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Chronic infection with Schistosoma mansoni parasites is associated with reduced allergic sensitization in humans, while schistosome eggs protects against allergic airway inflammation (AAI) in mice. One of the main secretory/excretory molecules from schistosome eggs is the glycosylated T2-RNAse Omega-1 (ω1). We hypothesized that ω1 induces protection against AAI during infection. Peritoneal administration of ω1 prior to sensitization with Ovalbumin (OVA) reduced airway eosinophilia and pathology, and OVA-specific Th2 responses upon challenge, independent from changes in regulatory T cells. ω1 was taken up by monocyte-derived dendritic cells, mannose receptor (CD206)-positive conventional type 2 dendritic cells (CD206+ cDC2), and by recruited peritoneal macrophages. Additionally, ω1 impaired CCR7, F-actin, and costimulatory molecule expression on myeloid cells and cDC2 migration in and ex vivo, as evidenced by reduced OVA+ CD206+ cDC2 in the draining mediastinal lymph nodes (medLn) and retainment in the peritoneal cavity, while antigen processing and presentation in cDC2 were not affected by ω1 treatment. Importantly, RNAse mutant ω1 was unable to reduce AAI or affect DC migration, indicating that ω1 effects are dependent on its RNAse activity. Altogether, ω1 hampers migration of OVA+ cDC2 to the draining medLn in mice, elucidating how ω1 prevents allergic airway inflammation in the OVA/alum mouse model., Competing Interests: HS receive research grants from the Lung foundation Netherlands and the Dutch Research Council and is a board member of the Netherlands Respiratory Society., (Copyright: © 2024 Patente et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The unfolded protein response (UPR) aims to restore ER homeostasis under conditions of high protein folding load, a function primarily serving secretory cells. Additional, non-canonical UPR functions have recently been unraveled in immune cells. We addressed the function of the inositol-requiring enzyme 1 (IRE1) signaling branch of the UPR in NK cells in homeostasis and microbial challenge. Cell-intrinsic compound deficiency of IRE1 and its downstream transcription factor XBP1 in NKp46 + NK cells, did not affect basal NK cell homeostasis, or overall outcome of viral MCMV infection. However, mixed bone marrow chimeras revealed a competitive advantage in the proliferation of IRE1-sufficient Ly49H + NK cells after viral infection. CITE-Seq analysis confirmed strong induction of IRE1 early upon infection, concomitant with the activation of a canonical UPR signature. Therefore, we conclude that IRE1/XBP1 activation is required during vigorous NK cell proliferation early upon viral infection, as part of a canonical UPR response., Competing Interests: E.V. is a cofounder and employee of Innate Pharma. All other authors declare no competing interests., (© 2023 The Author(s).)

Background: The most common endotype of asthma is type 2-high asthma, which is sometimes driven by adaptive allergen-specific T H 2 lymphocytes that react to allergens presented by dendritic cells (DCs), or sometimes by an innate immune response dominated by type 2 innate lymphocytes (ILC2s). Understanding the underlying pathophysiology of asthma is essential to improve patient-tailored therapy. The STE20 kinase thousand-and-one kinase 3 (TAOK3) controls key features in the biology of DCs and lymphocytes, but to our knowledge, its potential usefulness as a target for asthma therapy has not yet been addressed., Objective: We examined if and how loss of Taok3 affects the development of house dust mite (HDM)-driven allergic asthma in an in vivo mouse model., Methods: Wild-type Taok3 +/+ and gene-deficient Taok3 -/- mice were sensitized