Effect of Linear Energy Transfer on Cystamine's Radioprotective Activity: A Study Using the Fricke Dosimeter with 6-500 MeV per Nucleon Carbon Ions-Implication for Carbon Ion Hadrontherapy.

(1) Background: Radioprotective agents have garnered considerable interest due to their prospective applications in radiotherapy, public health medicine, and situations of large-scale accidental radiation exposure or impending radiological emergencies. Cystamine, an organic diamino-disulfide compound, is recognized for its radiation-protective and antioxidant properties. This study aims to utilize the aqueous ferrous sulfate (Fricke) dosimeter to measure the free-radical scavenging capabilities of cystamine during irradiation by fast carbon ions. This analysis spans an energy range from 6 to 500 MeV per nucleon, which correlates with "linear energy transfer" (LET) values ranging from approximately 248 keV/µm down to 9.3 keV/µm. (2) Methods: Monte Carlo track chemistry calculations were used to simulate the radiation-induced chemistry of aerated Fricke-cystamine solutions across a broad spectrum of cystamine concentrations, ranging from 10-6 to 1 M. (3) Results: In irradiated Fricke solutions containing cystamine, cystamine is observed to hinder the oxidation of Fe2+ ions, an effect triggered by oxidizing agents from the radiolysis of acidic water, resulting in reduced Fe3+ ion production. Our simulations, conducted both with and without accounting for the multiple ionization of water, confirm cystamine's ability to capture free radicals, highlighting its strong antioxidant properties. Aligning with prior research, our simulations also indicate that the protective and antioxidant efficiency of cystamine diminishes with increasing LET of the radiation. This result can be attributed to the changes in the geometry of the track structures when transitioning from lower to higher LETs. (4) Conclusions: If we can apply these fundamental research findings to biological systems at a physiological pH, the use of cystamine alongside carbon-ion hadrontherapy could present a promising approach to further improve the therapeutic ratio in cancer treatments.

Energy Deposition around Swift Carbon-Ion Tracks in Liquid Water.

Energetic carbon ions are promising projectiles used for cancer radiotherapy. A thorough knowledge of how the energy of these ions is deposited in biological media (mainly composed of liquid water) is required. This can be attained by means of detailed computer simulations, both macroscopically (relevant for appropriately delivering the dose) and at the nanoscale (important for determining the inflicted radiobiological damage). The energy lost per unit path length (i.e., the so-called stopping power) of carbon ions is here theoretically calculated within the dielectric formalism from the excitation spectrum of liquid water obtained from two complementary approaches (one relying on an optical-data model and the other exclusively on ab initio calculations). In addition, the energy carried at the nanometre scale by the generated secondary electrons around the ion's path is simulated by means of a detailed Monte Carlo code. For this purpose, we use the ion and electron cross sections calculated by means of state-of-the art approaches suited to take into account the condensed-phase nature of the liquid water target. As a result of these simulations, the radial dose around the ion's path is obtained, as well as the distributions of clustered events in nanometric volumes similar to the dimensions of DNA convolutions, contributing to the biological damage for carbon ions in a wide energy range, covering from the plateau to the maximum of the Bragg peak.

Endometrial Cancer: When Upfront Surgery Is Not an Option.

Background and Summary: The management of endometrial cancer, in an ever-older population with considerable comorbidity, remains a challenge for gynecological and radiation oncologists. Key Message: The present paper reviews literature data on treatment options for endometrial cancer patients unfit for surgery.

Healthy Tissue Damage Following Cancer Ion Therapy: A Radiobiological Database Predicting Lymphocyte Chromosome Aberrations Based on the BIANCA Biophysical Model.

Chromosome aberrations are widely considered among the best biomarkers of radiation health risk due to their relationship with late cancer incidence. In particular, aberrations in peripheral blood lymphocytes (PBL) can be regarded as indicators of hematologic toxicity, which is a major limiting factor of radiotherapy total dose. In this framework, a radiobiological database describing the induction of PBL dicentrics as a function of ion type and energy was developed by means of the BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations) biophysical model, which has been previously applied to predict the effectiveness of therapeutic-like ion beams at killing tumour cells. This database was then read by the FLUKA Monte Carlo transport code, thus allowing us to calculate the Relative Biological Effectiveness (RBE) for dicentric induction along therapeutic C-ion beams. A comparison with previous results showed that, while in the higher-dose regions (e.g., the Spread-Out Bragg Peak, SOBP), the RBE for dicentrics was lower than that for cell survival. In the lower-dose regions (e.g., the fragmentation tail), the opposite trend was observed. This work suggests that, at least for some irradiation scenarios, calculating the biological effectiveness of a hadrontherapy beam solely based on the RBE for cell survival may lead to an underestimation of the risk of (late) damage to healthy tissues. More generally, following this work, BIANCA has gained the capability of providing RBE predictions not only for cell killing, but also for healthy tissue damage.

