Oxygen Enhancement Research Articles

Electrical Properties of Li+-Substituted Solid Solutions Based on Gd2Zr2O7

Solid solution {text{G}}{{{text{d}}}_{{2 - x}}}{text{L}}{{{text{i}}}_{x}}{text{Z}}{{{text{r}}}_{2}}{{{text{O}}}_{{7 - x}}} with a pyrochlore structure is synthesized for the first time. The cationic composition is confirmed via chemical analysis and nuclear reactions. It is found that the stoichiometry with respect to lithium is retained up to 1100°C. The lattice parameter diminishes in the homogeneity range 0 ≤ x ≤ 0.30, while the free volume of migration grows. Introducing lithium into the Gd sublattice raises oxygen–ion conductivity, due to the emergence of oxygen vacancies and enhancement of their mobility. Maximum conductivity is reached for composition with х = 0.10 (~1 × 10−3 Ω−1 cm−1, 650°C). An assumption is made about the formation of associates of the type {{{ {text{Li}}_{{{text{Gd}}}}^{{''}} cdot {text{V}}_{{text{o}}}^{{ bullet bullet }}} }^{ times }} at high contents of the dopant (x = 0.30), accompanied by an increase in the activation energy of conductivity.

Performance Evaluation of PDMS or PEBAX-Coated Polyetherimide Membrane for Oxygen/Nitrogen Separation

Since the industrial revolution era, the Earth was suffering from serious air pollution. Millions of people are now suffering from indoor air pollution related diseases, especially in the industrialized countries such as China. One method to improve the indoor air quality is by oxygen enhancement. Membrane technology has been a key research over the past decades due to its low energy usage, minimum chemical consumption as well as small setting up layout. In this study, polyetherimide (PEI) membranes coated with polydimethylsiloxane (PDMS) or poly(ether block amide) (PEBAX) at different concentration (1, 3 or 5 wt%) were used to evaluate the oxygen/nitrogen gas separation. Prior to the gas permeation study, the membranes were characterized using scanning electron microscope (SEM) for morphology observation and surface elemental analysis by energy dispersive X-ray spectroscope (EDX). The morphology of the self-fabricated PEI membranes is composed of a thin and dense structure supported by the finger-like structure. The results obtained from oxygen/nitrogen separation studies shows membrane coated with 3 wt% PDMS yield a good separation results, exhibiting an improvement of oxygen and nitrogen permeance by 28.2% and 24.9%, selectivity by 10.4% (up to 5.08) relative to the base PEI membrane. Meanwhile, the 3 wt% PEBAX-coated PEI membrane only achieved selectivity of 3.56. The PDMS-coated PEI membrane yield a better separation performance attributed to the fact that PDMS coating on the hollow fiber membrane improve the surface morphology by reducing the defects.

B-Mg co-doping behavior of LiFePO4 cathode material: balance of oxygen vacancy and enhancement of electrochemical performance

B-Mg co-doping behavior of LiFePO4 cathode material: balance of oxygen vacancy and enhancement of electrochemical performance

A Modified Lethal and Potentially Lethal Model With Explicit Oxygen Tension Dependence for FLASH RT

To modify Curtis Lethal and Potentially Lethal (LPL) model to extend it from conventional (CONV) to ultra-high dose rate (FLASH) Radiotherapy (RT) domain with explicit intracellular oxygen tension dependence.After combining radiation-induced oxygen depletion, oxygen fixation hypothesis, and the Oxygen Enhancement Ratio (OER) concept, we incorporate intracellular oxygen tension dependence into the coefficients of the ordinary differential equations describing the original Curtis LPL model. Two biochemical pre-lesion states for the LPL lesions are amended into the model to explain the oxygen post-effect on the cell radiation survival fraction (SF). We perform analytical and numerical analyses for the solutions of the average numbers of LPL lesions. Using Poisson statistics, we can use the average number of LPL lesions to predict the cell SF for FLASH RT.Our modified LPL model maintains all original LPL model characteristics at fixed intracellular oxygen tension. For variable intracellular oxygen tensions, our new model extends prediction capabilities to FLASH RT. The comparisons of the two models are summarized below: CONCLUSION: Our modified LPL model has the potential to explain the observed FLASH phenomena, i.e., FLASH RT provides better normal tissue sparing while maintaining similar tumor control compared with CONV RT. Future studies are necessary to quantitatively validate our model predictions in systematically conducted FLASH irradiation experiments.

