Relative biological effectiveness in proton beam therapy - Current knowledge and future challenges.
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ABSTRACT:
SUBMITTER: Luhr A
PROVIDER: S-EPMC5862688 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
Publications
Relative biological effectiveness in proton beam therapy - Current knowledge and future challenges.
Lühr Armin A von Neubeck Cläre C Krause Mechthild M Troost Esther G C EGC
Clinical and translational radiation oncology 20180201
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Project description:Proton beam therapy (PBT) has been increasingly used in a variety of cancers due to its excellent physical properties and superior dosimetric parameters. PBT may improve patient survival by improving the local tumor treatment rate while reducing injury to normal organs, which may result in fewer radiation-induced adverse effects. However, the significant cost of establishing and maintaining proton facilities cannot be overlooked. In addition, there has been significant controversy regarding routine application of this treatment in certain types of cancer. The challenges of PBT in the future mainly include the lack of basic clinical trials, unclear biological effects, immature imaging technology and miniaturization of imaging guidance. Overcoming these limitations may promote the rapid development of PBT. We herein provide an overview of the existing literature on the efficacy and toxicity of common oncological applications of proton beam therapy.
| S-EPMC5772792 | biostudies-other
Project description:PurposeRelative biological effectiveness (RBE) accounts for the differences in biological effect from different radiation types. The RBE for proton therapy remains uncertain, as it has been shown to vary from the clinically used value of 1.1. In this work we investigated the RBE of protons and correlated the biological differences with the underlying physical quantities.Materials and methodsThree cell lines were irradiated (CHO, Chinese hamster ovary; A549, human lung adenocarcinoma; and T98, human glioma) and assessed for cell survival by using clonogenic assay. Cells were irradiated with 71- and 160-MeV protons at depths along the Bragg curve and 6-MV photons to various doses. The dose-averaged lineal energy ( y‒D ) was measured under similar conditions as the cells by using a microdosimeter. Dose-averaged linear energy transfer (LETd) was also calculated by using Monte Carlo (MC) simulations. Survival data were fit by using the linear quadratic model. The RBE values were calculated by comparing the physical dose (D6MV/Dp) that results in 50% (RBE0.5) and 10% (RBE0.1) cell survival, and survival after 2 Gy (RBE2Gy).ResultsProton RBE values ranged from 0.89 to 2.40. The RBE for all 3 cell lines increased with decreasing proton energy and was higher at 50% survival than at 10% survival. Additionally, both A549 and T98 cells generally had higher RBE values relative to the CHO cells, indicating a greater biological response to protons. An increase in RBE corresponded with an increase in y‒D and LETd.ConclusionProton RBE was found to depend on mean proton energy, survival end point, and cell type. Changes in both y‒D and LETd were also found to impact proton RBE values, but consideration of the energy spectrum may provide additional information. The RBE values in this study vary greatly, indicating the clinical value of 1.1 may not be suitable in all cases.
| S-EPMC6110616 | biostudies-literature
Project description:Human bocavirus (HBoV) is a parvovirus isolated about a decade ago and found worldwide in both respiratory samples, mainly from early life and children of 6-24 mo of age with acute respiratory infection, and in stool samples, from patients with gastroenteritis. Since then, other viruses related to the first HBoV isolate (HBoV1), namely HBoV2, HBoV3 and HBoV4, have been detected principally in human faeces. HBoVs are small non-enveloped single-stranded DNA viruses of about 5300 nucleotides, consisting of three open reading frames encoding the first two the non-structural protein 1 (NS1) and nuclear phosphoprotein (NP1) and the third the viral capsid proteins 1 and 2 (VP1 and VP2). HBoV pathogenicity remains to be fully clarified mainly due to the lack of animal models for the difficulties in replicating the virus in in vitro cell cultures, and the fact that HBoV infection is frequently accompanied by at least another viral and/or bacterial respiratory and/or gastroenteric pathogen infection. Current diagnostic methods to support HBoV detection include polymerase chain reaction, real-time PCR, enzyme-linked immunosorbent assay and enzyme immunoassay using recombinant VP2 or virus-like particle capsid proteins, although sequence-independent amplification techniques combined with next-generation sequencing platforms promise rapid and simultaneous detection of the pathogens in the future. This review presents the current knowledge on HBoV genotypes with emphasis on taxonomy, phylogenetic relationship and genomic analysis, biology, epidemiology, pathogenesis and diagnostic methods. The emerging discussion on HBoVs as true pathogen or innocent bystander is also emphasized.
