Activity Measurement of 44Sc and Calibration of Activity Measurement Instruments on Production Sites and Clinics.

44Sc is a promising radionuclide for positron emission tomography (PET) in nuclear medicine. As a part of the implementation of a production site for 44Sc, precise knowledge of the activity of the product is necessary. At the Paul Scherrer Institute (PSI) and the University of Bern (UniBE), 44Sc is produced by enriched 44CaO-target irradiation with a cyclotron. The two sites use different techniques for activity measurement, namely a dose calibrator at the PSI and a gamma-ray spectrometry system at UniBE and PSI. In this work, the 44Sc was produced at the PSI, and samples of the product were prepared in dedicated containers for onsite measurements at PSI, UniBE, and the Institute of Radiation Physics (IRA) in Lausanne for precise activity measurement using primary techniques and for the calibration of the reference ionization chambers. An accuracy of 1% was obtained for the activity measurement, allowing for a precise calibration of the dose calibrator and gamma-ray spectrometry of the two production sites. Each production site now has the capability of measuring 44Sc activity with an accuracy of 2%.

Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species.

Here, we highlight the potential translational benefits of delivering FLASH radiotherapy using ultra-high dose rates (>100 Gy⋅s-1). Compared with conventional dose-rate (CONV; 0.07-0.1 Gy⋅s-1) modalities, we showed that FLASH did not cause radiation-induced deficits in learning and memory in mice. Moreover, 6 months after exposure, CONV caused permanent alterations in neurocognitive end points, whereas FLASH did not induce behaviors characteristic of anxiety and depression and did not impair extinction memory. Mechanistic investigations showed that increasing the oxygen tension in the brain through carbogen breathing reversed the neuroprotective effects of FLASH, while radiochemical studies confirmed that FLASH produced lower levels of the toxic reactive oxygen species hydrogen peroxide. In addition, FLASH did not induce neuroinflammation, a process described as oxidative stress-dependent, and was also associated with a marked preservation of neuronal morphology and dendritic spine density. The remarkable normal tissue sparing afforded by FLASH may someday provide heretofore unrealized opportunities for dose escalation to the tumor bed, capabilities that promise to hasten the translation of this groundbreaking irradiation modality into clinical practice.

Implementation and validation of a beam-current transformer on a medical pulsed electron beam LINAC for FLASH-RT beam monitoring.

PURPOSE: To implement and validate a beam current transformer as a passive monitoring device on a pulsed electron beam medical linear accelerator (LINAC) for ultra-high dose rate (UHDR) irradiations in the operational range of at least 3 Gy to improve dosimetric procedures currently in use for FLASH radiotherapy (FLASH-RT) studies. METHODS: Two beam current transformers (BCTs) were placed at the exit of a medical LINAC capable of UHDR irradiations. The BCTs were validated as monitoring devices by verifying beam parameters consistency between nominal values and measured values, determining the relationship between the charge measured and the absorbed dose, and checking the short- and long-term stability of the charge-absorbed dose ratio. RESULTS: The beam parameters measured by the BCTs coincide with the nominal values. The charge-dose relationship was found to be linear and independent of pulse width and frequency. Short- and long-term stabilities were measured to be within acceptable limits. CONCLUSIONS: The BCTs were implemented and validated on a pulsed electron beam medical LINAC, thus improving current dosimetric procedures and allowing for a more complete analysis of beam characteristics. BCTs were shown to be a valid method for beam monitoring for UHDR (and therefore FLASH) experiments.

Dose assessment following an overexposure of a worker at a Swiss nuclear power plant.

AIM: The aim of this work was to assess the doses received by a diver exposed to a radiation source during maintenance work in the fuel transfer pool at a Swiss nuclear power plant, and to define whether the statutory limit was breached or not. METHOD: Onsite measurements were carried out and different scenarios were simulated using the MicroShield Software and the MCNPX Monte Carlo radiation transport code to estimate the activity of the irradiating object as well as the doses to the limbs and the effective dose delivered to the operator. RESULTS: The activity of the object was estimated to 1.8 TBq. From the various dose estimations, a conservative value of 7.5 Sv was proposed for the equivalent dose to the skin on the hands and an effective dose of 28 mSv. CONCLUSION: The use of different experimental and calculation methods allowed us to accurately estimate the activity of the object and the dose delivered to the diver, useful information for making a decision on the most appropriate scheme of follow up for the patient.

