Quasi-real-time range monitoring by in-beam PET: a case for 15O.

A fast and reliable range monitoring method is required to take full advantage of the high linear energy transfer provided by therapeutic ion beams like carbon and oxygen while minimizing damage to healthy tissue due to range uncertainties. Quasi-real-time range monitoring using in-beam positron emission tomography (PET) with therapeutic beams of positron-emitters of carbon and oxygen is a promising approach. The number of implanted ions and the time required for an unambiguous range verification are decisive factors for choosing a candidate isotope. An experimental study was performed at the FRS fragment-separator of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany, to investigate the evolution of positron annihilation activity profiles during the implantation of [Formula: see text]O and [Formula: see text]O ion beams in a PMMA phantom. The positron activity profile was imaged by a dual-panel version of a Siemens Biograph mCT PET scanner. Results from a similar experiment using ion beams of carbon positron-emitters [Formula: see text]C and [Formula: see text]C performed at the same experimental setup were used for comparison. Owing to their shorter half-lives, the number of implanted ions required for a precise positron annihilation activity peak determination is lower for [Formula: see text]C compared to [Formula: see text]C and likewise for [Formula: see text]O compared to [Formula: see text]O, but their lower production cross-sections make it difficult to produce them at therapeutically relevant intensities. With a similar production cross-section and a 10 times shorter half-life than [Formula: see text]C, [Formula: see text]O provides a faster conclusive positron annihilation activity peak position determination for a lower number of implanted ions compared to [Formula: see text]C. A figure of merit formulation was developed for the quantitative comparison of therapy-relevant positron-emitting beams in the context of quasi-real-time beam monitoring. In conclusion, this study demonstrates that among the positron emitters of carbon and oxygen, [Formula: see text]O is the most feasible candidate for quasi-real-time range monitoring by in-beam PET that can be produced at therapeutically relevant intensities. Additionally, this study demonstrated that the in-flight production and separation method can produce beams of therapeutic quality, in terms of purity, energy, and energy spread.

Production and separation of positron emitters for hadron therapy at FRS-Cave M.

The FRagment Separator FRS at GSI is a versatile spectrometer and separator for experiments with relativistic in-flight separated short-lived exotic beams. One branch of the FRS is connected to the target hall where the bio-medical cave (Cave M) is located. Recently a joint activity between the experimental groups of the FRS and the biophysics at the GSI and Department of physics at LMU was started to perform biomedical experiments relevant for hadron therapy with positron emitting carbon and oxygen beams. This paper presents the new ion-optical mode and commissioning results of the FRS-Cave M branch where positron emitting 15O-ions were provided to the medical cave for the first time. An overall conversion efficiency of 2.9±0.2×10-4 15O fragments per primary 16O ion accelerated in the synchrotron SIS18 was reached.

Novel unconventional radiotherapy techniques: Current status and future perspectives - Report from the 2nd international radiation oncology online seminar.

•Improvement of therapeutic ratio by novel unconventional radiotherapy approaches.•Immunomodulation using high-dose spatially fractionated radiotherapy.•Boosting radiation anti-tumor effects by adding an immune-mediated cell killing.

Are charged particles a good match for combination with immunotherapy? Current knowledge and perspectives.

Charged particle radiotherapy, mainly using protons and carbon ions, provides physical characteristics allowing for a volume conformal irradiation and a reduction of the integral dose to normal tissue. Carbon ion therapy additionally features an increased biological effectiveness resulting in peculiar molecular effects. Immunotherapy, mostly performed with immune checkpoint inhibitors, is nowadays considered a pillar in cancer therapy. Based on the advantageous features of charged particle radiotherapy, we review pre-clinical evidence revealing a strong potential of its combination with immunotherapy. We argue that the combination therapy deserves further investigation with the aim of translation in clinics, where a few studies have been set up already.

Precision of the PET activity range during irradiation with10C,11C, and12C beams.