Assessment of Lung Structure and Regional Function Using 0.55 T MRI in Patients With Lymphangioleiomyomatosis.

Contemporary lower-field magnetic resonance imaging (MRI) may offer advantages for lung imaging by virtue of the improved field homogeneity. The aim of this study was to evaluate the utility of lower-field MRI for combined morphologic imaging and regional lung function assessment. We evaluate low-field MRI in patients with lymphangioleiomyomatosis (LAM), a rare lung disease associated with parenchymal cysts and respiratory failure. We performed lung imaging on a prototype low-field (0.55 T) MRI system in 65 patients with LAM. T2-weighted imaging was used for assessment of lung morphology and to derive cyst scores, the percent of lung parenchyma occupied by cysts. Regional lung function was assessed using oxygen-enhanced MRI with breath-held ultrashort echo time imaging and inhaled 100% oxygen as a T1-shortening MR contrast agent. Measurements of percent signal enhancement from oxygen inhalation and percentage of lung with low oxygen enhancement, indicating functional deficits, were correlated with global pulmonary function test measurements taken within 2 days. We were able to image cystic abnormalities using T2-weighted MRI in this patient population and calculate cyst score with strong correlation to computed tomography measurements (R = 0.86, P < 0.0001). Oxygen-enhancement maps demonstrated regional deficits in lung function of patients with LAM. Heterogeneity of oxygen enhancement between cysts was observed within individual patients. The percent low-enhancement regions showed modest, but significant, correlation with FEV1 (R = -0.37, P = 0.007), FEV1/FVC (R = -0.33, P = 0.02), and cyst score (R = 0.40, P = 0.02). The measured arterial blood ΔT1 between normoxia and hyperoxia, used as a surrogate for dissolved oxygen in blood, correlated with DLCO (R = -0.28, P = 0.03). Using high-performance 0.55 T MRI, we were able to perform simultaneous imaging of pulmonary structure and regional function in patients with LAM.

Adaptation of stochastic microdosimetric kinetic model to hypoxia for hypo-fractionated multi-ion therapy treatment planning

For hypo-fractionated multi-ion therapy (HFMIT), the stochastic microdosimetric kinetic (SMK) model had been developed to estimate the biological effectiveness of radiation beams with wide linear energy transfer (LET) and dose ranges. The HFMIT will be applied to radioresistant tumors with oxygen-deficient regions. The response of cells to radiation is strongly dependent on the oxygen condition in addition to radiation type, LET and absorbed dose. This study presents an adaptation of the SMK model to account for oxygen-pressure dependent cell responses, and develops the oxygen-effect-incorporated stochastic microdosimetric kinetic (OSMK) model. In the model, following assumptions were made: the numbers of radiation-induced sublethal lesions (double-strand breaks) are reduced due to lack of oxygen, and the numbers of oxygen-mediated lesions are reduced for radiation with high LET. The model parameters were determined by fitting survival data under aerobic and anoxic conditions for human salivary gland tumor cells and V79 cells exposed to helium-, carbon-, and neon-ion beams over the LET range of 18.5–654.0 keV μm−1. The OSMK model provided good agreement with the experimental survival data of the cells with determination coefficients >0.9. In terms of oxygen enhancement ratio, the OSMK model reproduced the experimental data behavior, including slight dependence on particle type at the same LET. The OSMK model was then implemented into the in-house treatment planning software for the HFMIT to validate its applicability in clinical practice. A treatment plan with helium- and neon-ion beams was made for a pancreatic cancer case assuming an oxygen-deficient region within the tumor. The biological optimization based on the OSMK model preferentially placed the neon-ion beam to the hypoxic region, while it placed both helium- and neon-ion beams to the surrounding normoxic region. The OSMK model offered the accuracy and usability required for hypoxia-based biological optimization in HFMIT treatment planning.

