High Fluence Rates Research Articles

Review of high-precision femtosecond laser materials processing for fabricating microstructures: Effects of laser parameters on processing quality, ablation efficiency, and microhole shape

Femtosecond lasers are promising tools for achieving high-precision processing of thin materials without causing any thermal surface damage and bulk distortion. However, thermal damage can occur even with ultrashort laser pulses. This is because of high electron penetration depth and heat accumulation at high fluence and high repetition rate. Nanoparticle redeposition can be dramatically altered with variation in repetition rate. The symmetry of microholes and ablation efficiency vary with laser polarization. The laser wavelength affects the ablation efficiency and surface roughness. Therefore, understanding these laser–matter interactions that depend on the laser parameters is essential for high-precision laser processing. This article reviews laser–matter interactions in the 64FeNi alloy, as well as analytical models for designing the desired hole size and taper angles. This can help establish strategies for creating various high-precision microstructures using femtosecond lasers.

Application of UV LEDs to inactivate antibiotic resistant bacteria: Kinetics, efficiencies, and reactivations

Unregulated antibiotic use has led to the proliferation of antibiotic-resistant bacteria (ARB) in aquatic environments. Ultraviolet light-emitting diodes (UV LEDs) have evolved as an innovative technology for inactivating microorganisms offering several advantages over traditional mercury lamps. This research concentrated on utilizing UV LEDs with three distinct wavelengths (265 nm, 275 nm, and 285 nm) to inactivate E. coli DH10β encoding the ampicillin-resistant blaTEM-1 gene in its plasmid. Non-linear models, such as Geeraerd's and Weibull, provided more accurate characterization of the inactivation profiles than the traditional log-linear model due to the incorporation of both biological mechanisms and a deterministic approach within non-linear models. The inactivation rates of ARB were higher than antibiotic-sensitive bacteria (ASB) when subjected to UV LEDs. The highest inactivation rates were observed when all microorganisms were exposed to 265 nm. Photoreactivation emerged as the primary mechanism responsible for repairing DNA damage induced by UV LEDs. 285 nm showed the highest reactivation efficiencies for ARB under different fluences. At higher fluences, both 265 and 275 nm displayed similar effectiveness in suppressing reactivation, while at lower fluences, 275 nm exhibited better efficacies in controlling the reactivation. Therefore, the inhibition of reactivation was influenced by the extent of damage incurred to both DNA and enzymes. In nutrient-poor media (0.9 % NaCl), ASB did not exhibit any reactivation potential. However, the addition of Luria-Bertani (LB) broth promoted the reactivation of ASB. Lower fluence rate was more beneficial at 265 nm whereas higher fluence rates were more effective for longer wavelengths. The inactivation of ARB was enhanced by dissolved organic carbon (DOC) at low fluences. However, the removal of ARB was reduced due to the presence of DOC at higher fluences. The highest energy demand for ARB inactivation was reported at 285 nm. Environmental implicationThe excessive and unregulated utilization of antibiotics has emerged as a significant issue for public health. This paper presents a comprehensive analysis of the effectiveness of UV LEDs, an emerging technology, in the inactivation of antibiotic-resistant bacteria (ARB). This research paper explores the kinetics of UV LEDs with different wavelengths to inactivate ARB along with the reactivation efficiencies. This research work also explores the impact and relevant mechanisms of the impact of dissolved organic carbon (DOC) on the inactivation of ARB by UV LEDs.

Anti-Obesity Effect of Chlorin e6-Mediated Photodynamic Therapy on Mice with High-Fat-Diet-Induced Obesity.

