Heart Irradiation Research Articles

L-carnitine preserves cardiac function by activating p38 MAPK/Nrf2 signalling in hearts exposed to irradiation

Radiation-induced heart damage (RIHD) is now considered to be one of the causes of mortality in cancer patients undergoing radiotherapy. Cardiac function impairments are clinical manifestations of RIHD. L-carnitine shows protective effects against irradiation and heart disease. This study was aimed to investigate the cardioprotective effects and potential molecular mechanisms of L-carnitine against RIHD. Mouse hearts were exposed to γ-radiation to induce RIHD. L-carnitine at doses of 100mg/Kg and 200mg/Kg was used to treat animals intraperitoneally. Additionally, a specific inhibitor of p38 MAPK was used to treat animals by intraperitoneal injections. Cardiac systolic/diastolic functions were determined using invasive hemodynamic methods; myocyte apoptosis was assessed using the TUNEL assay; intracellular reactive oxygen species production was measured using DHE staining; and western blotting was used to evaluate the phosphorylation of p38MAPK, phosphorylation of Nrf2, and expression levels of HO1, NQO1, caspase3 and bax. L-carnitine treatments inhibited irradiation induced cardiac function impairments. Radiation exposure induced myocyte apoptosis and reactive oxygen species production, which were attenuated by L-carnitine treatments. However, administration of a p38 MAPK inhibitor (SB203580) dramatically impaired L-carnitine's effect on attenuating apoptosis, reactive oxygen species accumulation and cardiac functions in irradiated hearts. Our study showed that L-carnitine administration activated p38MAPK/Nrf2 signalling, initiating the expression of HO1 and NQO1, which have anti-apoptotic and anti-oxidative effects, respectively. In conclusion, L-carnitine attenuates cardiac function loss by inhibiting reactive oxygen species production and apoptosis in hearts exposed to radiation. The cardioprotective effects of L-carnitine were mediated by p38MAPK/Nrf2 signalling.

Late Administration of a Palladium Lipoic Acid Complex (POLY-MVA) Modifies Cardiac Mitochondria but Not Functional or Structural Manifestations of Radiation-Induced Heart Disease in a Rat Model.

Exposure of the heart to ionizing radiation can cause adverse myocardial remodeling. In small animal models, local heart irradiation causes persistent alterations in cardiac mitochondrial function and swelling. POLY-MVA is a dietary supplement that contains a palladium lipoic acid complex that targets mitochondrial complex I and has been demonstrated to have greater redox potential than lipoic acid alone. POLY-MVA improves mitochondrial function and anti-oxidant enzyme activity in the aged rat heart. In this study, we tested whether POLY-MVA can mitigate cardiac effects of ionizing radiation. Adult male rats were exposed to local heart X rays with a daily dose of 9 Gy for 5 consecutive days. Eighteen weeks after irradiation, POLY-MVA was administered orally at 1 ml/kg bodyweight per day during weekdays, for 6 weeks. Alterations in cardiac function as measured with echocardiography coincided with enhanced mitochondrial swelling, a reduction in mitochondrial expression of complex II, manifestations of adverse remodeling such as a reduction in myocardial microvessel density and an increase in collagen deposition and mast cell numbers. POLY-MVA enhanced left ventricular expression of superoxide dismutase 2, but only in sham-irradiated animals. In irradiated animals, POLY-MVA caused a reduction in markers of inflammatory infiltration, CD2 and CD68. Moreover, POLY-MVA mitigated the effects of radiation on mitochondria. Nonetheless, POLY-MVA did not mitigate adverse cardiac remodeling, suggesting that this tissue remodeling may not be alleviated by altering cardiac mitochondria alone. However, we cannot exclude the possibility that an earlier onset of POLY-MVA administration may have more profound effects on radiation-induced cardiac remodeling.

Radiation-induced non-targeted effect in vivo: Evaluation of cyclooygenase-2 and endothelin-1 gene expression in rat heart tissues.

