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Simple Summary: Around 50% of all human cancers are treated with radiotherapy. The effectiveness of radiotherapy is driven through causing DNA damage within the cancer cells; however, the cells respond by activating repair mechanisms that can lead to resistance to treatment. A promising strategy is to target one of these defence mechanisms, called the cell cycle checkpoint, using specific drugs/inhibitors that can be used in combination with radiotherapy. Here, we review evidence of investigations into inhibitors of two important proteins (Chk1 and Wee1) and how these can be used to increase the effectiveness of radiotherapy in cancer treatment. Radiotherapy is one of the main cancer treatments being used for ~50% of all cancer patients. Conventional radiotherapy typically utilises X-rays (photons); however, there is increasing use of particle beam therapy (PBT), such as protons and carbon ions. This is because PBT elicits significant benefits through more precise dose delivery to the cancer than X-rays, but also due to the increases in linear energy transfer (LET) that lead to more enhanced biological effectiveness. Despite the radiotherapy type, the introduction of DNA damage ultimately drives the therapeutic response through stimulating cancer cell death. To combat this, cells harbour cell cycle checkpoints that enables time for efficient DNA damage repair. Interestingly, cancer cells frequently have mutations in key genes such as TP53 and ATM that drive the G1/S checkpoint, whereas the G2/M checkpoint driven through ATR, Chk1 and Wee1 remains intact. Therefore, targeting the G2/M checkpoint through specific inhibitors is considered an important strategy for enhancing the efficacy of radiotherapy. In this review, we focus on inhibitors of Chk1 and Wee1 kinases and present the current biological evidence supporting their utility as radiosensitisers with different radiotherapy modalities, as well as clinical trials that have and are investigating their potential for cancer patient benefit. [ABSTRACT FROM AUTHOR]

Purpose: The Marburg Ion-Beam Therapy Center (MIT) is one of two particle therapy centers in Germany that enables the treatment of patients with both protons and carbon ions. The facility was build by Siemens Healthineers and is one of only two centers worldwide built by Siemens (Marburg, Germany and Shanghai, China). The present report provides an overview of technical and clinical operations as well as research activities at MIT. Methods: The MIT was completed in 2011 and uses a synchrotron for accelerating protons and carbon ions up to energies of 250 MeV/u and 430 MeV/u respectively. Three treatment rooms with a fixed horizontal beam-line and one room with a 45 degree beam angle are available. Results: Since the start of clinical operations in 2015, around 2.500 patients have been treated at MIT, about 40% with carbon ions and 60% with protons. Currently around 400 patients are treated each year. The majority of the patients suffered from benign and malign CNS tumors (around 40%) followed by head and neck tumors (around 23%). MIT is actively involved in clinical studies with its patients. In addition to clinical operations, there is active research at MIT in the fields of radiation biology and medical physics. The focus is on translational research to improve the treatment of H & N carcinomas and lung cancer (NSCLC). Moreover, intensive work is being carried out on the technical implementation of FLASH irradiation for research purposes. Conclusion: The MIT is one of two centers worldwide that were built by Siemens Healtineers and has been successfully in clinical operation since 2015. The service provided by Siemens is guaranteed until 2030, the future after 2030 is currently under discussion. [ABSTRACT FROM AUTHOR]

Purpose: To highlight merits and pitfalls of treatment plan comparison between photon-based conventional radiation therapy (XRT) and particle-based (proton and carbon ions) therapy (PT). Methods: The physical and dosimetric rationales for the use of PT will be explored looking at their advantages and disadvantages with a specific focus on sensitivity to range and biological uncertainties. Next, the analysis will focus on linear energy transfer (LET) and its correlation with relative biological effectiveness (RBE), particularly within the context of plan optimization and evaluation phases in proton therapy. This examination aims to address the impact of the LET/RBE interplay on radiobiological uncertainties. Results: There is a wide literature of planning studies comparing PT and the most advanced XRT techniques. Purely dosimetric advantages are translated into normal tissue complication probability (NTCP) variation to drive patient optimal allocation, but the impact of range uncertainty needs to be accounted for, together with the consequent need for plan adaptation and organ motion management. RBE modelling and entailed clinical effects are currently central in PT research, while new degrees of freedom are being introduced with LET-based plan optimization and evaluation. Conclusions: PT shows many dosimetric advantages but emphasizes challenges like range uncertainty. RBE modelling plays a crucial role, and LET-based optimization introduces new possibilities. Addressing uncertainties and embracing innovation are vital for enhancing PT's efficacy. [ABSTRACT FROM AUTHOR]

Purpose: To review experience and indications for head and neck (HN) tumors at our center in relation to the published literature. Methods: HN cancer patients treated at our center either with protons (PT) or carbon ions (CIRT) were extracted from our institutional retrospective and longitudinal Registry (NCT05203250 REGAL), including all the patients treated since the beginning of our clinical activity. A literature search was conducted with selection of most representative published studies for adenoid cystic carcinoma (ACC), mucosal melanoma (MM), sinonasal cancers (SNCs) and reirradiations. Results: Since the beginning of the clinical activity in 2011, 1311 HN tumors have been treated a tour center. Majority of treated patients were ACC (52%), non-ACC salivary gland tumors (18%), paranasal sinuses tumors (9%), MM (7%), and reirradiation of recurrent tumors after previous RT (14%). Oncological outcome in terms of safety and efficacy has been published on the series of 184 ACC and 40 MM, both treated with CIRT in the years 2013–2020. Reviewed reirradiation published series included a cohort of 52 recurrent salivary gland tumors retreated with CIRT from 2013 to 2016, and the experience of 2013–2020 of retreatment of 15 SNCs (13 with CIRT and 2 with PT). Conclusion: HN tumors are major indications for particle treatment around the world and at our center. Particle treatment might be personalized for each patient, with CIRT indicated for radioresistant tumors such as ACC and MM. Data on oncologic outcomes of CIRT at our center are consistent with published series. [ABSTRACT FROM AUTHOR]

Some cancers have a poor prognosis and often lead to local recurrence because they are resistant to available treatments, e.g., glioblastoma. Attempts have been made to increase the sensitivity of resistant tumors by targeting pathways involved in the resistance and combining it, for example, with radiotherapy (RT). We have previously reported that treating glioblastoma stem cells with an Nrf2 inhibitor increases their radiosensitivity. Unfortunately, the application of drugs can also affect normal cells. In the present study, we aim to investigate the role of the Nrf2 pathway in the survival and differentiation of normal human adipose-derived stem cells (ADSCs) exposed to radiation. We treated ADSCs with an Nrf2 inhibitor and then exposed them to X-rays, protons or carbon ions. All three radiation qualities are used to treat cancer. The survival and differentiation abilities of the surviving ADSCs were studied. We found that the enhancing effect of Nrf2 inhibition on cell survival levels was radiation-quality-dependent (X-rays > proton > carbon ions). Furthermore, our results indicate that Nrf2 inhibition reduces stem cell differentiation by 35% and 28% for adipogenesis and osteogenesis, respectively, using all applied radiation qualities. Interestingly, the results show that the cells that survive proton and carbon ion irradiations have an increased ability, compared with X-rays, to differentiate into osteogenesis and adipogenesis lineages. Therefore, we can conclude that the use of carbon ions or protons can affect the stemness of irradiated ADSCs at lower levels than X-rays and is thus more beneficial for long-time cancer survivors, such as pediatric patients. [ABSTRACT FROM AUTHOR]

Background: The present study is aimed at calculating relative absorbed-dose energy response correction (R) of commonly used thermoluminescent dosimeters (TLDs) such as LiF, Li2B4O7, and Al2O3 as a function of depth in water for protons (50–250 MeV/n) and carbon ion (80–480 MeV/n) beams using Monte Carlo-based FLUKA code. Materials and Methods: On-axis depth-dose profiles in water are calculated for protons (50–250 MeV/n) and carbon ion (80–480 MeV/n) beams using FLUKA code. For the calculation of R, selective depths are chosen based on the depth-dose profiles. In the simulations, the TLDs of dimensions 1 mm × 1 mm × 1 mm are positioned at the flat, dose gradient, and Bragg peak regions of the depth-dose profile. Absorbed dose to detector was calculated within the TLD material. In the second step, TLD voxels were replaced by water voxel of similar dimension and absorbed dose to water was scored. Results: The study reveals that for both proton and carbon ion beams, the value of R differs from unity significantly at the Bragg peak position and is close to unity at the flat region for the investigated TLDs. The calculated R value is sensitive to depth in water, beam energy, type of ion beam, and type of TLD. Discussion: For accurate dosimetry of protons and carbon ion beams using TLDs, the response of the TLD should be corrected to account for its absorbed-dose energy dependence.

