Linear Energy Transfer Values Research Articles

Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes.

The effect of carbon ion radiotherapy on hypoxic tumors has recently been questioned because of low linear energy transfer (LET) values in the spread-out Bragg peak (SOBP). The aim of this study was to investigate the role of hypoxia and local oxygenation changes (LOCs) in fractionated carbon ion radiotherapy. Three-dimensional tumors with hypoxic subvolumes were simulated assuming interfraction LOCs. Different fractionations were applied using a clinically relevant treatment plan with a known LET distribution. The surviving fraction was calculated, taking oxygen tension, dose and LET into account, using the repairable–conditionally repairable (RCR) damage model with parameters for human salivary gland tumor cells. The clinical oxygen enhancement ratio (OER) was defined as the ratio of doses required for a tumor control probability of 50% for hypoxic and well-oxygenated tumors. The resulting OER was well above unity for all fractionations. For the hypoxic tumor, the tumor control probability was considerably higher if LOCs were assumed, rather than static oxygenation. The beneficial effect of LOCs increased with the number of fractions. However, for very low fraction doses, the improvement related to LOCs did not compensate for the increase in total dose required for tumor control. In conclusion, our results suggest that hypoxia can influence the outcome of carbon ion radiotherapy because of the non-negligible oxygen effect at the low LETs in the SOBP. However, if LOCs occur, a relatively high level of tumor control probability is achievable with a large range of fractionation schedules for tumors with hypoxic subvolumes, but both hyperfractionation and hypofractionation should be pursued with caution.

Analysis of single-event upset of magnetic tunnel junction used in spintronic circuits caused by radiation-induced current

This paper describes the possibility of a switching upset of a magnetic tunnel junction (MTJ) caused by a terrestrial radiation-induced single-event-upset (SEU) current in spintronic integrated circuits. The current waveforms were simulated by using a 3-D device simulator in a basic circuit including MTJs designed using 90-nm CMOS parameters and design rules. The waveforms have a 400 -μA peak and a 200-ps elapsed time when neutron particles with a linear energy transfer value of 14 MeV cm2/mg enter the silicon surface. The authors also found that the SEU current may cause soft errors with a probability of more than 10−12 per event, which was obtained by approximate solution of the ordinary differential equation of switching probability when the intrinsic critical current (IC0) became less than 30 μA.

Patterns of Failure After Proton Therapy in Medulloblastoma; Linear Energy Transfer Distributions and Relative Biological Effectiveness Associations for Relapses

The pattern of failure in medulloblastoma patients treated with proton radiation therapy is unknown. For this increasingly used modality, it is important to ensure that outcomes are comparable to those in modern photon series. It has been suggested this pattern may differ from photons because of variations in linear energy transfer (LET) and relative biological effectiveness (RBE). In addition, the use of matching fields for delivery of craniospinal irradiation (CSI) may influence patterns of relapse. Here we report the patterns of failure after the use of protons, compare it to that in the available photon literature, and determine the LET and RBE values in areas of recurrence. Retrospective review of patients with medulloblastoma treated with proton radiation therapy at Massachusetts General Hospital (MGH) between 2002 and 2011. We documented the locations of first relapse. Discrete failures were contoured on the original planning computed tomography scan. Monte Carlo calculation methods were used to estimate the proton LET distribution. Models were used to estimate RBE values based on the LET distributions. A total of 109 patients were followed for a median of 38.8 months (range, 1.4-119.2 months). Of the patients, 16 experienced relapse. Relapse involved the supratentorial compartment (n=8), spinal compartment (n=11), and posterior fossa (n=5). Eleven failures were isolated to a single compartment; 6 failures in the spine, 4 failures in the supratentorium, and 1 failure in the posterior fossa. The remaining patients had multiple sites of disease. One isolated spinal failure occurred at the spinal junction of 2 fields. None of the 70 patients treated with an involved-field-only boost failed in the posterior fossa outside of the tumor bed. We found no correlation between Monte Carlo-calculated LET distribution and regions of recurrence. The most common site of failure in patients treated with protons for medulloblastoma was outside of the posterior fossa. The most common site for isolated local failure was the spine. We recommend consideration of spinal imaging in follow-up and careful attention to dose distribution in the spinal junction regions. Development of techniques that do not require field matching may be of benefit. We did not identify a direct correlation between lower LET values and recurrence in medulloblastoma patients treated with proton therapy. Patterns of failure do not appear to differ from those in patients treated with photon therapy.