In this study, we investigated expression levels of cyclooxygenase-2 (COX-2) and endothelin-1 (ET-1) genes after pelvis and heart irradiation in a rat model. These factors are involved in heart diseases (HDs). We used seven groups, including two groups of pelvic irradiation, two groups of whole body irradiation, two groups of heart irradiation, and one control nonirradiated group. Pelvis irradiations were conducted at a 2 cm × 2 cm in the pelvis area. Irradiation condition conducted using 1.25 MeV cobalt-60 gamma-rays (30 cGy/min). The changes at ET-1 and COX-2 gene expressions in heart tissue after pelvis and heart irradiation were measured and compared to the control and whole body irradiation groups at 24 h and 72 h after the exposure. In heart irradiation groups, 3-fold up-regulation of both ET-1 and COX-2 was observed. In pelvis irradiation groups, 3-fold up-regulation of ET-1 was seen, but not significant changes in COX-2 gene expression have observed at distant heart tissues after pelvis irradiation. This study reveals that nontargeted effect induced by radiation may be considered as an important phenomenon for induction of HD after radiotherapy.

Use of Three Dimensional Conformal Radiation Therapy for Node Positive Breast Cancer Does Not Result in Excess Lung and Heart Irradiation

Purpose: This work evaluates the use of target and organs at risk (OAR) dose-volume goals in 3D conformal radiotherapy (3DCRT) planning for node positive breast cancer (NPBC) patients undergoing regional nodal irradiation after lumpectomy/mastectomy. Methods: Dosimetric data for 262 NPBC patients receiving regional nodal and whole breast/chest wall (WB/CW) irradiation from 2000-2009 were analyzed. In all cases, target & OAR volumes were delineated on treatment CT scans for field generation and dose-volume histograms (DVHs) were generated. Cases were analyzed to identify how frequently they met treatment planning institutional dose-volume goals (“institutional guidelines” & standardized in 2005) and how this would affect OAR doses. Results: The incidence of cases from 2000-2009 meeting current institutional guidelines improved over the study period. Target coverage improved from 2005-2009, when guidelines were followed as a part of the plan approval. Those cases from 2000-2004 meeting acceptable target goals were found to be significantly different from those cases from 2005-2009 (p Conclusions: The use of institutional guidelines in 3DCRT for WB/CW and regional nodal irradiation for NPBC patients improved target coverage without a statistically significant increase in heart and lung doses.

Assessment Of The Dose To The Heart And The Left Anterior Descending Coronary Artery For The Left Breast Radiotherapy

Radiotherapy for left breast cancer may increase risk of cardiovascular diseases. Exposing the anterior portion of the heart and left anterior descending coronary artery (LAD) to the highest radiation dose depends on individual anatomical location of these structures. The purpose of this work was to assess the radiation doses delivered to the heart and the LAD for the left sided breast cancer patients treated with 3D conformal radiotherapy. Thirty two randomly selected patients referred for adjuvant radiotherapy after conservation surgery for left sided breast cancer were evaluated. The whole heart, the arch of the LAD (LADarch) and the whole LAD were contoured. The radiation doses (Dmax, Dmean) to these three anatomical cardiac structures were evaluated. For all 32 patients, the assessed radiotherapy plans were acceptable based on the dose constraints to critical structures: heart, LADarch. The average mean doses (Dmean) to the heart are well below 5 Gy and 7,3 (range, 3,82 – 17,15 Gy) for the LADarch respectively. For 21,9% of patients, the Dmean to the heart and dose to the LADarch was relatively low while the Dmean to the whole LAD was considerably higher. Conclusion. Evaluation of the mean dose to the heart only could lead to excessive heart irradiation. The results of the study indicate that it is necessary to assess the dose delivered to the whole heart as well as to the whole LAD for evaluation of the left breast irradiation treatment plan. This is very important to minimise the risk of clinically significant cardiac events after left breast radiotherapy.

13N-Ammonia PET/CT Detection of Myocardial Perfusion Abnormalities in Beagle Dogs After Local Heart Irradiation.