Purpose: To provide an introduction to the special issue containing the proceedings of the workshop on cancer therapy using hadrons (proton, carbon ions or boron neutron capture therapy) that was held in Pavia in October 2023 and organized by CNAO and IAEA. Methods: Papers contained in the issue are briefly summarized. Results: This issue contains a collection of papers from the workshop that provide a great opportunity to learn about the status and progress of this technology. Conclusions: Particle therapy is exponentially growing worldwide. While several clinical trials are now providing convincing evidence of the effectiveness of the treatment in tumor control and reduced toxicity, the technology remains expensive and the cost effectiveness is still under debate. The IAEA-CNAO workshop provided a clear picture of the state of the art and future prospective of this technology. [ABSTRACT FROM AUTHOR]

Abstract Without the protective shielding of Earth’s atmosphere, astronauts face higher doses of ionizing radiation in space, causing serious health concerns. Highly charged and high energy (HZE) particles are particularly effective in causing complex and difficult-to-repair DNA double-strand breaks compared to low linear energy transfer. Additionally, chronic cortisol exposure during spaceflight raises further concerns, although its specific impact on DNA damage and repair remains unknown. This study explorers the effect of different radiation qualities (photons, protons, carbon, and iron ions) on the DNA damage and repair of cortisol-conditioned primary human dermal fibroblasts. Besides, we introduce a new measure, the Foci-Integrated Damage Complexity Score (FIDCS), to assess DNA damage complexity by analyzing focus area and fluorescent intensity. Our results show that the FIDCS captured the DNA damage induced by different radiation qualities better than counting the number of foci, as traditionally done. Besides, using this measure, we were able to identify differences in DNA damage between cortisol-exposed cells and controls. This suggests that, besides measuring the total number of foci, considering the complexity of the DNA damage by means of the FIDCS can provide additional and, in our case, improved information when comparing different radiation qualities.

Lymphopenia is now generally recognized as a negative prognostic factor in radiotherapy. Already at the beginning of the century we demonstrated that high-energy carbon ions induce less damage to the lymphocytes of radiotherapy patients than X-rays, even if heavy ions are more effective per unit dose in the induction of chromosomal aberrations in blood cells irradiated ex-vivo. The explanation was based on the volume effect, i.e. the sparing of larger volumes of normal tissue in Bragg peak therapy. Here we will review the current knowledge about the difference in lymphopenia between particle and photon therapy and the consequences. There is nowadays an overwhelming evidence that particle therapy reduces significantly the radiotherapy-induced lymphopenia in several tumor sites. Because lymphopenia turns down the immune response to checkpoint inhibitors, it can be predicted that particle therapy may be the ideal partner for combined radiation and immunotherapy treatment and should be selected for patients where severe lymphopenia is expected after X-rays. [ABSTRACT FROM AUTHOR]

Background: The present study is aimed at calculating relative absorbed-dose energy response correction (R) of commonly used thermoluminescent dosimeters (TLDs) such as LiF, Li2B4O7, and Al2O3 as a function of depth in water for protons (50-250 MeV/n) and carbon ion (80-480 MeV/n) beams using Monte Carlo-based FLUKA code. Materials and Methods: On-axis depth-dose profiles in water are calculated for protons (50-250 MeV/n) and carbon ion (80-480 MeV/n) beams using FLUKA code. For the calculation of R, selective depths are chosen based on the depth-dose profiles. In the simulations, the TLDs of dimensions 1 mm × 1 mm × 1 mm are positioned at the flat, dose gradient, and Bragg peak regions of the depth-dose profile. Absorbed dose to detector was calculated within the TLD material. In the second step, TLD voxels were replaced by water voxel of similar dimension and absorbed dose to water was scored. Results: The study reveals that for both proton and carbon ion beams, the value of R differs from unity significantly at the Bragg peak position and is close to unity at the flat region for the investigated TLDs. The calculated R value is sensitive to depth in water, beam energy, type of ion beam, and type of TLD. Discussion: For accurate dosimetry of protons and carbon ion beams using TLDs, the response of the TLD should be corrected to account for its absorbed-dose energy dependence. [ABSTRACT FROM AUTHOR]

Background: Monte Carlo (MC) simulations are considered the gold‐standard for accuracy in radiotherapy dose calculation; so far however, no commercial treatment planning system (TPS) provides a fast MC for supporting clinical practice in carbon ion therapy. Purpose: To extend and validate the in‐house developed fast MC dose engine MonteRay for carbon ion therapy, including physical and biological dose calculation. Methods: MonteRay is a CPU MC dose calculation engine written in C++ that is capable of simulating therapeutic proton, helium and carbon ion beams. In this work, development steps taken to include carbon ions in MonteRay are presented. Dose distributions computed with MonteRay are evaluated using a comprehensive validation dataset, including various measurements (pristine Bragg peaks, spread out Bragg peaks in water and behind an anthropomorphic phantom) and simulations of a patient plan. The latter includes both physical and biological dose comparisons. Runtimes of MonteRay were evaluated against those of FLUKA MC on a standard benchmark problem. Results: Dosimetric comparisons between MonteRay and measurements demonstrated good agreement. In terms of pristine Bragg peaks, mean errors between simulated and measured integral depth dose distributions were between −2.3% and +2.7%. Comparing SOBPs at 5, 12.5 and 20 cm depth, mean absolute relative dose differences were 0.9%, 0.7% and 1.6% respectively. Comparison against measurements behind an anthropomorphic head phantom revealed mean absolute dose differences of 1.2%±1.1%$1.2\% \pm 1.1\;\%$ with global 3%/3 mm 3D‐γ passing rates of 99.3%, comparable to those previously reached with FLUKA (98.9%). Comparisons against dose predictions computed with the clinical treatment planning tool RayStation 11B for a meningioma patient plan revealed excellent local 1%/1 mm 3D‐γ passing rates of 98% for physical and 94% for biological dose. In terms of runtime, MonteRay achieved speedups against reference FLUKA simulations ranging from 14× to 72×, depending on the beam's energy and the step size chosen. Conclusions: Validations against clinical dosimetric measurements in homogeneous and heterogeneous scenarios and clinical TPS calculations have proven the validity of the physical models implemented in MonteRay. To conclude, MonteRay is viable as a fast secondary MC engine for supporting clinical practice in proton, helium and carbon ion radiotherapy. [ABSTRACT FROM AUTHOR]

The number of patients treated with charged-particle radiotherapy as well as the number of treatment centers is increasing worldwide, particularly regarding protons. However, high-linear energy transfer (LET) particles, mainly carbon ions, are of special interest for application in radiotherapy, as their special physical features result in high precision and hence lower toxicity, and at the same time in increased efficiency in cell inactivation in the target region, i.e., the tumor. The radiobiology of high-LET particles differs with respect to DNA damage repair, cytogenetic damage, and cell death type, and their increased LET can tackle cells' resistance to hypoxia. Recent developments and perspectives, e.g., the return of high-LET particle therapy to the US with a center planned at Mayo clinics, the application of carbon ion radiotherapy using cost-reducing cyclotrons and the application of helium is foreseen to increase the interest in this type of radiotherapy. However, further preclinical research is needed to better understand the differential radiobiological mechanisms as opposed to photon radiotherapy, which will help to guide future clinical studies for optimal exploitation of high-LET particle therapy, in particular related to new concepts and innovative approaches. Herein, we summarize the basics and recent progress in high-LET particle radiobiology with a focus on carbon ions and discuss the implications of current knowledge for charged-particle radiotherapy. We emphasize the potential of high-LET particles with respect to immunogenicity and especially their combination with immunotherapy. [ABSTRACT FROM AUTHOR]

