Co-option of a conserved host glutamine transporter facilitates aphid/Buchnera metabolic integration.

Organisms across the tree of life colonize novel environments by partnering with bacterial symbionts. These symbioses are characterized by intimate integration of host/endosymbiont biology at multiple levels, including metabolically. Metabolic integration is particularly important for sap-feeding insects and their symbionts, which supplement nutritionally unbalanced host diets. Many studies reveal parallel evolution of host/endosymbiont metabolic complementarity in amino acid biosynthesis, raising questions about how amino acid metabolism is regulated, how regulatory mechanisms evolve, and the extent to which similar mechanisms evolve in different systems. In the aphid/Buchnera symbiosis, the transporter ApGLNT1 (Acyrthosiphon pisum glutamine transporter 1) supplies glutamine, an amino donor in transamination reactions, to bacteriocytes (where Buchnera reside) and is competitively inhibited by Buchnera-supplied arginine-consistent with a role regulating amino acid metabolism given host demand for Buchnera-produced amino acids. We examined how ApGLNT1 evolved a regulatory role by functionally characterizing orthologs in insects with and without endosymbionts. ApGLNT1 orthologs are functionally similar, and orthology searches coupled with homology modeling revealed that GLNT1 is ancient and structurally conserved across insects. Our results indicate that the ApGLNT1 symbiotic regulatory role is derived from its ancestral role and, in aphids, is likely facilitated by loss of arginine biosynthesis through the urea cycle. Given consistent loss of host arginine biosynthesis and retention of endosymbiont arginine supply, we hypothesize that GLNT1 is a general mechanism regulating amino acid metabolism in sap-feeding insects. This work fills a gap, highlighting the broad importance of co-option of ancestral proteins to novel contexts in the evolution of host/symbiont systems.

Infrastructure platform for privacy-preserving distributed machine learning development of computer-assisted theragnostics in cancer.

INTRODUCTION: Emerging evidence suggests that data-driven support tools have found their way into clinical decision-making in a number of areas, including cancer care. Improving them and widening their scope of availability in various differing clinical scenarios, including for prognostic models derived from retrospective data, requires co-ordinated data sharing between clinical centres, secondary analyses of large multi-institutional clinical trial data, or distributed (federated) learning infrastructures. A systematic approach to utilizing routinely collected data across cancer care clinics remains a significant challenge due to privacy, administrative and political barriers. METHODS: An information technology infrastructure and web service software was developed and implemented which uses machine learning to construct clinical decision support systems in a privacy-preserving manner across datasets geographically distributed in different hospitals. The infrastructure was deployed in a network of Australian hospitals. A harmonized, international ontology-linked, set of lung cancer databases were built with the routine clinical and imaging data at each centre. The infrastructure was demonstrated with the development of logistic regression models to predict major cardiovascular events following radiation therapy. RESULTS: The infrastructure implemented forms the basis of the Australian computer-assisted theragnostics (AusCAT) network for radiation oncology data extraction, reporting and distributed learning. Four radiation oncology departments (across seven hospitals) in New South Wales (NSW) participated in this demonstration study. Infrastructure was deployed at each centre and used to develop a model predicting for cardiovascular admission within a year of receiving curative radiotherapy for non-small cell lung cancer. A total of 10,417 lung cancer patients were identified with 802 being eligible for the model. Twenty features were chosen for analysis from the clinical record and linked registries. After selection, 8 features were included and a logistic regression model achieved an area under the receiver operating characteristic (AUROC) curve of 0.70 and C-index of 0.65 on out-of-sample data. CONCLUSION: The infrastructure developed was demonstrated to be usable in practice between clinical centres to harmonize routinely collected oncology data and develop models with federated learning. It provides a promising approach to enable further research studies in radiation oncology using real world clinical data.

Trading amino acids at the aphid-Buchnera symbiotic interface.

