Comparison of conventional and hippocampus-sparing radiotherapy in nasopharyngeal carcinoma: In silico study and systematic review.

Background and purpose: Radiation-induced damage to the hippocampi can cause cognitive decline. International recommendations for nasopharyngeal cancer (NPC) radiotherapy (RT) lack specific guidelines for protecting the hippocampi. Our study evaluates if hippocampi-sparing (HS) RT in NPC ensures target coverage and meets recommended dose limits for other at-risk organs. Materials and methods: In a systematic literature review, we compared hippocampal D40% in conventional and HS RT plans. In an in silico dosimetric study, conventional and HS-VMAT plans were created for each patient, following international recommendations for OAR delineation, dose prioritization and acceptance criteria. We assessed the impact on neurocognitive function using a previously published normal tissue complication probability (NTCP) model. Results: In four previous studies (n = 79), researchers reduced D40% hippocampal radiation doses in HS plans compared to conventional RT on average from 24.9 Gy to 12.6 Gy.Among 12 NPC patients included in this in silico study, statistically significant differences between HS and conventional VMAT plans were observed in hippocampal EQD2 Dmax (23.8 vs. 46.4 Gy), Dmin (3.8 vs. 4.6 Gy), Dmean (8.1 vs. 15.1 Gy), and D40% (8.3 vs. 15.8 Gy). PTV coverage and OAR doses were similar, with less homogeneous PTV coverage in HS plans (p = 0.038). This translated to a lower probability of memory decline in HS plans (interquartile range 15.8-29.6 %) compared to conventional plans (33.8-81.1 %) based on the NTCP model (p = 0.002). Conclusion: Sparing the hippocampus in NPC RT is safe and feasible. Given the life expectancy of many NPC patients, their cognitive well-being must be paramount in radiotherapy planning.

vOARiability: Interobserver and intermodality variability analysis in OAR contouring from head and neck CT and MR images.

BACKGROUND: Accurate and consistent contouring of organs-at-risk (OARs) from medical images is a key step of radiotherapy (RT) cancer treatment planning. Most contouring approaches rely on computed tomography (CT) images, but the integration of complementary magnetic resonance (MR) modality is highly recommended, especially from the perspective of OAR contouring, synthetic CT and MR image generation for MR-only RT, and MR-guided RT. Although MR has been recognized as valuable for contouring OARs in the head and neck (HaN) region, the accuracy and consistency of the resulting contours have not been yet objectively evaluated. PURPOSE: To analyze the interobserver and intermodality variability in contouring OARs in the HaN region, performed by observers with different level of experience from CT and MR images of the same patients. METHODS: In the final cohort of 27 CT and MR images of the same patients, contours of up to 31 OARs were obtained by a radiation oncology resident (junior observer, JO) and a board-certified radiation oncologist (senior observer, SO). The resulting contours were then evaluated in terms of interobserver variability, characterized as the agreement among different observers (JO and SO) when contouring OARs in a selected modality (CT or MR), and intermodality variability, characterized as the agreement among different modalities (CT and MR) when OARs were contoured by a selected observer (JO or SO), both by the Dice coefficient (DC) and 95-percentile Hausdorff distance (HD 95 $_{95}$ ). RESULTS: The mean (±standard deviation) interobserver variability was 69.0 ± 20.2% and 5.1 ± 4.1 mm, while the mean intermodality variability was 61.6 ± 19.0% and 6.1 ± 4.3 mm in terms of DC and HD 95 $_{95}$ , respectively, across all OARs. Statistically significant differences were only found for specific OARs. The performed MR to CT image registration resulted in a mean target registration error of 1.7 ± 0.5 mm, which was considered as valid for the analysis of intermodality variability. CONCLUSIONS: The contouring variability was, in general, similar for both image modalities, and experience did not considerably affect the contouring performance. However, the results indicate that an OAR is difficult to contour regardless of whether it is contoured in the CT or MR image, and that observer experience may be an important factor for OARs that are deemed difficult to contour. Several of the differences in the resulting variability can be also attributed to adherence to guidelines, especially for OARs with poor visibility or without distinctive boundaries in either CT or MR images. Although considerable contouring differences were observed for specific OARs, it can be concluded that almost all OARs can be contoured with a similar degree of variability in either the CT or MR modality, which works in favor of MR images from the perspective of MR-only and MR-guided RT.

HaN-Seg: The head and neck organ-at-risk CT and MR segmentation dataset.

