Risk Of Normal Tissue Toxicity Research Articles

DNA-PK inhibition shows differential radiosensitization in orthotopic GBM PDX models based on DDR pathway deficits.

Glioblastoma (GBM) remains one of the most therapy-resistant malignancies with frequent local failures despite aggressive surgery, chemotherapy, and ionizing radiation (IR). Small molecule inhibitors of DNA-dependent protein kinase (DNA-PKi's) are potent radiosensitizers currently in clinical trials. Determining which patients may benefit from radiosensitization with DNA-PKi's is critical to avoid unnecessary increased risk of normal tissue toxicity. In this study we used GBM patient derived xenografts (PDXs) in orthotopic murine models to study the relationship between molecular features, pharmacokinetics, and the radiosensitizing potential of the DNA-PKi peposertib. We show that peposertib radiosensitizes established and PDX GBM lines in vitro at 300nM and above, with significant increase in radiosensitization by maintaining post-IR exposure for >12 hours. Radiosensitization by peposertib is mediated by catalytic inhibition of DNA-PK, and knock-down of DNA-PK by short hairpin RNA (shRNA) largely abolished the radiosensitizing effect. Peposertib decreased auto-phosphorylation of DNA-PKcs after IR in a dose-dependent manner with delay in resolution of γH2AX foci at 24 hours. The addition of peposertib to IR significantly increased survival in GBM120 orthotopic xenografts, but not in GBM10. There was no difference in plasma or average tumor concentrations of peposertib in the two cohorts. While the mechanism underpinning this discordant effect in vitro vs. in vivo is not clear, there was an association for greater sensitization in TP53 mutant lines. Transfection of a dominant-negative TP53 mutant in baseline TP53 wildtype GBM lines significantly delayed growth and decreased NHEJ efficiency (but not Homologous Recombination), after peposertib exposure.

Hypofractionated Stereotactic Radiosurgery in the Management of Brain Metastases.

Stereotactic radiosurgery (SRS) is an important weapon in the management of brain metastases. Single-fraction SRS is associated with local control rates ranging from approximately 70% to 100%, which are largely dependent on lesion and postoperative cavity size. The rates of local control and improved neurocognitive outcomes compared with conventional whole-brain radiation therapy have led to increased adoption of SRS in these settings. However, when treating larger targets and/or targets located in eloquent locations, the risk of normal tissue toxicity and adverse radiation effects within healthy brain tissue becomes significantly higher. Thus, hypofractionated SRS has become a widely adopted approach, which allows for the delivery of ablative doses of radiation while also minimizing the risk of toxicity. This approach has been studied in multiple retrospective reports in both the postoperative and intact settings. While there are no reported randomized data to date, there are trials underway evaluating this paradigm. In this article, we review the role of hypofractionated SRS in the management of brain metastases and emerging data that will serve to validate this treatment approach. Pertinent articles and references were obtained from a comprehensive search of PubMed/MEDLINE and clinicaltrials.gov .

Radiation Exposure of Peripheral Mononuclear Blood Cells Alters the Composition and Function of Secreted Extracellular Vesicles.

Normal tissue toxicity is a dose-limiting factor in radiation therapy. Therefore, a detailed understanding of the normal tissue response to radiation is necessary to predict the risk of normal tissue toxicity and to development strategies for tissue protection. One component of normal tissue that is continuously exposed during therapeutic irradiation is the circulating population of peripheral blood mononuclear cells (PBMC). PBMCs are highly sensitive to ionizing radiation (IR); however, little is known about how IR affects the PBMC response on a systemic level. It was the aim of this study to investigate whether IR was capable to induce changes in the composition and function of extracellular vesicles (EVs) secreted from PBMCs after radiation exposure to different doses. Therefore, whole blood samples from healthy donors were exposed to X-ray radiation in the clinically relevant doses of 0, 0.1, 2 or 6 Gy and PBMC-secreted EVs were isolated 72 h later. Proteome and miRNome analysis of EVs as well as functional studies were performed. Secreted EVs showed a dose-dependent increase in the number of significantly deregulated proteins and microRNAs. For both, proteome and microRNA data, principal component analysis showed a dose-dependent separation of control and exposed groups. Integrated pathway analysis of the radiation-regulated EV proteins and microRNAs consistently predicted an association of deregulated molecules with apoptosis, cell death and survival. Functional studies identified endothelial cells as an efficient EV recipient system, in which irradiation of recipient cells further increased the uptake. Furthermore an apoptosis suppressive effect of EVs from irradiated PBMCs in endothelial recipient cells was detected. In summary, this study demonstrates that IR modifies the communication between PBMCs and endothelial cells. EVs from irradiated PBMC donors were identified as transmitters of protective signals to irradiated endothelial cells. Thus, these data may lead to the discovery of biomarker candidates for radiation dosimetry and even more importantly, they suggest EVs as a novel systemic communication pathway between irradiated normal, non-cancer tissues.

