Evaluating the relationship between contouring variability and modelled treatment outcome for prostate bed radiotherapy.

Objectives.Contouring similarity metrics are often used in studies of inter-observer variation and automatic segmentation but do not provide an assessment of clinical impact. This study focused on post-prostatectomy radiotherapy and aimed to (1) identify if there is a relationship between variations in commonly used contouring similarity metrics and resulting dosimetry and (2) identify the variation in clinical target volume (CTV) contouring that significantly impacts dosimetry.Approach.The study retrospectively analysed CT scans of 10 patients from the TROG 08.03 RAVES trial. The CTV, rectum, and bladder were contoured independently by three experienced observers. Using these contours reference simultaneous truth and performance level estimation (STAPLE) volumes were established. Additional CTVs were generated using an atlas algorithm based on a single benchmark case with 42 manual contours. Volumetric-modulated arc therapy (VMAT) treatment plans were generated for the observer, atlas, and reference volumes. The dosimetry was evaluated using radiobiological metrics. Correlations between contouring similarity and dosimetry metrics were calculated using Spearman coefficient (Γ). To access impact of variations in planning target volume (PTV) margin, the STAPLE PTV was uniformly contracted and expanded, with plans created for each PTV volume. STAPLE dose-volume histograms (DVHs) were exported for plans generated based on the contracted/expanded volumes, and dose-volume metrics assessed.Mainresults. The study found no strong correlations between the considered similarity metrics and modelled outcomes. Moderate correlations (0.5 <Γ< 0.7) were observed for Dice similarity coefficient, Jaccard, and mean distance to agreement metrics and rectum toxicities. The observations of this study indicate a tendency for variations in CTV contraction/expansion below 5 mm to result in minor dosimetric impacts.Significance. Contouring similarity metrics must be used with caution when interpreting them as indicators of treatment plan variation. For post-prostatectomy VMAT patients, this work showed variations in contours with an expansion/contraction of less than 5 mm did not lead to notable dosimetric differences, this should be explored in a larger dataset to assess generalisability.

The assessment of the clinical impact of using a single set of radiotherapy planning data for two kilovoltage therapy units.

Kilovoltage therapy units are used for superficial radiotherapy treatment delivery. Peer reviewed studies for MV linear accelerators describe tolerances to dosimetrically match multiple linear accelerators enabling patient treatment on any matched machine. There is an absence of literature on using a single planning data set for multiple kilovoltage units which have limited ability for beam adjustment. This study reviewed kilovoltage dosimetry and treatment planning scenarios to evaluate the feasibility of using ACPSEM annual QA tolerances to determine whether two units (of the same make and model) were dosimetrically matched. The dosimetric characteristics, such as measured half value layer (HVL), percentage depth dose (PDD), applicator factor and output variation with stand-off distance for each kV unit were compared to assess the agreement. Independent planning data based on the measured HVL for each beam energy from each kV unit was prepared. Monitor unit (MU) calculations were performed using both sets of planning data for approximately 200 clinical scenarios and compared with an overall agreement between units of < 2%. Additionally, a dosimetry measurement comparison was completed at each site for a subset of nine scenarios. All machine characterisation measurements were within the ACPSEM Annual QA tolerances, and dosimetric testing was within 2.5%. This work demonstrates that using a single set of planning data for two kilovoltage units is feasible, resulting in a clinical impact within published uncertainty.

Molecular and functional correction of a deep intronic splicing mutation in CFTR by CRISPR-Cas9 gene editing.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. The 10th most common mutation, c.3178-2477C>T (3849+10kb C>T), involves a cryptic, intronic splice site. This mutation was corrected in CF primary cells homozygous for this mutation by delivering pairs of guide RNAs (gRNAs) with Cas9 protein in ribonucleoprotein (RNP) complexes that introduce double-strand breaks to flanking sites to excise the 3849+10kb C>T mutation, followed by DNA repair by the non-homologous end-joining pathway, which functions in all cells of the airway epithelium. RNP complexes were delivered to CF basal epithelial cell by a non-viral, receptor-targeted nanocomplex comprising a formulation of targeting peptides and lipids. Canonical CFTR mRNA splicing was, thus, restored leading to the restoration of CFTR protein expression with concomitant restoration of electrophysiological function in airway epithelial air-liquid interface cultures. Off-target editing was not detected by Sanger sequencing of in silico-selected genomic sites with the highest sequence similarities to the gRNAs, although more sensitive unbiased whole genome sequencing methods would be required for possible translational developments. This approach could potentially be used to correct aberrant splicing signals in several other CF mutations and other genetic disorders where deep-intronic mutations are pathogenic.