PURPOSE: For the cancer in the head and neck (HaN), radiotherapy (RT) represents an important treatment modality. Segmentation of organs-at-risk (OARs) is the starting point of RT planning, however, existing approaches are focused on either computed tomography (CT) or magnetic resonance (MR) images, while multimodal segmentation has not been thoroughly explored yet. We present a dataset of CT and MR images of the same patients with curated reference HaN OAR segmentations for an objective evaluation of segmentation methods. ACQUISITION AND VALIDATION METHODS: The cohort consists of HaN images of 56 patients that underwent both CT and T1-weighted MR imaging for image-guided RT. For each patient, reference segmentations of up to 30 OARs were obtained by experts performing manual pixel-wise image annotation. By maintaining the distribution of patient age and gender, and annotation type, the patients were randomly split into training Set 1 (42 cases or 75%) and test Set 2 (14 cases or 25%). Baseline auto-segmentation results are also provided by training the publicly available deep nnU-Net architecture on Set 1, and evaluating its performance on Set 2. DATA FORMAT AND USAGE NOTES: The data are publicly available through an open-access repository under the name HaN-Seg: The Head and Neck Organ-at-Risk CT & MR Segmentation Dataset. Images and reference segmentations are stored in the NRRD file format, where the OAR filenames correspond to the nomenclature recommended by the American Association of Physicists in Medicine, and OAR and demographics information is stored in separate comma-separated value  files. POTENTIAL APPLICATIONS: The HaN-Seg: The Head and Neck Organ-at-Risk CT & MR Segmentation Challenge is launched in parallel with the dataset release to promote the development of automated techniques for OAR segmentation in the HaN. Other potential applications include out-of-challenge algorithm development and benchmarking, as well as external validation of the developed algorithms.

Assessment of set-up errors in the radiotherapy of patients with head and neck cancer: standard vs. individual head support.

Background The aim of the study was to (a) compare the accuracy of two different immobilization strategies for patients with head and neck tumors, and (b) compare the set-up errors on treatment units with different portal imaging systems. Patients and methods Variations in the position of the isocenter (IC) relative to the reference point determined on the computed tomography simulator were measured in a vertical (anterior-posterior), longitudinal (superior-inferior), and lateral (medial-lateral) direction in 120 head and neck cancer patients irradiated with curative intent. Depending on the treatment unit (unit A - 2D/2D image previews; unit B- 2D image previews) and the time of irradiation, patients were divided into 6 groups of 20 patients. In patients irradiated in 2014, standard head supports were used (groups 1 and 2), whereas in those treated in 2015 and 2017 (groups 3-6) individual head supports were employed. The clinical-to-planning target volume safety margin was calculated according to the formula proposed by Van Herk. Results In total, 2,454 portal images and 3,681 set-up errors were analysed. Implementation of individual head supports in 2015 resulted in a statistically significant reduction in the average inter-fraction displacement in the vertical direction and in decreased number of IC displacements in the vertical and longitudinal direction (applies to both treatment units). The largest reduction of the safety margin was calculated in the longitudinal direction and the safety margins were larger for unit B than for unit A. Conclusions The use of individual head supports and a more advanced imaging system were found to increase set-up precision.

Treating lung cancer with dynamic conformal arc therapy: a dosimetric study.

BACKGROUND: Lung cancer patients are often in poor physical condition, and a shorter treatment time would reduce their discomfort. Dynamic conformal arc therapy (DCAT) offers a shorter treatment time than conventional 3D conformal radiotherapy (3D CRT) and is usually available even in departments without inverse planning possibilities. We examined its suitability as a treatment modality for lung cancer patients. METHODS: On a cohort of 35 lung cancer patients, relevant dosimetric parameters were compared in respective DCAT and 3D CRT treatment plans. Radiochromic film dosimetry in an anthropomorphic phantom was used to compare both DCAT and 3D CRT dose distributions against their planned counterparts. RESULTS: In comparison with their 3D CRT counterparts, DCAT plans equal or exceed the agreement between the calculated dose and the dose measured using film dosimetry. In dosimetric comparison, DCAT performed significantly better than 3D CRT in dose conformity to PTV and the number of monitor units used per plan, and significantly worse in dose homogeneity, mean lung dose and lung volume exposed to 5 Gy or more (V5Gy). No significant difference was found in the V20Gy value to lung, dose to 1 cm3 of spinal cord, and the mean dose to oesophagus. Improvements in V20Gy and V5Gy were found to be negatively correlated. DCAT plans differ from 3D CRT by exhibiting a moderate negative correlation between target volume sphericity and dose homogeneity. CONCLUSIONS: With respect to the agreement between the planned and the irradiated dose distribution, DCAT appears at least as reliable as 3D CRT. In specific conditions concerning the patient anatomy and treatment prescription, DCAT may yield more favourable dosimetric parameters. On average, however, conventional 3D CRT usually obtains better dosimetric parameters. We can thus only recommend DCAT as a complementary technique to the conventional 3D CRT.