In this study, ZrCuO2 nanoparticles were made using the hydrothermal method and potassium hydroxide as the precipitant. The material was irradiated with 500 keV carbon (C++) ions at doses of 1 × 1014, 1 × 1016, and 1 × 1018 ions/cm2. The ZrCuO2 nanoparticles exhibited cubic crystal structures with clear peaks on different orientation planes, both before and after being irradiated with carbon ions (C++). By incorporating carbon ions, the peak intensity and crystallinity of CuO nanostructures were enhanced. The non-irradiated micrographs display groups of tiny pebbles, whereas the carbon ion irradiated ZrCuO2 nanoparticles show flake-like structures. The material became denser because of carbon ion irradiation, which increased the carrier concentration. The absorption rate increase of the material reveals the impact of a carbon ion on irradiated ZrCuO2 nanoparticles. The absorbance of ZrCuO2 nanoparticles is enhanced through carbon ion implantation. The material has a bandgap energy of 1.95 eV without irradiation. The bandgap energy range of the irradiated material is 1.55–1.82 eV. The energy bandgap of the synthesized material was reduced because of carbon ion irradiation. The ZrCuO2 nanoparticle electrode with a specific capacitance value of 225 F/g. The electrodes prepared at 500 keV carbon (C++) ions with dosages of 1 × 1014, 1 × 1016, and 1 × 1018 ions/cm2 yielded specific capacitance values of 275 F/g, 300 F/g, and 312.5 F/g, respectively.

Some cancers have a poor prognosis and often lead to local recurrence because they are resistant to available treatments, e.g., glioblastoma. Attempts have been made to increase the sensitivity of resistant tumors by targeting pathways involved in the resistance and combining it, for example, with radiotherapy (RT). We have previously reported that treating glioblastoma stem cells with an Nrf2 inhibitor increases their radiosensitivity. Unfortunately, the application of drugs can also affect normal cells. In the present study, we aim to investigate the role of the Nrf2 pathway in the survival and differentiation of normal human adipose-derived stem cells (ADSCs) exposed to radiation. We treated ADSCs with an Nrf2 inhibitor and then exposed them to X-rays, protons or carbon ions. All three radiation qualities are used to treat cancer. The survival and differentiation abilities of the surviving ADSCs were studied. We found that the enhancing effect of Nrf2 inhibition on cell survival levels was radiation-quality-dependent (X-rays > proton > carbon ions). Furthermore, our results indicate that Nrf2 inhibition reduces stem cell differentiation by 35% and 28% for adipogenesis and osteogenesis, respectively, using all applied radiation qualities. Interestingly, the results show that the cells that survive proton and carbon ion irradiations have an increased ability, compared with X-rays, to differentiate into osteogenesis and adipogenesis lineages. Therefore, we can conclude that the use of carbon ions or protons can affect the stemness of irradiated ADSCs at lower levels than X-rays and is thus more beneficial for long-time cancer survivors, such as pediatric patients.

We studied the effects of single and combined action of protons and carbon ions 12C6+ on the pool of MCF-7 human breast cancer stem cells. Single irradiation with a beam of protons or carbon ions had no significant effects on the relative number of cancer stem cells (CSC). The effects of combined irradiation in a total equieffective dose of 4 Gy depended on the sequence of exposure to ionizing radiations: the relative number of CSC did not change after irradiation with carbon ions and then with protons, but increased in the case of the reverse sequence. The most favorable result, i.e. a decrease in the CSC pool, was observed in the case of sequential irradiation with carbon ions and protons and their equal contribution to total equieffective dose. In this case, the absolute number of CSC decreased by on average 2.1 times in comparison with the control (p<0.05). The revealed regularities are of interest for the further development of new methods of radiation therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Carbon-ion radiotherapy is a potential elective treatment option for hypoxic tumors. Its high linear energy transfer enables enhanced cell killing in radiation-resistant tumors, while the Bragg peak ensures precise targeting. Clinical evidence in pancreatic and cervical cancers supports positive outcomes of carbon treatments. However, the power of carbon ions against tumor hypoxia is generally underexploited and should be considered to improve the clinical benefit. Hypoxia, which is associated with abnormal vessel growth, is a characteristic feature of many solid tumors that increases their metastatic potential and resistance to radiotherapy. Carbon-ion radiation therapy, either alone or in combination with other treatments, is one of the most promising treatments for hypoxic tumors because the oxygen enhancement ratio decreases with increasing particle LET. Nevertheless, current clinical practice does not yet fully benefit from the use of carbon ions to tackle hypoxia. Here, we provide an overview of the existing experimental and clinical evidence supporting the efficacy of C-ion radiotherapy in overcoming hypoxia-induced radioresistance, followed by a discussion of the strategies proposed to enhance it, including different approaches to maximize LET in the tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck cancers are highly prevalent worldwide. Despite the recent advances in cancer diagnosis and treatment, more than 50% of the cases relapse within 2 years after the initial treatment. Radiation therapy, a leading option in the head and neck tumor management, has increasing potential as a repeated treatment. This review outlined recent advances in radiotherapy as applied to recurrent head and neck cancers in terms of clinical outcomes. The recurrence rate of head and neck cancers (HNCs) after initial treatment may reach 70%, and poor prognosis is reported in most cases. Curative options for recurrent HNCs mainly depend on the treatment history and the recurrent tumor localization. Reirradiation for HNCs is effective and has been included in most guidelines. However, the option remains clinically challenging due to high incidence of severe toxicity, especially in cases of quick infield recurrence. Recent technical advances in radiation therapy (RT) provide the means for upgrade in reirradiation protocols. While the majority of hospitals stay focused on conventional and widely accessible modulated RTs, the particle therapy options emerge as tolerable and providing further treatment opportunities for recurrent HNCs. Still, the progress is impeded by high heterogeneity of the data and the lack of large-scale prospective studies. This review aimed to summarize the outcomes of reirradiation for HNCs in the clinical perspective. [ABSTRACT FROM AUTHOR]

Quiescent cancer cells are major impediments to effective radiotherapy (RT) and exhibit limited sensitivity to traditional photon therapy. Herein, the functional role and underlying mechanism of carbon ions in overcoming the radioresistance of quiescent cervical cancer HeLa cells were determined. Briefly, serum withdrawal was used to induce synchronized quiescence in HeLa cells. Quiescent HeLa cells displayed strong radioresistance and DNA repair potential. After irradiation with carbon ions, the DNA damage repair pathway may markedly rely on error‐prone nonhomologous end‐joining in proliferating cells, whereas the high‐precision homologous recombination pathway is more relevant in quiescent cells. This phenomenon could be explained by the ionizing radiation (IR)‐induced cell cycle re‐entry of quiescent cancer cells. There are three strategies for eradicating quiescent cancer cells using high‐linear energy transfer (LET) carbon ions: direct cell death through complex DNA damage; apoptosis via an enhanced mitochondria‐mediated intrinsic pathway; forced re‐entry of quiescent cancer cells into the cell cycle, thereby improving their susceptibility to IR. Silencing β‐catenin signaling is essential for maintaining the dormant state in quiescent cells. Herein, carbon ions activated the β‐catenin pathway in quiescent cells, and inhibition of this pathway improved the resistance of quiescent HeLa cells to carbon ions by alleviating DNA damage, improving DNA damage repair, maintaining quiescent depth, and inhibiting apoptosis. Collectively, carbon ions conquer the radioresistance of quiescent HeLa cells by activating β‐catenin signaling, which provides a theoretical basis for improved therapeutic effects in patients with middle‐advanced‐stage cervical cancer with radioresistance. [ABSTRACT FROM AUTHOR]