Plant sap-feeding insects are widespread, having evolved to occupy diverse environmental niches despite exclusive feeding on an impoverished diet lacking in essential amino acids and vitamins. Success depends exquisitely on their symbiotic relationships with microbial symbionts housed within specialized eukaryotic bacteriocyte cells. Each bacteriocyte is packed with symbionts that are individually surrounded by a host-derived symbiosomal membrane representing the absolute host-symbiont interface. The symbiosomal membrane must be a dynamic and selectively permeable structure to enable bidirectional and differential movement of essential nutrients, metabolites, and biosynthetic intermediates, vital for growth and survival of host and symbiont. However, despite this crucial role, the molecular basis of membrane transport across the symbiosomal membrane remains unresolved in all bacteriocyte-containing insects. A transport protein was immunolocalized to the symbiosomal membrane separating the pea aphid Acyrthosiphon pisum from its intracellular symbiont Buchnera aphidicola The transporter, A. pisum nonessential amino acid transporter 1, or ApNEAAT1 (gene: ACYPI008971), was characterized functionally following heterologous expression in Xenopus oocytes, and mediates both inward and outward transport of small dipolar amino acids (serine, proline, cysteine, alanine, glycine). Electroneutral ApNEAAT1 transport is driven by amino acid concentration gradients and is not coupled to transmembrane ion gradients. Previous metabolite profiling of hemolymph and bacteriocyte, alongside metabolic pathway analysis in host and symbiont, enable prediction of a physiological role for ApNEAAT1 in bidirectional host-symbiont amino acid transfer, supplying both host and symbiont with indispensable nutrients and biosynthetic precursors to facilitate metabolic complementarity.

A system for real-time monitoring of breath-hold via assessment of internal anatomy in tangential breast radiotherapy.

The deep inspiration breath-hold (DIBH) technique assists in sparing the heart, lungs, and liver during breast radiotherapy (RT). The quality of DIBH is currently assessed via surrogates which correlate to varying degrees with the patient's internal anatomy. Since modern linacs are equipped with an electronic portal imaging device (EPID), images of the irradiated anatomy streamed from EPIDs and analyzed in real time could significantly improve assessment of the quality of DIBH. A system has been developed to quantify the quality of DIBH during tangential breast RT by analyzing the "beam's eye view" images of the treatment fields. The system measures the lung depth (LD) and the distance from the breast surface to the posterior tangential radiation field edge (skin distance, SD) at three user-defined locations. LD and SD measured in real time in EPID images of two RT phantoms showing different geometrical characteristics of their chest wall regions (computed tomography dose index [CTDI] and "END-TO-END" stereotactic body radiation therapy [E2E SBRT]) were compared with ground truth displacements provided by a precision motion platform. Performance of the new system was evaluated via static and dynamic (sine wave motion) measurements of LD and SD, covering clinical situations with stable and unstable breath-hold. The accuracy and precision of the system were calculated as the mean and standard deviation of the differences between the ground truth and measured values. The accuracy of the static measurements of LD and SD for the CTDI phantom was 0.31 (1.09) mm [mean (standard deviation)] and -0.10 (0.14) mm, respectively. The accuracy of the static measurements for E2E SBRT phantom was 0.01 (0.18) mm and 0.05 (0.08) mm. The accuracy of the dynamic LD and SD measurements for the CTDI phantom was -0.50 (1.18) mm and 0.01 (0.12) mm, respectively. The accuracy of the dynamic measurements for E2E SBRT phantom was -0.03 (0.19) mm and 0.01 (0.11) mm.

Intrinsic detector sensitivity analysis as a tool to characterize ArcCHECK and EPID sensitivity to variations in delivery for lung SBRT VMAT plans.

