Development and feasibility of an evidence-informed self-management education program in pediatric concussion rehabilitation.

BACKGROUND: Concussion is a considerable public health problem in youth. However, identifying, understanding and implementing best evidence informed recovery guidelines may be challenging for families given the vast amount of information available in the public domains (e.g. Internet). The objective of this study was to develop, implement and evaluate the feasibility of an evidence-informed self-management education program for concussion recovery in youth. METHODS: Synthesis of best evidence, principles of knowledge translation and exchange, and expert opinion were integrated within a self-management program framework to develop a comprehensive curriculum. The program was implemented and evaluated in a children's rehabilitation hospital within a universal health care system. A retrospective secondary analysis of anonymous data from a program evaluation survey was used to evaluate program feasibility, to identify features of importance to program participants and to assess changes in participants' knowledge. RESULTS: The program, "Concussion & You" includes a comprehensive, evidence informed, population specific curriculum that teaches participants practical strategies for management of return to school and play, sleep, nutrition, relaxation and energy conservation. A 'wheel of health' is used to facilitate participants' self-management action plan. Results from eighty-seven participant surveys indicate that the program is feasible and participant knowledge increased in all areas of the program with the highest changes reported in knowledge about sleep hygiene, rest and energy conservation. CONCLUSION: Findings indicate that "Concussion & You" is a feasible program that is acceptable to youth and their families, and fills a health system service gap.

Oculomotor-Based Vision Assessment in Mild Traumatic Brain Injury: A Systematic Review.

OBJECTIVE: The purpose of this article is to synthesize and appraise the evidence regarding the use of oculomotor-based vision assessment to identify and monitor recovery from mild traumatic brain injury (mTBI). Specific objectives are to (1) identify changes in oculomotor-based vision following mTBI; (2) distinguish methods of assessment; (3) appraise the level and quality of evidence; and, if warranted, (4) determine clinical recommendations for assessment. METHODS: A systematic review was undertaken to identify and appraise relevant literature. A search was conducted of 7 databases of peer-reviewed literature from January 1990 to January 2015. Articles were included if study populations were clearly identified as having mTBI and used an assessment of oculomotor-based vision. Articles with pooled data (eg, mTBI and stroke), addressing afferent visual function (eg, visual field deficits) or using single case designs, were excluded. RESULTS: Twenty articles were selected for inclusion. Exploratory findings suggest that measurements of saccades, smooth pursuit, and vergence are useful in detecting changes associated with mTBI. Assessment methods included eye tracker protocols, optometric assessment, and the King-Devick test. CONCLUSION: The strength of this evidence is not yet sufficient to warrant clinical recommendations. Research using rigorous methods is required to develop reliable, valid, and clinically useful assessment protocols.

Toward magnetic resonance-only simulation: segmentation of bone in MR for radiation therapy verification of the head.

PURPOSE: To develop a practical method to localize bones in magnetic resonance (MR) images, to create "computed tomography-like" MR images (ctMRI) that could be used for radiation therapy verification, and to generate MR-based digitally reconstructed radiographs (DRR). METHODS AND MATERIALS: Using T1-weighted MR images, an air mask was derived from the manual contouring of all airways within the head and neck region using axial images at 6 anatomic levels. Compact bone, spongy bone, and soft tissue masks were then automatically generated using the statistical data derived from MR intensities and the air mask. ctMRI were then generated by mapping the MR intensities of the voxels within these masks into the CT number ranges of corresponding tissues. MR-based DRRs created from ctMRI were quantitatively evaluated using the co-registered MR and CT head images of 20 stereotactic radiosurgery patients. Ten anatomical points, positioned on the skull segmented using a threshold of 300 HU, in CT and ctMRI, were used to determine the differences in distance between MR-based DRRs and CT-based DRRs, and to evaluate the geometric accuracy of ctMRI and MR-based DRRs. RESULTS: The bony structures were identified on ctMRI and were visible in the MR-based DRRs. From the 20 patient cases, the mean geometric difference and standard deviation between the 10 anatomical points on MR-based and CT-based DRRs was -0.05 ± 0.85 mm, respectively. This included uncertainty in image fusion. The maximum distance difference was 1.88 mm. CONCLUSIONS: A practical method was developed to segment bone from MR images. The ctMRI created can be used for radiation treatment verification when MR-only simulation is performed. MR-based DRRs can be used in place of CT-based DRRs.