Commissioning of a RayStation structure template for the iBEAM evo Couchtop.

Accurate radiotherapy treatment planning requires attenuation through the treatment couch to be accounted for in dose calculation. This is commonly performed by using contouring tools to add a virtual structure in the shape of the treatment couch and assigning the preferred absorption properties. The RayStation treatment planning system (TPS) allows users to assign a material that comprises both an elemental structure and a physical density. The selection of such parameters should be made so that modelled attenuation through the couch closely matches measured data. When these measurements involve the use of plastic phantoms and rotational beams, the validity of the data is dependent upon aspects of TPS and linear accelerator performance that can be difficult to quantify. A fundamental measure of couch attenuation using an ionisation chamber in water and perpendicular beam geometry that required no gantry movement was implemented to eliminate the identified uncertainties. This data was used to determine the combination of elemental composition and density assigned to a modelled couch structure that provided the most accurate representation of beam attenuation in this simple geometry. The preferred material was then validated using a cylindrical phantom and rotational beams. The findings were equivalent between the static gantry with water phantom and rotating gantry with cylindrical phantom. Of the elemental compositions investigated, it was possible to achieve suitable agreement with the measured data for each option provided the density was optimised. Choice of the elemental composition was not observed to be an important factor in achieving a good model.

S-adenosylmethionine synthases specify distinct H3K4me3 populations and gene expression patterns during heat stress.

Methylation is a widely occurring modification that requires the methyl donor S-adenosylmethionine (SAM) and acts in regulation of gene expression and other processes. SAM is synthesized from methionine, which is imported or generated through the 1-carbon cycle (1 CC). Alterations in 1 CC function have clear effects on lifespan and stress responses, but the wide distribution of this modification has made identification of specific mechanistic links difficult. Exploiting a dynamic stress-induced transcription model, we find that two SAM synthases in Caenorhabditis elegans, SAMS-1 and SAMS-4, contribute differently to modification of H3K4me3, gene expression and survival. We find that sams-4 enhances H3K4me3 in heat shocked animals lacking sams-1, however, sams-1 cannot compensate for sams-4, which is required to survive heat stress. This suggests that the regulatory functions of SAM depend on its enzymatic source and that provisioning of SAM may be an important regulatory step linking 1 CC function to phenotypes in aging and stress.

An investigation of the conformity, feasibility, and expected clinical benefits of multiparametric MRI-guided dose painting radiotherapy in glioblastoma.

Background: New technologies developed to improve survival outcomes for glioblastoma (GBM) continue to have limited success. Recently, image-guided dose painting (DP) radiotherapy has emerged as a promising strategy to increase local control rates. In this study, we evaluate the practical application of a multiparametric MRI model of glioma infiltration for DP radiotherapy in GBM by measuring its conformity, feasibility, and expected clinical benefits against standard of care treatment. Methods: Maps of tumor probability were generated from perfusion/diffusion MRI data from 17 GBM patients via a previously developed model of GBM infiltration. Prescriptions for DP were linearly derived from tumor probability maps and used to develop dose optimized treatment plans. Conformity of DP plans to dose prescriptions was measured via a quality factor. Feasibility of DP plans was evaluated by dose metrics to target volumes and critical brain structures. Expected clinical benefit of DP plans was assessed by tumor control probability. The DP plans were compared to standard radiotherapy plans. Results: The conformity of the DP plans was >90%. Compared to the standard plans, DP (1) did not affect dose delivered to organs at risk; (2) increased mean and maximum dose and improved minimum dose coverage for the target volumes; (3) reduced minimum dose within the radiotherapy treatment margins; (4) improved local tumor control probability within the target volumes for all patients. Conclusions: A multiparametric MRI model of GBM infiltration can enable conformal, feasible, and potentially beneficial dose painting radiotherapy plans.