Adenoid Cystic Carcinoma of Bartholin's Gland: What Is the Best Approach?

Background and summary: Among all vulvar cancers, primary adenoid cystic carcinoma (ACC) of Bartholin's gland is a very rare tumor characterized by a slow growth, a high local aggressiveness, and a remarkable recurrence rate. Due to its rarity, treatment remains a challenge for oncologists and gynecological surgeons. Key message: The present paper reports clinical, radiological, and histological features of ACC of Bartholin's gland and reviews the literature data on the treatment options with a particular focus on the potential role of particle radiation therapy.

Bragg Peak Localization with Piezoelectric Sensors for Proton Therapy Treatment.

A full chain simulation of the acoustic hadrontherapy monitoring for brain tumours is presented in this work. For the study, a proton beam of 100 MeV is considered. In the first stage, Geant4 is used to simulate the energy deposition and to study the behaviour of the Bragg peak. The energy deposition in the medium produces local heating that can be considered instantaneous with respect to the hydrodynamic time scale producing a sound pressure wave. The resulting thermoacoustic signal has been subsequently obtained by solving the thermoacoustic equation. The acoustic propagation has been simulated by FEM methods in the brain and the skull, where a set of piezoelectric sensors are placed. Last, the final received signals in the sensors have been processed in order to reconstruct the position of the thermal source and, thus, to determine the feasibility and accuracy of acoustic beam monitoring in hadrontherapy.

[The Italian National Center for Oncological Adrotherapy (CNAO): status and perspectives]. / Il Centro Nazionale di Adroterapia Oncologica (CNAO): stato e prospettive.

SUMMARY: A complex particle accelerator has been built at the Italian National Centre for Oncological Adrotherapy in Pavia, called synchrotron, which is able to decompose atoms and create beams of particles to be directed to tumour cells in order to destroy them. It is the hadrontherapy, a very advanced radiation therapy for the treatment of X-ray resistant or inoperable tumours. In particular, the CNAO synchrotron in Pavia is the only one in Italy capable of extracting carbon ions from the atom, which are the most powerful particles capable of destroying the DNA of cancer cells while preserving the surrounding healthy tissues. Hadrontherapy has been recently included by the Italian Ministry of Health into the essential levels of assistance, recognizing its scientific validity. All Italian citizens can access treatments within the National Health System, according to defined modalities. More than 50 patients are treated at CNAO every day and to date more than 2300 cancer patients from all over Italy have been able to benefit from hadrontherapy. The article will illustrate the technological innovation of the centre in Pavia and will focus on the most interesting research and development projects.

[Exposure risk for the workers of a hadrontherapy center and collective and individual protection measures]. / Rischio espositivo per i lavoratori di un centro di adroterapia e misure di protezione collettiva e individuale.

SUMMARY: In the last few years a wide dissemination of hadrontherapy facilities is taking place. In these facilities, proton or heavy ion (mainly carbon) accelerators are used to treat cancers in peculiar positions (i.e. close to critical organs), or with peculiar biological features that make them not eligible for conventional radiation therapy with photons. During the design, the commissioning and the use of these facilities many radiation safety issues are to be addressed, that are different from the ones that the professionals in the field are used to facing. Many problems need to be solved, among which the characterization of the radiations fields produced by the accelerators, the shielding design, the design of the interlock systems, and the management of the activated materials (PE11). Both the personal and environmental dosimetry systems need to be set up and implemented, taking into consideration the peculiarities of the involved radiation fields, that are often made of many different high energy particles. So, the approach to this kind of problems is usually much more complex than the one that is required for lower energy machines, and the adopted techniques are much more similar to the ones used for the high energy research accelerators. Due to the complexity of the physics involved in the radiation/matter interaction at these energies, the radiation safety calculations are often based on Monte Carlo simulations (that take into account all the physical processes for all the particles involved), and the data should be cross-checked with the experimental data available in literature (e.g. Na06). Moreover, all the radiation measurements must be carried out with instruments conceived for this kind of radiation fields, or anyway with instruments whose behavior can be foreseen also when measuring in high energy mixed fields (Na04). The shielding design and the activation evaluations obviously depend on the different accelerator technologies (e.g. if synchrotrons, or cyclotrons, are used) and on the energy and nature of the accelerated beam. On the other hand, while the technologies used for the interlock safety systems are well known, a big research and development effort is still ongoing about the technologies adopted for personal or environmental dosimetry. Anyway, while the state-of-the-art of instrumentation is still far from being completely satisfactory, many detectors are available, that can be a good option to solve some of the measurement problems found in such environments.