Probing the Kinetic Parameters of Plutonium-Naturally Occurring Organic Matter Interactions in Freshwaters Using the Diffusive Gradients in Thin Films Technique.

The interaction of trace metals with naturally occurring organic matter (NOM) is a key process of the speciation of trace elements in aquatic environments. The rate of dissociation of metal-NOM complexes will impact the amount of free metal available for biouptake. Assessing the bioavailability of plutonium (Pu) helps to predict its toxic effects on aquatic biota. However, the rate of dissociation of Pu-NOM complexes in natural freshwaters is currently unknown. Here, we used the technique of diffusive gradients in thin films (DGT) with several diffusive layer thicknesses to provide new insights into the dissociation kinetics of Pu-NOM complexes. Results show that Pu complexes with NOM (mainly fulvic acid) are somewhat labile (0.2 ≤ ξ ≤ 0.4), with kd = 7.5 × 10(-3) s(-1). DGT measurements of environmental Pu in organic-rich natural water confirm these findings. In addition, we determined the effective diffusion coefficients of Pu(V) in polyacrylamide (PAM) gel in the presence of humic acid using a diffusion cell (D = 1.70 ± 0.25 × 10(-6) cm(2) s(-1)). These results show that Pu(V) is a more mobile species than Pu(IV).

Construction and dosimetric characterization of a motorized scanning-slit system for electron FLASH experiments.

BACKGROUND: Beam scanning is a useful technique for the treatment of large tumors when the primary beam size is limited, which is the case with radiation beams used in FLASH radiotherapy. PURPOSE: To optimize beam scanning as a dose delivery method for FLASH radiotherapy, it is necessary to first understand the effects of beam scanning on the FLASH effect. To do so, biological FLASH experiments need to be done using defined beam parameters with beam scanning and compared to the situation without beam scanning. In this regard, we propose implementation of a simple slit scanning system with an electron FLASH beam to obtain a scanned radiation field that closely resembles a static field. METHODS: A pulsed electron linear accelerator (linac) was used in combination with a scanning slit system in order to simulate a scanned electron beam. Three configurations that produced homogeneous lateral profiles and high enough doses per pulse for FLASH experiments were established. The optimal scanning parameters were found for each configuration by examining the flatness of the obtained lateral dose profiles. Using the optimal scanning parameters, the scanned FLASH beams were dosimetrically characterized and compared to non-scanned open field beam. RESULTS: A final electron FLASH beam scanning configuration was found for a 1 mm wide slit at a distance of 350 mm from the linac and a 2 mm wide slit at distances of 350 and 490 mm from the linac. The lateral profiles for these final configurations were found to have a homogeneity that is comparable to the open field profiles. The percentage depth dose (PDD) values found for these final configurations closely matched (by a few percentage) the PDD of the open field beam. CONCLUSIONS: Three electron FLASH beam scanning configurations achieved by the motorized slit system were found to produce radiation fields similar to a non-scanned open field electron beam. These final configurations can therefore be used in future biological FLASH experiments to compare to non-scanned beam experiments in order to optimize beam scanning as a technique permitting the treatment of larger tumors with FLASH radiotherapy.

Metrology for advanced radiotherapy using particle beams with ultra-high dose rates.

Dosimetry of ultra-high dose rate beams is one of the critical components which is required for safe implementation of FLASH radiotherapy (RT) into clinical practice. In the past years several national and international programmes have emerged with the aim to address some of the needs that are required for translation of this modality to clinics. These involve the establishment of dosimetry standards as well as the validation of protocols and dosimetry procedures. This review provides an overview of recent developments in the field of dosimetry for FLASH RT, with particular focus on primary and secondary standard instruments, and provides a brief outlook on the future work which is required to enable clinical implementation of FLASH RT.

Acute Hypoxia Does Not Alter Tumor Sensitivity to FLASH Radiation Therapy.