Particle minibeam therapy has demonstrated the potential for better healthy tissue sparing due to spatial fractionation of the delivered dose. Especially for heavy ions, the spatial fractionation could enhance the already favorable differential biological effectiveness at the target and the entrance region. Moreover, spatial fractionation could even be a viable option for bringing ions heavier than carbon back into patient application. To understand the effect of minibeam therapy, however, requires careful conduction of pre-clinical experiments, for which precise knowledge of the minibeam characteristics is crucial. This work introduces the use of high-spatial-resolution CMOS sensors to characterize collimator-produced carbon ion minibeams in terms of lateral fluence distribution, secondary fragments, track-averaged linear energy transfer distribution, and collimator alignment. Additional simulations were performed to further analyze the parameter space of the carbon ion minibeams in terms of beam characteristics, collimator positioning, and collimator manufacturing accuracy. Finally, a new concept for reducing the neutron dose to the patient by means of an additional neutron shield added to the collimator setup is proposed and validated in simulation. The carbon ion minibeam collimator characterized in this work is used in ongoing pre-clinical experiments on heavy ion minibeam therapy at the GSI. [ABSTRACT FROM AUTHOR]

Primary mucosal melanoma (PMM) and pancreatic ductal adenocarcinoma (PDAC) are two aggressive malignancies, characterized by intrinsic radio-chemoresistance and neurotropism, a histological feature resulting in frequent perineural invasion (PNI), supported by neurotrophic factors secreted in the tumour microenvironment (TME), such as neurotrophin-3 (NT-3). Carbon-ion radiotherapy (CIRT) could represent an effective option in unresectable PMM and PDAC. Only a few data about the effects of CIRT on PNI in relation to NT-3 are available in the literature, despite the numerous pieces of evidence revealing the peculiar effects of this type of radiation on tumour cell migration. This in vitro study investigated for the first time the response of PMM and PDAC cells to NT-3 and evaluated the effects of conventional photon beam radiotherapy (XRT) and CIRT on cell viability, proliferation, and migration. Our results demonstrated the greater capacity of C-ions to generally decrease cell viability, proliferation, and migration, while the addition of NT-3 after both types of irradiation determined an increase in these features, maintaining a dose-dependent trend and acting more effectively as a chemoattractant than inductor in the case of migration. [ABSTRACT FROM AUTHOR]

Radiotherapy (ionising radiation; IR) is utilised in the treatment of ~50% of all human cancers, and where the therapeutic effect is largely achieved through DNA damage induction. In particular, complex DNA damage (CDD) containing two or more lesions within one to two helical turns of the DNA is a signature of IR and contributes significantly to the cell killing effects due to the difficult nature of its repair by the cellular DNA repair machinery. The levels and complexity of CDD increase with increasing ionisation density (linear energy transfer, LET) of the IR, such that photon (X-ray) radiotherapy is deemed low-LET whereas some particle ions (such as carbon ions) are high-LET radiotherapy. Despite this knowledge, there are challenges in the detection and quantitative measurement of IR-induced CDD in cells and tissues. Furthermore, there are biological uncertainties with the specific DNA repair proteins and pathways, including components of DNA single and double strand break mechanisms, that are engaged in CDD repair, which very much depends on the radiation type and associated LET. However, there are promising signs that advancements are being made in these areas and which will enhance our understanding of the cellular response to CDD induced by IR. There is also evidence that targeting CDD repair, particularly through inhibitors against selected DNA repair enzymes, can exacerbate the impact of higher LET, which could be explored further in a translational context. [ABSTRACT FROM AUTHOR]

The strong cell killing effect of high linear energy transfer (LET) carbon ions is dependent on lethal DNA damage. Our recent studies suggest that induction of clusters of double-strand breaks (DSBs) in close proximity is one of the potential mechanisms. However, the relationship between LET, the degree of DSB clustering and the cell killing effect of carbon ions remains unclear. Here, we used high-resolution imaging technology to analyze the volume of γH2AX foci induced by monoenergetic carbon ions with a clinically-relevant range of LET (13–100 keV/μm). We obtained data from 3317 γH2AX foci and used a gaussian function to approximate the probability (p) that 1 Gy-carbon ions induce γH2AX foci of a given volume (vth) or greater per nucleus. Cell killing effects were assessed in clonogenic assays. The cell killing effect showed high concordance with p at vth  = 0.7 μm3 across various LET values; the difference between the two was 4.7% ± 2.2%. This relationship was also true for clinical carbon ion beams harboring a mixed LET profile throughout a spread-out Bragg peak width (30–120 mm), with the difference at vth  = 0.7 μm3 being 1.6% ± 1.2% when a Monte Carlo simulation-derived dose-averaged LET was used to calculate p. These data indicate that the cell killing effect of carbon ions is predictable by the ability of carbon ions to induce γH2AX foci containing clustered DSBs, which is linked to LET, providing the biological basis for LET modulation in the planning of carbon ion radiotherapy. [ABSTRACT FROM AUTHOR]

Objective: To explore the effect of carbon ion radiotherapy (CIRT) on the bone marrow adjacent to or within the treatment fields, and to observe the bone marrow toxicities after CIRT alone. Methods: Twenty-one patients with malignant tumors of different body parts and treated with CIRT in Heavy Ion Center, Wuwei Cancer Hospital were analyzed retrospectively. The data of white blood cells, neutrophils, hemoglobin, platelets, lymphocytes and globulin before treatment, 7, 14 and 28 ​d during treatment, and 1 and 3 months after treatment were collected. Hematological toxicities were measured according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03) criteria. Dose-volume histogram parameters were obtained for all patients and analyzed for their correlation with myelosuppression. Univariate analysis was performed for patients’ sex, age group, tumor site, radiation dose, and Karnofsky performance score (KPS) was used as an independent factor to find predictors factors for the risk of myelosuppression. Results: CIRT minimized the dose radiated to the bone marrow. Overall, volume receiving 3 GyE(V3) or more of the bone marrow were less than 0.5%, especially V5 less than 0.1%. No patients treated with carbon ion radiotherapy developed grade III or IV myelosuppression. Seven patients (33.3%) developed grade I myelosuppression and one patient (4.8%) developed grade II myelosuppression, and most of them showed reduced white blood cell counts. There were no significant differences in hemoglobin and globulin levels before and after CIRT. Univariate analysis did not find any statistically significant predictors for myelosuppression. Conclusions: CIRT is effective in preserving bone marrow function regardless of tumor site. Patients receiving CIRT alone have a low incidence of grade I−II myelosuppression and a mild effect on globulins. There was no significant correlation between occurrence of myelosuppression and the dose and site irradiated by CIRT.