and challenged with HDM, and bronchoalveolar lavage fluid composition, mediastinal lymph node cytokine production, lung histology, and bronchial hyperreactivity measured. Conditional Taok3 fl/fl mice were crossed to tissue- and cell-specific specific deletor Cre mice to understand how Taok3 acted on asthma susceptibility. Kinase-dead (KD) Taok3 KD mice were generated to probe for the druggability of this pathway. Activation of HDM-specific T cells was measured in adoptively transferred HDM-specific T-cell receptor-transgenic CD4 + T cells. ILC2 biology was assessed by in vivo and in vitro IL-33 stimulation assays in Taok3 -/- and Taok3 +/+ , Taok3 KD , and Red5-Cre Taok3 fl/fl mice., Results: Taok3 -/- mice failed to mount salient features of asthma, including airway eosinophilia, T H 2 cytokine production, IgE secretion, airway goblet cell metaplasia, and bronchial hyperreactivity compared to controls. This was due to intrinsic loss of Taok3 in hematopoietic and not epithelial cells. Loss of Taok3 resulted in hampered HDM-induced lung DC migration to the draining lymph nodes and defective priming of HDM-specific T H 2 cells. Strikingly, HDM and IL-33-induced ILC2 proliferation and function were also severely affected in Taok3-deficient and Taok3 KD mice., Conclusions: Absence of Taok3 or loss of its kinase activity protects from HDM-driven allergic asthma as a result of defects in both adaptive DC-mediated T H 2 activation and innate ILC2 function. This identifies Taok3 as an interesting drug target, justifying further testing as a new treatment for type 2-high asthma., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Genome-wide association studies in asthma have repeatedly identified single nucleotide polymorphisms in the ORM (yeast)-like protein isoform 3 (ORMDL3) gene across different populations. Although the ORM homologues in yeast are well-known inhibitors of sphingolipid synthesis, it is still unclear whether and how mammalian ORMDL3 regulates sphingolipid metabolism and whether altered sphingolipid synthesis would be causally related to asthma risk., Objective: We sought to examine the in vivo role of ORMDL3 in sphingolipid metabolism and allergic asthma., Methods: Ormdl3-LacZ reporter mice, gene-deficient Ormdl3 -/- mice, and overexpressing Ormdl3 Tg/wt mice were exposed to physiologically relevant aeroallergens, such as house dust mite (HDM) or Alternaria alternata, to induce experimental asthma. Mass spectrometry-based sphingolipidomics were performed, and airway eosinophilia, T H 2 cytokine production, immunoglobulin synthesis, airway remodeling, and bronchial hyperreactivity were measured., Results: HDM challenge significantly increased levels of total sphingolipids in the lungs of HDM-sensitized mice compared with those in control mice. In Ormdl3 Tg/wt mice the allergen-induced increase in lung ceramide levels was significantly reduced, whereas total sphingolipid levels were not affected. Conversely, in liver and serum, levels of total sphingolipids, including ceramides, were increased in Ormdl3 -/- mice, whereas they were decreased in Ormdl3 Tg/wt mice. This difference was independent of allergen exposure. Despite these changes, all features of asthma were identical between wild-type, Ormdl3 Tg/wt , and Ormdl3 -/- mice across several models of experimental asthma., Conclusion: ORMDL3 regulates systemic ceramide levels, but genetically interfering with Ormdl3 expression does not result in altered experimental asthma., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20 -/- cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a well-established inhibitor of mTOR, also strongly protected NK-A20 -/- cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis., (© 2019 Vetters et al.)

