Non-randomized therapy trial to determine the safety and efficacy of heavy ion radiotherapy in patients with non-resectable osteosarcoma

<p>Abstract</p> <p>Background</p> <p>Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. For effective treatment, local control of the tumor is absolutely critical, because the chances of long term survival are <10% and might effectively approach zero if a complete surgical resection of the tumor is not possible. Up to date there is no curative treatment protocol for patients with non-resectable osteosarcomas, who are excluded from current osteosarcoma trials, e.g. <it>EURAMOS1</it>. Local photon radiotherapy has previously been used in small series and in an uncontrolled, highly individualized fashion, which, however, documented that high dose radiotherapy can, in principle, be used to achieve local control. Generally the radiation dose that is necessary for a curative approach can hardly be achieved with conventional photon radiotherapy in patients with non-resectable tumors that are usually located near radiosensitive critical organs such as the brain, the spine or the pelvis. In these cases particle Radiotherapy (proton therapy (PT)/heavy ion therapy (HIT) may offer a promising new alternative. Moreover, compared with photons, heavy ion beams provide a higher physical selectivity because of their finite depth coverage in tissue. They achieve a higher relative biological effectiveness. Phase I/II dose escalation studies of HIT in adults with non-resectable bone and soft tissue sarcomas have already shown favorable results.</p> <p>Methods/Design</p> <p>This is a monocenter, single-arm study for patients ≥ 6 years of age with non-resectable osteosarcoma. Desired target dose is 60-66 Cobalt Gray Equivalent (Gy E) with 45 Gy PT (proton therapy) and a carbon ion boost of 15-21 GyE. Weekly fractionation of 5-6 × 3 Gy E is used. PT/HIT will be administered exclusively at the Ion Radiotherapy Center in Heidelberg. Furthermore, FDG-PET imaging characteristics of non-resectable osteosarcoma before and after PT/HIT will be investigated prospectively. Systemic disease before and after PT/HIT is targeted by standard chemotherapy protocols and is not part of this trial.</p> <p>Discussion</p> <p>The primary objectives of this trial are the determination of feasibility and toxicity of HIT. Secondary objectives are tumor response, disease free survival and overall survival. The aim is to improve outcome for patients with non-resectable osteosarcoma.</p> <p>Trail Registration</p> <p>Registration number (ClinicalTrials.gov): NCT01005043</p

Differential Effects of HIF-1 Inhibition by YC-1 on the Overall Outcome and Blood-Brain Barrier Damage in a Rat Model of Ischemic Stroke

Hypoxia-inducible factor 1 (HIF-1) is a master regulator of cellular adaptation to hypoxia and has been suggested as a potent therapeutic target in cerebral ischemia. Here we show in an ischemic stroke model of rats that inhibiting HIF-1 and its downstream genes by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) significantly increases mortality and enlarges infarct volume evaluated by MRI and histological staining. Interestingly, the HIF-1 inhibition remarkably ameliorates ischemia-induced blood-brain barrier (BBB) disruption determined by Evans blue leakage although it does not affect brain edema. The result demonstrates that HIF-1 inhibition has differential effects on ischemic outcomes and BBB permeability. It indicates that HIF-1 may have different functions in different brain cells. Further analyses show that ischemia upregulates HIF-1 and its downstream genes erythropoietin (EPO), vascular endothelial growth factor (VEGF), and glucose transporter (Glut) in neurons and brain endothelial cells and that YC-1 inhibits their expression. We postulate that HIF-1-induced VEGF increases BBB permeability while certain other proteins coded by HIF-1's downstream genes such as epo and glut provide neuroprotection in an ischemic brain. The results indicate that YC-1 lacks the potential as a cerebral ischemic treatment although it confers certain protection to the cerebral vascular system

Initial development of the DIII-D snowflake divertor control

Simultaneous control of two proximate magnetic field nulls in the divertor region is demonstrated on DIII-D to enable plasma operations in an advanced magnetic configuration known as the snowflake divertor (SFD). The SFD is characterized by a second-order poloidal field null, created by merging two first-order nulls of the standard divertor configuration. The snowflake configuration has many magnetic properties, such as high poloidal flux expansion, large plasma-wetted area, and additional strike points, that are advantageous for divertor heat flux management in future fusion reactors. However, the magnetic configuration of the SFD is highly-sensitive to changes in currents within the plasma and external coils and therefore requires complex magnetic control. The first real-time snowflake detection and control system on DIII-D has been implemented in order to stabilize the configuration. The control algorithm calculates the position of the two nulls in real-time by locally-expanding the Grad-Shafranov equation in the divertor region. A linear relation between variations in the poloidal field coil currents and changes in the null locations is then analytically derived. This formulation allows for simultaneous control of multiple coils to achieve a desired SFD configuration. It is shown that the control enabled various snowflake configurations on DIII-D in scenarios such as the double-null advanced tokamak. The SFD resulted in a 2.5× reduction in the peak heat flux for many energy confinement times (2-3 s) without any adverse effects on core plasma performance

Assessment of systolic and diastolic LV function by MR myocardial tagging.