Investigating the potential of proton therapy for hypoxia-targeted dose escalation in non-small cell lung cancer

BackgroundHypoxia is known to be prevalent in solid tumors such as non-small cell lung cancer (NSCLC) and reportedly correlates with poor prognostic clinical outcome. PET imaging can provide in-vivo hypoxia measurements to support targeted radiotherapy treatment planning. We explore the potential of proton therapy in performing patient-specific dose escalation and compare it with photon volumetric modulated arc therapy (VMAT).MethodsDose escalation has been calibrated to the patient specific tumor response of ten stage IIb-IIIb NSCLC patients by combining HX4-PET imaging and radiobiological modelling of oxygen enhancement ratio (OER) to target variable tumor hypoxia. In a dose-escalation-by-contour approach, escalated dose levels were simulated to the most hypoxic region of the primary target and its effectiveness in improving loco-regional tumor control was assessed. Furthermore, the impact on normal tissue of proton treatments including dose escalation was evaluated in comparison to the normal tissue complication probability (NTCP) of conventional VMAT plans.ResultsIgnoring regions of tumor hypoxia can cause overestimation of TCP values by up to 10%, which can effectively be recovered on average to within 0.9% of the nominal TCP, using patient-specific dose escalations of up to 22% of the prescribed dose to PET defined hypoxic regions. Despite such dose escalations, the use of protons could also simultaneously reduce mean doses to the heart (− 14.3 GyRBE), lung (− 8.3 GyRBE), esophagus (− 6.9 GyRBE) and spinal cord (− 3.8 Gy) compared to non-escalated VMAT plans. These reductions are predicted to lead to clinically relevant decreases in NTCP for radiation-induced pneumonitis (− 11.3%), high grade heart toxicity (− 7.4%) and esophagitis (− 7.5%).ConclusionsThis study suggests that the administration of proton therapy for dose escalation to patient specific regions of tumor hypoxia in the treatment of NSCLC can mitigate TCP reduction due to hypoxia-induced radio resistance, while simultaneously reducing NTCP levels even when compared to non-escalated treatments delivered with state-of-the-art photon techniques.

Simulated dose painting of hypoxic sub-volumes in pancreatic cancer stereotactic body radiotherapy

Dose painting of hypoxic tumour sub-volumes using positron-emission tomography (PET) has been shown to improve tumour control in silico in several sites, predominantly head and neck and lung cancers. Pancreatic cancer presents a more stringent challenge, given its proximity to critical gastro-intestinal organs-at-risk (OARs), anatomic motion, and impediments to reliable PET hypoxia quantification. A radiobiological model was developed to estimate clonogen survival fraction (SF), using 18F-fluoroazomycin arabinoside PET (FAZA PET) images from ten patients with unresectable pancreatic ductal adenocarcinoma to quantify oxygen enhancement effects. For each patient, four simulated five-fraction stereotactic body radiotherapy (SBRT) plans were generated: (1) a standard SBRT plan aiming to cover the planning target volume with 40 Gy, (2) dose painting plans delivering escalated doses to a maximum of three FAZA-avid hypoxic sub-volumes, (3) dose painting plans with simulated spacer separating the duodenum and pancreatic head, and (4), plans with integrated boosts to geometric contractions of the gross tumour volume (GTV). All plans saturated at least one OAR dose limit. SF was calculated for each plan and sensitivity of SF to simulated hypoxia quantification errors was evaluated. Dose painting resulted in a 55% reduction in SF as compared to standard SBRT; 78% with spacer. Integrated boosts to hypoxia-blind geometric contractions resulted in a 41% reduction in SF. The reduction in SF for dose-painting plans persisted for all hypoxia quantification parameters studied, including registration and rigid motion errors that resulted in shifts and rotations of the GTV and hypoxic sub-volumes by as much as 1 cm and 10 degrees. Although proximity to OARs ultimately limited dose escalation, with estimated SFs (∼10−5) well above levels required to completely ablate a ∼10 cm3 tumour, dose painting robustly reduced clonogen survival when accounting for expected treatment and imaging uncertainties and thus, may improve local response and associated morbidity.

In silico simulation of the effect of hypoxia on MCF-7 cell cycle kinetics under fractionated radiotherapy.

