Concurrent radiotherapy with temozolomide followed by adjuvant temozolomide and cis-retinoic acid in children with diffuse intrinsic pontine glioma.

The prognosis of children with diffuse intrinsic pontine glioma (DIPG) is very poor. Radiotherapy remains the standard treatment for these patients, but the median survival time is only 9 months. Currently, the use of concurrent radiotherapy with temozolomide (TMZ) has become the standard care for adult patients with malignant gliomas. We therefore investigated this approach in 12 children diagnosed with DIPG. The treatment protocol consisted of concurrent radiotherapy at a dose of 55.8-59.4 Gy at the tumor site with TMZ (75 mg/m(2)/day) for 6 weeks followed by TMZ (200 mg/m(2)/day) for 5 days with cis-retinoic acid (100 mg/m(2)/day) for 21 days with a 28-day cycle after concurrent radiotherapy. Ten of the 12 patients had a clinical response after the completion of concurrent radiotherapy. Seven patients had a partial response, four had stable disease, and one had progressive disease. At the time of the report, 9 of the 12 patients had died of tumor progression, one patient was alive with tumor progression, and two patients were alive with continuous partial response and clinical improvement. The median time to progression was 10.2 +/- 3.0 months (95% confidence interval [CI], 4.2-16.1 months). One-year progression-free survival was 41.7% +/- 14.2%. The median survival time was 13.5 +/- 3.6 months (95% CI, 6.4-20.5 months). One-year overall survival was 58% +/- 14.2%. The patients who had a partial response after completion of concurrent radiotherapy had a longer survival time (p = 0.036) than did the other patients (those with stable or progressive disease). We conclude that the regimen of concurrent radiotherapy and TMZ should be considered for further investigation in a larger series of patients.

Synaptic depression and short-term habituation are located in the sensory part of the mammalian startle pathway.

BACKGROUND: Short-term habituation of the startle response represents an elementary form of learning in mammals. The underlying mechanism is located within the primary startle pathway, presumably at sensory synapses on giant neurons in the caudal pontine reticular nucleus (PnC). Short trains of action potentials in sensory afferent fibers induce depression of synaptic responses in PnC giant neurons, a phenomenon that has been proposed to be the cellular correlate for short-term habituation. We address here the question whether both this synaptic depression and the short-term habituation of the startle response are localized at the presynaptic terminals of sensory afferents. If this is confirmed, it would imply that these processes take place prior to multimodal signal integration, rather than occurring at postsynaptic sites on PnC giant neurons that directly drive motor neurons. RESULTS: Patch-clamp recordings in vitro were combined with behavioral experiments; synaptic depression was specific for the input pathway stimulated and did not affect signals elicited by other sensory afferents. Concordant with this, short-term habituation of the acoustic startle response in behavioral experiments did not influence tactile startle response amplitudes and vice versa. Further electrophysiological analysis showed that the passive properties of the postsynaptic neuron were unchanged but revealed some alterations in short-term plasticity during depression. Moreover, depression was induced only by trains of presynaptic action potentials and not by single pulses. There was no evidence for transmitter receptor desensitization. In summary, the data indicates that the synaptic depression mechanism is located presynaptically. CONCLUSION: Our electrophysiological and behavioral data strongly indicate that synaptic depression in the PnC as well as short-term habituation are located in the sensory part of the startle pathway, namely at the axon terminals of sensory afferents in the PnC. Our results further corroborate the link between synaptic depression and short-term habituation of the startle response.

Radiation-induced rhombencephalopathy.

We report the case of a patient who underwent radiotherapy of the neck because of an epidermoid carcinoma in Rosenmuller's fossa. Eleven months later, T1-weighted brain magnetic resonance imaging (MRI) revealed a bulbo-pontine lesion, and the clinical course and sequential MRI results led to a diagnosis of radionecrosis-induced rhombencephalopathy. At a distance of more than three years, the lesion is no longer visible on MRI images but the severe neurological deficits remain. The clinical picture has not been improved by treatment with prednisone, hyperbaric oxygen, symptomatic therapies or anticoagulants.

In vivo biological effects of stereotactic radiosurgery: a primate model.

Single-fraction, closed skull, small-volume irradiation (radiosurgery) of intact intracranial structures requires accurate knowledge of radiation tolerance. We have developed a baboon model to assess the in vivo destructive radiobiological effects of stereotactic radiosurgery. Three baboons received a single-fraction, 150-Gy lesion of the caudate nucleus, the thalamus, or the pons using the 8-mm diameter collimator of the gamma unit. Serial standard neurodiagnostic tests (neurological examination, computed tomographic scan, magnetic resonance imaging, stable xenon-enhanced computed tomographic scan of cerebral blood flow, somatosensory and brain stem evoked potentials, and myelin basic protein levels of cerebrospinal fluid) were compared with preoperative studies. Magnetic resonance imaging revealed the development of a lesion at the target site between 45 and 60 days after irradiation. Deterioration of the brain stem evoked potentials preceded imaging changes when the lesion encroached on auditory pathways. Myelin basic protein levels increased subsequent to imaging changes. Postmortem neuropathological examination confirmed a well-demarcated radionecrosis of the target volume. The baboon model appears to be an excellent method to study the in vivo biological effects of radiosurgery.