Our objective was to determine the potential value of 13N-ammonia PET/CT myocardial perfusion imaging (MPI) for early detection of myocardial perfusion changes induced by radiation damage. Methods: Thirty-six Beagle dogs were randomly divided into a control group (n = 18) or an irradiation group (n = 18). The latter underwent local irradiation to the left ventricular anterior cardiac wall with a single dose of 20 Gy, whereas the former received sham irradiation. All dogs underwent 13N-ammonia PET/CT MPI 1 wk before irradiation and at 3, 6, and 12 mo after sham or local irradiation. One week after undergoing 13N-ammonia PET/CT MPI, the irradiation group underwent coronary angiography. Six randomly selected dogs from each group were sacrificed and used to detect pathologic cardiac injury at 3, 6, and 12 mo after irradiation. Results: Compared with the control group and baseline, the irradiation group showed significantly increased perfusion in the irradiated area of the heart at 3 mo after irradiation, perfusion reduction at 6 mo after irradiation, and a perfusion defect at 12 mo after irradiation. There was no significant difference in the left ventricular ejection fraction between the control and irradiation groups at baseline or at 3 mo after irradiation. The irradiation group showed a reduction of left ventricular ejection fraction compared with the control group at 6 mo (50.0% ± 8.1% vs. 59.3% ± 4.1%, P = 0.016) and 12 mo (47.2% ± 6.7% vs. 57.4% ± 3.3%, P = 0.002) after irradiation. No coronary stenosis was observed in the irradiation group. Regional wall motion abnormalities appeared in the irradiated area at 6 mo after irradiation, and its extent was enlarged at 12 mo after irradiation. Pathologic changes were observed; radiation-induced myocardial tissue damage and microvascular fibrosis in the irradiated area progressively increased over time. Conclusion:13N-ammonia PET/CT MPI can dynamically detect myocardial perfusion changes together with global and regional left ventricular dysfunction induced by irradiation and may be a valuable method for monitoring radiation-induced heart disease.

Role of TGF Beta and PPAR Alpha Signaling Pathways in Radiation Response of Locally Exposed Heart: Integrated Global Transcriptomics and Proteomics Analysis.

Epidemiological data from patients undergoing radiotherapy for thoracic tumors clearly show the damaging effect of ionizing radiation on cardiovascular system. The long-term impairment of heart function and structure after local high-dose irradiation is associated with systemic inflammatory response, contraction impairment, microvascular damage, and cardiac fibrosis. The goal of the present study was to investigate molecular mechanisms involved in this process. C57BL/6J mice received a single X-ray dose of 16 Gy given locally to the heart at the age of 8 weeks. Radiation-induced changes in the heart transcriptome and proteome were investigated 40 weeks after the exposure. The omics data were analyzed by bioinformatics tools and validated by immunoblotting. Integrated network analysis of transcriptomics and proteomics data elucidated the signaling pathways that were similarly affected at gene and protein level. Analysis showed induction of transforming growth factor (TGF) beta signaling but inactivation of peroxisome proliferator-activated receptor (PPAR) alpha signaling in irradiated heart. The putative mediator role of mitogen-activated protein kinase cascade linking PPAR alpha and TGF beta signaling was supported by data from immunoblotting and ELISA. This study indicates that both signaling pathways are involved in radiation-induced heart fibrosis, metabolic disordering, and impaired contractility, a pathophysiological condition that is often observed in patients that received high radiation doses in thorax.

Pathological manifestations of acute-stage radioactive myocardial damage and related mechanisms

Objective To investigate the pathological manifestations of acute-stage radioactive myocardial damage and related mechanisms using an experimental animal model. Methods A total of 12 adult male Sprague-Dawley rats were randomly divided into control group and radiation group. In the radiation group, the model of radiation-induced myocardial damage was established by the irradiation of the anterior myocardial territory with 6-MV X-ray at a single dose of 20 Gy, and at 14 days after irradiation, HE staining was used to observe the morphological changes of cardiomyocytes and intercellular matrix, and Masson staining was used to observe the distribution of collagen fibers. The collagen volume fraction (CVF) was used for semi-quantitative analysis. ELISA was used to measure the activity of total superoxide dismutase (T-SOD) and the concentration of malondialdehyde (MDA), and Western blot was used to measure the expression of the fibrosis marker protein collagen type I (COL-1) and the endoplasmic reticulum stress-related proteins GRP78 and CHOP. The t-test, t’-test, or nonparametric rank sum test was used for comparison between groups. Results At 14 days after local irradiation of the heart, the radiation group had disordered arrangement of cardiomyocytes, marked edema, rupture of some cardiomyocytes, mild karyopyknosis in cardiomyocytes, and infiltration of inflammatory cells in the myocardial interstitium, compared with the control group. Collagen fibers in the myocardial tissue were mainly distributed in the perivascular area and cardiomyocyte interstitium. The radiation group had a significantly higher CVF than the control group (11.35% vs. 5.23%, P=0.000) and a significant increase in the expression of COL-1 compared with the control group (P=0.000). The radiation group had significant increases in the activity of T-SOD and the concentration of MDA in the myocardial tissue compared with the control group (T-SOD: 156.61 U/mgprot vs. 137.06 U/mgprot, P=0.042; MDA: 2.36 nmol/mgprot vs. 1.31 U/mgprot, P=0.007). Compared with the control group, the radiation group showed significant increases in the expression of endoplasmic reticulum stress-related proteins GRP78 and CHOP (P=0.037 and 0.009). Conclusions The pathological manifestations of acute-stage myocardial damage include degeneration of cardiomyocytes, inflammatory exudation in the interstitium, and deposition of collagen in the perivascular area and myocardial interstitium. Myocardial fibrosis can be observed in the acute stage of radiation-induced myocardial damage, and the mechanism may be related to oxidative stress and endoplasmic reticulum stress induced by radioactive rays. Key words: Radiation induced heart disease; Histopathology; Fibrosis; Oxidative stress; Endoplasmic reticulum stress