[The risk of second radiation-induced cancer from hadrontherapy compared to traditional radiotherapy]. / Il rischio di secondo tumore radioindotto da adroterapia rispetto alla radioterapia tradizionale.

SUMMARY: Radiation therapy increasingly plays a fundamental role in the treatment of cancer. Since the survival of cancer patients is continuously improving, the late effects of treatments, including those related to radiation treatment, can affect the quality of life and health and of the patients themselves to a greater extent. Especially in the last 20 years, with the implementation of new techniques/forms of radiation therapy, the risk of developing radiation-induced tumors following radiation therapy has become a hotly debated topic. Malignant tumors induced by radiation therapy represent a particularly important problem for pediatric patients, who are intrinsically more sensitive to carcinogens than adults and have a longer life expectancy. To date, there is only one study in the literature, from 2019, which analyzes the risk of secondary tumors after carbon ion radiation compared to surgery or photon treatment and refers to patients treated for prostate cancer. Despite the high degree of uncertainty, the data acquired so far suggest that particle radiation therapy, especially with protons delivered with active scanning, carries a lower risk of radiation-induced tumors than conventional photon therapies. This is largely due to the lower doses to which healthy tissues are exposed and the low relative risk associated with exposure to neutrons throughout the body, especially when active scanning beams are used.

Acoustic Localization of Bragg Peak Proton Beams for Hadrontherapy Monitoring.

Hadrontherapy makes it possible to deliver high doses of energy to cancerous tumors by using the large energy deposition in the Bragg-peak. However, uncertainties in the patient positioning and/or in the anatomical parameters can cause distortions in the calculation of the dose distribution. In order to maximize the effectiveness of heavy particle treatments, an accurate monitoring system of the deposited dose depending on the energy, beam time, and spot size is necessary. The localized deposition of this energy leads to the generation of a thermoacoustic pulse that can be detected using acoustic technologies. This article presents different experimental and simulation studies of the acoustic localization of thermoacoustic pulses captured with a set of sensors around the sample. In addition, numerical simulations have been done where thermo-acoustic pulses are emitted for the specific case of a proton beam of 100 MeV.

Hadrontherapy Interactions in Molecular and Cellular Biology.

The resistance of cancer cells to radiotherapy is a major issue in the curative treatment of cancer patients. This resistance can be intrinsic or acquired after irradiation and has various definitions, depending on the endpoint that is chosen in assessing the response to radiation. This phenomenon might be strengthened by the radiosensitivity of surrounding healthy tissues. Sensitive organs near the tumor that is to be treated can be affected by direct irradiation or experience nontargeted reactions, leading to early or late effects that disrupt the quality of life of patients. For several decades, new modalities of irradiation that involve accelerated particles have been available, such as proton therapy and carbon therapy, raising the possibility of specifically targeting the tumor volume. The goal of this review is to examine the up-to-date radiobiological and clinical aspects of hadrontherapy, a discipline that is maturing, with promising applications. We first describe the physical and biological advantages of particles and their application in cancer treatment. The contribution of the microenvironment and surrounding healthy tissues to tumor radioresistance is then discussed, in relation to imaging and accurate visualization of potentially resistant hypoxic areas using dedicated markers, to identify patients and tumors that could benefit from hadrontherapy over conventional irradiation. Finally, we consider combined treatment strategies to improve the particle therapy of radioresistant cancers.

Hadrontherapy from the Italian Radiation Oncologist point of view: face the reality. The Italian Society of Oncological Radiotherapy (AIRO) survey.