This study aimed to evaluate the efficacy of Chlorin e6 (Ce6)-based photodynamic therapy (PDT) for anti-obesity activities in high-fat-diet (HFD)-induced obesity mouse models. We induced obesity in C57BL/6 mice by HFD and administered Ce6 (2.5 or 5 mg/kg) orally with 3 h of incubation. The mice were then exposed to light of high fluence rate (4.96 mW/cm2) or low fluence rate (2.56 mW/cm2) in the designed LED mouse chamber 2-3 days a week for up to 8 weeks. The study also analyzed the pharmacokinetics and optimization of the drug by evaluating the absorption, distribution, metabolism, and excretion (ADME) of Ce6 in the rat models. Both low doses (2.5 mg/kg) and high doses (5 mg/kg) of Ce6 with high irradiation dose showed better anti-obesity effects than other groups with decreased body weight. The lipid accumulation in the liver and adipocyte size in epididymal adipose tissues were found to be decreased by Ce6-PDT in comparison to vehicle-treated HFD groups. We also observed increased levels of the lipidomic biomarkers, such as leptin and LDL cholesterol, while observing decreasing levels of total cholesterol and adiponectin in the Ce6-PDT-treated mice. These findings may provide valuable insight into Ce6-PDT as an alternative and non-invasive therapeutic methodology for obesity and obesity-related diseases.

The photosensory function of Zmphot1 differs from that of Atphot1 due to the C-terminus of Zmphot1 during phototropic response

The role of phot1 in triggering hypocotyl phototropism and optimizing growth orientation has been well-characterized in Arabidopsis, whereas the role of Zmphot1 in maize remains largely unclear. Here, we show that Zmphot1 is involved in blue light-induced phototropism. Compared with Atphot1, Zmphot1 exhibited a weaker phototropic response to very low-fluence rates of blue light (< 0.01 μmol m−2 s−1), but stronger phototropic response to high-fluence rates of blue light (> 10 μmol m−2 s−1) than Atphot1. Notably, blue light exposure induced Zmphot1-green fluorescent protein (GFP), but not Atphot1-GFP, to form the aggregates in the cytoplasm of Nicotiana benthamiana cells. Furthermore, by generating the chimeric phot1 proteins, we found that the serine-threonine kinase (STK) domain at the C-terminus is responsible for a more volatile membrane association of Zmphot1. Consistently, the chimeric phot1 protein fusing the STK domain of Zmphot1 with other domains of Atphot1 responded similarly as Zmphot1 to both low and high fluence rates of blue light. Interestingly, although both Zmphot1 and Atphot1 interact with AtNPH3, Zmphot1 induced weaker dephosphorylation of NON-PHOTOTROPIC HYPOCOTYL 3 (NPH3) than Atphot1. Together, our findings indicate that Zmphot1 and Atphot1 exhibit different photosensory function during phototropic response and that the STK domain may play a key role in determining their properties.

Fluence Beam Monitor for High-Intensity Particle Beams Based on a Multi-Gap Ionization Chamber and a Method for Ion Recombination Correction

This work presents the tests of a multi-gap detector (MGD), composed of three parallel-plate ionization chambers (ICs) with different gap widths, assembled to prove the capability of correcting for charge volume recombination which is expected to occur when high fluence rates are delivered. Such beam conditions occur with a compact accelerator for charged particle therapy developed to reduce the costs, to accomplish faster treatments and to exploit different beam delivery techniques and dose rates as needed, for example, for range modulation and FLASH irradiations, respectively. The MGD was tested with carbon ions at the Centro Nazionale di Adroterapia Oncologica (CNAO Pavia, Italy), and with protons in two different beam lines: at Bern University Hospital with continuous beams and at the Laboratori Nazionale del Sud (Catania, Italy) of the Italian National Center of Nuclear Physics (INFN) with pulsed beams. For each accelerator, we took measurements with different beam intensities (up to the maximum rate of ionization achievable) and changed the detector bias voltage (V) in order to study the charge collection efficiency. Charge recombination models were used to evaluate the expected collected charge and to measure the linearity of the rate of ionization with the beam fluence rate. A phenomenological approach was used to determine the collection efficiency (f1) of the chamber with thinnest gap from the relative efficiencies, f1/f2 and f1/f3, exploiting the condition that, for each measurement, the three chambers were exposed to the same rate of ionization. Results prove that two calibration curves can be determined and used to correct the online measurements for the charge losses in the ICs for recombination.