PURPOSE: To investigate intrinsic sensitivity of an electronic portal imaging device (EPID) and the ArcCHECK detector and to use this in assessing their performance in detecting delivery variations for lung SBRT VMAT. The effect of detector spatial resolution and dose matrix interpolation on the gamma pass rate was also considered. MATERIALS AND METHODS: Fifteen patients' lung SBRT VMAT plans were used. Delivery variations (errors) were introduced by modifying collimator angles, multi-leaf collimator (MLC) field sizes and MLC field shifts by ±5, ±2, and ±1 degrees or mm (investigating 103 plans in total). EPID and ArcCHECK measured signals with introduced variations were compared to measured signals without variations (baseline), using OmniPro-I'mRT software and gamma criteria of 3%/3 mm, 2%/2 mm, 2%/1 mm, and 1%/1 mm, to test each system's basic performance. The measurement sampling resolution for each was also changed to 1 mm and results compared to those with the default detector system resolution. RESULTS: Intrinsic detector sensitivity analysis, that is, comparing measurement to baseline measurement, rather than measurement to plan, demonstrated the intrinsic constraints of each detector and indicated the limiting performance that users might expect. Changes in the gamma pass rates for ArcCHECK, for a given introduced error, were affected only by dose difference (DD %) criteria. However, the EPID showed only slight changes when changing DD%, but greater effects when changing distance-to-agreement criteria. This is pertinent for lung SBRT where the minimum dose to the target will drop dramatically with geometric errors. Detector resolution and dose matrix interpolation have an impact on the gamma results for these SBRT plans and can lead to false positives or negatives in error detection if not understood. CONCLUSION: The intrinsic sensitivity approach may help in the selection of more meaningful gamma criteria and the choice of optimal QA device for site-specific dose verification.

A novel method to determine linac mechanical isocenter position and size and examples of specific QA applications.

The most important geometric characteristic of stereotactic treatment is the accuracy of positioning the target at the treatment isocenter and the accuracy of directing the radiation beam at the treatment isocenter. Commonly, the radiation isocenter is used as the reference for the treatment isocenter, but its method of localization is not strictly defined, and it depends on the linac-specific beam steering parameters. A novel method is presented for determining the linac mechanical isocenter position and size based on the localization of the collimator axis of rotation at arbitrary gantry angle. The collimator axis of rotation position is determined from the radiation beam center position corrected for the focal spot offset. The focal spot offset is determined using the image center shift method with a custom-design rigid phantom with two sets of ball-bearings. Three specific quality assurance (QA) applications and assessment methods are also presented to demonstrate the functionality of linac mechanical isocenter position and size determination in clinical practice. The first is a mechanical and radiation isocenters coincidence test suitable for quick congruence assessment of these two isocenters for a selected energy, usually required after a nonroutine linac repair and/or energy adjustment. The second is a stereotactic beam isocentricity assessment suitable for pretreatment stereotactic QA. The third is a comprehensive linac geometrical performance test suitable for routine linac QA. The uncertainties of the method for determining mechanical isocenter position and size were measured to be 0.05 mm and 0.04 mm, respectively, using four available photon energies, and were significantly smaller than those of determining the radiation isocenter position and size, which were 0.36 mm and 0.12 mm respectively. It is therefore recommended that the mechanical isocenter position and size be used as the reference linac treatment isocenter and a linac mechanical characteristic parameter respectively.

Evaluation of the ability of three commercially available dosimeters to detect systematic delivery errors in step-and-shoot IMRT plans.

BACKGROUND: There is limited data on error detectability for step-and-shoot intensity modulated radiotherapy (sIMRT) plans, despite significant work on dynamic methods. However, sIMRT treatments have an ongoing role in clinical practice. This study aimed to evaluate variations in the sensitivity of three patient-specific quality assurance (QA) devices to systematic delivery errors in sIMRT plans. MATERIALS AND METHODS: Four clinical sIMRT plans (prostate and head and neck) were edited to introduce errors in: Multi-Leaf Collimator (MLC) position (increasing field size, leaf pairs offset (1-3 mm) in opposite directions; and field shift, all leaves offset (1-3 mm) in one direction); collimator rotation (1-3 degrees) and gantry rotation (0.5-2 degrees). The total dose for each plan was measured using an ArcCHECK diode array. Each field, excluding those with gantry offsets, was also measured using an Electronic Portal Imager and a MatriXX Evolution 2D ionisation chamber array. 132 plans (858 fields) were delivered, producing 572 measured dose distributions. Measured doses were compared to calculated doses for the no-error plan using Gamma analysis with 3%/3 mm, 3%/2 mm, and 2%/2 mm criteria (1716 analyses). RESULTS: Generally, pass rates decreased with increasing errors and/or stricter gamma criteria. Pass rate variations with detector and plan type were also observed. For a 3%/3 mm gamma criteria, none of the devices could reliably detect 1 mm MLC position errors or 1 degree collimator rotation errors. CONCLUSIONS: This work has highlighted the need to adapt QA based on treatment plan type and the need for detector specific assessment criteria to detect clinically significant errors.