Human spaceflight is associated with several health-related issues as a result of long-term exposure to microgravity, ionizing radiation, and higher levels of psychological stress. Frequent reported skin problems in space include rashes, itches, and a delayed wound healing. Access to space is restricted by financial and logistical issues; as a consequence, experimental sample sizes are often small, which limits the generalization of the results. Earth-based simulation models can be used to investigate cellular responses as a result of exposure to certain spaceflight stressors. Here, we describe the development of an in vitro model of the simulated spaceflight environment, which we used to investigate the combined effect of simulated microgravity using the random positioning machine (RPM), ionizing radiation, and stress hormones on the wound-healing capacity of human dermal fibroblasts. Fibroblasts were exposed to cortisol, after which they were irradiated with different radiation qualities (including X-rays, protons, carbon ions, and iron ions) followed by exposure to simulated microgravity using a random positioning machine (RPM). Data related to the inflammatory, proliferation, and remodeling phase of wound healing has been collected. Results show that spaceflight stressors can interfere with the wound healing process at any phase. Moreover, several interactions between the different spaceflight stressors were found. This highlights the complexity that needs to be taken into account when studying the effect of spaceflight stressors on certain biological processes and for the aim of countermeasures development. [ABSTRACT FROM AUTHOR]

Objective. Beams of stable ions have been a well-established tool for radiotherapy for many decades. In the case of ion beam therapy with stable 12C ions, the positron emitters 10,11C 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 isotopes 11C and 10C 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 × 107 ions in 4 spills for a total duration of 19.2 s, the PET activity range uncertainty for 10C, 11C and 12C 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 from 11C to 10C than when going from 12C to 11C. The much better precision for 10C is due to its much shorter half-life, which, contrary to the case of 11C, 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. [ABSTRACT FROM AUTHOR]

A study of the long-term consequences of the combined effect of synchronous quasi-chronic γ‑irradiation and anti-orthostatic suspension (AOS) with further irradiation of the head of rats with carbon 12C ions, taking into account the typological characteristics of higher nervous activity (HNA) of experimental animals, was carried out. It is shown that within six months the integrative effects of the studied effects are quite successfully leveled. At the same time, significant differences related to the typological characteristics of animals persist in the long term. Study of the spectral and amplitude–frequency characteristics of the EEG of rats after these effects was carried out. Significant differences in the average amplitudes and frequencies of the EEG were revealed in animals with different typological characteristics of the HNA. The change of the dominant rhythm in animals subjected to experimental influences is shown. Thus, in control animals, the θ‑rhythm is dominant, while in irradiated animals, the δ-rhythm dominates. The most important result was the registered significant changes in the electrophysiological activity of the rat brain even six months after irradiation. A significant frequency shift in the area of all rhythms indicates long-term violation of the electrophysiological activity of the brain. The results of neurochemical studies revealed significant differences in the metabolism of monoamines in key brain structures of animals with different typological characteristics of HNA, combined with their manifestation at the integrative level (in animal behavior). [ABSTRACT FROM AUTHOR]

The combined effect of protective agents (helium-neon laser, ibuprofen, mexidol) and 3 Gy of accelerated carbon ions (12C) on the cognitive abilities of mice was studied. It was shown that the irradiated animals did not exhibit an altered behavior pattern: the level of anxiety was not increased, there was a slower positive dynamics of learning compared to the control, and there was no deficit in the hippocampus-dependent memory. Analysis of variance of learning curves revealed different coefficients of skill acquisition within the experimental groups, with the lowest characteristic for the group irradiated with a dose of 3 Gy 12C without protective agents. In addition, the analysis of the preference for novelty when testing for recognition of a new object showed that this group of animals has a violation of the nonspatial hippocampus-mediated short-term memory. [ABSTRACT FROM AUTHOR]

The goal of this study is to experimentally validate PIXE modelling using the Geant4-ANSTO model (" G4-ANSTO "), distributed for the first time in Geant4 11.0, as well as the Geant4 default model (" G4-default "), for targets bombarded with carbon ions of energies up to 3 MeV/amu, an energy range of importance for PIXE applications. The experimental validation was performed using a variety of target materials, spanning a broad atomic number range. The reference experimental measurements were performed at the ANSTO heavy ion microprobe beamline ANTARES. To the authors' knowledge, this is the first benchmarking investigation for PIXE simulations in Geant4 utilising carbon ions and it is significant for PIXE-based elemental analysis, encompassing archaeological samples, gas samples, environmental and planetary samples for geological and planetary research studies. It is also of relevance for any physics application, requiring the modelling of particle induced atomic de-excitation or atomic de-excitation only. [ABSTRACT FROM AUTHOR]

The data of the study of the radioprotective properties of nanocerium (nCeO2) after total irradiation of mice with carbon ions in medium and lethal doses according to the micronucleus test and the criterion of 30-day survival are presented. A significant protective effect of nCeO2 upon irradiation at medium doses was observed at per os administration for 5 days before irradiation (that is, at long-term prophylactic use). Mouse survival data showed no protective effect of per os administration of nCeO2 in contrast to the micronucleus test results. After injections of both nCeO2 and saline solution 24 h before or immediately after irradiation, the radioprotective effect was detected using both methods. The data obtained revealed the dependence of the observed effects on the mode and time of nCeO2 administration, the influence of the solvent, the level of doses and the quality of radiation, as well as demonstrated the possibility of using nanocerium preparations to protect organisms from radiation with high LET values and the importance of further studies of the radioprotective properties of new nanomaterials. [ABSTRACT FROM AUTHOR]

• Phase II study on safety and feasibility of hypofractionated proton and carbon ion beam therapy for sacrococcygeal chordomas. • The trial enrolled 82 patients, achieving 96% 2-year and 81% 4-year overall survival rates. • Local progression-free survival rates were 84% at 2 years and 70% at 4 years. • The treatment with carbon ions or protons was delivered in 16 fractions of 4 Gy RBE over 5-6 fractions per week. • No significant differences were observed between the proton and carbon ion therapy groups with this distinct fractionation scheme. Sacrococcygeal chordomas have high recurrence rates and are challenging to treat. In this phase II prospective, randomized, stratified trial, the safety and feasibility of hypofractionated ion radiation therapy were investigated. The primary focus was monitored through the incidence of Grade 3–5 NCI-CTC-AE toxicity. Secondary endpoints included local progression-free (LPFS) and overall survival (OS). The study enrolled 82 patients with primary (87 %) and recurrent (13 %) inoperable or incompletely resected sacral chordomas from January 2013 to July 2022, divided equally into proton therapy (Arm A) and carbon ion beam therapy (Arm B) groups, each receiving a total dose of 64 Gy (RBE) in 16 fractions, 5–6 fractions per week. Overall 74 % of patients received no previous surgery and 66 % of tumors were confirmed by a brachyury staining. The mean and median Gross Tumor Volume at the time of treatment (GTV) was 407 ml and 185 ml, respectively. The median follow-up of the surviving patients was 44.7 months, and the 2-year and 4-year OS rates were 96 % and 81 %, respectively. Factors such as smaller GTV and younger age trended towards better OS. The LPFS after 2-year and 4-year was 84 % and 70 %, respectively. Male gender emerged as a significant predictor of LPFS. There was no significant difference between the treatment groups. We observed five grade 4 wound healing disorders (6 %). The initial response rates were promising; however local control was not sustained. More comparative research on fractionation schemes is essential to refine treatment approaches for inoperable sacral chordoma. [ABSTRACT FROM AUTHOR]

• K X-ray production cross by impact of 12C and 13C ions were measured. • This is the first time that 13C ions are used to induce K X-rays of transition metals. • An isotopic effect is observed. • The cross sections measured for 13C are lower than those for 12C at the same energies. • The cross sections are similar for equal velocity ions. K X-ray production cross sections of Co, Ni, and Zn due to the impact of 2.48 MeV to 3.84 MeV 12C3+ and 13C3+ ions were experimentally determined using the thick target approach. It was possible to observe differences in the cross sections due to the distinct mass of the ions. A reduced variable v 1 / v 2K , where v 1 is the ion velocity and v 2K is the (Bohr) electron orbital velocity, was considered to scale the ion energies. When the data were plotted as a function of the reduced variable, a single curve was obtained for all targets and both isotopes. Comparisons with several models were also made, including corrections due to electron capture and multiple ionization. It was found that the adiabatic perturbation with molecular orbitals formation, plus electron capture and multiple ionization corrections, is the theory that better describes the experimental results. [ABSTRACT FROM AUTHOR]