Changes of microRNA-1, -15b and -21 levels in irradiated rat hearts after treatment with potentially radioprotective drugs.

The aim of this study was to measure expression levels of microRNAs (miRNAs) (miRNA-1, -15b and -21) in the rat myocardium after a single dose of ionizing radiation (6-7 Gy/min, total 25 Gy). The rats were treated with selected drugs (Atorvastatin, acetylsalicylic acid (ASA), Tadalafil, Enbrel) for six weeks after irradiation. MiRNAs levels were measured by RT-qPCR. Irradiation down-regulated miRNA-1 in irradiated hearts. In Tadalafil- and Atorvastatin-treated groups, miRNA-1 expression levels were further decreased compared with irradiated controls. However, Enbrel increased miRNA-1 level in irradiated hearts similarly to that in non-irradiated untreated group. Increase of miRNA-15b is pro-apoptotic in relationship with ischemia. Irradiation caused down-regulation of miRNA-15b. Administration of ASA in the irradiated group resulted in the increase of miRNA-15b expression compared to non-treated controls without irradiation. After Enbrel administration, miRNA-15b levels were overexpressed compared to non-treated normal group. MiRNA-21 belongs to the most markedly up-regulated miRNAs in response to cardiogenic stress. MiRNA-21 was increased nearly 2-fold compared to non-treated hearts whereas Tadalafil reduced miRNA-21 levels (about 40 %). Our study suggests that Enbrel and Tadalafil changed miRNAs expression values of the irradiated rats to the values of non-irradiated controls, thus they might be helpful in mitigation of radiation-induced toxicity.

A dose-dependent perturbation in cardiac energy metabolism is linked to radiation-induced ischemic heart disease in Mayak nuclear workers.

Epidemiological studies show a significant increase in ischemic heart disease (IHD) incidence associated with total external gamma-ray dose among Mayak plutonium enrichment plant workers. Our previous studies using mouse models suggest that persistent alteration of heart metabolism due to the inhibition of peroxisome proliferator-activated receptor (PPAR) alpha accompanies cardiac damage after high doses of ionising radiation. The aim of the present study was to elucidate the mechanism of radiation-induced IHD in humans. The cardiac proteome response to irradiation was analysed in Mayak workers who were exposed only to external doses of gamma rays. All participants were diagnosed during their lifetime with IHD that also was the cause of death. Label-free quantitative proteomics analysis was performed on tissue samples from the cardiac left ventricles of individuals stratified into four radiation dose groups (0 Gy, < 100 mGy, 100–500 mGy, and > 500 mGy). The groups could be separated using principal component analysis based on all proteomics features. Proteome profiling showed a dose-dependent increase in the number of downregulated mitochondrial and structural proteins. Both proteomics and immunoblotting showed decreased expression of several oxidative stress responsive proteins in the irradiated hearts. The phosphorylation of transcription factor PPAR alpha was increased in a dose-dependent manner, which is indicative of a reduction in transcriptional activity with increased radiation dose. These data suggest that chronic external radiation enhances the risk for IHD by inhibiting PPAR alpha and altering the expression of mitochondrial, structural, and antioxidant components of the heart.