Assessment of error in the MV radiation isocenter position calculated with the Elekta XVI software.

The assessment of the coincidence of imaging and radiation isocenters is an important task of regular quality assurance of medical linear accelerators (linacs) as recommended in national and international quality assurance guidelines. A previously reported investigation of the accuracy of the Elekta XVI software to localize the linac radiation isocenter, by comparing statistically with other independent software, has shown some discrepancies at the sub-mm level. A further investigation is carried out here using a set of reference images and mathematical operations to observe how the Elekta XVI software analyses them. Symmetric mathematical operations on reference images should result in symmetrical outcomes. Three different rotation functions are used in increasing degree of complexity to characterize the Elekta XVI software error in the linac radiation isocenter position. No independent algorithms or phantoms are used in this methodology. The magnitude and direction of the radiation isocenter localization error has been determined to be consistently 0.13 mm or 0.14 mm in the longitudinal direction towards the target depending on the case. The radiation isocenter localization error comprises two separated errors of the Ball Bearing Center by 0.13 mm and MV Field Center by either 0.00 mm or -0.01 mm in the longitudinal direction towards the target. The calculation of the MV Field Center is influenced by the polymethyl methacrylate rod supporting the ball-bearing. The precise value and the root cause of the error cannot be assessed due to the rounding effect of the results reported by the Elekta XVI software and lack of access to the source code.

Testing the methodology for a dosimetric end-to-end audit of IMRT/VMAT: results of IAEA multicentre and national studies.

Introduction: Within an International Atomic Energy Agency (IAEA) co-ordinated research project (CRP), a remote end-to-end dosimetric quality audit for intensity modulated radiation therapy (IMRT)/ volumetric arc therapy (VMAT) was developed to verify the radiotherapy chain including imaging, treatment planning and dose delivery. The methodology as well as the results obtained in a multicentre pilot study and national trial runs conducted in close cooperation with dosimetry audit networks (DANs) of IAEA Member States are presented.Material and methods: A solid polystyrene phantom containing a dosimetry insert with an irregular solid water planning target volume (PTV) and organ at risk (OAR) was designed for this audit. The insert can be preloaded with radiochromic film and four thermoluminescent dosimeters (TLDs). For the audit, radiotherapy centres were asked to scan the phantom, contour the structures, create an IMRT/VMAT treatment plan and irradiate the phantom. The dose prescription was to deliver 4 Gy to the PTV in two fractions and to limit the OAR dose to a maximum of 2.8 Gy. The TLD measured doses and film measured dose distributions were compared with the TPS calculations.Results: Sixteen hospitals from 13 countries and 64 hospitals from 6 countries participated in the multicenter pilot study and in the national runs, respectively. The TLD results for the PTV were all within ±5% acceptance limit for the multicentre pilot study, whereas for national runs, 17 participants failed to meet this criterion. All measured doses in the OAR were below the treatment planning constraint. The film analysis identified seven plans in national runs below the 90% passing rate gamma criteria.Conclusion: The results proved that the methodology of the IMRT/VMAT dosimetric end-to-end audit was feasible for its intended purpose, i.e., the phantom design and materials were suitable; the phantom was easy to use and it was robust enough for shipment. Most importantly the audit methodology was capable of identifying suboptimal IMRT/VMAT delivery.

Resculpting the binding pocket of APC superfamily LeuT-fold amino acid transporters.

Amino acid transporters are essential components of prokaryote and eukaryote cells, possess distinct physiological functions, and differ markedly in substrate specificity. Amino acid transporters can be both drug targets and drug transporters (bioavailability, targeting) with many monogenic disorders resulting from dysfunctional membrane transport. The largest collection of amino acid transporters (including the mammalian SLC6, SLC7, SLC32, SLC36, and SLC38 families), across all kingdoms of life, is within the Amino acid-Polyamine-organoCation (APC) superfamily. The LeuT-fold is a paradigm structure for APC superfamily amino acid transporters and carriers of sugars, neurotransmitters, electrolytes, osmolytes, vitamins, micronutrients, signalling molecules, and organic and fatty acids. Each transporter is specific for a unique sub-set of solutes, specificity being determined by how well a substrate fits into each binding pocket. However, the molecular basis of substrate selectivity remains, by and large, elusive. Using an integrated computational and experimental approach, we demonstrate that a single position within the LeuT-fold can play a crucial role in determining substrate specificity in mammalian and arthropod amino acid transporters within the APC superfamily. Systematic mutation of the amino acid residue occupying the equivalent position to LeuT V104 titrates binding pocket space resulting in dramatic changes in substrate selectivity in exemplar APC amino acid transporters including PAT2 (SLC36A2) and SNAT5 (SLC38A5). Our work demonstrates how a single residue/site within an archetypal structural motif can alter substrate affinity and selectivity within this important superfamily of diverse membrane transporters.

