Irradiation with Carbon Ions Effectively Counteracts Hypoxia-related Radioresistance in a Rat Prostate Carcinoma.

Purpose: Hypoxia in tumors is associated with increased malignancy and resistance to conventional photon radiation therapy. This study investigated the potential of particle therapy to counteract radioresistance in syngeneic rat prostate carcinoma.

Methods And Materials: Subcutaneously transplanted R3327-HI tumors were irradiated with photons or carbon ions under acute hypoxic conditions, induced by clamping the tumor-supplying artery 10 min before and during irradiation.

Effects of Photon versus Carbon-Ion Irradiation in the Rat Cervical Spinal Cord - a Serial T2 and Diffusion-weighted Magnetic Resonance Imaging Study.

Carbon-ion irradiation is increasingly used at the skull base and spine near the radiation-sensitive spinal cord. To better characterize the in vivo radiation response of the cervical spinal cord, radiogenic changes in the high-dose area were measured in rats using magnetic resonance imaging (MRI) diffusion measurements in comparison to conventional photon irradiations. In this longitudinal MRI study, we examined the gray matter (GM) of the cervical spinal cord in 16 female Sprague-Dawley rats after high-dose photon (n = 8) or carbon-ion (12C) irradiation (n = 8) and in 6 sham-exposed rats until myelopathy occurred.

Relative biological effectiveness of oxygen ion beams in the rat spinal cord: Dependence on linear energy transfer and dose and comparison with model predictions.

Background And Purpose: Ion beams exhibit an increased relative biological effectiveness (RBE) with respect to photons. This study determined the RBE of oxygen ion beams as a function of linear energy transfer (LET) and dose in the rat spinal cord.

Materials And Methods: The spinal cord of rats was irradiated at four different positions of a 6 cm spread-out Bragg-peak (LET: 26, 66, 98 and 141 keV/µm) using increasing levels of single and split oxygen ion doses.

Relative biological effectiveness of single and split helium ion doses in the rat spinal cord increases strongly with linear energy transfer.

Background And Purpose: Determination of the relative biological effectiveness (RBE) of helium ions as a function of linear energy transfer (LET) for single and split doses using the rat cervical spinal cord as model system for late-responding normal tissue.

Material And Methods: The rat cervical spinal cord was irradiated at four different positions within a 6 cm spread-out Bragg-peak (SOBP) (LET 2.9, 9.

DCE-MRI detected vascular permeability changes in the rat spinal cord do not explain shorter latency times for paresis after carbon ions relative to photons.

Background And Purpose: Radiation-induced myelopathy, an irreversible complication occurring after a long symptom-free latency time, is preceded by a fixed sequence of magnetic resonance- (MR-) visible morphological alterations. Vascular degradation is assumed the main reason for radiation-induced myelopathy. We used dynamic contrast-enhanced (DCE-) MRI to identify different vascular changes after photon and carbon ion irradiation, which precede or coincide with morphological changes.

Longitudinal MRI study after carbon ion and photon irradiation: shorter latency time for myelopathy is not associated with differential morphological changes.

Background: Radiation-induced myelopathy is a severe and irreversible complication that occurs after a long symptom-free latency time if the spinal cord was exposed to a significant irradiation dose during tumor treatment. As carbon ions are increasingly investigated for tumor treatment in clinical trials, their effect on normal tissue needs further investigation to assure safety of patient treatments. Magnetic resonance imaging (MRI)-visible morphological alterations could serve as predictive markers for medicinal interventions to avoid severe side effects.

Oxygen-Sensitive MRI: A Predictive Imaging Biomarker for Tumor Radiation Response?

Purpose: To develop a noninvasive prognostic imaging biomarker related to hypoxia to predict SABR tumor control.

Methods And Materials: A total of 145 subcutaneous syngeneic Dunning prostate R3327-AT1 rat tumors were focally irradiated once using cone beam computed tomography guidance on a small animal irradiator at 225 kV. Various doses in the range of 0 to 100 Gy were administered, while rats breathed air or oxygen, and tumor control was assessed up to 200 days.

Effectiveness of fractionated carbon ion treatments in three rat prostate tumors differing in growth rate, differentiation and hypoxia.

Purpose: To quantify the fractionation dependence of carbon (C) ions and photons in three rat prostate carcinomas differing in growth rate, differentiation and hypoxia.

Material And Methods: Three sublines (AT1, HI, H) of syngeneic rat prostate tumors (R3327) were treated with six fractions of either C-ions or 6 MV photons. Dose-response curves were determined for the endpoint local tumor control within 300 days.

The RBE in ion beam radiotherapy: In vivo studies and clinical application.

