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Biomedical subjects

G Kraft

Publications and source records attributed to G Kraft.

At least 37 records · Page 2Linked to original sources

Three-dimensional BANG gel dosimetry in conformal carbon ion radiotherapy.

In this study we applied BANG polymer-gel dosimetry using magnetic resonance imaging (MRI) to densely ionizing radiation such as carbon ion beams. BANG polymer gels were irradiated with a quadratic field of monoenergetic 12C ions at different beam energies in the range of 135 MeV u(-1) to 410 MeV u(-1). They were irradiated at the radiotherapy facility of the GSI, Darmstadt, Germany. Our object was to examine the saturation effect for densely ionizing radiation that occurs at high values of linear energy transfer (LET). The examination yielded the first effectiveness values that will be discussed in the following sections. A solid sphere and a hollow sphere were both irradiated with a horizontal pencil beam from the raster scanning facility at energies of 268 MeV u(-1) (solid sphere) and 304 MeV u(-1) (hollow sphere) respectively. MR dosimetry measurements were compared with data from a planning system. As far as quality is concerned, there is good agreement between the measured dose distributions of both samples and the dose maps from the planning software. The measured MR signals cannot be converted into absolute dose, since the relative efficiency is still unknown for mixed radiation fields of primary carbon ions and it is known only to a limited extent for nuclear fragments with different energies from highly energetic photon radiation. Model calculations are in progress in order to facilitate conversions of measured MR signals into dose.

Acrylamides↗

Peripheral neuropathy caused by proteolipid protein gene mutations.

Pelizaeus-Merzbacher disease (PMD) is a dysmyelinating disorder of the central nervous system typically caused by duplications or missense mutations of the proteolipid protein (PLP) gene. Most investigators have found that peripheral nerve function and structure is normal in PMD patients. We have found that null mutations of the PLP gene cause demyelinating peripheral neuropathy, whereas duplications and a proline 14 to leucine mutation do not affect nerve function. A family with a nonsense mutation at position 144, which affects only PLP but not the alternatively spliced gene product DM20, has a very mild syndrome, including normal peripheral nerve function. Our findings suggest that DM20 alone is sufficient to maintain normal nerve function and that there may be domains of PLP/DM20 that have a relatively more active role in the peripheral nervous system compared with that in the central nervous system.

Amino Acid Sequence↗

Treatment planning for light ions: how to take into account relative biological effectiveness (RBE).

A new treatment planning program was developed for the heavy ion therapy facility at GSI, which is tailored to the special needs for an active beam delivery using a magnetic raster scanner. It also includes a biological model for the estimation of biological effective dose for carbon ions and realizes a fully biological treatment planning. Biological effective dose distributions and RBE maps can be displayed and assessed from the graphical user interface.

Chondrosarcoma↗

Treatment planning for the heavy-ion facility at GSI.

A new treatment planning program was developed for the heavy-ion therapy facility at GSI. In addition, a concise quality standard for treatment planning has been set up. It covers acceptance and constancy checks of all critical aspects in treatment planning. Dose verification measurements done during the commissioning phase show an overall good agreement with the treatment planning calculations.

Algorithms↗

The GSI Cancer Therapy Project.

At the Heavy Ion Research Institute GSI in Darmstadt an experimental cancer treatment program with a five years duration has been developed. A new method for cancer treatment with ions is applied, using rasterscan method in addition to an active pulse to pulse variation of ion beam properties, including the energy, intensity and focusing. An overview of this Cancer Therapy Project is presented, that covers both accelerator aspects to provide the required beam variations within a short time and the installations at the treatment place for rasterscan control. In addition to a description of the technical design (control-hard- and software) experimental results will be shown, containing the achieved beam properties and measurements of rasterscan performance.

Academies and Institutes↗

Quality assurance at the heavy-ion therapy facility at GSI.

In the present stage between the technological realization and the clinical phase, quality management gains a predominant role at the heavy ion therapy facility at GSI. Specific quality inspection procedures had to be developed for the subsequent parts of the beam delivery system, the treatment planning, the raster scanning device, the patient positioning, the dose verification and the safety interlock system. In the meantime the acceptance test of the whole facility has been carried out and an overview about our first experience with quality assurance procedures at the heavy ion irradiation facility is given, with a special emphasis on the medical physics part.