Background: The emergence of IL-33 as a key molecular player in the development and propagation of widespread inflammatory diseases, including asthma and atopic dermatitis, has established the need for effective IL-33-neutralizing biologics., Objective: Here we describe the development and validation of a new antagonist of IL-33, termed IL-33trap, which combines the extracellular domains of the IL-33 receptor (ST2) and its coreceptor, IL-1 receptor accessory protein, into a single fusion protein., Methods: We produced and purified recombinant IL-33trap from human cells and analyzed its IL-33-binding affinity and IL-33 antagonistic activity in cultured cells and mice. IL-33trap activity was also benchmarked with a recombinant soluble ST2 corresponding to the naturally occurring IL-33 decoy receptor. Finally, we studied the effect of IL-33trap in the Alternaria alternata mouse model of allergic airway inflammation., Results: In vitro IL-33trap binds IL-33 and inhibits IL-33 activity to a much stronger degree than soluble ST2. Furthermore, IL-33trap inhibits eosinophil infiltration, splenomegaly, and production of signature cytokines in splenic lymphocytes and lung tissue on IL-33 injection. Finally, administration of IL-33trap at the time of allergen challenge inhibits inflammatory responses in a preclinical mouse model of acute allergic airway inflammation., Conclusions: IL-33trap is a novel IL-33 antagonist that outperforms the natural IL-33 decoy receptor and shows anti-inflammatory activities in a preclinical mouse model of acute allergic airway inflammation when administered at the time of allergen challenge., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Asthma is a chronic inflammatory airway disease in which innate and adaptive immune cells act together to cause eosinophilic inflammation, goblet cell metaplasia (GCM), and bronchial hyperreactivity (BHR). In clinical trials using biologicals against IL-4 receptor (IL-4R) α or IL-5, only a subset of patients with moderate-to-severe asthma responded favorably, suggesting that distinct pathophysiologic mechanisms are at play in subgroups of patients called endotypes. However, the effect of multiple cytokine blockade using bispecific antibodies has not been tested., Objective: We sought to target simultaneously the IL-4, IL-13, and IL-5 signaling pathways with a novel IL-4Rα/IL-5-bispecific antibody in a murine house dust mite (HDM) model of asthma., Methods: Two mAbs neutralizing IL-4Rα and IL-5 were generated by using a llama-based antibody platform. Their heavy and light chains were then cotransfected in mammalian cells, resulting in a heterogeneous antibody mixture from which the bispecific antibody was isolated by using a dual anti-idiotypic purification process. C57BL/6J mice were finally sensitized and challenged to HDM extracts and treated during challenge with the antibodies., Results: We successfully generated and characterized the monospecific and bispecific antibodies targeting IL-4Rα and IL-5. The monospecific antibodies could suppress eosinophilia, IgE synthesis, or both, whereas only the IL-4Rα/IL-5-bispecific antibody and the combination of monospecific antibodies additionally inhibited GCM and BHR., Conclusion: Type 2 cytokines act synergistically to cause GCM and BHR in HDM-exposed mice. These preclinical results show the feasibility of generating bispecific antibodies that target multiple cytokine signaling pathways as superior inhibitors of asthma features, including the difficult-to-treat GCM., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The IRE1-XBP1 signalling pathway is part of a cellular programme that protects against endoplasmic reticulum (ER) stress, but also controls development and survival of immune cells. Loss of XBP1 in splenic type 1 conventional dendritic cells (cDC1s) results in functional alterations without affecting cell survival. However, in mucosal cDC1s, loss of XBP1 impaired survival in a tissue-specific manner-while lung cDC1s die, intestinal cDC1s survive. This was not caused by differential activation of ER stress cell-death regulators CHOP or JNK. Rather, survival of intestinal cDC1s was associated with their ability to shut down protein synthesis through a protective integrated stress response and their marked increase in regulated IRE1-dependent messenger RNA decay. Furthermore, loss of IRE1 endonuclease on top of XBP1 led to cDC1 loss in the intestine. Thus, mucosal DCs differentially mount ATF4- and IRE1-dependent adaptive mechanisms to survive in the face of ER stress.

Notch2 and B cell antigen receptor (BCR) signaling determine whether transitional B cells become marginal zone B (MZB) or follicular B (FoB) cells in the spleen, but it is unknown how these pathways are related. We generated Taok3 -/- mice, lacking the serine/threonine kinase Taok3, and found cell-intrinsic defects in the development of MZB but not FoB cells. Type 1 transitional (T1) B cells required Taok3 to rapidly respond to ligation by the Notch ligand Delta-like 1. BCR ligation by endogenous or exogenous ligands induced the surface expression of the metalloproteinase ADAM10 on T1 B cells in a Taok3-dependent manner. T1 B cells expressing surface ADAM10 were committed to becoming MZB cells in vivo, whereas T1 B cells lacking expression of ADAM10 were not. Thus, during positive selection in the spleen, BCR signaling causes immature T1 B cells to become receptive to Notch ligands via Taok3-mediated surface expression of ADAM10.