PURPOSE: Tumor hypoxia is a major cause of treatment resistance, especially to radiation therapy at conventional dose rate (CONV), and we wanted to assess whether hypoxia does alter tumor sensitivity to FLASH. METHODS AND MATERIALS: We engrafted several tumor types (glioblastoma [GBM], head and neck cancer, and lung adenocarcinoma) subcutaneously in mice to provide a reliable and rigorous way to modulate oxygen supply via vascular clamping or carbogen breathing. We irradiated tumors using a single 20-Gy fraction at either CONV or FLASH, measured oxygen tension, monitored tumor growth, and sampled tumors for bulk RNAseq and pimonidazole analysis. Next, we inhibited glycolysis with trametinib in GBM tumors to enhance FLASH efficacy. RESULTS: Using various subcutaneous tumor models, and in contrast to CONV, FLASH retained antitumor efficacy under acute hypoxia. These findings show that in addition to normal tissue sparing, FLASH could overcome hypoxia-mediated tumor resistance. Follow-up molecular analysis using RNAseq profiling uncovered a FLASH-specific profile in human GBM that involved cell-cycle arrest, decreased ribosomal biogenesis, and a switch from oxidative phosphorylation to glycolysis. Glycolysis inhibition by trametinib enhanced FLASH efficacy in both normal and clamped conditions. CONCLUSIONS: These data provide new and specific insights showing the efficacy of FLASH in a radiation-resistant context, proving an additional benefit of FLASH over CONV.

More May Not be Better: Enhanced Spacecraft Shielding May Exacerbate Cognitive Decrements by Increasing Pion Exposures during Deep Space Exploration.

The pervasiveness of deep space radiation remains a confounding factor for the transit of humans through our solar system. Spacecraft shielding both protects astronauts but also contributes to absorbed dose through galactic cosmic ray interactions that produce secondary particles. The resultant biological effects drop to a minimum for aluminum shielding around 20 g/cm2 but increase with additional shielding. The present work evaluates for the first time, the impact of secondary pions on central nervous system functionality. The fractional pion dose emanating from thicker shielded spacecraft regions could contribute up to 10% of the total absorbed radiation dose. New results from the Paul Scherrer Institute have revealed that low dose exposures to 150 MeV positive and negative pions, akin to a Mars mission, result in significant, long-lasting cognitive impairments. These surprising findings emphasize the need to carefully evaluate shielding configurations to optimize safe exposure limits for astronauts during deep space travel.

Multi-Institutional Audit of FLASH and Conventional Dosimetry With a 3D Printed Anatomically Realistic Mouse Phantom.

PURPOSE: We conducted a multi-institutional dosimetric audit between FLASH and conventional dose rate (CONV) electron irradiations by using an anatomically realistic 3-dimensional (3D) printed mouse phantom. METHODS AND MATERIALS: A computed tomography (CT) scan of a live mouse was used to create a 3D model of bony anatomy, lungs, and soft tissue. A dual-nozzle 3D printer was used to print the mouse phantom using acrylonitrile butadiene styrene (∼1.02 g/cm3) and polylactic acid (∼1.24 g/cm3) simultaneously to simulate soft tissue and bone densities, respectively. The lungs were printed separately using lightweight polylactic acid (∼0.64 g/cm3). Hounsfield units (HU), densities, and print-to-print stability of the phantoms were assessed. Three institutions were each provided a phantom and each institution performed 2 replicates of irradiations at selected anatomic regions. The average dose difference between FLASH and CONV dose distributions and deviation from the prescribed dose were measured with radiochromic film. RESULTS: Compared with the reference CT scan, CT scans of the phantom demonstrated mass density differences of 0.10 g/cm3 for bone, 0.12 g/cm3 for lung, and 0.03 g/cm3 for soft tissue regions. Differences in HU between phantoms were <10 HU for soft tissue and bone, with lung showing the most variation (54 HU), but with minimal effect on dose distribution (<0.5%). Mean differences between FLASH and CONV decreased from the first to the second replicate (4.3%-1.2%), and differences from the prescribed dose decreased for both CONV (3.6%-2.5%) and FLASH (6.4%-2.7%). Total dose accuracy suggests consistent pulse dose and pulse number, although these were not specifically assessed. Positioning variability was observed, likely due to the absence of robust positioning aids or image guidance. CONCLUSIONS: This study marks the first dosimetric audit for FLASH using a nonhomogeneous phantom, challenging conventional calibration practices reliant on homogeneous phantoms. The comparison protocol offers a framework for credentialing multi-institutional studies in FLASH preclinical research to enhance reproducibility of biologic findings.

Activity standardisation of 177Lu.

177Lu decays through low-energy ß-- and γ-emissions in addition to conversion and Auger electrons. To support the use of this radiopharmaceutical in Switzerland, a 177Lu solution was standardised using the ß-γ coincidence technique, as well as the TDCR method. The solution had no 177mLu impurity. Primary coincidence measurements, with plastic scintillators for beta detection, were carried out using both analogue and digital electronics. TDCR measurements using only defocusing were also made. Monte Carlo calculations were used to compute the detection efficiency. The coincidence measurements with both analogue and digital electronics are compatible within one standard uncertainty, but they are lower than (and discrepant with) the TDCR measurements. An ampoule of this solution was submitted to the BIPM as a contribution to the Système International de Référence.

