S. Brandenburg

Physiological interaction of heart and lung in thoracic irradiation

INTRODUCTIONnThe risk of early radiation-induced lung toxicity (RILT) limits the dose and efficacy of radiation therapy of thoracic tumors. In addition to lung dose, coirradiation of the heart is a known risk factor in the development RILT. The aim of this study was to identify the underlying physiology of the interaction between lung and heart in thoracic irradiation.nnnMETHODS AND MATERIALSnRat hearts, lungs, or both were irradiated to 20 Gy using high-precision proton beams. Cardiopulmonary performance was assessed using breathing rate measurements and F(18)-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) scans biweekly and left- and right-sided cardiac hemodynamic measurements and histopathology analysis at 8 weeks postirradiation.nnnRESULTSnTwo to 12 weeks after heart irradiation, a pronounced defect in the uptake of (18)F-FDG in the left ventricle (LV) was observed. At 8 weeks postirradiation, this coincided with LV perivascular fibrosis, an increase in LV end-diastolic pressure, and pulmonary edema in the shielded lungs. Lung irradiation alone not only increased pulmonary artery pressure and perivascular edema but also induced an increased LV relaxation time. Combined irradiation of lung and heart induced pronounced increases in LV end-diastolic pressure and relaxation time, in addition to an increase in right ventricle end-diastolic pressure, indicative of biventricular diastolic dysfunction. Moreover, enhanced pulmonary edema, inflammation and fibrosis were also observed.nnnCONCLUSIONSnBoth lung and heart irradiation cause cardiac and pulmonary toxicity via different mechanisms. Thus, when combined, the loss of cardiopulmonary performance is intensified further, explaining the deleterious effects of heart and lung coirradiation. Our findings show for the first time the physiological mechanism underlying the development of a multiorgan complication, RILT. Reduction of dose to either of these organs offers new opportunities to improve radiation therapy treatment of thoracic tumors, potentially facilitating increased treatment doses and tumor control.

Sparing the region of the salivary gland containing stem cells preserves saliva production after radiotherapy for head and neck cancer

Avoiding irradiation of the region of the parotid gland containing stem cells reduces the risk of xerostomia (dry mouth). Preserving saliva flow after radiotherapy Radiotherapy for head and neck cancer may damage the salivary glands, resulting in reduced salivation with consequent xerostomia (dry mouth). Xerostomia affects the quality of life of patients with head and neck cancer. van Luijk and co-workers reported the location of salivary (parotid) gland stem cells in the mouse, rat, and human. Next, they showed in rat and human that irradiation of the salivary gland region containing the highest number of stem cells resulted in the greatest loss of saliva production after treatment. Finally, the authors showed that it is possible to avoid irradiation of this specific area during therapy, which may reduce the patient’s risk of developing post-radiotherapy xerostomia. Each year, 500,000 patients are treated with radiotherapy for head and neck cancer, resulting in relatively high survival rates. However, in 40% of patients, quality of life is severely compromised because of radiation-induced impairment of salivary gland function and consequent xerostomia (dry mouth). New radiation treatment technologies enable sparing of parts of the salivary glands. We have determined the parts of the major salivary gland, the parotid gland, that need to be spared to ensure that the gland continues to produce saliva after irradiation treatment. In mice, rats, and humans, we showed that stem and progenitor cells reside in the region of the parotid gland containing the major ducts. We demonstrated in rats that inclusion of the ducts in the radiation field led to loss of regenerative capacity, resulting in long-term gland dysfunction with reduced saliva production. Then we showed in a cohort of patients with head and neck cancer that the radiation dose to the region of the salivary gland containing the stem/progenitor cells predicted the function of the salivary glands one year after radiotherapy. Finally, we showed that this region of the salivary gland could be spared during radiotherapy, thus reducing the risk of post-radiotherapy xerostomia.

Bath and Shower Effects in the Rat Parotid Gland Explain Increased Relative Risk of Parotid Gland Dysfunction After Intensity-Modulated Radiotherapy

PURPOSEnTo assess in a rat model whether adding a subtolerance dose in a region adjacent to a high-dose irradiated subvolume of the parotid gland influences its response (bath-and-shower effect).nnnMETHODS AND MATERIALSnIrradiation of the whole, cranial 50%, and/or the caudal 50% of the parotid glands of Wistar rats was performed using 150-MeV protons. To determine suitable (i.e., subtolerance) dose levels for a bath-dose, both whole parotid glands were irradiated with 5 to 25 Gy. Subsequently groups of Wistar rats received 30 Gy to the caudal 50% (shower) and 0 to 10 Gy to the cranial 50% (bath) of both parotid glands. Stimulated saliva flow rate (function) was measured before and up to 240 days after irradiation.nnnRESULTSnIrradiation of both glands up to a dose of 10 Gy did not result in late loss of function and is thus regarded subtolerance. Addition of a dose bath of 1 to 10 Gy to a high-dose in the caudal 50% of the glands resulted in enhanced function loss.nnnCONCLUSIONnSimilar to the spinal cord, the parotid gland demonstrates a bath and shower effect, which may explain the less-than-expected sparing of function after IMRT.