A 2D DNA Lattice as an Ultrasensitive Detector for Beta Radiations

There is growing demand for the development of efficient ultrasensitive radiation detectors to monitor the doses administered to individuals during therapeutic nuclear medicine which is often based on radiopharmaceuticals, especially those involving beta emitters. Recently biological materials are used in sensors in the nanobio disciplines due to their abilities to detect specific target materials or sites. Artificially designed two-dimensional (2D) DNA lattices grown on a substrate were analyzed after exposure to pure beta emitters, (90)Sr-(90)Y. We studied the Raman spectra and reflected intensities of DNA lattices at various distances from the source with different exposure times. Although beta particles have very low linear energy transfer values, the significant physical and chemical changes observed throughout the extremely thin, ∼0.6 nm, DNA lattices suggested the feasibility of using them to develop ultrasensitive detectors of beta radiations.

Calculation of single event upset based on Monte Carlo and device simulations

An extraction method for single event upset cross section based on Monte Carlo code and device simulation is proposed, which can be used to calculate single event effects and sensitive regions in memories accurately. Single event upset cross sections of domestic static random access memory (SRAM) and field programmatic gate array (FPGA) devices are calculated, and results agree well with these from heavy ion test. Simulation results reveal the physical mechanism of the relationship between single event upset sensitivity and surface area of off-state NMOSFET and PMOSFET. Sensitive regions of single event upset under different linear energy transfer (LET) values are obtained. The radial ionization profiles of heavy ions with different energy, but the same LET, are also calculated using the Monte Carlo method. The track radius of high-energy ion is significantly larger than that of low-energy ion, while the charge density at the track center of low-energy ion is higher by two or three orders of magnitude. With decreasing technology scaling, the impact of these differences on single event effects will be more pronounced, and the threshold LET and saturated cross-section will not be capable of describing the single event response completely.

Simulated microgravity increases heavy ion radiation-induced apoptosis in human B lymphoblasts

AimsMicrogravity and radiation, common in space, are the main factors influencing astronauts' health in space flight, but their combined effects on immune cells are extremely limited. Therefore, the effect of simulated microgravity on heavy ion radiation-induced apoptosis, and reactive oxygen species (ROS)-sensitive apoptosis signaling were investigated in human B lymphoblast HMy2.CIR cells. Main methodsSimulated microgravity was achieved using a Rotating Wall Vessel Bioreactor at 37°C for 30min. Heavy carbon-ion irradiation was carried out at 300MeV/u, with a linear energy transfer (LET) value of 30keV/μm and a dose rate of 1Gy/min. Cell survival was evaluated using the Trypan blue exclusion assay. Apoptosis was indicated by Annexin V/propidium iodide staining. ROS production was assessed by cytometry with a fluorescent probe dichlorofluorescein. Malondialdehyde was detected using a kit. Extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase phosphatase-1 (MKP-1) and caspase-3 activation were measured by immunoblotting. Key findingsSimulated microgravity decreased heavy ion radiation-induced cell survival and increased apoptosis in HMy2.CIR cells. It also amplified heavy ion radiation-elicited intracellular ROS generation, which induced ROS-sensitive ERK/MKP-1/caspase-3 activation in HMy2.CIR cells. The above phenomena could be reversed by the antioxidants N-acetyl cysteine (NAC) and quercetin. SignificanceThese results illustrated that simulated microgravity increased heavy ion radiation-induced cell apoptosis, mediated by a ROS-sensitive signal pathway in human B lymphoblasts. Further, the antioxidants NAC and quercetin, especially NAC, might be good candidate drugs for protecting astronauts' and space travelers' health and safety.

Technology Scaling Comparison of Flip-Flop Heavy-Ion Single-Event Upset Cross Sections

Heavy-ion experimental results from flip-flops in 180-nm to 28-nm bulk technologies are used to quantify single-event upset trends. The results show that as technologies scale, D flip-flop single-event upset cross sections decrease while redundant storage node flip-flops cross sections may stay the same or increase depending on the layout spacing of storage nodes. As technology feature sizes become smaller, D flip-flop single-event upset cross sections approach redundant storage node hardened flip-flops cross sections for particles with high linear energy transfer values. Experimental results show that redundant storage node designs provide > 100X improvement in single-event upset cross section over DFF for ion linear energy transfer values below 10 MeV-cm2/mg down to 28-nm feature sizes.