The general-purpose Geant4 Monte Carlo toolkit and its Geant4-DNA extension to investigate mechanisms underlying the FLASH effect in radiotherapy: Current status and challenges.

FLASH radiotherapy is a promising approach to cancer treatment that offers several advantages over conventional radiotherapy. With this novel technique, high doses of radiation are delivered in a short period of time, inducing the so-called FLASH effect - a phenomenon characterized by healthy tissue sparing without alteration of tumor control. The mechanisms behind the FLASH effect remain unknown. One way to approach this problem is to gain insight into the initial parameters that can distinguish FLASH from conventional irradiation by simulating particle transport in aqueous media using the general-purpose Geant4 Monte Carlo toolkit and its Geant4-DNA extension. This review article discusses the current status of Geant4 and Geant4-DNA simulations to investigate mechanisms underlying the FLASH effect, as well as the challenges faced in this research field. One of the primary challenges is to accurately simulate the experimental irradiation parameters. Another challenge is the temporal extension of the simulations. This review also focuses on two hypotheses to explain the FLASH effect - namely the oxygen depletion hypothesis and the inter-track interactions hypothesis - and discusses how the Geant4 toolkit can be used to investigate them. The aim of this review is to provide an overview of Geant4 and Geant4-DNA simulations for FLASH radiotherapy and to highlight the challenges that need to be overcome in order to better study the FLASH effect.

Effect of Conventional and Ultrahigh Dose Rate FLASH Irradiations on Preclinical Tumor Models: A Systematic Analysis.

PURPOSE: Compared with conventional dose rate irradiation (CONV), ultrahigh dose rate irradiation (UHDR) has shown superior normal tissue sparing. However, a clinically relevant widening of the therapeutic window by UHDR, termed "FLASH effect," also depends on the tumor toxicity obtained by UHDR. Based on a combined analysis of published literature, the current study examined the hypothesis of tumor isoefficacy for UHDR versus CONV and aimed to identify potential knowledge gaps to inspire future in vivo studies. METHODS AND MATERIALS: A systematic literature search identified publications assessing in vivo tumor responses comparing UHDR and CONV. Qualitative and quantitative analyses were performed, including combined analyses of tumor growth and survival data. RESULTS: We identified 66 data sets from 15 publications that compared UHDR and CONV for tumor efficacy. The median number of animals per group was 9 (range 3-15) and the median follow-up period was 30.5 days (range 11-230) after the first irradiation. Tumor growth assays were the predominant model used. Combined statistical analyses of tumor growth and survival data are consistent with UHDR isoefficacy compared with CONV. Only 1 study determined tumor-controlling dose (TCD50) and reported statistically nonsignificant differences. CONCLUSIONS: The combined quantitative analyses of tumor responses support the assumption of UHDR isoefficacy compared with CONV. However, the comparisons are primarily based on heterogeneous tumor growth assays with limited numbers of animals and short follow-up, and most studies do not assess long-term tumor control probability. Therefore, the assays may be insensitive in resolving smaller response differences, such as responses of radioresistant tumor subclones. Hence, tumor cure experiments, including additional TCD50 experiments, are needed to confirm the assumption of isoeffectiveness in curative settings.

Modeling of scavenging systems in water radiolysis with Geant4-DNA.

PURPOSE: This paper presents the capabilities of the Geant4-DNA Monte Carlo toolkit to simulate water radiolysis with scavengers using the step-by-step (SBS) or the independent reaction times (IRT) methods. It features two examples of application areas: (1) computing the escape yield of H2O2 following a 60Co γ-irradiation and (2) computing the oxygen depletion in water irradiated with 1 MeV electrons. METHODS: To ease the implementation of the chemical stage in Geant4-DNA, we developed a user interface that helps define the chemical reactions and set the concentration of scavengers. The first application area example required two computational steps to perform water radiolysis using NO2- and NO3- as scavengers and a 60Co irradiation. The oxygen depletion computation technique for the second application area example consisted of simulating track segments of 1 MeV electrons and determining the radio-induced loss and gain of oxygen molecules. RESULTS: The production of H2O2 under variable scavenging levels is consistent with the literature; the mean relative difference between the SBS and IRT methods is 7.2 % ± 0.5 %. For the oxygen depletion 1 µs post-irradiation, the mean relative difference between both methods is equal to 9.8 % ± 0.3 %. The results in the microsecond scale depend on the initial partial pressure of oxygen in water. In addition, the computed oxygen depletions agree well with the literature. CONCLUSIONS: The Geant4-DNA toolkit makes it possible to simulate water radiolysis in the presence of scavengers. This feature offers perspectives in radiobiology, with the possibility of simulating cell-relevant scavenging mechanisms.

