Cumulative Dose from Recurrent CT Scans: Exploring the DNA Damage Response in Human Non-Transformed Cells.

Recurrent computed tomography (CT) examination has become a common diagnostic procedure for several diseases and injuries. Though each singular CT scan exposes individuals at low doses of low linear energy transfer (LET) radiation, the cumulative dose received from recurrent CT scans poses an increasing concern for potential health risks. Here, we evaluated the biological effects of recurrent CT scans on the DNA damage response (DDR) in human fibroblasts and retinal pigment epithelial cells maintained in culture for five months and subjected to four CT scans, one every four weeks. DDR kinetics and eventual accumulation of persistent-radiation-induced foci (P-RIF) were assessed by combined immunofluorescence for γH2AX and 53BP1, i.e., γH2AX/53BP1 foci. We found that CT scan repetitions significantly increased both the number and size of γH2AX/53BP1 foci. In particular, after the third CT scan, we observed the appearance of giant foci that might result from the overlapping of individual small foci and that do not associate with irreversible growth arrest, as shown by DNA replication in the foci-carrying cells. Whether these giant foci represent coalescence of unrepaired DNA damage as reported following single exposition to high doses of high LET radiation is still unclear. However, morphologically, these giant foci resemble the recently described compartmentalization of damaged DNA that should facilitate the repair of DNA double-strand breaks but also increase the risk of chromosomal translocations. Overall, these results indicate that for a correct evaluation of the damage following recurrent CT examinations, it is necessary to consider the size and composition of the foci in addition to their number.

How direct measurements of worker eyes with a Scheimpflug camera can affect lensdose coefficients in interventional radiology.

The 2013/59/Euratom Directive reduced the occupational exposure limits for the lens. Since it has become crucial to estimate the dose absorbed by the lens, we have studied the individual variability of exposed workers' ocular conformations with respect to the data estimated from their personal dosimetry. The anterior eye conformations of 45 exposed workers were acquired using Scheimpflug imaging and classified according to their sight conditions (emmetropia, myopia or hypermetropia). Three eye models were computed, with two lens reconstructions, and implemented in an interventional radiology scenario using Monte Carlo code. The models were dosimetrically analysed by simulating setup A, a theoretical monoenergetic and isotropic photon source (10-150 keV) and setup B, a more realistic interventional setting with an angiographic x-ray unit (50, 75, 100 kV peak). Scheimpflug imaging provided an average anterior chamber depth of (6.4 ± 0.5) mm and a lens depth of (3.9 ± 0.3) mm, together with a reconstructed equatorial lens length of (7.1-10.1) mm. Using these data for model reconstruction, dose coefficients (DCs) were simulated for all ocular structures. Regardless of the eye model used, the DCs showed a similar trend with radiation energy, which highlighted that for the same energy and setup, no significant dependence on ocular morphology and workers' visual conditions was observed. The maximum difference obtained did not exceed 1% for all eye models or structures analysed. Therefore, the individual variabilities of worker ocular anatomy do not require any additional correction, compared to the personal dosimetry data measured with a dedicated lens dosimeter. To estimate the dose absorbed by the other eye structures, it is, instead, essential to know the spectrum of the source that has generated the irradiation, since there are differences between monoenergetic sources and more realistic angiographic units.

A real-time system to report abnormal events involving staff in a nuclear medicine therapy unit.

A system for internal and voluntary reporting of abnormal events in a Nuclear Medicine Therapy Unit is described. This system is based on the Internet of Things and is composed of an application for mobile devices and a wireless network of detectors. The application is addressed to healthcare professionals and is intended to be a user-friendly tool to make the reporting procedure little laborious. The network of detectors allows for a real-time measurement of the dose distribution in the patient's room. The staff was involved in all stages, from the design of the dosimetry system and mobile application up to their final testing. Face-to-face interviews were carried out with 24 operators in different roles in the Unit (radiation protection experts, physicians, physicists, nuclear medicine technicians and nurses). The preliminary results of the interviews and the current state of development of the application and the detection network will be described.

Factors to Consider for the Correct Use of γH2AX in the Evaluation of DNA Double-Strand Breaks Damage Caused by Ionizing Radiation.