Angular dependence of multiple-bit upset response in static random access memories under heavy ion irradiation

Experimental evidence is presented relevant to the angular dependences of multiple-bit upset (MBU) rates and patterns in static random access memories (SRAMs) under heavy ion irradiation. The single event upset (SEU) cross sections under tilted ion strikes are overestimated by 23.9%–84.6%, compared with under normally incident ion with the equivalent linear energy transfer (LET) value of ∼ 41 MeV/(mg/cm2), which can be partially explained by the fact that the MBU rate for tilted ions of 30° is 8.5%–9.8% higher than for normally incident ions. While at a lower LET of ∼ 9.5 MeV/(mg/cm2), no clear discrepancy is observed. Moreover, since the ion trajectories at normal and tilted incidences are different, the predominant double-bit upset (DBU) patterns measured are different in both conditions. Those differences depend on the LET values of heavy ions and devices under test. Thus, effective LET method should be used carefully in ground-based testing of single event effects (SEE) sensitivity, especially in MBU-sensitive devices.

Influence of acute hypoxia and radiation quality on cell survival

To measure the effect of acute oxygen depletion on cell survival for different types of radiation, experiments have been performed using Chinese hamster ovary (CHO) cells and RAT-1 rat prostate cancer cells. A special chamber has been developed to perform irradiations under different levels of oxygenation. The oxygen concentrations used were normoxia (air), hypoxia (94.5% N2, 5% CO2, 0.5% O2) and anoxia (95% N2, 5% CO2). Cells were exposed to X-rays and to C-, N- or O-ions with linear energy transfer (LET) values ranging from 100–160 keV/µm. The oxygen enhancement ratio (OER) and relative biological effectiveness (RBE) values have been calculated from the measured clonogenic survival curves. For both cell lines, the X-ray OER depended on the survival level. For particle irradiation, OER was not dependent on the survival level but decreased with increasing LET. The RBE of CHO cells under oxic conditions reached a plateau for LET values above 100 keV/µm, while it was still increasing under anoxia. In conclusion, the results demonstrated that our chamber could be used to measure radiosensitivity under intermediate hypoxia. Measurements suggest that ions heavier than carbon could be of additional advantage in the irradiation, especially of radioresistant hypoxic tumor regions.

A novel nanometric DNA thin film as a sensor for alpha radiation.

The unexpected nuclear accidents have provided a challenge for scientists and engineers to develop sensitive detectors, especially for alpha radiation. Due to the high linear energy transfer value, sensors designed to detect such radiation require placement in close proximity to the radiation source. Here we report the morphological changes and optical responses of artificially designed DNA thin films in response to exposure to alpha radiation as observed by an atomic force microscope, a Raman and a reflectance spectroscopes. In addition, we discuss the feasibility of a DNA thin film as a radiation sensing material. The effect of alpha radiation exposure on the DNA thin film was evaluated as a function of distance from an 241Am source and exposure time. Significant reflected intensity changes of the exposed DNA thin film suggest that a thin film made of biomolecules can be one of promising candidates for the development of online radiation sensors.

Linear Energy Transfer-Guided Optimization in Intensity Modulated Proton Therapy: Feasibility Study and Clinical Potential