Introduction: Radiotherapy represents a major treatment option for patients with pancreatic cancer, however, its benefits remain limited also due to the ability of cancer cells to migrate to the surrounding tissues. Low-LET ionizing radiation is well known to promote tumor cell migration and invasion, nevertheless, little data provided by studies using high-LET radiation has led to ambiguous findings. What is hypothesized to be fundamental in the modulation of migration of tumor cells exposed to ionizing radiation is the influence of the microenvironment. Therefore, the properties of cells that populate the tumor stroma cannot be ignored when studying the influence of radiation on the migratory and invasive capacity of cancer cells. This is especially important in the case of pancreatic malignancies that are characterized by an abundance of stromal cells, including cancer-associated fibroblasts, which are known to orchestrate the cross-talk with tumor cells. Aim: The current study aims to investigate whether the presence of factors released by irradiated fibroblasts affects the migratory and invasive capacity of pancreatic cancer cells exposed to different doses of photons or C-ions. Materials and methods: AsPC-1 and AG01522 cells were irradiated with the same dose of photons or C-ions at room temperature. Through Boyden chamber assay, we tested whether factors secreted by irradiated fibroblasts may influence tumor cell migration, while the invasiveness of AsPC-1 cells was assessed using matrigel precoated inserts in which medium collected from non-irradiated (0 Gy), photon and C-ion irradiated fibroblasts, was added. Data were analyzed by Student t-test using GraphPad software. The mean ± s.d. was determined with a significance level of p<0.05. Results: In the presence of conditioned medium collected from 1 Gy and 2 Gy photon irradiated fibroblasts, the number of migrated tumor cells increased (P<0.0360, P<0.0001) but decreased at 4 Gy dose (P<0.002). There was a trend of reduction in migration (P<0.0460, P<0.038, P<0.0024, P<0.0002), as well as a decrease in invasiveness (P<0.0525, P<0.0035, P<0.0868, P<0.0310) after exposure to 0.5 Gy, 1 Gy, 2 Gy and 4 Gy of C-ions. Conclusions: The presence of irradiated fibroblasts affected the invasiveness capability of pancreatic cancer cells, probably by the reciprocal release of soluble factors whose production is differently modulated after high or low- LET radiation. Understanding the effects of irradiation on the metastatic potential of pancreatic cancer cells is of utmost importance for improving the outcome and tailoring the therapeutic approach. This challenging scenario requires a continuous and multidisciplinary approach that involves clinicians together with researcher experts in oncological and radiation treatment. In the last years, including preclinical experiences in a multidisciplinary approach has proved to be a winning strategy in clinical oncological research. [ABSTRACT FROM AUTHOR]

[Display omitted] • FLASH radiotherapy with carbon ions was demonstrated for the first time in vivo. • FLASH (100 Gy/s) reduced normal tissue toxicity and tumor growth. • FLASH irradiation reduces the number of lung metastases. The FLASH effect is a potential breakthrough in radiotherapy because ultra-high dose-rate irradiation can substantially widen the therapeutic window. While the normal tissue sparing at high doses and short irradiation times has been demonstrated with electrons, photons, and protons, so far evidence with heavy ions is limited to in vitro cell experiments. Here we present the first in vivo results with high-energy 12C-ions delivered at an ultra-high dose rate. LM8 osteosarcoma cells were subcutaneously injected in the posterior limb of female C3H/He mice 7 days before radiation exposure. Both hind limbs of the animals were irradiated with 240 MeV/n 12C-ions at ultra-high (18 Gy in 150 ms) or conventional dose rate (∼18 Gy/min). Tumor size was measured until 28 days post-exposure, when animals were sacrificed and lungs, limb muscles, and tumors were collected for further histological analysis. Irradiation with carbon ions was able to control the tumour both at conventional and ultra-high dose rate. FLASH decreases normal tissue toxicity as demonstrated by the reduced structural changes in muscle compared to conventional dose-rate irradiation. Carbon ion irradiation in FLASH conditions significantly reduced lung metastasis compared to conventional dose-rate irradiation and sham-irradiated animals. We demonstrated the FLASH effect in vivo with high-energy carbon ions. In addition to normal tissue sparing, we observed tumor control and a substantial reduction of lung metastasis in an osteosarcoma mouse model. [ABSTRACT FROM AUTHOR]

Chondrosarcomas are particularly difficult to treat due to their resistance to chemotherapy and radiotherapy. However, particle therapy can enhance local control and patient survival rates. To improve our understanding of the basic cellular radiation response, as a function of dose and linear energy transfer (LET), we developed a novel water phantom-based setup for cell culture experiments and characterized it dosimetrically. In a direct comparison, human chondrosarcoma cell lines were analyzed with regard to their viability, cell proliferation, cell cycle, and DNA repair behavior after irradiation with X-ray, proton, and carbon ions. Our results clearly showed that cell viability and proliferation were inhibited according to the increasing ionization density, i.e., LET, of the irradiation modes. Furthermore, a prominent G2/M arrest was shown. Gene expression profiling proved the upregulation of the senescence genes CDKN1A (p21), CDKN2A (p16NK4a), BMI1, and FOXO4 after particle irradiation. Both proton or C-ion irradiation caused a positive regulation of the repair genes ATM, NBN, ATXR, and XPC, and a highly significant increase in XRCC1/2/3, ERCC1, XPC, and PCNA expression, with C-ions appearing to activate DNA repair mechanisms more effectively. The link between the physical data and the cellular responses is an important contribution to the improvement of the treatment system. [ABSTRACT FROM AUTHOR]

Purpose: Primary gynecological melanomas are uncommon with lower survival rates compared to cutaneous melanomas. Although melanocytes have been identified in a variety of mucosal membranes, little is known about their interactions or roles inside the mucosa layer. Melanin is a common pigment in nature and is endowed with several peculiar chemical, paramagnetic, and semiconductive characteristics. One of its latest explored functions is its interaction with ionizing radiation as a protective mechanism as well as its implication in the metastatic cascade of tumor cells., Materials and Methods: In this work, we analyzed in vitro the effects of different doses of photon and carbon ion irradiation on dendrite formation, pigmentation, migration, and invasion abilities of human mucosal melanoma cells of the vagina. We evaluated the morphology and melanin production of HMV-II cells exposed to photon and carbon ion beams with single doses between 0.5 and 10 Gy., Results: Our results showed that irradiation induces dendrite formation or elongation and pigmentation in HMV-II cells in a dose-type-dependent and radiation-type-dependent way but also a decrease in cell motility., Conclusion: The present study describes for the first time an induction of dendritic formation, melanin production, and alterations in migration and invasion abilities by low-linear energy transfer and high-linear energy transfer radiation in human mucosal melanoma cells, suggesting a radioprotective response to further possible exposures increasing the radioresistance of these cells., (© 2024 The Author(s).)

IntroductionRadiotherapy represents a major treatment option for patients with pancreatic cancer, however, its benefits remain limited also due to the ability of cancer cells to migrate to the surrounding tissues. Low-LET ionizing radiation is well known to promote tumor cell migration and invasion, nevertheless, little data provided by studies using high-LET radiation has led to ambiguous findings. What is hypothesized to be fundamental in the modulation of migration of tumor cells exposed to ionizing radiation is the influence of the microenvironment. Therefore, the properties of cells that populate the tumor stroma cannot be ignored when studying the influence of radiation on the migratory and invasive capacity of cancer cells. This is especially important in the case of pancreatic malignancies that are characterized by an abundance of stromal cells, including cancer-associated fibroblasts, which are known to orchestrate the cross-talk with tumor cells.AimThe current study aims to investigate whether the presence of factors released by irradiated fibroblasts affects the migratory and invasive capacity of pancreatic cancer cells exposed to different doses of photons or C-ions.Materials and methodsAsPC-1 and AG01522 cells were irradiated with the same dose of photons or C-ions at room temperature. Through Boyden chamber assay, we tested whether factors secreted by irradiated fibroblasts may influence tumor cell migration, while the invasiveness of AsPC-1 cells was assessed using matrigel precoated inserts in which medium collected from non-irradiated (0 Gy), photon and C-ion irradiated fibroblasts, was added. Data were analyzed by Student t-test using GraphPad software. The mean ± s.d. was determined with a significance level of p

Particle minibeam therapy has demonstrated the potential for better healthy tissue sparing due to spatial fractionation of the delivered dose. Especially for heavy ions, the spatial fractionation could enhance the already favorable differential biological effectiveness at the target and the entrance region. Moreover, spatial fractionation could even be a viable option for bringing ions heavier than carbon back into patient application. To understand the effect of minibeam therapy, however, requires careful conduction of pre-clinical experiments, for which precise knowledge of the minibeam characteristics is crucial. This work introduces the use of high-spatial-resolution CMOS sensors to characterize collimator-produced carbon ion minibeams in terms of lateral fluence distribution, secondary fragments, track-averaged linear energy transfer distribution, and collimator alignment. Additional simulations were performed to further analyze the parameter space of the carbon ion minibeams in terms of beam characteristics, collimator positioning, and collimator manufacturing accuracy. Finally, a new concept for reducing the neutron dose to the patient by means of an additional neutron shield added to the collimator setup is proposed and validated in simulation. The carbon ion minibeam collimator characterized in this work is used in ongoing pre-clinical experiments on heavy ion minibeam therapy at the GSI.