Objective. Beams of stable ions have been a well-established tool for radiotherapy for many decades. In the case of ion beam therapy with stable12C ions, the positron emitters10,11C are produced via projectile and target fragmentation, and their decays enable visualization of the beam via positron emission tomography (PET). However, the PET activity peak matches the Bragg peak only roughly and PET counting statistics is low. These issues can be mitigated by using a short-lived positron emitter as a therapeutic beam.Approach.An experiment studying the precision of the measurement of ranges of positron-emitting carbon isotopes by means of PET has been performed at the FRS fragment-separator facility of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany. The PET scanner used in the experiment is a dual-panel version of a Siemens Biograph mCT PET scanner.Main results.High-quality in-beam PET images and activity distributions have been measured from the in-flight produced positron emitting isotopes11C and10C implanted into homogeneous PMMA phantoms. Taking advantage of the high statistics obtained in this experiment, we investigated the time evolution of the uncertainty of the range determined by means of PET during the course of irradiation, and show that the uncertainty improves with the inverse square root of the number of PET counts. The uncertainty is thus fully determined by the PET counting statistics. During the delivery of 1.6 × 107ions in 4 spills for a total duration of 19.2 s, the PET activity range uncertainty for10C,11C and12C is 0.04 mm, 0.7 mm and 1.3 mm, respectively. The gain in precision related to the PET counting statistics is thus much larger when going from11C to10C than when going from12C to11C. The much better precision for10C is due to its much shorter half-life, which, contrary to the case of11C, also enables to include the in-spill data in the image formation.Significance. Our results can be used to estimate the contribution from PET counting statistics to the precision of range determination in a particular carbon therapy situation, taking into account the irradiation scenario, the required dose and the PET scanner characteristics.

The genus Aphis (Hemiptera, Aphididae) living on Asteraceae species in southern South America: Argentina and Chile, with five new species.

In the whole of Argentina and Chile, southern South America in this paper, 20 species of the genus Aphis hosted in species of Asteraceae were known; eleven of them are native South American, and those introduced are mostly polyphagous and widespread. The Chilean regions and the Argentine provinces in which each one of them is known, as well as the host plants on which it has been recorded, are listed. New data of 15 of them are presented, with several first records in different Argentine provinces or hosted on diverse plants: The knowledge of A. conspicua and A. fuentesi, which were recently described living on species of Baccharis, is improved from specimens respectively collected on Senecio and Gutierrezia. A. rogerblackmani Nieto Nafra, Ortego Mier Durante sp. n. is described from apterous and alate viviparous females, oviparous females and males collected on Baccharis in Argentina. Other four species are described from apterous and alate viviparae: A. gutierreziae Ortego, Mier Durante Nieto Nafra sp. n., collected on species of Gutierrezia in Argentina, A. hyalis Mier Durante, Nieto Nafra Ortego sp. n., collected on Hyalis argentea in Argentina, A. pulverea Nieto Nafra, Moreno-Gonzlez Ortego sp. n., collected on species of Senecio in Chile and Argentina, and A. sanrafaelina Ortego, Mier Durante Nieto Nafra sp. n., collected on Tagetes mendocina, Thymophylla pentachaeta and Pectis odorata in Argentina. The intraspecific diversity of Aphis pulverea has been analysed by a principal component analysis followed by hierarchical clustering of principal components. An identification key to viviparous females of the species of Aphis hosted in Asteraceae and known in southern South America is presented.

Blanchardaphis poikila syn. n. to B. capitophoroides and Blanchardaphis syn. n. to Lambersius (Hemiptera, Aphididae, Aphidinae, Macrosiphini, Uroleucon).

Blanchardaphis was erected for two Argentinian species of aphids very similar to Uroleucon, but distinguished by several characters. Here, we examined morphology and DNA sequences of Blanchardaphis specimens from Argentina and Chile. We further conducted a phylogenetic analysis to determine the relationship of Blanchardaphis to Uroleucon. We found minor morphological and genetic differences between Blanchardaphis samples based on geography, which appear to be population-level variation. On the basis of current evidence, we conclude that B. poikila (Ortego, Nieto Nafra Mier Durante, 1997) is synonymous with B. capitophoroides (Blanchard, 1942), and that Blanchardaphis Ortego, Nieto Nafra Mier Durante, 1998 is synonymous with Lambersius Olive, 1965 (subgenus of Uroleucon) sensu Nieto Nafra et al. 2007 or alternatively with the subgenus Uroleucon.

Aphis mirabilis sp. n. (Hemiptera, Aphididae, Aphidina), a South American species resembling A. craccivora, and further data on A. tropaeoli.