WITHDRAWN: Chronic intermittent hypobaric hypoxia attenuates radiation-induced heart damage in rats

Radiation-induced heart damage (RIHD) is a side effect of thoracic radiotherapy that can cause late cardiac problems in patients. Here, we report this side effect can be reduced in rats by chronic intermittent hypobaric hypoxia (CIHH) treatment prior to irradiation. This pretreatment (PB = 404 mmHg, PO2 = 84 mmHg, 6 h/day×28 days) improved the functional recovery of the isolated rat hearts that received cardiac irradiation (20 Gy, single fraction) during Langendorff reperfusion. These tissue slices showed smaller infarct sizes as compared to those irradiated hearts that received no CIHH pretreatment. Histopathological examination revealed the ameliorated myocyte necrosis and myocardial fibrosis in the irradiated hearts by CIHH pretreatment. Biochemical analyses of the total homogenate of heart tissues demonstrated the reduced concentration of malondialdehyde (a metabolite marker of oxidative stress) concomitant with the elevated activity of superoxide dismutase (a reactive oxygen specie scavenger) in irradiated hearts when they had received CIHH pretreatment. Moreover, Western blotting showed two cellular ER stress markers, GRP78 and CHOP, were increased in irradiated rat hearts; but were reduced back to normal level by CIHH pretreatment. Taken together, our results demonstrate that CIHH pretreatment attenuates RIHD in rats. Therefore, patients with cardiac exposure to irradiation might benefit from similar hypobaric hypoxia treatments to reduce the potential cardiac problems later.

Clinical characteristics and dose-volume histogram parameters associated with the development of pleural effusions in non-small cell lung cancer patients treated with chemoradiation therapy

Background: To investigate descriptive characteristics and dose metric (DM) parameters associated with development of pleural effusions (PlEf) in non-small cell lung cancer (NSCLC) treated with definitive chemoradiation therapy (CRT).Materials and methods: We retrospectively assessed treatment records and follow-up imaging of 66 NSCLC patients to identify PlEf formation after CRT. PlEf association between mean heart dose (MHD), mean lung dose (MLD), heart V5–V60 (HV), and lung V5–V60 (LV) were evaluated using Cox Proportional Hazard Models.Results: A total of 52% (34 of 66 patients) of our population developed PlEf and the actuarial rates at 6 months, 12 months, and 18 months were 7%, 30%, and 42%, respectively. Median time to diagnosis was five months (range 0.06–27 months). The majority of PlEfs were grade one (67%) and developed at a median of four (0.06–13) months, followed by grade two (15%) at a median 11 (5–12) months, and grade three (18%) at a median of 11 (3–27) months. On multivariate analysis, increasing HV5–HV50, LV5–LV50, MHD, and MLD were associated with greater risk of PlEf. Higher grade PlEf was also associated with higher doses of radiation to the heart, while lung DM parameters were not significantly associated with higher PlEf grades. At five-months post-CRT, MHD of 25 Gy was associated with a 100% chance of grade one PlEf, an 82% risk of grade two PlEf, and a 19% risk of grade three PlEf.Conclusions: Post-CRT PlEf is common in NSCLC with the majority being grade one. Increasing heart and lung irradiation was associated with increased risk of PlEf. Increasing heart irradiation also correlated with development of increasing grades of PlEf. The impact of potential cardiopulmonary toxicity and resultant PlEfs after CRT requires additional study.

Effects of local irradiation combined with sunitinib on early remodeling, mitochondria, and oxidative stress in the rat heart

Background and purposeThoracic (chemo)radiation therapy is increasingly administered with tyrosine kinase inhibitors (TKI). While TKI have adverse effects on the heart, it is unknown whether combination with other cancer therapies causes enhanced toxicity. We used an animal model to investigate whether radiation and sunitinib interact in their effects on the heart. Material and methodsMale Sprague–Dawley rats received local heart irradiation (9Gy per day, 5days). Oral sunitinib (8 or 15mg/kg bodyweight per day) started on day 1 of irradiation and continued for 2weeks. Cardiac function was examined with echocardiography. Cardiac remodeling, cell death, left ventricular (LV) oxidative stress markers, mitochondrial morphology and mitochondrial permeability transition pore (mPTP) opening were assessed. ResultsCardiac diameter, stroke volume, and LV volume, mass and anterior wall thickness increased in time, but only in the vehicle group. Sunitinib reduced LV inner diameter and volume in systole, which were counteracted by radiation. Sunitinib and radiation showed enhanced effects on mitochondrial morphology and mPTP opening, but not on cardiac troponin I, mast cell numbers or markers of oxidative stress. ConclusionsThis study found no early enhanced effects of radiation and sunitinib on cardiac function or structure. Long-term effects remain to be determined.