The treatment outcome of a given fractionated radiotherapy scheme is affected by oxygen tension and cell cycle kinetics of the tumor population. Numerous experimental studies have supported the variability of radiosensitivity with cell cycle phase. Oxygen modulates the radiosensitivity through hypoxia-inducible factor (HIF) stabilization and oxygen fixation hypothesis (OFH) mechanism. In this study, an existing mathematical model describing cell cycle kinetics was modified to include the oxygen-dependent G1/S transition rate and radiation inactivation rate. The radiation inactivation rate used was derived from the linear-quadratic (LQ) model with dependence on oxygen enhancement ratio (OER), while the oxygen-dependent correction for the G1/S phase transition was obtained from numerically solving the ODE system of cyclin D-HIF dynamics at different oxygen tensions. The corresponding cell cycle phase fractions of aerated MCF-7 tumor population, and the resulting growth curve obtained from numerically solving the developed mathematical model were found to be comparable to experimental data. Two breast radiotherapy fractionation schemes were investigated using the mathematical model. Results show that hypoxia causes the tumor to be more predominated by the tumor subpopulation in the G1 phase and decrease the fractional contribution of the more radioresistant tumor cells in the S phase. However, the advantage provided by hypoxia in terms of cell cycle phase distribution is largely offset by the radioresistance developed through OFH. The delayed proliferation caused by severe hypoxia slightly improves the radiotherapy efficacy compared to that with mild hypoxia for a high overall treatment duration as demonstrated in the 40-Gy fractionation scheme.

Excitation of helical shape argon atmospheric pressure plasma jet using RF pulse modulation

The article reports the excitation of a helical argon atmospheric pressure plasma jet using a pulse-modulated 13.56 MHz radio frequency (RF) power source. This helical structure is observed in open ambient air, which is far different from the conventional conical shape. This helical structure originates due to the periodic pressure variation in the discharge region caused by pulse-modulated RF (2 kHz modulation frequency) and propagates downstream into the ambient air. The geometrical characteristics of the observed structure are explored using optical imaging. Moreover, the influence of various input parameters, viz., duty cycle, gas flow rate, and RF power, of the modulated pulse on the formation of a helical structure are studied. These helical structures have an implication on the plasma jet chemical features (enhancement of reactive oxygen and nitrogen species) as these are involved in an increase in air entrainment into the ionization region desired for various plasma applications.

Tumor Modeling and Microwave Heating for Increasing Oxygen in Tumors during Photodynamic Therapy

Tumor destruction due to Photodynamic Therapy (PDT) is mainly governed by the amount of molecular oxygen present in the tumor. Oxygen is one of the rate-limiting factors in PDT. This rate-limiting factor always makes PDT a lengthy process, as it necessitates interruption in treatment in order to restore the depleted oxygen levels to normal range. In this paper, a microwave (MW) heating technique is proposed as a mechanism to elevate the local tissue temperature for oxygen enhancement.

Incorporating oxygenation levels in analytical DNA-damage models—quantifying the oxygen fixation mechanism

Purpose. To develop a framework to include oxygenation effects in radiation therapy treatment planning which is valid for all modalities, energy spectra and oxygen levels. The framework is based on predicting the difference in DNA-damage resulting from ionising radiation at variable oxygenation levels. Methods. Oxygen fixation is treated as a statistical process in a simplified model of complex and simple damage. We show that a linear transformation of the microscopic oxygen fixation process allows to extend this to all energies and modalities, resulting in a relatively simple rational polynomial expression. The model is expanded such that it can be applied for polyenergetic beams. The methodology is validated using Microdosimetric Monte Carlo Damage Simulation code (MCDS). This serves as a bootstrap to determine relevant parameters in the analytical expression, as MCDS is shown to be extensively verified with published empirical data. Double-strand break induction as calculated by this methodology is compared to published proton experiments. Finally, an example is worked out where the oxygen enhancement ratio (OER) is calculated at different positions in a clinically relevant spread out Bragg peak (SOBP) dose deposition in water. This dose deposition is obtained using a general Monte Carlo code (FLUKA) to determine dose deposition and locate fluence spectra. Results. For all modalities (electrons, protons), the damage categorised as complex could be parameterised to within 0.3% of the value calculated using microdosimetric Monte Carlo. The proton beam implementation showed some variation in OERs which differed slightly depending on where the assessment was made; before the SOBP, mid-SOBP or at the distal edge. Environment oxygenation was seen to be the more important variable. Conclusions. An analytic expression calculating complex damage depending on modality, energy spectrum, and oxygenation levels was shown to be effective and can be readily incorporated in treatment planning software, to take into account the impact of variable oxygenation, forming a first step to an optimised treatment based on biological factors.