Self-recoverable near-infrared mechanoluminescence from ZnS:Mn by controlling manganese clusterization

Near-infrared (NIR)-emitting mechanoluminescence (ML) materials are highly desirable since they are biological transparency and suitable for deep-imaging inside biological tissues. So far, NIR emission can be found in very limited number ML materials. Moreover, reported NIR ML materials suffer from limitations associated with the incompetence in self-reproducibility. Herein, we observe sustainable and self-recoverable NIR ML emission in pulsed laser deposition (PLD) method grown ZnS:Mn film, for the first time. ML emission in ZnS:Mn can be explained by the piezoelectricity-induced detrapping model. Broad ML emission covering both red and NIR ranges arises from the presence of (Mn)n clusters, which facilitates the energy transfer from excited Mn2+ ions to them. During the PLD growth, high laser fluence and deposition rate contribute to the formation of (Mn)n clusters, which was verified by electron paramagnetic resonance EPR and X-ray photoelectron spectroscopy XPS analysis. The device exhibits durable NIR ML over 105 repeated mechanical stresses, suggesting new possibilities aiming for constructing self-recoverable NIR ML materials.

Practical X-ray beam spectrometry with cadmium telluride detector in 10–300 kVp range at Czech Metrology Institute. Part I. Instrumentation

The paper describes instrumentation used at Czech Metrology Institute for measurement of photon fluence spectra directly in X-ray beams. Detector with a cadmium telluride (CdTe) sensor was characterized by means of energy resolution and precise energy calibration. The hole trapping effect in CdTe causing full-energy peak deformations in measured spectra was adopted consisting of analytical models of incomplete charge collection and carrier trapping based on Hecht equation. The detector collimator provided by the manufacturer was modified with additional tungsten shielding that effectively absorbs the majority of photons scattered in the collimator body resulting in significant improvement of the consistency of measured and Monte Carlo simulated detector response. The purpose-made alignment platform increased the accuracy of orientation of the collimator axis improving the measurement in high photon fluence rate beams using collimation disks with very small apertures (down to 100 μm in diameter). The adopted instrumentation and methods for X-ray beam spectrometry enabled to fulfil the requirements of the new ISO 4037:2019-ed.2.0 standard for reference metrology laboratories. Software-focused part dealing with Monte Carlo simulations and procedures for photon fluence spectra unfolding is summarized in [1].

The influence of hypoxia on LET and RBE relationships with implications for ultra-high dose rates and FLASH modelling

Objective. To investigate relationships between linear energy transfer (LET), fluence rates, changes in radiosensitivity and the oxygen enhancement ratio (OER) in different ion beams and extend these concepts to ultra-high dose rate (UHDR) or FLASH effects. Approach. LET values providing maximum relative biological effect (RBE), designated as LETU, are found for neon, carbon and helium beams. Proton experiments show reduced RBEs with depth in scattered (divergent) beams, but not with scanned beams, suggesting that instantaneous fluence rates (related to track separation distances) can modify RBE, all other RBE-determining factors being equal. Micro-volumetric energy transfer per μm3 (mVET) is defined by LET × fluence. High fluence rates will increase mVET rates, with proportional shifts of LETU to lower values due to more rapid energy transfer. From the relationship between LETU and OER at conventional dose rates, OER reductions in UHDR/FLASH exposures can be estimated and biological effective dose analysis of experimental lung and skin reactions becomes feasible. Main results. The Furusawa et al data show that hypoxic LETU values exceed their oxic counterparts. OER reduces from around 3–1.25 at LETU, although the relative radiosensitivities of the oxic and hypoxic α parameters (the OER(α)) exceed those of the standard OER values. Increased fluence rates are predicted to reduce LETU and OER. Large FLASH single doses will minimise RBE increments due to the β parameter reducing by a factor of 0.5–0.25 consistent with oxygen depletion, causing radioresistance. Similar results will occur for photons. Tissue α/β ratios increase by around 10 in FLASH conditions, agreeing with derived ion-beam dose rate equations. Significance. Increasing dose rates enhance local energy deposition rate per unit volume, probably causing oxygen depletion and radioresistance in pre-existing hypoxic sites during UHDR/FLASH exposures. The modelled equations provide testable hypotheses for further dose rate investigations in photon, proton and ion beams.