QUANTIFYING LOCAL RADIATION-INDUCED LUNG DAMAGE FROM COMPUTED TOMOGRAPHY

PURPOSEnOptimal implementation of new radiotherapy techniques requires accurate predictive models for normal tissue complications. Since clinically used dose distributions are nonuniform, local tissue damage needs to be measured and related to local tissue dose. In lung, radiation-induced damage results in density changes that have been measured by computed tomography (CT) imaging noninvasively, but not yet on a localized scale. Therefore, the aim of the present study was to develop a method for quantification of local radiation-induced lung tissue damage using CT.nnnMETHODS AND MATERIALSnCT images of the thorax were made 8 and 26 weeks after irradiation of 100%, 75%, 50%, and 25% lung volume of rats. Local lung tissue structure (S(L)) was quantified from local mean and local standard deviation of the CT density in Hounsfield units in 1-mm(3) subvolumes. The relation of changes in S(L) (DeltaS(L)) to histologic changes and breathing rate was investigated. Feasibility for clinical application was tested by applying the method to CT images of a patient with non-small-cell lung carcinoma and investigating the local dose-effect relationship of DeltaS(L).nnnRESULTSnIn rats, a clear dose-response relationship of DeltaS(L) was observed at different time points after radiation. Furthermore, DeltaS(L) correlated strongly to histologic endpoints (infiltrates and inflammatory cells) and breathing rate. In the patient, progressive local dose-dependent increases in DeltaS(L) were observed.nnnCONCLUSIONnWe developed a method to quantify local radiation-induced tissue damage in the lung using CT. This method can be used in the development of more accurate predictive models for normal tissue complications.

ACE inhibition attenuates radiation-induced cardiopulmonary damage

BACKGROUND AND PURPOSEnIn thoracic irradiation, the maximum radiation dose is restricted by the risk of radiation-induced cardiopulmonary damage and dysfunction limiting tumor control. We showed that radiation-induced sub-clinical cardiac damage and lung damage in rats mutually interact and that combined irradiation intensifies cardiopulmonary toxicity. Unfortunately, current clinical practice does not include preventative measures to attenuate radiation-induced lung or cardiac toxicity. Here, we investigate the effects of the ACE inhibitor captopril on radiation-induced cardiopulmonary damage.nnnMATERIAL AND METHODSnAfter local irradiation of rat heart and/or lungs captopril was administered orally. Cardiopulmonary performance was assessed using biweekly breathing rate measurements. At 8 weeks post-irradiation, cardiac hemodynamics were measured, CT scans and histopathology were analyzed.nnnRESULTSnCaptopril significantly improved breathing rate and cardiopulmonary density/structure, but only when the heart was included in the radiation field. Consistently, captopril reduced radiation-induced pleural and pericardial effusion and cardiac fibrosis, resulting in an improved left ventricular end-diastolic pressure only in the heart-irradiated groups.nnnCONCLUSIONnCaptopril improves cardiopulmonary morphology and function by reducing acute cardiac damage, a risk factor in the development of radiation-induced cardiopulmonary toxicity. ACE inhibition should be evaluated as a strategy to reduce cardiopulmonary complications induced by radiotherapy to the thoracic area.

High and Low LET Radiation Differentially Induce Normal Tissue Damage Signals

PURPOSEnRadiotherapy using high linear energy transfer (LET) radiation is aimed at efficiently killing tumor cells while minimizing dose (biological effective) to normal tissues to prevent toxicity. It is well established that high LET radiation results in lower cell survival per absorbed dose than low LET radiation. However, whether various mechanisms involved in the development of normal tissue damage may be regulated differentially is not known. Therefore the aim of this study was to investigate whether two actions related to normal tissue toxicity, p53-induced apoptosis and expression of the profibrotic gene PAI-1 (plasminogen activator inhibitor 1), are differentially induced by high and low LET radiation.nnnMETHODS AND MATERIALSnCells were irradiated with high LET carbon ions or low LET photons. Cell survival assays were performed, profibrotic PAI-1 expression was monitored by quantitative polymerase chain reaction, and apoptosis was assayed by annexin V staining. Activation of p53 by phosphorylation at serine 315 and serine 37 was monitored by Western blotting. Transfections of plasmids expressing p53 mutated at serines 315 and 37 were used to test the requirement of these residues for apoptosis and expression of PAI-1.nnnRESULTSnAs expected, cell survival was lower and induction of apoptosis was higher in high -LET irradiated cells. Interestingly, induction of the profibrotic PAI-1 gene was similar with high and low LET radiation. In agreement with this finding, phosphorylation of p53 at serine 315 involved in PAI-1 expression was similar with high and low LET radiation, whereas phosphorylation of p53 at serine 37, involved in apoptosis induction, was much higher after high LET irradiation.nnnCONCLUSIONSnOur results indicate that diverse mechanisms involved in the development of normal tissue damage may be differentially affected by high and low LET radiation. This may have consequences for the development and manifestation of normal tissue damage.