A prediction model for early death in non-small cell lung cancer patients following curative-intent chemoradiotherapy.

BACKGROUND: Early death after a treatment can be seen as a therapeutic failure. Accurate prediction of patients at risk for early mortality is crucial to avoid unnecessary harm and reducing costs. The goal of our work is two-fold: first, to evaluate the performance of a previously published model for early death in our cohorts. Second, to develop a prognostic model for early death prediction following radiotherapy. MATERIAL AND METHODS: Patients with NSCLC treated with chemoradiotherapy or radiotherapy alone were included in this study. Four different cohorts from different countries were available for this work (N = 1540). The previous model used age, gender, performance status, tumor stage, income deprivation, no previous treatment given (yes/no) and body mass index to make predictions. A random forest model was developed by learning on the Maastro cohort (N = 698). The new model used performance status, age, gender, T and N stage, total tumor volume (cc), total tumor dose (Gy) and chemotherapy timing (none, sequential, concurrent) to make predictions. Death within 4 months of receiving the first radiotherapy fraction was used as the outcome. RESULTS: Early death rates ranged from 6 to 11% within the four cohorts. The previous model performed with AUC values ranging from 0.54 to 0.64 on the validation cohorts. Our newly developed model had improved AUC values ranging from 0.62 to 0.71 on the validation cohorts. CONCLUSIONS: Using advanced machine learning methods and informative variables, prognostic models for early mortality can be developed. Development of accurate prognostic tools for early mortality is important to inform patients about treatment options and optimize care.

Patient education using virtual reality increases knowledge and positive experience for breast cancer patients undergoing radiation therapy.

PURPOSE: Improved access to technology in the radiation therapy (RT) workforce education has resulted in opportunities for innovative patient education methods. This study investigated the impact of a newly developed education tool using the Virtual Environment for Radiotherapy Training (VERT) system on patients' RT knowledge and anxiety. METHOD: Breast cancer patients were recruited into a control group (CG) (n = 18) who underwent the standard pre-RT education package at a targeted cancer therapy centre, followed by a VERT group (VG) (n = 19). VG patients attended a VERT-based education session detailing RT immobilisation, planning and treatment. All patients completed questionnaires at four time points throughout their treatment, with survey sub-sections on RT knowledge, experience and anxiety. RESULTS: For both groups, anxiety levels were highest at time point 1(T1 after initial radiation oncologist consultation) (CG, 41.2; VG, 43.1), with a gradual decrease observed thereafter at time points before simulation, at the beginning of treatment and at the end of treatment (p > 0.05). The VG's RT knowledge scores were statistically significantly higher than those of the CG scores at all time points following VERT education (p < 0.05). CONCLUSION: This study reports the high value of VERT breast cancer-targeted education programs in improving RT knowledge and perhaps decreasing patient anxiety. Continued efforts are required to improve patients' accessibility to VERT in Australia, and to better understand the effect of VERT's unique educational features on patients' emotional and physical needs throughout their RT.

Beam focal spot position determination for an Elekta linac with the Agility® head; practical guide with a ready-to-go procedure.

A novel phantomless, EPID-based method of measuring the beam focal spot offset of a linear accelerator was proposed and validated for Varian machines. In this method, one set of jaws and the MLC were utilized to form a symmetric field and then a 180o collimator rotation was utilized to determine the radiation isocenter defined by the jaws and the MLC, respectively. The difference between these two isocentres is directly correlated with the beam focal spot offset of the linear accelerator. In the current work, the method has been considered for Elekta linacs. An Elekta linac with the Agility® head does not have two set of jaws, therefore, a modified method is presented making use of one set of diaphragms, the MLC and a full 360o collimator rotation. The modified method has been tested on two Elekta Synergy® linacs with Agility® heads and independently validated. A practical guide with instructions and a MATLAB® code is attached for easy implementation.

