A Promising Treatment Strategy for Lung Cancer: A Combination of Radiotherapy and Immunotherapy

Lung cancer is a leading cause of cancer-related deaths worldwide despite advances in treatment. In the past few decades, radiotherapy has achieved outstanding technical advances and is being widely used as a definitive, prophylactic, or palliative treatment of patients with lung cancer. The anti-tumor effects of radiotherapy are considered to result in DNA damage in cancer cells. Moreover, recent evidence has demonstrated another advantage of radiotherapy: the induction of anti-tumor immune responses, which play an essential role in cancer control. In contrast, radiotherapy induces an immunosuppressive response. These conflicting reactions after radiotherapy suggest that maximizing immune response to radiotherapy by combining immunotherapy has potential to achieve more effective anti-tumor response than using each alone. Immune checkpoint molecules, such as cytotoxic T-lymphocyte-associated protein 4, programmed cell death-1/programmed death-ligand 1, and their inhibitors, have attracted significant attention for overcoming the immunosuppressive conditions in patients with cancer. Therefore, the combination of immune checkpoint inhibitors and radiotherapy is promising. Emerging preclinical and clinical studies have demonstrated the rationale for these combination strategies. In this review, we outlined evidence suggesting that combination of radiotherapy, including particle therapy using protons and carbon ions, with immunotherapy in lung cancer treatment could be a promising treatment strategy.

Synchrotron FTIR Microspectroscopy Investigations on Biochemical Changes Occurring in Human Cells Exposed to Proton Beams

Fourier transform infrared microspectroscopy using a synchrotron radiation source (SR-μFTIR) has great potential in the study of the ionizing radiation effects of human cells by analyzing the biochemical changes occurring in cell components. SR-μFTIR spectroscopy has been usefully employed in recent years in some seminal work devoted to shedding light on processes occurring in cells treated by hadron therapy, that is, radiotherapy with charged heavy particles (mainly protons and carbon ions), which is gaining popularity as a cancer treatment modality. These studies are particularly useful for increasing the effectiveness of radiotherapy cancer treatments with charged particles that can offer significant progress in the treatment of deep-seated and/or radioresistant tumors. In this paper, we present a concise revision of these studies together with the basic principles of μFTIR spectroscopy and a brief presentation of the main characteristics of infrared SR sources. From the analysis of the literature regarding the SR-μFTIR spectroscopy investigation on human cells exposed to proton beams, it is clearly shown that changes in DNA, protein, and lipid cell components are evident. In addition, this review points out that the potential offered by SR-μFTIR in investigating the effects induced by charged particle irradiation have not been completely explored. This is a crucial point for the continued improvement of hadron therapy strategies.

Synergetic effects of the combined action of carbon ions and the chemotherapy drug doxorubicin on HeLa cancer cells

Proton and carbon beam therapy is currently recognized as the most effective and highly accurate form of radiation therapy for deeply located tumors, including radioresistant ones. This is due to the fact that they have all the advantages of spatial dose distribution and, at the same time, are densely ionizing radiations capable of effectively affecting hypoxic, slow-growing tumors and other neoplasms that are insensitive to traditional types of radiation. It is well known that one of the main methods for treating neoplasms is chemotherapy. The predominant mechanism of action of anti-tumor drugs is the induction of DNA damage with the subsequent impossibility of repair. In our study, we used an anti-tumor antibiotic of the anthracycline series, doxorubicin. The assessment of the potential significance of the synergistic interaction of ionizing radiation with chemical preparations in medical radiology remains an urgent and unresolved problem. It is possible to achieve the maximum effect of the combined action of two agents when they act simultaneously. The phenomenon of synergy can be used to optimize the combined use of radiation and chemotherapy in clinical practice. In this regard, it seems relevant to conduct a study for HeLa cancer cells exposed to ionizing radiation, an antitumor drug, as well as their combination. In the course of the study, results were obtained on the manifestation of the synergistic nature of the agents used, which is of great practical and theoretical importance for understanding the mechanism of the combined effect of ionizing radiation and the chemotherapy drug (doxorubicin). The obtained data can be helpful in optimizing the combined effects in order to achieve maximum synergistic interaction.