Insight into the Improvement Effect of Nitrogen Dopant in Ag/Co3O4 Nanocubes for Soot Oxidation: Experimental and Theoretical Studies

Different doping amounts of N-doped Ag/Co3O4 nanocubes were synthesized for the first time for catalytic soot oxidation. The N-doped sample exhibited remarkably improved catalytic activity, of which the maximum decrease in temperature for 90% soot conversion was almost 40 ℃. Characterization results analyzed by TEM, XPS, EPR, H2-TPR, O2-TPD, etc. revealed that the incorporation of N atoms can alter the electronic structure, leading to the generation of more oxygen vacancies and enhancement of lattice oxygen mobility. Meanwhile, larger surface area, rugged morphology and promoted reducibility also contribute to the performance improvement. DFT calculations on the differential charge density, Gibbs free energy, etc. were performed to investigate the intrinsic reasons on an atomic level. Due to the relatively higher electronegativity, N dopant could be an electron-appealing center to promote efficient electron transfer, resulting in the redistribution of charge density and formation of conductive Co–N bonds. This variation in electronic structure favors lowering the formation energy of oxygen vacancies and facilitating the activation of the lattice oxygen originated from the highly hybridized Co–O bonds, which ultimately reduces the activation barriers for reactants/intermediates and accelerates the reaction kinetics. This study evidenced that N doping could be an effective strategy to promote catalytic soot oxidation.

May oxygen depletion explain the FLASH effect? A chemical track structure analysis

Background and purposeRecent observations in animal models show that ultra-high dose rate (“FLASH”) radiation treatment significantly reduces normal tissue toxicity maintaining an equivalent tumor control. The dependence of this “FLASH” effect on target oxygenation has led to the assumption that oxygen “depletion” could be its major driving force. Materials and MethodsIn a bottom-up approach starting from the chemical track evolution of 1 MeV electrons in oxygenated water simulated with the TRAX-CHEM Monte Carlo code, we determine the oxygen consumption and radiolytic reactive oxygen species production following a short radiation pulse. Based on these values, the effective dose weighted by oxygen enhancement ratio (OER) or the in vitro cell survival under dynamic oxygen pressure is calculated and compared to that of conventional exposures, at constant OER. ResultsWe find an excellent agreement of our Monte Carlo predictions with the experimental value for radiolytic oxygen removal from oxygenated water. However, the application of the present model to published radiobiological experiment conditions shows that oxygen depletion can only have a negligible impact on radiosensitivity through oxygen enhancement, especially at typical experimental oxygenations where a FLASH effect has been observed. ConclusionWe show that the magnitude and dependence of the “oxygen depletion” hypothesis are not consistent with the observed biological effects of FLASH irradiation. While oxygenation plays an undoubted role in mediating the FLASH effect, we conclude that state-of-the-art radiation chemistry models do not support oxygen depletion and radiation-induced transient hypoxia as the main mechanism.

Technological Advances in Charged-Particle Therapy.

Charted-particle therapy (CPT) benefits cancer patients by localizing doses in the tumor volume while minimizing the doses delivered to normal tissue through its unique physical and biological characteristics. The world’s first CPT applied on humans was proton beam therapy (PBT), which was performed in the mid-1950s. Among heavy ions, carbon ions showed the most favorable biological characteristics for the treatment of cancer patients. Carbon ions show coincidence between the Bragg peak and maximum value of relative biological effectiveness. In addition, they show low oxygen enhancement ratios. Therefore, carbon-ion radiotherapy (CIRT) has become mainstream in the treatment of cancer patients using heavy ions. CIRT was first performed in 1977 at the Lawrence Berkeley Laboratory. The CPT technology has advanced in the intervening decades, enabling the use of rotating gantry, beam delivery with fast pencil-beam scanning, image-guided particle therapy, and intensity-modulated particle therapy. As a result, as of 2019, a total of 222,425 and 34,138 patients with cancer had been treated globally with PBT and CIRT, respectively. For more effective and efficient CPT, many groups are currently conducting further studies worldwide. This review summarizes recent technological advances that facilitate clinical use of CPT.