Purpose: Dose distribution in carbon‐ion irradiations is generally envisaged to have therapeutic advantages over protons, primarily due to the carbon ion's comparatively higher relative biological effectiveness in the tumor than in the encompassing healthy tissues. The objective of this work was to simulate the overall physical and chemical reactions of primary carbon ions impinging on liquid water and, as such, to investigate the DNA‐damage yields in the form of strand breaks (SBs) and in connection with the expected microdosimetric quantities. Materials and methods: Using a B‐DNA model and Geant4‐DNA, we simulated the primary and secondary interactions in a spherical medium of water. Subsequently, we categorized DNA damages based on their complexity utilizing the concept of μ‐randomness. We assumed a threshold of 17.5 eV for a direct SB and a probability of 0.13 for an indirect SB triggered by chemical reactions of hydroxyl radicals. Microdosimetric quantities were extracted for three cylindrical volumes representing typical subcellular organisms. Results: For fully ionized carbons of 8–256 MeV/u, the yield results appeared to be considerably influenced by the chemical reactions—indicating the important role of secondary electrons in inflicting damage. However, it was mostly the direct‐damage spectrum that determined the overall shape of the damage spectrum. At all primary energies, it was more probable to break each DNA strand at one point—the two points being less than 10 bp apart—than to break only one strand at two random points. Unlike proton's mean‐specific‐energy results, which showed more sensitivity to the volume increase of the smallest cylinder than of the larger ones, carbon‐ion results showed no such sensitivity. Conclusion: The growth of the yield ratio of the single‐ and double‐strand breaks (DSB) with the particle energy was estimated for protons to be about 2 times that of alphas and 92 times that of carbon ions. Unlike the proton results, which suggested significant correlations between the DSB yields and mean‐specific (and lineal) energies, carbon ions exhibited no such correlations. [ABSTRACT FROM AUTHOR]

We study the impact of radiation LET on manifestation of HRS/IRR response in Chinese hamster cells ovary cells exposed to radiations used in radiotherapy. Earlier we have investigated this response to carbon ions (455 MeV/amu) in the pristine Bragg curve plateau and behind the Bragg peak, 60Co γ-rays, and 14.5 MeV neutrons. Now we present results of cytogenetic metaphase analysis in plateau-phase CHO-K1 cells irradiated with scanning beam protons (83 MeV) at doses < 1 Gy and additional data for 14.5 MeV neutrons. Dose curves for frequency of total chromosome aberrations (CA, protons), paired fragments (protons, neutrons), aberrant cells (neutrons) had typical HRS/IRR structure: HRS region (up to 0.1 and 0.15 Gy), IRR region (0.1–0.6 Gy and 0.15–0.35 Gy) for protons and neutrons, respectively, and regular dose dependence. Taken together with previous results, the data show that LET increase shifts the HRS upper border (from 0.08–0.1 Gy for γ-rays, protons and plateau carbons to 0.12–0.15 Gy for "tail" carbons and neutrons). The IRR regions shortens (0.52–0.4 γ-rays and protons, 0.25 plateau carbons, 0.2 Gy "tail" carbons and neutrons). CA level of IRR increases by 1.5–2.5 times for carbons as compared to γ-rays and protons. Outside HRS/IRR the yield of CA also enhanced with LET increase. The results obtained for different LET radiations suggest that CHO-K1 cells with G1-like CA manifested the general feature of the HRS/IRR phenomena. [ABSTRACT FROM AUTHOR]

Purpose: The Local Effect Model version one (LEM I) is applied clinically across Europe to quantify the relative biological effectiveness (RBE) of carbon ion beams. It requires the full particle fluence spectrum differential in energy in each voxel as input parameter. Treatment planning systems (TPSs) use beamline‐specific look‐up tables generated with Monte Carlo (MC) codes. In this study, the changes in RBE weighted dose were quantified using different levels of details in the simulation or different MC codes. Methods: The particle fluence differential in energy was simulated with FLUKA and Geant4 at 500 depths in water in 1‐mm steps for 58 initial carbon ion energies (between 120.0 and 402.8 MeV/u). A dedicated beam model was applied, including the full description of the Nozzle using GATE‐RTionV1.0 (Geant4.10.03p03). In addition, two tables generated with FLUKA were compared. The starting points of the FLUKA simulations were phase space (PhS) files from, firstly, the Geant4 nozzle simulations, and secondly, a clinical beam model where an analytic approach was used to mimic the beamline. Treatment plans (TPs) were generated with RayStation 8B (RaySearch Laboratories AB, Sweden) for cubic targets in water and 10 clinical patient cases using the clinical beam model. Subsequently, the RBE weighted dose was re‐computed using the two other fluence tables (FLUKA PhS or Geant4). Results: The fluence spectra of the primary and secondary particles simulated with Geant4 and FLUKA generally agreed well for the primary particles. Differences were mainly observed for the secondary particles. Interchanging the two energy spectra (FLUKA vs. GEANT4) to calculate the RBE weighted dose distributions resulted in average deviations of less than 1% in the entrance up to the end of the target region, with a maximum local deviation at the distal edge of the target. In the fragment tail, larger discrepancies of up to 5% on average were found for deep‐seated targets. The patient and water phantom cases demonstrated similar results. Conclusion: RBE weighted doses agreed well within all tested setups, confirming the clinical beam model provided by the TPS vendor. Furthermore, the results showed that the open source and generally available MC code Geant4 (in particular using GATE or GATE‐RTion) can also be used to generate basic beam data required for RBE calculation in carbon ion therapy. [ABSTRACT FROM AUTHOR]

Abstract Background Adenoid cystic carcinoma is a rare form of head and neck cancer with a slow, but aggressive growth pattern which remains a challenge for local tumor control. Based on phase II data, radiation treatment using partially high LET radiation results in a prolonged PFS and OS. There is a paucity of randomized clinical data examining the role of the use of high LET radiation only. Therefore, the purpose of this prospective clinical trial is to analyze local control rates in patients with node negative ACC treated with carbon ion radiotherapy alone compared to a combined modality approach. Methods This trial is conducted as a prospective, open-label, phase II, two-armed, investigator-initiated study comparing the local control rates in node negative ACCs of the head and neck treated either with sole carbon ion radiotherapy or a combination of carbon ions and photons. Secondary outcomes investigated are progression-free survival, overall survival, acute and late toxicity, and quality of life. A total of 314 patients will be randomly assigned to C12 treatment alone or bimodal treatment: Patients in the experimental group will receive a dose of 51 Gy (RBE) in 17 fractions and a boost of 15 Gy (RBE) in 5 fractions. Patients in the control group will receive 25 fractions photon IMRT 50Gy and a boost using 8 × 3 Gy (RBE) carbon ions. Local control will be assessed in regular follow up examinations until 5 years after the completion of treatment. Discussion The present trial aims to evaluate local control rates to compare sole carbon ion radiotherapy to bimodal radiotherapy with carbon ions and photons in patients with node negative ACCs of the head and neck region. Local control is selected as the primary endpoint due to its major clinical relevance because of slow but aggressive growth patterns. Trial registration The study was prospectively registered on 2nd January 2020: ClinicalTrials.gov, NCT04214366 . “Adenoid Cystic Carcinoma and Carbon Ion Only Irradiation (ACCO)”. Study status Under recruitment, participant recruitment is not completed. Start of recruitment was January 2020. There are no results been published or submitted to any journal.