Ion beams used for radiotherapy exhibit an increased relative biological effectiveness (RBE), which depends on several physical treatment parameters as well as on biological factors of the irradiated tissues. While the RBE is an experimentally well-defined quantity, translation to patients is complex and requires radiobiological studies, dedicated models to calculate the RBE in treatment planning as well as strategies for dose prescription. Preclinical in vivo studies and analysis of clinical outcome are important to validate and refine RBE-models.

High Doses of Photons and Carbon Ions Comparably Increase Vascular Permeability in R3327-HI Prostate Tumors: A Dynamic Contrast-Enhanced MRI Study.

Carbon- (12C-) ion radiotherapy exhibits enhanced biological effectiveness compared to photon radiotherapy, however, the contribution of its interaction with the vasculature remains debatable. The effect of high-dose 12C-ion and photon irradiation on vascular permeability in moderately differentiated rat prostate tumors was compared using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Syngeneic R3327-HI rat prostate tumors were irradiated with a single dose of either 18 or 37 Gy 12C ions, or 37 or 75 Gy 6-MV photons (sub-curative and curative dose levels, respectively).

Ramipril reduces incidence and prolongates latency time of radiation-induced rat myelopathy after photon and carbon ion irradiation.

To test the hypothesis that the use of an angiotensin-converting enzyme inhibitor (ACEi) during radiotherapy may be ameliorative for treatment-related normal tissue damage, a pilot study was conducted with the clinically approved (ACE) inhibitor ramipril on the outcome of radiation-induced myelopathy in the rat cervical spinal cord model. Female Sprague Dawley rats were irradiated with single doses of either carbon ions (LET 45 keV/μm) at the center of a 6 cm spread-out Bragg peak (SOBP) or 6 MeV photons. The rats were randomly distributed into 4 experimental arms: (i) photons; (ii) photons + ramipril; (iii) carbon ions and (iv) carbon ions + ramipril.

Fractionated carbon ion irradiations of the rat spinal cord: comparison of the relative biological effectiveness with predictions of the local effect model.

Background: To determine the relative biological effectiveness (RBE) and α/β-values after fractionated carbon ion irradiations of the rat spinal cord with varying linear energy transfer (LET) to benchmark RBE-model calculations.

Material And Methods: The rat spinal cord was irradiated with 6 fractions of carbon ions at 6 positions within a 6 cm spread-out Bragg-peak (SOBP, LET: 16-99 keV/μm). TD-values (dose at 50% complication probability) were determined from dose-response curves for the endpoint radiation induced myelopathy (paresis grade II) within 300 days after irradiation.

Impact of Single Dose Photons and Carbon Ions on Perfusion and Vascular Permeability: A Dynamic Contrast-Enhanced MRI Pilot Study in the Anaplastic Rat Prostate Tumor R3327-AT1.

We collected initial quantitative information on the effects of high-dose carbon (C) ions compared to photons on vascular damage in anaplastic rat prostate tumors, with the goal of elucidating differences in response to high-LET radiation, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Syngeneic R3327-AT1 rat prostate tumors received a single dose of either 16 or 37 Gy C ions or 37 or 85 Gy 6 MV photons (iso-absorbed and iso-effective doses, respectively). The animals underwent DCE-MRI prior to, and on days 3, 7, 14 and 21 postirradiation.

Structural and Functional Characterization of an Electron Transfer Flavoprotein Involved in Toluene Degradation in Strictly Anaerobic Bacteria.

()-Benzylsuccinate is the characteristic initial intermediate of anaerobic toluene metabolism, which is formed by a radical-type addition of toluene to fumarate. Its further degradation proceeds by activation to the coenzyme A (CoA)-thioester and β-oxidation involving a specific ()-2-benzylsuccinyl-CoA dehydrogenase (BbsG) affiliated with the family of acyl-CoA dehydrogenases. In this report, we present the biochemical properties of electron transfer flavoproteins (ETFs) from the strictly anaerobic toluene-degrading species and and the facultatively anaerobic bacterium We determined the X-ray structure of the ETF paralogue involved in toluene metabolism of , revealing strong overall similarities to previously characterized ETF variants but significantly different structural properties in the hinge regions mediating conformational changes.

Examining correlations of oxygen sensitive MRI (BOLD/TOLD) with [F]FMISO PET in rat prostate tumors.

Hypoxia is regarded as a potential prognostic biomarker for tumor aggressiveness, progression, and response to therapy. The radiotracer F-fluoromisonidazole ([F]FMISO) has been used with positron emission tomography (PET) to reveal tumor hypoxia. Meanwhile, blood oxygen level dependent (BOLD) MRI and tissue oxygen level dependent (TOLD) MRI offer insight into oxygenation based on endogenous signals without the need for radiolabels.

Intrinsic and extrinsic tumor characteristics are of minor relevance for the efficacy of split-dose carbon ion irradiation in three experimental prostate tumors.