Hadrontherapy has been in constant progress in the past decades. Due to the increasing interest in this field and the spreading of the technique in Italy and worldwide, the Italian Society of Radiation Oncology surveyed (by an online survey) its members regarding their perception of hadrontherapy. The survey outline addressed different items all related to hadrontherapy, such as: demographics (3 items), personal knowledge (5 items), actual use in clinical practice (5 items), and future perspectives and development (5 items). The survey was filled in by 224 radiation oncologists (RO). Among them, 74.6 % were RO with more than 5 years of clinical practice, and only 10.4 % RO in training. Median age was 46 years (range 27-77). 32.24 % admitted average knowledge about heavy particles radiobiology rationale and 32.42 % about the ongoing particle therapy clinical trials. Radioresistant tumors are perceived as-principal indications for carbon ions in 39.3 % of responders, and pediatric malignancies for protons in 37 %. Re-irradiation is highly recommended for 52.2 %. Strikingly, 38.8 % of participating ROs reported that, in the daily clinical practice, approximately less than 1 out of 10 patients asks to be referred for hadrontherapy. On the other side, 35.7 % claimed need for at least 3 up to 5 particle therapy centers in Italy. Overall, the results of the present survey highlight the interest of the Italian RO community for particle therapy among the other radiotherapy technique. Analysis of our results might picture the clinical attitude of the RO community towards hadrontherapy in Italy, and help in promoting targeted initiatives to spread clinical results and knowledge about technical innovations in this field.

Gadolinium-based nanoparticles to improve the hadrontherapy performances.

Nanomedicine is proposed as a novel strategy to improve the performance of radiotherapy. High-Z nanoparticles are known to enhance the effects of ionizing radiation. Recently, multimodal nanoparticles such as gadolinium-based nanoagents were proposed to amplify the effects of x-rays and g-rays and to improve MRI diagnosis. For tumors sited in sensitive tissues, childhood cases and radioresistant cancers, hadrontherapy is considered superior to x-rays and g-rays. Hadrontherapy, based on fast ion radiation, has the advantage of avoiding damage to the tissues behind the tumor; however, the damage caused in front of the tumor is its major limitation. Here, we demonstrate that multimodal gadolinium-based nanoparticles amplify cell death with fast ions used as radiation. Molecular scale experiments give insights into the mechanisms underlying the amplification of radiation effects. This proof-of-concept opens up novel perspectives for multimodal nanomedicine in hadrontherapy, ultimately reducing negative radiation effects in healthy tissues in front of the tumor. FROM THE CLINICAL EDITOR: Gadolinium-chelating polysiloxane nanoparticles were previously reported to amplify the anti-tumor effects of x-rays and g-rays and to serve as MRI contrast agents. Fast ion radiation-based hadrontherapy avoids damage to the tissues behind the tumor, with a major limitation of tissue damage in front of the tumor. This study demonstrates a potential role for the above nanoagents in optimizing hadrontherapy with preventive effects in healthy tissue and amplified cell death in the tumor.

Beam monitor detectors for medical applications.

Beam monitoring is fundamental for any particle accelerator. In particular, it is a crucial issue in medical applications of particle physics due to the required high precision and reliability. Radioisotope production and cancer radiotherapy require specific beam monitor detectors. In this paper, three recently designed instruments are reviewed. One of them is a newly designed beam monitor detector based on doped silica and optical fibres. It represents a promising solution. This apparatus can be used with various types of beams and for both hadrontherapy and radioisotope production. For this reason, a more detailed description of this multipurpose detector is provided.

Pulsed RF knock-out extraction: a potential enabler for FLASH hadrontherapy in the Bragg peak.

One challenge on the path to delivering FLASH-compatible beams with a synchrotron is facilitating an accurate dose control for the required ultra-high dose rates. We propose the use of pulsed RFKO extraction instead of continuous beam delivery as a way to control the dose delivered per Voxel. In a first feasibility test, dose rates in pulses of up to 600 Gy s-1were observed, while the granularity at which the dose was delivered is expected to be well below 0.5 Gy.

Light flashes and other sensory illusions perceived in space travel and on ground, including proton and heavy ion therapies.

Most of the astronauts experience visual illusions, apparent flashes of light (LF) in absence of light. The first reported observation of this phenomenon was in July 1969 by Buzz Aldrin, in the debriefing following the Apollo 11 mission. Several ground-based experiments in the 1970s tried to clarify the mechanisms behind these light flashes and to evaluate possible related risks. These works were supported by dedicated experiments in space on the following Apollo flights and in Low Earth Orbit (LEO). It was soon demonstrated that the LF could be caused by charged particles (present in the space radiation) traveling through the eye, and, possibly, some other visual cortical areas. In the 1990s the interest in these phenomena increased again and additional experiments in Low Earth Orbit and others ground-based were started. Recently patients undergoing proton and heavy ion therapy for eye or head and neck tumors have reported the perception of light flashes, opening a new channel to investigate these phenomena. In this paper the many LF studies will be reviewed, presenting an historical and scientific perspective consistent with the combined set of observations, offering a single comprehensive summary aimed to provide further insights on these phenomena. While the light flashes appear not to be a risk by themselves, they might provide information on the amount of radiation induced radicals in the astronauts' eyes. Understanding their generation mechanisms might also support radiation countermeasures development. However, even given the substantial progress outlined in this paper, many questions related to their generation are still under debate, so additional studies are suggested. Finally, it is also conceivable that further LF investigations could provide evidence about the possible interaction of single particles in space with brain function, impacting with the crew ability to optimally perform a mission.