Development of a vendor neutral MRI distortion quality assurance workflow.

With the utilization of magnetic resonance (MR) imaging in radiotherapy increasing, routine quality assurance (QA) of these systems is necessary. The assessment of geometric distortion in images used for radiotherapy treatment planning needs to be quantified and monitored over time. This work presents an adaptable methodology for performing routine QA for systematic MRI geometric distortion. A software tool and compatible protocol (designed to work with any CT and MR compatible phantom on any scanner) were developed to quantify geometric distortion via deformable image registration. The MR image is deformed to the CT, generating a deformation field, which is sampled, quantifying geometric distortion as a function of distance from scanner isocenter. Configurability of the QA tool was tested, and results compared to those provided from commercial solutions. Registration accuracy was investigated by repeating the deformable registration step on the initial deformed MR image to define regions with residual distortions. The geometric distortion of four clinical systems was quantified using the customisable QA method presented. Maximum measured distortions varied from 2.2 to 19.4 mm (image parameter and sampling volume dependent). The workflow was successfully customized for different phantom configurations and volunteer imaging studies. Comparison to a vendor supplied solution showed good agreement in regions where the two procedures were sampling the same imaging volume. On a large field of view phantom across various scanners, the QA tool accurately quantified geometric distortions within 17-22 cm from scanner isocenter. Beyond these regions, the geometric integrity of images in clinical applications should be considered with a higher degree of uncertainty due to increased gradient nonlinearity and B0 inhomogeneity. This tool has been successfully integrated into routine QA of the MRI scanner utilized for radiotherapy within our department. It enables any low susceptibility MR-CT compatible phantom to quantify the geometric distortion on any MRI scanner with a configurable, user friendly interface for ease of use and consistency in data collection and analysis.

Repeatability of radiotherapy dose-painting prescriptions derived from a multiparametric magnetic resonance imaging model of glioblastoma infiltration.

Background and purpose: Glioblastoma (GBM) patients have a dismal prognosis. Tumours typically recur within months of surgical resection and post-operative chemoradiation. Multiparametric magnetic resonance imaging (mpMRI) biomarkers promise to improve GBM outcomes by identifying likely regions of infiltrative tumour in tumour probability (TP) maps. These regions could be treated with escalated dose via dose-painting radiotherapy to achieve higher rates of tumour control. Crucial to the technical validation of dose-painting using imaging biomarkers is the repeatability of the derived dose prescriptions. Here, we quantify repeatability of dose-painting prescriptions derived from mpMRI. Materials and methods: TP maps were calculated with a clinically validated model that linearly combined apparent diffusion coefficient (ADC) and relative cerebral blood volume (rBV) or ADC and relative cerebral blood flow (rBF) data. Maps were developed for 11 GBM patients who received two mpMRI scans separated by a short interval prior to chemoradiation treatment. A linear dose mapping function was applied to obtain dose-painting prescription (DP) maps for each session. Voxel-wise and group-wise repeatability metrics were calculated for parametric, TP and DP maps within radiotherapy margins. Results: DP maps derived from mpMRI were repeatable between imaging sessions (ICC > 0.85). ADC maps showed higher repeatability than rBV and rBF maps (Wilcoxon test, p = 0.001). TP maps obtained from the combination of ADC and rBF were the most stable (median ICC: 0.89). Conclusions: Dose-painting prescriptions derived from a mpMRI model of tumour infiltration have a good level of repeatability and can be used to generate reliable dose-painting plans for GBM patients.

Novel methodology to quantify dehydration in head and neck cancer radiotherapy using DIXON MRI.