Quantifying Tumor Stiffness With Magnetic Resonance Elastography

The viscoelastic properties of tissue are significantly altered with the development of tumors and these alterations can be assessed with magnetic resonance elastography (MRE). Accurate detection and characterization of malignant and benign lesions can be obtained by quantifying tumor stiffness, improving the specificity and diagnostic accuracy of conventional magnetic resonance imaging. Furthermore, MRE can be used to stratify patients for treatment based on risk of normal tissue toxicity and surgical considerations including consistency and adherence of the tumor to surrounding structures. MRE is a reliable reproducible technique demonstrated in studies that include both patients with cancer and normal volunteers, and an average technical failure rate of <1%. The addition of MRE into a multiparametric magnetic resonance imaging assessment may improve the diagnosis and treatment of cancer.

Generating amorphous target margins in radiation therapy to promote maximal target coverage with minimal target size

Background and significanceThis work provides proof-of-principle for two versions of a heuristic approach that automatically creates amorphous radiation therapy planning target volume (PTV) margins considering local effects of tumor shape and motion to ensure adequate voxel coverage with while striving to minimize PTV size. The resulting target thereby promotes disease control while minimizing the risk of normal tissue toxicity. MethodsThis work describes the mixed-PDF algorithm and the independent-PDF algorithm which generate amorphous margins around a radiation therapy target by incorporating user-defined models of target motion. Both algorithms were applied to example targets – one circular and one “cashew-shaped.” Target motion was modeled by four probability density functions applied to the target quadrants. The spatially variant motion model illustrates the application of the algorithms even with tissue deformation. Performance of the margins was evaluated in silico with respect to voxelized target coverage and PTV size, and was compared to conventional techniques: a threshold-based probabilistic technique and an (an)isotropic expansion technique. To demonstrate the algorithm's clinical utility, a lung cancer patient was analyzed retrospectively. For this case, 4D CT measurements were combined with setup uncertainty to compare the PTV from the mixed-PDF algorithm with a PTV equivalent to the one used clinically. ResultsFor both targets, the mixed-PDF algorithm performed best, followed by the independent-PDF algorithm, the threshold algorithm, and lastly, the (an)isotropic algorithm. Superior coverage was always achieved by the amorphous margin algorithms for a given PTV size. Alternatively, the margin required for a particular level of coverage was always smaller (8–15%) when created with the amorphous algorithms. For the lung cancer patient, the mixed-PDF algorithm resulted in a PTV that was 13% smaller than the clinical PTV while still achieving ≥99.9% coverage. ConclusionsThe amorphous margin algorithms are better suited for the local effects of target shape and positional uncertainties than conventional margins. As a result, they provide superior target coverage with smaller PTVs, ensuring dose delivered to the target while decreasing the risk of normal tissue toxicity.

Impact of CT slice thickness on volume and dose evaluation during thoracic cancer radiotherapy.