Effects of ROI Placement on PET-Based Assessment of Tumor Response to Therapy.

Purpose. Quantitative PET response assessment during therapy requires regions of interest (ROI). Commonly, a fixed-size ROI is placed at the maximum uptake point in the pretreatment study. For intratreatment, the ROI is placed either at the maximum uptake point (ROIpeak) or at the same location as the pretreatment ROI (ROIsame). We have evaluated the effects of the ROI placement on response assessment. Methods. PET scans of 15 head and neck cancer patients were used to evaluate the effects of the two ROI methods on response assessment. Results. The average intratreatment ROIpeak uptake was 13.4% higher than the ROIsame uptake (range -14% to 38%). The average relative change in ROIpeak uptake was 7.9% lower than ROIsame uptake (range -5% to 36%), resulting in ambiguous tumour classification in 19% of the tumours. Conclusion. Quantitative PET response assessment using a fixed-size ROI is sensitive the ROI placement. The difference between ROIpeak and ROIsame could be substantial resulting in ambiguous response assessment. Although the fixed-size ROI is simple to implement, it is also prone to the limitations and should be used with caution. Clinical trial data are necessary to establish reliable thresholds for fixed-size ROI techniques and to evaluate their efficacy for response assessment.

Comparison of bulk electron density and voxel-based electron density treatment planning.

The use of magnetic resonance imaging (MRI) alone for radiation planning is limited by the lack of electron density for dose calculations. The purpose of this work is to evaluate the dosimetric accuracy of using bulk electron density as a substitute for computed tomography (CT)-derived electron density in intensity-modulated radiation therapy (IMRT) treatment planning of head and neck (HN) cancers. Ten clinically-approved, CT-based IMRT treatment plans of HN cancer were used for this study. Three dose distributions were calculated and compared for each treatment plan. The first calculation used CT-derived density and was assumed to be the most accurate. The second calculation used a homogeneous patient density of 1 g/cm3. For the third dose calculation, bone and air cavities were contoured and assigned a uniform density of 1.5 g/cm3 and 0 g/cm3, respectively. The remaining tissues were assigned a density of 1 g/cm3. The use of homogeneous anatomy resulted in up to 4%-5% deviations in dose distribution as compared to CT-derived electron density calculations. Assigning bulk density to bone and air cavities significantly improved the accuracy of the dose calculations. All parameters used to describe planning target volume coverage were within 2% of calculations based on CT-derived density. For organs at risk, most of the parameters were within 2%, with the few exceptions located in low-dose regions. The data presented here show that if bone and air cavities are overridden with the proper density, it is feasible to use a bulk electron density approach for accurate dose calculation in IMRT treatment planning of HN cancers. This may overcome the problem of the lack of electron density information should MRI-only simulation be performed.

Assessing the role of volumetric modulated arc therapy (VMAT) relative to IMRT and helical tomotherapy in the management of localized, locally advanced, and post-operative prostate cancer.

PURPOSE: To quantify differences in treatment delivery efficiency and dosimetry between step-and-shoot intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and helical tomotherapy (HT) for prostate treatment. METHODS AND MATERIALS: Twenty-five prostate cancer patients were selected retrospectively for this planning study. Treatment plans were generated for: prostate alone (n = 5), prostate + seminal vesicles (n = 5), prostate + seminal vesicles + pelvic lymph nodes (n = 5), prostate bed (n = 5), and prostate bed + pelvic lymph nodes (n = 5). Target coverage, dose homogeneity, integral dose, monitor units (MU), and sparing of organs at risk (OAR) were compared across techniques. Time required to deliver each plan was measured. RESULTS: The dosimetric quality of IMRT, VMAT, and HT plans were comparable for target coverage (planning target volume V95%, clinical target volume V100% all >98.7%) and sparing of organs at risk (OAR) for all treatment groups. Although HT resulted in a slightly higher integral dose and mean doses to the OAR, it yielded a lower maximum dose to all OAR examined. VMAT resulted in reductions in treatment times over IMRT (mean = 75%) and HT (mean = 70%). VMAT required 15-38% fewer monitor units than IMRT over all treatment volumes, with the reduction per fraction ranging from 100-423 MU from the smallest to largest volumes. CONCLUSIONS: VMAT improves efficiency of delivery for equivalent dosimetric quality as IMRT and HT across various prostate cancer treatment volumes in the intact and postoperative settings.