Heart failure has been divided into several different forms depending on etiology, clinical course and pathophysiology of left ventricular (LV) dysfunction. Systolic and diastolic dysfunction are characterized by a reduced cardiac output with normal (= diastolic dysfunction) or depressed (= systolic dysfunction) LV pump function. New diagnostic techniques such as magnetic resonance imaging (MRI) allow to determine noninvasively LV 3D motion by labelling specific myocardial regions (= myocardial "tagging") with a rectangular or radial grid. From the deformation of this grid rotational and translational motion of the heart can be derived. A "wringing" motion of the left ventricle has been described during systole which includes a clockwise rotation at the base and a counterclockwise rotation at the apex. During diastole, an "untwisting" motion has been demonstrated. In the normal heart, diastolic "untwisting" occurs primarily during isovolumic relaxation, analogous to the systolic "wringing" which takes place mainly during isovolumic contraction. A prolongation of the "untwisting" motion was found in the hypertrophied (aortic stenosis) and hibernating myocardium. Thus, heart failure is associated with profound alterations in the mechanical function of the heart which are manifested by changes in systolic "wringing" and diastolic "untwisting" motion

Validation of on- and off-axis neutral beam current drive against experiment in DIII-Da

Neutral beam current drive (NBCD) experiments in DIII-D using vertically shifted plasmas to move the current drive away from the axis have clearly demonstrated robust off-axis NBCD. Time-dependent measurements of magnetic field pitch angles by the motional Stark effect diagnostic are used to obtain the evolution of the poloidal magnetic flux, which indicates a broad off-axis NBCD profile with a peak at about half the plasma minor radius. In most cases, the measured off-axis NBCD profile is consistent with calculations using an orbit-following Monte Carlo code for the beam ion slowing down including finite-orbit effects provided there is no large-scale magnetohydrodynamic activity such as Alfv́n eigenmodes modes or sawteeth. An alternative analysis method shows good agreement between the measured pitch angles and those from simulations using transport-equilibrium codes. Two-dimensional image of Doppler-shifted fast ion Dα light emitted by neutralized energetic ions shows clear evidence for a hollow profile of beam ion density, consistent with classical beam ion slowing down. The magnitude of off-axis NBCD is sensitive to the alignment of the beam injection relative to the helical pitch of the magnetic field lines. If the signs of toroidal magnetic field and plasma current yield the proper helicity, both measurement and calculation indicate that the efficiency is as good as on-axis NBCD because the increased fraction of trapped electrons reduces the electron shielding of the injected ion current, in contrast with electron current drive schemes where the trapping of electrons degrades the efficiency. The measured off-axis NBCD increases approximately linearly with the injection power, although a modest amount of fast ion diffusion is needed to explain an observed difference in the NBCD profile between the measurement and the calculation at high injection power. © 2009 American Institute of Physics

Validation of on- and off-axis neutral beam current drive against experiment in DIII-Da

Neutral beam current drive (NBCD) experiments in DIII-D using vertically shifted plasmas to move the current drive away from the axis have clearly demonstrated robust off-axis NBCD. Time-dependent measurements of magnetic field pitch angles by the motional Stark effect diagnostic are used to obtain the evolution of the poloidal magnetic flux, which indicates a broad off-axis NBCD profile with a peak at about half the plasma minor radius. In most cases, the measured off-axis NBCD profile is consistent with calculations using an orbit-following Monte Carlo code for the beam ion slowing down including finite-orbit effects provided there is no large-scale magnetohydrodynamic activity such as Alfv́n eigenmodes modes or sawteeth. An alternative analysis method shows good agreement between the measured pitch angles and those from simulations using transport-equilibrium codes. Two-dimensional image of Doppler-shifted fast ion Dα light emitted by neutralized energetic ions shows clear evidence for a hollow profile of beam ion density, consistent with classical beam ion slowing down. The magnitude of off-axis NBCD is sensitive to the alignment of the beam injection relative to the helical pitch of the magnetic field lines. If the signs of toroidal magnetic field and plasma current yield the proper helicity, both measurement and calculation indicate that the efficiency is as good as on-axis NBCD because the increased fraction of trapped electrons reduces the electron shielding of the injected ion current, in contrast with electron current drive schemes where the trapping of electrons degrades the efficiency. The measured off-axis NBCD increases approximately linearly with the injection power, although a modest amount of fast ion diffusion is needed to explain an observed difference in the NBCD profile between the measurement and the calculation at high injection power. © 2009 American Institute of Physics