Quality control in cone-beam computed tomography (CBCT) EFOMP-ESTRO-IAEA protocol (summary report).

The aim of the guideline presented in this article is to unify the test parameters for image quality evaluation and radiation output in all types of cone-beam computed tomography (CBCT) systems. The applications of CBCT spread over dental and interventional radiology, guided surgery and radiotherapy. The chosen tests provide the means to objectively evaluate the performance and monitor the constancy of the imaging chain. Experience from all involved associations has been collected to achieve a consensus that is rigorous and helpful for the practice. The guideline recommends to assess image quality in terms of uniformity, geometrical precision, voxel density values (or Hounsfield units where available), noise, low contrast resolution and spatial resolution measurements. These tests usually require the use of a phantom and evaluation software. Radiation output can be determined with a kerma-area product meter attached to the tube case. Alternatively, a solid state dosimeter attached to the flat panel and a simple geometric relationship can be used to calculate the dose to the isocentre. Summary tables including action levels and recommended frequencies for each test, as well as relevant references, are provided. If the radiation output or image quality deviates from expected values, or exceeds documented action levels for a given system, a more in depth system analysis (using conventional tests) and corrective maintenance work may be required.

Influence of the Integral Quality Monitor transmission detector on high energy photon beams: A multi-centre study.

PURPOSE: The influence of the Integral Quality Monitor (IQM) transmission detector on photon beam properties was evaluated in a preclinical phase, using data from nine participating centres: (i) the change of beam quality (beam hardening), (ii) the influence on surface dose, and (iii) the attenuation of the IQM detector. METHODS: For 6 different nominal photon energies (4 standard, 2 FFF) and square field sizes from 1×1cm2 to 20×20cm2, the effect of IQM on beam quality was assessed from the PDD20,10 values obtained from the percentage dose depth (PDD) curves, measured with and without IQM in the beam path. The change in surface dose with/without IQM was assessed for all available energies and field sizes from 4×4cm2 to 20×20cm2. The transmission factor was calculated by means of measured absorbed dose at 10cm depth for all available energies and field sizes. RESULTS: (i) A small (0.11-0.53%) yet statistically significant beam hardening effect was observed, depending on photon beam energy. (ii) The increase in surface dose correlated with field size (p<0.01) for all photon energies except for 18MV. The change in surface dose was smaller than 3.3% in all cases except for the 20×20cm2 field and 10MV FFF beam, where it reached 8.1%. (iii) For standard beams, transmission of the IQM showed a weak dependence on the field size, and a pronounced dependence on the beam energy (0.9412 for 6MV to 0.9578 for 18MV and 0.9440 for 6MV FFF; 0.9533 for 10MV FFF). CONCLUSIONS: The effects of the IQM detector on photon beam properties were found to be small yet statistically significant. The magnitudes of changes which were found justify treating IQM either as tray factors within the treatment planning system (TPS) for a particular energy or alternatively as modified outputs for specific beam energy of linear accelerators, which eases the introduction of the IQM into clinical practice.

Reducing the dosimetric impact of positional errors in field junctions for craniospinal irradiation using VMAT.

AIM: To improve treatment plan robustness with respect to small shifts in patient position during the VMAT treatment by ensuring a linear ramp-like dose profile in treatment field overlap regions. BACKGROUND: Craniospinal irradiation (CSI) is considered technically challenging because the target size exceeds the maximal field size, which necessitates using abutted or overlapping treatment fields. Volumetric modulated arc therapy (VMAT) is increasingly being examined for CSI, as it offers both better dose homogeneity and better dose conformance while also offering a possibility to create field junctions which are more robust towards small shifts in patient position during the treatment. MATERIALS AND METHODS: A VMAT treatment plan with three isocenters was made for a test case patient. Three groups of overlapping arc field pairs were used; one for the cranial and two for the spinal part. In order to assure a ramp-like dose profile in the field overlap region, the upper spinal part was optimised first, with dose prescription explicitly enforcing a ramp-like dose profile. The cranial and lower spinal part were done afterwards, taking into account the dose contribution of the upper spinal fields. RESULTS: Using simple geometrical reasoning, we demonstrated that hot- and cold spots which arise from small displacement of one treatment field relative to the other treatment field can be reduced by taking two precautions: (a) widening the field overlap region, and (b) reducing the field gradient across the overlap region. The function with the smallest maximal gradient is a linear ramp. We present a treatment planning technique which yields the desired dose profile of the two contributing fields, and minimises dosimetric dependence on minor positional errors in patient set-up.

Partitioning of oleic acid into phosphatidylcholine membranes is amplified by strain.