Calibration↗

RBE and its interpretation.

Beams of heavy ions like carbon offer both, an improved dose distribution superior to any other type of radiation and an increased relative biological efficiency, RBE, which is restricted to the target volume only. The various dependencies of RBE on dose, atomic number and tissue sensitivity are described in this paper and are discussed in the framework of the local effect model.

Humans↗

The role of high-LET radiotherapy compared to conformal photon radiotherapy in adenoid cystic carcinoma.

Tumors of the base of skull represent a challenging radiooncological target due to their close proximity to dose limiting critical normal tissue structures. A critical review of the literature provides evidence that high-LET radiotherapy offers a therapeutic gain factor compared to low-LET radiation and should be the treatment of choice in advanced salivary gland malignancies, which are inoperable or not completely resected, and in recurrent disease. Modern techniques of conformal high LET radiotherapy, e.g. heavy ion beam radiotherapy, will help to reduce the long and the short term toxicity of radiotherapy.

Carcinoma, Adenoid Cystic↗

A rapid procedure for the quantitation of natriuretic peptide RNAs by competitive RT-PCR in congenital heart defects.

We report an original application of quantitative reverse transcription-polymerase chain reaction (Q.RT-PCR) for the evaluation of atrial natriuretic factor (ANF), brain natriuretic peptide (BNP) and beta-actin mRNA in small atrial samples (10-15 mg). A fixed amount of total RNA was simultaneously reverse transcribed and amplified with dilutions of a competitor RNA fragment used as a control. We constructed a single synthetic RNA competitor for ANF, BNP and beta-actin. The competitors and targets shared the same primer sequences but yielded PCR products of different sizes. We have investigated ANF, BNP and beta-actin gene expression in patients affected by congenital heart defects (CHD) during the surgical correction of the defect. We collected a right atrial sample from each patient before the start of cardiopulmonary bypass. We studied 14 patients affected by tetralogy of fallot (no. 6), complex CHD (no. 4), and ventricular septal defect (no. 4). The results indicate that the Q.RT-PCR represents a simple, highly specific, non radioactive procedure for the quantification of natriuretic peptide gene expression and is particularly suitable for evaluation of gene expression in small myocardial samples. Our data also suggest that: 1) there is a significant relationship between the levels of ANF, BNP and beta-actin mRNA and the type of CHD; 2) the levels of BNP mRNA are more variable than ANF; 3) the beta-actin seems to be unsuitable for normalising cardiac gene expression in CHD because mRNA basal levels of this protein vary greatly among patients with different type of CHD.

Actins↗

Response of pig lung to irradiation with accelerated 12C-ions.

The response of pig lungs to irradiation with 12C-ions was assessed in two experiments to validate the procedures for heavy ion therapy planning at the Gesellschaft für Schwerionenforschung (GSI) and to explore their range of applicability. In both experiments, the target volume (spread-out Bragg peak, SOBP) was planned to be a 4 cm long cylinder with a diameter of 4 cm. Doses in the SOBP were prescribed to be equivalent to 5x4 Gy, 5x5.5 Gy and 5x7 Gy of x-rays in the first experiment, and to 5 fractions of 7 Gy and 9 Gy in the second experiment. The lung response in the first experiment was less than expected on the basis of earlier experiments with photons. Pneumonitis reaction and chronic fibrotic changes were observed outside the prescribed high-dose region. In the second experiment, the effects were more pronounced than had been expected on the basis of the first experiment. Changes were most intense in the high-dose region, but were also seen throughout the lung along the beam channel. Moreover, significant skin reactions were observed at the beam entrance site in all animals and - less pronounced - at the beam exit site in 3 of the 6 animals. In conclusion, the complex irradiation geometry of the pig lung, the changes of body weight between the two experiments, and insufficient accounting for a change in the relative biological effectiveness (RBE) computation led to substantial deviations of the observed reactions from expectations, the reasons for which could be identified in a subsequent analysis. The less pronounced lung reaction in the first experiment was due to an overestimation of RBE in a preliminary version of the algorithm for its determination. The extension of the fibrotic reaction resulted from the smear-out of the high-dose region due to density variations in tissue structures, respiratory movement, and limited positioning accuracy. The skin reactions at the entrance port reflect the different treatment geometry in the two experiments. The one unexplained observation is the mild skin reaction that was observed in the second experiment at the beam exit site.