| S-EPMC5075545 | biostudies-literature
Project description:Background and purposeIn proton therapy, a relative biological effectiveness (RBE) of 1.1 is used to convert proton dose into an equivalent photon dose. However, RBE varies with tissue type, fraction dose, and beam quality parameters beyond dose such as linear energy transfer (LET) raising concerns about increased local effectiveness and potential toxicity. This work aims to harmonize quantities used for clinical consideration of variable RBE for proton therapy.Materials and methodsA survey was distributed to proton centres to determine agreement on RBE-related concerns and clinical implementations. A subsequent clinical expert meeting facilitated by the European Particle Therapy Network was held to achieve consensus and to make clinical recommendations how to prescribe and report beyond using dose and constant RBE.ResultsThe survey was answered by 17 out of 23 centres contacted (74%). For proton RBE, most concerns existed regarding toxicity in serial organs, while the assumption of an RBE of 1.1 was considered valid for targets. Most physicists intended to consider a physical quantity beyond dose in clinical decision making.ConclusionsA constant RBE of 1.1 was the consensus for prescribing dose. However, current practice of recording and reporting dose in proton therapy must be complemented: the recommended quantity beyond dose was the dose-averaged LET in water from primary and secondary protons, normalized to unit density. This will facilitate analyses of treatment data on effectiveness beyond dose and between centres. No consensus on a single variable RBE model was found. More clinical training on proton RBE is needed.
| S-EPMC11750264 | biostudies-literature
Project description:Proton therapy is increasingly being used as a radiation therapy modality. There is uncertainty about the biological effectiveness of protons relative to photon therapies as it depends on several physical and biological parameters. Radiation oncology currently applies a constant and generic value for the relative biological effectiveness (RBE) of 1.1, which was chosen conservatively to ensure tumor coverage. The use of a constant value has been challenged particularly when considering normal tissue constraints. Potential variations in RBE have been assessed in several published reviews but have mostly focused on data from clonogenic cell survival experiments with unclear relevance for clinical proton therapy. The goal of this review is to put in vitro findings in relation to clinical observations. Relevant in vivo pathways determining RBE for tumors and normal tissues are outlined, including not only damage to tumor cells and parenchyma but also vascular damage and immune response. Furthermore, the current clinical evidence of varying RBE is reviewed. The assessment can serve as guidance for treatment planning, personalized dose prescriptions, and outcome analysis.
| S-EPMC8688199 | biostudies-literature
Project description:PurposeProton beam therapy is a commonly accepted treatment for intraocular melanomas, but the literature is lacking in descriptions of patient preferences of clinical outcomes and economic impact. In addition, no economic evaluations have been published regarding the incremental cost-effectiveness of proton beam therapy compared with enucleation or plaque brachytherapy, typical alternative treatments. We, therefore, conducted a cost-utility analysis of these three approaches for the treatment of intraocular melanomas.Materials and methodsA Markov model was constructed. Model parameters were identified from the published literature and publicly available data sources. Cost-effectiveness of each treatment was calculated in 2011 US Dollars per quality-adjusted life-year. Incremental cost-effectiveness ratios were calculated assuming enucleation as reference. One-way sensitivity analyses were conducted on all model parameters. A decision threshold of $50,000/quality-adjusted life-year was used to determine cost-effectiveness.ResultsEnucleation had the lowest costs and quality-adjusted life-years, and plaque brachytherapy had the highest costs and quality-adjusted life-years. Compared with enucleation, the base-case incremental cost-effectiveness ratios for plaque brachytherapy and proton beam therapy were $77,500/quality-adjusted life-year and $106,100/quality-adjusted life-year, respectively. Results were highly sensitive to multiple parameters. All three treatments were considered optimal, and even dominant, depending on the values used for sensitive parameters.ConclusionBase-case analysis results suggest enucleation to be optimal. However, the optimal choice was not robust to sensitivity analyses and, depending on the assumption, both plaque brachytherapy and proton beam therapy could be considered cost-effective. Future clinical studies should focus on generating further evidence with the greatest parameter uncertainty to inform future cost-effectiveness analyses.
| S-EPMC4436277 | biostudies-literature
Project description:Despite the conformality of modern X-ray therapy limiting high dose received by normal tissues the physical properties of X-rays make it impossible to avoid dose being delivered distal to the target. This "exit dose" is likely clinically significant especially for patients with gastrointestinal (GI) cancers when considering that even low dose received by the heart, lungs, bowel, and other radiosensitive structures can lead to morbidity and even may affect long-term tumor control. In contrast, proton beam therapy (PBT) delivers no "exit dose" and a growing body of literature suggests that this may improve clinical outcomes by reducing toxicity and even allowing for safe dose intensification to enhance tumor control. While there are not yet robust prospective data demonstrating the role of PBT for GI cancers, emerging retrospective data provide a strong rationale for continued study of how PBT may improve the therapeutic ratio for these patients. Here we review these data as well as discuss ongoing clinical trials of PBT for GI cancers.