Measurement of the 171Tm beta spectrum.

The beta spectrum of the main transition of the ß- decay of 171Tm was measured using a double focalizing spectrometer. The instrument was lately improved in order to reduce its low energy threshold to 34 keV. We used the spectrometer to measure the beta spectrum end-point energy of the main transition of 171Tm decay using the Kurie plot formalism. We report a new value of 97.60(38) keV, which is in agreement with previous measurements. In addition, the spectrum shape was compared with the ξ-approximation calculation where the shape factor is equal to 1 and good agreement was found between the theory and the measurement at the 1% level.

Activity standardisation of 32Si at IRA-METAS.

This work explores the primary activity standardisation of 32Si as part of the SINCHRON project that aims at filling the geochronological dating gap by making a new precise measurement of the half-life of this nuclide. The stability of some of the radioactive test solutions, providing 32Si as hexafluorosilicic acid (H232SiF6), was monitored over long periods, pointing to the adequate sample composition and vial type to ensure stability. These solutions were standardised using liquid scintillation counting with the triple to double coincidence ratio (TDCR) technique and the CIEMAT-NIST efficiency tracing (CNET) method. Complementary backup measurements, using 4πß-γ coincidence counting with 60Co as a tracer, were performed with both liquid and plastic scintillation for beta detection. While 60Co coincidence tracing with a liquid scintillator predicted activities in agreement with the TDCR and CNET determinations, using plastic scintillation turned out to be unfeasible as the addition of lanthanum nitrate and ammonia to fix the silicon during the drying process generated large crystals that compromised the linearity of the efficiency function.

Elucidating the neurological mechanism of the FLASH effect in juvenile mice exposed to hypofractionated radiotherapy.

BACKGROUND: Ultrahigh dose-rate radiotherapy (FLASH-RT) affords improvements in the therapeutic index by minimizing normal tissue toxicities without compromising antitumor efficacy compared to conventional dose-rate radiotherapy (CONV-RT). To investigate the translational potential of FLASH-RT to a human pediatric medulloblastoma brain tumor, we used a radiosensitive juvenile mouse model to assess adverse long-term neurological outcomes. METHODS: Cohorts of 3-week-old male and female C57Bl/6 mice exposed to hypofractionated (2 × 10 Gy, FLASH-RT or CONV-RT) whole brain irradiation and unirradiated controls underwent behavioral testing to ascertain cognitive status four months posttreatment. Animals were sacrificed 6 months post-irradiation and tissues were analyzed for neurological and cerebrovascular decrements. RESULTS: The neurological impact of FLASH-RT was analyzed over a 6-month follow-up. FLASH-RT ameliorated neurocognitive decrements induced by CONV-RT and preserved synaptic plasticity and integrity at the electrophysiological (long-term potentiation), molecular (synaptophysin), and structural (Bassoon/Homer-1 bouton) levels in multiple brain regions. The benefits of FLASH-RT were also linked to reduced neuroinflammation (activated microglia) and the preservation of the cerebrovascular structure, by maintaining aquaporin-4 levels and minimizing microglia colocalized to vessels. CONCLUSIONS: Hypofractionated FLASH-RT affords significant and long-term normal tissue protection in the radiosensitive juvenile mouse brain when compared to CONV-RT. The capability of FLASH-RT to preserve critical cognitive outcomes and electrophysiological properties over 6-months is noteworthy and highlights its potential for resolving long-standing complications faced by pediatric brain tumor survivors. While care must be exercised before clinical translation is realized, present findings document the marked benefits of FLASH-RT that extend from synapse to cognition and the microvasculature.

Independent Reproduction of the FLASH Effect on the Gastrointestinal Tract: A Multi-Institutional Comparative Study.