Interferon regulatory factor-8 (IRF8) has been proposed to be essential for development of monocytes, plasmacytoid dendritic cells (pDCs) and type 1 conventional dendritic cells (cDC1s) and remains highly expressed in differentiated DCs. Transcription factors that are required to maintain the identity of terminally differentiated cells are designated "terminal selectors." Using BM chimeras, conditional Irf8(fl/fl) mice and various promotors to target Cre recombinase to different stages of monocyte and DC development, we have identified IRF8 as a terminal selector of the cDC1 lineage controlling survival. In monocytes, IRF8 was necessary during early but not late development. Complete or late deletion of IRF8 had no effect on pDC development or survival but altered their phenotype and gene-expression profile leading to increased T cell stimulatory function but decreased type 1 interferon production. Thus, IRF8 differentially controls the survival and function of terminally differentiated monocytes, cDC1s, and pDCs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Liver X receptors (LXRs) are nuclear receptors that function as cholesterol sensors and regulate cholesterol homeostasis. High cholesterol has been recognized as a risk factor in asthma; however, the mechanism of this linkage is not known., Methods: To explore the importance of cholesterol homeostasis for asthma, we investigated the contribution of LXR activity in an ovalbumin- and a house dust mite-driven eosinophilic asthma mouse model., Results: In both models, airway inflammation, airway hyper-reactivity, and goblet cell hyperplasia were reduced in mice deficient for both LXRα and LXRβ isoforms (LXRα(-/-)β(-/-)) as compared to wild-type mice. Inversely, treatment with the LXR agonist GW3965 showed increased eosinophilic airway inflammation. LXR activity contributed to airway inflammation through promotion of type 2 cytokine production as LXRα(-/-)β(-/-) mice showed strongly reduced protein levels of IL-5 and IL-13 in the lungs as well as reduced expression of these cytokines by CD4(+) lung cells and lung-draining lymph node cells. In line herewith, LXR activation resulted in increased type 2 cytokine production by the lung-draining lymph node cells., Conclusions: In conclusion, our study demonstrates that the cholesterol regulator LXR acts as a positive regulator of eosinophilic asthma in mice, contributing to airway inflammation through regulation of type 2 cytokine production.

Growing up on a dairy farm protects children from allergy, hay fever, and asthma. A mechanism linking exposure to this endotoxin (bacterial lipopolysaccharide)-rich environment with protection has remained elusive. Here we show that chronic exposure to low-dose endotoxin or farm dust protects mice from developing house dust mite (HDM)-induced asthma. Endotoxin reduced epithelial cell cytokines that activate dendritic cells (DCs), thus suppressing type 2 immunity to HDMs. Loss of the ubiquitin-modifying enzyme A20 in lung epithelium abolished the protective effect. A single-nucleotide polymorphism in the gene encoding A20 was associated with allergy and asthma risk in children growing up on farms. Thus, the farming environment protects from allergy by modifying the communication between barrier epithelial cells and DCs through A20 induction., (Copyright © 2015, American Association for the Advancement of Science.)