People exposed to ionizing radiation (IR) both for diagnostic and therapeutic purposes is constantly increasing. Since the use of IR involves a risk of harmful effects, such as the DNA DSB induction, an accurate determination of this induced DNA damage and a correct evaluation of the risk-benefit ratio in the clinical field are of key relevance. γH2AX (the phosphorylated form of the histone variant H2AX) is a very early marker of DSBs that can be induced both in physiological conditions, such as in the absence of specific external agents, and by external factors such as smoking, heat, background environmental radiation, and drugs. All these internal and external conditions result in a basal level of γH2AX which must be considered for the correct assessment of the DSBs after IR exposure. In this review we analyze the most common conditions that induce H2AX phosphorylation, including specific exogenous stimuli, cellular states, basic environmental factors, and lifestyles. Moreover, we discuss the most widely used methods for γH2AX determination and describe the principal applications of γH2AX scoring, paying particular attention to clinical studies. This knowledge will help us optimize the use of available methods in order to discern the specific γH2AX following IR-induced DSBs from the basal level of γH2AX in the cells.

Exploring CT Texture Parameters as Predictive and Response Imaging Biomarkers of Survival in Patients With Metastatic Melanoma Treated With PD-1 Inhibitor Nivolumab: A Pilot Study Using a Delta-Radiomics Approach.

In the era of artificial intelligence and precision medicine, the use of quantitative imaging methodological approaches could improve the cancer patient's therapeutic approaches. Specifically, our pilot study aims to explore whether CT texture features on both baseline and first post-treatment contrast-enhanced CT may act as a predictor of overall survival (OS) and progression-free survival (PFS) in metastatic melanoma (MM) patients treated with the PD-1 inhibitor Nivolumab. Ninety-four lesions from 32 patients treated with Nivolumab were analyzed. Manual segmentation was performed using a free-hand polygon approach by drawing a region of interest (ROI) around each target lesion (up to five lesions were selected per patient according to RECIST 1.1). Filtration-histogram-based texture analysis was employed using a commercially available research software called TexRAD (Feedback Medical Ltd, London, UK; https://fbkmed.com/texrad-landing-2/) Percentage changes in texture features were calculated to perform delta-radiomics analysis. Texture feature kurtosis at fine and medium filter scale predicted OS and PFS. A higher kurtosis is correlated with good prognosis; kurtosis values greater than 1.11 for SSF = 2 and 1.20 for SSF = 3 were indicators of higher OS (fine texture: 192 HR = 0.56, 95% CI = 0.32-0.96, p = 0.03; medium texture: HR = 0.54, 95% CI = 0.29-0.99, p = 0.04) and PFS (fine texture: HR = 0.53, 95% CI = 0.29-0.95, p = 0.03; medium texture: HR = 0.49, 209 95% CI = 0.25-0.96, p = 0.03). In delta-radiomics analysis, the entropy percentage variation correlated with OS and PFS. Increasing entropy indicates a worse outcome. An entropy variation greater than 5% was an indicator of bad prognosis. CT delta-texture analysis quantified as entropy predicted OS and PFS. Baseline CT texture quantified as kurtosis also predicted survival baseline. Further studies with larger cohorts are mandatory to confirm these promising exploratory results.

Novel cancer therapies for advanced cutaneous melanoma: The added value of radiomics in the decision making process-A systematic review.

Advanced malignant melanoma represents a public health matter due to its rising incidence and aggressiveness. Novel therapies such as immunotherapy are showing promising results with improved progression free and overall survival in melanoma patients. However, novel targeted and immunotherapies could generate atypical patterns of response which are nowadays a big challenge since imaging criteria (ie Recist 1.1) have not been proven to be always reliable to assess response. Radiomics and in particular texture analysis (TA) represent new quantitative methodologies which could reduce the impact of these limitations providing most robust data in support of clinical decision process. The aim of this paper was to review the state of the art of radiomics/TA when it is applied to the imaging of metastatic melanoma patients.

DNA damage in lens epithelial cells exposed to occupationally-relevant X-ray doses and role in cataract formation.