INTRODUCTION: Head and neck cancer (HNC) patients are at risk of weight change, due to inadequate nutrition intake or dehydration, when receiving radiotherapy (RT). This study aimed to develop methodology to measure water content changes on magnetic resonance imaging (MRI) scans of the head and neck region over the course of RT. METHODS: Retrospective datasets of 54 patients were analysed. Eligible patients had been treated for HNC with cisplatin chemoradiation (CRT) or RT alone and underwent a minimum of 2 MRI scans from weeks 0, 3 and 6 of their treatment. Anatomical regions consisting of ≥90% water, on T2-weighted DIXON MRI sequences, were contoured. Water volume changes of all patients were evaluated, within an anatomically standardised external volume, by comparing the absolute water fraction volume (cc) (VEx90WF) and relative water fraction volume (%) (RelVEx90WF) at weeks 0 and 6 of RT. RESULTS: There was a statistically significant difference between the RelVEx90WF at weeks 0 and 6 (P = 0.005). However, no statistically significant difference was identified between weeks 0 and 6 VEx90WF (P = 0.064). There were no statistically significant differences identified between patients who received CRT versus RT alone. CONCLUSION: This study developed a novel method for measuring changes in water fraction volumes over time, using T2-weighted DIXON MRIs. The methodology created in this study requires further validation through phantom imaging, with known fat and water values.

Conformance of a 3T radiotherapy MRI scanner to the QIBA Diffusion Profile.

PURPOSE: To assess the technical performance of the apparent diffusion coefficient (ADC) on a dedicated 3T radiotherapy scanner, using a standardized phantom and sequences. Investigations into factors that could impact the technical performance of ADC in the clinic were also completed, including changing the slice-encoded imaging direction and the reference sample ADC value. METHODS: ADC acquisitions were performed monthly on an isotropic diffusion phantom over 1 year. Measurements of ADC %bias, coefficients of variation for short-/long-term repeatability and precision (CVST /CVLT and CVP ), and b-value dependency (Depb ) were calculated. The measurements were then assessed according to the Quantitative Imaging Biomarker Alliance (QIBA) Diffusion Profile specifications. RESULTS: The average of all measurements over the year was within Profile recommended ranges. This included when testing was performed in different imaging directions, and on samples that had different ADC reference values (0.4-1.1 µm2 /ms). Results in the axial plane for the central water vial included a bias of +0.05%, CVST /CVLT /CVP  = 0.1%/ 0.9%/0.4% and Depb  = 0.4%. CONCLUSIONS: The technical performance of ADC on a radiotherapy dedicated MRI scanner over the course of 12 months was considered conformant to the QIBA Profile. Quantifying these metrics and factors that may affect the performance is essential in progressing the use of ADC clinically: ensuring that the observed change of ADC in a tissue is due to a physiological response and not measurement variability.

Determining the longitudinal accuracy and reproducibility of T1 and T2 in a 3T MRI scanner.

PURPOSE: To determine baseline accuracy and reproducibility of T1 and T2 relaxation times over 12 months on a dedicated radiotherapy MRI scanner. METHODS: An International Society of Magnetic Resonance in Medicine/National Institute of Standards and Technology (ISMRM/NIST) System Phantom was scanned monthly on a 3T MRI scanner for 1 year. T1 was measured using inversion recovery (T1 -IR) and variable flip angle (T1 -VFA) sequences and T2 was measured using a multi-echo spin echo (T2 -SE) sequence. For each vial in the phantom, accuracy errors (%bias) were determined by the relative differences in measured T1 and T2 times compared to reference values. Reproducibility was measured by the coefficient of variation (CV) of T1 and T2 measurements across monthly scans. Accuracy and reproducibility were mainly assessed on vials with relaxation times expected to be in physiological ranges at 3T. RESULTS: A strong linear correlation between measured and reference relaxation times was found for all sequences tested (R2  > 0.997). Baseline bias (and CV[%]) for T1 -IR, T1 -VFA and T2 -SE sequences were +2.0% (2.1), +6.5% (4.2), and +8.5% (1.9), respectively. CONCLUSIONS: The accuracy and reproducibility of T1 and T2 on the scanner were considered sufficient for the sequences tested. No longitudinal trends of variation were deduced, suggesting less frequent measurements are required following the establishment of baselines.

Relationships Between Adolescents with Cancer and Healthy Peers: A Qualitative Study.