Two-step irradiance schedule for condyloma acuminatum and the influencing factors of analgesic effect: A prospective randomized study.

The two-step irradiance schedule in photodynamic therapy (PDT) is an emerging treatment method with a remarkable analgesic effect. We evaluated the influencing factors of pain in condyloma acuminate (CA) treatment with a two-step irradiance schedule. All patients were randomly divided into a two-step irradiance group and control group. The two-step irradiance group used 40mW/cm2 for the first 8min, followed by 80mW/cm2 for 16min, while the control group used 80mW/cm2 for 20min. The Numerical Rating Scale (NRS) scores and pain-influencing factors were recorded accordingly. In the two-step irradiance and control groups, 64 and 63 patients completed the treatment, respectively. The NRS scores of the two-step irradiance group were significantly lower than that of the control group (p<.001), with a low fluence rate inducing less pain compared with a high fluence rate (p<.001). Moreover, when the total fluence accumulated to 57.6J/cm2 , the pain experienced by patients reached its peak. The NRS score of the urethral orifice group was the highest, and the male external genitalia group was the lowest. The NRS score was at its lowest in the first session and highest in the second session. There was a linear relationship between pain and wart size. Among these influencing factors, the fluence rate had the greatest impact on pain. The two-step irradiance schedule provides better analgesic effects than standard treatment irradiation while showing similar treatment efficacy. Factors that influence pain include high fluence rate, CA at the urethral orifice, second therapy session, wart size, and the interval between CO2 laser and ALA-PDT.

Determination method of high fluence rate for D-T neutron source with long counter

A method of determining high fluence rate for D-T neutron source by using two long counters is introduced. One long counter contains a BF3 proportional counter, and a response of 1.1 cm2 is determined by calibration. The other long counter contains a gamma compensated boron neutron ionization chamber, and a response of 2.06e-5 cm2 is determined by comparing with the results of long counter containing BF3 proportional counter. By appropriately arranging the two long counters, fluence measurements are performed at the high intensity D-T neutron generator (HINEG). The results of the experimental characterization to the long counter are presented at this paper.

Optical filtering based neutron/[formula omitted]-ray discrimination in a phoswich detector

Neutron/γ-ray (n∕γ) discrimination is a crucial issue in neutron measurements and is usually accomplished employing detectors transparent to γ-rays (3He proportional counters), or techniques for γ rejection (such as Pulse Shape Discrimination). The aim of this work is to test a system able to perform a quasi-digital n∕γ discrimination without using techniques based on pulse shape analysis. The system is based on a phoswich consisting of a LiCAF:Eu crystal sensitive to neutrons and two LuAG:Ce ceramics sensitive to γ-rays. Optical filtering allows obtaining two separate acquisition channels, which selectively collect the light emitted by only one of the two scintillators. Photon induced events are then discarded through an anti-coincidence algorithm.The results show that the proposed technique is actually capable of discarding γ-induced events, but the implemented setup downgrades the LiCAF:Eu light collection because of the light attenuation of glasses serving as filters. In some situations, it is preferable to employ the LiCAF:Eu crystal alone, discarding the γ-induced events on the basis of the signal amplitude. Therefore, the discrimination technique proposed with this setup is intended for situations in which the energy of the incoming photons or the pile-up effects related to the high fluence rate can generate pulses whose amplitude is comparable to a neutron event. In addition, it was noted that some optical filters contain impurities (10B in our case) which capture neutrons lowering the system detection efficiency.A Monte Carlo model was also implemented to replicate the system response and predict an optimal configuration for further development.