| S-EPMC6219962 | biostudies-literature
Project description:Autophagy (a process of cellular self-eating) is a conserved cellular degradative process that plays important roles in maintaining homeostasis and preventing nutritional, metabolic, and infection-mediated stresses. Surprisingly, little attention has been paid to the role of this cellular function in species of agronomical interest, and the details of how autophagy functions in the development of phenotypes of agricultural interest remain largely unexplored. Here, we first provide a brief description of the main mechanisms involved in autophagy, then review our current knowledge regarding autophagy in species of agronomical interest, with particular attention to physiological functions supporting livestock animal production, and finally assess the potential of translating the acquired knowledge to improve animal development, growth and health in the context of growing social, economic and environmental challenges for agriculture.Abbreviations: AKT: AKT serine/threonine kinase; AMPK: AMP-activated protein kinase; ASC: adipose-derived stem cells; ATG: autophagy-related; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; BVDV: bovine viral diarrhea virus; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CMA: chaperone-mediated autophagy; CTSB: cathepsin B; CTSD: cathepsin D; DAP: Death-Associated Protein; ER: endoplasmic reticulum; GFP: green fluorescent protein; Gln: Glutamine; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; IF: immunofluorescence; IVP: in vitro produced; LAMP2A: lysosomal associated membrane protein 2A; LMS: lysosomal membrane stability; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MDBK: Madin-Darby bovine kidney; MSC: mesenchymal stem cells; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NBR1: NBR1 autophagy cargo receptor; NDV: Newcastle disease virus; NECTIN4: nectin cell adhesion molecule 4; NOD1: nucleotide-binding oligomerization domain 1; OCD: osteochondritis dissecans; OEC: oviduct epithelial cells; OPTN: optineurin; PI3K: phosphoinositide-3-kinase; PPRV: peste des petits ruminants virus; RHDV: rabbit hemorrhagic disease virus; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy.
| S-EPMC8386602 | biostudies-literature
Project description:There are twenty-five known inherited cardiac arrhythmia susceptibility genes, all of which encode either ion channel pore-forming subunits or proteins that regulate aspects of ion channel biology such as function, trafficking, and localization. The human KCNE gene family comprises five potassium channel regulatory subunits, sequence variants in each of which are associated with cardiac arrhythmias. KCNE gene products exhibit promiscuous partnering and in some cases ubiquitous expression, hampering efforts to unequivocally correlate each gene to specific native potassium currents. Likewise, deducing the molecular etiology of cardiac arrhythmias in individuals harboring rare KCNE gene variants, or more common KCNE polymorphisms, can be challenging. In this review we provide an update on putative arrhythmia-causing KCNE gene variants, and discuss current thinking and future challenges in the study of molecular mechanisms of KCNE-associated cardiac rhythm disturbances.
| S-EPMC3900874 | biostudies-literature
Project description:PURPOSE:We introduce a methodology to calculate the microdosimetric quantity dose-mean lineal energy for input into the microdosimetric kinetic model (MKM) to model the relative biological effectiveness (RBE) of proton irradiation experiments. METHODS AND MATERIALS:The data from 7 individual proton RBE experiments were included in this study. In each experiment, the RBE at several points along the Bragg curve was measured. Monte Carlo simulations to calculate the lineal energy probability density function of 172 different proton energies were carried out with use of Geant4 DNA. We calculated the fluence-weighted lineal energy probability density function (fw(y)), based on the proton energy spectra calculated through Monte Carlo at each experimental depth, calculated the dose-mean lineal energy yD¯ for input into the MKM, and then computed the RBE. The radius of the domain (rd) was varied to reach the best agreement between the MKM-predicted RBE and experimental RBE. A generic RBE model as a function of dose-averaged linear energy transfer (LETD) with 1 fitting parameter was presented and fit to the experimental RBE data as well to facilitate a comparison to the MKM. RESULTS:Both the MKM and LETD-based models modeled the RBE from experiments well. Values for rd were similar to those of other cell lines under proton irradiation that were modeled with the MKM. Analysis of the performance of each model revealed that neither model was clearly superior to the other. CONCLUSIONS:Our 3 key accomplishments include the following: (1) We developed a method that uses the proton energy spectra and lineal energy distributions of those protons to calculate dose-mean lineal energy. (2) We demonstrated that our application of the MKM provides theoretical validation of proton irradiation experiments that show that RBE is significantly greater than 1.1. (3) We showed that there is no clear evidence that the MKM is better than LETD-based RBE models.
| S-EPMC6499683 | biostudies-literature