The current framework of radiological protection of occupational exposed medical workers reduced the eye-lens equivalent dose limit from 150 to 20 mSv per year requiring an accurate dosimetric evaluation and an increase understanding of radiation induced effects on Lens cells considering the typical scenario of occupational exposed medical operators. Indeed, it is widely accepted that genomic damage of Lens epithelial cells (LEC) is a key mechanism of cataractogenesis. However, the relationship between apoptosis and cataractogenesis is still controversial. In this study biological and physical data are combined to improve the understanding of radiation induced effects on LEC. To characterize the occupational exposure of medical workers during angiographic procedures an INNOVA 4100 (General Electric Healthcare) equipment was used (scenario A). Additional experiments were conducted using a research tube (scenario B). For both scenarios, the frequencies of binucleated cells, micronuclei, p21-positive cells were assessed with different doses and dose rates. A Monte-Carlo study was conducted using a model for the photon generation with the X-ray tubes and with the Petri dishes considering the two different scenarios (A and B) to reproduce the experimental conditions and validate the irradiation setups to the cells. The simulation results have been tallied using the Monte Carlo code MCNP6. The spectral characteristics of the different X-ray beams have been estimated. All irradiated samples showed frequencies of micronuclei and p21-positive cells higher than the unirradiated controls. Differences in frequencies increased with the delivered dose measured with Gafchromic films XR-RV3. The spectrum incident on eye lens and Petri, as estimated with MCNP6, was in good agreement in the scenario A (confirming the experimental setup), while the mean energy spectrum was higher in the scenario B. Nevertheless, the response of LEC seemed mainly related to the measured absorbed dose. No effects on viability were detected. Our results support the hypothesis that apoptosis is not responsible for cataract induced by low doses of X-ray (i.e. 25 mGy) while the induction of transient p21 may interfere with the disassembly of the nuclear envelop in differentiating LEC, leading to cataract formation. Further studies are needed to better clarify the relationship we suggested between DNA damage, transient p21 induction and the inability of LEC enucleation.

DVHs evaluation in brain metastases stereotactic radiotherapy treatment plans.

PURPOSE: The aim of this work is to report a retrospective study of radiobiological indicators based on Dose-Volume Histograms analysis obtained by stereotactic radiotherapy treatments. METHODS AND MATERIALS: Fifty-five patients for a total of sixty-seven brain metastases with a mean target volume of 8.49 cc were treated by Dynamic Conformal Arc Therapy (DCAT) and Intensity-Modulated Stereotactic Radiotherapy (IMRST). The Delivered prescription dose was chosen on the basis of tumor size and location so as to ensure a 100% isodose coverage to the target volume. RESULTS: The treatment plans reported a mean value of 10% and 2.19% for the inhomogeneity and conformal index, respectively. The F factor showed we overdosed sixty-three patients delivering an additional 7% dose more than calculated values. The radiobiological parameters: TCP and NTCP showed a complete tumor control limiting the organs at risk damage. CONCLUSION: One goal of stereotactic radiotherapy is to design a treatment plan in which the steep dose gradient achievable minimizes the amount of radiation delivered outside the tumor region. This technique allows to deliver a much larger dose to the target without exceeding the radiation-related tolerance of normal tissues and improving patients' quality of life.

Relationships between rectal wall dose-volume constraints and radiobiologic indices of toxicity for patients with prostate cancer.

PURPOSE: The purpose of this article was to investigate how exceeding specified rectal wall dose-volume constraints impacts on the risk of late rectal bleeding by using radiobiologic calculations. METHODS AND MATERIALS: Dose-volume histograms (DVH) of the rectal wall of 250 patients with prostate cancer were analyzed. All patients were treated by three-dimensional conformal radiation therapy, receiving mean target doses of 80 Gy. To study the main features of the patient population, the average and the standard deviation of the distribution of DVHs were generated. The mean dose , generalized equivalent uniform dose formulation (gEUD), modified equivalent uniform dose formulation (mEUD)(0), and normal tissue complication probability (NTCP) distributions were also produced. The DVHs set was then binned into eight classes on the basis of the exceeding or the fulfilling of three dose-volume constraints: V(40) = 60%, V(50) = 50%, and V(70) = 25%. Comparisons were made between them by , gEUD, mEUD(0), and NTCP. RESULTS: The radiobiologic calculations suggest that late rectal toxicity is mostly influenced by V(70). The gEUD and mEUD(0) are risk factors of toxicity always concordant with NTCP, inside each DVH class. The mean dose, although a reliable index, may be misleading in critical situations. CONCLUSIONS: Both in three-dimensional conformal radiation therapy and particularly in intensity-modulated radiation therapy, it should be known what the relative importance of each specified dose-volume constraint is for each organ at risk. This requires a greater awareness of radiobiologic properties of tissues and radiobiologic indices may help to gradually become aware of this issue.