IntroductionAccurate delineation of targets and organs at risk (OAR) is required to ensure treatment efficacy and minimize risk of normal tissue toxicity with radiotherapy. Therefore, we evaluated the impacts of computed tomography (CT) slice thickness and reconstruction methods on the volume and dose evaluations of targets and OAR.Patients and methodsEleven CT datasets from patients with thoracic cancer were included. 3D images with a slice thickness of 2 mm (2–CT) were created automatically. Images of other slice thickness (4–CT, 6–CT, 8–CT, 10–CT) were reconstructed manually by the selected 2D images using two methods; internal tumor information and external CT Reference markers. Structures and plans on 2–CT images, as a reference data, were copied to the reconstructed images.ResultsThe maximum error of volume was 84.6% for the smallest target in 10–CT, and the maximum error (≥20 cm3) was 10.1%, 14.8% for the two reconstruction methods, internal tumor information and external CT Reference, respectively. Changes in conformity index for a target of <20 cm3 were 5.4% and 17.5% in 8–CT. Changes on V30 and V40 of the heart were considerable. In the internal tumor information method, volumes of hearts decreased by 3.2% in 6–CT, while V30 and V40 increased by 18.4% and 46.6%.ConclusionThe image reconstruction method by internal tumor information was less affected by slice thickness than the image reconstruction method by external CT Reference markers. This study suggested that before positioning scanning, the largest section through the target should be determined and the optimal slice thickness should be estimated.

Application of radiogenomics in radiation oncology

Radiotherapy (RT) can be used in the treatment of cancers, instead of surgery to achieve better functional results by using external beam RT and brachytherapy. Elevation of radiation response in tumor cells and reduction of sensitivity to radiation in adjacent normal tissues are the core issues in the radiotherapeutic field of tumor. Radiogenomics addresses possible associations between germline genetic variation and normal tissue toxicity after RT. The objective of radiation genomics is to identify the genetic markers for personalized RT, in which cancer management is formulated so that the treatment plan will be optimized for each patient based on their genetic background. Combinatorial approaches to radiation-induced gene expression study and genome-wide SNP genotype study may discover candidate biomarkers for personalization of RT treatment and identify genetic alterations that affect risk of normal tissue toxicity.

Clinical Application of a Hybrid RapidArc Radiotherapy Technique for Locally Advanced Lung Cancer.

Radiation treatment planning for locally advanced lung cancer can be technically challenging, as delivery of ≥60 Gy to large volumes with concurrent chemotherapy is often associated with significant risk of normal tissue toxicity. We clinically implemented a novel hybrid RapidArc technique in patients with lung cancer and compared these plans with 3-dimensional conformal radiotherapy and RapidArc-only plans. Hybrid RapidArc was used to treat 11 patients with locally advanced lung cancer having bulky mediastinal adenopathy. All 11 patients received concurrent chemotherapy. All underwent a 4-dimensional computed tomography planning scan. Hybrid RapidArc plans concurrently combined static (60%) and RapidArc (40%) beams. All cases were replanned using 3- to 5-field 3-dimensional conformal radiotherapy and RapidArc technique as controls. Significant reductions in dose were observed in hybrid RapidArc plans compared to 3-dimensional conformal radiotherapy plans for total lung V20 and mean (-2% and -0.6 Gy); contralateral lung mean (-2.92 Gy); and esophagus V60 and mean (-16.0% and -2.2 Gy; all P < .05). Contralateral lung doses were significantly lower for hybrid RapidArc plans compared to RapidArc-only plans (all P < .05). Compared to 3-dimensional conformal radiotherapy, heart V60 and mean dose were significantly improved with hybrid RapidArc (3% vs 5%, P = .04 and 16.32 Gy vs 16.65 Gy, P = .03). However, heart V40 and V45 and maximum spinal cord dose were significantly lower with RapidArc plans compared to hybrid RapidArc plans. Conformity and homogeneity were significantly better with hybrid RapidArc plans compared to 3-dimensional conformal radiotherapy plans ( P < .05). Treatment was well tolerated, with no grade 3+ toxicities. To our knowledge, this is the first report on the clinical application of hybrid RapidArc in patients with locally advanced lung cancer. Hybrid RapidArc permitted safe delivery of 60 to 66 Gy to large lung tumors with concurrent chemotherapy and demonstrated advantages for reduction in low-dose lung volumes, esophageal dose, and mean heart dose.