We examined 1367 apterous viviparae from 151 samples to study Aphis craccivora, A. tropaeoli and a third, possibly new species in Argentina, resembling both. Principal component analysis (PCA), followed by hierarchical clustering of principal components (HCPC), revealed clusters based on 33 morphological characters of 206 selected specimens. The delimitation of possible taxonomic entities was assessed by logistic regression. PCA confirmed that A. tropaeoli is a valid species. HCPC revealed the existence of a new species distinct from A. craccivora. Recently published data on the variability of A. craccivora, mainly regarding Asian populations, are presented and discussed; the general appearance of the sexuals of this species is also presented. The new species is described with the name Aphis mirabilis Nieto Nafra and Ortego sp. n., based on apterous and alate viviparae, oviparae, and males collected in Mendoza and Neuqun (Argentina) on Adesmia volckmannii (Fabaceae), Atriplex nummularia and At. lampa (Amaranthaceae), Bougainvillea spinosa (Nyctaginaceae), and Robinia pseudoacacia (Fabaceae). This new species has also been collected on plants of another 18 species from 8 additional families, although these specimens are not included in the type series. Features to distinguish A. mirabilis Nieto Nafra and Ortego sp. n. from A. craccivora are presented together with a logistic regression model. The males of A. tropaeoli are described. The list of host plants of A. craccivora in Argentina is updated.

Interaction of therapeutic12C ions with bone-like targets: physical characterization and dosimetric effect at material interfaces.

Carbon therapy is a promising treatment option for cancer. The physical and biological properties of carbon ions can theoretically allow for the delivery of curative doses to the tumor, while simultaneously limiting risks of toxicity to adjacent healthy structures. The treatment effectiveness can be further improved by decreasing the uncertainties stemming from several sources, including the modeling of tissue heterogeneity. Current treatment plans employ density-based conversion methods to translate patient-specific anatomy into a water system, where dose distribution is calculated. This approach neglects differences in nuclear interactions stemming from the elemental composition of each tissue. In this work, we investigated the interaction of therapeutic carbon ions with bone-like materials. The study concentrated on nuclear interactions and included attenuation curves of 200 and 400 AMeV beams in different types of bones, as well as kinetic energy spectra of all charged fragments produced up to 29 degrees from the beam direction. The comparison between measurements and calculations of the treatment planning system TRiP98 indicated that bone tissue causes less fragmentation of carbon ions than water. Overall, hydrogen and helium particles were found to be the most abundant species, while heavier fragments were mostly detected within 5 degrees from the beam direction. We also investigated how the presence of a soft tissue-bone interface could affect the depth-dose profile. The results revealed a dose spike in the transition region, that extended from the entry channel to the target volume. The findings of this work indicated that the tissue-to-water conversion method based only on density considerations can result in dose inaccuracies. Tissue heterogeneity regions containing bones can potentially produce dose spikes, whose magnitude will depend on the patient anatomy. Dose uncertainties can be decreased by modeling nuclear interactions directly in bones, without applying the tissue-to-water conversion.

Application of response surface methodology (RSM) for the optimization of supercritical CO2 extraction of oil from patè olive cake: Yield, content of bioactive molecules and biological effects in vivo.

The two-phase technology for olive oil extraction generates large amounts of patè olive cake (POC), a by-product that is rich in bioactive health-promoting compounds. Here, response surface methodology (RSM) was used to maximize supercritical-CO2 oil extraction from POC, while minimizing operative temperature, pressure and time. Under the optimal parameters (40.2 °C, 43.8 MPa and time 30 min), the oil yield was 14.5 g·100 g-1 dw (~65% of the total oil content of the freeze-dried POC matrix), as predicted by RSM. Compared with freeze-dried POC, the oil contained more phytosterols (13-fold), tocopherols (6-fold) and squalene (8-fold) and was a good source of pentacyclic triterpenes. When the biological effects of POC oil intake (20-40 µL·die-1) were evaluated in the livers of BALB/c mice, no significant influence on redox homeostasis was observed. Notably, a decline in liver triglycerides alongside increased activities of NAD(P)H:Quinone Oxidoreductase 1, Carnitine Palmitoyl-CoA Transferase and mitochondrial respiratory complexes suggested a potential beneficial effect on liver fatty acid oxidation.

Robust treatment planning with 4D intensity modulated carbon ion therapy for multiple targets in stage IV non-small cell lung cancer.