Automated radiation targeting in head-and-neck cancer using region-based texture analysis of PET and CT images.

PURPOSE: A co-registered multimodality pattern analysis segmentation system (COMPASS) was developed to automatically delineate the radiation targets in head-and-neck cancer (HNC) using both (18)F-fluoro-deoxy glucose-positron emission tomography (PET) and computed tomography (CT) images. The performance of the COMPASS was compared with the results of existing threshold-based methods and radiation oncologist-drawn contours. METHODS AND MATERIALS: The COMPASS extracted texture features from corresponding PET and CT voxels. Using these texture features, a decision-tree-based K-nearest-neighbor classifier labeled each voxel as either "normal" or "abnormal." The COMPASS was applied to the PET/CT images of 10 HNC patients. Automated segmentation results were validated against the manual segmentations of three radiation oncologists using the volume, sensitivity, and specificity. The performance of the COMPASS was compared with three PET-based threshold methods: standard uptake value of 2.5, 50% maximal intensity, and signal/background ratio. RESULTS: The tumor delineations of the COMPASS were both quantitatively and qualitatively more similar to those of the radiation oncologists than the delineations from the other methods. The specificity was 95% +/- 2%, 84% +/- 9%, 98% +/- 3%, and 96% +/- 4%, and the sensitivity was 90% +/- 12%, 93% +/- 10%, 48% +/- 20%, and 68% +/- 25% for the COMPASS, for a standard uptake value of 2.5, 50% maximal intensity, and signal/background ratio, respectively. The COMPASS distinguished HNC from adjacent normal tissues with high physiologic uptake and consistently defined tumors with large variability in (18)F-fluoro-deoxy glucose uptake, which are often problematic with the threshold-based methods. CONCLUSION: Automated segmentation using texture analysis of PET/CT images has the potential to provide accurate delineation of HNC. This could lead to reduced interobserver variability, reduced uncertainty in target delineation, and improved treatment planning accuracy.

Coregistered FDG PET/CT-based textural characterization of head and neck cancer for radiation treatment planning.

Coregistered fluoro-deoxy-glucose (FDG) positron emission tomography/computed tomography (PET/CT) has shown potential to improve the accuracy of radiation targeting of head and neck cancer (HNC) when compared to the use of CT simulation alone. The objective of this study was to identify textural features useful in distinguishing tumor from normal tissue in head and neck via quantitative texture analysis of coregistered 18F-FDG PET and CT images. Abnormal and typical normal tissues were manually segmented from PET/CT images of 20 patients with HNC and 20 patients with lung cancer. Texture features including some derived from spatial grey-level dependence matrices (SGLDM) and neighborhood gray-tone-difference matrices (NGTDM) were selected for characterization of these segmented regions of interest (ROIs). Both K nearest neighbors (KNNs) and decision tree (DT)-based KNN classifiers were employed to discriminate images of abnormal and normal tissues. The area under the curve (AZ) of receiver operating characteristics (ROC) was used to evaluate the discrimination performance of features in comparison to an expert observer. The leave-one-out and bootstrap techniques were used to validate the results. The AZ of DT-based KNN classifier was 0.95. Sensitivity and specificity for normal and abnormal tissue classification were 89% and 99%, respectively. In summary, NGTDM features such as PET Coarseness, PET Contrast, and CT Coarseness extracted from FDG PET/CT images provided good discrimination performance. The clinical use of such features may lead to improvement in the accuracy of radiation targeting of HNC.