Individual patient data meta-analysis shows a significant association between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients

PurposeSeveral small studies have indicated that the ATM rs1801516 SNP is associated with risk of normal tissue toxicity after radiotherapy. However, the findings have not been consistent. In order to test this SNP in a well-powered study, an individual patient data meta-analysis was carried out by the International Radiogenomics Consortium. Materials and methodsThe analysis included 5456 patients from 17 different cohorts. 2759 patients were given radiotherapy for breast cancer and 2697 for prostate cancer. Eight toxicity scores (overall toxicity, acute toxicity, late toxicity, acute skin toxicity, acute rectal toxicity, telangiectasia, fibrosis and late rectal toxicity) were analyzed. Adjustments were made for treatment and patient related factors with potential impact on the risk of toxicity. ResultsFor all endpoints except late rectal toxicity, a significantly increased risk of toxicity was found for carriers of the minor (Asn) allele with odds ratios of approximately 1.5 for acute toxicity and 1.2 for late toxicity. The results were consistent with a co-dominant pattern of inheritance. ConclusionThis study convincingly showed a significant association between the ATM rs1801516 Asn allele and increased risk of radiation-induced normal tissue toxicity.

Circulating miR-29a and miR-150 correlate with delivered dose during thoracic radiation therapy for non-small cell lung cancer.

BackgroundRisk of normal tissue toxicity limits the amount of thoracic radiation therapy (RT) that can be routinely prescribed to treat non-small cell lung cancer (NSCLC). An early biomarker of response to thoracic RT may provide a way to predict eventual toxicities—such as radiation pneumonitis—during treatment, thereby enabling dose adjustment before the symptomatic onset of late effects. MicroRNAs (miRNAs) were studied as potential serological biomarkers for thoracic RT. As a first step, we sought to identify miRNAs that correlate with delivered dose and standard dosimetric factors.MethodsWe performed miRNA profiling of plasma samples obtained from five patients with Stage IIIA NSCLC at five dose-points each during radical thoracic RT. Candidate miRNAs were then assessed in samples from a separate cohort of 21 NSCLC patients receiving radical thoracic RT. To identify a cellular source of circulating miRNAs, we quantified in vitro miRNA expression intracellularly and within secreted exosomes in five NSCLC and stromal cell lines.ResultsmiRNA profiling of the discovery cohort identified ten circulating miRNAs that correlated with delivered RT dose as well as other dosimetric parameters such as lung V20. In the validation cohort, miR-29a-3p and miR-150-5p were reproducibly shown to decrease with increasing radiation dose. Expression of miR-29a-3p and miR-150-5p in secreted exosomes decreased with radiation. This was concomitant with an increase in intracellular levels, suggesting that exosomal export of these miRNAs may be downregulated in both NSCLC and stromal cells in response to radiation.ConclusionsmiR-29a-3p and miR-150-5p were identified as circulating biomarkers that correlated with delivered RT dose. miR-150 has been reported to decrease in the circulation of mammals exposed to radiation while miR-29a has been associated with fibrosis in the human heart, lungs, and kidneys. One may therefore hypothesize that outlier levels of circulating miR-29a-3p and miR-150-5p may eventually help predict unexpected responses to radiation therapy, such as toxicity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-016-0636-4) contains supplementary material, which is available to authorized users.

Radiogenomics – current status, challenges and future directions

Radiogenomics designates a scientific field that addresses possible associations between genetic germline alterations and normal tissue toxicity after radiotherapy. The ultimate aim of this research is to establish a gene-based predictive test for normal tissue radiosensitivity. During the last 5 years, substantial progress has been achieved in this field. Several compelling associations for SNPs have been demonstrated in large candidate gene studies as well as genome wide association studies. These findings shed new light on radiobiology and expand our understanding of the processes that lead to side effects after radiotherapy. Despite this, certain fundamental challenges still relate to genomic approaches. Based on the latest insights into complex trait genetics and molecular genetics, we provide an analysis of these challenges and propose putative strategies to further advance the field. These strategies include ‘big data approaches’ and collaborative research within international consortia. Furthermore, research that combines the study of radiation-induced gene expression and genome-wide SNP genotype may discover genetic alterations that regulate the biological response to ionizing radiation. Thus, such integrative approaches may lead to genetic alterations that affect risk of normal tissue toxicity.