Lung cancer arises in a context of tumour-induced immune suppression. Dendritic cells (DCs) are central players in the induction of anti-tumoural immunity, providing critical signals that drive the induction of cytotoxic T-cell responses. Meanwhile, microRNAs are associated with tumour development as well as immune regulation. We postulated that lung tumours escape immune control by reprogramming DC immunogenicity at the microRNA level. Using an orthotopic model of lung cancer, we first identified the DC population responsible for transport and cross-presentation of lung tumour-derived antigens to naïve T cells in the draining mediastinal lymph nodes (LNs). Profiling the full microRNA repertoire of these DCs revealed a restricted set of microRNAs that was consistently dysregulated in the presence of lung tumours, with miR-301a as one of the top upregulated transcripts. Overexpression of miR-301a in DCs suppressed IL-12 secretion, decreased IFN-γ release from antigen-specific cytotoxic T cells, and shifted antigen-specific T helper cytokine profile away from IFN-γ towards IL-13 and IL-17A-secreting T cells. Strikingly, DC-selective Dicer1 gene deletion resulted in delayed lung tumour growth and a survival benefit. Taken together, our data reveal that lung tumours induce an immunosuppressive microRNA signature in pulmonary DCs. Interfering with the DC-intrinsic capacity to remodel microRNA repertoires affects lung tumour outcome., (© 2014 UICC.)

A polymer hydrogel foam is proposed as a potential three dimensional experimental dosimeter for radiation treatment verification in low-density tissue such as the lung. A gel foam is created by beating a radiation sensitive polymer gel mixture in an anoxic atmosphere. The mass density of the gel foam is in the order of 0.25-0.35 kg/dm3. Both nuclear magnetic resonance (NMR) spin-spin relaxation rate (R2) and magnetization transfer ratio (MTR) have been used to map the dose distribution from the gel dosimeter. It is found that MTR has significant advantages compared to R2 for mapping the dose distribution in the polymer gel foam dosimeters. The magnetization transfer ratio is found to be less dependent on the density and microstructure of the gel foam dosimeter while spin-spin relaxation dispersion has been observed making the spin-spin relaxation rate dependent on the interecho time interval. Optical microscopy reveals a microstructure that shows great similarity with human lung tissue. It is also shown how NMR hydrogen proton density measurements can be used to map the density distributions in gel dosimeters.

Polymer gel dosimeters offer a wide range of applications in the three-dimensional verification of complex dose distributions such as in intensity-modulated radiotherapy. One of the major difficulties with polymer gel dosimeters is their sensitivity to oxygen, as oxygen inhibits the radiation-induced polymerization reaction. For several years, oxygen was removed from the gels by bubbling the sol with inert gases for several hours during the gel fabrication. Also, the gel had to be poured in containers with low oxygen permeability and solubility. Recently, it was found that these technical difficulties can easily be solved by adding an antioxidant to the gel. These gels are called 'normoxic' gels as they can be produced under normal atmospheric conditions. In this study several properties of polymer gel dosimeters have been investigated: the dose sensitivity, the temporal and spatial stability of the gel, the sensitivity of the dose response to temperature during irradiation and during MR imaging, the energy dependence and the dose-rate dependence. This study reveals that the normoxic polymer gel dosimeter based on methacrylic acid (nMAG) studied in this work has inferior radiation properties as compared to the polyacrylamide gelatine (PAG) gel dosimeters. It is shown that from the three different gel dosimeters investigated in this study, the nPAG gel dosimeter results in a less sensitive gel dosimeter but with superior radiation properties as compared to the nMAG gel dosimeter. The importance of investigating relevant radiation properties of gel dosimeters apart from the radiation sensitivity-prior to their use for dosimetric validation experiments-is illustrated and emphasized throughout this study. Other combinations of monomer and gelling agent may result in more reliable normoxic polymer gel dosimeters.