Intensity modulated particle therapy (IMPT) with carbon ions can generate highly conformal treatment plans; however, IMPT is limited in robustness against range and positioning uncertainty. This is particularly true for moving targets, even though all motion states of a 4DCT are considered in 4D-IMPT. Here, we expand 4D-IMPT to include robust non-linear RBE-weighted optimization to explore its potential in improving plan robustness and sparing critical organs. In this study, robust 4D-optimization-based on worst-case optimization on 9 scenarios-was compared to conventional 4D-optimization with PTV margins using 4D dose calculation and robustness analysis for 21 uncertainty scenarios. Slice-by-slice rescanning was used for motion mitigation. Both 4D-optimization strategies were tested on a cohort of 8 multi-lesion lung cancer patients with the goal of prioritizing OAR sparing in a hypofractionated treatment plan. Planning objectives were to keep the OAR volume doses below corresponding limits while simultaneously achieve CTV coverage with D95% ≥ 95 %. For the conventional plans, average D95% was at 98.7% which fulfilled the target objective in 83.2% of scenarios. For the robust plans, average D95% was reduced to 97.6% which still fulfilled the target objective in 80.7% of cases, but led to significantly improved overall OAR sparing: Volume doses were below the limits in 96.2% of cases for the conventional and 99.5% for the robust plans. When considering the particularly critical smaller airways only, fulfillment rates could be increased from 76.2% to 96% for the robust plans. This study has shown that plan robustness of 4D-IMPT could be improved by using robust 4D-optimization, offering greater control over uncertainties in the actual delivered dose. In some cases, this required sacrificing target coverage for the benefit of better OAR sparing.

Microdosimetric measurements as a tool to assess potential in-field and out-of-field toxicity regions in proton therapy.

Relative biological effectiveness (RBE) variations are thought to be one of the primary causes of unexpected normal-tissue toxicities during tumor treatments with charged particles. Unlike carbon therapy, where treatment planning is optimized on the basis of the RBE-weighted dose, a constant RBE value of 1.1 is currently used in proton therapy. Assuming a uniform value can lead to under- or over-dosage, not just to the tumor but also to surrounding normal tissue. RBE changes have been linked with dose/fraction, the biological endpoint and beam properties. Understanding radiation quality and the associated RBE can improve the prediction of normal-tissue toxicities. In this study, we exploited microdosimetry for characterizing radiation quality in proton therapy in-field, and off-beam at 20 (beam edge), 50 (close out-of-field) and 100 (far out-of-field) mm from the beam center. We measured the lineal energy y spectra in a water phantom irradiated with 152 MeV protons, from which beam quality as well as the physical dose could be obtained. Taking advantage of the linear quadratic model and a modified version of the microdosimetric kinetic model, the microdosimetric data were combined with radiobiological parameters (α and ß) of human salivary gland tumor cells for assessing cell survival RBE and RBE-weighted dose. The results indicate that if a dose of 60 Gy is delivered to the peak, the beam edge receives up to 6 Gy while the close and far out-of-field regions receive doses on the order of 10-3 Gy and 10-4 Gy, respectively. The RBE estimate in-beam shows large variations, ranging from 1.0 ± 0.2 at the entrance channel to 2.51 ± 0.15 at the tail. The beam edge follows a similar trend but the RBE calculated at the Bragg peak depth is 2.27 ± 0.17, i.e. twice the RBE in-beam (1.05 ± 0.15). Out-of-field, the estimated RBE is always significantly higher than 1.1 and increases with increasing lateral distance, reaching the overall highest value of 3.4 ± 0.3 at a depth of 206 mm and a lateral distance of 10 mm. The combination of RBE and dose into the biological dose points to the beam edge and the end-of-range in-beam as the areas with the highest risk of potential toxicities.

Industrial scale bio-detoxification of raw olive mill wastewaters by the use of selected microbial yeast and bacterial strains to obtain a new source for fertigation.

The Olive Mill Wastewaters (OMWs) are one of the most important agro-industrial wastes of the Mediterranean Countries and the disposal by draining them onto land has been proved to be damaging for soils, plants and groundwater due to their polluting power. The present report describes a new method for bio-detoxification of undiluted fresh OMW based on the driven selection of aerobic yeasts and bacteria. The identified yeast Candida boidinii A5y and the bacterium Paenibacillus albidus R32b strains allowed the treatment of freshly produced raw OMW characterized by very high COD value and phenolic content, when applied as sequential inoculum. The treated OMW showed the absence of antimicrobial effects and a strongly reduction of phytotoxic activity on the germination of several plant seeds. The process was successfully validated on an industrial scale without any pre-treatment, dilution and/or supplementation of the raw waste. Bio-detoxified OMW produced by this sustainable and low-cost process would be suitable for new non-chemical fertigation or soilless applications. The described procedure represents a virtuous example of circular economy efficaciously applied for a depleting agri-food resource.