Cardiac Exposure in the Dynamic Conformal Arc Therapy, Intensity-Modulated Radiotherapy and Volumetric Modulated Arc Therapy of Lung Cancer.

PurposeTo retrospectively evaluate the cardiac exposure in three cohorts of lung cancer patients treated with dynamic conformal arc therapy (DCAT), intensity-modulated radiotherapy (IMRT), or volumetric modulated arc therapy (VMAT) at our institution in the past seven years.Methods and MaterialsA total of 140 lung cancer patients were included in this institutional review board approved study: 25 treated with DCAT, 70 with IMRT and 45 with VMAT. All plans were generated in a same commercial treatment planning system and have been clinically accepted and delivered. The dose distribution to the heart and the effects of tumor laterality, the irradiated heart volume and the beam-to-heart distance on the cardiac exposure were investigated.ResultsThe mean dose to the heart among all 140 plans was 4.5 Gy. Specifically, the heart received on average 2.3, 5.2 and 4.6 Gy in the DCAT, IMRT and VMAT plans, respectively. The mean heart doses for the left and right lung tumors were 4.1 and 4.8 Gy, respectively. No patients died with evidence of cardiac disease. Three patients (2%) with preexisting cardiac condition developed cardiac disease after treatment. Furthermore, the cardiac exposure was found to increase linearly with the irradiated heart volume while decreasing exponentially with the beam-to-heart distance.ConclusionsCompared to old technologies for lung cancer treatment, modern radiotherapy treatment modalities demonstrated better heart sparing. But the heart dose in lung cancer radiotherapy is still higher than that in the radiotherapy of breast cancer and Hodgkin’s disease where cardiac complications have been extensively studied. With strong correlations of mean heart dose with beam-to-heart distance and irradiated heart volume, cautions should be exercised to avoid long-term cardiac toxicity in the lung cancer patients undergoing radiotherapy.

Atorvastatin Ameliorates Radiation-Induced Cardiac Fibrosis in Rats.

Radiation-induced heart injury is one of the major side effects of radiotherapy for thoracic malignancies. Previous studies have shown that radiotherapy induced myocardial fibrosis and intensified myocardial remodeling. In this study, we investigated whether atorvastatin could inhibit radiation-induced heart fibrosis in Sprague-Dawley rats, which were randomly divided into six groups: control; radiation only; and four treatment groups receiving atorvastatin plus radiation (E1, E2, E3 and E4). All rats, except the control group, received local heart irradiation in 7 daily fractions of 3 Gy for a total of 21 Gy. Rats in groups E1 (10 mg/kg/day) and E2 (20 mg/kg/day) received atorvastatin and radiation treatment until week 12 after exposure. Rats in groups E3 (10 mg/kg/day) and E4 (20 mg/kg/day) received atorvastatin treatment from 3 months before irradiation to week 12 after irradiation. The expressions of TGF-β1, Smad2, Smad3, fibronectin, ROCK I and p-Akt in heart tissues were evaluated using real-time PCR or Western blot analyses. Atorvastatin significantly reduced the expression of TGF-β1, Smad3/P-Smad3, ROCK I and p-Akt in rats of the E1-E4 groups and in a dose-dependent manner. Fibronectin exhibited a similar pattern of expression changes. In addition, echocardiography showed that atorvastatin treatment can inhibit the increase of left ventricular end-diastolic dimension, left ventricular end-systolic diameter and left ventricular posterior wall thickness, and prevent the decrease of ejection fraction and fraction shortening in E1-E4 groups compared with the radiation only group. This study demonstrated that radiation exposure increased the expression of fibronectin in cardiac fibroblasts and induced cardiac fibrosis through activation of the TGF-β1/Smad3, RhoA/ROCK, and PI3K/AKT signaling pathways. Statins ameliorated radiation-induced cardiac fibrosis in Sprague-Dawley rats. Our results suggest that atorvastatin is effective for the treatment of radiation-induced cardiac fibrosis, especially with longer and higher dose atorvastatin treatment, as demonstrated in experimental group E4.