Convection enhanced delivery of light responsive antigen capturing oxygen generators for chemo-phototherapy triggered adaptive immunity

In recent years, combination therapy has emerged as the cornerstone of clinical practice in treating glioblastoma multiforme. However, their ability to trigger and leverage the body's adaptive immunity has rarely been studied. Tumour heterogeneity, the presence of the blood-brain barrier, and an immunosuppressive tumor microenvironment play a crucial role in the 90% local tumor recurrence post-treatment. Herein, we report an improved combination therapy approach capable of stimulating an immune response that utilizes Light responsive antigen-capturing oxygen generators (LAGs). The engineered LAGs loaded with a non-genotoxic molecule, Nutlin-3a, and a photosensitizer, Protoporphyrin IX, can release the payload on-demand when exposed to light of a specific wavelength. The in-situ oxygen generation capability of LAGs enables tumor oxygenation enhancement, thereby alleviating the tumor hypoxia and enhancing the efficacy of chemo-photodynamic therapy. Furthermore, by modulating the surface properties of LAGs, we demonstrated that the tumor-derived protein antigens released can be captured and retained in-situ, which improves antigen uptake and presentation by the antigen-presenting cells. Dual drug-loaded LAGs (DD-LAGs) upregulated the expression of cell surface CD83 maturation and CD86 costimulatory markers on monocyte-derived-dendritic cells, suggesting intrinsic immune adjuvancy. In the presence of 3D printed hypoxic U87 spheroids (h-U87), DD-LAGs induced cancer cell death, upregulated IL-1β, and downregulated IL-10 resulting in CD3+, helper CD4+, and cytotoxic CD8+ proliferation. Finally, we have investigated convection-enhanced delivery as a potential route of administration for DD-LAGs. Our work presents a novel strategy to induce tumor cell death both during and post-treatment, thereby reducing the possibility of recurrence.

Impact of Hypoxia on Relative Biological Effectiveness and Oxygen Enhancement Ratio for a 62-MeV Therapeutic Proton Beam.

Simple SummaryThis study presents an algorithm to estimate the relative biological effectiveness (RBE) for cell survival under hypoxic conditions using the repair-misrepair-fixation model. The study finds that the RBE values are in the range of 1.0–3.0 for the linear energy transfer equal to 1.1 to 22.6 keV/μm under aerobic condition (21% O2) and further increase to the range of 1.1–4.4 under severe hypoxia (0.1% O2). This study uses the yields of double-strand breaks (DSBs) to determine the relative biological effectiveness (RBE) of proton beams, using cell survival as a biological endpoint. DSB induction is determined when cells locate at different depths (6 positions) along the track of 62 MeV proton beams. The DNA damage yields are estimated using Monte Carlo Damage Simulation (MCDS) software. The repair outcomes are estimated using Monte Carlo excision repair (MCER) simulations. The RBE for cell survival at different oxygen concentrations is calculated using the repair-misrepair-fixation (RMF) model. Using 60Co γ-rays (linear energy transfer (LET) = 2.4 keV/μm) as the reference radiation, the RBE for DSB induction and enzymatic DSB under aerobic condition (21% O2) are in the range 1.0–1.5 and 1.0–1.6 along the track depth, respectively. In accord with RBE obtained from experimental data, RMF model-derived RBE values for cell survival are in the range of 1.0–3.0. The oxygen enhancement ratio (OER) for cell survival (10%) decreases from 3.0 to 2.5 as LET increases from 1.1 to 22.6 keV/μm. The RBE values for severe hypoxia (0.1% O2) are in the range of 1.1–4.4 as LET increases, indicating greater contributions of direct effects for protons. Compared with photon therapy, the overall effect of 62 MeV proton beams results in greater cell death and is further intensified under hypoxic conditions.