Animals↗

Tumor therapy and track structure.

The elevated relative biological effectiveness (RBE) of heavy ions like carbon is the main reason for their use in radiotherapy and is due to the microscopic distribution of dose inside each particle track. High local doses produce lesions that are expected to have a diminished possibility of repair. Thus, RBE depends on track structure and on the biological repair capacity of the tissue that is affected by the irradiation. For tumor treatment planning with heavy ions, the beam quality and the tissue sensitivity have to be taken into account. Using the dependence of radial dose distribution on particle energy and atomic number on the physical side and x-ray dose response for the repair capacity on the biological side, the response to particle irradiation can be calculated in the local effect model (LEM) and used for treatment planning. This article traces the route from electron emission as the basis of track structure to the RBE calculation and the application in treatment planning.

Electrons↗

Long-term follow-up of stents implanted to relieve peripheral pulmonary arterial stenosis: hemodynamic findings and results of lung perfusion scanning.

In recent years, percutaneous placement of stents has been used as an alternative to surgery or balloon angioplasty for the treatment of adults with peripheral pulmonary arterial stenosis. This therapy has also been proposed for children, but questions still remain about its indications in this group of patients. We describe here the results of intravascular placement of stents in a group of 29 patients, with a mean age of 12+/-7 (range 3-31) years and weighing 35+/-19 (range 11-74) kg. All were affected by postsurgical or congenital isolated pulmonary arterial stenosis, and have now been followed for 38+/-19 (range 6-65) months. The early hemodynamic results have been excellent, with a significant reduction of the pulmonary arterial systolic pressure, the systolic pressure gradient, and the ratio of systolic pressures in the pulmonary and systemic circuits, and with a significant increase of the diameter of the stented vessels in all the patients. Of the 29 patients, 24 have been recatheterized 18+/-10 months after the procedure, demonstrating the stability of the results, with a low incidence of late restenosis, this seen in only 1 patient (2%). Lung perfusion scanning, performed in 17 patients each year after the follow-up catheterization, has showed that the results are maintained at long-term follow-up (51+/-9 months).

Adolescent↗

RBE for carbon track-segment irradiation in cell lines of differing repair capacity.

PURPOSE: The LET position of the RBE maximum and its dependence on the cellular repair capacity was determined for carbon ions. Hamster cell lines of differing repair capacity were irradiated with monoenergetic carbon ions. RBE values for cell inactivation at different survival levels were determined and the differences in the RBE-LET patterns were compared with the individual sensitivity to photon irradiation of the different cell lines. MATERIAL AND METHODS: Three hamster cell lines, the wild-type cell lines V79 and CHO-K1 and the radiosensitive CHO mutant xrs5, were irradiated with carbon ions of different energies (2.4-266.4 MeV/u) and LET values (13.7-482.7 keV/microm) and inactivation data were measured in comparison to 250 kV x-rays. RESULTS: For the repair-proficient cell lines a RBE maximum was found at LET values between 150 and 200 keV/microm. For the repair-deficient cell line the RBE failed to show a maximum and decreased continuously for LET values above 100 keV/microm. CONCLUSIONS: The carbon RBE LET relationship for inactivation is shifted to higher LET values compared with protons and alpha-particles. RBE correlated with the repair capacity of the cells.

Animals↗

Design and construction of a ripple filter for a smoothed depth dose distribution in conformal particle therapy.

The ripple filter was designed to broaden the Bragg maximum of carbon beams for the raster-scan technique, a special type of tumour-conformal ion beam treatment. In this technique the target volume is divided into individual layers that are treated sequentially by varying the energy from the accelerator stepwise. Because the unmodified Bragg maximum has a small half-width, below 1 mm for small energies (< 160 MeV u(-1)), homogeneous irradiation at small penetration depths of 2-6 cm can only be obtained by using a large number of energy steps. If the energy step is too large, ripples are produced in the superimposed depth dose distribution. The ripple filter widens a Bragg peak to a Gaussian peak with a half-width of more than 2 mm. This helps to smooth the extended Bragg peak and to reduce the number of energy steps required by a factor of two to three, leading to significantly shorter overall irradiation times and a higher particle fluence per layer. The ripple filter consists of a 2 mm thick Plexiglass (PMMA) plate with a periodic structure of fine grooves. It can be mounted 60 cm upstream of the patient as a stationary device, because the fine structure of the grooves is completely washed out by the lateral scattering of the beam.