RTOG Chest Wall Contouring Guidelines for Post-Mastectomy Radiation Therapy: Is It Evidence-Based?

Adoption of 3-dimensional planning has brought a great renaissance in radiation oncology; however, its use in breast radiation therapy has lagged substantially. Recently, Radiation Therapy Oncology Group published an invaluable atlas describing consensus recommendations based on expert opinion for chest wall contouring. Although the atlas represents an important step toward 3-dimensional planning, continued reappraisal is essential, especially because the atlas guides ongoing protocols. Prior to opening Radiation Therapy Oncology Group (RTOG) study 1304 within our large comprehensive cancer network, a pretreatment review encountered a discrepancy in the recommended posterior border for the chest wall clinical target volume (CTV) relative to conventional clinical field boarders. This discrepancy significantly increases heart (mean V10Gy increase of 3%4%) and lung (mean V20Gy increase of 4%-11%) irradiation relative to the traditional techniques (1). Although chest wall recurrence accounts for 60% to 80% of locoregional recurrences after mastectomy, detailed information for the anatomic location of chest wall recurrences should guide CTV design. As such, we instituted a publications search to identify locations of chest wall recurrences to better guide CTV contouring. Querying electronic databases (PubMed), bibliographies for studies published since 1952, and Brand & Copeland’s textbook The Breast using search terms including

Modeling the risk of radiation-induced lung fibrosis: Irradiated heart tissue is as important as irradiated lung

PurposeWe used normal tissue complication probability (NTCP) modeling to explore the impact of heart irradiation on radiation-induced lung fibrosis (RILF). Materials and methodsWe retrospectively reviewed for RILF 148 consecutive Hodgkin lymphoma (HL) patients treated with sequential chemo-radiotherapy (CHT-RT). Left, right, total lung and heart dose–volume and dose–mass parameters along with clinical, disease and treatment-related characteristics were analyzed. NTCP modeling by multivariate logistic regression analysis using bootstrapping was performed. Models were evaluated by Spearman Rs coefficient and ROC area. ResultsAt a median time of 13months, 18 out of 115 analyzable patients (15.6%) developed RILF after treatment. A three-variable predictive model resulted to be optimal for RILF. The two models most frequently selected by bootstrap included increasing age and mass of heart receiving >30Gy as common predictors, in combination with left lung V5 (Rs=0.35, AUC=0.78), or alternatively, the lungs near maximum dose D2% (Rs=0.38, AUC=0.80). ConclusionCHT-RT may cause lung injury in a small, but significant fraction of HL patients. Our results suggest that aging along with both heart and lung irradiation plays a fundamental role in the risk of developing RILF.

Role of the bradykinin B2 receptor in a rat model of local heart irradiation

Purpose: Radiation-induced heart disease (RIHD) is a delayed effect of radiotherapy for cancers of the chest, such as breast, esophageal, and lung. Kinins are small peptides with cardioprotective properties. We previously used a rat model that lacks the precursor kininogen to demonstrate that kinins are involved in RIHD. Here, we examined the role of the kinin B2 receptor (B2R) in early radiation-induced signaling in the heart.Materials and methods: Male Brown Norway rats received the B2R-selective antagonist HOE-140 (icatibant) via osmotic minipump from 5 days before until 4 weeks after 21 Gy local heart irradiation. At 4 weeks, signaling events were measured in left ventricular homogenates and nuclear extracts using western blotting and real-time polymerase chain reaction. Numbers of CD68-positive (monocytes/macrophages), CD2-positive (T-lymphocytes), and mast cells were measured using immunohistochemistry.Results: Radiation-induced c-Jun phosphorylation and nuclear translocation were enhanced by HOE-140. HOE-140 did not modify endothelial nitric oxide synthase (eNOS) phosphorylation or alter numbers of CD2-positive or mast cells, but enhanced CD68-positive cell counts in irradiated hearts.Conclusions: B2R signaling may regulate monocyte/macrophage infiltration and c-Jun signals in the irradiated heart. Although eNOS is a main target for kinins, the B2R may not regulate eNOS phosphorylation in response to radiation.