Tumor control probability in hypofractionated radiotherapy as a function of total and hypoxic tumor volumes

Clinical studies in the hypofractionated stereotactic body radiotherapy (SBRT) have shown a reduction in the probability of local tumor control with increasing initial tumor volume. In our earlier work, we obtained and tested an analytical dependence of the tumor control probability (TCP) on the total and hypoxic tumor volumes using conventional radiotherapy model with the linear-quadratic (LQ) cell survival. In this work, this approach is further refined and tested against clinical observations for hypofractionated radiotherapy treatment schedules. Compared to radiotherapy with conventional fractionation schedules, simulations of hypofractionated radiotherapy may require different models for cell survival and the oxygen enhancement ratio (OER). Our TCP simulations in hypofractionated radiotherapy are based on the LQ model and the universal survival curve (USC) developed for the high doses used in SBRT. The predicted trends in local control as a function of the initial tumor volume were evaluated in SBRT for non-small cell lung cancer (NSCLC). Our results show that both LQ and USC based models cannot describe the TCP reduction for larger tumor volumes observed in the clinical studies if the tumor is considered completely oxygenated. The TCP calculations are in agreement with the clinical data if the subpopulation of radio-resistant hypoxic cells is considered with the volume that increases as initial tumor volume increases. There are two conclusions which follow from our simulations. First, the extent of hypoxia is likely a primary reason of the TCP reduction with increasing the initial tumor volume in SBRT for NSCLC. Second, the LQ model can be an acceptable approximation for the TCP calculations in hypofractionated radiotherapy if the tumor response is defined primarily by the hypoxic fraction. The larger value of OER in the hypofractionated radiotherapy compared to the conventional radiotherapy effectively extends the applicability of the LQ model to larger doses.

Monitoring Carbon Ion Beams Transverse Position Detecting Charged Secondary Fragments: Results From Patient Treatment Performed at CNAO.

Particle therapy in which deep seated tumours are treated using 12C ions (Carbon Ions RadioTherapy or CIRT) exploits the high conformity in the dose release, the high relative biological effectiveness and low oxygen enhancement ratio of such projectiles. The advantages of CIRT are driving a rapid increase in the number of centres that are trying to implement such technique. To fully profit from the ballistic precision achievable in delivering the dose to the target volume an online range verification system would be needed, but currently missing. The 12C ions beams range could only be monitored by looking at the secondary radiation emitted by the primary beam interaction with the patient tissues and no technical solution capable of the needed precision has been adopted in the clinical centres yet. The detection of charged secondary fragments, mainly protons, emitted by the patient is a promising approach, and is currently being explored in clinical trials at CNAO. Charged particles are easy to detect and can be back-tracked to the emission point with high efficiency in an almost background-free environment. These fragments are the product of projectiles fragmentation, and are hence mainly produced along the beam path inside the patient. This experimental signature can be used to monitor the beam position in the plane orthogonal to its flight direction, providing an online feedback to the beam transverse position monitor chambers used in the clinical centres. This information could be used to cross-check, validate and calibrate, whenever needed, the information provided by the ion chambers already implemented in most clinical centres as beam control detectors. In this paper we study the feasibility of such strategy in the clinical routine, analysing the data collected during the clinical trial performed at the CNAO facility on patients treated using 12C ions and monitored using the Dose Profiler (DP) detector developed within the INSIDE project. On the basis of the data collected monitoring three patients, the technique potential and limitations will be discussed.

Non-Homogeneous Tumor Growth and Its Implications for Radiotherapy: A Phenomenological Approach.

Tumor regrowth and heterogeneity are important clinical parameters during radiotherapy, and the probability of treatment benefit critically depends on the tumor progression pattern in the interval between the fractional irradiation treatments. We propose an analytic, easy-to-use method to take into account clonal subpopulations with different specific growth rates and radiation resistances. The different strain regrowth effects, as described by Gompertz law, require a dose-boost to reproduce the survival probability of the corresponding homogeneous system and for uniform irradiation. However, the estimate of the survival fraction for a tumor with a hypoxic subpopulation is more reliable when there is a slow specific regrowth rate and when the dependence on the oxygen enhancement ratio of radiotherapy is consistently taken into account. The approach is discussed for non-linear two-population dynamics for breast cancer and can be easily generalized to a larger number of components and different tumor phenotypes.