Genetic heterogeneity among Fanconi anemia heterozygotes and risk of cancer.

Fanconi anemia (FA) is a rare autosomal recessive disease characterized by a greatly increased risk of cancer among those diagnosed with the syndrome. The question as to whether FA heterozygotes are at increased risk for cancer is of great importance to those at risk for being a carrier. To address this question, we formed a cohort of grandparents of probands identified through the International Fanconi Anemia Registry. We obtained informed consent, a short questionnaire, and either blood or buccal swab DNA. After diagnosis of the proband was confirmed and complementation studies or DNA sequencing on the proband were completed, mutation analyses of the putative carriers and noncarriers was carried out. Standardized incidence ratios (SIR) were calculated to compare the observed cancer incidence of the grandparents and other relatives with the expected rates of cancer, using the Surveillance, Epidemiology, and End Results registries and the Connecticut Cancer registry. In the 944 study subjects who participated (784 grandparents and 160 other relatives), there was no suggestion of an increase in overall cancer incidence. On the other hand, a significantly higher rate of breast cancer than expected was observed among carrier grandmothers [SIR, 1.7; 95% confidence interval (95% CI), 1.1-2.7]. Among the grandmothers, those who were carriers of FANCC mutations were found to be at highest risk (SIR, 2.4; 95% CI, 1.1-5.2). Overall, there was no increased risk for cancer among FA heterozygotes in this study of Fanconi relatives, although there is some evidence that FANCC mutations are possibly breast cancer susceptibility alleles.

Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia.

The breast cancer susceptibility gene BRCA2 has recently been identified as identical to the Fanconi anemia (FA) gene FANCD1. Here we expand the clinical implications of this discovery. Notably, we identified 6 children in 5 kindreds exhibiting the co-occurrence of BRCA2 mutations, FA, and early onset acute leukemia. Leukemia occurred at a median of 2.2 years of age in the BRCA2 patients in contrast to a median onset of 13.4 years in all other FA patients in the International Fanconi Anemia Registry (IFAR; P <.0001). Breast cancer was noted in 4 of the 5 kindreds. Of the 6 children with leukemia, 4 were treated with bone marrow transplantation and 2 are alive at 3 and 9 months after treatment. Our results suggest that BRCA2 testing should be considered in all patients with FA in whom the complementation group cannot be defined or in whom leukemia is diagnosed at or before 5 years of age.

Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia.

Fanconi anemia is an inherited disease characterized by bone marrow failure, congenital malformations, and predisposition to cancer. The breast cancer susceptibility gene BRCA2 was recently found to be associated with Fanconi anemia complementation group D1 (FA-D1). We examined four kindreds afflicted with Fanconi anemia for the presence of germline BRCA2 mutations. One kindred, of Ashkenazi Jewish ancestry, had five members who were diagnosed with breast cancer and two cousins who were BRCA2*6174delT/C3069X compound heterozygotes and had Fanconi anemia and brain tumors. In another kindred of Ashkenazi Jewish and Lithuanian Catholic ancestry, a child with Fanconi anemia and a medulloblastoma was a BRCA2*6174delT/886delGT compound heterozygote. Two other kindreds each contained a Fanconi anemia-afflicted child who developed medulloblastoma; one child was of Latin American ancestry and a compound heterozygote for BRCA2*I2490T/ 5301insA and the other was African American and a compound heterozygote for BRCA2*Q3066X/E1308X. Median age of the Fanconi anemia-afflicted children at brain tumor diagnosis was 3.5 years. The co-occurrence of brain tumors, Fanconi anemia, and breast cancer observed in one of these kindreds constitutes a new syndromic association. Individuals who carry a germline BRCA2 mutation and who plan to have children with a partner of Ashkenazi Jewish descent should consider undergoing genetic counseling.

Can PET provide the 3D extent of tumor motion for individualized internal target volumes? A phantom study of the limitations of CT and the promise of PET.