SP-0009: Uncomplicated cures - a paradigm shift in cancer survivorship research

Changes in cancer incidence and mortality have been modest during the past several decades, but the number of cancer survivors has almost tripled during the same period. With the increasing cohort of cancer survivors, efforts to prevent, diagnose and manage adverse effects of cancer therapy, in general, and those of radiation therapy specifically, have intensified. Considerable progress towards reducing toxicity of radiation therapy has been achieved by the introduction of so-called dose-sculpting treatment techniques. Moreover, new insights into the underlying pathophysiology have resulted in an improved understanding of mechanisms of radiation-induced normal tissue toxicity and in development of new diagnostic strategies and management opportunities. However, the risk of normal tissue toxicity still limits the dose of cytotoxic therapy that can be given, thus limiting the curability of cancer. The steadily increasing number of cancer survivors and the demand for uncomplicated cancer cures require a paradigm shift in cancer survivorship research. Research must shift from simply describing and palliating side effects (“doing head-counts”) to adopt a more modern, goal-oriented approach. The new approach encompasses 1) epidemiological, psychosocial, and outcomes research aimed at characterizing and ameliorating the problems that afflict current cancer survivors; 2) applied clinical and preclinical research aimed at developing new treatments or response modifiers to prevent or minimize shortand longterm side effects of cancer therapy; and 3) basic research aimed at improving our understanding of the cellular and molecular mechanisms that are responsible for treatmentrelated toxicities. This three-pronged approach will ensure that progress is made toward our ultimate goal, i.e., to increase the uncomplicated cancer cure rate.

Defining the Target in Cancer of the Oesophagus: Direct Radiotherapy Planning with Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography

AimsTarget definition in radiotherapy treatment planning (RTP) of oesophageal cancer is challenging and guided by a combination of diagnostic modalities. This planning study aimed to evaluate the contribution of single positron emission tomography-computed tomography (PET-CT) in the treatment position to RTP. Materials and methodsNineteen patients referred for radiotherapy from April to December 2008 were retrospectively identified. Two sets of target volumes were delineated using the planning CT and the 18F-fluoro-deoxy-D-glucose (18F-FDG) PET-CT data sets, respectively. Target volumes were compared in length, volume and geographic conformality. Radiotherapy plans were generated and compared for both data sets. ResultsPET-CT planning target volume (PET-CTPTV) was larger than the CT target (CTPTV) in 12 cases and smaller in seven. The median PTV conformality index was 0.82 (range 0.44–0.98). Radiotherapy plans conforming to normal tissue dose constraints were achieved for both sets of PTV in 16 patients (three patients could not be treated to the prescription dose with either technique due to very large target volumes and significant risk of normal tissue toxicity). Previously undetected locoregional nodal involvement seen on PET-CT in three cases was localised and included in the PTV. In nine cases, the CTPTV plan delivered less than 95% dose to 95% of the PET-CTPTV, raising concern about potential for geographical miss. ConclusionA single scan with diagnostic PET-CT in the treatment position for RTP allows greater confidence in anatomical localisation and interpretation of biological information. The use of PET-CT may result in larger PTV volumes in selected cases, but did not exclude patients from radical treatment within accepted normal tissue tolerance.