Purpose: Despite the developmental relevance and role in social support, research on relationships between adolescents with cancer and healthy peers is limited. To address this gap, we aimed to describe adolescents' perceptions of their friendships during the 1st year following a cancer diagnosis, including relationship changes, factors that promote/inhibit relationships, and definitions and experiences of peer support. Methods: Eligible adolescents were 12-20 years old, <1 year of a new cancer diagnosis, and English speaking. Participants completed 1:1 semistructured interviews that were analyzed using inductive content analysis. Results: Fourteen adolescents enrolled and completed interviews (mean [M]age = 14.8, standard deviation [SD] = 1.8; M = 6.3 months postdiagnosis, SD = 3.2 months). Domains included (1) shifting relationships, (2) staying connected, (3) making it hard to stay close, and (4) showing me they care. Relationship changes were positive and negative, and many described a process of recognizing true friends. Staying connected with peers through communication, technology, and feeling up to date promoted closeness, while distance, treatment-related restrictions, and friends' discomfort were hindrances. Adolescents defined supportive friends as those who were there for them, checked in often, and gave them gifts. Conclusion: Despite relationship changes, adolescents with cancer desire connection with peers during treatment and perceive that healthy peers provide valuable support. Supporting connectedness to healthy peers during treatment may be a promising future direction to mitigate social disruption and promote well-being.

An international survey on the clinical use of rigid and deformable image registration in radiotherapy.

OBJECTIVES: Rigid image registration (RIR) and deformable image registration (DIR) are widely used in radiotherapy. This project aims to capture current international approaches to image registration. METHODS: A survey was designed to identify variations in use, resources, implementation, and decision-making criteria for clinical image registration. This was distributed to radiotherapy centers internationally in 2018. RESULTS: There were 57 responses internationally, from the Americas (46%), Australia/New Zealand (32%), Europe (12%), and Asia (10%). Rigid image registration and DIR were used clinically for computed tomography (CT)-CT registration (96% and 51%, respectively), followed by CT-PET (81% and 47%), CT-CBCT (84% and 19%), CT-MR (93% and 19%), MR-MR (49% and 5%), and CT-US (9% and 0%). Respondent centers performed DIR using dedicated software (75%) and treatment planning systems (29%), with 84% having some form of DIR software. Centers have clinically implemented DIR for atlas-based segmentation (47%), multi-modality treatment planning (65%), and dose deformation (63%). The clinical use of DIR for multi-modality treatment planning and accounting for retreatments was considered to have the highest benefit-to-risk ratio (69% and 67%, respectively). CONCLUSIONS: This survey data provides useful insights on where, when, and how image registration has been implemented in radiotherapy centers around the world. DIR is mainly in clinical use for CT-CT (51%) and CT-PET (47%) for the head and neck (43-57% over all use cases) region. The highest benefit-risk ratio for clinical use of DIR was for multi-modality treatment planning and accounting for retreatments, which also had higher clinical use than for adaptive radiotherapy and atlas-based segmentation.

Deforming to Best Practice: Key considerations for deformable image registration in radiotherapy.

Image registration is a process that underlies many new techniques in radiation oncology - from multimodal imaging and contour propagation in treatment planning to dose accumulation throughout treatment. Deformable image registration (DIR) is a subset of image registration subject to high levels of complexity in process and validation. A need for local guidance to assist in high-quality utilisation and best practice was identified within the Australian community, leading to collaborative activity and workshops. This report communicates the current limitations and best practice advice from early adopters to help guide those implementing DIR in the clinic at this early stage. They are based on the state of image registration applications in radiotherapy in Australia and New Zealand (ANZ), and consensus discussions made at the 'Deforming to Best Practice' workshops in 2018. The current status of clinical application use cases is presented, including multimodal imaging, automatic segmentation, adaptive radiotherapy, retreatment, dose accumulation and response assessment, along with uptake, accuracy and limitations. Key areas of concern and preliminary suggestions for commissioning, quality assurance, education and training, and the use of automation are also reported. Many questions remain, and the radiotherapy community will benefit from continued research in this area. However, DIR is available to clinics and this report is intended to aid departments using or about to use DIR tools now.

Comparative implementation-effectiveness of three strategies to perform hearing screening among older adults in primary care clinics: study design and protocol.