Breast Cancer Patients' Perceptions of a Virtual Learning Environment for Pretreatment Education.

The process and technicalities of radiation therapy (RT) for cancer treatment can be challenging for patients to understand as RT involves complex procedures, highly specialised equipment, and radiation itself has limited sensory characteristics. Hence, it is imperative that education programs are specifically planned and developed to suit the needs of patients, address radiation as an entity and include salient visual aids. In this context, the Virtual Environment for Radiotherapy Training (VERT) system, primarily created for RT practitioner simulation, may provide unique opportunities for patient education. This article reports on patient feedback of a newly developed breast cancer patient education program, which integrates the VERT system as the focal education tool. The education program content included RT immobilisation, simulation, planning and treatment components, along with an introduction to the VERT system. Nineteen breast cancer patients (n = 19) completed an evaluation questionnaire at the completion of their VERT education program. Open-ended questions were used to detect the least and most useful aspects of the education session. Patient feedback indicated a high regard for the comprehensiveness of the education program, with particular acknowledgement of the three dimensional visual features of the VERT system. It is proposed that VERT's high visual impact should be exploited in tailored patient education programs in order to obtain maximum patient engagement and make significant gains in effective knowledge transfer.

Beam focal spot position: The forgotten linac QA parameter. An EPID-based phantomless method for routine Stereotactic linac QA.

Modern day Stereotactic treatments require high geometric accuracy of the delivered treatment. To achieve the required accuracy the IGRT imaging isocenter needs to closely coincide with the treatment beam isocenter. An influence on this isocenter coincidence and on the spatial positioning of the beam itself is the alignment of the treatment beam focal spot with collimator rotation axis. The positioning of the focal spot is dependent on the linac beam steering and on the stability of the monitor chamber and beam steering servo system. As such, there is the potential for focal spot misalignment and this should be checked on a regular basis. Traditional methods for measuring focal spot position are either indirect, inaccurate, or time consuming and hence impractical for routine use. In this study a novel, phantomless method has been developed using the EPID (Electronic Portal Imaging Device) that utilizes the different heights of the MLC and jaws. The method has been performed on four linear accelerators and benchmarked against an alternate ion chamber-based method. The method has been found to be reproducible to within ±0.012 mm (1 SD) and in agreement with the ion chamber-based method to within 0.001 ± 0.015 mm (1 SD). The method could easily be incorporated into a departmental routine linac QA (Quality Assurance) program.

Testing the methodology for dosimetry audit of heterogeneity corrections and small MLC-shaped fields: Results of IAEA multi-center studies.

UNLABELLED: The International Atomic Energy Agency (IAEA) has a long tradition of supporting development of methodologies for national networks providing quality audits in radiotherapy. A series of co-ordinated research projects (CRPs) has been conducted by the IAEA since 1995 assisting national external audit groups developing national audit programs. The CRP 'Development of Quality Audits for Radiotherapy Dosimetry for Complex Treatment Techniques' was conducted in 2009-2012 as an extension of previously developed audit programs. MATERIAL AND METHODS: The CRP work described in this paper focused on developing and testing two steps of dosimetry audit: verification of heterogeneity corrections, and treatment planning system (TPS) modeling of small MLC fields, which are important for the initial stages of complex radiation treatments, such as IMRT. The project involved development of a new solid slab phantom with heterogeneities containing special measurement inserts for thermoluminescent dosimeters (TLD) and radiochromic films. The phantom and the audit methodology has been developed at the IAEA and tested in multi-center studies involving the CRP participants. RESULTS: The results of multi-center testing of methodology for two steps of dosimetry audit show that the design of audit procedures is adequate and the methodology is feasible for meeting the audit objectives. A total of 97% TLD results in heterogeneity situations obtained in the study were within 3% and all results within 5% agreement with the TPS predicted doses. In contrast, only 64% small beam profiles were within 3 mm agreement between the TPS calculated and film measured doses. Film dosimetry results have highlighted some limitations in TPS modeling of small beam profiles in the direction of MLC leave movements. DISCUSSION: Through multi-center testing, any challenges or difficulties in the proposed audit methodology were identified, and the methodology improved. Using the experience of these studies, the participants could incorporate the auditing procedures in their national programs.

Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis.

Nephrolithiasis is a prevalent condition with a high morbidity. Although dozens of monogenic causes have been identified, the fraction of single-gene disease has not been well studied. To determine the percentage of cases that can be molecularly explained by mutations in 1 of 30 known kidney stone genes, we conducted a high-throughput mutation analysis in a cohort of consecutively recruited patients from typical kidney stone clinics. The cohort comprised 272 genetically unresolved individuals (106 children and 166 adults) from 268 families with nephrolithiasis (n=256) or isolated nephrocalcinosis (n=16). We detected 50 likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 14.9% (40 of 268) of all cases; 20 of 50 detected mutations were novel (40%). The cystinuria gene SLC7A9 (n=19) was most frequently mutated. The percentage of monogenic cases was notably high in both the adult (11.4%) and pediatric cohorts (20.8%). Recessive causes were more frequent among children, whereas dominant disease occurred more abundantly in adults. Our study provides an in-depth analysis of monogenic causes of kidney stone disease. We suggest that knowledge of the molecular cause of nephrolithiasis and nephrocalcinosis may have practical implications and might facilitate personalized treatment.

Comparison of automatic image registration uncertainty for three IGRT systems using a male pelvis phantom.

A series of phantom images using the CIRS Virtual Human Male Pelvis was acquired across available dose ranges for three image-guided radiotherapy (IGRT) imaging systems: Elekta XVI CBCT, Varian TrueBeam CBCT, and TomoTherapy MV CT. Each image was registered to a fan-beam CT within the XVI software 100 times with random initial offsets. The residual registration error was analyzed to assess the role of imaging hardware and reconstruction in the uncertainty of the IGRT process. Residual translation errors were similar for all systems and < 0.5 mm. Over the clinical dose range for prostate IGRT images (10-25 mGy), all imaging systems provided acceptable matches in > 90% of registrations when incorporating residual rotational error using a dual quaternion derived distance metric. Outside normal dose settings, large uncertainties were observed at very low and very high dose levels. No trend between initial offset and residual registration error was observed. Patient images may incur higher uncertainties than this phantom study; however, these results encourage automatic matching for standard dose settings with review by treatment staff.

A simple model for predicting the signal for a head-mounted transmission chamber system, allowing IMRT in-vivo dosimetry without pretreatment linac time.

The DAVID is a transparent, multi-wire transmission-style detector that attaches to a linear accelerator (linac) collimator for use as an in vivo detector. Currently, the normal method for using the DAVID is to measure a signal at the time of phantom-based pretreatment verification and use that signal as a baseline to compare with in vivo measurements for subsequent treatment fractions. The device has previously been shown to be both stable and accurate.(1,2) This work presents the development of a predictive algorithm for the expected signal, eradicating the need to spend time on the linac prior to treatment, and thereby making the process more efficient. The DAVID response at each wire is a consequence of both primary radiation, from the leaf pair associated with the wire, and scatter radiation as a result of radiation incident on other parts of the detector scattering in the Perspex plate. The primary radiation was shown to be linearly proportional to both leaf separation and delivered monitor units (MU). The scatter signal dropped off exponentially with regard to distance. Both of these effects were modeled; the resulting algorithm was used to predict the response from ten five-field IMRT head and neck plans. The system predicted all DAVID signals to within 5%, and was able to detect artificially generated changes in linac output. Having shown that the algorithm works, a new working paradigm is suggested, and the errors that can be detected are outlined.

The rationale for a carbon ion radiation therapy facility in Australia.

Australia has taken a collaborative nationally networked approach to achieve particle therapy capability. This supports the under-construction proton therapy facility in Adelaide, other potential proton centres and an under-evaluation proposal for a hybrid carbon ion and proton centre in western Sydney. A wide-ranging overview is presented of the rationale for carbon ion radiation therapy, applying observations to the case for an Australian facility and to the clinical and research potential from such a national centre.