To investigate the feasibility and potential clinical benefit of linear energy transfer (LET) guided plan optimization in intensity modulated proton therapy (IMPT). A multicriteria optimization (MCO) module was used to generate a series of Pareto-optimal IMPT base plans (BPs), corresponding to defined objectives, for 5 patients with head-and-neck cancer and 2 with pancreatic cancer. A Monte Carlo platform was used to calculate dose and LET distributions for each BP. A custom-designed MCO navigation module allowed the user to interpolate between BPs to produce deliverable Pareto-optimal solutions. Differences among the BPs were evaluated for each patient, based on dose-volume and LET-volume histograms and 3-dimensional distributions. An LET-based relative biological effectiveness (RBE) model was used to evaluate the potential clinical benefit when navigating the space of Pareto-optimal BPs. The mean LET values for the target varied up to 30% among the BPs for the head-and-neck patients and up to 14% for the pancreatic cancer patients. Variations were more prominent in organs at risk (OARs), where mean LET values differed by a factor of up to 2 among the BPs for the same patient. An inverse relation between dose and LET distributions for the OARs was typically observed. Accounting for LET-dependent variable RBE values, a potential improvement on RBE-weighted dose of up to 40%, averaged over several structures under study, was noticed during MCO navigation. We present a novel strategy for optimizing proton therapy to maximize dose-averaged LET in tumor targets while simultaneously minimizing dose-averaged LET in normal tissue structures. MCO BPs show substantial LET variations, leading to potentially significant differences in RBE-weighted doses. Pareto-surface navigation, using both dose and LET distributions for guidance, provides the means for evaluating a large variety of deliverable plans and aids in identifying the clinically optimal solution.

TH‐A‐116‐02: Radiobiological Implications of Various Target and Beam Geometry Utilization in Treatment Planning for Intensity Modulated Proton Therapy

Purpose: To investigate how different target definition and beam utilization techniques in intensity modulated proton therapy (IMPT) treatment planning (TP) can influence the radiobiological effectiveness of a deliverable patient plan. Methods: Our multi‐criteria optimization (MCO) IMPT planning system (ASTROID) allows assigning separate target volume for each beam, such as in split target plans. For pediatric chordoma cases, a variety of target sub‐volumes (TSV) were generated by 4mm and 8mm uniform constriction of the original clinical target volume (CTV), and their subtraction from CTV and each other, forming a co‐centric shell structure arrangement. In addition to the original plan, utilizing three beams all assigned to the full CTV, five plans were optimized for the same beam angles but different assigned TSV combinations. To increase the degrees of freedom the original beams were duplicated to allow for TSVs to be assigned to multiple beam‐angles, having a total of up to 9 beams. All plans utilized all three beam angles and single dose prescription to CTV. Dose and linear energy transfer (LET) distributions were calculated by TOPAS (TOol for PArticle Simulation) Monte Carlo system and evaluated via dose‐and LET‐volume histograms and a relative biological effectiveness (RBE) model. Results: While dose variations for the CTV were negligible, mean LET value deviations of more than 30% were noticed among the different plans. For the organs at risk (OARs), variations in dosimetric, LET and RBE values were more prominent. The amount of variation among the plans seemed to be dependent on their volume and location relative to the target. Conclusion: We show that the definition of sub‐targets at the treatment plan optimization level may impact the biological effectiveness of proton treatments.

SU-E-T-47: Peak Temperature Ratio Analysis of TLD Glow Curves to Characterize Orthovoltage X-Rays in Terms of Their LET

Purpose: Investigate using the ratio of the two high temperature peaks (HTR) to analyze the glow curves of TLD700 to characterize orthovoltage x‐rays in terms of their linear energy transfer (LET) as well as well as their HVL. LET is related to relative biological effectiveness (RBE) and studies have demonstrated RBE values from 1.1 to 2 for orthovoltage x‐rays compared to megavoltage x‐rays which have implications for radiobiological studies. Methods: TLD700 chips.015cm and.038cm thick were irradiated to about 0.20 Gy with x‐rays with photon effective energies from 13 KeV to 6 MeV with an orthovoltage therapy unit, a linac and gamma rays from I‐125, Ir‐192 and Cs‐137 radioactive isotopes. The different thickness detectors are used to correct for possible self‐attenuation effects in the detectors at the lower energies. Since the 280 C high temperature peak is more sensitive to high LET radiation than the 210 C lower temperature peak, the ratio of the areas under the two temperature peaks for the TLDs irradiated to the different beam qualities normalized to the peak ratio for 6 MV is used to determine their HTR. These HTR values are compared to the calculated LET values obtained from the effective photon energies of the irradiations. Results: The data show that the HTR generally increases with decreasing photon energy from 1 for megavoltage x‐rays to 1.94 for 13 KeV x‐rays with a local maximum of 1.65 occurring at about 100 KeV. This dependence is similar to that of the calculated LET values which also exhibit a local maximum of 1.85 KeV/micron around 100 KeV. No measurable difference is observed for different thickness TLDs. Conclusion: The HTR analysis of the TLD glow curves provides another method to characterize orthovoltage x‐rays in terms of their LET that provides information on their biological effectiveness.