PURPOSE: To characterize the limitations of fast, spiral computed tomography (CT) when imaging a moving object and to investigate whether positron emission tomography (PET) can predict the internal target volume (ITV) and ultimately improve the planning target volume (PTV) for moving tumors. METHODS AND MATERIALS: To mimic tumors, three fillable spheres were imaged while both stationary and during periodic motion using spiral CT and PET. CT- and PET-imaged volumes were defined quantitatively using voxel values. Ideal PTVs for each scenario were calculated. CT-based PTVs were generated using margins of 7.5, 10, and 15 mm to account for both organ motion and setup uncertainties. PET-based PTVs were derived with the assumption that motion was captured in the PET images and only a margin (7.5 mm) for setup errors was necessary. Comparisons between CT-based and PET-based PTVs with ideal PTVs were performed. RESULTS: CT imaging of moving spheres resulted in significant distortions in the three-dimensional (3D) image-based representations, and did not, in general, result in images well representative of either moving or stationary spheres. PET images were similar to the ideal capsular shape encompassing the sphere and its motion. In all cases, CT-imaged volumes were larger than that for the stationary sphere (range of excess volume from 0.4 to 29 cm(3) for stationary volumes of 2.14 to 172 cm(3)), but smaller than that for the true motion volume. PET-imaged volumes were larger than the true motion volume (difference from ideal ranged from 3 to 94 cm(3) for motion volumes of 1.2 to 243 cm(3)) and much larger than the stationary volume. Using CT data, geographic miss of some part of the ideal PTV occurred for 0 of 24 cases, 11 of 24 cases, and 18 of 24 cases using a 15-mm, 10-mm, and 7.5-mm margin, respectively. Geographic miss did not occur in any case for the PET-based PTV. The amount of "normal tissue" included in CT-based PTVs was dramatically greater than that included in PET-based PTVs. CONCLUSION: Fast CT imaging of a moving tumor can result in poor representation of the time-averaged position and shape of the tumor. PET imaging can provide a more accurate representation of the 3D volume encompassing motion of model tumors and has potential to provide patient-specific motion volumes for an individualized ITV.

The impact of (18)FDG-PET on target and critical organs in CT-based treatment planning of patients with poorly defined non-small-cell lung carcinoma: a prospective study.

PURPOSE: To prospectively study the impact of coregistering (18)F-fluoro-deoxy-2-glucose hybrid positron emission tomographic (FDG-PET) images with CT images on the planning target volume (PTV), target coverage, and critical organ dose in radiation therapy planning of non-small-cell lung carcinoma. METHODS AND MATERIALS: Thirty patients with poorly defined tumors on CT, referred for radical radiation therapy, underwent both FDG-PET and CT simulation procedures on the same day, in radiation treatment position. Image sets were coregistered using external fiducial markers. Three radiation oncologists independently defined the gross tumor volumes, using first CT data alone and then coregistered CT and FDG-PET data. Standard margins were applied to each gross tumor volume to generate a PTV, and standardized treatment plans were designed and calculated for each PTV. Dose-volume histograms were used to evaluate the relative effect of FDG information on target coverage and on normal tissue dose. RESULTS: In 7 of 30 (23%) cases, FDG-PET information changed management strategy from radical to palliative. In 5 of the remaining 23 (22%) cases, new FDG-avid nodes were found within 5 cm of the primary tumor and were included in the PTV. The PTV defined using coregistered CT and FDG-PET would have been poorly covered by the CT-based treatment plan in 17--29% of cases, depending on the physician, implying a geographic miss had only CT information been available. The effect of FDG-PET on target definition varied with the physician, leading to a reduction in PTV in 24-70% of cases and an increase in 30-76% of cases. The relative change in PTV ranged from 0.40 to 1.86. On average, FDG-PET information led to a reduction in spinal cord dose but not in total lung dose, although large differences in dose to the lung were seen for a few individuals. CONCLUSION: The coregistration of planning CT and FDG-PET images made significant alterations to patient management and to the PTV. Ultimately, changes to the PTV resulted in changes to the radiation treatment plans for the majority of cases. Where possible, we would recommend that FDG-PET data be integrated into treatment planning of non-small-cell lung carcinoma, particularly for three-dimensional conformal techniques.