BACKGROUND: The burden of hearing loss among older adults could be mitigated with appropriate care. This study compares implementation of three hearing screening strategies in primary care, and examines the reliability and validity of patient self-assessment, primary care providers (PCP) and diagnostic audiologists in the identification of 'red flag' conditions (those conditions that may require medical consultation and/or intervention). METHODS: Six primary care practices will implement one of three screening strategies (2 practices per strategy) with 660 patients (220 per strategy) ages 65-75 years with no history of hearing aid use or diagnosis of hearing loss. Strategies differ on the location and use of PCP encouragement to complete a telephone-based hearing screen (tele-HS). Group 1: instructions for tele-HS to complete at home and educational materials on warning signs and consequences of hearing loss. Group 2: PCP counseling/encouragement on importance of hearing screening, instructions to take the tele-HS from home, educational materials. Group 3: PCP counseling/encouragement, in-office tele-HS, and educational materials. Patients from all groups who fail the tele-HS will be referred for diagnostic audiological testing and medical evaluation, and complete a self-assessment of red flag conditions at this follow-up appointment. Due to the expected low incidence of ear disease in the PCP cohort, we will enroll a complementary population of patients (N = 500) from selected otolaryngology head and neck surgery clinics in a national practice-based research network to increase the likelihood of occurrence of medical conditions that might contraindicate hearing aid fitting. The primary outcome is the proportion of patients who complete the tele-HS within 2 months of the PCP appointment comparing Group 3 (PCP encouragement, in-office tele-HS, education) versus Groups 2 and 1 (education and tele-HS at home, with and without PCP encouragement, respectively). The several secondary outcomes include direct and indirect costs, patient, family and provider attitudes of hearing healthcare, and accuracy of red flag condition evaluations compared with expert medical assessment by an otolaryngology provider. DISCUSSION: Determining the relative effectiveness of three different strategies for hearing screening in primary care and the assessment accuracy of red flag conditions can each lead to practice and policy changes that will reduce individual, family and societal burden from hearing loss among older adults. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02928107; 10/10/2016 protocol version 1.

Walking on Eggshells: Parents' First Year After Their Adolescent Completes Their Cancer Treatment [Formula: see text].

Background: Despite an awareness that parents experience distress and heightened uncertainty at the end of their adolescent's treatment for cancer, little is known about the specific challenges and concerns parents hold for their adolescent survivors or how they manage these challenges. This study described challenges parents experience in the first year after their adolescent's cancer treatment and what parents did to manage those challenges. Method: Single occasion semistructured interviews were conducted with parents and were transcribed verbatim. Data were coded using inductive content analysis methods adapted from grounded theory. Results: Participants were 30 parents of adolescent survivors (13-18 years) who were in the first year following treatment completion. The core construct, "Walking on Eggshells," explained the processes and experiences parents faced once treatment was complete. Two additional domains captured how parents managed posttreatment challenges ("Doing What We Can") and the ways parents helped their adolescents adjust ("Balancing"). Conclusion: Study results suggest that services and materials are needed to help parents know common struggles that arise after treatment and ways to mitigate the severity of distress parents experience.

New approaches to genetic therapies for cystic fibrosis.

Gene therapy offers great promise for cystic fibrosis which has never been quite fulfilled due to the challenges of delivering sufficient amounts of the CFTR gene and expression persistence for a sufficient period of time in the lungs to have any effect. Initial trials explored both viral and non-viral vectors but failed to achieve a significant breakthrough. However, in recent years, new opportunities have emerged that exploit our increased knowledge and understanding of the biology of CF and the airway epithelium. New technologies include new viral and non-viral vector approaches to delivery, but also alternative nucleic acid technologies including oligonucleotides and siRNA approaches for gene silencing and gene splicing, described in this review, as presented at the 2019 annual European CF Society Basic Science meeting (Dubrovnik, Croatia). We also briefly discuss other emerging technologies including mRNA and CRISPR gene editing that are advancing rapidly. The future prospects for genetic therapies for CF are now diverse and more promising probably than any time since the discovery of the CF gene.

Geometric distortion characterization and correction for the 1.0 T Australian MRI-linac system using an inverse electromagnetic method.