Radiobiological Optimization in Lung Stereotactic Body Radiation Therapy: Are We Ready to Apply Radiobiological Models?

Lung tumors are often associated with a poor prognosis although different schedules and treatment modalities have been extensively tested in the clinical practice. The complexity of this disease and the use of combined therapeutic approaches have been investigated and the use of high dose-rates is emerging as effective strategy. Technological improvements of clinical linear accelerators allow combining high dose-rate and a more conformal dose delivery with accurate imaging modalities pre- and during therapy. This paper aims at reporting the state of the art and future direction in the use of radiobiological models and radiobiological-based optimizations in the clinical practice for the treatment of lung cancer. To address this issue, a search was carried out on PubMed database to identify potential papers reporting tumor control probability and normal tissue complication probability for lung tumors. Full articles were retrieved when the abstract was considered relevant, and only papers published in English language were considered. The bibliographies of retrieved papers were also searched and relevant articles included. At the state of the art, dose-response relationships have been reported in literature for local tumor control and survival in stage III non-small cell lung cancer. Due to the lack of published radiobiological models for SBRT, several authors used dose constraints and models derived for conventional fractionation schemes. Recently, several radiobiological models and parameters for SBRT have been published and could be used in prospective trials although external validations are recommended to improve the robustness of model predictive capability. Moreover, radiobiological-based functions have been used within treatment planning systems for plan optimization but the advantages of using this strategy in the clinical practice are still under discussion. Future research should be directed toward combined regimens, in order to potentially improve both local tumor control and survival. Indeed, accurate knowledge of the relevant parameters describing tumor biology and normal tissue response is mandatory to correctly address this issue. In this context, the role of medical physicists and the AAPM in the development of radiobiological models is crucial for the progress of developing specific tool for radiobiological-based optimization treatment planning.

Zero field PDD and TMR data for unflattened beams in conventional linacs: A tool for independent dose calculations.

PURPOSE: To investigate the applicability of the formalism described in BJR supplement n.25 for Flattening Filter Free (FFF) beams in determining the zero-field tissue maximum ratio (TMR) for an independent calculation method of Percentage Depth Doses (PDDs) and relative dose factors (RDFs) at different experimental setups. METHODS: Experimental PDDs for field size from 40×40cm2 to 2×2cm2 with Source Surface Distance (SSD) 100cm were acquired. The normalized peak scatter factor for each square field was obtained by fitting experimental RDFs in water and collimator factors (CFs) in air. Maximum log-likelihood methods were used to extract fit parameters in competing models and the Bayesian Information Criterion was used to select the best one. In different experimental setups additional RDFs and TPR1020s for field sizes other than reference field were measured and Monte Carlo simulations of PDDs at SSD 80cm were carried out to validate the results. PDD agreements were evaluated by gamma analysis. RESULTS: The BJR formalism allowed to predict the PDDs obtained with MC within 2%/2mm at SSD 80cm from 100% down to 50% of the maximum dose. The agreement between experimental TPR1020s and RDFs values at SSD=90cm and BJR calculations were within 1% for field sizes greater than 5×5cm2 while it was within 3% for fields down to 2×2cm2. CONCLUSIONS: BJR formalism can be used for FFF beams to predict PDD and RDF at different SSDs and can be used for independent MU calculations.

Intensity-modulated pelvic radiation therapy and simultaneous integrated boost to the prostate area in patients with high-risk prostate cancer: a preliminary report of disease control.