A further contribution to the knowledge of Uroleucon species (Hemiptera, Aphididae) living on Adesmia (Fabaceae) in southern South America, with description of a new species from Chile.

Uroleucon (Hemiptera, Aphididae, Macrosiphini) is a highly diverse and widely distributed genus. Most of its species are hosted by plants of the Asteraceae or Campanulaceae, but three species from the southern end of South America have specialized to live on plants of the genus Adesmia (Fabaceae). New morphological and chorological data are provided for U. adesmiae Mier Durante and Ortego and U. naheulhuapense Nieto Nafría von Dohlen, with a description of the alate viviparous female of the latter species. U. australe Nieto Nafría Mier Durante, sp. n. is described from apterous viviparous females, oviparous females and males from four localities in the Chilean regions of Aysén and Magallanes; it is very close to U. nahuelhuapense, both morphologically and genetically. Contrary to what is typical for aphids, the males of U. australe have a greater number of distinguishing characters than are found in viviparous females. A modification of the identification key to the apterous viviparous females of the known Uroleucon species in South America by Nieto Nafría et al. (2019) is presented.

Systematic quantification of nanoscopic dose enhancement of gold nanoparticles in ion beams.

High-Z material nanoparticles are being studied as localized dose enhancers in radiotherapeutic applications. Here, the nano-scale physical dose enhancement of proton, carbon and oxygen ion beam radiation by gold nanoparticles was studied by means of Monte Carlo track structure simulation with the TRAX code. We present 2D distributions and radial profiles of the additional dose and the dose enhancement factor for two geometries which consider an isolated and a water-embedded nanoparticle, respectively. Different nanoparticle sizes (radius of 1.2-22 nm) were found to yield qualitatively different absolute and relative dose enhancement distributions and different maximum dose enhancement factors (up to 20). Whereas the smallest nanoparticles produced the highest local dose enhancement factor close to the metal, larger ones led to lower, more diffuse dose enhancement factors that contributed more at larger distances. Differential absorption effects inside the metal were found to be responsible for those characteristics. For the energy range 15-204 MeVu-1, also a mild trend with ion E/A, regardless of the ion species, was found for embedded nanoparticles. In analogy to the width of the ion track itself, slower ions increased the enhancement at the nanoparticle surface. In contrast, no dependence on linear energy transfer was encountered. For slower ions (3-10 MeVu-1), the enhancement effect began to break down over all distances. Finally, the significance of any indirect physical effect was excluded, giving important hints especially in view of the low probabilities (at realistic concentrations and fluences) of direct ion-NP-hits. The very localized nature of the physical dose enhancement found suggests a strong action upon targets closeby, but no relevant effect at cellular distances. When pondering different possible damage enhancement mechanisms of gold nanoparticles in the context of published in vitro and in vivo experimental results, biological pathways are likely to play the key role.

Three new species of the genus Neuquenaphis (Hemiptera, Aphididae, Spicaphidinae) from southernmost South America.

Three new species of Neuquenaphis Blanchard are described from aphids collected in southernmost South America on several species of Nothofagus, southern beeches: Neuquenaphis blackmani Nieto Nafría and Brown, sp. n. from apterous and alate viviparous females and alatoid nymphs collected on Nothofagus dombeyi in Los Lagos and Los Ríos regions (Chile) and on Nothofagus nitida in Los Ríos region, Neuquenaphis aurata Mier Durante and von Dohlen, sp. n. from apterous and alate viviparous females collected on Nothofagus betuloides in Magallanes region (Chile) and Tierra del Fuego province (Argentina), and Neuquenaphis ramireziNieto Nafría and Ortego, sp. n. from apterous viviparous females collected on Nothofagus pumilio and N. antarctica in Tierra del Fuego province (Argentina) and La Araucanía, Aysén and Magallanes regions (Chile). Sequences of the mitochondrial COI "barcode" region and the tRNAleu-COII locus support the distinction of these new species from described Neuquenaphis species. Morphological characteristics that differentiate the new species from already described species of the genus are discussed. Partial identification keys for known apterous and alate viviparous females of Neuquenaphis species are presented on the basis of those established by Quednau (2010).