PURPOSE: The magnetic resonance imaging (MRI)-Linac system combines a MRI scanner and a linear accelerator (Linac) to realize real-time localization and adaptive radiotherapy for tumors. Given that the Australian MRI-Linac system has a 30-cm diameter of spherical volume (DSV) with a shimmed homogeneity of ±4.05 parts per million (ppm), a gradient nonlinearity (GNL) of <5% can only be assured within 15 cm from the system's isocenter. GNL increases from the isocenter and escalates close to and outside of the edge of the DSV. Gradient nonlinearity can cause large geometric distortions, which may provide inaccurate tumor localization and potentially degrade the radiotherapy treatment. In this study, we aimed to characterize and correct the geometric distortions both inside and outside of the DSV. METHODS: On the basis of phantom measurements, an inverse electromagnetic (EM) method was developed to reconstitute the virtual current density distribution that could generate gradient fields. The obtained virtual EM source was capable of characterizing the GNL field both inside and outside of the DSV. With the use of this GNL field information, our recently developed "GNL-encoding" reconstruction method was applied to correct the distortions implemented in the k-space domain. RESULTS: Both phantom and in vivo human images were used to validate the proposed method. The results showed that the maximal displacements within an imaging volume of 30 cm × 30 cm × 30 cm after using the fifth-order spherical harmonic (SH) method and the proposed method were 6.1 ± 0.6 mm and 1.8 ± 0.6 mm, respectively. Compared with the fifth-order SH-based method, the new solution decreased the percentage of markers (within an imaging volume of 30 cm × 30 cm × 30 cm) with ≥1.5-mm distortions from 6.3% to 1.3%, indicating substantially improved geometric accuracy. CONCLUSIONS: The experimental results indicated that the proposed method could provide substantially improved geometric accuracy for the region outside of the DSV, when comparing with the fifth-order SH-based method.

Trying to Feel Normal Again: Early Survivorship for Adolescent Cancer Survivors.

BACKGROUND: Despite knowing the potential medical consequences of cancer treatment, little is known about how adolescents cognitively and emotionally frame, process, and manage in the early survivorship period. OBJECTIVE: The specific aims were to describe the worries, perceived challenges, and ways of dealing with these issues for adolescent cancer survivors in the early period of survivorship. METHODS: Twenty-nine adolescent survivors (12-18 years) completed a semistructured interview. Inductive coding methods adapted from grounded theory were used to analyze the data. RESULTS: Seven domains and 18 categories organized the adolescent's experience with early posttreatment survivorship. The domains included getting back to school; relationships with parents, siblings, friends; feeling changed by the experience; and concerns about relapse. CONCLUSIONS: This study contributes to our understanding of survivors' relationships with parents, siblings, and friends and survivors' models of the illness. Future studies are needed to understand how parents can help adolescents assume greater responsibility for their care, to understand what it is like for friends to have a peer with cancer and what behaviors by healthcare providers contribute to feelings of abandonment later in survivorship, and to better understand adolescent survivors' models of the illness and survivorship. IMPLICATIONS FOR PRACTICE: Study results suggest that nurses are in an ideal position to begin and to continue discussions with adolescent survivors about the adolescent's view of medical follow- up, its purpose and importance, and ways in which the adolescent can begin, early on, to engage in planning their own health during survivorship.

Stress-responsive and metabolic gene regulation are altered in low S-adenosylmethionine.

S-adenosylmethionine (SAM) is a donor which provides the methyl groups for histone or nucleic acid modification and phosphatidylcholine production. SAM is hypothesized to link metabolism and chromatin modification, however, its role in acute gene regulation is poorly understood. We recently found that Caenorhabditis elegans with reduced SAM had deficiencies in H3K4 trimethylation (H3K4me3) at pathogen-response genes, decreasing their expression and limiting pathogen resistance. We hypothesized that SAM may be generally required for stress-responsive transcription. Here, using genetic assays, we show that transcriptional responses to bacterial or xenotoxic stress fail in C. elegans with low SAM, but that expression of heat shock genes are unaffected. We also found that two H3K4 methyltransferases, set-2/SET1 and set-16/MLL, had differential responses to survival during stress. set-2/SET1 is specifically required in bacterial responses, whereas set-16/MLL is universally required. These results define a role for SAM in the acute stress-responsive gene expression. Finally, we find that modification of metabolic gene expression correlates with enhanced survival during stress.