FLASH radiation therapy (RT) is a promising new paradigm in radiation oncology. However, a major question that remains is the robustness and reproducibility of the FLASH effect when different irradiators are used on animals or patients with different genetic backgrounds, diets, and microbiomes, all of which can influence the effects of radiation on normal tissues. To address questions of rigor and reproducibility across different centers, we analyzed independent data sets from The University of Texas MD Anderson Cancer Center and from Lausanne University (CHUV). Both centers investigated acute effects after total abdominal irradiation to C57BL/6 animals delivered by the FLASH Mobetron system. The two centers used similar beam parameters but otherwise conducted the studies independently. The FLASH-enabled animal survival and intestinal crypt regeneration after irradiation were comparable between the two centers. These findings, together with previously published data using a converted linear accelerator, show that a robust and reproducible FLASH effect can be induced as long as the same set of irradiation parameters are used.

Multi-Institutional Audit of FLASH and Conventional Dosimetry with a 3D-Printed Anatomically Realistic Mouse Phantom.

We conducted a multi-institutional audit of dosimetric variability between FLASH and conventional dose rate (CONV) electron irradiations by using an anatomically realistic 3D-printed mouse phantom. A CT scan of a live mouse was used to create a 3D model of bony anatomy, lungs, and soft tissue. A dual-nozzle 3D printer was used to print the mouse phantom using acrylonitrile butadiene styrene ($~1.02 g/cm^3$) and polylactic acid ($~1.24 g/cm^3$) simultaneously to simulate soft tissue and bone densities, respectively. The lungs were printed separately using lightweight polylactic acid ($~0.64 g/cm^3$). Hounsfield units (HU) and densities were compared with the reference CT scan of the live mouse. Print-to-print reproducibility of the phantom was assessed. Three institutions were each provided a phantom, and each institution performed two replicates of irradiations at selected mouse anatomic regions. The average dose difference between FLASH and CONV dose distributions and deviation from the prescribed dose were measured with radiochromic film. Compared to the reference CT scan, CT scans of the phantom demonstrated mass density differences of $0.10 g/cm^3$ for bone, $0.12 g/cm^3$ for lung, and $0.03 g/cm^3$ for soft tissue regions. Between phantoms, the difference in HU for soft tissue and bone was <10 HU from print to print. Lung exhibited the most variation (54 HU) but minimally affected dose distribution (<0.5% dose differences between phantoms). The mean difference between FLASH and CONV from the first replicate to the second decreased from 4.3% to 1.2%, and the mean difference from the prescribed dose decreased from 3.6% to 2.5% for CONV and 6.4% to 2.7% for FLASH. The framework presented here is promising for credentialing of multi-institutional studies of FLASH preclinical research to maximize the reproducibility of biological findings.

Ultra-high dose rate dosimetry: Challenges and opportunities for FLASH radiation therapy.

The clinical translation of FLASH radiotherapy (RT) requires challenges related to dosimetry and beam monitoring of ultra-high dose rate (UHDR) beams to be addressed. Detectors currently in use suffer from saturation effects under UHDR regimes, requiring the introduction of correction factors. There is significant interest from the scientific community to identify the most reliable solutions and suitable experimental approaches for UHDR dosimetry. This interest is manifested through the increasing number of national and international projects recently proposed concerning UHDR dosimetry. Attaining the desired solutions and approaches requires further optimization of already established technologies as well as the investigation of novel radiation detection and dosimetry methods. New knowledge will also emerge to fill the gap in terms of validated protocols, assessing new dosimetric procedures and standardized methods. In this paper, we discuss the main challenges coming from the peculiar beam parameters characterizing UHDR beams for FLASH RT. These challenges vary considerably depending on the accelerator type and technique used to produce the relevant UHDR radiation environment. We also introduce some general considerations on how the different time structure in the production of the radiation beams, as well as the dose and dose-rate per pulse, can affect the detector response. Finally, we discuss the requirements that must characterize any proposed dosimeters for use in UDHR radiation environments. A detailed status of the current technology is provided, with the aim of discussing the detector features and their performance characteristics and/or limitations in UHDR regimes. We report on further developments for established detectors and novel approaches currently under investigation with a view to predict future directions in terms of dosimetry approaches, practical procedures, and protocols. Due to several on-going detector and dosimetry developments associated with UHDR radiation environment for FLASH RT it is not possible to provide a simple list of recommendations for the most suitable detectors for FLASH RT dosimetry. However, this article does provide the reader with a detailed description of the most up-to-date dosimetric approaches, and describes the behavior of the detectors operated under UHDR irradiation conditions and offers expert discussion on the current challenges which we believe are important and still need to be addressed in the clinical translation of FLASH RT.