Purpose: In rectal cancer, combined radiotherapy and chemotherapy, either pre- or postoperatively, is an accepted treatment. Late small bowel (SB) toxicity is a feared side effect and limits radiation-dose escalation in a volume-dependent way. A planning strategy for intensity- modulated arc therapy (IMAT) was developed, and IMAT was clinically implemented with the aim to reduce the volume of SB irradiated at high doses and thus reduce SB toxicity. We report on the treatment plans of the first 7 patients, on the comparison of IMAT with conventional 3D planning (3D), and on the feasibility of IMAT delivery., Methods and Materials: Seven patients, who were referred to our department for preoperative (n = 4) or postoperative (n = 3) radiotherapy for rectal cancer, gave written consent for IMAT treatment. All patients had a planning CT in prone position. The delineation of the clinical target volume was done after fusion of CT and MRI, with the help of a radiologist. For the IMAT plan, arcs were generated using an anatomy-based segmentation tool. The optimization of the arcs was done by weight optimization (WO) and leaf position optimization (LPO), both of which were adapted for IMAT purposes. The 3D plans used one posterior and two lateral wedged beams, of which the outlines were shaped to the beam's-eye view projection of the planning target volume (PTV). Beam WO was done by constrained matrix inversion. For dose-volume histogram analysis, all plans were normalized to 45 Gy as median PTV dose. Polymer gel dosimetry (PGD) on a humanoid phantom was used for the validation of the total chain (planning to delivery). IMAT treatments were delivered by an Elekta SliPlus linear accelerator using prototype software with the same interlock class as in clinical mode., Results: The IMAT plan resulted in 3 to 6 arcs, with a mean delivery time of 6.3 min and a mean of 456 monitor units (MU) for a 180 cGy fraction. The minimal dose in the PTV was not significantly different between 3D and IMAT plans. Inhomogeneity was highest for the IMAT plans (14.1%) and lowest for the 3D plans (9.9%). Mean dose to the SB was significantly lower for the IMAT plans (12.4 Gy) than for the 3D plans (17.0 Gy). The volume of SB receiving less than any dose level was lower for the IMAT plans than for 3D plans. Integral dose was lower in the IMAT plans than for the 3D plans (respectively 244 J and 262 J to deliver 45 Gy). Differences between the PGD measured dose and the calculated dose were as small for IMAT as for 3D treatments., Conclusion: IMAT plans are deliverable within a 5-10-minute time slot, and result in a lower dose to the SB than 3D plans, without creating significant underdosages in the PTV. PGD showed that IMAT delivery is as accurate as 3D delivery.

Purpose: Whole abdominopelvic radiation therapy (WAPRT) is a treatment option in the palliation of patients with relapsed ovarian cancer. With conventional techniques, kidneys and liver are the dose- and homogeneity-limiting organs. We developed a planning strategy for intensity-modulated arc therapy (IMAT) and report on the treatment plans of the first 5 treated patients., Methods and Materials: Five consecutive patients with histologically proven relapsed ovarian cancer were sent to our department for WAPRT. The target volumes and organs at risk (OAR) were delineated on 0.5-cm-thick CT slices. The clinical target volume (CTV) was defined as the total peritoneal cavity. CTV and kidneys were expanded with 0.5 cm. In a preset range of 8 degrees interspaced gantry angles, machine states were generated with an anatomy-based segmentation tool. Machine states of the same class were stratified in arcs. The optimization of IMAT was done in several steps, using a biophysical objective function. These steps included weight optimization of machine states, leaf position optimization adapted to meet the maximal leaf speed constraint, and planner-interactive optimization of the start and stop angles. The final control points (machine states plus associated cumulative monitor unit counts) were calculated using a collapsed cone convolution/superposition algorithm. For comparison, two conventional plans (CONV) were made, one with two fields (CONV2), and one with four fields (CONV4). In these CONV plans, dose to the kidneys was limited by cerrobend blocks. The IMAT and the CONV plans were normalized to a median dose of 33 Gy to the planning target volume (PTV). Monomer/polymer gel dosimetry was used to assess the dosimetric accuracy of the IMAT planning and delivery method., Results: The median volume of the PTV was 8306 cc. The mean treatment delivery time over 4 patients was 13.8 min. A mean of 444 monitor units was needed for a fraction dose of 150 cGy. The fraction of the PTV volume receiving more than 90% of the prescribed dose (V(90)) was 9% higher for the IMAT plan than for the CONV4 plan (89.9% vs. 82.5%). Outside a build-up region of 0.8 cm and 1 cm away from both kidneys, the inhomogeneity in the PTV was 15.1% for the IMAT plans and 24.9% for the CONV4 plans (for CONV2 plans, this was 34.9%). The median dose to the kidneys in the IMAT plans was lower for all patients. The 95th percentile dose for the kidneys was significantly higher for the IMAT plans than for the CONV4 and CONV2 plans (28.2 Gy vs. 22.2 Gy and 22.6 Gy for left kidney, respectively). No relevant differences were found for liver. The gel-measured dose was within clinical planning constraints., Conclusion: IMAT was shown to be deliverable in an acceptable time slot and to produce dose distributions that are more homogeneous than those obtained with a CONV plan, with at least equal sparing of the OARs.