The aim of the study was to report the clinical results in patients with high-risk prostate cancer treated with pelvic intensity-modulated radiation therapy (IMRT) and simultaneous integrated boost (SIB) to the prostate area. A total of 110 patients entered our study, 37 patients presented with localized prostate cancer and radiological evidence of node metastases or ≥15% estimated risk of lymph node (LN) involvement, while 73 patients underwent postoperative adjuvant or salvage irradiation for biochemical or residual/recurrent disease, LN metastases, or high risk of harboring nodal metastases. All patients received androgen deprivation therapy (ADT) for 2 years. The median follow-up was 56.5 months. For the whole patient group, the 3- and 5-year freedom from biochemical failure were 82.6% and 74.6%, respectively, with a better outcome in patients treated with radical approach. The 3- and 5-year freedom from local failure were 94.4% and 90.2%, respectively, while the 3- and 5-year distant metastasis-free survival were 87.8% and 81.7%, respectively. For all study patients, the rate of freedom from G2 acute rectal, intestinal, and urinary toxicities was 60%, 77%, and 61%, respectively. There was no G3 acute toxicity, ≥G2 late intestinal toxicity, or G3 late urinary or rectal toxicity. The 3- and 5-year ≥G2 freedom from late rectal toxicity rate were 98% and 95%, respectively, while the 3- and 5-year ≥G2 freedom from late urinary toxicity rate were 95% and 88%, respectively. The study concludes that pelvic IMRT and SIB to the prostatic area in association with 2-year ADT was a well-tolerated technique, providing high disease control in patients with prostate cancer requiring LN treatment.

Repeat stereotactic radiosurgery in the management of brain metastases from NSCLC: A case report and review of the literature.

The aims of radiotherapeutic treatment of brain metastases include maintaining neurocognitive function and improvement of survival. Based on these premises, we present a case report in which the role of repeat stereotactic radiosurgery (SRS) was investigated in a patient with a recurrent brain metastasis from non-small cell lung cancer in the same area as previously treated with radiosurgery. A 40-year-old male caucasian patient was diagnosed with brain metastasis from non-small cell lung cancer (NSCLC) and underwent SRS. The patient developed a recurrence of the disease and a second SRS on the same area was performed. After 8 months, tumor restaging demonstrated a lesion compatible with a recurrence and the patient underwent surgery. Histological diagnosis following surgery revealed only the occurrence of radionecrosis. Radiotherapy was well-tolerated and no grade 3/4 neurological toxicity occurred. To date, no consensus exists on the efficacy of retreatment with SRS. Despite the limited number of studies in this field, in the present case report, we outline the outcomes of this unconventional approach.

Dosimetric and clinical advantages of deep inspiration breath-hold (DIBH) during radiotherapy of breast cancer.

BACKGROUND: To investigate the potential dosimetric and clinical benefits of Deep Inspiration Breath-Hold (DIBH) technique during radiotherapy of breast cancer compared with Free Breathing (FB). METHODS: Eight left-sided breast cancer patients underwent a supervised breath hold during treatment. For each patient, two CT scans were acquired with and without breath hold, and virtual simulation was performed for conventional tangential fields, utilizing 6 or 15 MV photon fields. The resulting dose-volume histograms were calculated, and the volumes of heart/lung irradiated to given doses were assessed. The left anterior descending coronary artery (LAD) mean and maximum doses were calculated, together with tumour control probability (TCP) and normal tissue complication probabilities (NTCP) for lung and heart. RESULTS: For all patients a reduction of at least 16% in lung mean dose and at least 20% in irradiated pulmonary volumes was observed when DIBH was applied. Heart and LAD maximum doses were decreased by more than 78% with DIBH. The NTCP values for pneumonitis and long term cardiac mortality were also reduced by about 11% with DIBH. The NTCP values for pericarditis were zero for both DIBH and FB. CONCLUSION: Delivering radiation in DIBH conditions the dose to the surrounding normal structures could be reduced, in particular heart, LAD and lung, due to increased distance between target and heart, and to reduced lung density.

SNPs in DNA repair or oxidative stress genes and late subcutaneous fibrosis in patients following single shot partial breast irradiation.