Partitioning of fatty acids into phospholipid membranes is studied on giant unilamellar vesicles (GUVs) utilizing phase-contrast microscopy. With use of a micropipet, an individual GUV is transferred from a vesicle suspension in a mixed glucose/sucrose solution into an isomolar glycerol solution with a small amount of oleic acid added. Oleic acid molecules intercalate into the phospholipid membrane and thus increase the membrane area, while glycerol permeates into the vesicle interior and thus via osmotic inflation causes an increase of the vesicle volume. The conditions are chosen at which a vesicle swells as a sphere. At sufficiently low oleic acid concentrations, when the critical membrane strain is reached, the membrane bursts and part of vesicle content is ejected, upon which the membrane reseals and the swelling commences again. The radius of the vesicle before and after the burst is determined at different concentrations of oleic acid in suspension. The results of our experiments show that the oleic acid partitioning increases when the membrane strain is increased. The observed behavior is interpreted on the basis of a tension-dependent intercalation of oleic acid into the membrane.

Frequency-dependent electrodeformation of giant phospholipid vesicles in AC electric field.

A model of vesicle electrodeformation is described which obtains a parametrized vesicle shape by minimizing the sum of the membrane bending energy and the energy due to the electric field. Both the vesicle membrane and the aqueous media inside and outside the vesicle are treated as leaky dielectrics, and the vesicle itself is modeled as a nearly spherical shape enclosed within a thin membrane. It is demonstrated (a) that the model achieves a good quantitative agreement with the experimentally determined prolate-to-oblate transition frequencies in the kilohertz range and (b) that the model can explain a phase diagram of shapes of giant phospholipid vesicles with respect to two parameters: the frequency of the applied alternating current electric field and the ratio of the electrical conductivities of the aqueous media inside and outside the vesicle, explored in a recent paper (S. Aranda et al., Biophys J 95:L19-L21, 2008). A possible use of the frequency-dependent shape transitions of phospholipid vesicles in conductometry of microliter samples is discussed.

Growth and shape transformations of giant phospholipid vesicles upon interaction with an aqueous oleic acid suspension.

The interaction of two types of vesicle systems was investigated: micrometer-sized, giant unilamellar vesicles (GUVs) formed from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and submicrometer-sized, large unilamellar vesicles (LUVs) formed from oleic acid and oleate, both in a buffered aqueous solution (pH 8.8). Individual POPC GUVs were transferred with a micropipette into a suspension of oleic acid/oleate LUVs, and the shape changes of the GUVs were monitored using optical microscopy. The behavior of POPC GUVs upon transfer into a 0.8mM suspension of oleic acid, in which oleic acid/oleate forms vesicular bilayer structures, was qualitatively different from the behavior upon transfer into a 0.3mM suspension of oleic acid/oleate, in which oleic acid/oleate is predominantly present in the form of monomers and possibly non-vesicular aggregates. In both cases, changes in vesicle morphology were observed within tens of seconds after the transfer. After an initial increase of the vesicle cross-section, the vesicle started to evaginate, spawning dozens of satellite vesicles connected to the mother vesicle with narrow necks or tethers. In 60% of the cases of transfer into a 0.8mM oleic acid suspension, the evagination process reversed and proceeded to the point where the membrane formed invaginations. In some of these cases, several consecutive transitions between invaginated and evaginated shapes were observed. In the remaining 40% of the cases of transfer into the 0.8mM oleic acid suspension and in all cases of vesicle transfer into the 0.3mM oleic acid suspension, no invaginations nor subsequent evaginations were observed. An interpretation of the observed vesicle shape transformation on the basis of the bilayer-couple model is proposed, which takes into account uptake of oleic acid/oleate molecules by the POPC vesicles, oleic acid flip-flop processes and transient pore formation.

Electroformation in a flow chamber with solution exchange as a means of preparation of flaccid giant vesicles.

A recently described technique [Estes and Mayer, Biochim. Biophys. Acta 1712 (2005) 152-160] for the preparation of giant unilamellar vesicles (GUVs) in solutions with high ionic strength is examined. By observing a series of osmotic swellings followed by vesicle bursts upon a micropipette transfer of a single POPC GUV from a sucrose solution into an iso-osmolar glycerol solution, a value for the permeability of POPC membrane for glycerol, P=(2.09+/-0.82) x 10(-8)m/s, has been obtained. Based on this result, an alternative mechanism is proposed for the observed exchange of vesicle interior. With modifications, the method of Estes and Mayer is then applied to preparation of flaccid GUVs.

The frequency dependence of phospholipid vesicle shapes in an external electric field.

Experiments show that phospholipid vesicles exposed to AC electric field undergo a shape transition from prolate to oblate ellipsoidal shape when the frequency of the field is increased. A theoretical model, based on the minimization of total free energy of the vesicle, was devised to explain this phenomenon. The model exhibits the same frequency-dependent prolate-to-oblate shape transition as observed in the experiment.