Liquid ionization chamber initial recombination dependence on LET for electrons and photons

The possibility of indirect measurements of linear energy transfer (LET) with a liquid ionization chamber (LIC) has been investigated by studying initial recombination losses at different applied voltages. A linear fit is made to the voltage–signal curve and the intersection point of the fit and the voltage-axis is shown to correlate with LET. The LIC applied voltages were 100–700 V, which corresponds to electric field strengths between 0.3 and 2.0 MV m–1. Several different photon and electron beams have been studied, and by using MCNPX™ the respective LET spectra have been determined. The beam qualities in this study were found to have a fluence averaged LET between 0.17 and 1.67 keV µm–1 and a corresponding dose averaged LET between 0.97 and 4.62 keV µm–1. For the experimental data in this study the linear fit method yields consistent results with respect to Monte Carlo simulated LET values. A calibration curve for LET determination is provided for the LIC used in the present work.

Chromosome aberrations in normal human fibroblasts analyzed in G0/G1 and G2/M phases after exposure in G0 to radiation with different linear energy transfer (LET)

We have studied the induction of chromosome aberrations in human fibroblasts exposed in G0/G1 to X-rays or heavy ions to study the influence of G1 cell cycle arrest. Confluent normal fibroblasts were exposed to X-rays or accelerated particles with different LET values and chromosome aberrations were investigated in the first G0/G1 and G2//M phase. The particles used here were 490MeV/nucleon Si, 500MeV/nucleon Fe, and 200MeV/nucleon Fe ions. Cells were subcultured 24h after exposure and premature chromosome condensation (PCC) was performed by fusion-induced method for analysis of G0/G1 cells, and chemically-induced method for analysis of G2 and metaphase cells. Chromosome damage was assessed in chromosomes 1 and 3 using whole chromosome fluorescence in situ hybridization (FISH). Cell cycle was analyzed by flow cytometry at different incubation times following subculture. After irradiation with 2Gy of high-LET particles, the yields of chromosome aberrations and fragments were significantly higher in G0/G1 phase than in G2/M phase, whereas similar yields of damage were measured in both phases after exposure to X-rays. In contrast, the yield of misrepair, assessed by the number of color junctions, was similar in the G0/G1 and G2/M phases after exposure to either X-rays or high-LET particles. The yields of chromosome aberrations, fragments, and color junctions in both the G0/G1 and the G2/M phases, increased with LET up to 200keV/μm, then decreased for 440keV/μm Fe particles. A good correlation was found between chromosome aberrations in both G0/G1 and G2/M cells and survival fractions after 2Gy of different LET radiations, although the slopes were steeper for the G0/G1 cells. Flow cytometry analysis indicated that high-LET particles induce more non cycling G0/G1 cells within 48h of subculture than X-rays, suggesting that chromosome aberrations scored at the G2/M phase may not accurately describe the true radiation effect.

Biodamage via shock waves initiated by irradiation with ions

Radiation damage following the ionising radiation of tissue has different scenarios and mechanisms depending on the projectiles or radiation modality. We investigate the radiation damage effects due to shock waves produced by ions. We analyse the strength of the shock wave capable of directly producing DNA strand breaks and, depending on the ion's linear energy transfer, estimate the radius from the ion's path, within which DNA damage by the shock wave mechanism is dominant. At much smaller values of linear energy transfer, the shock waves turn out to be instrumental in propagating reactive species formed close to the ion's path to large distances, successfully competing with diffusion.

Single event upset sensitivity of 45 nm FDSOI and SOI FinFET SRAM

In this work single event upset (SEU) sensitivity of 45 nm fully depleted silicon-on-insulator (FDSOI) static random access memory (SRAM) cell and that of SOI fin-shaped field-effect-transistor (FinFET) SRAM cell have been investigated by 3D TCAD simulations. The critical charges and SEU threshold linear energy transfer (LET) value of the two SRAM cells are consistent due to similar gate capacitance. The low electrical field and the high recombination rate account for the non-sensitivity to SEU in heavily doped drain region. Compared with FDSOI SRAM, SOI FinFET SRAM cell exhibits lower SEU sensitivity at the center of the gate. The smaller sensitive area in SOI FinFET SRAM cell may result in a smaller SEU saturation cross section than that of SOI FinFET SRAM.

