-Karzinomen

Approximately 60% of patients initially treated for squamous cell cancer of the upper gastrointestinal tract suffer from advanced tumor disease (UICC stages III and IV). Multimodal strategies lead to overall survival rates of up to 50%. Recent studies show indications that the risk of distant metastases after induction chemotherapy (CT) is less than after primary radiotherapy (RT) or radiochemotherapy (RCT). Hyperfractionation or accelerated radiation with concomitant boost shows superior results compared to classic RT. Intensity-modulated radiotherapy (IMRT) is a new method for better adjusted dose distribution. Targeted therapy with specific antibodies against biological targets, such as epidermal growth factor receptor (EGFR), showed superiority over RT but the comparison to classic RCT is still pending. Targeted therapy against vascular endothelial growth factor (VEGR) showed antiangiogenetic effects on tumors. In cases of non-resectability or distant metastases, palliative CT and target therapy are recommended. Reirradiation or IMRT offer increased locoregional tumor control at the expense of higher toxicity. Overall, advances in research on tumor biology offer increasingly more prognostic factors and markers for customized individual targeted therapy and CT.     

Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells

A central role for polo-like kinases (PLK) in regulating several stages of mitotic progression has been born out in several species. Overexpression of PLK1 is observed in the majority of hitherto analysed human tumors. PLK1 overexpression is a negative prognostic factor in patients suffering from non-small cell lung cancer, head and neck tumors, esophageal carcinomas and melanomas. In order to define the role of PLK1 for mitotic progression of human cells and for neoplastic cell growth, phosphorothioate antisense oligonucleotides (ASOs) were tested to selectively downregulate PLK1 expression in MDA-MB-435 (breast cancer), HeLa S3 (cervical carcinoma) and A549 (non-small cell lung cancer) cells. ASOs were identified which suppress PLK1 mRNA and protein in a dose-dependent and sequence-specific manner. This approach also led to reduced PLK1 serine/threonine kinase activity. Downregulation of cellular PLK1 levels in cancer cells altered cell cycle progression moderately with an elevated percentage (20-30%) of cells in G(2)/M. Furthermore, cells with reduced PLK1 protein gained a rounded phenotype with multiple centrosomes. Moreover, ASO treatment resulted in potent antiproliferative effects in cell culture. Considerable antitumor activity was observed in vivo against A549 cells. This study suggests that antisense inhibitors targeted against PLK1 at well tolerated doses may be considered as a cancer therapeutic agent.     

Synaptotagmin I and IV are differentially regulated in the brain by the recreational drug 3,4-methylenedioxymethamphetamine (MDMA)

3,4-Methylenedioxymethamphetamine (MDMA or Ecstasy) is a widely abused drug. In brains of mice exposed to MDMA, we recently detected altered expression of several cDNAs and genes by using the differential display polymerase chain reaction (PCR) method. Expression of one such cDNA, which exhibited 98% sequence homology with the synaptic vesicle protein synaptotagmin IV, decreased 2 h after MDMA treatment. Herein, the effect of MDMA on expression of both synaptotagmin I and IV was studied in detail, since the two proteins are functionally interrelated. PCR analyses (semi-quantitative and real-time) confirmed that upon treatment with MDMA, expression of synaptotagmin IV decreased both in the midbrain and frontal cortex of mice. Decreases in the protein levels of synaptotagmin IV were confirmed by Western immunoblotting with anti-synaptotagmin IV antibodies. In contrast, the same exposure to MDMA increased expression of synaptotagmin I in the midbrain, a region rich in serotonergic neurons, but not in the frontal cortex. This differential expression was confirmed at the protein level with anti-synaptotagmin I antibodies. MDMA did not induce down- or up-regulation of synaptotagmin IV and I, respectively, in serotonin transporter knockout mice (-/-) that are not sensitive to MDMA. Therefore, psychoactive drugs, such as MDMA, appear to modulate expression of synaptic vesicle proteins, and possibly vesicle trafficking, in the brain.     