Effects of Beam Conditions in Ground Irradiation Tests on Degradation of Photovoltaic Characteristics of Space Solar Cells

We investigated the effects of irradiation beam conditions on the performance degradation of silicon and triple-junction solar cells for use in space. The fluence rates of electron and proton beams were varied. Degradation did not depend on the fluence rate of protons for both cells. A higher fluence rate of electrons caused greater degradation of the Si cell, but the dependence was due to the temperature increase during irradiation. Two beam-area expansion methods, defocusing and scanning, were examined for proton irradiation of various energies (50 keV–10 MeV). In comparing the output degradation from irradiation with defocused and scanned proton beams, no significant difference in degradation was found for any proton energy. We plan to reflect these findings into ISO standard of irradiation test method of space solar cells.

Utilizing neutron generators in boron neutron capture therapy

Neutron capture therapy (NCT) is a radiotherapeutic technique that is designed to utilize the neutron capture reaction and damage the tumor cells through the energy release from the reaction. Nuclear reactors are typically utilized in this therapy because of the high neutron fluence rate that can be achieved. There has been minimal work to evaluate the effectiveness of neutron generators in NCT. This work presents the preliminary simulation results of utilizing of a deuterium-deuterium generator in boron neutron capture therapy. MCNP 6.1 was used to model the detailed geometry of the neutron generator and the phantom. Neutron moderators and photon shielding were used to optimize the neutron fluence rate in the tumor and decrease the photon dose in the phantom respectively. The study showed that a good localization of the neutron dose can be achieved in the tumor area with a reduction of the photon dose in the surrounding areas.

Precise U[sbnd]Pb dating of grandite garnets by LA-ICP-MS: Assessing ablation behaviors under matrix-matched and non-matrix-matched conditions and applications to various skarn deposits

LA-ICP-MS UPb dating of garnet has become one of the important geochronometric methods in recent years. Both the matrix-matched and non-matrix-matched external standards were used for dating. However, under which conditions reliable ages can be obtained and the difference between the matrix-matched and non-matrix-matched methods have not been well constrained. In this contribution, a series of ablation experiments (including spot analysis and line scanning) were conducted on different grandite garnets using various ablation parameters (spot size, repetition rate and fluence) under both the matrix-matched (garnet as external standard) and non-matrix-matched (zircon as external standard) conditions, with the aim to obtain the optimal conditions for precise LA-ICP-MS garnet UPb dating. The results show that UPb fractionation associated with downhole depth, intrinsic properties of U (more refractory) and Pb (more volatile) and radiation damage (alpha dose) of crystal lattice occurs in zircon and garnet. The fractionation can be minimized or even eliminated by optimizing the ablation parameters (e.g., large spot size and low repetition rate) or the analytical modes (e.g., line scanning). This makes it feasible to use zircon as external standard for garnet UPb dating. Line scanning is most favorable for garnet UPb dating at broad ablation parameters regardless of matrix-matched or non-matrix-matched. In spot analysis mode, all the garnets can be precisely dated using a large spot size (e.g., ≥90 μm) coupled with moderate-low repetition rate (e.g., 2–5 J/cm2) and fluence (e.g., 2–5 J/cm2) under matrix-matched condition. Under non-matrix-matched condition, all the garnets can also be precisely dated when a larger spot size (e.g., ≥120 μm) coupled with moderate repetition rate (e.g., 5 Hz) and fluence (e.g., 5 J/cm2) is used. Too high or too low repetition rates (e.g., <2 Hz and > 10 Hz) and fluences (e.g., <2 J/cm2 and > 10 J/cm2) were found to be unsuitable for garnet UPb dating. Low-U and high-U samples are best treated differently due to their different UPb fractionation coefficients, especially at the high fluence and repetition rate conditions. Equally, U-concentration matched garnet standards are required to improve the accuracy and precision of the UPb datingNatural grandite garnets selected from Fe, W and CuMo skarn deposits can be precisely dated using the optimized methods. These garnets have compositions varying widely between andradite and grossular with variable U (1–100 ppm) and common Pb (f206 of 0–0.7) concentrations, indicating that the methods are reliable and thus suitable for wide applications.