Circulating tRNA-Derived Small RNAs as Novel Radiation Biomarkers of Heavy Ion, Proton and X-ray Exposure

The effective and minimally invasive radiation biomarkers are valuable for exposure scenarios in nuclear accidents or space missions. Recent studies have opened the new sight of circulating small non-coding RNA (sncRNA) as radiation biomarkers. The tRNA-derived small RNA (tsRNA) is a new class of sncRNA. It is more abundant than other kinds of sncRNAs in extracellular vesicles or blood, presenting great potential as promising biomarkers. However, the circulating tsRNAs in response to ionizing radiation have not been reported. In this research, Kunming mice were total-body exposed to 0.05–2 Gy of carbon ions, protons, or X-rays, and the RNA sequencing was performed to profile the expression of sncRNAs in serum. After conditional screening and validation, we firstly identified 5 tsRNAs including 4 tRNA-related fragments (tRFs) and 1 tRNA half (tiRNA) which showed a significant level decrease after exposure to three kinds of radiations. Moreover, the radiation responses of these 5 serum tsRNAs were reproduced in other mouse strains, and the sequences of them could be detected in serum of humans. Furthermore, we developed multi-factor models based on tsRNA biomarkers to indicate the degree of radiation exposure with high sensitivity and specificity. These findings suggest that the circulating tsRNAs can serve as new minimally invasive biomarkers and can make a triage or dose assessment from blood sample collection within 4 h in exposure scenarios.

Assessment of secondary neutrons in particle therapy by Monte Carlo simulations

Objective: The purpose of this study is to estimate the energy and angular distribution of secondary neutrons inside a phantom in hadron therapy, which will support decisions on detector choice and experimental setup design for in-phantom secondary neutron measurements. Approach: Dedicated Monte Carlo simulations were implemented, considering clinically relevant energies of protons, helium and carbon ions. Since scored quantities can vary from different radiation transport models, the codes FLUKA, TOPAS and MCNP were used. The geometry of an active scanning beam delivery system for heavy ion treatment was implemented, and simulations of pristine and spread-out Bragg peaks were carried out. Previous studies, focused on specific ion types or single energies, are qualitatively in agreement with the obtained results. Main results: The secondary neutrons energy distributions present a continuous spectrum with two peaks, one centred on the thermal/epithermal region, and one on the high-energy region, with the most probable energy ranging from 19 MeV up to 240 MeV, depending on the ion type and its initial energy. The simulations show that the secondary neutron energies may exceed 400 MeV and, therefore, suitable neutron detectors for this energy range shall be needed. Additionally, the angular distribution of the low energy neutrons is quite isotropic, whereas the fast/relativistic neutrons are mainly scattered in the down-stream direction. Significance: It would be possible to minimize the influence of the heavy ions when measuring the neutron-generated recoil protons by selecting appropriate measurement positions within the phantom. Although there are discrepancies among the three Monte Carlo codes, the results agree qualitatively and in order of magnitude, being sufficient to support further investigations with the ultimate goal of mapping the secondary neutron doses both in- and out-of-field in hadrontherapy. The obtained secondary neutron spectra are available as supplementary material.

Ion beam technology for the resource enhancement of responsible parts of a high speed friction unit

The needles from carbon steel “U10”, a details of high speed couple of friction “needle-thrust plate” of the gas centrifuge is investigated, in the initial, post-operational state and after irradiation by C+ ions different doses on the pulse-frequency “Raduga” accelerator. The purpose of this study is to increase the operability and service life of the responsible friction unit of the gas centrifuge. This purpose is achieved by mod-ification of the working sliding surface of the needle (which is a responsible part of the high-speed friction pair “needle-thrust plate”) by the pulse-frequency implantation with carbon ions. The dose of implantation (1018 cm−2 of C+ ions), was established, at which an optimal combination of mechanical and tribological properties of the working surface is achieved, which provides wear resistance increase during the operation of the friction pair. This method of surface treatment is recommended to use in case of operation of couple of friction “needle-thrust plate” for the purpose of increase in working capacity and a resource of operation of high speed couple of friction of the gas centrifuge.

Medipix3 proton and carbon ion measurements across full energy ranges and at clinical flux rates in MedAustron IR1

The Medipix3, a hybrid pixel detector with a silicon sensor, has been evaluated as a beam instrumentation device with proton and carbon ion measurements in the non-clinical research room (IR1) of MedAustron Ion Therapy Center. Protons energies are varied from 62.4 to 800 MeV with 104 to 108 protons per second impinging on the detector surface. For carbon ions, energies are varied from 120 to 400 MeV/amu with 107 to 108 carbon ions per second. Measurements include simultaneous high resolution, beam profile and beam intensity with various beam parameters at up to 1000 FPS (frames per second), count rate linearity and an assessment of radiation damage after the measurement day using an x-ray tube to provide a homogeneous radiation measurement. The count rate linearity is found to be linear within the uncertainties (dominated by accelerator related sources due to special setup) for the measurements without degraders. Various frequency components are identified within the beam intensity over time firstly including 49.98 Hz with standard deviation, σ = 0.29, secondly 30.55 Hz σ = 0.55 and thirdly 252.51 Hz σ = 0.83. A direct correlation between the number of zero counting and noisy pixels is observed in the measurements with the highest flux. No conclusive evidence of long term radiation damage was found as a result of these measurements over one day.