Development and Characterization of Large La-Halide Gamma-Ray Scintillators for Future Planetary Missions

Future planetary missions such as BepiColombo are resource limited in both mass and power. Due to the proximity of the spacecraft to the Sun, the instrumentation will encounter harsh environments as far as radiation levels and thermal loads are concerned. Only radiation hard detectors that need little or no cooling will be able to successfully operate after long cruise times and over the expected mission lifetimes. The next generation of lanthanum halide scintillators promises to provide sufficient resolution in the spectral range between 1 and 10 MeV where most of the elemental gamma-ray emission lines can be detected. In order to be suitable for planetary gamma-ray spectrometers with sufficient sensitivity it had to be proven that larger crystals of size 3 can be produced and that they maintain their resolution of 3% at 662 keV. For that purpose we have produced and characterized several larger crystals and assessed their radiation hardness by exposing the crystals to radiation doses that are representative of the expected conditions in the space environment. Systematic measurements on several crystals allowed the determination of the activation potential and the performance verification from which the consequences for instrument flight performance can be derived. From these investigations we conclude that these scintillators are well suited for planetary missions, with excellent and stable performance.

Relative electron density determination using a physics based parameterization of photon interactions in medical DECT

Radiotherapy and particle therapy treatment planning require accurate knowledge of the electron density and elemental composition of the tissues in the beam path to predict the local dose deposition. We describe a method for the analysis of dual energy computed tomography (DECT) images that provides the electron densities and effective atomic numbers of tissues. The CT measurement process is modelled by system weighting functions, which apply an energy dependent weighting to the parameterization of the total cross sectionxa0for photon interactions with matter. This detailed parameterization is based on the theoretical analysis of Jackson and Hawkes and deviates, at most, 0.3% from the tabulated NIST values for the elements H to Zn. To account for beam hardening in the object as present in the CT image we implemented an iterative process employing a local weighting function, derived from the method proposed by Heismann and Balda. With this method effective atomic numbers between 1 and 30 can be determined. The method has been experimentally validated on a commercially available tissue characterization phantom with 16 inserts made of tissue substitutes and aluminium that has been scanned on a dual source CT system with tube potentials of 100u2009kV and 140u2009kV using a clinical scan protocol. Relative electron densities of all tissue substitutes have been determined with accuracy better than 1%. The presented DECT analysis method thus provides high accuracy electron densities and effective atomic numbers for radiotherapy and especially particle therapy treatment planning.

AGOR status report

The past three years of AGOR operation have been a period of steady improvement of the cyclotron. The two problems causing most down time: failure of the helium refrigerator system and water leaks in the RF acceleration electrodes have been solved. The latter required redesign of the connection between the electrode and the coaxial line and a four month shutdown to implement the modifications.

Volume-Dependent Expression of In-Field and Out-of-Field Effects in the Proton-Irradiated Rat Lung

PURPOSEnTo investigate whether occurrence of early radiation effects in lung tissue depends on local dose only.nnnMETHODS AND MATERIALSnTwenty-five percent, 50%, 66%, 88%, or 100% of the rat lung was irradiated using single fractions of 150-MeV protons. For all volumes, in-field and out-of-field dose-response curves were obtained 8 weeks after irradiation. The pathohistology of parenchymal inflammation, infiltrates, fibrosis, and vascular damage and the relative expression of proinflammatory cytokines interleukin (IL)-1α, transforming growth factor-β, IL-6, and tumor necrosis factor-α were assessed.nnnRESULTSnFor all histologic endpoints, irradiated dose- and volume-dependent in-field and out-of-field effects were observed, albeit with different dynamics. Of note, the out-of-field effects for vascular damage were very similar to the in-field effects. Interestingly, only IL-6 showed a clear dose-dependent increase in expression both in-field and out-of-field, whereas the expression levels of IL-1α, transforming growth factor-β, and tumor necrosis factor-α were either very low or without a clear dose-volume relation. As such, none of the radiation effects studied depended only on local dose to the tissue.nnnCONCLUSIONnThe effects of radiation to lung tissue do not only depend on local dose to that tissue. Especially at high-volume irradiation, lung damage seems to present globally rather than locally. The accuracy of predictive modeling may be improved by including nonlocal effects.