Algorithms↗

Influence of radiation quality on the yield of DNA strand breaks in SV40 DNA irradiated in solution.

Using highly energetic particles to irradiate plasmid DNA in aerobic aqueous solution, we have compiled an extensive database on how yields of DNA single- and double-strand breaks (SSBs and DSBs) vary with radiation quality. This study was performed in a low-scavenging buffer system and covers a wide range of ion species (helium to uranium) and LETs (5 to 16,000 keV/microm). For LETs up to around 40 keV/microm for SSBs and 400 keV/microm for DSBs, the total energy deposition determines cross section. At higher LET, cross sections level off and individual plateaus for particles of different atomic numbers are observed. For each ion species this is more pronounced and occurs at lower LET for SSBs than for DSBs, leading to an increase in the DSB:SSB ratio from 1:70 for X rays to 1:6 at 500 keV/microm. At this LET, the influence of track structure becomes evident, with high local concentrations of ionization events favoring the formation of DSBs and also intratrack recombination reactions. For lower-energy ions, a saturation in production of measurable DSBs is apparent, due to correlated lesion induction within densely ionizing particle tracks. For very heavy low-energy ions, both SSB and DSB cross sections decrease with particle velocity at nearly constant LET, forming individual hooked curves when plotted as a function of LET.

DNA Damage↗

Photochemical identification of transmembrane segment IVS6 as the binding region of semotiadil, a new modulator for the L-type voltage-dependent Ca2+ channel.

To identify the binding domain of a new Ca2+ antagonist semotiadil on L-type Ca2+ channels from skeletal muscle, photolabeling was carried out by using an azidophenyl derivative of [3H]semotiadil. Photoincorporation was observed in several polypeptides of membrane triad preparations; the only specific photoincorporation was in the alpha1 subunit of the Ca2+ channel. After solubilization and purification, the photolabeled alpha1 subunit was subjected to proteolytic and CNBr cleavage followed by antibody mapping. Specific labeling was associated solely with the region of transmembrane segment S6 in repeat IV. Quantitative immunoprecipitation was found in the tryptic and the Lys-C/Glu-C fragments of 6.6 and 6.1 kDa, respectively. Further CNBr cleavage of the Lys-C digests produced two smaller fragments of 3.4 and 1.8 kDa that were included in the tryptic and Lys-C/Glu-C fragments. The smallest labeled fragments were: Tyr1350-Met1366 and Leu1367-Met1381 containing IVS6, a possible pore-forming region. The data suggest that semotiadil binds to a region that is overlapped with but not identical to those for phenylalkylamines, dihydropyridines and benzothiazepines. The present study also provides evidence that region IV represents an important component of a binding pocket for Ca2+ antagonists.

Animals↗

Is there a role for heavy ion beam therapy?

The aim of this contribution is to review the radio-oncological rationale of heavy ion beam radiotherapy in the management of cancer. Protons and helium ions are being investigated because of the improved dose distributions, perhaps superior in many clinical situations to those obtainable with photons or electrons. Heavy ions also bear the advantage of superior dose distribution and may additionally provide higher biological effectivity. A substantial database of historical results supports the hypothesis that conformal radiotherapy is superior to conventional radiotherapy. For the selection of patients for ion beam therapy, the following questions have to be evaluated: Can any significant radiation morbidity by conventional treatment expected? Is the radiation morbidity caused by unintended irradiation of non-target tissue outside the planning target volume? Can the tumor control be improved due to dose escalation with less radiation morbidity? A substantial number of patients have been treated by light ion radiotherapy. There are only a few clinical trials attempting to compare conventional photon radiotherapy with light ion radiotherapy. Clinical results with heavy ions such as carbon ions seem very promising in certain tumors. However results of randomized trials are still to be seen. Clearly the control arm has to be designed to be as close as possible to the optimal photon/electron treatment methods in use. The feasibility of heavy ion treatment has been demonstrated worldwide, with more than 10,000 patients. In the near future more centers worldwide will start patient treatments. The wider availability of light ion beams for clinical use will enable the establishment of a database of clinical results and the elucidation of the role of heavy ion beams in the treatment of cancer.

Humans↗