Development of a passive gold-foil Nested Neutron Spectrometer to validate the active current-mode He-3 measurements in a high neutron fluence rate radiotherapy environment

Nested Neutron SpectrometersTM (NNS) can be used to measure neutron fluence rate spectra under diverse circumstances with a working principle similar to Bonner sphere systems. Conventionally, the NNS consists of an active-readout He-3 detector core and concentric moderator shells. In environments where the neutron fluence rate exceeds ∽104 neutrons/s, these spectrometers may be operated in a current-mode to avoid the effects of pulse pile-up and deadtime. A current-to-pulse conversion factor is used to convert current-mode measurements to pulse-mode. However, the conversion factor can only be directly calibrated under low-flux conditions due to the pulse pile-up in high-flux situations. In order to have confidence in the use of the conversion factor in high neutron fluence rate environments such as in high-energy radiotherapy, its use must be experimentally validated. To perform this validation, we developed a passive-readout NNS with gold activation foils. Our work included the generation of system response functions using the Monte Carlo toolkit, GEANT4, and an experimental workflow. The passive NNS and the active NNS were then used to measure the secondary neutron fluence rate spectra produced by a Varian TrueBeamTM STx linac under identical experimental conditions. We found that the spectrum obtained using the active NNS agreed well with that obtained using the passive NNS within uncertainties. This serves as validation of the use of the current-mode of the active NNS in the high neutron fluence rate conditions encountered in radiotherapy.

DD6 single-crystal superalloy with thermal barrier coating in femtosecond laser percussion drilling

In recent years, single-crystal superalloy and thermal barrier coating (TBC) have attracted considerable attentions in femtosecond laser drilling. Surface morphology changes in DD6 single-crystal superalloy and TBC induced by incident laser pulses with a wide range of powers (2.28–11.18 W) at 50 kHz are studied. The ablation thresholds of DD6 single-crystal superalloy and TBC are calculated, and the ablation mechanisms of different femtosecond laser spot regions are discussed in details. Results show that the ablation threshold of DD6 single-crystal superalloy is 1.16 J/cm2, which is close to that of TBC (0.998 J/cm2). The femtosecond laser spot regions in the DD6 single-crystal superalloy and TBC can be divided into four (ablation, melting, laser-induced, and irradiated regions) on the basis of the energy distribution of the Gaussian laser beam. However, the physics behind femtosecond laser on single-crystal superalloy is laser-induced periodic surface structures (LIPSS), where is laser-induced cracks (LIC) on TBC. The dominant mechanism differs in different regions. The reason for cracks on the TBC may be the combined action of thermal stress and mechanism stress under high fluence and high repetition rate femtosecond laser.

Photoacoustic visualization of the fluence rate dependence of photodynamic therapy.

This study investigates the fluence rate effect, an essential modulating mechanism of photodynamic therapy (PDT), by using photoacoustic imaging method. To the best of our knowledge, this is the first time that the fluence rate dependence is investigated at a microscopic scale, as opposed to previous studies that are based on tumor growth/necrosis or animal surviving rate. This micro-scale examination enables subtle biological responses, including the vascular damage and the self-healing response, to be studied. Our results reveal the correlations between fluence rate and PDT efficacy/self-healing magnitude, indicating that vascular injuries induced by high fluence rates are more likely to recover and by low fluence rates (≤126 mW/cm2) are more likely to be permanent. There exists a turning point of fluence rate (314 mW/cm2), above which PDT practically produces no permanent therapeutic effect and damaged vessels can fully recover. These findings have practical significance in clinical setting. For cancer-related diseases, the 'effective fluence rate' is useful to provoke permanent destruction of tumor vasculature. Likewise, the 'non effective range' can be applied when PDT is used in applications such as opening the blood brain barrier to avoid permanent brain damage.

Blood Flow Measurements Enable Optimization of Light Delivery for Personalized Photodynamic Therapy.