Computational approaches in the estimation of radiobiological damage for human-malignant cells irradiated with clinical proton and carbon beams.

PURPOSE: The use of Monte Carlo (MC) simulations capable of reproducing radiobiological effects of ionising radiation on human cell lines is of great importance, especially for cases involving protons and heavier ion beams. In the latter, huge uncertainties can arise mainly related to the effects of the secondary particles produced in the beam-tissue interaction. This paper reports on a detailed MC study performed using Geant4-based approach on three cancer cell lines, the HTB-177, CRL-5876 and MCF-7, that were previously irradiated with therapeutic proton and carbon ion beams. METHODS: A Geant4-based approach used jointly with analytical calculations has been developed to provide a more realistic estimation of the radiobiological damage produced by proton and carbon beams in tissues, reproducing available data obtained from in vitro cell irradiations. The MC "Hadrontherapy" Geant4 application and the Local Effect Model: LEM I, LEM II and LEM III coupled with the different numerical approaches: RapidRusso (RR) and RapidScholz (RS) were used in the study. RESULTS: Experimental survival curves are compared with those evaluated using the highlighted Geant4 MC-based approach via chi-square statistical analysis, for the combinations of radiobiological models and numerical approaches, as outlined above. CONCLUSION: This study has presented a comparison of the survival data from MC simulations to experimental survival data for three cancer cell lines. An overall best level of agreement was obtained for the HTB-177 cells.

Radiotherapy for salivary gland cancer: REFCOR recommendations by the formal consensus method.

OBJECTIVE: To determine the indications for radiotherapy in salivary gland cancer and to specify the modalities and target radiation volumes. MATERIAL AND METHODS: The French Network of Rare Head and Neck Tumors (REFCOR) formed a steering group which drafted a narrative review of the literature published on Medline and proposed recommendations. The level of adherence to the recommendations was then assessed by a rating group, according to the formal consensus method. RESULTS: Postoperatively, radiotherapy to the primary tumor site±to the lymph nodes is indicated if one or more of the following adverse histoprognostic factors are present (risk>10% of locoregional recurrence): T3-T4 category, lymph node invasion, extraglandular invasion, close or positive surgical margins, high tumor grade, perineural invasion, vascular emboli, and/or bone invasion. Intensity-modulated radiation therapy (IMRT) is the gold standard. For unresectable cancers or inoperable patients, carbon ion hadrontherapy may be considered. CONCLUSION: Radiotherapy in salivary gland cancer is indicated in postoperative situations in case of adverse histoprognostic factors and for inoperable tumors.

Short-lived radioactive8Li and8He ions for hadrontherapy: a simulation study.

Purpose.Although charged particle therapy (CPT) for cancer treatment has grown these past years, the use of protons and carbon ions for therapy remains debated compared to x-ray therapy. While a biological advantage of protons is not clearly demonstrated, therapy using carbon ions is often pointed out for its high cost. Furthermore, the nuclear interactions undergone by carbons inside the patient are responsible for an additional dose delivered after the Bragg peak, which deteriorates the ballistic advantage of CPT. Therefore, a renewed interest for lighter ions with higher biological efficiency than protons was recently observed. In this context, helium and lithium ions represent a good compromise between protons and carbons, as they exhibit a higher linear energy transfer (LET) than protons in the Bragg peak and can be accelerated by cyclotrons. The possibility of accelerating radioactive8Li, decaying in 2α-particles, and8He, decaying in8Li byß-decay, is particularly interesting.Methods. This work aims to assess the interest of the use of8Li and8He ions for therapy by Monte Carlo simulations carried out withGeant4.Results. It was calculated that the8Li and8He decay results in an increase of the LET of almost a factor 2 in the Bragg peak compared to stable7Li and4He. This results also in a higher dose deposited in the Bragg peak without an increase of the dose in the plateau region. It was also shown that both8He and8Li can have a potential interest for prompt-gamma monitoring techniques. Finally, the feasibility of accelerating facilities delivering8Li and8He was also discussed.Conclusion. In this study, we demonstrate that both8Li and8He have interesting properties for therapy. Indeed, simulations predict that8Li and8He are a good compromise between proton and12C, both in terms of LET and dose.