Objective: To quantify the impact of tumor-associated resistance factors on local tumor control after split doses of carbon (C-) ions or photons in an experimental prostate tumor model.

Material And Methods: Three sublines (AT1, H, HI) of syngeneic rat prostate tumors (R3327) differing in growth rate, differentiation and hypoxic status were irradiated with split doses of either C-ions or 6MV photons. Dose-response curves were determined for the endpoint local tumor control within 300 days.

Mechanically metastable structures generated by single pulse laser-induced periodic surface structures (LIPSS) in the photoresist SU8.

Laser-induced periodic surface structures (LIPSS) with a periodicity of 351 nm are generated in the negative photoresist SU8 by single nanosecond laser pulse impact. Friction scans indicate the periodic pattern to comprise alternating regions of crosslinked and non-crosslinked SU8. Intriguingly, even minor mechanical stimuli in the order of nanonewtons cause the unfolding or rather the deletion of the characteristic periodic pattern similarly to the release of a pre-loaded spring.

Determination of the proton RBE in the rat spinal cord: Is there an increase towards the end of the spread-out Bragg peak?

Background And Purpose: To determine the relative biological effectiveness (RBE) of protons in the rat spinal cord as a function of linear energy transfer (LET) and dose.

Materials And Methods: The rat cervical spinal cord was irradiated with single or two equal fractions (split doses) of protons at four positions (LET 1.4-5.

Late normal tissue response in the rat spinal cord after carbon ion irradiation.

Background: The present work summarizes the research activities on radiation-induced late effects in the rat spinal cord carried out within the "clinical research group ion beam therapy" funded by the German Research Foundation (DFG, KFO 214).

Methods And Materials: Dose-response curves for the endpoint radiation-induced myelopathy were determined at 6 different positions (LET 16-99 keV/μm) within a 6 cm spread-out Bragg peak using either 1, 2 or 6 fractions of carbon ions. Based on the tolerance dose TD of carbon ions and photons, the relative biological effectiveness (RBE) was determined and compared with predictions of the local effect model (LEM I and IV).

Carbon ion radiotherapy: impact of tumor differentiation on local control in experimental prostate carcinomas.

Background: To summarize the research activities of the "clinical research group heavy ion therapy", funded by the German Research Foundation (DFG, KFO 214), on the impact of intrinsic tumor characteristics (grading, hypoxia) on local tumor control after carbon (C-) ion- and photon irradiations.

Methods: Three sublines of syngeneic rat prostate tumors (R3327) with various differentiation levels (highly (-H), moderately (-HI) or anaplastic (-AT1), (diameter 10 mm) were irradiated with 1, 2 and 6 fractions of either C-ions or 6 MV photons using increasing dose levels. Primary endpoint was local tumor control at 300 days.

RBE and related modeling in carbon-ion therapy.

Carbon ion therapy is a promising evolving modality in radiotherapy to treat tumors that are radioresistant against photon treatments. As carbon ions are more effective in normal and tumor tissue, the relative biological effectiveness (RBE) has to be calculated by bio-mathematical models and has to be considered in the dose prescription. This review (i) introduces the concept of the RBE and its most important determinants, (ii) describes the physical and biological causes of the increased RBE for carbon ions, (iii) summarizes available RBE measurements in vitro and in vivo, and (iv) describes the concepts of the clinically applied RBE models (mixed beam model, local effect model, and microdosimetric-kinetic model), and (v) the way they are introduced into clinical application as well as (vi) their status of experimental and clinical validation, and finally (vii) summarizes the current status of the use of the RBE concept in carbon ion therapy and points out clinically relevant conclusions as well as open questions.

Effects of CTGF Blockade on Attenuation and Reversal of Radiation-Induced Pulmonary Fibrosis.

Background: Radiotherapy is a mainstay for the treatment of lung cancer that can induce pneumonitis or pulmonary fibrosis. The matricellular protein connective tissue growth factor (CTGF) is a central mediator of tissue remodeling.

Methods: A radiation-induced mouse model of pulmonary fibrosis was used to determine if transient administration of a human antibody to CTGF (FG-3019) started at different times before or after 20 Gy thoracic irradiation reduced acute and chronic radiation toxicity.

Developing oxygen-enhanced magnetic resonance imaging as a prognostic biomarker of radiation response.

Oxygen-Enhanced Magnetic Resonance Imaging (OE-MRI) techniques were evaluated as potential non-invasive predictive biomarkers of radiation response. Semi quantitative blood-oxygen level dependent (BOLD) and tissue oxygen level dependent (TOLD) contrast, and quantitative responses of relaxation rates (ΔR1 and ΔR2*) to an oxygen breathing challenge during hypofractionated radiotherapy were applied. OE-MRI was performed on subcutaneous Dunning R3327-AT1 rat prostate tumors (n=25) at 4.