Fluence rate is an effector of photodynamic therapy (PDT) outcome. Lower light fluence rates can conserve tumor perfusion during some illumination protocols for PDT, but then treatment times are proportionally longer to deliver equivalent fluence. Likewise, higher fluence rates can shorten treatment time but may compromise treatment efficacy by inducing blood flow stasis during illumination. We developed blood-flow-informed PDT (BFI-PDT) to balance these effects. BFI-PDT uses real-time noninvasive monitoring of tumor blood flow to inform selection of irradiance, i.e., incident fluence rate, on the treated surface. BFI-PDT thus aims to conserve tumor perfusion during PDT while minimizing treatment time. Pre-clinical studies in murine tumors of radiation-induced fibrosarcoma (RIF) and a mesothelioma cell line (AB12) show that BFI-PDT preserves tumor blood flow during illumination better than standard PDT with continuous light delivery at high irradiance. Compared to standard high irradiance PDT, BFI-PDT maintains better tumor oxygenation during illumination and increases direct tumor cell kill in a manner consistent with known oxygen dependencies in PDT-mediated cytotoxicity. BFI-PDT promotes vascular shutdown after PDT, thereby depriving remaining tumor cells of oxygen and nutrients. Collectively, these benefits of BFI-PDT produce a significantly better therapeutic outcome than standard high irradiance PDT. Moreover, BFI-PDT requires ~40% less time on average to achieve outcomes that are modestly better than those with standard low irradiance treatment. This contribution introduces BFI-PDT as a platform for personalized light delivery in PDT, documents the design of a clinically-relevant instrument, and establishes the benefits of BFI-PDT with respect to treatment outcome and duration.

Light Fluence Rate and Tissue Oxygenation (St O2 ) Distributions Within the Thoracic Cavity of Patients Receiving Intraoperative Photodynamic Therapy for Malignant Pleural Mesothelioma.

The distributions of light and tissue oxygenation (St O2 ) within the chest cavity were determined for 15 subjects undergoing macroscopic complete resection followed by intraoperative photodynamic therapy (PDT) as part of a clinical trial for the treatment of malignant pleural mesothelioma (MPM). Over the course of light delivery, detectors at each of eight different sites recorded exposure to variable fluence rate. Nevertheless, the treatment-averaged fluence rate was similar among sites, ranging from a median of 40-61mWcm-2 during periods of light exposure to a detector. St O2 at each tissue site varied by subject, but posterior mediastinum and posterior sulcus were the most consistently well oxygenated (median St O2 >90%; interquartile ranges ~85-95%). PDT effect on St O2 was characterized as the St O2 ratio (post-PDT St O2 /pre-PDT St O2 ). High St O2 pre-PDT was significantly associated with oxygen depletion (St O2 ratio<1), although the extent of oxygen depletion was mild (median St O2 ratio of 0.8). Overall, PDT of the thoracic cavity resulted in moderate treatment-averaged fluence rate that was consistent among treated tissue sites, despite instantaneous exposure to high fluence rate. Mild oxygen depletion after PDT was experienced at tissue sites with high pre-PDT St O2 , which may suggest the presence of a treatment effect.

Immune Responses after Vascular Photodynamic Therapy with Redaporfin.

Photodynamic therapy (PDT) relies on the administration of a photosensitizer (PS) that is activated, after a certain drug-to-light interval (DLI), by the irradiation of the target tumour with light of a specific wavelength absorbed by the PS. Typically, low light doses are insufficient to eradicate solid tumours and high fluence rates have been described as poorly immunogenic. However, previous work with mice bearing CT26 tumours demonstrated that vascular PDT with redaporfin, using a low light dose delivered at a high fluence rate, not only destroys the primary tumour but also reduces the formation of metastasis, thus suggesting anti-tumour immunity. This work characterizes immune responses triggered by redaporfin-PDT in mice bearing CT26 tumours. Our results demonstrate that vascular-PDT leads to a strong neutrophilia (2–24 h), systemic increase of IL-6 (24 h), increased percentage of CD4+ and CD8+ T cells producing IFN-γ or CD69+ (2–24 h) and increased CD4+/CD8+ T cell ratio (2–24 h). At the tumour bed, T cell tumour infiltration disappeared after PDT but reappeared with a much higher incidence one day later. In addition, it is shown that the therapeutic effect of redaporfin-PDT is highly dependent on neutrophils and CD8+ T cells but not on CD4+ T cells.