Background and Purpose: When planning an intensity-modulated radiation therapy (IMRT) treatment in a heterogeneous region (e.g. the thorax), the dose computation algorithm of a treatment planning system may need to account for these inhomogeneities in order to obtain a reliable prediction of the dose distribution. An accurate dose verification technique such as monomer/polymer gel dosimetry is suggested to verify the outcome of the planning system., Materials and Methods: The effects of low-density structures: (a) on narrow high-energy (18 MV) photon beams; and (b) on a class-solution IMRT treatment delivered to a thorax phantom have been examined using gel dosimetry. The used phantom contained air cavities that could be filled with water to simulate a homogeneous or heterogeneous configuration. The IMRT treatment for centrally located lung tumors was delivered on both cases, and gel derived dose maps were compared with computations by both the GRATIS and Helax-TMS planning system., Results: Dose rebuildup due to electronic disequilibrium in a narrow photon beam is demonstrated. The gel measurements showed good agreement with diamond detector measurements. Agreement between measured IMRT dose maps and dose computations was demonstrated by several quantitative techniques. An underdosage of the planning target volume (PTV) was revealed. The homogeneity of the phantom had only a minor influence on the dose distribution in the PTV. An expansion of low-level isodoses in the lung volume was predicted by collapsed cone computations in the heterogeneous case., Conclusions: For the class-solution described, the dose in centrally located mediastinal tumors can be computed with sufficient accuracy, even when neglecting the lower lung density. Polymer gel dosimetry proved to be a valuable technique to verify dose calculation algorithms for IMRT in 3D in heterogeneous configurations.

Polymer gel dosimeters offer a wide range of potential applications in the three-dimensional verification of complex dose distribution such as in intensity-modulated radiotherapy (IMRT). Until now, however, polymer gel dosimeters have not been widely used in the clinic. One of the reasons is that they are difficult to manufacture. As the polymerization in polymer gels is inhibited by oxygen, all free oxygen has to be removed from the gels. For several years this was achieved by bubbling nitrogen through the gel solutions and by filling the phantoms in a glove box that is perfused with nitrogen. Recently another gel formulation was proposed in which oxygen is bound in a metallo-organic complex thus removing the problem of oxygen inhibition. The proposed gel consists of methacrylic acid, gelatin, ascorbic acid, hydroquinone and copper(II)sulphate and is given the acronym MAGIC gel dosimeter. These gels are fabricated under normal atmospheric conditions and are therefore called 'normoxic' gel dosimeters. In this study, a chemical analysis on the MAGIC gel was performed. The composition of the gel was varied and its radiation response was evaluated. The role of different chemicals and the reaction kinetics are discussed. It was found that ascorbic acid alone was able to bind the oxygen and can thus be used as an anti-oxidant in a polymer gel dosimeter. It was also found that the anti-oxidants N-acetyl-cysteine and tetrakis(hydroxymethyl)phosphonium were effective in scavenging the oxygen. However, the rate of oxygen scavenging is dependent on the anti-oxidant and its concentration with tetrakis(hydroxymethyl)phosphonium being the most reactive anti-oxidants. Potentiometric oxygen measurements in solution provide an easy way to get a first impression on the rate of oxygen scavenging. It is shown that cupper(II)sulphate operates as a catalyst in the oxidation of ascorbic acid. We, therefore, propose some new normoxic gel formulations that have a less complicated chemical formulation than the MAGIC gel.