Optimized activation of the primary sensorimotor cortex for clinical functional MR imaging

BACKGROUND AND PURPOSE: One application of functional MR imaging is to identify the primary sensorimotor cortex (M1 and S1) around the central sulcus before brain surgery. However, it has been shown that undesirable coactivation of nonprimary motor areas, such as the supplementary motor area and the premotor area, can interfere with the identification of the primary motor cortex, especially in patients with distorted anatomic landmarks. We therefore sought to design a simple functional MR imaging paradigm for selective activation of the primary sensorimotor cortex. METHODS: Different paradigms using finger tapping for motor activation were examined and compared with respect to the distribution of activated voxels in primary and nonprimary cortical areas. Studies were conducted in 14 healthy volunteers using a blood oxygen level-dependent multislice echo-planar imaging sequence. RESULTS: The most selective activation of the primary sensorimotor cortex was obtained with a paradigm combining right-sided finger tapping as the activation condition with left-sided finger tapping as the control condition. Analysis of the signal time course of primary and nonprimary areas revealed that the highly selective primary motor activation was due to it being restricted to contralateral finger movements, as opposed to the nonprimary motor areas, which were activated by ipsilateral, contralateral, and bilateral finger movements alike. CONCLUSION: When performing functional MR imaging to determine the location of the primary sensorimotor cortex, one should compare unilateral voluntary movements as the activation condition with contralateral movements as the control condition to accentuate activation of the primary motor area and to suppress undesirable coactivation of nonprimary motor areas.     

Language and spatial attention can lateralize to the same hemisphere in healthy humans

BACKGROUND: Disorders of language classically occur after left brain lesions, and disorders of spatial attention after right brain lesions. It is unclear whether the hemispheric dissociation of functions is a fixed pattern of brain organization. OBJECTIVE: The authors determined whether lateralization of language and lateralization of spatial attention also dissociate in people with atypical (i.e., right hemispheric) language dominance. METHODS: The authors selected 10 subjects with typical, i.e., left hemispheric, and 10 with atypical, i.e., right hemispheric, language representation on a random basis from a sample of 326 healthy volunteers examined with functional transcranial Doppler sonography (fTCD) for language dominance. In these subjects, hemispheric lateralization of cerebral perfusion during a line bisection task was determined with fTCD. RESULTS: The authors found a dissociation between dominance for language and spatial attention in all but four subjects. In the latter subjects, there was a significant lateralization to the right hemisphere for both tasks. The four subjects showed normal intellectual, linguistic, and spatial performance, with normal EEG and MRI scans of the brain. CONCLUSION: Even in the absence of brain pathology, the same hemisphere can be dominant in control of both language and spatial attention.     

Compensatory weight gain due to dopaminergic hypofunction: new evidence and own incidental observations

There is increasing evidence for a role of dopamine in the development of obesity. More specifically, dopaminergic hypofunction might lead to (over)compensatory food intake. Overeating and resulting weight gain may be induced by genetic predisposition for lower dopaminergic activity, but might also be a behavioral mechanism of compensating for decreased dopamine signaling after dopaminergic overstimulation, for example after smoking cessation or overconsumption of high palatable food. This hypothesis is in line with our incidental finding of increased weight gain after discontinuation of pharmaceutical dopaminergic overstimulation in rats. These findings support the crucial role of dopaminergic signaling for eating behaviors and offer an explanation for weight-gain after cessation of activities associated with high dopaminergic signaling. They further support the possibility that dopaminergic medication could be used to moderate food intake.     

Biological monitoring of standardized exposure to ethylbenzene: evaluation of a biological tolerance (BAT) value

The results of standardized 8 h lasting exposures of n=18 volunteers to ethylbenzene (EthBz) at levels of 25 and 100% of the maximum allowable concentrations at the workplace (MAK) value of 100 ppm as well as the results of field studies are considered to evaluate a biological tolerance (BAT) value for EthBz. On the basis of the relationship between the external and internal exposure a BAT value of 1.5 mg/l has been set for the EthBz concentration in blood as the most sensitive and specific parameter of exposure to this aromatic hydrocarbon. The interpretation of EthBz blood values has to take into account the short half-life of t _1/2=0.5 ± 0.08 h in the first hour after the end of exposure in which this aromatic hydrocarbon is eliminated from the blood. The additional determination of the EthBz metabolites mandelic acid (MA) and phenylglyoxylic acid (PGA), respectively, excreted in post shift urine as well as in urine samples at the beginning of the next shift shows good correlations with the external exposure. The biological half-life of MA was calculated to t _1/2=5.3 ± 1.1 h. Because the time of sampling can vary the relationship between the levels of MA to PGA the total concentration of the excreted metabolites depends less on this influence and is therefore better suited for monitoring exposed persons. On the basis of the standardized experiments a BAT value has been proposed of 2 g MA plus PGA corrected per gram creatinine. Both BAT values are adjusted to data which result from earlier standardized exposures during 30 min to EthBz under physical activity of 50 watt on a bicycle ergometer. Received: 10 August 1999 / Accepted: 2 November 1999