Radiotherapy (ionising radiation; IR) is utilised in the treatment of ~50% of all human cancers, and where the therapeutic effect is largely achieved through DNA damage induction. In particular, complex DNA damage (CDD) containing two or more lesions within one to two helical turns of the DNA is a signature of IR and contributes significantly to the cell killing effects due to the difficult nature of its repair by the cellular DNA repair machinery. The levels and complexity of CDD increase with increasing ionisation density (linear energy transfer, LET) of the IR, such that photon (X-ray) radiotherapy is deemed low-LET whereas some particle ions (such as carbon ions) are high-LET radiotherapy. Despite this knowledge, there are challenges in the detection and quantitative measurement of IR-induced CDD in cells and tissues. Furthermore, there are biological uncertainties with the specific DNA repair proteins and pathways, including components of DNA single and double strand break mechanisms, that are engaged in CDD repair, which very much depends on the radiation type and associated LET. However, there are promising signs that advancements are being made in these areas and which will enhance our understanding of the cellular response to CDD induced by IR. There is also evidence that targeting CDD repair, particularly through inhibitors against selected DNA repair enzymes, can exacerbate the impact of higher LET, which could be explored further in a translational context.

Primary mucosal melanoma (PMM) and pancreatic ductal adenocarcinoma (PDAC) are two aggressive malignancies, characterized by intrinsic radio-chemoresistance and neurotropism, a histological feature resulting in frequent perineural invasion (PNI), supported by neurotrophic factors secreted in the tumour microenvironment (TME), such as neurotrophin-3 (NT-3). Carbon-ion radiotherapy (CIRT) could represent an effective option in unresectable PMM and PDAC. Only a few data about the effects of CIRT on PNI in relation to NT-3 are available in the literature, despite the numerous pieces of evidence revealing the peculiar effects of this type of radiation on tumour cell migration. This in vitro study investigated for the first time the response of PMM and PDAC cells to NT-3 and evaluated the effects of conventional photon beam radiotherapy (XRT) and CIRT on cell viability, proliferation, and migration. Our results demonstrated the greater capacity of C-ions to generally decrease cell viability, proliferation, and migration, while the addition of NT-3 after both types of irradiation determined an increase in these features, maintaining a dose-dependent trend and acting more effectively as a chemoattractant than inductor in the case of migration.

Simple Summary: We present the early results of a novel partial bulky-tumor irradiation using carbon ions and protons. This approach explores the radiation-induced bystander and abscopal effects in patients with recurrent unresectable bulky tumors who failed previous state-of-the-art treatments including radio-chemotherapy. Early tumor response, symptom relief and minimal toxicity suggest that the partial bulky-tumor irradiation was an effective, safe and well tolerated treatment. Abscopal effects elucidate an immunogenic pathway contribution. Background: We present the early results of a novel partial bulky-tumor irradiation using particles for patients with recurrent unresectable bulky tumors who failed previous state-of-the-art treatments. Methods: First, eleven consecutive patients were treated from March 2020 until December 2021. The targeted Bystander Tumor Volume (BTV) was created by subtracting 1 cm from Gross Tumor Volume (GTV) surface. It reflected approximately 30% of the central GTV volume and was irradiated with 30–45 Gy RBE (Relative Biological Effectiveness) in three consecutive fractions. The Peritumoral Immune Microenvironment (PIM) surrounding the GTV, containing nearby tissues, blood-lymphatic vessels and lymph nodes, was considered an organ at risk (OAR) and protected by highly conservative constraints. Results: With the median follow up of 6.3 months, overall survival was 64% with a median survival of 6.7 months; 46% of patients were progression-free. The average tumor volume regression was 61% from the initial size. The symptom control rate was 91%, with an average increase of the Karnofsky Index of 20%. The abscopal effect has been observed in 60% of patients. Conclusions: Partial bulky-tumor irradiation is an effective, safe and well tolerated treatment for patients with unresectable recurrent bulky disease. Abscopal effects elucidate an immunogenic pathway contribution. Extensive tumor shrinkage in some patients might permit definitive treatment—otherwise previously impossible. [ABSTRACT FROM AUTHOR]

Simple Summary: Using a consistent experimental protocol, we found a large heterogeneity in the relative biological effectiveness (RBE) values of both proton and carbon-ion beams in various sarcomas and normal-tissue-derived cell lines. Our data suggest that proton beam therapy may be more beneficial for some types of tumors. In carbon-ion therapy, for some types of tumors, large heterogeneity in RBE should prompt consideration of dose reduction or an increased dose per fraction. In particular, a higher RBE value in normal tissues requires caution. Specific dose evaluations for tumor and normal tissues are needed for both proton and carbon-ion therapies. This study investigated variations in the relative biological effectiveness (RBE) values among various sarcoma and normal-tissue-derived cell lines (normal cell line) in proton beam and carbon-ion irradiations. We used a consistent protocol that specified the timing of irradiation after plating cells and detailed the colony formation assay. We examined the cell type dependence of RBE for proton beam and carbon-ion irradiations using four human sarcoma cell lines (MG63 osteosarcoma, HT1080 fibrosarcoma, SW872 liposarcoma, and SW1353 chondrosarcoma) and three normal cell lines (HDF human dermal fibroblast, hTERT-HME1 mammary gland, and NuLi-1 bronchus epithelium). The cells were irradiated with gamma rays, proton beams at the center of the spread-out Bragg peak, or carbon-ion beams at 54.4 keV/μm linear energy transfer. In all sarcoma and normal cell lines, the average RBE values in proton beam and carbon-ion irradiations were 1.08 ± 0.11 and 2.08 ± 0.36, which were consistent with the values of 1.1 and 2.13 used in current treatment planning systems, respectively. Up to 34% difference in the RBE of the proton beam was observed between MG63 and HT1080. Similarly, a 32% difference in the RBE of the carbon-ion beam was observed between SW872 and the other sarcoma cell lines. In proton beam irradiation, normal cell lines had less variation in RBE values (within 10%), whereas in carbon-ion irradiation, RBE values differed by up to 48% between hTERT-HME1 and NuLi-1. Our results suggest that specific dose evaluations for tumor and normal tissues are necessary for treatment planning in both proton and carbon-ion therapies. [ABSTRACT FROM AUTHOR]

The results of the effect of high-fluence irradiation (fluence ~3 × 1018 cm–2) with 30-keV C+ ions at a temperature of 250°C on the structure and surface morphology of polyacrylonitrile-based carbon fibers reinforcing the composite KUP-VM are presented and discussed. Scanning electron microscopy shows that the irradiation of carbon fibers with their own ions does not lead, as in the cases of irradiation with ions of inert gases and nitrogen, to corrugation of the fiber surface. The roughness of the composite surface remains comparable to the nonirradiated sample. According to Raman-spectroscopy data, irradiation with carbon ions at temperatures above that of dynamic annealing of radiation-induced damage leads to the formation of a disordered graphite-like layer, as in the cases of irradiation with inert-gas ions. The lack of corrugation of the carbon-fiber surface under irradiation with carbon ions is associated with the lack of a gradient of radiation-induced damage in the modified layer and a texture characteristic of a carbon-fiber shell based on polyacrylonitrile. [ABSTRACT FROM AUTHOR]