Strategies of Dose Escalation in the Treatment of Locally Advanced Non-Small Cell Lung Cancer: Image Guidance and Beyond

Radiation dose in the setting of chemo-radiation for locally advanced non-small cell lung cancer (NSCLC) has been historically limited by the risk of normal tissue toxicity and this has been hypothesized to correlate with the poor results in regard to local tumor recurrences. Dose escalation, as a means to improve local control, with concurrent chemotherapy has been shown to be feasible with three-dimensional conformal radiotherapy in early phase studies with good clinical outcome. However, the potential superiority of moderate dose escalation to 74 Gy has not been shown in phase III randomized studies. In this review, the limitations in target volume definition in previous studies; and the factors that may be critical to safe dose escalation in the treatment of locally advanced NSCLC, such as respiratory motion management, image guidance, intensity modulation, FDG–positron emission tomography incorporation in the treatment planning process, and adaptive radiotherapy, are discussed. These factors, along with novel treatment approaches that have emerged in recent years, are proposed to warrant further investigation in future trials in a more comprehensive and integrated fashion.

Role of Stereotactic Body Radiation Therapy and Proton/Carbon Nuclei Therapies

Locally advanced non-small cell lung cancer is a disease typified by poor clinical outcomes. Patients treated with definitive radiation or chemoradiation have high rates of local tumor progression and distant metastasis. Tumor dose escalation using conventionally fractionated radiation is limited by toxicity to adjacent normal tissues. Novel treatment modalities such as stereotactic body radiation therapy or charged particle therapies potentially represent methods to dose escalate without increasing the risk of normal tissue toxicity. Here, we review the technologies of stereotactic body radiation therapy and charged particles, the reported clinical success with these modalities, and potential implementation into treatment regimens for locally advanced non-small cell lung cancer.

The use of PET/CT in radiotherapy planning: contribution of deformable registration

Medical imaging provides information for diagnosis and staging, evaluation of treatment response, and also plays pivotal role in advanced radiotherapy treatment planning. In the era of the innovative conventional and functional imaging techniques, the main goal of radiation therapy, which is to maximize the dose to the target while minimizing the dose to adjacent healthy organs, can be actualized. On the basis of this, accurate delineation has led to the safe decrease of radiotherapy volumes, in terms of resulting in a reduced risk of normal tissue toxicity, and increasing tumor control probability (De Ruysscher et al., 2005; van Der Wel et al., 2005). Computed tomography (CT) is the primary modality for image-based treatment planning, but conventional anatomic imaging with CT has limited sensitivity to identify distinctly the anatomic borders of the tumor (Nestle et al., 2009). Integration of multimodality imaging data for radiotherapy treatment planning is beneficial and indespensable for perfect delineation (Kessler et al., 1991; Rosenman et al., 1998). Currently, several studies showed that positron emission tomography–computed tomography (PET/CT) is significantly used for staging for various type of tumor. PET/CT combines biological activity and anatomical information in a single study session, and provides to distinguish viable tumor focus. The use of PET/CT for fused images with planning CT (pCT) may allow adequate tumor visualization (De Ruysscher et al., 2005; van Der Wel et al., 2005). Otherwise, implementation of PET/CT information for radiation therapy planning (RTP) to accurate delineation is under investigation, but is not recommended for a routine procedure. In this paper, we focus on the clinical adoption of PET/CT and the use of PET/CT in RTP.

Normal Tissue Complications From Low-dose Proton Therapy

Proton therapy is an attractive method to attenuate toxicities of radiotherapy because of the decrease of integral radiation dose to normal tissues, which should lead to fewer late side effects. This potential benefit is of particular interest in the pediatric population, since children are more vulnerable to the risks of radiation. In addition, overall survival rates for pediatric malignancies continue to improve, which will lead to more long-term survivors who will be at risk from the late effects of radiation therapy that was used for treatment. In this review, the potential benefits afforded by proton therapy in the low-dose area for radiosensitive organs will be evaluated. Because robust clinical information is not available for low-dose proton therapy, information from the experience of photon therapy in radiosensitive structures will be reviewed. In general, because the low-dose bath is reduced or on occasion eliminated with the use of proton therapy, a reduction of early and late toxicities related to low-dose radiotherapy such as vomiting, mucositis, cardiovascular complications, pulmonary injury, and developmental effects in children is expected. Other authors review the current evidence and potential benefits supporting the use of proton therapy for the reduction in neuro-cognitive sequelae and secondary malignancies. Currently, a relative biological effectiveness of 1.1 is used in clinical situations to calculate the equivalent biologic dose for proton therapy relative to photon therapy. The unit of dose is commonly referred to as gray equivalent (GyEq). The interaction of a proton at a cellular level is postulated to lead to a higher frequency of double-strand breaks, so in theory there is a higher probability of cell kill and a lower probability of mutagenesis. At this time, however, once the physical properties of the interaction of proton with matter are accounted for, there is no definite data that 1 GyEq has any different biologic outcome than 1 Gy delivered with photon therapy. In the Bragg peak, there is greater uncertainty of dose deposition and associated biologic effect. In clinical practice, therefore, one avoids placing the Bragg peak on critical structures such as the brainstem, spinal cord, or optic chiasm. In summary, it appears that normal tissue tolerance of proton radiotherapy is likely to be similar to photon radiation for equivalent biologic doses. Overall, it is anticipated that there will be a lower risk of normal tissue toxicity associated with proton therapy because of a lower delivered dose outside of the target tissue.