The Relative Biologic Effectiveness versus Linear Energy Transfer Curve as a Cell Trait

The magnitude of biological response varies with different radiation types. Using Linear Energy Transfer (LET) to differentiate types of incident radiation beam, the Relative Biologic Effectiveness (RBE) as a function of LET (RBE-LET) was found to have a characteristic shape with a peak around LET values 100 - 200 eV/nm. This general feature is believed to be a property of the incident beam. Our systems engineering model, however, suggests that the shape of the RBE-LET curve is a cell trait, a property of the cell. Like any other trait, phenotypic variations result from interactions of the genes and their context. State-space block diagram of the differential equation model suggests the genes are those in the DNA double strand break (dsb) repair pathway; and the context is cellular stress responsing to DNA damage by both external stimuli and internal redox state. At a deeper level, the block diagram suggests cell using mathematical calculations in its decision-making when facing a stress signal. The MRN protein complex, in particular, may perform addition to count the degree of DNA twisting for the homeostatic regulation of DNA supercoiling. The ATM protein may act as a feedback amplifier.

Quenching correction for volumetric scintillation dosimetry of proton beams

Volumetric scintillation dosimetry has the potential to provide fast, high-resolution, three-dimensional radiation dosimetry. However, scintillators exhibit a nonlinear response at the high linear energy transfer (LET) values characteristic of proton Bragg peaks. The purpose of this study was to develop a quenching correction method for volumetric scintillation dosimetry of proton beams. Scintillation light from a miniature liquid scintillator detector was measured along the central axis of a 161.6 MeV proton pencil beam. Three-dimensional dose and LET distributions were calculated for 85.6, 100.9, 144.9 and 161.6 MeV beams using a validated Monte Carlo model. LET values were also calculated using an analytical formula. A least-squares fit to the data established the empirical parameters of a quenching correction model. The light distribution in a tank of liquid scintillator was measured with a CCD camera at all four beam energies. The quenching model and LET data were used to correct the measured light distribution. The calculated and measured Bragg peak heights agreed within ±3% for all energies except 85.6 MeV, where the agreement was within ±10%. The quality of the quenching correction was poorer for sharp low-energy Bragg peaks because of blurring and detector size effects. The corrections performed using analytical LET values resulted in doses within 1% of those obtained using Monte Carlo LET values. The proposed method can correct for quenching with sufficient accuracy for dosimetric purposes. The required LET values may be computed effectively using Monte Carlo or analytical methods. Future detectors should improve blurring correction methods and optimize the pixel size to improve accuracy for low-energy Bragg peaks.

Impact of variable RBE on proton fractionation

To explore the impact of variable proton relative biological effectiveness (RBE) on dose fractionation for clinically relevant situations. A generic RBE = 1.1 is generally used for isoeffect calculations, while experimental studies showed that proton RBE varies with tissue type, dose, and linear energy transfer (LET). An analytical expression for the LET and α∕β dependence of the linear-quadratic (LQ) model has been used for proton simulations in parallel with the assumption of a generic RBE = 1.1. Calculations have been performed for ranges of LET values and fractionation sensitivities to describe clinically relevant cases, such as the treatment of head and neck and prostate tumors. Isoeffect calculations were compared with predictions from a generic RBE value and reported clinical results. The generic RBE = 1.1 appears to be a reasonable estimate for the proton RBE of rapidly growing tissues irradiated with low LET radiation. However, the use of a variable RBE predicts larger differences for tissues with low α∕β (both tumor and normal) and at low doses per fraction. In some situations these differences may appear in contrast to the findings from photon studies highlighting the importance of accurate accounting for the radiobiological effectiveness of protons. Furthermore, the use of variable RBE leads to closer predictions to clinical results. The LET dependence of the RBE has a strong impact on the predicted effectiveness of fractionated proton radiotherapy. The magnitude of the effect is modulated by the fractionation sensitivity and the fractional dose indicating the need for accurate analyses both in the target and around it. Care should therefore be employed for changing clinical fractionation patterns or when analyzing results from clinical studies for this type of radiation.