BACKGROUND: The aim of this study was to evaluate the potential association between single nucleotide polymorphisms related response to radiotherapy injury, such as genes related to DNA repair or enzymes involved in anti-oxidative activities. The paper aims to identify marker genes able to predict an increased risk of late toxicity studying our group of patients who underwent a Single Shot 3D-CRT PBI (SSPBI) after BCS (breast conserving surgery). METHODS: A total of 57 breast cancer patients who underwent SSPBI were genotyped for SNPs (single nucleotide polymorphisms) in XRCC1, XRCC3, GST and RAD51 by Pyrosequencing technology. Univariate analysis (ORs and 95% CI) was performed to correlate SNPs with the risk of developing ≥ G2 fibrosis or fat necrosis. RESULTS: A higher significant risk of developing ≥ G2 fibrosis or fat necrosis in patients with: polymorphic variant GSTP1 (Ile105Val) (OR = 2.9; 95%CI, 0.88-10.14, p = 0.047). CONCLUSIONS: The presence of some SNPs involved in DNA repair or response to oxidative stress seem to be able to predict late toxicity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01316328.

IsoBED: a tool for automatic calculation of biologically equivalent fractionation schedules in radiotherapy using IMRT with a simultaneous integrated boost (SIB) technique.

BACKGROUND: An advantage of the Intensity Modulated Radiotherapy (IMRT) technique is the feasibility to deliver different therapeutic dose levels to PTVs in a single treatment session using the Simultaneous Integrated Boost (SIB) technique. The paper aims to describe an automated tool to calculate the dose to be delivered with the SIB-IMRT technique in different anatomical regions that have the same Biological Equivalent Dose (BED), i.e. IsoBED, compared to the standard fractionation. METHODS: Based on the Linear Quadratic Model (LQM), we developed software that allows treatment schedules, biologically equivalent to standard fractionations, to be calculated. The main radiobiological parameters from literature are included in a database inside the software, which can be updated according to the clinical experience of each Institute. In particular, the BED to each target volume will be computed based on the alpha/beta ratio, total dose and the dose per fraction (generally 2 Gy for a standard fractionation). Then, after selecting the reference target, i.e. the PTV that controls the fractionation, a new total dose and dose per fraction providing the same isoBED will be calculated for each target volume. RESULTS: The IsoBED Software developed allows: 1) the calculation of new IsoBED treatment schedules derived from standard prescriptions and based on LQM, 2) the conversion of the dose-volume histograms (DVHs) for each Target and OAR to a nominal standard dose at 2Gy per fraction in order to be shown together with the DV-constraints from literature, based on the LQM and radiobiological parameters, and 3) the calculation of Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) curve versus the prescribed dose to the reference target.

A novel dose constraint to reduce xerostomia in head-and-neck cancer patients treated with intensity-modulated radiotherapy.

PURPOSE: To investigate the predictors of incidence and duration of xerostomia (XT) based on parotid glands (PG), submandibular glands (SMG), and both glands taken as a whole organ (TG) in head-and-neck cancer patients treated with intensity-modulated radiotherapy. METHODS AND MATERIALS: A prospective study was initiated in May 2003. Sixty-three head-and-neck patients (44 with nasopharynx cancer) were included in the analysis. Using the dose-volume histogram the PG, SMG, and TG mean doses were calculated. Unstimulated and stimulated salivary flow were measured and XT-related questionnaires were compiled before and at 3, 6, 12, 18, and 24 months after radiotherapy. Salivary gland toxicity was evaluated using the Radiation Therapy Oncology Group scale, and Grade >or=3 toxicity was used as the endpoint. The XT incidence was investigated according to descriptive statistics and univariate and multivariate analysis. The Bonferroni method was used for multiple comparison adjustment. RESULTS: After a reduced flow at 3 months after radiotherapy, recovery of salivary flow was observed over time. Primary site and salivary gland mean doses and volumes were identified in univariate analysis as prognostic factors. Multivariate analysis confirmed that TG mean dose (p = 0.00066) and pretreatment stimulated salivary flow (p = 0.00420) are independent factors for predicting XT. CONCLUSION: The TG mean dose correlates with XT as assessed by Radiation Therapy Oncology Group criteria, salivary output, and XT-related questionnaires. Our results suggest that TG mean dose is a candidate dose constraint for reducing XT, requiring considerably more validation in non-nasopharyngeal cancer patients.