Dosimetric Correlate of Cardiac-Specific Survival Among Patients Undergoing Coronary Artery Stenting After Thoracic Radiotherapy for Cancer.

To retrospectively evaluate outcomes among cancer survivors previously treated with thoracic radiotherapy (RT) who later underwent percutaneous coronary intervention (PCI). From 1998 to 2012, 76 patients first received curative RT (>30 Gy, except for Hodgkin lymphoma patients) involving the heart and lungs followed by PCI. Heart and lung-specific dosimetric parameters were correlated with overall survival (OS) and cardiac-specific survival by Cox variate methods. The mean interval between cancer diagnosis and PCI was 3.7 years (range, 0.1 to 12.6 y). Median follow-up since cancer diagnosis was 5.5 years. At analysis, 46 patients (61%) were alive, 5 (7%) died of cardiac causes, and 9 (12%) of cancer. Higher maximum RT heart dose was related to poorer OS since PCI (P=0.009). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (P=0.005) and higher mean heart dose (P<0.001) were related to poorer OS since cancer diagnosis. β-Blockers, higher mean heart dose (hazard ratio [HR]=1.49, P<0.001), and percentage of targeted volume or organ receiving ≥40 Gy for heart doses (HR=1.32, P<0.001) were associated with poorer non-cancer-specific survival since cancer diagnosis. Diabetes (HR=3.84, P=0.008) and increased percentage of targeted volume or organ receiving ≥45 Gy (HR=1.01 per additional 100 cm irradiated, P=0.01) for the heart decreased major adverse cardiac event-free survival. Prior heart and lung-directed RT had volume-dependent and dose-dependent adverse effects on long-term cardiac outcomes for patients subsequently treated with PCI. RT planning that minimizes heart and lung irradiation doses should be encouraged.

SU‐E‐T‐532: Left‐Sided Breast Cancer Irradiation Using Volumatric Modulated Arc Therapy: An Evaluation of Multiple Commercial Systems

Purposes:There has been growing interest in treating breast cancer using VMAT technique. Our goal is to compare the dosimetry and treatment delivery parameters for the left‐sided breast cancer treatment using various VMAT platforms from commercially available planning systems.Methods:Five consecutive left‐sided breast cancer patients initially treated with conventional 3D‐conformal radiotherapy (3DCRT) were selected. Four VMAT plans using most popular treatment planning systems, including Eclipse (Version 11, Varian), Pinnacle (Version 9.8, Philips), Monaco (Version 2.03, Elekta) and helical Tomotherapy (V4.0, Accuray). The same structure set and same planning goals were used for all VMAT plans. The dosimetric parameters including target coverage and minimum/maximum/mean, dose‐volume endpoints for the selected normal structures: the heart, ipsilateral‐/contralateral lung and breast, were evaluated. Other dosimetric indices including heterogeneity index (HI) were evaluated. The treatment delivery parameters, such as monitor unit (MUs) and delivery time were also compared.Results:VMAT increases dose homogeneity to the treated volume and reduces the irradiated heart and left‐lung volumes. Compared to the 3DCRT technique, all VMAT plans offer better heart and left‐lung dose sparing; the mean heart doses were 4.5±1.6(Monaco), 1.2±0.4(Pinnacle), 1.3± (Eclipse) and 5.6±4.4(Tomo), the mean left‐lung doses were 5.9±1.5(Monaco), 3.7±0.7(Pinnacle), 1.4± (Eclipse) and 5.2±1.6 (Tomo), while for the 3DCRT plan, the mean heart and left‐Lung doses were 2.9±2.0, and 6.8±4.4 (Gy) respectively. The averaged contralateral‐breast and lung mean doses were higher in VMAT plans than the 3DCRT plans but were not statistically significant. Among all the VMAT plans, the Pinnacle plans often yield the lowest right‐lung/breast mean doses, and slightly better heterogeneity indices that are similar to Tomotherapy plans. Treatment delivery time of the VMAT plans (except helical Tomotherapy IMRT) is estimated to be comparable with the conventional 3DCRT.Conclusion:VMAT achieves equal or better PTV coverage and comparable OARs sparing compared to the conventional 3DCRT techniques.