No Effect of the Transforming Growth Factor β1 Promoter Polymorphism C-509T on TGFB1 Gene Expression, Protein Secretion, or Cellular Radiosensitivity

To study whether the promoter polymorphism (C-509T) affects transforming growth factor β1 gene (TGFB1) expression, protein secretion, and/or cellular radiosensitivity for both human lymphocytes and fibroblasts. Experiments were performed with lymphocytes taken either from 124 breast cancer patients or 59 pairs of normal monozygotic twins. We used 15 normal human primary fibroblast strains as controls. The C-509T genotype was determined by polymerase chain reaction-restriction fragment length polymorphism or TaqMan single nucleotide polymorphism (SNP) genotyping assay. The cellular radiosensitivity of lymphocytes was measured by G0/1 assay and that of fibroblasts by colony assay. The amount of extracellular TGFB1 protein was determined by enzyme-linked immunosorbent assay, and TGFB1 expression was assessed via microarray analysis or reverse transcription-polymerase chain reaction. The C-509T genotype was found not to be associated with cellular radiosensitivity, neither for lymphocytes (breast cancer patients, P=.811; healthy donors, P=.181) nor for fibroblasts (P=.589). Both TGFB1 expression and TGFB1 protein secretion showed considerable variation, which, however, did not depend on the C-509T genotype (protein secretion: P=.879; gene expression: lymphocytes, P=.134, fibroblasts, P=.605). There was also no general correlation between TGFB1 expression and cellular radiosensitivity (lymphocytes, P=.632; fibroblasts, P=.573). Our data indicate that any association between the SNP C-509T of TGFB1 and risk of normal tissue toxicity cannot be ascribed to a functional consequence of this SNP, either on the level of gene expression, protein secretion, or cellular radiosensitivity.

The role of radiation therapy in the management of adrenal carcinoma and adrenal metastases

The use of radiation therapy (RT) to treat adrenal tumors has historically been limited by the risk of normal tissue toxicity, given the proximity of the adrenals to radiosensitive structures, such as the kidney, stomach, intestine, and spinal cord. However, contemporary techniques have made RT safe and effective for use in the management of adrenal carcinoma and adrenal metastases. Data on recent advances in the use of RT to treat adrenocortical carcinoma and adrenal metastases are reviewed, in both surgical and non-surgical settings.

Radiothérapie stéréotaxique par accélérateurs adaptés ou dédiés

Stereotactic radiation therapy, consisting in irradiating the tumor with a high dose per fraction, has a therapeutic potential because of excellent local control. This technique requires a high accuracy level in order to minimize the risk of normal tissue toxicity. Initially used for cerebral localization, the stereotactic radiation therapy can be used for lung and liver tumors thanks to personalized immobilization devices, time resolved tomodensitometry for tumor deformation, collimators with small size leaves, advanced dose distribution calculation algorithms and 3D imaging for patient set-up. This article will review the different clinical applications and the different aspects (mechanical, dosimetric and biological) to evaluate before implementing this complex irradiation technique using adapted or dedicated linear accelerators.