Aphis (Hemiptera, Aphididae) species living on Baccharis (Asteraceae) in southern South America, with description of three new species.

Aphid specimens belonging to the genus Aphis (Hemiptera, Aphididae, Aphidinae) collected on species of Baccharis (Asteraceae) in localities of Argentina and Chile, preserved in the Natural History Museum in London and in the Universidad de León collections, have been studied. They belong to six species: Aphis craccivora, Aphis gossypii and Aphis spiraecola, which are widely-distributed and polyphagous, and the new species: Aphis ingeborgae Nieto Nafría and Brown sp. n., Aphis conspicua Nieto Nafría and Mier Durante sp. n. and Aphis fuentesi Nieto Nafría and Ortego sp. n. which are here described from apterous and alate viviparous females, and also from oviparous females and males in the case of Aphis fuentesi. These six species plus the native and monophagous A. coridifoliae are those known in southern South America living on plants of Baccharis. Diagnostic features of new species and an identification key for apterous viviparous females of these seven species are presented.

Research plans in Europe for radiation health hazard assessment in exploratory space missions.

The European Space Agency (ESA) is currently expanding its efforts in identifying requirements and promoting research towards optimizing radiation protection of astronauts. Space agencies use common limits for tissue (deterministic) effects on the International Space Station. However, the agencies have in place different career radiation exposure limits (for stochastic effects) for astronauts in low-Earth orbit missions. Moreover, no specific limits for interplanetary missions are issued. Harmonization of risk models and dose limits for exploratory-class missions are now operational priorities, in view of the short-term plans for international exploratory-class human missions. The purpose of this paper is to report on the activity of the ESA Topical Team on space radiation research, whose task was to identify the most pertinent research requirements for improved space radiation protection and to develop a European space radiation risk model, to contribute to the efforts to reach international consensus on dose limits for deep space. The Topical Team recommended ESA to promote the development of a space radiation risk model based on European-specific expertise in: transport codes, radiobiological modelling, risk assessment, and uncertainty analysis. The model should provide cancer and non-cancer radiation risks for crews implementing exploratory missions. ESA should then support the International Commission on Radiological Protection to harmonize international models and dose limits in deep space, and guarantee continuous support in Europe for accelerator-based research configured to improve the models and develop risk mitigation strategies.

The species of Uroleucon (Hemiptera: Aphididae) living on Adesmia (Fabaceae) in Argentina, with the description of a new species.

Uroleucon Mordvilko is the largest genus in the Macrosiphini (Hemiptera, Aphididae) and most of its species live on species of Asteraceae. Uroleucon nahuelhuapense Nieto Nafría von Dohlen sp. n. is described from apterous viviparous females collected on Adesmia boronioides (Fabaceae) in a locality of Neuquén province (Argentina). The morphological characters and the sequence of the tRNAleu-COII mitochondrial locus support the inclusion of the new species in the genus Uroleucon. Apterous viviparous females of Uroleucon adesmiae Mier Durante Ortego collected in two Argentinean localities have also been studied and ranges of several quantitative features have been modified. The identification key for the Uroleucon species known in South America by Nieto Nafría et al. (2007) has been modified to include the new species.

Kill painting of hypoxic tumors with multiple ion beams.

We report on a novel method for simultaneous biological optimization of treatment plans for hypoxic tumors using multiple ion species. Our previously introduced kill painting approach, where the overall cell killing is optimized on biologically heterogeneous targets, was expanded with the capability of handling different ion beams simultaneously. The current version (MIBO) of the research treatment planning system TRiP98 has now been augmented to handle 3D (voxel-by-voxel) target oxygenation data. We present a case of idealized geometries where this method can identify optimal combinations leading to an improved peak-to-entrance effective dose ratio. This is achieved by the redistribution of particle fluences, when the heavier ions are preferentially forwarded to hypoxic target areas, while the lighter ions deliver the remaining dose to its normoxic regions. Finally, we present an in silico skull base chordoma patient case study with a combination of 4He and 16O beams, demonstrating specific indications for its potential clinical application. In this particular case, the mean dose, received by the brainstem, was reduced by 3%-5% and by 10%-12% as compared to the pure 4He and 16O plans, respectively. The new method allows a full biological optimization of different ion beams, exploiting the capabilities of actively scanned ion beams of modern particle therapy centers. The possible experimental verification of the present approach at ion beam facilities disposing of fast ion switch is presented and discussed.